Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: C1CCNCC1
Product: Clc1ccc(-c2nsc3cc(OCCCCN4CCCCC4)ccc23)cc1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and Piperidine were converted to yield 3-(4-Chloro-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole, MS: 401 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([OH:11])=[O:10].CS(C)=O>O>[C:9]([C:12]1[CH:19]=[CH:18][C:15]([C:16]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1)([OH:11])=[O:10]
Reactant: Nc1ccccc1S
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(-c2nc3ccccc3s2)cc1
Temperature: 145 °C
Reaction time: 3.5 h
Yield: 82 %

Procedure:
A mixture of 2-aminothiophenol (9.00 ml, 0.08 mol), 4-carboxybenzaldehyde (10.1 g, 0.07 mol) and DMSO (40 mL) was heated to 145° C., and held at this temperature for 3.5 hours. The reaction mixture was diluted with water, and separated solids were collected, dried and recrystallized from acetic acid; 14.15 g, (82% yield), white solid, m.p. 294.1-295.5° C. Mass Spectrum: m/z, 255 (M+), 238 (M—OH), 210 (M—COOH), 108. FT-IR (KBr; cm−1): 3051 (br; OH), 1684 (CO), 1609, 1424, 1407, 1291, 970, 756. Anal. Calcd for C14H9NO2S: C, 65.87; H, 3.55; N, 5.49; S, 12.56%. Found: C, 65.71; H, 3.96; N, 5.30; S, 12.66%. NMR: not available due to poor solubility.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][N:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26]Br)[CH3:23]>CN(C)C=O>[CH2:3]([O:10][N:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:26][CH:25]([O:28][CH2:29][CH3:30])[O:24][CH2:22][CH3:23])[C:13]1=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1Nc2ccccc2C1=NOCc1ccccc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CN1C(=O)C(=NOCc2ccccc2)c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a suspension of 0.35 g of sodium hydride (60%) in 20 ml of N,N-dimethylformamide was added dropwise a solution of 2.00 g of 3-(benzyloxyimino)indolin-2-one in 20 ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After stirring the mixture at room temperature for 1 hour, 1.40 ml of bromoacetaldehyde diethyl acetal was added thereto, and the mixture was stirred for 12 hours at 70° C. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=100/1) to give 2.20 g (76%) of 3-(benzyloxyimino)-1-(2,2-diethoxyethyl)indolin-2-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([C:27]#[N:28])=[CH:3][CH:4]=3)[CH2:11][CH2:12]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc(Br)cc3)CC2)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)cc1

Procedure:
A solution of 1-[2-(4-bromophenyl)ethyl]-4-[2-(4-nitrophenyl)ethyl]piperazine (100 mg, 0.24 mmol), Zinc cyanide (84 mg, 0.72 mmol), and tetrakis(triphenylphosphine)palladium in DMF (1 mL) was heated to 85° C. for 1 hour. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 365 (M+1)+. (0.079 μM)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([C:11]#[C:12][C:13]([F:16])([F:15])[F:14])[CH2:9][CH3:10])=[CH:4][CH:3]=1>CO.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:11][CH2:12][C:13]([F:14])([F:15])[F:16])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(C#CC(F)(F)F)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: O=[Pt]=O
Solvent: CO
Product: CCC(CCC(F)(F)F)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from Step B (63 mg, 0.108 mmol, enantiomer A) and PtO2 (2.4 mg, 0.0108 mmol) in MeOH (3 mL) was purged air three times and then backfilled with H2. The mixture was stirred at RT overnight. The suspension was filtered off and filtrate was concentrated to give the title compound which was used for next step without purification. LC/MS m/z=610.7 [M+Na]+.
Reaction SMILES: C[N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]2[C:11]([CH2:21][C:22]([OH:24])=O)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:13]=[C:3]12.[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>O1CCCC1>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:22](=[O:24])[CH2:21][C:11]1[N:4]2[C:3]([NH:2][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=32)=[N:13][C:12]=1[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1
Reactant: COCCN
Reactant: Cc1ccc(-c2nc3n(C)c4ccccc4n3c2CC(=O)O)cc1
Solvent: C1CCOC1
Product: COCCNC(=O)Cc1c(-c2ccc(C)cc2)nc2[nH]c3ccccc3n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.3 %

