Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[C:35](=O)[NH:36][CH2:37][CH2:38][NH:39]C)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](=[O:21])[N:36]([CH2:37][CH2:38][NH2:39])[CH3:35])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CNCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N(C)CCN)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.8 %

Procedure:
A solution of 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (100 mg, 0.25 mmol) in DMF is added (2-methylamino ethyl)-carbamic acid tert-butyl ester (53 mg, 0.25 mmol), HBTU (140 mg, 0.38 mmol), and DIPEA (0.088 mL, 0.51 mmol). After 48 h stirring at room temperature, the resulting mixture is concentrated and diluted with saturated NaHCO3 solution and extracted with ethyl acetate (3×100 mL). The combine organics are dried over Na2CO3 and concentrated to give a reddish residue. Followed by deprotection using General Procedure A to give 2-{5-[(2-amino-ethyl)-methyl-carbamoyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 77%). MS (ESI) m/z 451.3 (M+H)+
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]#N)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.Cl.[OH-:22].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:9]([CH:10]=[O:22])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cccnc1C1CC1
Reactant: [OH-]
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1cccnc1C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-cyclopropyl-3-cyano-pyridine (18.5 g, 128 mmol) was dissolved in toluene (400 ml) and DIBAL (1.01M in toluene, 153 ml) was added thereto at 0° C. After stirred at 0° C. for 1 h, the reaction mixture was poured into 2N HCl aq (90 ml); and 5N NaOH aq. (40 ml) was added thereto. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4. The desiccant was removed through filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/EtOAc=10/0 to 7/3) to obtain the intended compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:27]1[C:28](=O)[C:29]2[C:34](C=1C1C=CC=CC=1)=CC=C(O)[CH:30]=2.CC(C)CCO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:27][CH2:28][CH:29]([CH3:34])[CH3:30])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)CCO
Product: CC(C)CCOc1ccc2c(c1)C(=O)C(c1cccnc1)=C2c1cc(F)cc(F)c1
Reaction time: 4 h
Yield: 59 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 3-methylbutan-1-ol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 4 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (59%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[C@@H:19]([CH3:30])[CH2:18]3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=2)[C:40](O)=[O:41])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][C@@H:19]([CH3:30])[CH2:18]3)[CH:11]=2)=[CH:4][C:3]=1[CH2:2][NH:1][C:40](=[O:41])[C:39]1[CH:43]=[CH:44][CH:45]=[C:37]([CH:34]2[CH2:33][CH2:32][NH:31][CH2:36][CH2:35]2)[CH:38]=1
Reactant: O=C(O)c1cccc(C2CCNCC2)c1
Reactant: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(CN)c3)c2)CCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(CNC(=O)c4cccc(C5CCNCC5)c4)c3)c2)CCN1
Yield: 19.8 %

Procedure:
Following the procedure outlined in Example 40, 1,1-dimethylethyl (2S)-4-{[3′-(aminomethyl)-4′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (0.100 g, 0.242 mmol), 3-(4-piperidinyl)benzoic acid (0.074 g, 0.243 mmol), HATU (0.103 g, 0.271 mmol), and diisopropylethylamine (0.10 mL, 0.574 mmol) in DMF (2.5 mL) were reacted to give the desired product (0.024 g, 21.0%). EI-MS m/z 501 (M−H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[N:9][N:10]=1)=[O:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH3:18])=[O:24])=[CH:15][CH:16]=2)=[N:9][N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnc(-c2ccc(SC)cc2)o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nnc(-c2ccc(S(C)=O)cc2)o1
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethoxycarbonyl-5-(4-methylthiophenyl)-1,3,4-oxadiazole (0.7 g) in chloroform (14 ml), m-chloroperoxybenzoic acid (0.57 g) was added dropwise at 4°-6° C. with stirring. After 30 minutes, the reaction mixture was extracted with chloroform (50 ml), washed with a sodium iodide aqueous solution, a sodium thiosulfate aqueous solution, a sodium hydrogencarbonate aqueous solution and brine successively and dried over magnesium sulfate. After evaporating the solvent, the residue was crystallized from diethyl ether to afford 2-ethoxycarbonyl-5-(4-methylsulfinylphenyl)-1,3,4-oxadiazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C>[C:8]1([C:7](=[N:6][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:33])([CH3:34])[O:27]2)[C:4]([O:3][CH2:1][CH3:2])=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)OB(CCCCBr)OC1(C)C
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)N=C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 64.3 %

