Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11]CCCC[C@@H](C(O)=O)N)(OCC1C=CC=CC=1)=O.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25].Cl>[OH-].[Na+]>[NH2:11][C@H:22]([C:21]([OH:28])=[O:27])[CH2:23][C:24](=[O:26])[OH:25]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 5 h

Procedure:
N6-Carbobenzyloxy-L-lysine (6.15 g) and excess maleic acid (17.6 g) were dissolved in 2 M NaOH (35 mL). The solution was refluxed for 24 hr and allowed to cool to ambient. The pH was adjusted to 3 with 6 M HCl and chilled. The mixture was filtered to remove the unreacted maleic acid which was washed with water (15 mL). The filtrate and washings were combined and evaporated. The residue was dissolved in 4% ammonium formate (120 mL) and degassed briefly. 10% Pd/C (600 mg) was added and the mixture was refluxed under Ar with stirring for 5 hr. The mixture was filtered through celite and the filtrate evaporated. The residue was dissolved in a solution of sodium hydroxide (1.3 g) and sodium carbonate (8.7 g) in dd H2O (40 mL). The final pH was adjusted to 11. This solution is added to the oxirane-derivatized resin (40 ml bed volume) prepared as described in Example 1. The mixture was stirred at 60° with mechanical stirring for 4hr and at ambient for 16 hr. The resin was collected by filtration, washed with ddH2O (6×100 mL), 10% HOAc (6×100 mL), and ddH2O (6×100 mL) or until the pH reached about 6 by litmus paper test. The C-Linked CM-Asp chelating resin was suction dried in preparation for metal loading.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=4)[CH2:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:12]=2)[CH:8]=[N:7]1.CO.CCOCC.[ClH:60]>>[ClH:60].[F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:39]=[CH:38][CH:37]=[C:22]([CH2:23][CH:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]5)[CH:21]=4)[CH:18]=3)[N:13]([S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=3)(=[O:41])=[O:42])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(CC5CCNCC5)c4)cnc32)cc1
Yield: 72.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (compound of step 1 of example 102) (32 mg, 0.44 mmol) was deprotected in methanol/ether HCl (5/0.3 ml). This afforded 210 mg (72.4% yield) of the titled compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][CH2:14][C:15]1[CH:16]=[C:17]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([NH2:34])[C:24]2=[O:35])[C:18]([F:22])=[CH:19][C:20]=1[Cl:21].[CH2:36]([O:38][C:39]([NH:41]O)=[O:40])[CH3:37]>O1CCCC1>[CH2:36]([O:38][C:39]([NH:41][O:13][CH2:14][C:15]1[CH:16]=[C:17]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([NH2:34])[C:24]2=[O:35])[C:18]([F:22])=[CH:19][C:20]=1[Cl:21])=[O:40])[CH3:37]
Reactant: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(CO)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)NOCc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
0.9 g of carbonyldiimidazole was added to a solution of 1.8 g of 3-(3-hydroxymethyl-4-chloro-6-fluorophenyl)-1-amino-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione in 100 ml of tetrahydrofuran. After the reaction mixture had been stirred for 1 hour, 0.58 g of N-ethoxycarbonylhydroxylamine was added. The mixture was subsequently stirred for a further 14 hours at 20° C. whereupon the solvent was removed by distillation. The residue was taken up in 100 ml of methylene chloride. The resulting organic phase was washed with water, dried over sodium sulfate and finally concentrated. The crude product was purified by means of chromatography on silica gel (eluent: methylene chloride). Yield: 0.2 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:13][CH3:14])[C:10]([OH:12])=O.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10](=[O:12])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[O:13][CH3:14])=[CH:19][CH:18]=1)#[N:15]
Reactant: COC(C(=O)O)c1ccc(O)cc1F
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1F

