Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-:18].O.[Cl:20][C:21]1[CH:22]=[C:23]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([N:54]3[CH2:59][CH2:58][CH:57]([C:60]([F:63])([F:62])[F:61])[CH2:56][CH2:55]3)=[O:53])=[CH:48][CH:47]=2)[CH:24]=[C:25]([Cl:45])[C:26]=1[CH2:27][C@@H:28]1[CH2:32][CH2:31][N:30]([C@H:33]2[CH2:38][CH2:37][C@H:36](OS(C)(=O)=O)[CH2:35][CH2:34]2)[C:29]1=[O:44]>C(#N)C>[Cl:20][C:21]1[CH:22]=[C:23]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([N:54]3[CH2:55][CH2:56][CH:57]([C:60]([F:62])([F:61])[F:63])[CH2:58][CH2:59]3)=[O:53])=[CH:48][CH:47]=2)[CH:24]=[C:25]([Cl:45])[C:26]=1[CH2:27][C@@H:28]1[CH2:32][CH2:31][N:30]([C@H:33]2[CH2:38][CH2:37][C@@H:36]([F:18])[CH2:35][CH2:34]2)[C:29]1=[O:44]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@@H](F)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Dissolve TBAF.3H2O (0.436 g, 1.36 mmol) in 5 ml of acetonitrile. Add water (0.05 ml. 2.72 mmol) and stir for 10 minutes. Add Methanesulfonic acid trans-4-{(R)-3-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-2-oxo-pyrrolidin-1-yl}-cyclohexyl ester (Preparation 24) (0.458 g, 0.68 mmol). Stir at 80° C. for 12 hours. Quench with saturated NaHCO3 and extract with ethyl acetate. Wash the extract with brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.036 g (9%) of the title compound: Mass spectrum (apci) m/z=599 (M+H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[OH:22].[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[C:14]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:24])[F:25])=[O:23])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Yield: 6.6 %

Procedure:
Using N-[2,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:20]3[CH2:24][C:23]4([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[O:22][N:21]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:20]3[CH2:24][C:23]4([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[O:22][N:21]=3)[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][C:16](=[O:19])[CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCC(O)CC3)c(C3=NOC4(CCCCC4)C3)cnc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCn1ncc2c(NC3CCC(=O)CC3)c(C3=NOC4(CCCCC4)C3)cnc21
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
4-{[1-Ethyl-5-(1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}cyclohexanol (100 mg, 0.251 mmol) (example 9) was dissolved in dichloromethane and the reaction mixture was cooled up to 5° C. Pyridinium chlorochromate (108 mg, 0.502 mmol) was added and the reaction mixture was stirred for about 5 minutes at the same temperature. It was warmed to room temperature and stirred at room temperature for about 16 h. Dilution was done with dichloromethane and filtration was done using celite. The organic layers were combined, concentrated and purified by preparative thin layer chromatography by using ethyl acetate.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([CH2:32][S:33][CH2:34][C@H:35]([NH:40][C:41](=[O:64])[CH2:42][CH2:43][O:44]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:36]([O:38][CH3:39])=[O:37])=[C:11]([C:20]([CH3:31])=[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:22]=1)[C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Si:1]([O:8][C:9]1[C:10]([CH2:32][S:33][CH2:34][C@H:35]([NH:40][C:41](=[O:64])[CH2:42][CH2:43][OH:44])[C:36]([O:38][CH3:39])=[O:37])=[C:11]([C:20]([CH3:31])=[C:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:22]=1)[C:12]([O:14][CH2:15][C:16]([Cl:18])([Cl:19])[Cl:17])=[O:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](CSCc1c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c1C(=O)OCC(Cl)(Cl)Cl)NC(=O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)[C@H](CSCc1c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c1C(=O)OCC(Cl)(Cl)Cl)NC(=O)CCO
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A mixture of 6.85 g of 2,2,2-trichloroethyl (R)-3,5-bis (tert-butyldimethylsilyloxy)-6-methyl-2-[[[2-(3-trityloxypropionylamino)-2-(methoxycarbonyl)ethyl] thio]methyl]benzoate and 0.11 g of p-toluenesulfonic acid in 115 ml of methanol was stirred at 60° C. for 30 minutes. The mixture was cooled and the solvent was evaporated in vacuo. Chromatography of the residue on silica gel using ethyl acetate/methylene chloride/hexane (1:1:1, v/v/v) as eluent afforded 3.97 g of 2,2,2-trichloroethyl (R)-3,5-bis(tert-butyldimethylsilyloxy)2-[[[2-(3-hydroxypropionylamino)-2-(methoxycarbonyl)ethyl]thio]methyl]-6-methyl-benzoate as white-off solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:19]1([CH2:22][CH2:23][C:24](O)=[O:25])[CH2:21][CH2:20]1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:24](=[O:25])[CH2:23][CH2:22][CH:19]3[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)CCC1CC1
Reactant: CC(C)c1ccc(NC(=O)C2CCNCC2)cc1
Product: CC(C)c1ccc(NC(=O)C2CCN(C(=O)CCC3CC3)CC2)cc1

