Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14].C[Li].O.[C:22](OCC)(=O)C>O1CCCC1.C(OCC)C>[F:14][C:13]([F:16])([F:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:6]=[CH:5][C:4](=[O:17])[CH3:22]
Reactant: CON(C)C(=O)C=Cc1ccccc1C(F)(F)F
Reactant: CCOC(C)=O
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C=Cc1ccccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
11 g of N-methoxy-N-methyl-3-(2-trifluoromethylphenyl)acrylamide are dissolved in 150 ml of dry tetrahydrofuran under a nitrogen atmosphere, cooled to −78° C. and treated dropwise with 36 ml of a 1.4N solution of methyllithium in diethyl ether in 10 minutes. The solution is subsequently furthermore stirred at −78° C. for 2 h and then hydrolysed with water. 200 ml of ethyl acetate are now added at ambient temperature and the mixture is washed three times with saturated sodium chloride solution. The organic phase is finally separated, dried with magnesium sulfate and evaporated under reduced pressure. After purifying by flash chromatography, the title compound is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1>>[F:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([F:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(F)cncc2F)s1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(F)cncc3F)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 5-((3,5-difluoropyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid (200 mg, 0.63 mmol) from above and 1-methylpiperidin-4-amine (86.0 mg, 0.76 mmol). The title compound was obtained as a solid (50.0 mg, 19% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.89 (2H, s), 8.64 (1H, m), 8.48 (1H, s), 3.57 (1H, m), 2.72 (2H, m), 2.14 (3H, s), 1.91 (2H, m), 1.73 (2H, m), 1.52 (2H, m). MS m/z: 415.13 [M+H]+.
Reaction SMILES: O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[C:31]([N:50]2[CH2:54][CH2:53][C@@H:52]([OH:55])[CH2:51]2)=[N:32][CH:33]=[C:34]([CH:49]=1)[C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([Cl:48])([F:47])[F:46])=[CH:40][CH:39]=1)=[O:36]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CO.C(Cl)Cl.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>[Cl:48][C:45]([F:46])([F:47])[O:44][C:41]1[CH:42]=[CH:43][C:38]([NH:37][C:35](=[O:36])[C:34]2[CH:49]=[C:30]([C:11]3[NH:7][N:8]=[CH:9][CH:10]=3)[C:31]([N:50]3[CH2:54][CH2:53][C@@H:52]([OH:55])[CH2:51]3)=[N:32][CH:33]=2)=[CH:39][CH:40]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (29.6 g, 102 mmol), K3PO4 (51.6 g, 236 mmol) and Pd(PPh3)4 (4.55 g, 3.93 mmol) were added to a suspension of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 36.4 g, 79 mmol) in toluene (360 mL) under an argon atmosphere and the mixture was stirred at 110° C. for 4 h. The RM was poured into brine (500 mL) and extracted with EtOAc (2×1 L). The combined extracts were washed with brine (500 mL), dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give a residue which was purified by chromatography (Silica gel column, 1.5 kg, DCM/MeOH 95:5) to afford a dark yellow foam, that was dissolved in MeOH/DCM (1 L of 3:1) and treated with Si-Thiol (Biotage, 35 g, 45.5 mmol) for 17 h at 30° C. The resin was filtered off, and solvent was evaporated off under reduced pressure, until the desired compound crystallized. The product was filtered washed with MeOH and dried to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[N+:20]([O-])([OH:22])=[O:21]>>[Br:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:9])[F:10]
Reactant: Cn1nc(-c2cc(F)ccc2F)c(Br)c1C(F)(F)F
Reactant: O=[N+]([O-])O
Product: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Br)c1C(F)(F)F
Temperature: 28 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
At 15° C., 9.5 g (0.03 mole) 4-bromo-3-(2,5-difluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole was slowly added to 100 mL of fuming nitric acid. The reaction warmed to 28° C. over a period of 20 minutes. The reaction mixture was stirred at 30° C. for 4 hours. The mixture was poured into 500 mL of ice. After stirring for 1 hour, the slurry was extracted 3 times with methylene chloride. The methylene chloride extracts were washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chroma-tographically using 10% ethyl acetate in hexane as the eluent to give 5.84 g (55%) of 4-bromo-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole as a white solid, mp 45.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[N:19][OH:20]
Reactant: Cc1cccc(Nc2ccccc2C=O)c1C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc(Nc2ccccc2C=NO)c1C

