Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([C@H:13]1[CH2:18][C@H:17]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[O:21])[CH2:16][CH2:15][N:14]1[C:31](OC(C)(C)C)=O)=O.C=O.C([BH3-])#N.[Na+].C1COCC1>C(O)(=O)C.O.CO>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]([NH:19][C@@H:17]2[CH2:16][CH2:15][N:14]([CH3:31])[C@@H:13]([C:11]3[NH:10][C:3]4[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=4[N:1]=3)[CH2:18]2)=[O:21])=[CH:28][CH:27]=1)#[N:30]
Reactant: Cc1cc(N)c(NC(=O)[C@H]2C[C@H](NC(=O)Nc3ccc(C#N)cc3)CCN2C(=O)OC(C)(C)C)cc1C
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc([C@H]3C[C@H](NC(=O)Nc4ccc(C#N)cc4)CCN3C)[nH]c2cc1C
Temperature: 65 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
(2R,4R)-tert-butyl 2-((2-amino-4,5-dimethylphenyl)carbamoyl)-4-(3-(4-cyanophenyl)ureido)piperidine-1-carboxylate (104 mg, 0.205 mmol) was dissolved in acetic acid (1 mL) and stirred at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove acetic acid. Then TFA (1 mL) was added to the residue. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove TFA and did next reaction without further purification. 37% formaldehyde solution (0.046 mL, 0.616 mmol) in water was added to a solution of the residue in methanol (2 mL) and the reaction mixture was stirred at room temperature for 1 hour, then 1M sodium cyanoborohydride in THF (0.62 mL, 0.62 mmol) was added carefully at 0° C. The reaction mixture was stirred at room temperature for 18 hours and then solvent was evaporated in vacuum. Saturated sodium bicarbonate solution (5 mL) and ethyl acetate (20 mL) were added and the mixture was stirred about 30 min. The organic layer was separated and dried over MgSO4, and concentrated. Product was purified by Companion (ReadySep 12 g, silica gel packed) with CH3OH/CH2Cl2 from 1-5% to give the title compound as an off-white solid 71 mg (73%). LC-MS: 403.3, 401.4 (t=1.8 min).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:32]=[CH:31][C:10]2[N:11]([C:14]3[N:15]=[C:16]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]4=[N:18][CH:19]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1.CN([CH:36]=[O:37])C>>[Cl:6][C:7]1[CH:32]=[CH:31][C:10]2[N:11]([C:14]3[N:15]=[C:16]4[C:22]([CH:36]=[O:37])=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:17]4=[N:18][CH:19]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-n3cnc4cc(Cl)ccc43)cnc21
Solvent: O=P(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-n3cnc4cc(Cl)ccc43)cnc21
Temperature: 67.5 °C
Reaction time: 7 h

Procedure:
A solution of DMF at 5° C. was treated with phosphoryl trichloride (483 mg, 3.2 mmol) for 0.5 h. 2-(5-Chloro-benzoimidazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (210 mg, 0.52 mmol) was added and the mixture was stirred at 65-70° C. for 7 h. The reaction was cooled and quenched with NaHCO3 (aq) then extracted into ethyl acetate (2×). The organics were washed with water and brine then dried (MgSO4). Purification was by flash chromatography gave 2-(5-chloro-benzoimidazol-1-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde. LCMS: (M+H)+=428.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:15][CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:16]([OH:18])=O)[S:9][C:8]=3[C:7]=2[CH:19]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[Cl:26][C:27]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=1[NH:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C=O)C.C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:15][CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:16]([N:29]([C:28]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:27]=4[Cl:26])[CH3:30])=[O:18])[S:9][C:8]=3[C:7]=2[CH:19]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CCO2
Reactant: CNc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2c(s1)-c1cc(C#N)ccc1OCC2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-cyano-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (300 mg) in dichloromethane (10 mL) was added DMF (1 drop) and oxalyl chloride (0.165 mL) and the reaction stirred at room temperature for 30 min. The solvent was then reduced in vacuo and the residue redissolved in acetonitrile (10 mL). To this solution was added 2,4-dichloro-N-methylaniline (0.16 mL) and potassium carbonate (308 mg) and the reaction stirred at room temperature for 16 h. The mixture was partitioned between water (40 mL) and ethyl acetate (30 mL). The organic layer was dried (Na2SO4), reduced in vacuo and purified on silica to give 336. (CDCl3): 3.11 (2H, t), 3.39 (3H, s), 4.32 (2H, t), 6.91 (1H, s), 7.07 (1H, d), 7.32 (1H, d), 7.37-7.44 (2H, m), 7.58 (1H, s), 7.79 (1H, s). MH+ 429:431:433 (3:2:1)
Reaction SMILES: CCN(CC)CC.[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[NH2:16][C:17]1[S:21][C:20]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:19][N:18]=1.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:16][C:17]1[S:21][C:20]([S:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][N:18]=1)=[O:14]
Reactant: O=C(Cl)CCCCCl
Reactant: Nc1nnc(SCc2ccccc2)s1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCCCCl)Nc1nnc(SCc2ccccc2)s1
Reaction time: 3 h
Yield: 88.7 %