Procedure:
(RS)-(2-Fluoro-4-hydroxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-hydroxy-phenyl)-2-methoxy-acetamide. White solid. MS 315.1 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>CS(C)=O>[Br:1][C:2]1[C:3]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([F:12])=[CH:14][CH:15]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Nc2ccc(F)cc2)c(Br)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
3-Bromo-2-chloro-5-nitropyridine (3.936 g, 16.58 mmol), 4-fluoroaniline (5.53 g, 49.7 mmol) and dimethylsulfoxide (33.2 mL) were combined and stirred at 120° C. for 1 hour. The reaction mixture was cooled to ambient temperature producing a solid. Precipitation was induced further by the addition of 150 mL of water. The solid was collected by filtration and rinsed with 600 mL of water. The solid was purified by flash chromatography (silica gel, 0 to 20% ethyl acetate in heptanes) and then triturated in 15% ethyl acetate in heptanes to give 4.2 g (81%) of the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16]>CN(C)C=O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][N:10]=1)[CH3:16]
Reactant: CCOC(CBr)OCC
Reactant: Nc1nnnn1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CNc1nnnn1-c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A solution of 1-phenyl-5-amino-1H-tetrazole (10 g.) in dried dimethylformamide (50 ml.) was dropwise added to a suspension of 50% sodium hydride (5.1g.) in dried dimethylformamide (5 ml.) over 15 minutes under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. To the resultant mixture was added a solution of bromoacetaldehyde diethyl acetal (13.5 g.) in dried dimethylformamide (15 ml.). The mixture was stirred for 1 hour at ambient temperature and for 2 hours and 20 minutes at 60° C. The reaction mixture was cooled to at ambient temperature, ice-water was added thereto and the mixture was extracted 3 times with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oil was purified by column chromatography on silica gel (250 g.) using chloroform as developing solvent to give (1-phenyl-1H-tetrazol-5-yl)aminoacetaldehyde diethyl acetal (11 g.), oil.
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][C:21]([O:30][CH3:31])=[CH:22][C:23]=4[O:28][CH3:29])[N:18]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C>Cl>[N:7]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][C:21]([O:30][CH3:31])=[CH:22][C:23]=4[O:28][CH3:29])[N:18]=3)=[CH:13][CH:12]=2)[CH2:8][CH2:9][CH2:10][NH:4][CH2:5][CH2:6]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCCN(C(C)=O)CC4)cc3)nc2c1
Agent: Cl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCCNCC4)cc3)nc2c1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
A mixture of 2-(4-(4-acetyl-1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.135 g, 0.32 mmol) and 2 N HCl (10 mL) was heated at 100° C. for 4 hours. Then, the reaction mixture was cooled to room temperature, basified to pH 8, and extracted with CH2Cl2 (8×125 mL). The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (0.040 g, 33%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.98 (s, 1H), 7.86 (d, J=9.0 Hz, 2H), 6.76-6.79 (m, 3H), 6.40 (d, J=2.3 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.61-3.69 (m, 5H), 3.05 (t, J=4.9 Hz, 2H), 2.83 (t, J=5.7 Hz, 2H), 1.92 (t, J=5.4 Hz, 2H). ESI MS m/z 379 [M−H]−.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:19][CH2:20][N:21]=[C:22]=[O:23]>O1CCCC1>[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:19][CH2:20][NH:21][C:22]2=[O:23])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1sc(N2CCNC2=O)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of 5-acetyl-2-amino-4-methylthiazole (5.50 g, 35.20 mmol) in tetrahydrofuran (200 mL) was added triethylamine (15.0 mL, 107.6 mmol) and 2-chloroethyl isocyanate (3.90 mL, 45.70 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, and then heated to reflux for 27 hours. The solvent was removed in vacuo, and the residue was washed with water (200 mL) and ethyl acetate/hexanes (1/1, 50 mL) to afford the title compound in 99% yield (7.9 g): MS (ES+) m/z 226.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:10]3[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](O)=[O:28])=[O:21])[CH3:18].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:30][N:25]1[C:26]([C:27](=[O:28])[NH:15][C:12]2[CH:13]=[CH:14][N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:16]=[C:10]3[CH:11]=2)=[C:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH:23]=[N:24]1
Reactant: Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 76.2 %

Procedure:
A mixture of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (945 mg, 4.49 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (1.07 g, 5.39 mmol), propylphosphonic anhydride (50% in ethyl acetate, 6.62 ml, 11.2 mmol) and diisopropylethylamine (3.93 ml, 22.5 mmol) in tetrahydrofurane (50 ml) is stirred for 2.5 days at 25° C. The crude material is loaded on silicagel and purified by flash chromatography on a 50 g silica column using heptane/ethyl acetate 20-100% and then ethyl acetate/methanol 10-30% as eluent. The fractions containing product are evaporated to dryness and the residue (4.23 g light yellow solid) is dissolved in tetrahydrofurane (20 ml); sodium bicarbonate solution (30 ml) is added and the mixture is stirred for 30 minutes at 25° C. The solid is collected by filtration, washed with water and dried affording ethyl 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (1.336 g, 76.1%) as an off-white solid. mp.: 242-3° C. MS: m/z=391.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1.[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([N:11]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccccc1Oc1cccc(NCc2cccnc2)c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: Cc1ccccc1Oc1cccc(N(Cc2cccnc2)S(=O)(=O)CC(F)(F)F)c1