Procedure:
This material was prepared in analogy to example 8 step C) from piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide (0.123 g), 3-cyclopropylpropionic acid (0.057 g) as white solid (0.124 g). MS (ESI): 343.17 (MH+).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[N:8]([CH2:26][CH3:27])[C:9]2[C:14]([C:15](=[O:19])[C:16]=1[C:17]#[N:18])=[CH:13][CH:12]=[C:11]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH:10]=2.S(=O)(=O)(O)[OH:29].[OH-].[NH4+]>>[NH2:6][C:7]1[N:8]([CH2:26][CH3:27])[C:9]2[C:14]([C:15](=[O:19])[C:16]=1[C:17]([NH2:18])=[O:29])=[CH:13][CH:12]=[C:11]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH:10]=2
Reactant: O=S(=O)(O)O
Reactant: CCn1c(N)c(C#N)c(=O)c2ccc(-c3ccncc3)cc21
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1c(N)c(C(N)=O)c(=O)c2ccc(-c3ccncc3)cc21
Temperature: 100 °C

Procedure:
A mixture of 2.70 g 2-amino-3-cyano-1,4-dihy- dro-1-ethyl-4-oxo-7-(4-pyridinyl)quinoline methanesulfonate and 25 ml sulfuric acid was heated at 100° C. for 4 hrs. The reaction mixture was cooled, poured onto ice and made basic with ammonium hydroxide. The solid product was collected and recrystallized twice from DMF to give 2.45 g 2-amino-1,4-dihydro-1-ethyl-4-oxo-7-(4-pyridinyl)-3quinolinecarboxamide, m.p. above 300° C.
Reaction SMILES: C1(COC2C(C3N(CC4C=CC(CCC(O)=O)=CC=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.[CH3:69][O:70][C:71](=[O:82])[CH2:72][CH2:73]C1C=CC(CBr)=CC=1>>[CH3:69][O:70][C:71](=[O:82])[CH2:72][CH2:73][C:51]1[CH:52]=[CH:53][C:48]([CH2:47][N:46]2[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=[C:42]2[C:39]2[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][C:38]=2[O:60][CH3:61])=[CH:49][CH:50]=1
Reactant: COC(=O)CCc1ccc(CBr)cc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Agent: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Product: COC(=O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OC)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 3-(4-bromomethyl-phenyl)-propionic acid methyl ester (CAS Reg. No. 56607-18-2). Brown sticky solid (75%). MS (Turbo Spray): m/z=471.0 (M+H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:6]=1[CH:15]=[CH2:16])C=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[F:14][C:7]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:5]2[C:6]=1[CH:15]=[CH:16][CH2:1][NH:4]2
Reactant: C=CCNc1c([N+](=O)[O-])ccc(F)c1C=C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c2c1NCC=C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
To a solution of allyl-(3-fluoro-6-nitro-2-vinylphenyl)amine (109 mg, 0.49 mmol) in DCM (10 mL) was added Grubbs catalyst (2nd generation, benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium) (8.5 mg, 0.01 mmol). The reaction mixture was stirred at RT for 16 h, and then purified by column chromatography (Si—PCC, eluant DCM) affording the title compound as a red solid (83.6 mg, 88%). 1H NMR (CDCl3, 300 MHz): 8.17 (1H, bs), 7.88 (1H, dd, J=9.6, 6.0 Hz), 6.52 (1H, dt, J=10.3, 2.2 Hz), 6.22 (1H, dd, J=9.7, 8.3 Hz), 5.77-5.71 (1H, m), 4.55-4.52 (2H, m)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][N:16](COCCOC)[C:13]3=[N:14][CH:15]=2)[CH:5]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[N:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:5]=1
Reactant: COCCOCn1nc(-c2ccccc2OC)c2cc(-c3cccc(C(=O)OC)c3)cnc21
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A solution of 3-[1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (573 mg, 1.28 mmol) in dichloromethane (25 mL) was cooled down to 0-5° C. and boron trifluoride etherate (0.8 ml, 6.4 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 16 h. A yellow precipitate was formed was filtered off to afford 3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (110 mg (0.29 mmol; 23% yield).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)S(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-bromo-N,N-dimethyl-benzenesulfonamide (example B.25) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (390 mg, 74%). MS (ISP) 521.3 [(M+H)+]; mp 211-212° C.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[C:21]1([CH:27]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:28]([NH2:51])[CH:29]=[CH:30][S:31]([CH:34]=[CH:35][C@H:36]([NH2:50])[CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:33])=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:52]1([CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:28]([NH:51][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH:1][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:29]=[CH:30][S:31]([CH:34]=[CH:35][C@H:36]([NH:50][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:5])[CH3:6])[NH:1][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)(=[O:33])=[O:32])[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](C=CS(=O)(=O)C=C[C@H](N)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C=CS(=O)(=O)C=C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 81 %

