Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([CH3:10])[N:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[CH3:45])=[O:8])[N:4]([CH3:10])[N:3]=1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cn1nc(Cl)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(Cl)nn1C
Yield: 76.2 %

Procedure:
In the same manner as in Example 259 and using 3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (60 mg, 0.37 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (130 μL, 1.5 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.31 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (110 mg, 74%) was obtained as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1.[NH2:15][C:16]1[C:17]([F:29])=[CH:18][C:19]([F:28])=[C:20]([CH:27]=1)[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:24]1([NH:23][C:21](=[O:22])[C:20]2[CH:27]=[C:16]([NH:15][CH2:13][C:10]3[S:9][C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:12][CH:11]=3)[C:17]([F:29])=[CH:18][C:19]=2[F:28])[CH2:25][CH2:26]1
Reactant: O=Cc1cnc(Nc2ccccn2)s1
Reactant: Nc1cc(C(=O)NC2CC2)c(F)cc1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CC1)c1cc(NCc2cnc(Nc3ccccn3)s2)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
A mixture of 2-[pyridin-2-ylamino]-thiazole-5-carbaldehyde (41.0 mg, 0.2 mmol) and 5-amino-N-cyclopropyl-2,4-difluorobenzamide (46.6 mg, 0.22 mmol) in TFA/DCM (1:1, 1 mL) was stirred at RT for 10 min and triethylsilane (0.1 mL) was added. The mixture was stirred for 1 h, then concentrated and the residue was neutralized with NaHCO3 solution and the precipitates occurred. The precipitates were collected, washed with water and dried. The solid was triturated with MeOH and filtered to afford the title compound as a grayish solid (38 mg, 47%). Small amount of solid was boiled in methanol, the mixture was cooled to RT and filtered to afford a white solid. MS m/z 402 (M+H)+. 1H NMR (DMSO-d6) δ 8.23 (d, 1H, J=4.0 Hz), 8.15 (s, 1 H), 7.65 (t, 1 H, J=7.15 Hz), 7.26 (s, 1 H), 7.16 (m, 1 H), 7.01 (d, 1 H, J=8.75 Hz), 6.95 (m, 1 H), 6.89 (t, 1 H, J=7.15 Hz), 6.12 (s 1 H), 4.43 (m, 2 H), 2.79 (m, 1 H), 0.69 (m, 2 H), 0.51 (m, 2 H).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@@H:46]([C:49]([NH:51][CH2:52][C:53]([NH:55][C@H:56]([C:59]([NH:61][C@H:62]([C:67]([O:69]C(C)(C)C)=[O:68])[CH2:63][C:64](=[O:66])[NH2:65])=[O:60])[CH2:57][OH:58])=[O:54])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])[CH3:11])=[O:8].FC(F)(F)C(O)=O.Cl.N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCC(=O)O.NCC(O)=O.N[C@H](C(O)=O)C>O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@@H:46]([C:49]([NH:51][CH2:52][C:53]([NH:55][C@H:56]([C:59]([NH:61][C@H:62]([C:67]([OH:69])=[O:68])[CH2:63][C:64](=[O:66])[NH2:65])=[O:60])[CH2:57][OH:58])=[O:54])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:13])[CH3:11])=[O:8]
Reactant: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CO)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Agent: C[C@H](N)C(=O)O
Agent: Cl
Agent: NCC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CO)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O

Procedure:
Using 550 mg of pGlu-Ala-Lys(Boc)-Ser-Gln-(D)-Ser-Gly-Ser-Asn-OBut and 20 ml of trifluoroacetic acid, the same procedure as Example 5-(VIII) is followed to prepare the above-indicated compound. Yield 320 mg; [α]D24 -56.3°(c=0.5, water); Rf4 (Avicel)=0.17; amino acid analysis (hydrolyzed with HCl); Lys, 1.10(1); Asp, 1.00(1); Ser, 3.02(3); Glu, 2.14(2); Gly, 1.10(1); Ala, 1.00(1); average recovery 87.0%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19](=[O:26])[CH2:20][C:21]([O:23]CC)=[O:22])=[C:13]([F:27])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[OH-].[Na+].Cl>CO>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19](=[O:26])[CH2:20][C:21]([OH:23])=[O:22])=[C:13]([F:27])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)CC(=O)Nc1cc(F)c(Oc2ccnc(C(N)=O)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)CC(=O)O)cc2F)ccn1
Reaction time: 1 h
Yield: 112.8 %

