Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[C:23]([C:25]#[N:26])[CH:24]=4)[NH:21][C:20]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:26][CH2:25][C:23]1[CH:24]=[C:16]([NH:15][C:13]([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:11][CH2:12]2)=[O:14])[CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19]2
Reactant: [H][H]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(C#N)c2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CN)c2[nH]1
Yield: 31.9 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-cyano-1H-indol-5-yl)cyclopropanecarboxamide (375 mg, 0.934 mmol) was dissolved in 35 mL of ethyl acetate. The solution was recirculated through a continuous flow hydrogenation reactor containing 10% palladium on carbon at 100° C. under 100 bar of hydrogen for 8 h. The crude product was then evaporated to dryness and purified on 12 g of silica gel utilizing a gradient of 0-100% ethyl acetate (containing 0.5% triethylamine) in hexanes to yield N-(7-(aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]-dioxol-5-yl)-cyclopropanecarboxamide (121 mg, 32%). ESI-MS m/z calc. 405.2, found 406.5 (M+1)+. Retention time of 1.48 minutes.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].N1C=CC=CC=1.Cl.[CH3:23][N:24]([CH3:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(OCCO)C>[CH3:23][N:24]([CH3:32])[C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3cccc(N(C)C)c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 250.0 mg (1.1 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 273.3 mg (3.0 mmol) of pyridine and 261.4 mg (1.25 mmol) of 3-dimethylaminoaniline hydrochloride in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. The work up gave 294.8 mg (73.4%) of the product as a deep greenish yellow solid, m.p. 222-225° C., mass spectrum (electrospray, m/e): M+H 319.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C@H:28]([NH2:34])[CH2:27]2>CS(C)=O.CO>[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C@H:28]([NH:34][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH2:27]2
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: N[C@@H]1CN2CCC1CC2
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2N[C@@H]2CN3CCC2CC3)ccc2c1OCC1CC21
Temperature: 140 °C
Yield: 13.8 %

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.6 g) and (S)-1-azabicyclo[2.2.2]oct-3-ylamine (6.0 g) in DMSO (6 mL) was stirred and heated in a sealed vessel at 140° C. for 22 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((S)-1-azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.107 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:31])=[O:30].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:40][CH:39]=1)[CH3:2]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)Cc1ccc(OCC)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1)c1ccc(OCC)cc1
Yield: 96.2 %

Procedure:
499 mg of 4-ethoxyphenylacetic acid ethyl ester, 480 mg of carbonyldiimidazole, and 0.5 g of 4-methanesulfonyl benzoic acid were dissolved in 10 ml of dimethy formamide, and 119 mg of sodium hydride were slowly added dropwise to the solution and the mixture was reacted at the room temperature for 12 hours. Afterwards, water was added to dilute the resultant, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate to give 0.9 g of the titled compound as a light yellow liquid (yield 92%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.O.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH:19]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:24](=[O:26])[CH3:25])=[CH:22][CH:21]=1)=[O:20]
Reactant: O=Cc1ccc(OCCCCCCCCCCCCO)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OCCCCCCCCCCCCOc1ccc(C=O)cc1

Procedure:
4-(12-Hydroxyl-dodecyloxy)-benzaldehyde (1.1 g, 3.6 mmol, see Example 2 above) was heated at reflux in acetic anhydride (15 ml) for 90 minutes. After cooling, the solution was poured into water with stirring. The title compound formed as a precipitate which was collected by filtration, washed with water and dried.
Reaction SMILES: CC[CH2:3][CH:4]([C:7]1S[C:10]([C:12]2[S:13][C:14]([C:17]3[S:18][C:19](C4SC(C(CC)CCC)=CC=4)=[CH:20][CH:21]=3)=[CH:15][CH:16]=2)=[CH:9][CH:8]=1)CC.S1C=CC=C1C1SC=CC=1.C(OC(=O)CCCCC)(=[O:49])CCCCC.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:10]([C:12]1[S:13][C:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][CH:16]=1)(=[O:49])[CH2:9][CH2:8][CH2:7][CH2:4][CH3:3]
Reactant: CCCCCC(=O)OC(=O)CCCCC
Reactant: CCCC(CC)c1ccc(-c2ccc(-c3ccc(-c4ccc(C(CC)CCC)s4)s3)s2)s1
Agent: FB(F)F
Agent: c1csc(-c2cccs2)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCC(=O)c1ccc(-c2cccs2)s1
Temperature: 100 °C

