Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(NC2OC3C=C(C(C)C#N)C=CC=3N=2)=CC=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][C:29]=1[OH:30].C(O[C:41]([S-])=[S:42])C.[K+].C(O)C>O>[S:42]=[C:41]1[NH:23][C:24]2[CH:25]=[C:26]([CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][C:29]=2[O:30]1
Reactant: CCOC(=S)[S-]
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Agent: COc1ccc(Nc2nc3ccc(C(C)C#N)cc3o2)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc2oc(=S)[nH]c2c1

Procedure:
2-[2-(4-methoxyanilino)-6-benzoxazolyl]propionitrile (i) A stirred mixture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (8.4 g.), potassium ethylxanthate (6.33 g.), ethanol (38 ml.) and water (6.5 ml.) was heated under reflux for 4 hours. The solution was evaporated to half volume and diluted with water (65 ml.). The mixture was acidified with 2N-hydrochloric acid and extracted several times with ether. The ethereal solution was washed with water, then dried with anhydrous sodium sulphate, and evaporated to give ethyl 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl)propionate as an oil. Dry chlorine was passed into a solution of the thione (9 g.) in freshly dried and distilled chloroform (150 ml.) with stirring for 4 hours. The solution was then washed with water, N-sodium hydroxide solution, then water (3x). The dried (Na2SO4) organic solution was evaporated to yield ethyl 2-(2-chloro-5-benzoxazolyl]propionate as a brown oil which was shown to be a single compound by thin layer chromatography. (j) A mixture of the 2-chloro compound (12.5 g.) of Example 3 (i) and p-chloroaniline (25 g.) was heated on a steam bath for one hour. The reaction mixture was dissolved in chloroform and the solution was washed with 2N hydrochloric acid (2x), water, 2N sodium hydroxide solution (2x) and water (3x). The chloroform solution was stirred with charcoal and anhydrous sodium sulphate, then filtered and evaporated. The residue was purified using prep t.l.c. plates to give ethyl-2-[2-(4-chloroanilino) -5-benzoxazolyl]propionate, mpt 135°-7° C., which was characterised by ir uv and nmr spectroscopy and by micro analysis which gave C 62.45% H 5.11% N 7.97% C18H17ClN3O2 requires C 62.70% H 4.93% N 8.13%
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[N+:9]([O-:22])[C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2)c[n+]1[O-]

Procedure:
A solution of 3-phenyl-6-methyl pyridine (2.36 g, 13.95 mmol), in CH2Cl2 (40 mL) at 0° C. was treated with MCPBA (3.58 g, 13.95 mmol) for 1 hour. Saturated aq. Na2CO3 (50 mL) was added and the reaction was extracted with CH2Cl2 (20 mL). The organic extracts were dried (MgSO4), and the solvent evaporated in vacuo to afford the title compound.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:20]1([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:12]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1](=[O:10])[N:13]=3)[CH:19]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cc(-c2ccccc2)ccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cc(-c3ccccc3)ccn2)sc2ccccc12
Yield: 53 %