Procedure:
A solution of 2-[(2,3-dimethylphenyl)amino]benzaldehyde (11 g, 0.049 mol) and hydroxylamine hydrochloride (17 g, 0.25 mol) in pyridine (250 ml) is stirred at room temperature overnight. The solvent is evaporated and the residue is partitioned between ethyl acetate (200 ml) and 10% aqueous HCl (200 ml). The organic layer is washed with 10% aqueous HCl (200 ml) and water (2×100 ml). The organic layer is dried (MgSO4) and the solvent is evaporated to give 2-[(2,3-dimethylphenyl) amino]benzaldehyde oxime which is recrystallized from hexane. Yield 7.3 g (62%); mp 107°-108° C.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24](O)=[O:25])=[CH:9][N:8]=1)[CH2:2]2.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)=[O:25])=[CH:9][N:8]=1)[CH2:2]2
Reactant: NCc1ccc(F)cc1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ccc(F)cc2)cc1Cl
Reaction time: 4 h
Yield: 15.6 %

Procedure:
In THF (10 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (150 mg, 0.40 mmol), 4-fluorobenzylamine (56 mg, 0.45 mmol) and triethylamine (101 mg, 1 mmol). The reaction mixture was cooled in an ice bath and HATU (266 mg, 0.70 mmol) was added. The reaction was conducted at ambient temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(4-fluorobenzyl) pyrimidine-5-formamide (30 mg, 16% yield).
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:31][C:32]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:33]=1[C:34](O)=[O:35]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:8]2([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:34]([C:33]4[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:32]=4[CH3:31])=[O:35])=[CH:25][CH:24]=3)=[O:7])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:15][CH:16]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4cc([N+](=O)[O-])ccc4C)cc3)C(=O)O)CCCC2)cc1
Yield: 72.1 %

Procedure:
4-Amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (23.4 mg, 0.057 mmol) and 2-methyl-5-nitrobenzoic acid 13 mg, 0.07 mmol) were reacted as described in example 40 to give 23 mg (69%) of N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-[[(2-methyl-5-nitrophenyl)carbonyl]amino]-L-phenylalanine, HR-FAB-MS: obs. mass 560.2413. Calcd. mass 560.2397 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH2:26][C@H:27]5[CH2:31][CH2:30][CH2:29][N:28]5C(OC(C)(C)C)=O)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH2:26][C@H:27]5[CH2:31][CH2:30][CH2:29][NH:28]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OC[C@H]5CCCN5C(=O)OC(C)(C)C)c4n3)cnc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COCCOc1ccn2c(-c3ccc4cccc(OC[C@H]5CCCN5)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 40.7 %

Procedure:
(R)-tert-butyl 2-((2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)methyl)pyrrolidine-1-carboxylate (241 mg, 0.47 mmol) was dissolved in 10 mL of chloroform, followed by addition of 4.0M HCl in dioxane (4.65 ml, 9.3 mmol). The reaction was allowed to stir for 30 hours at ambient temperature at which time all starting material was consumed by LC/TLC. The reaction was concentrated in vacuo, followed by flash column chromatography (eluting with a 1-20% MeOH/DCM gradient), affording an oil on concentration. The crude oil was treated with 1000 uL of 4.0 M HCl in dioxane, affording the desired product (80 mg, 41% yield). MS APCI (+) m/z 419.1 (M+1) detected.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH3:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([Sn](CCCC)(CCCC)CCCC)[N:53]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:54]2[CH:55]=[CH:56][CH:57]=[C:52]([CH3:51])[N:53]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)n1
Yield: 98.1 %