Procedure:
Preparation of 5,5′″-Bis(4-n-hexyl)-2,2′:5′,2″:5″,2′″-quaterthiophene (6TTTT6) is now discussed. A mixture of 6.2 g of bithiophene, 8.0 g of hexanoic anhydride, and 0.4 g boron trifluoride etherate is heated to about 100° C. and allowed to cool. The resulting mixture is dissolved in toluene, washed with aqueous sodium bicarbonate (allowing for venting of carbon dioxide gas), dried with magnesium sulfate, filtered, concentrated on a rotary evaporator, and chromatographed on 160 grams of silica gel eluting with hexane/methylene chloride mixtures. The product 5′-hexanoylbithiophene is isolated. The 5′-hexanoylbithiophene (3.9 g sample) is added to a stirred mixture of 3.0 g of aluminum chloride and 3.4 g of lithium aluminum hydride suspended in 300 mL of ethyl ether. After 1 hour, 50 mL ethyl acetate and 15 mL of concentrated hydrochloric acid are cautiously added, and the mixture is filtered, concentrated, and eluted through 30 g of silica gel with hexane. The product 5′-hexylbithiophene is isolated. A measured 2.4 g of this compound is dissolved in 150 mL of tetrahydrofuran. A measured 9.6 mmol of butyllithium as a hexane solution is added with stirring and cooling to −78° C. After 20 minutes, 2.6 g of cupric chloride is added. The mixture is allowed to warm to room temperature. After one day, dilute hydrochloric acid is added to dissolve the copper salts, and the mixture is dissolved in toluene, washed with concentrated hydrochloric acid and dilute aqueous ammonia, dried with magnesium sulfate, filtered, concentrated, and triturated with hexane, methanol, and petroleum ether.
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH2:43][CH2:44][CH3:45])[CH:42]=1)[C:37]([OH:39])=O)=[O:33].[CH2:46]([C:48]1[CH:63]=[C:62]([C:64](=[NH:67])[NH:65]O)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]>>[CH2:46]([C:48]1[CH:63]=[C:62]([C:64]2[N:67]=[C:37]([C:36]3[CH:40]=[C:41]([CH2:43][CH2:44][CH3:45])[CH:42]=[C:34]([CH:32]=[O:33])[CH:35]=3)[O:39][N:65]=2)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]
Reactant: CCCc1cc(C=O)cc(C(=O)O)c1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCCc1cc(C=O)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)c1
Yield: 37.8 %

Procedure:
The title compound (552 mg) was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 3-formyl-5-propyl-benzoic acid (582 mg, 3.03 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (985 mg, 3.03 mmol). LC-MS**: tR=0.78 min; [M+1]+=481.82; 1H NMR (D6-DMSO): δ 0.95 (t, J=7.3 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 1.71 (h, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.74 (q, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 3.20-3.29 (m, 1H), 3.40-3.48 (m, 1H), 3.71-3.81 (m, 2H), 3.84 (d, J=4.8 Hz, 2H), 3.93-4.01 (m, 1H), 5.31 (d, J=5.0 Hz, 1H), 5.55 (t, J=5.3 Hz, 1H), 7.70 (t, J=5.5 Hz, 1H), 7.82 (s, 2H), 8.07 (s, 1H), 8.33 (s, 1H), 8.52 (s, 1H), 10.15 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][NH:5]2.C=O.O.[C:16](O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][N:5]2[CH3:16]
Reactant: O=C1CNc2cc(Br)ccc2N1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC(=O)Nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 6-bromo-3,4-dihydroquinoxalin-2(1H)-one (370 mg, 1.63 mmol) in 10 ml methanol was added a solution of 37% formaldehyde in water (59 mg, 1.95 mmol) and acetic acid (196 mg, 3.26 mmol). The mixture was stirred at room temperature for 2 h, then refluxed for 1 h. After addition of NaBH3CN (307 mg, 4.89 mmol) stirring was continued for 2.5 h at room temperature. Then methanol was removed under vacuum. To the remaining mixture water was added. Then the solution was basified to pH 8-9 with an aqueous solution of sodium hydrogen carbonate and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated, affording 6-bromo-4-methyl-3,4-dihydroquinoxalin-2(1H)-one (369 mg, 1.53 mmol, 94%) as off-white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[C:7](Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[N:4][C:3]([NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[N:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1nc[nH]n1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1nc[nH]n1
Temperature: 110 °C
Yield: 25 %