Procedure:
A suspension of 3.5 g (0.11 mol) of 9-methyl-2-(4-methylphenyl)-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 70 ml of dry tetrahydrofuran, 2.67 g (0.165 mol) of N,N'-carbonyldiimidazole are added in small portions, over 10 min, and the mixture is stirred at room temperature for 1 h. It is cooled in an ice-cold water bath, and 1.65 g (0.165 mol) of 2-methoxyethylamine in solution in 4 ml of dry tetrahydrofuran are added. Stirring is continued for 1 h at cold temperature, and then at room temperature for 4 h. The solvent is evaporated under reduced pressure. The residue is crystallized from water. The solid is collected by filtration, washed, dried and recrystallized from ethanol. 2.9 g of compound are finally obtained. Melting point: 189°-190° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][OH:11])=[NH:9])[CH:5]=[C:4]([S:12][CH3:13])[CH:3]=1.[C:14](OC(=O)C)(=O)[CH3:15]>>[CH3:14][C:15]1[O:11][N:10]=[C:8]([C:6]2[N:7]=[C:2]([NH2:1])[CH:3]=[C:4]([S:12][CH3:13])[CH:5]=2)[N:9]=1
Reactant: CSc1cc(N)nc(C(=N)NO)c1
Reactant: CC(=O)OC(C)=O
Product: CSc1cc(N)nc(-c2noc(C)n2)c1

Procedure:
A solution of 0.094 g 6-Amino-N-hydroxy-4-methylsulfanyl-pyridine-2-carboxamidine in 1.5 ml acetic acid anhydride was heated to reflux for 6 h. The solvent was evaporated and the solidifying residue was taken up in 1.5 ml 1N hydrochloric acid and heated to reflux for 1 h. The reaction mixture was partitioned between 2 ml 1N aqueous sodium hydroxide and ethyl acetate. The phases were separated and the organic phase was washed with water and brine dried over magnesium sulfate and evaporated. The residue triturated in ethyl acetate (1 ml) and the resulting solid was collected by filtration to yield 0.057 g of the title compound as light yellow solid MS (ISP) M+H+=223.3
Reaction SMILES: FC1C=C(C=CC=1)C([N:7]1[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]1[C:14]1[C:22](F)=[C:21]([C:24]([C:26]2C=C[CH:29]=[C:28]([F:32])[CH:27]=2)=C)C=CC=1C([O-])=O)=O.[OH2:36].[ClH:37]>>[ClH:37].[CH3:13][C:10]1[N:9]=[C:8]([CH2:14][C:22]([C:21]2[CH:24]=[CH:26][CH:27]=[C:28]([F:32])[CH:29]=2)=[O:36])[NH:7][C:11]=1[CH3:12]
Reactant: C=C(c1cccc(F)c1)c1ccc(C(=O)[O-])c(-c2nc(C)c(C)n2C(=O)c2cccc(F)c2)c1F
Reactant: O
Agent: Cl
Product: Cc1nc(CC(=O)c2cccc(F)c2)[nH]c1C
Yield: 23 %