Procedure:
Cbz-Leu-D-Phe-VS-Ph was prepared from Cbz-Leu-OH and D-Phe-VS-Ph.HCl using standard mixed anhydride coupling method, yield 81%. 1H-NMR (CDCl3) δ 0.8-0.9 (2d, 6H, 2×Leu-CH3), 1.4-1.6 (m, 2H, Leu-CH2), 2.06 (m, 1H, Leu-CH), 2.9-3.0 (m, 2H, CH2-Phe), 3.9-4.0 (m, 1H, α-H), 4.8-4.9 (b, 1H, α-H), 4.9-5.0 (m, 1H, NH), 5.1 (m, 2H, Cbz), 6.3-6.4 (d & b, 2H, NH and CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.4 (m, 10H, 2×Ph), 7.5-7.7 (m, 5H, SO2-Ph). MS (ESI) m/z 535.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=3)[C:19](O)=[O:20])=[CH:9][CH:8]=2)[N:3]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH2:19][OH:20])[CH:22]=3)=[CH:9][CH:8]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(Oc3ccc([N+](=O)[O-])c(C(=O)O)c3)cn2)no1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Oc3ccc([N+](=O)[O-])c(CO)c3)cn2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
282 mg of N,N′-carboxydiimidazole was added to a tetrahydrofuran (5 ml) solution of 399 mg of the above carboxylic acid, and stirred at room temperature for 30 minutes. With cooling with ice, the above reaction liquid was added to an aqueous 5 ml solution of 219 mg of sodium borohydride, and stirred for 20 minutes. This was neutralized with aqueous 10% citric acid solution added thereto, then extracted with ethyl acetate, the organic layer was dried, and the solvent was evaporated away under reduced pressure to obtain 367 mg of (5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-nitrophenyl)methanol as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)=[C:12]([N+:24]([O-])=O)[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].O1CCCC1.O>C(O)C.[Fe]>[NH2:24][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:27]
Reactant: O=C(Nc1cccc(Br)c1)c1ccc(Sc2cccc(O)c2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(C(=O)Nc2cccc(Br)c2)ccc1Sc1cccc(O)c1
Yield: 101.8 %

Procedure:
A solution of the product of Example 79A (0.43 g, 0.97 mmol), iron powder (0.28 g, 5.0 mmol) and ammonium chloride (0.08 g, 1.5 mmol) in an ethanol (18 mL), tetrahydrofuran (18 mL), and water (6 mL) solution was heated to reflux for 3 hours. The resultant mixture was diluted with ethanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound (0.41 g, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:10]=[CH:9][C:8]=1[CH3:18])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]1[CH:12]=[C:11]2[C:10](=[CH:9][C:8]=1[CH3:18])[C:15](=[O:17])[CH2:14][CH2:13]2)[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(CCC(=O)O)ccc1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(=O)OCC)c1cc2c(cc1C)C(=O)CC2
Temperature: 40 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
To dichloromethane (68 ml) were added the compound (4.79 g, 13.6 mmol) obtained in step C, N,N-dimethylformamide (5 drops) and oxalyl chloride (2.59 g, 20.4 mmol), and the mixture was stirred at 40° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained oil was diluted with dichloroethane (68 ml) and cooled in an ice water bath. To this solution was added aluminum chloride (2.54 g, 19.0 mmol) by small portions, and the mixture was stirred at 90° C. for 4 hr. The reaction mixture was diluted with dichloromethane, washed with water and saturated brine, and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (2.59 g, yield 57%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:12][C:11]=1[CH2:27]Br.[NH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[NH2:30]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:19][CH:18]([Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[CH2:9][N:30]([NH:29][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[CH2:27]2)[CH3:20]
Reactant: NNc1ccccn1
Reactant: CC(C)[Si](Oc1ccc(CBr)c(CBr)c1)(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[Si](Oc1ccc2c(c1)CN(Nc1ccccn1)C2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.1 %