Procedure:
To a heterogeneous mixture of ethyl 3-(4-(2-carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoate (305 mg, 0.80 mmol) in MeOH (8 mL) was added aqueous 1 M NaOH (1.70 mL, 1.70 mmol). After one hour of stirring, the mixture was acidified with aqueous 1N HCl (5 mL). The reaction was extracted with EtOAc before the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (317 mg) which was used without further purification. HRMS(ESI+), 352.0745 (M+H)+ calcd., 352.0752 (M+H)+ found.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)(O)[C:6]=2[CH:23]=1>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: OC1(c2ccncc2)Cc2ccccc2Oc2ccc(Br)cc21
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2c(c1)C(c1ccncc1)=Cc1ccccc1O2
Yield: 73.6 %

Procedure:
A mixture of 8-bromo-10,11-dihydro-10-(4-pyridinyl)dibenz[b,f]oxepin-10-ol (3.0 g) in trifluoroacetic acid (18 ml) was heated at reflux under argon for five hours. The reaction mixture was concentrated to dryness in vacuo and the residual material was triturated using 1N sodium hydroxide aqueous solution (40 ml). The solids that formed were filtered off, washed thoroughly with water and the dried material was crystallized from dichloromethane-methanol. After the mixture was cooled overnight at 0°-5°, the solids were recovered by filtration, washed well with cold methanol to give 2.1 g of 4-(8-bromodibenz[b,f]oxepin-10-yl)pyridine, mp 195°-197°.
Reaction SMILES: [Na:1].[CH:2](OCC)=[O:3].[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[N:8]>CO>[Na:1].[CH3:13][O:12][C:10](=[O:11])[C:9](=[CH:2][OH:3])[C:7]#[N:8]
Reactant: CCOC=O
Reactant: COC(=O)CC#N
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C#N)=CO
Yield: 61.2 %