Procedure:
A solution of N-(diphenylmethylene)glycine ethyl ester (8.24 g, 30.8 mmol) and 2-(4-bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.92 g, 33.9 mmol) in freshly distilled THF (77 mL, 0.4 M) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (32.3 mL, 1.0 M in THF). Once the addition was complete, the reaction was warmed to 50° C. and heated for 8 h. After being complete by TLC, the reaction mixture was cooled to 0° C., diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Rapid purification by MPLC (1-15% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave ethyl 2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (8.9 g, 64%). Rf 0.40 (30% ethyl acetate in heptane).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:14]C(OC(C)(C)C)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+].O>CN(C=O)C>[N:22]([CH2:6][C@@H:7]([NH2:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@@H](N)c1ccccc1
Temperature: 65 °C
Yield: 135.7 %

Procedure:
To a solution of (2S)-2-[(tert-Butoxycabonyl)amino]-2-phenylethyl methanesulfonate (ref. Org. Syn. 2008, 85, 219) (5.0 g, 15.9 mmol) in DMF (40 mL) was added solid sodium azide (2.2 g, 33 mmol). The reaction was heated to 65° C. for 48 h. The reaction was cooled to room temperature and water was added to provide a white precipitate. The precipitate was filtered and dried under vacuum to afford the desired compound (3.5 g, 85%). To a solution of azide (0.75 g, 2.86 mmol) in THF (14 mL) was added HCl (as a 4M solution in dioxane, 7 mL, 28 mmol). The reaction was stirred at RT for 16 hours, then solvents were removed under reduced pressure to give the amine hydrochloride, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Product: Cc1ccnc(-n2cc(C#Cc3cccc(C#N)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=300.4 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloro-4-methyl-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:10][C:3]=12.[C:16]1([C:22](=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:23]#[N:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:15])[C:12]([N:28]3[CH2:27][CH2:26][C:25](=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:23]#[N:24])[CH2:30][CH2:29]3)=[O:14])=[CH:9][NH:10][C:3]=12
Reactant: N#CC(=C1CCNCC1)c1ccccc1
Reactant: O=C(O)C(=O)c1c[nH]c2c(Cl)ccnc12
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Reaction time: 20 h
Yield: 11 %

Procedure:
To a solution of (7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-oxo-acetic acid (1.5 g, 6.7 mmol) and phenylpiperidine-4-ylidene acetonitrile (1.3 g, 6.7 mmol) in DMF (50 mL) was added DEPBT (3.15 g, 10.5 mmol) and ethyl diisopropylamine (6.1 mL, 35 mmol). The solution was stirred 20 h, concentrated under vacuum and partitioned between 5% Na2CO3(aq) (80 mL) and EtOAc (5×100 mL). The combine organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by Biotage Chromatography (SiO2, 30% EtOAc/Hex to 100% EtOAc) and by preparative HPLC to yield the title compound (300 mg, 0.74 mmol, 11%) as a yellow solid.
Reaction SMILES: Cl(O[C:6]([C:44]1[CH:49]=[CH:48][C:47]([N:50]([CH2:53][CH3:54])[CH2:51][CH3:52])=[CH:46][CH:45]=1)([C:33]1[CH:38]=[CH:37][C:36]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:35][CH:34]=1)[CH:7]=[CH:8][CH:9]=[C:10]([C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=1)(=O)(=O)=O.[OH-:55].[Na+]>CO>[CH2:51]([N:50]([CH2:53][CH3:54])[C:47]1[CH:46]=[CH:45][C:44]([C:6]([C:33]2[CH:34]=[CH:35][C:36]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:37][CH:38]=2)=[CH:7][CH:8]([OH:55])[CH:9]=[C:10]([C:22]2[CH:23]=[CH:24][C:25]([N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:26][CH:27]=2)[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:49][CH:48]=1)[CH3:52]
Reactant: CCN(CC)c1ccc(C(=CC=CC(O[Cl+3]([O-])([O-])[O-])(c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)c1ccc(C(=CC(O)C=C(c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)cc1
Yield: 87 %

Procedure:
15.1 g of 1,1,5,5-tetra-(p-diethylaminophenyl)-2,4-pentadiene-1-ol perchlorate prepared in Synthesis Example 5 was dissolved in 200 ml of methanol. To this solution, 2.53 g of sodium hydroxide was added. The mixture was refluxed for 2 hours and then cooled. Crystals separated out in the reaction mixture. The crystals were filtered off, washed with water several times, and dried in reduced pressure. The crystals were recrystallized from cyclohexane, whereby 11.7 g of 1,1,5,5-tetra-(p-diethylaminophenyl)-3-hydroxy-1,4-pentadiene was obtained in the form of light green crystals. The melting point of the product was 136.5° to 137.5° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[F:20][CH2:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:25][CH2:24][NH:23][CH:22]([CH2:21][F:20])[CH2:27]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: FCC1CNCCN1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(CF)C3)c(F)cc2c1=O
Temperature: 115 °C
Yield: 36.1 %