Procedure:
To a mixture of 1H-1,2,4-triazol-3-amine (500 mg, 5.95 mmol) and TEA (0.829 mL, 5.95 mmol) in toluene (25 mL) was added pivaloyl chloride (0.732 mL, 5.95 mmol). The mixture was heated up at 110° C. for 13 h. The reaction mixture was quenched with water, filtered and the extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford N-(1H-1,2,4-triazol-3-yl)pivalamide (250 mg, 25%) as white solid. 1H NMR (500 MHz, MeOD) δ ppm 1.48 (s, 9H) 7.48 (s, 1H).
Reaction SMILES: C([N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:34]([O:38][C:39]([NH:41][CH:42]1[CH:59]([C:60]([OH:62])=O)[CH2:58][N:45]2[CH2:46][CH2:47][C:48]3[C:53]([CH:44]2[CH2:43]1)=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=3)=[O:40])([CH3:37])([CH3:36])[CH3:35].N1CCCC1>CN(C=O)C>[C:34]([O:38][C:39](=[O:40])[NH:41][CH:42]1[CH:59]([C:60]([N:3]2[CH2:4][CH2:6][CH2:9][CH2:7]2)=[O:62])[CH2:58][N:45]2[CH2:46][CH2:47][C:48]3[C:53]([CH:44]2[CH2:43]1)=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=3)([CH3:37])([CH3:36])[CH3:35]
Reactant: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(C(=O)O)CN1CC2
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(C(=O)N3CCCC3)CN1CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
N-Ethyldiisopropylamine (96 mg, 0.74 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 103 mg, 0.27 mmol) were added at r.t. to a suspension of (RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (100 mg, 0.25 mmol) in N,N,dimethylformamide (2 mL), then after 45 min pyrrolidine (19 mg, 0.27 mmol) was added. The homogeneous solution was stirred 90 min at r.t., then partitioned between hexane/ethyl acetate 1:1 and water. The organic layer was washed with brine, dried (MgSO4), and evaporated, and the residue chromatographed (SiO2, CH2Cl2/MeOH/NH4OH 80:1:0.2) to produce the title compound (58 mg, 51%). Light yellow solid, MS (ISP) 460.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:32][C:33]1[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:34]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)ncnc2c1
Reaction time: 2 h
Yield: 23.1 %

Procedure:
To a mixture of 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (Intermediate KKKK; 0.07 g, 0.147 mmol), (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (0.049 mg, 0.220 mmol) and potassium carbonate (0.101 g, 0.734 mmol) in Dioxane (Solvent Ratio: 3, Solvent Volume: 0.734 ml) and Water (Solvent Ratio: 1.000, Solvent Volume: 0.245 ml) was added Pd (PPh3)4 (17 mg, 0.015 mmol), degassed with nitrogen and irradiated in microwave at 100° C. for 1 h. The aqueous layer was discarded and the reaction mixture was filtered through SPE and concentrated. To this was then added DCM (1 ml) and TFA (1 ml) and the reaction was stirred for 2 h. The crude mixture was purified using reverse phase HPLC to obtain 4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (16 mg, 23% yield) as white solid. m/z (ESI) 470.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25](C2C=CC=C(C3N4C=CC(C(O)(C)C)=NC4=NC=3)N=2)=[C:26]([CH:29]=1)[C:27]#[N:28]>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[C:26]([CH:29]=1)[C:27]#[N:28]
Reactant: CC(C)(O)c1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)n3)cnc2n1
Reactant: FC(F)(F)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Product: N#Cc1cc(F)ccc1-c1nccc(-c2cnc3nc(C(F)(F)F)ccn23)n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled to 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (synthesised as in Example 22) by the method of Example 1 to afford 5-fluoro-2-{4-[7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}benzonitrile as a white solid: δH (400 MHz, CDCl3) 7.48-7.53 (2H, m), 7.63 (1H, dd, J 2.5, 8.0), 7.78 (1H, d, J 5.5), 8.39 (1H, dd, J 5.5, 9.0), 8.74 (1H, s), 8.95 (1H, d, J 5.5), 10.67 (1H, d, J 6.7); m/z (ES+) 385 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)n2ncc3ccc(Br)cc32)cc1
Yield: 87.9 %