Procedure:
Sodium metal (11.8 g, 0.511 mol) was dissolved in 450 mL of methanol and to this warm solution was added a solution of ethyl formate (104 g, 1.41 mol) and methyl cyanoacetate (43.8 g, 0.440 mol) over two minutes. A small amount of precipitate formed during the addition. The reaction mixture was heated to reflux and maintained there for 1.5 hours. The thick white suspension was allowed to cool to 20° C.-25° C. and the precipitate was filtered, washed with diethylether, and dried in vacuo at 45° C. to give 40.4 g (61.6%) of the title compound which was of sufficient purity for use in Preparation 6.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH2:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C.Cl>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8])=[CH:5][CH:4]=1
Reactant: CCCCCCCCO
Reactant: O=C(Cl)c1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCOC(=O)c1ccc(CBr)cc1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
In 30 ml of benzene was dissolved 2.3 g of 4-bromomethylbenzoic acid chloride, 1.37 g of n-octyl alcohol and 5 ml of triethylamine were added to the solution, and a reaction was carried out at room temperature with stirring overnight. Then, 30 ml of ethyl acetate and 10 ml of 2N HCl were added to the reaction mixture, and the organic layer was separated, washed with water and dried on magnesium sulfate. The solvent was removed by distillation, and the residue was separated and purified by the silica gel column chromatography to obtain 3.0 g of octyl 4-bromomethylbenzoate.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.[CH3:8][C:9]1[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1.Br[C:33]1[N:38]=[C:37]([CH2:39][NH:40][C:41]2[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][CH:44]=[CH:43][C:42]=2[CH:50]([CH3:52])[CH3:51])[CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH:50]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([CH:47]([CH3:49])[CH3:48])[C:41]=1[NH:40][CH2:39][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][NH:11][C:10]2[CH:28]=[CH:29][CH:30]=[CH:31][C:9]=2[CH3:8])[N:38]=1)([CH3:52])[CH3:51]
Reactant: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1
Reactant: Cc1ccccc1NCc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccccc1NCc1ccccc1-c1cccc(CNc2c(C(C)C)cccc2C(C)C)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of 4.00 g (14 mmol) of Na2CO3×10H2O, 60 ml of water and 20 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 1.82 g (5.6 mmol) of 2-methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]aniline, 1.95 g (6.7 mmol) of N-[(6-Bromopyridin-2-yl)methyl]-2,6-diisopropylaniline, and 0.32 g (0.28 mmol) of Pd(PPh3)4 in 75 ml of toluene. This mixture was stirred for 12 h at 70° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×50 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was re-crystallized from 15 ml of diethyl ether. Yield 1.79 g (69%) of white crystalline powder. Anal. calc. for C32H37N3: C, 82.89; H, 8.04; N, 9.04. Found: C, 82.68; H, 7.98; N, 8.80. 1H NMR (CDCl3): δ 7.70 (m, 1H), 7.49-7.55 (m, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.37-7.40 (m, 2H), 7.28 (m, 1H), 6.99-7.11 (m, 5H), 6.60 (m, 1H), 6.55 (m, 1H), 4.48 (d, J=4.6 Hz, 2H), 4.21 (s, 2H), 4.07 (br.s, 1H), 3.98 (br.s, 1H), 3.33 (sept, J=6.8 Hz, 2H), 2.04 (s, 3H), 1.19 (d, J=6.8 Hz, 12H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[NH2:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[S:20][CH2:21][C:22]#[N:23]>C1COCC1>[C:22]([CH2:21][S:20][C:13]1[CH:14]=[C:15]([F:19])[CH:16]=[C:17]([F:18])[C:12]=1[NH:11][C:1](=[O:3])[CH3:2])#[N:23]
Reactant: CC(=O)Cl
Reactant: N#CCSc1cc(F)cc(F)c1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1c(F)cc(F)cc1SCC#N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Acetyl chloride (575 μl, 8 mmol) in THF (2 ml) and subsequently pyridine (645 μl, 8 mmol) in THF (2 ml) were added to a stirred solution of (2-amino-3,5-difluorophenylsulfanyl)acetonitrile (1.53 g) in THF (20 ml) at 0° C. The mixture was stirred at 0° C. for 15 min, then at ambient temperature for 1 h. Additional amounts of acetyl chloride (57 μl) and pyridine (65 μl) were added, and stirring was continued for 1 h. Then the solvent was removed in vacuo and the residue was triturated with water (25 ml). The precipitate was filtered off and dried. Recrystallization from 96% ethanol gave the title compound. Yield 1.16 g (63%), mp 148.5-149° C. An additional crop of the title compound (0.25 g, 13%) was obtained from the mother liqueor; 1H-NMR (DMSO-d6), δ (ppm): 9.65 (s, 1H, NH), 7.40-7.20 (m, 2H, Ar—H), 4.34 (s, 2H, CH2), 2.09 (s, 3H, CH3).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:8]=1
Reactant: C1CNCCN1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Product: O=C(CCN1CCNCC1)c1ccc(Cl)cc1

Procedure:
4′-Chloro-3-(piperazin-1-yl)propiophenone was prepared from commercially available 3,4′-dichloropropiophenone (Aldrich, 14,159-3) and piperazine according to the general methodology described at step A of example 1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([F:36])[CH:35]=1)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12](/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25]C(=O)OC(C)(C)C)=[O:17])[CH:11]=[N:10]1>O1CCOCC1.CCOC(C)=O>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:16](=[O:17])/[CH:15]=[CH:14]/[C:12]1[CH:11]=[N:10][N:9]([CH2:8][CH2:7][O:6][C:5]2[CH:33]=[C:34]([F:36])[CH:35]=[C:3]([Cl:2])[CH:4]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(Cl)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 107.4 %