Procedure:
Triethylamine (10.9 ml) was added to a solution of 1,2-dibromomethyl-4-[[tri(1-methylethyl)silyl]oxy]benzene (17 g) and 2-hydrazinopyridine (4.3 g) in dimethylformamide (300 ml), and the reaction mixture was stirred, under nitrogen, at ambient temperature for about 20 mins and then diluted with water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with ethyl acetate to yield 5.7 g (38%) of product. Recrystallization of the product from ethyl acetate gave the analytical sample mp 95-96° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[F:16])[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].Cl.Cl[CH2:19][C:20]1[S:24][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[N:22][CH:21]=1.OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH:10]1([NH:9][C:7](=[O:8])[C:6]2[CH:13]=[CH:14][C:15]([F:16])=[C:4]([O:3][CH2:19][C:20]3[S:24][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:22][CH:21]=3)[CH:5]=2)[CH2:11][CH2:12]1
Reactant: O=C(NC1CC1)c1ccc(F)c(O)c1
Reactant: ClCc1cnc(Nc2ccccn2)s1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(F)c(OCc2cnc(Nc3ccccn3)s2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.8 %

Procedure:
To a suspension of NaH (16 mg, 60% in oil) in DMF (1 mL) was added a solution of 3-hydroxy-4-fluoro-N-cyclopropylbenzamide (58.5 mg, 0.3 mmol) in DMF (1 mL) at RT. After 10 min, (5-chloromethylthiazol-2-yl)pyridin-2-ylamine hydrochloride (Example 10A) (52.4 mg, 0.2 mmol) was added. The mixture was stirred at RT for 1 h and poured onto ice. The mixture was neutralized with 1 N KHSO4 solution and the precipitates were collected, washed with water and ethyl acetate to give the title compound as a light yellow solid (25.2 mg, 33%). MS m/z 385 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:24])[CH2:4][CH2:3]2.[CH3:25]I>>[CH3:25][N:6]1[C@H:7]2[C@@:2]([CH3:1])([C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)=[CH:15][C:10]=3[CH2:9][CH2:8]2)[CH2:3][CH2:4][C:5]1=[O:24]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Sc3cccc(Cl)c3)ccc12
Reactant: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4cccc(Cl)c4)cc3CC[C@@H]12

Procedure:
A 612 mg portion of (4aR)-(10bR)-10b-methyl-8-(3-chlorophenylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one was methylated with methyl iodide substantially as shown in Example 95. Attempts at crystallization of the product were unsuccessful, so it was characterized as an opaque colorless oil, 525 mg. FDMS: m/e=371. α[D]589 =+72.9, α[D]365 =+265.2 (chloroform).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=[C:4](N)[CH:3]=1.C(ON=O)(C)(C)C.[Br:29]CBr>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[Br:29][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:6][N:5]=1
Reactant: BrCBr
Reactant: Cc1cc(N)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: CC(C)(C)ON=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of Example A2 (0.2 g, 0.71 mmol) in dibromomethane (5 mL) was treated with tetrabutylammonium bromide (0.92 g, 2.84 mmol) and t-butylnitrite (0.7 g, 7.11 mmol) and stirred at RT for 4 h. The mixture was diluted with EtOAc, washed successively with satd. NaHCO3, water, and brine, dried over Na2SO4 and concentrated to dryness to afford 2-bromo-4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine as off-white solid (0.21 g, 86%). MS (ESI) m/z: 345.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I:46][C:47]1[N:48]=[C:49]([C@@H:52]2[CH2:56][C@H:55]([CH3:57])[CH2:54][NH:53]2)[NH:50][CH:51]=1.Cl>CN(C=O)C.CCOC(C)=O.O>[I:46][C:47]1[N:48]=[C:49]([C@@H:52]2[CH2:56][C@H:55]([CH3:57])[CH2:54][N:53]2[C:7]([C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:10]([CH3:12])[CH3:11])=[O:8])[NH:50][CH:51]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[C@@H]1CN[C@H](c2nc(I)c[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(I)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.3 %

Procedure:
To a solution of (2S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (644.5 mg, 3.68 mmol) in DMF (25 mL) at 0° C. is added HATU (1.4 g, 3.68 mmol), DIPEA (2.5 mL, 14.57 mmol) followed by 4-iodo-2-[(2S,4S)-4-methylpyrrolidin-2-yl]-1H-imidazole as HCl salt (1.28 g, 3.64 mmol). The reaction mixture is stirred at rt for 20 hours, diluted with EtOAc and H2O. The organic phase is separated, washed with H2O, dried over Na2SO4, filtered and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (0 to 100% EtOAC/Hexane) to afford methyl N-[(1S)-1-[(2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (1.3 g, 87.3%) as a white solid.