Procedure:
1.5 ml (13 mmole) of Et3N, 1.38 g of 5-chlorovaleroyl chloride and 80 ml of 4-DMAP are successively added to 2 g of 5-amino-2-benzylmercapto-1,3,4-thiadiazole (8.9 mmole) suspended in 5 ml of anhydrous methylene chloride at room temperature with stirring and under nitrogen atmosphere. The reaction is checked by TLC (10% methanol in chloroform) and it is complete after 3 hours. The solid product so formed is filtered, washed with water and purified by crystallization from ethanol. 2.7 g of 5-chlorovaleroylamino-2-benzylmercapto-1,3,4-thiadiazole is obtained with melting point 145°-148° C. and 90% yield.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24]>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: Clc1cccc(Br)c1Cl
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1c1cccc(Cl)c1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 1-bromo-2,3-dichlorobenzene were used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([NH:41][CH2:42][C:43](O)=[O:44])=O)(C)(C)C>>[CH3:1][N:2]([CH3:33])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([C:43](=[O:44])[CH2:42][NH2:41])[CH2:23][CH2:22]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCN(C(=O)CN)CC4)cn3)nc2n1C1CCCC1
Yield: 71.4 %

Procedure:
By repeating procedures outlined in Example 12, 7-cyclopentyl-2-(5-piperazin-1-ylmethyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.108 g, 0.241 mmol) and tert-butoxycarbonylamino-acetic acid (42 mg, 0.241 mmol) gave 2-{5-[4-(2-amino-acetyl)-piperazin-1-ylmethyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as a white solid (87 mg, 69%). MS (ESI) m/z 506.3 (M+H)+ (method B).
Reaction SMILES: ClNC(=O)[O-].C([O:8][C:9]([C:11]1([NH:16][C:17]([CH:19]2[CH2:23][CH:22]([O:24][C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=4)[N:28]=[C:27]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:26]=3)[CH2:21][N:20]2[C:43](=[O:63])[NH:44][CH:45]([C:50](=[O:62])[NH:51][CH:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)C[CH:53]2[OH:61])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:18])[CH2:13][CH:12]1[CH:14]=[CH2:15])=[O:10])C>>[OH:61][CH2:53][C@H:52]([NH:51][C:50]([C@@H:45]([NH:44][C:43]([N:20]1[CH2:21][C@H:22]([O:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=3)[N:28]=[C:27]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:26]=2)[CH2:23][C@H:19]1[C:17]([NH:16][C@:11]1([C:9]([OH:10])=[O:8])[CH2:13][C@H:12]1[CH:14]=[CH2:15])=[O:18])=[O:63])[C:46]([CH3:48])([CH3:49])[CH3:47])=[O:62])[C:60]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Agent: O=C([O-])NCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)N[C@@H](CO)c1ccccc1)C(C)(C)C)C(=O)O

Procedure:
The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC >95%. M+H+750.3.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:12][C:8]1[C:7]2[NH:13][CH2:2][CH2:3][CH2:4][O:5][C:6]=2[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(OCCCBr)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc2c1NCCCO2
Temperature: 70 °C
Yield: 68.9 %

Procedure:
To 2-(3-bromo-propoxy)-6-methyl-phenylamine (4.8 g, 20 mmol) in acetonitrile (200 mL) was added potassium carbonate (13.8 g, 100 mmol). The mixture was heated at 70° C. for 24 hrs, followed by the filtration to remove solids. After evaporation, the mixture was repartitioned with ethyl acetate (250 mL) and water (150 mL). The organic layer was then washed with brine (150 mL) and dried over MgSO4. Evaporation followed by purification by silica gel column chromatography eluting with hexane/ethyl acetate (11/1 to 4/1) yielded 1-methyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene 2-3 as a pale yellow oil (2.25 g). MS: 164.0 (M+H)+; tR=1.191 min (method 1). NMR (CDCl3), δ, 6.789-6.858 (2H, m), 6.664 (1H, t), 4.158 (2H, t), 3.343 (2H, t), 2.198 (3H, s), 1.191-2.067 (2H, m).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[N:39]1([CH2:45][CH2:46][CH2:47]Cl)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O>[CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([CH2:47][CH2:46][CH2:45][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH2:29][CH2:30]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Reactant: ClCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCN2CCCCC2)CC1
Temperature: 100 °C