Procedure:
A mixture of methyl thiosalicylate (1.00 g, 5.9 mmol), 2-cyano-4-phenylpyridine (1.10 g, 5.9 mmol), triethylamine (1.30 ml, 9.0 mmol) and toluene (2.5 ml) was refluxed for 20 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.99 g, 53%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][C:6]=1[O:23][CH2:24][O:25][CH3:26])[CH3:2].[CH2:28]([O:35][C:36](=[O:41])[NH:37][CH2:38][CH2:39]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:39][CH2:38][NH:37][C:36]([O:35][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:41])[CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][C:6]=1[O:23][CH2:24][O:25][CH3:26])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(O)cc32)cc1OCOC
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCNC(=O)OCc4ccccc4)cc32)cc1OCOC
Temperature: 50 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a solution of 4-(3-cyano-6-hydroxyindol-1-yl)-2-methoxymethoxybenzoic acid ethyl ester (0.37 g) in N,N-dimethylformamide (10 mL) were added (2-bromoethyl)carbamic acid benzyl ester (0.39 g) and potassium carbonate (0.28 g), and this mixture was stirred at 50° C. overnight. This reaction mixture was poured into water, and the precipitated solid was collected by filtration. This solid was washed with methanol, and dried to give the title compound (0.40 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1([CH2:32]O)[CH2:31][O:30][CH2:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:27][C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(CO)COC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Product: CC1(COc2ccc(C(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)c(Cl)c3)cc2)COC1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and (3-methyl-oxetan-3-yl)-methanol in analogy to Example 9c): MS (ISN): 478.1 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:39]3[CH2:40][CH2:41][NH:36][C:37](=[O:42])[CH2:38]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-4,5-bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12b) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 681.3 [(M+H)+]
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:11])[CH2:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[NH2:12][CH2:13][CH2:14][OH:15].CO>ClCCl>[OH:15][CH2:14][CH2:13][NH:12][CH2:2][C@@H:3]([OH:11])[CH2:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)C#CC[C@H](O)CCl
Reactant: NCCO
Solvent: CO
Solvent: ClCCl
Product: C[Si](C)(C)C#CC[C@H](O)CNCCO
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of (2S)-1-chloro-5-(trimethylsilyl)pent-4-yn-2-ol (80 g, 420 mmol) and 2-aminoethanol (110 g, 1.8 mol) was stirred at 80° C. for 18 hours. Silica gel chromatography (Gradient: 1% to 10% methanol in dichloromethane) provided the product as a yellow oil. Yield: 30 g, 140 mmol, 33%. 1H NMR (400 MHz, CD3OD) δ 3.80-3.88 (m, 1H), 3.61-3.72 (m, 2H), 2.84 (dd, J=12.3, 3.3 Hz, 1H), 2.69-2.81 (m, 2H), 2.64 (dd, J=12.0, 8.5 Hz, 1H), 2.45 (dd, half of ABX pattern, J=16.6, 5.5 Hz, 1H), 2.37 (dd, half of ABX pattern, J=16.6, 7.0 Hz, 1H), 0.12 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]([S:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH2:1]([N:8]([S:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:20])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C(O)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2cccnc2)c1
Product: CC(C)NC(=O)c1cccc(N(Cc2ccccc2)S(=O)(=O)c2cccnc2)c1

Procedure:
3[Benzyl-(pyridine-3-sulfonyl)-amino]-N-isopropyl-benzamide was prepared from 3-[benzyl-(pyridine-3-sulfonyl)-amino]-benzoic acid and isopropylamine according to the method described for Example 2. HPLC retention time 5.46 min. Mass spectrum (APCI+) m/z 410 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[CH2:15][CH2:16]Cl)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][N:31]([CH2:16][CH2:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19])=[CH:8][CH:9]=2)=[O:18])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCCl)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCN2CCC(O)(Cc3ccccc3)CC2)cc1

Procedure:
The title compound, MS: m/e=468 (M+), was prepared from N-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-3-chloro-propionamide and 4-benzyl-4-hydroxypiperidin.
Reaction SMILES: BrC1C=CC(OC2C=CC=CC=2)=C(C)C=1.[O:16]([C:23]1[CH:30]=[CH:29][C:28]([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)=[CH:27][C:24]=1[C:25]#N)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCCC.C(OCC)(=O)C>[C:17]1([O:16][C:23]2[CH:30]=[CH:29][C:28]([B:31]3[O:35][C:34]([CH3:36])([CH3:37])[C:33]([CH3:39])([CH3:38])[O:32]3)=[CH:27][C:24]=2[CH3:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)c(C#N)c2)OC1(C)C
Agent: Cc1cc(Br)ccc1Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Oc1ccccc1

Procedure:
The title compound was prepared in a 77% from 4-bromo-2-methyl-1-phenoxybenzene in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 7.67(s, 1H), 7.50(d, 1H), 7.38(t, 2H), 7.14(t, 1H), 6.94(d, 2H), 6.80(d, 1H), 2.21(t, 3H); TLC (heptane/ethyl acetate 9:1) Rf0.6.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44].[Cl-].[NH4+]>C(Cl)Cl>[CH3:42][S:43]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])(=[O:45])=[O:44]
Reactant: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 23 h
Yield: 79.7 %

Procedure:
6.62 gram (14.1 mmol) of (−)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-1a-1)) was dissolved in 282 ml of methylene chloride, followed by the addition of 4.7 ml (57.8 mmol) of pyridine and 4.1 ml (53.6 mmol) of methanesulfonyl chloride at 0° C. The reaction solution was stirred at room temperature for 23 hours. To the reaction solution, 200 ml of saturated aqueous solution of ammonium chloride was added and extracted with 200 ml of methylene chloride. The extract was washed with 200 ml of brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 2:3 mixture of ethyl acetate and hexane) to obtain 6.15 gram of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][N:10]1[CH:11]=[CH:12][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[CH2:8][C:9]1=[O:13]
Reactant: ClCCCBr
Reactant: COc1ccc2c(c1)CC(=O)NC=C2
Product: COc1ccc2c(c1)CC(=O)N(CCCCl)C=C2