Procedure:
A solution containing the product from Example 23I (0.113 g, 0.160 mmol) in DMF (1.5 mL) was treated with LiCl (0.068 g, 1.60 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.034 g, 0.048 mmol), and the product from Example 68A (0.367 g, 0.961 mmol), heated at 110° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-50% ethyl acetate in dichloromethane to give the title compound (0.102 g, 98% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:12]([O:11][C:4]1[CH:3]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([C:15](=[O:17])[CH3:16])[CH2:19][CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])([CH3:14])[CH3:13]
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CC1

Procedure:
The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80° C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH3:25])=[C:12]2[CH2:26][C:27]([NH:29][NH2:30])=[O:28])C.[OH-].[Na+].Cl>CCO.C1COCC1.O>[NH:29]([C:27](=[O:28])[CH2:26][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[CH3:25])[NH2:30]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)NN)c2cc(OCCCC(=O)O)ccc2n1Cc1ccccc1
Yield: 18.5 %

Procedure:
A solution of 310 mg (1 mmol) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide (Example 62) in 25 mL of DMSO was treated with 45 mg (1.1 mmol) of 60% NaH/mineral oil and after 0.25 hours, 0.16 mL (1.1 mmol) of ethyl 4-bromobutyrate was added. The mixture was stirred for 4 hours, diluted with water and extracted with EtOAc. The EtOAc solution was washed with NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with CH2Cl2 →4% MeOH/CH2C2, to give 290 mg (68% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid ethyl ester. This ester (0.685 mmol) and 2 mL of 2N NaOH in 25 mL of EtOH and 5 mL of THF was stirred for 22.5 hours. The mixture was diluted with water, made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (Na2SO4), and concentrated at reduced pressure. The residue was dissolved in EtOH and precipitated with ether to give 50 mg (47% yield) of 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indole-5-yl]oxy]butanoic acid, mp, 160° C. (decomposition).
Reaction SMILES: [N:1]1[C:10]2[N:9]=[CH:8][CH:7]=[C:6](O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:10]1[N:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: Oc1ccnc2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2ncccc12
Temperature: 80 °C
Yield: 87 %