Procedure:
In a 25 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole (69.9 mg, 0.13 mmol), potassium carbonate (161.9 mg, 1.17 mmol), potassium iodide (21.6 mg, 0.13 mmol), 3-(piperidin-1-yl)propyl chloride (33.52 mg, 0.17 mmol) and N,N-dimethylformamide (3 ml). The resulting mixture was heated to 100° C. and maintained at this temperature. The progress of the reaction was monitored by thin layer chromatography. The reaction was quenched by the addition of water. The aqueous fraction was extracted wtih ethyl acetate. The organic fractions were combined, washed with water, and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9]Cl.[I-].[K+].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16]>CN(C)C(=O)C>[C:15]([C:14]1([C:13]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8]1)(=[O:16])[CH3:17]
Reactant: ClCCCl
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1(C(C)=O)CC1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A total of 165.6 g of potassium carbonate, 390.0 g of 1,2-dichloroethane, 234.0 g of N,N-dimethylacetamide, 5.0 g of potassium iodide, and 78.0 g of ethyl acetoacetate were mixed, followed by a reaction at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and was filtrated, the resulting filtrate was washed with two portions of 5% by weight hydrochloric acid, and the organic layer was washed with water. The organic layer was then concentrated under a reduced pressure to distill off 1,2-dichloroethane, was subjected to distillation under a reduced pressure and thereby yielded 31.7 g of ethyl 1-acetyl-1-cyclopropanecarboxylate as a colorless liquid as a fraction at 80° C./20 mmHg.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4nnc(C(F)(F)F)s4)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole following a procedure analogous to that described for Example 79. LC (method 7): tR=1.46 min; Mass spectrum (ESI+): m/z=516 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>C1COCC1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzyl chloroformate (14 ml) in THF (30 ml) was added dropwise over 40 minutes to an ice-cold solution of 4-aminophenol (11 g) in THF (500 ml), the temperature of the reaction mixture being maintained at 0°-5° C. On completion of the addition, the reaction mixture was stirred at ambient temperature for 2 hours and the precipitated solid was collected and crystallised from a mixture of ethyl acetate and hexane to give 4-benzyloxycarbonylaminophenol (11.3 g) as a white solid: m.p. 153°-154° C.; Elemental Analysis: calculated for C14H13NO3 : C, 69.1%; H, 5.4%; N, 5.8%; found: C, 69.3%; H, 5.3%; N, 5.8%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cu](C#N)[C:10]#[N:11]>CN(C)C=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1ccc(Br)nc1
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)nc1
Temperature: 50 °C

Procedure:
36 g (209 mmol) 2-Bromo-5-methylpyridine and 37.5 g (418 mmol) copper cyanide are refluxed for two hours in 500 ml dimethylformamide. After cooling down to 50° C., 10% aqueous armnoia solution (500 ml) is added with stirring. The product is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo. The product is purified by column chromatography (silica, eluent cyclohexane/ethyl acetate 9:1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=1[C:8]#N.[CH3:17]C(C[AlH]CC(C)C)C.CC(O)=O.C([BH3-])#N.[Na+]>C(Cl)Cl.C1COCC1.O>[CH2:1]([N:2]1[CH2:8][C:7]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:6]=2[NH:5][CH2:4][CH2:3]1)[CH3:17]
Reactant: CNCCNc1cc([N+](=O)[O-])ccc1C#N
Reactant: CC(C)C[AlH]CC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCNc2cc([N+](=O)[O-])ccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(2-methylamino-ethylamino)-4-nitro-benzonitrile (1 g) in methylene chloride (100 mL) was cooled to −78° C. and treated with 1 M DIBAL-H in hexanes (8.5 mL). The mixture was allowed to slowly warm to room temperature and stirred for 16 hours. The mixture was treated with HOAc (2 mL) followed by 1 M sodium cyanoborohydride in THF (4 mL). After 1 hour, the mixture was diluted with water and the organic layer was separated. The aqueous phase was extracted again with methylene chloride and the combined organics were dried over sodium sulfate, filtered and concentrated. Silica gel chromatography (1→2% MeOH/methylene chloride) provided 4-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, which was heated in acetic anhydride at 100° C. for 2 hours to provide, after concentration and silica gel chromatography 1-(4-ethyl-8-nitro-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl)-ethanone (90 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH3:24])(C)C>ClCCl>[C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[C:16](=[O:18])[O:17][C:16](=[O:17])[C:15]=3[C:24]3[C:27]4[C:25](=[CH:26][CH:2]=[CH:1][CH:6]=4)[N:22]([CH3:19])[CH:23]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)Cc1ccn(S(=O)(=O)c2ccccc2)c1
Solvent: ClCCl
Product: Cn1cc(C2=C(c3ccn(S(=O)(=O)c4ccccc4)c3)C(=O)OC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 66.3 %