Procedure:
3-(3-Chloro-propyl)-8-methoxy-1,3-dihydro-benzo[d]azepin-2-one was prepared from 8-methoxy-1,3-dihydro-benzo[d]azepin-2-one and 1-bromo-3-chloropropane in an analogous manner to Example 251a. Product isolated as a brown solid (5.87 g, 84%). LC/MS (ESI+) 266 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:7]12.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[C:14]([CH:25]=[O:26])=[C:13]([CH3:15])[N:12]=[C:7]12
Reactant: Cc1cn2ccc3c(Cl)cccc3c2n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2c3cccc(Cl)c3ccn2c1C=O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 7-chloro-2-methylimidazo[2,1-a]isoquinoline (4 g) in N,N-dimethylformamide (40 ml) was added dropwise to a mixture of N,N-dimethylformamide (5.7 ml) and phosphoryl chloride (1.86 ml) under ice cooling. After being stirred at 85°-90° C. for 6 hours, the mixture was poured into ice-water, basified with aqueous sodium hydroxide, heated at 80° C. for 20 minutes and cooled. The resulting precipitate was collected by filtration, washed with water and recrystallized from methanol to give 7-chloro-3-formyl-2methylimidazo[2,1-a]isoquinoline (0.356 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1N)([O-:3])=[O:2].N(OC(C)(C)C)=O.O.[ClH:24]>C(#N)C.[Cu](Cl)Cl>[F:13][C:12]([F:15])([F:14])[S:11][C:9]1[CH:8]=[CH:7][C:5]([Cl:24])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: Nc1ccc(SC(F)(F)F)cc1[N+](=O)[O-]
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(SC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Nitro-4-trifluoromethylthioaniline (0.5 g) in dry acetonitrile (3 cm3) was added over 0.5 hr. with stirring to copper (II) chloride (0.34 g) and tert-butyl nitrite (0.32 g) in dry acetonitrile (5 cm3) at 60° C. After 1 hr. the reaction was cooled to ambient temperature, poured into water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water (3×50 cm3) dried (magnesium sulphate) and evaporated under reduced pressure to give the required product as an oil; M+ =257; 1H NMR (CDCl3): δ7.65(d 1H); 7.80(dd 1H); 8.20(d 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:28]=[CH:27][C:7]2[S:8][CH:9]=[C:10]([CH:11]([CH2:25][OH:26])[C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[O:13])[C:6]=2[CH:5]=1.[S:29](Cl)(=[O:32])(=[O:31])[NH2:30]>CN(C=O)C>[Cl:3][C:4]1[CH:28]=[CH:27][C:7]2[S:8][CH:9]=[C:10]([CH:11]([C:12](=[O:13])[NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[CH2:25][O:26][S:29](=[O:32])(=[O:31])[NH2:30])[C:6]=2[CH:5]=1
Reactant: O=C(Nc1ccc2ccccc2c1)C(CO)c1csc2ccc(Cl)cc12
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)OCC(C(=O)Nc1ccc2ccccc2c1)c1csc2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 95% NaH (0.017 g, 0.68 mmol) in DMF (2 mL) at 0° C. was added a solution of Compound 136 (0.10 g, 0.26 mmol) in DMF (2 mL) dropwise. The suspension was stirred at 0° C. for 1 h, then sulfamoyl chloride (0.067 g, 0.58 mmol) was added as a solid. After stirring for 1 h at 0° C., the mixture was treated with excess sulfamoyl chloride. After stirring overnight, the reaction was, quenched with water and extracted with EtOAc (3×5 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure at rt. The residue was purified by flash column chromatography (silica, 0-40% EtOAc/hexanes) to yield Compound 120 (0.1.0 g) as a white foam: HPLC: 4.12 min; MS (ES) m/z 461 (MH+); 1H NMR (DMSO-d6) δ 4.29-4.34 (m, 1H), 4.65-4.75 (m, 2H), 7.39-7.50 (m, 3H), 7.57-7.64 (m, 1H), 7.81-7.90 (m, 4H), 8.09 (d, 1H, J=8.5 Hz), 8.215 (d, 1H, J=2 Hz), 8.34 (s, 1H), 10.55 (s, 1H).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=O)[CH3:2].Cl[C:7]1[N:12]=[N:11][C:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[C:9]([CH3:21])[CH:8]=1>C(O)CCC>[CH3:2][C:1]1[N:12]2[N:11]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[C:9]([CH3:21])=[CH:8][C:7]2=[N:5][N:4]=1
Reactant: Cc1cc(Cl)nnc1-c1ccc(C#N)cc1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1cc2nnc(C)n2nc1-c1ccc(C#N)cc1