Procedure:
A suspension of 530.4 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 590.7 mg of 2-(fluoromethyl)piperazine and 2 ml of pyridine was heated at 115° C. for 30 minutes, then filtered and the filtrate refrigerated overnight. The resulting crystals were collected, washed with water, ether and dried, giving 262 mg of the desired compound as light yellow crystals, mp 202°-203° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 92.9 %

Procedure:
3-Hydroxy-2-nitrobenzoic acid (2.00 g) was dissolved in 110 ml of N,N-dimethylformamide, then 1.53 g of 4-chloroaniline, 3.15 g of 1-ethyl-3-[3-(N,N-dimethylamino) propyl]carbodiimide hydrochloride and 2.21 g of 1-hydroxybenzotriazole were added thereto and the mixture was stirred at room temperature for 4 days. The reaction solution was concentrated in vacuo, a saturated saline was added to the concentrate and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by means of a silica gel column chromatography using chloroform:methanol (100:1) as an eluate to give 2.97 g of 4′-chloro-3-hydroxy-2-nitrobenzanilide.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17]>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:16](=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14]
Reactant: NCCCBr
Reactant: CC(C)(C)C(=O)Cl
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCCCBr
Reaction time: 0.08 h
Yield: 55.4 %

Procedure:
To a suspension of 3-bromopropylamine hydrobromide (290 mg, 1.3 mmol) in CH2Cl2 (10 mL) cooled in ice bath was added triethylamine (470 uL). The resulting mixture was stirred for 5 min and trimethylacetyl chloride (163 uL, 1.3 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hrs, condensed under vacuum, purified by flash chromatography to yield N-(3-bromopropyl)pivalamide as colorless oil (160 mg, 55%). 1H NMR (500 MHz, CDCl3): 8 (5.97 (br s, 1H), 3.40 (m, 4H), 2.07 (m, 2H), 1.17 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 178.7, 37.2, 32.1, 31.1, 27.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][C:6]1[NH:7][C:8](=[S:11])[NH:9][N:10]=1.Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][C:6]1[NH:10][N:9]=[C:8]([S:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: COc1ccc(Cc2n[nH]c(=S)[nH]2)c(OC)c1
Reactant: BrCc1ccccn1
Agent: Br
Product: COc1ccc(Cc2nc(SCc3ccccn3)n[nH]2)c(OC)c1
Yield: 34 %

Procedure:
Prepared in a similar manner to example 1 using 5-(2,4-dimethoxybenzyl)-2H-1,2,4-triazole-3(4H)-thione (example 9a) and 2-(bromomethyl)pyridine hydrobromide. Yield 34%. 1H NMR (500 MHz, CDCl3): δ 3.77 (s, 3H), 3.79 (s, 3H), 4.0 (s, 2H), 4.34 (s, 2H), 6.35-6.45 (m, 2H), 7.1 (d, 1H), 7.15 (t, 1H), 7.3 (d, 1H), 7.7 (t, 1H), 8.5 (s, 1H). MS (M+H, 343).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:28]=[O:29])C>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:28]=[O:29])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(Br)ccc2C1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCc2cc(C=O)ccc2C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (Step C) (1.080 g, 3.311 mmol) was dissolved in THF (30 mL) and cooled to −78° C. n-Butyllithium (2.5 M) (3.311 mL, 8.276 mmol) was added drop-wise to the stirred solution. The reaction was stirred at −78° C. for 30 min and DMF (1.282 mL, 16.55 mmol) was added drop-wise and the mixture was slowly warmed to RT overnight. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated in vacuo to afford the crude material, which was purified by flash column chromatography to furnish the pure title compound. MS (APCI pos) 217 (M-t-Bu).
Reaction SMILES: C(O[C:4](=[O:7])[C:5]#[CH:6])C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][NH:14][NH2:15])=[CH:11][CH:10]=1>C(O)CCC>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][N:14]2[C:4](=[O:7])[CH:5]=[CH:6][NH:15]2)=[CH:11][CH:10]=1
Reactant: C#CC(=O)OCC
Reactant: NNCc1ccc(Cl)cc1
Solvent: CCCCO
Product: O=c1cc[nH]n1Cc1ccc(Cl)cc1