Procedure:
6-Bromo-1H-indazole (500 mg, 2.54 mmol) was treated with 4-methoxybenzene-1-sulfonyl chloride (576 mg, 2.79 mmol) according to the method described in Preparation 15b to give 820 mg (81% yield) of the title compound. Purity 92%.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15](#[N:18])[CH2:16][OH:17].C(=O)([O-])O.[Na+].Cl>O.CC(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[O:17][CH2:16][C:15]#[N:18])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Reactant: N#CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4.5 h
Yield: 84.6 %

Procedure:
To a mixture of 1,5-difluoro-2,4-dinitrobenzene (2 g), acetone (20 g) and 50% aqueous glycolonitrile solution (1.2 g), a solution of sodium hydrogen carbonate (0.9 g) in water (18 g) was dropwise added at 27° to 30° C. in 5 minutes, and stirring was continued at 27° to 41° C. for 4.5 hours. After completion of the reaction, the reaction mixture was poured into 1% hydrochloric acid, extracted with ethyl acetate and concentrated. The precipitated crystals were collected by filtration and dried to give 2,4-dinitro-5-fluorophenoxyacetonitrile (2.0 g; yield, 83.0%).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:16][C:17]1[CH:31]=[CH:30][CH:29]=[CH:28][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=O.NC1C=CC=CC=1C(C1C=CC(F)=CC=1)=O>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:18]3[C:17](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
47.9 g of methyl 3-cyclopropyl-3-oxopropionate and 100 g of 2-amino-4′-fluorobenzophenone methanesulfonate were added to 584 g of toluene, and the mixture was dehydrated and refluxed at an internal temperature of 79 to 81° C. under a reduced pressure of 40 kPa. The reaction mixture was analyzed with HPLC during the reaction, and methyl 3-cyclopropyl-3-oxopropionate was added thereto by dividing it into several parts until the residual amount of 2-amino-4′-fluorobenzophenone was less than 2%. An additional amount of methyl 3-cyclopropyl-3-oxopropionate was 13.8 g. After 40 hours of reaction time, the residual amount of 2-amino-4′-fluorobenzophenone was 1.7%. The reaction solution was washed with 320 g of 4% aqueous solution of sodium hydroxide and then 140 g of 2% aqueous solution of sodium hydroxide. The reaction solution was further washed with 100 g of 5% brine solution, and then dried over 10 g of anhydrous magnesium sulfate. Toluene was removed under a reduced pressure, and crystallization was carried out in 740 g of cyclohexane to obtain 88.4 g of methyl 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carboxylate.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([C:14]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([O:30]CC)=[O:29])[CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1.Cl>CO.C(OCC)(=O)C>[C:28]([C:24]1[CH:23]=[C:22]([CH2:21][S:20][C:15]2[C:14]([C:12]([NH:11][C:6]3[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[CH:5]=3)=[O:13])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:27]=[CH:26][N:25]=1)([OH:30])=[O:29]
Reactant: CCOC(=O)c1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(C(=O)O)c2)c1
Yield: 84 %

Procedure:
A 1N aqueous sodium hydroxide solution (0.5 mL) was added to a solution of N-(3,5-dimethylphenyl)-2-(2-ethoxycarbonylpyridin-4-ylmethylthio)pyridine-3-carboxamide (95 mg, 0.22 mmol, Compound No. 1-241) in methanol (2 mL), then the mixture was stirred at room temperature for 1.5 hours. 1N hydrochloric acid (1 mL) was added to the reaction mixture, and this mixture was diluted with ethyl acetate (35 mL). The mixture was washed with brine (20 mL), and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, then the resulting residue was filtered off. The solid was washed with diethyl ether, and then dried at 50° C. under reduced pressure to give 74 mg of the target compound as an orange solid. (Yield 84%)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Br:16][C:17]1[CH:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(N(CC)CC)C>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Br)ncc2[N+](=O)[O-])CC1
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A solution of 4-(aminomethyl)-1-boc-piperidine (370 mg, 1.73 mmol) in acetonitrile (1 mL) was added over 1 minute to a solution of 2-bromo-4-chloro-5-nitropyridine (373 mg, 1.57 mmol) and triethylamine (0.24 mL, 1.73 mmol) in acetonitrile (5 mL). The solution was stirred for 30 minutes then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (×3) and the combined organic phases were dried (Na2SO4) and concentrated to give tert-butyl 4-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate as a light brown foam (640 mg, 98%) which was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:14]=23)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(C(=O)O)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c2) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.