Procedure:
A 1.48 g. portion of acetic acid hydrazide is dissolved in 50 ml. of butyl alcohol with heating, then 4.58 g. of p-(6-chloro-4-methyl-3-pyridazinyl)benzonitrile (prepared as in Example 1) is added and complete solution occurs after heating for an additional 10 minutes. The solution is then heated at reflux for 18 hours. The reaction mixture is concentrated to afford 5.8 g. of orange solid which is washed with petroleum ether. This product is dissolved in 1:1 ethyl alcohol/acetone and is filtered through a pad of silica gel. The filter is washed copiously with acetone and the combined filtrates are concentrated to a yellow solid. The solid is dissolved in 100 ml. of acetone and the solution is cooled in dry ice-acetone to afford a tan solid which is collected by filtration, washed copiously with petroleum ether and air dried. This product is dissolved in methyl alcohol, is treated with activated charcoal and is filtered. The filtrate is used to recrystallize 1.06 g. of yellowish crystals. A 500 mg. portion of the above is recrystallized twice from methanol and the resultant product is dried in vacuo to give the product of the example, m.p. 242°-244° C.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]2[N:7]([CH3:15])[CH:8]3[CH:13]([CH:5]2[CH2:4][CH2:3]1)[CH:12]=[C:11]([OH:14])[CH:10]=[CH:9]3.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH3:15][N:7]1[CH:8]2[CH:13]([CH:12]=[C:11]([OH:14])[CH:10]=[CH:9]2)[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH:6]12
Reactant: CN1C2C=CC(O)=CC2C2CCC(N)C21
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2C=CC(O)=CC2C2CCC(NC(=O)OCc3ccccc3)C21
Reaction time: 2 h

Procedure:
To a solution of 3-amino-1,2,3,3a,4,8a-hexahydro-4-methylcyclopent[b]-indol-7-ol (10.7 grams) in methylene chloride (125 ml) was added triethylamine (5.6 grams) followed by the dropwise addition of benzyl chloroformate (10.0 grams) in methylene chloride (25 ml). The mixture as stirred for 2 hours, extracted with water, dried (Na2SO4) an concentrated. The product was purified by chromatography on silica gel, eluting with 2:1 hexane/acetone to provide 1,2,3,3a,4,8a-hexahydro-4-methyl-3-phenylmethyloxycarbonylaminocyclopent[b]indol-7-ol.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+].CS(C)=O>O>[N:14]([CH2:2][C@@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@H](CCl)COc1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC[C@@H](O)COc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of (S)-1-Chloro-3-(4-fluoro-phenoxy)-propan-2-ol (5.0 g, 24.5 mmol), sodium azide (3.19 g, 49.0 mmol) and DMSO (25 mL) was stirred at 80° C. for 6 h. Then the reaction mixture was poured into water (100 mL), extracted with hexane-Et2O (1:1) mixture (2×100 mL). Extracts were washed with brine (100 mL), dried over Na2SO4 and evaporated. The residue was dried under vacuum at RT. Colorless oil, 4.83 g (22.9 mmol, 93%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][C:28]([CH3:42])([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:42][C:28]1([O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1
Reactant: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of Intermediate A (111 mg, 0.680 mmol) in DMF (2 mL) was added NaH (60% in oil, 68 mg, 1.70 mmol) and the mixture stirred at RT for 20 min, before Intermediate 79d (230 mg, 0.566 mmol) was added. This mixture was stirred at 60° C. for 1 h. The cooled reaction mixture was diluted with EtOAc (100 mL), washed with water (2×), brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (160 mg, 51%). LCMS (Method 1): Rt 3.06 min, m/z 550 [MH+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].Cl[C:22]([O:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:22](=[O:23])[O:24][CH3:25])[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: COC(=O)Cl
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(=O)OC)C2=O)cc1

Procedure:
The title compound 26a was prepared from compound 76 (101 mg, 0.25 mmol), methyl chloroformate (21 μL, 0.28 mmol) and DIPEA (131 μL, 0.75 mmol) in a manner similar to that described for 25a in 98.2% (86 mg) yield as a yellow solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:15][NH2:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25])(=[O:19])[CH3:18]>>[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24]([NH:16][CH2:15][C:5]1[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Br:2])[CH:4]=1)=[O:25])(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: NCc1cnc(OCC(F)(F)F)c(Br)c1
Agent: Cl
Product: CC(=O)Nc1cc(C(=O)NCc2cnc(OCC(F)(F)F)c(Br)c2)ccn1
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (380 mg, a white solid) from (5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (450 mg, 1.4 mmol, Amine-67) and 2-acetamidoisonicotinic acid (250 mg, 1.4 mmol) by the similar manner in Step-1 of Example 8.