Procedure:
The product from Example 228d (0.250 g, 1.71 mmol) was combined with phosphorous oxychloride (4 mL) and heated under a nitrogen atmosphere at 80° C. for 18.5 h followed by vacuum distillation to remove the volatiles. The residue was slurried with ice and made basic (pH 7-8) with concentrated ammonium hydroxide. The title compound was collected by vacuum filtration, water washed and dried under vacuum to give a gray solid (0.245 g, 87%) sufficiently pure for use as isolated.
Reaction SMILES: C1(COC2C(C3N([CH2:17][C:18]4[CH:23]=[CH:22][C:21](CCC(O)=O)=[CH:20][CH:19]=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[F:35][C:36]1[C:61]([F:62])=[CH:60][C:39]2[NH:40][C:41]([C:43]3[CH:59]=[CH:58][CH:57]=[CH:56][C:44]=3[CH2:45][O:46][C:47]3[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[C:49]([F:55])[CH:48]=3)=[N:42][C:38]=2[CH:37]=1.BrCC1CCCCC1>>[CH:18]1([CH2:17][N:42]2[C:38]3[CH:37]=[C:36]([F:35])[C:61]([F:62])=[CH:60][C:39]=3[N:40]=[C:41]2[C:43]2[CH:59]=[CH:58][CH:57]=[CH:56][C:44]=2[CH2:45][O:46][C:47]2[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[C:49]([F:55])[CH:48]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Reactant: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3[nH]2)cc1F
Agent: BrCC1CCCCC1
Product: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 4-[2-(5,6-difluoro-1H-benzoimidazol-2-yl)-benzyloxy]-2-fluoro-benzonitrile and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Light yellow solid (58%). MS (Turbo Spray): m/z=476.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]1[O:33]C(C)(C)[O:31][C:30](=O)[CH:29]=1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:20][C:30](=[O:31])[CH2:29][C:28]([C:24]1[S:25][CH:26]=[CH:27][C:23]=1[Cl:22])=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2sccc2Cl)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1sccc1Cl
Yield: 77 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (100 mg, 0.35 mmol) and 6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2) (95 mg, 0.39 mmol) according to the general procedure K. Obtained as a white solid (127 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH2:41]1COCC1.CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:36]([NH:35][CH2:34][C:32]1[CH:33]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]2)[CH:29]=[C:30]([F:37])[CH:31]=1)[CH3:41]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Reactant: C1CCOC1
Agent: CN
Solvent: O=C(O)C(F)(F)F
Product: CCNCc1cc(F)cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 15.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2 M ethanamine in THF (210 ul, 0.42 mmol) for methanamine to afford 6.5 mg of the title compound (15.5%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=2[F:30])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:18])([F:20])[F:19])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[F:30])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
tert-Butyl((4aS,5S,7aS)-7a-(2-fluoro-5-nitrophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (16.61 g) was dissolved in ethanol (250 mL) and tin chloride dihydrate (25.0 g) was added. After stirring at RT for 18 h, the solution was poured onto NaOH (2N aq., 300 mL) and celite° (˜50 g) was added. The resulting mixture was filtered through more celite° and extracted with EtOAc (2×500 mL). The combined organic portions were dried over MgSO4 and evaporated to afford the title compound (15.52 g). This material could be used crude but a portion was purified by silica gel column chromatography (20% to 50% EtOAc in hexanes) to afford pure material (recovery 79%). 1H NMR (400 MHz, CDCl3) δ ppm 1.53 (s, 9H), 2.77 (d, J=14.4 Hz, 1H), 3.09 (br. s., 1H), 3.46 (br. s., 1H), 3.62 (br. s., 2H), 3.87 (br. s., 1H), 4.61 (d, J=8.6 Hz, 1H), 4.71 (br. s., 1H), 6.61 (br. s., 2H), 6.85-6.95 (m, 1H)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[O:8][N:7]=1.Cl.C([O-])([O-])=O.[K+].[K+]>[Pd]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[O:8][N:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccco3)no2)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Product: Nc1ccc(-c2nc(-c3ccco3)no2)cc1

Procedure:
A suspension of 3-(2-furyl)-5-(4-nitrophenyl)-1,2,4-oxadiazole (8.0 g, 0.03 mole) in 200 ml of absolute alcohol containing 5.2 ml of concentrated HCl is hydrogenated using 0.5 g of 5% Pd on carbon as catalyst. The solid obtained is slurried with saturated K2CO3 solution and extracted with CHCl3. Evaporation of the CHCl3 in vacuo gives the amine, 5.1 g (72%), m.p. 183°-185° .
Reaction SMILES: [CH3:1][C:2]12[C:9](=O)[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.S(O)(O)(=O)=O.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>O>[CH3:1][C:2]12[C:9](=[N:17][OH:18])[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2
Reactant: NO
Reactant: CC12CCCC(C)(CC1)C2=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC12CCCC(C)(CC1)C2=NO
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
At 60° C., 91.2 g (0.6 mole) of 1.5-dimethyl-bicyclo[3.2.1]octane-8-one (1) was dripped into a solution of 78.7 g (0.6 mole) hydroxylamin hydrogensulfate and 54.2 g (0.66 mole) sodium acetate in 135 g water. This was stirred for 1 h at 60° C. and then allowed to cool to room temperature and sodium extracted with ether. The combined organic phases were neutralized by washing with a saturated solution of chloride, dried and concentrated by evaporation. 95 g (95%) 2 crystalline solid is obtained. By crystallising 9 g of the raw product from 15 ml ethanol, 8 g 2 are obtained having a m.p. of 129°-130° C. IR: 3400, 3250, 1685, 930 cm-1 (oxim). NMR (CCl4): δ=1.05, s (--CH3, transoid to --C=N--OH), 1.43, s (--CH3, cisoid to -- C=N--OH), 9.03 ppm (--C=N--OH). MS: m/z (%)=167 (M+, 2%), 150(85), 133(15), 123(17), 108(23), 93(100). C10H17ON (M: 167.24)