Procedure:
9.8 g (0.1 mol) of propiolic acid ethyl ester and 15.6 g (0.1 mol) of p-chlorobenzylhydrazine in 100 ml of n-butanol were heated for 8 hours under reflux.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=3)[CH2:12][CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1nc(N2CCNCC2)ccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(CN2CCN(c3ccc(Br)c(OC)n3)CC2)cc1OC
Temperature: 25 °C

Procedure:
A quantity of 0.1 g (0.4 mmole, 1 eq) of 1-(5-Bromo-6-methoxy-pyridin-2-yl)-piperazine and 0.061 g (0.4 mmole, 1 eq) of 3,4-dimethoxybenzaldehyde is dissolved in 5 mL of anhydrous toluene, and 3 drops of glacial acetic acid is added. An excess of NaBH(OAc)3 is added to the solution and stirred at room temperature under a nitrogen atmosphere until no starting material is detectable by TLC. At that time the reaction is quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate. The ethyl acetate extracts are dried over anhydrous MgSO4 and concentrated in vacuo. The residue is chromatographed on SiO2 with 10% CH3OH (2M NH3)/CH2Cl2 to afford 1-(5-bromo-6-methoxypyridin-2-yl)-4-(3,4-dimethoxybenzyl)piperazine (compound 1). Analysis: 1H NMR (400 MHz, DMSO): 7.71 (1H, d), 7.36 (1H, s), 7.05 (2H, m), 6.39 (1H, d), 4.38 (4H, m), 3.80 (9H, m), 3.39 (4H, m), 3.02 (2H, m). MS (LC-MS): Calculated for C19H24BrN3O3 422.32. Found 436.3424.31 (M+2).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.[H-].[Na+].F[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH2:3]1
Reactant: N#Cc1cccc(F)c1
Reactant: CN1CCCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC(Oc2cccc(C#N)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-Methylpiperidin-3-ol (500 mg, 4.341 mmol) was dissolved in DMF (10 ml) and cooled to 0° C. NaH (312 mg, 6.52 mmol) was added in small portions, stirred for 30 minutes and 3-fluorobenzonitrile (557 μl, 5.21 mmol) was subsequently added. The mixture was allowed to reach r.t. over 1 h and stirred for a further 16 h. Cooled to 0° C. and quenched with water. The reaction mixture was separated between water (150 ml) and DCM (2×150 ml). The combined organics were washed with water (150 ml), dried through a phase separator and evaporated in vacuo. Purification by flash silica gel chromatography using a 40 g Biotage column with a gradient of 10-100% EtOAc/MeOH/TEA 100:10:1 in heptane yielded the title compound as a colorless oil. Yield: 0.628 g (56%). 1H NMR (400 MHz, CDCl3) δ 7.32 (dt, 1H, J=7.6 Hz, J=0.9 Hz), 7.19 (m, 1H), 7.16-7.11 (m, 2H), 4.36 (m, 1H, J=4.0 Hz), 2.84 (m, 1H), 2.55 (m, 1H), 2.30-2.11 (m, 5H), 1.94 (m, 1H), 1.82 (m, 1H), 1.67-1.43 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[S:13][C:14]4[CH2:20][CH2:19][CH2:18][C:17](=O)[C:15]=4[N:16]=3)[CH:9]=[N:8]2)[CH:2]=1.Cl.[CH3:23][O:24][NH2:25].C([O-])(=O)C.[Na+]>C1COCC1>[CH3:23][O:24][N:25]=[C:17]1[C:15]2[N:16]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:11]=3)[S:13][C:14]=2[CH2:20][CH2:19][CH2:18]1
Reactant: CON
Reactant: O=C1CCCc2sc(-c3cnn(-c4cccnc4)c3)nc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CON=C1CCCc2sc(-c3cnn(-c4cccnc4)c3)nc21

Procedure:
2-[1-(3-pyridyl)pyrazol-4-yl]-6,7-dihydro-5H-1,3-benzothiazol-4-one (0.40 mmol, 0.119 g) was suspended in 4 ml THF, and O-methylhydroxylamine hydrochloride (0.44 mmol, 0.0367 g) followed by sodium acetate (0.80 mmol, 0.0656 g) were added. The reaction mixture was heated at reflux. After evaporation of the solvent, the residue was submitted to chromatography (Combiflash) to yield the title compound as a yellow solid.