Procedure:
A 4 M solution of HCl in dioxane (2 mL) was added to a solution of (E)-tert-butyl (2-(3-(1-(2-(3-chloro-5-fluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (118 mg, 0.23 mmol) in dioxane (3 mL) and the mixture was stirred for 6 h at room temperature under a nitrogen atmosphere. The reaction mixture was then diluted with EtOAc (15 mL). The salt was filtered, washed with EtOAc and dried overnight to give 99 mg of the hydrochloric acid salt of (E)-N-(2-aminophenyl)-3-(1-(2-(3-chloro-5-fluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamide as an off-white solid. MS: ES+(M+Na)+: 423
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.[SH:17][CH2:18][CH2:19][OH:20].C(OC(=O)C)C>C(Cl)Cl.CCCCCC>[OH:20][CH2:19][CH2:18][S:17][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: OCCS
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CSCCO
Temperature: 25 °C
Yield: 62.1 %

Procedure:
tert-butyl bromoacetate 1 (15 g, 0.077 mol, 1 eqv.) and triethylamine (16 g, 0.16 mol, 2 eqv.) were dissolved in CH2Cl2 (100 mL) under nitrogen and cooled to 0 C. 2-mercaptoethanol (6.3 g, 0.081 mol, 1.05 eqv.) was slowly added to the mixture and the reaction mixture was warmed to room temperature. The reaction was stirred for 1 additional hour. Completion of the reaction was monitored by TLC (ethylacetate (EtOAc):hexane (Hex), 1:1 (v/v), Rf: 0.88). Base and acid extractions were carried out with 1M KCO3, pH 10 and 1M NaOAc pH 3.5, twice, respectively. The combined organic layers were washed with brine, dried with MgSO4 and filtered through Ø 185 mm whatman filter papers. The filtrate was concentrated in vacuo (CH2Cl2) to obtain 9.2 g (62% yield) 2 as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[CH3:27][NH:28][C:29]1[C:30]([NH2:37])=[CH:31][C:32]([CH3:36])=[C:33]([CH3:35])[CH:34]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[N:28]([CH3:27])[C:29]4[CH:34]=[C:33]([CH3:35])[C:32]([CH3:36])=[CH:31][C:30]=4[N:37]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: CNc1cc(C)c(C)cc1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1-c1nc2cc(C)c(C)cc2n1C
Yield: 24.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), N1,4,5-trimethylbenzene-1,2-diamine (Intermediate-31, 0.048 g, 0.32 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.33 (s, 3H), 2.36 (s, 3H), 3.56 (s, 3H), 3.85 (s, 3H), 7.33 (s, 1H), 7.41 (s, 1H), 7.47-7.59 (m, 3H), 7.66-7.78 (m, 3H), 12.5 (br s, 1H); MS (m/z): 478.29 (M+H+).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.2 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-phenylethylamine (0.35 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.45 g, 1.8 mmol, yield: 68%) as colorless needles.
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Br)C.[C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH3:13].[Br:20][C:21]1[CH:22]=[C:23]([C:27]#[N:28])[CH:24]=[N:25][CH:26]=1.[Cl-].[NH4+]>C(OCC)C>[NH2:28][C:27]([C:23]1[CH:24]=[N:25][CH:26]=[C:21]([Br:20])[CH:22]=1)=[CH:13][C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: N#Cc1cncc(Br)c1
Reactant: CC(=O)OC(C)(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C=C(N)c1cncc(Br)c1
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
Diisopropylamine (9.2 mL, 65 mmol) was added at 0° C. to a 3M solution of ethyl magnesium bromide in diethyl ether (10.9 mL, 32.7 mmol) and additional diethyl ether (20 mL). After one hour at 0° C. tert-butyl acetate (4.3 mL, 32.7 mmol) was added and stirring was continued for 30 minutes. 5-Bromopyridine-3-carbonitrile (2.0 g, 10.9 mmol) in diethyl ether (42 mL) was added at 0° C. After two hours at 0° C. saturated aqueous ammonium chloride solution was added. Phases were separated and the aqueous phase was extracted with diethyl ether. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 0 to 60%) to yield 1.12 g tert-butyl 3-amino-3-(5-bromopyridin-3-yl)prop-2-enoate.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:22])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.[I-].[Li+]>N1C=CC=CC=1>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:11]([NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=1)[C:3]([OH:23])=[O:2])=[O:22]
Reactant: COC(=O)c1ccnc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)O)ccn1
Yield: 41.9 %