Procedure:
Using the method of Example 342 using N-(3-(2-methylphenoxy)phenyl)pyridin-3-ylmethylamine and 2,2,2-trifluoroethanesulfonyl chloride and purifying via radial chromatography eluting with 40:60 to 50:50 THF/hexanes gave the title compound. Anal Calcd for C21H19F3N2O3S.0.1H2O: C, 57.55; H, 4.42; N, 6.39. Found: C, 57.28; H, 4.15; N, 6.33. MS found 437.2 [M+H]+
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:61](Br)[CH3:62].CN(C)C=O>C(OCC)(=O)C>[CH2:61]([N:9]1[CH2:10][CH2:11][C:6]2[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[N:35]([C:36]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[N:34]=[N:33][N:32]=4)=[CH:23][CH:24]=3)[C:7]=2[CH:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:62]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)NCC2
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)N(CC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A mixture of ethyl 2-n-propyl-3-[2'-(1-trityl-1 H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.00 g), potassium carbonate (1.16 g), ethyl bromide (0.61 g) and dimethylformamide (10 ml) is stirred overnight at room temperature. The mixture is diluted with ethyl acetate, and the solution is washed with water, dried and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 5-ethyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.12 g) as a white foam.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[CH:42]=[C:41]([Cl:43])[N:40]=[N:39][C:38]=1[CH3:44]>>[Cl:43][C:41]1[N:40]=[N:39][C:38]([CH3:44])=[C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)[CH:42]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1nnc(Cl)cc1Cl
Product: Cc1nnc(Cl)cc1-c1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
The isomeric title compounds were prepared by reaction of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4,6-dichloro-3-methylpyridazine following a procedure analogous to that described in Example 14.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:18]1>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:29][CH:27]([CH3:28])[CH2:26][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)Oc1ccccc1
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (760 μl, 6.03 mmol.) and pyridine (510 μl, 6.31 mmol.) were added to a solution of rac. 2-(1H-indol-3-yl)-1-methylethylamine (1.0 g, 5.74 mmol.) in abs. DCM (20 ml), and stirring was carried out for 24 h at RT. For working up, the mixture was washed with water (2×20 ml), with 1M HCl (2×20 ml) and with 1M NaOH (2×20 ml), then dried, filtered and concentrated. [2-(1H-Indol-3-yl)-1-methylethyl]carbamic acid phenyl ester was obtained in the form of a white solid in a yield of 1.35 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:12]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCOCC1>[CH2:12]([N:16]([CH2:17][CH2:18][CH2:19][CH3:20])[C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[O:9][CH3:10])[CH2:13][CH2:14][CH3:15]
Reactant: COc1cc(Br)cc(OC)c1
Reactant: CCCCNCCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCN(CCCC)c1c(OC)cccc1OC
Temperature: 0 °C
Yield: 88.2 %

Procedure:
In a stream of argon, to 300 ml of dioxane were added 21.7 g (100 mmol) of 3,5-dimethoxybromobenzene and 13.0 g (100 mmol) of dibutylamine, and 22.0 g (110 mmol) of potassium bistrimethylsilylamide was added thereto with stirring. After well-stirred, the mixture was heated under reflux with stirring overnight. The reactant was poured into 2 L of ice water and subjected to 3 times of extraction with 200 ml of chloroform. Washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 23.4 g (yield: 88%) of 4-dibutylamino-3,5-dimethoxybenzene as a colorless transparent oily matter.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][Cl:12])[CH:6]=[CH:5][N:4]=1.[OH-].[NH4+].[CH:15](O)=[O:16]>>[CH:15]([NH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][Cl:12])[CH:6]=[CH:5][N:4]=1)=[O:16]
Reactant: O=CO
Reactant: NCc1cc(CCCCl)ccn1
Agent: [NH4+]
Agent: [OH-]
Product: O=CNCc1cc(CCCCl)ccn1