Procedure:
1 g of 1-(benzenesulphonyl)-3-pyrrolylacetic acid in 25 ml of dichloromethane was treated at 0° C. with a solution of 837 mg of 1-methylindole-3-glyoxylyl chloride in 25 ml of dichloromethane and then with 975 mg of diisopropylethylamine. The mixture was allowed to warm to room temperature and was then stirred for 22 hours. After concentration and chromatography of the residue on silica gel with ethyl acetate/hexane (1:1) there were obtained 540 mg of 3-[1-(benzenesulphonyl)-3-pyrrolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione.
Reaction SMILES: C(Cl)Cl.Cl.Cl.[Cl:6][C:7]1[C:8]([CH:18]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:9][C:10]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[N:11][CH:12]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>CCOCC>[Cl:6][C:7]1[C:8]([CH:18]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:9][C:10]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][S:45]([CH3:44])(=[O:47])=[O:46])=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
To a methylene chloride solution (5.0 ml) of the N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diamine dihydrochloride (60 mg, 0.107 mmol) obtained in Example 173 were added triethylamine (70 μl, 0.05 mmol) and methanesulfonyl chloride (10 μl, 0.13 mmol). The resulting mixture was stirred for 20 minutes. To the reaction mixture was added ether (50 ml). The resulting mixture was washed with water and brine, dried and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the title compound (60 mg, 99%). The resulting compound was crystallized in ethanol to afford a white solid (46 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[C:4]([C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:14])(=[O:13])=[O:12])#[N:5]
Reactant: NS(N)(=O)=O
Reactant: Cc1cccc(N)c1C#N
Solvent: C1COCCO1
Product: Cc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C

Procedure:
A solution of 2-amino-6-methylbenzonitrile (1.32 g, 10 mmol) and sulfamide (4.81 g, 50 mmol) in dry 1,4-dioxane (50 mL) was refluxed under nitrogen for 3 days. After the reaction mixture was cooled down to room temperature, the precipitate was filtered and washed with dioxane. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (3:7) to give the title compound as a pale-white solid. 1H NMR (400 MHz, DMSO-d6) δ2.44 (s, 3H), 7.19-7.21 (m, 3H), 7.39-7.41 (d, J=8.4 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 9.41 (s, 1H).
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[N:14]=[C:3]21.CCN(CC)CC.[CH3:35][N:36]([CH3:41])[S:37](Cl)(=[O:39])=[O:38].[O-]CC.[Na+]>C(Cl)Cl.CO>[CH3:35][N:36]([CH3:41])[S:37]([NH:1][C:2]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[O:16])[N:14]=[C:3]21)(=[O:39])=[O:38]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
To a solution of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.067 mmol) in CH2Cl2 (2 mL) was added Et3N (0.047 mL, 0.336 mmol) followed by dimethylsulfamoyl chloride (0.036 mL, 0.336 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give crude product which was dissolved in methanol (2 mL) and treated with sodium ethoxide (0.2 ml, 21 wt % in ethanol) and the heated at 70° C. overnight. The mixture was then cooled, concentrated and purified by preparative HPLC to afford the title compound as a white solid (3.5 mg, 11% yield). 1H NMR (500 MHz, CDCl3) δ: 12.00 (s, 1H), 8.90 (s, 1H), 7.34 (dd, 2H, J=8.39 & 5.34 Hz), 7.01 (t, 2H, J=8.55 Hz), 4.53 (d, 2H, J=6.41 Hz), 4.15 (d, 2H, J=3.97 Hz), 2.77 (s, 6H), 2.50 (s, 1H), 2.12 (t, 4H, J=7.63 Hz), 1.85-1.97 (m, 2H), 1.64-1.73 (m, 2H). LCMS (M+H)=480.21. HPLC purity: >95%.