Procedure:
A solution of 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester (50 mg, 0.14 mmol) and lithium Iodide (189 mg, 1.41 mmol) in pyridine (3 mL) was heated to reflux until reaction completion, then cooled and distilled off the solvent under reduced pressure. The residue was taken up in water, neutralized and extracted with methanol/MC mixture (10%). The combined extracts were washed with brine and water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resultant crude product was purified by HPLC (MeOH/MC=10%) to afford 2-[2-(2,4-dichloro-phenoxy)acetylamino]-isonicotinic acid as a colorless solid (0.02 g, 41% yield).
Reaction SMILES: CS[C:3](=[N:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[NH:4][C:5]#[N:6].[C:14]1([S:20][CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:5]([NH:4][C:3]([NH:23][CH2:22][CH2:21][S:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)#[N:6]
Reactant: CSC(=Nc1cccnc1)NC#N
Reactant: NCCSc1ccccc1
Solvent: c1ccncc1
Product: N#CNC(=Nc1cccnc1)NCCSc1ccccc1
Reaction time: 96 h

Procedure:
S-Methyl N-cyano-N'-3-pyridylisothiourea (1.92 g) was dissolved in pyridine (10 ml), and 2-phenylthioethylamine (3.06 g) was added. The mixture was kept at room temperature for 4 days, when it was evaporated in vacuo. The residue was triturated with ether (40 ml), and the resulting suspension was filtered and washed with ether.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[N:16]2)[C:12]([Cl:24])=[CH:11][N:10]=1>C1COCC1>[N:15]1([C:13]2[C:12]([Cl:24])=[CH:11][N:10]=[C:9]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: NC1CCCCC1
Reactant: Clc1ncc(Cl)c(-n2nnc3ccccc32)n1
Solvent: C1CCOC1
Product: Clc1cnc(NC2CCCCC2)nc1-n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
Cyclohexylamine (0.21 mL, 1.88 mmol) was added in portions to a solution of 1-(2,5-dichloro-pyrimidin-4-yl)-1H-benzotriazole (250 mg, 0.94 mmol) in THF (30 mL) at RT under nitrogen atmosphere. The resultant colorless solution was stirred at RT for 4 hours. TEA (2.82 mmol) was then added and the reaction mixture was stirred at RT overnight. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed twice with water (50 mL) and once with brine (50 mL), then dried over Na2SO4, filtered and evaporated under reduced pressure to give an off-white solid. This crude material was purified via flash chromatography (toluene/EtOAc, 98/2) to afford 162 mg (53% yield) of (4-benzotriazol-1-yl-5-chloro-pyrimidin-2-yl)-cyclohexyl-amine as an off-white solid. MS: 329.14 (M+1)+, 301.14 ((M+1)+−28).
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]=[C:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.CCOC(C)=O>C1COCC1>[C:5]([C:1]1([C:16]2([OH:15])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17]2)[CH2:4][CH2:3][CH2:2]1)#[N:6]
Reactant: N#CC1CCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C2(C#N)CCC2)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 15.7 %

Procedure:
To a solution of cyclobutanecarbonitrile (1.75 g, 21.5 mmol) in THF (15 mL) was added 2.0M lithium diisopropylamide (11 mL, 22.5 mmol) dropwise and the solution was stirred at −78° C. for 45 minutes. Then a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (4.0 g, 21.5 mmol) in THF (2 mL) was added to the solution and the mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (25 mL×3). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluted with petroleum ether:EtOAc=2:1 to obtain the title compound (0.9 g, 38.2% yield) as a white solid. 1H NMR: (400 MHz, CDCl3): δ 3.64-3.40 (m, 4H), 2.44 (t, J=7.8 Hz, 2H), 2.33-2.23 (m, 2H), 2.13-1.88 (m, 4H), 1.47 (s, 9H)