Procedure:
12.97 g crude compound of Example VII are refluxed 1.5 h in 200 ml concentrated hydrochloric acid. The mixture is cooled to rT and 200 mL water are added. The solution is extracted twice with toluene and the aqueous phase is concentrated under vacuum. The residue is stirred with ethanol, filtered, washed once with ethyl acetate and once with petrol ether and dried to yield 1.7 g (23% of th.) 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(3-fluorophenyl)ethanone hydrochloride.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8]O)[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(Cl)Cl>[Br:31][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:10])([F:1])[CH2:3][CH2:4]1
Reactant: OCC1CCC(F)(F)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC1(F)CCC(CBr)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
(4,4-Difluorocyclohexyl)methanol (7.22 g, 48.08 mmol) and triphenylphosphine (25.2 g, 96.16 mmol) were dissolved in DCM (75 mL) and cooled to 0° C. under nitrogen atmosphere. Carbon tetrabromide (31.9 g, 96.16 mmol) was dissolved in DCM (75 mL) and added to the reaction mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated. Pentane (250 mL) was added to the orange residue, which caused triphenylphosphineoxide to precipitate. The off-white solids were filtered off. The filtrate was evaporated and purified on a ISOLUTE Silica Flash column (50 g). Pentane followed by EtOAc:pentane (1% EtOAc) was used as eluent. 4-(Bromomethyl)-1,1-difluorocyclohexane (5.48 g, 54%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.32-1.46 (m, 2H), 1.64-1.84 (m, 3H), 1.90-1.99 (m, 2H), 2.05-2.18 (m, 2H), 3.31 (d, 2H).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[NH2:31][C:32]1[N:37]=[CH:36][C:35]([C:2]2[N:6]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:4]([CH3:17])[C:3]=2[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:34][N:33]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(-c2cnc(N)nc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with 2-amino-pyrimidin-5-yl-boronic acid to give the title compound as colorless solid. MS: 499.7 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[N:47]([CH2:50][CH3:51])=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:48]([NH:47][CH2:50][CH3:51])=[O:49])[CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Reactant: CCN=C=O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N1CCCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 36 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and isocyanato-ethane as starting materials in 36% yield. LCMS for C27H31ClN7O2 (M+H)+: m/z=520.2.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(O)=O>[CH3:23][S:20]([NH:19][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[CH:18]=1)(=[O:21])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(NS(C)(=O)=O)cc2CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CS(=O)(=O)Nc1ccc2c(c1)CCNCC2

Procedure:
3-Tertiary-butoxycarbonyl-7-methanesulphonamido-1,2,4,5-tetrahydro-3H-3-benzazepine (0.6 g) and 98% formic acid (10 ml) were stirred together at room temperature for 2 hours. The solvent was evaporated in vacuo to give an oil which was basified with aqueous sodium bicarbonate. The aqueous solution was evaporated in vacuo and the residue was triturated with hot isopropanol. The isopropanol was decanted and evaporated in vacuo to give a solid which was recrystallised from ethyl acetate/hexane to give the title compound, yield 0.22 g.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:55]=[CH:56][CH:57]=[CH:58][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:42]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:55]=[CH:56][CH:57]=[CH:58][C:4]=2[NH:3]1
Reactant: O=C(O[C@H](Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)N1CCC(N2CCN(Cc3ccccc3)CC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O[C@H](Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)N1CCC(N2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 64 mg (0.08 mmol) of (R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 52) in 10 mL MeOH was combined with 50 mg 10% Pd/C and shaken for 3 h at RT and 50 psi hydrogen. The catalyst was suction filtered, the solvent was evaporated down i.vac., the residue was combined with acetonitrile and water and lyophilised.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][N:34]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:33][CH2:32]1
Reactant: O=C(Cl)c1cccs1
Reactant: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 72 (397 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 280 mg (55%) of white solids. M.P. 253° C. 1H NMR (DMSO-d6): δ 3.70 (m, 4H), 3.93 (m, 4H), 5.46 (s, 2H), 7.13-7.17 (m, 3H), 7.27 (m, 2H), 7.44 (d, J=9.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.68 (dd, J=2.6, 9.0 Hz, 1H), 7.79 (d, J=4.0 Hz, 1H), 7.89 (s, 1H). EIMS m/z 508 (M+1). Anal. (C26H20FClN4O2S) C, H, N.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11]N2C(=O)CCC2=O)=O)=[C:7]([Cl:21])[CH:6]=1)=[N+:2]=[N-:3].Cl.[C:23]([NH:31][CH2:32][C@@H:33]([C:35]([O:37][CH3:38])=[O:36])[NH2:34])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>>[N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:34][C@H:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32][NH:31][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])=[C:7]([Cl:21])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1ccc(C(=O)ON2C(=O)CCC2=O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Yield: 69.6 %