Procedure:
A solution of 2-aminomethyl-4-(3-chloropropyl)pyridine (0.47 g) in 1 ml of formic acid is heated at 90° for 18 hours, cooled to 0° and made basic by the addition of saturated ammonium hydroxide solution. Extraction with methylene chloride (4×10 ml), drying over sodium sulfate and evaporation yields 2-(N-formylaminomethyl)-4-(3-chloropropyl)pyridine (IR 1674 cm-1) which is heated at 90° in phosphorus oxychloride (0.75 g) for 15 hours. Excess phosphorus oxychloride is evaporated with toluene and the residue is suspended in methylene chloride (15 ml), cooled to 0° and made basic with saturated ammonium hydroxide. Extraction with methylene chloride (4×15 ml), drying over sodium sulfate and preparative thin layer chromatography (silica gel, EtOAc) of the residue yields 7-(3-chloropropyl)-imidazo[1,5-a]pyridine (Rf=0.24, EtOAc) as a gum; NMR (CDCl3) 3.58 (t, 2H), 6.42 (q, 1H), 7.21 (s, 1H), 7.32 (s, 1H), 7.88 (d, 1H), 8.07 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22]>COCCOC>[O:23]=[C:21]([CH3:22])[CH2:20][N:6]([S:7]([CH3:10])(=[O:9])=[O:8])[C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(=O)CCl
Reactant: CS(=O)(=O)Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(=O)CN(c1ccc(Cl)cc1)S(C)(=O)=O

Procedure:
A mixture of 4'-chloro-methanesulphonanilide (10.0 g), anhydrous potassium carbonate (4.0 g), chloroacetone (4.8 ml), and 1,2-dimethoxyethane was stirred and boiled under reflux for 24 hours, and then filtered, and the filtrate was evaporated. The oily residue was dissolved in ether, and the solution was washed with water, dried (MgSO4) and evaporated. The residue gave almost colourless crystals from acetone/40°-60° petrol. Melting point 108°. Yield 4.1 g.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1=[CH:8][C:9]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)=[CH:22][C:10]=2[N:11]=[C:12]([NH:14]C(=O)OC(C)(C)C)[CH2:13]1)=[O:6])[CH2:2][CH3:3].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:14][C:12]1[CH2:13][C:7]([C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])=[CH:8][C:9]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)=[CH:22][C:10]=2[N:11]=1
Reactant: CCCNC(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a solution of tert-butyl (1E,4E)-4-(propylcarbamoyl)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepin-2-ylcarbamate (450 mg, 0.87 mmol) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (1.36 mL, 17.4 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude material that was diluted with CH2Cl2 (10 mL) and sat'd aq NaHCO3 (15 mL) again. The resulting mixture was stirred for 30 min at room temperature. The aqueous layer was separated and extracted with CH2Cl2 (1×10 mL). The combined organic layers were washed with sat'd aq NaHCO3 (2×10 mL) and brine (1×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material again that was purified by silica gel flash column chromatography (1 to 5% MeOH in CH2Cl2, gradient) to yield 27 mg (7%) of (1E,4E)-2-amino-N-propyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide. MS APCI(+) m/z 417 (M+1) detected; 1H-NMR (400 MHz, d6-DMSO) δ 8.27 (t, 1H), 7.75 (d, 2H), 7.62 (d, 2H), 7.50 (d, 2H), 7.41 (d, 2H), 3.43-3.51 (m, 4H), 3.18 (q, 2H), 2.99 (s, 2H), 1.81-1.90 (m, 4H), 1.48-1.58 (m, 2H), 0.90 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].C1C(=O)N([Cl:18])C(=O)C1>CN(C=O)C.CCOCC>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([Cl:18])[C:3]=1[F:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(F)c(Br)c(F)c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Br)c(F)c1Cl
Reaction time: 48 h

Procedure:
4-Bromo-3,5-difluoroaniline (10.5 g, 50.5 mmol) is dissolved in DMF (100 mL). NCS (28.6 g, 50.5 mmol) is added portionwise at room temperature. After 48 hours, the reaction is diluted with Et2O and washed with brine. The separated organic phase is dried (Na2SO4) and concentrated to give an oil. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-bromo-2-chloro-3,5-difluoroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]=O)=[N:21][CH:22]=1.[BH4-].[Na+]>CO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][NH:15][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[N:21][CH:22]=1
Reactant: O=Cc1ccc(Cl)cn1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)nc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and 5-chloro-2-formylpyridine (60 mg, 424 μmol) in MeOH (3 ml) was stirred at room temperature for one day and then at 45° C. for two days to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (163 mg, 4.3 mmol) was added in a few portions and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated. Crystallization from DCM afforded a white solid as desired product (96.6 mg, 90% yield). MS +m/z: 369 (M+H)+