Procedure:
A solution of 1-[[4-(azidomethyl)-2-chlorobenzoyl]oxy]-2,5-pyrrolidinedione (4.64 g, 15.0 mmol), 3-(benzoyl)amino-L-alanine, methyl ester hydrochloride (4.00 g, 15.5 mmol), and triethylamine (4.00 g, 39.5 mmol) in N,N-dimethylformnamide (50 mL) was stirred at room temperature for 3 h. The solvent was evaporated, and 1 M HCl (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried (MgSO4), filtered, evaporated, and chromatographed (50-75% ethyl acetate/hexanes) to give N-[4-(azidomethyl)-2-chlorobenzoyl]-3-(benzoyl)amino-L-alanine, methyl ester (4.34 g, 69%) as a colorless oil that solidified on standing, mp 112-114° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:27])[N:9]3[CH2:26][CH2:25][CH2:24][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]=[C:19](N(C)C)[CH3:20])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:28][NH:29][NH2:30]>C(O)(=O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:27])[N:9]3[CH2:26][CH2:25][CH2:24][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:29]([CH3:28])[N:30]=[C:19]([CH3:20])[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2)N(C)C
Reactant: CNN
Solvent: CC(=O)O
Product: Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n(C)n1
Reaction time: 1.75 h

Procedure:
A mixture of 3.96 g (10.3 mmol) of (S)-8-chloro-N-[1-(dimethylamino)ethylidene]-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide, 25 ml of glacial acetic acid and 0.65 ml (12.4 mmol) of methylhydrazine is stirred at 90° for 1.75 hours. The solution is then evaporated in vacuo and the residue is chromatographed on silica gel while eluting with ethyl acetate/methanol (19:1). After recrystallization from methylene chloride/ethyl acetate there is obtained (S)-8-chloro-1-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 221°-222°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:30][CH2:31][CH2:32][CH3:33])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1>[CH2:31]([NH:30][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:40][N:39]=[N:38][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH2:32][CH3:33]
Reactant: CCCNc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCNc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 758.9 %

Procedure:
A solution of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-propylaminobenzimidazole-7-carboxylate (1.20 g) and trimethyltin azide (2.7 g) in toluene (15 ml) was heated for 50 hours under reflux. Precipitates were collected by filtration and suspended in methanol (20 ml). After addition of 1N-HCl (15 ml), the reaction mixture was stirred at room temperature for 10 minutes. The mixture was adjusted to about pH 5 with 1N-NaOH, followed by extraction with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by column chromatography on silica gel to give crystals. Recrystallization from methanol-ethyl acetate gave colorless crystals (10 g, 77%), m.p. 170°-17° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:39][C:40]([F:52])([F:51])[C:41]1[N:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[S:47]([C:44]3[CH:45]=[N:46][C:41]([C:40]([F:52])([F:39])[F:51])=[CH:42][CH:43]=3)(=[O:49])=[O:48])=[CH:16][CH:15]=2)[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(CNCc2ccc(F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C(F)(F)F)nc1)N(Cc1ccc(F)cc1)Cc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To a solution of 3,5-dichloro-N-(4-fluorobenzyl)-N-(4-((4-fluorobenzylamino)methyl)benzyl)-2-hydroxybenzenesulfonamide (47 mg, 0.10 mmol) in CH2Cl2 (1 mL) were added 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (25 mg, 0.10 mmol, Aldrich) and diisopropylethylamine (0.042 mL, 0.30 mmol). The reaction mixture was stirred at rt for 2 h, and then concentrated. The residue was dissolved in methanol and purified by prep HPLC to give the title compound (24.0 mg, 57%) as a white solid. 1H NMR (DMSO-d6) δ 11.17 (br s, 1H), 9.15 (s, 1H), 8.50 (d, 1H, J=8.1 Hz), 8.11 (d, 1H, J=8.1 Hz), 7.83 (d, 2H, J=2.3 Hz), 7.56 (d, 1H, J=2.3 Hz), 7.17-6.97 (m, 12H), 4.40 (s, 2H), 4.39 (s, 2H), 4.37 (s, 2H), 4.34 (s, 2H); MS (ESI): 786.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:22]([F:24])[F:23])[N:6]2[CH:13]([CH3:21])[C:14]([O:16]C(C)(C)C)=[O:15].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:22]([F:23])[F:24])[N:6]2[CH:13]([CH3:21])[C:14]([OH:16])=[O:15]
Reactant: CC(C(=O)OC(C)(C)C)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)O)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]propanoate (0.072 g, 0.2 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL) and stirred at rt for 4 h. The mixture was concentrated in vacuo. The residue was diluted with Et2O and hexane was added while stirring. The solids were collected by filtration and washed with hexane to afford the title compound as a white solid (0.058 g, 95% yield): MS (ES) m/z 299 (M+1).