Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([NH:25][CH3:26])=[O:24])[CH:17]=[CH:16]2.[CH:27]1[N:31]=[CH:30][N:29]2[CH2:32][CH2:33][C:34](=[O:35])[C:28]=12.[Cl-].[NH4+]>C1COCC1>[OH:35][C:34]1([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C:23]([NH:25][CH3:26])=[O:24])[CH:17]=[CH:16]3)[C:28]2[N:29]([CH:30]=[N:31][CH:27]=2)[CH2:32][CH2:33]1
Reactant: O=C1CCn2cncc21
Reactant: CNC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Reaction time: 1 h
Yield: 36.6 %

Procedure:
Dry THF (150 ml) was cooled to −65° C. in a dry ice-acetone bath under an argon atmosphere and n-butyl lithium hexane solution (1.6M: 45.2 ml) was added. A solution of 6-bromo-N-methyl-2-naphthamide (8.68 g) in dry THF (700 ml) cooled to 10° C. was added to this solution at not more than −55° C., and the mixture was stirred for 1 h. A dry THF solution (60 ml) of 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (3.65 g) was added dropwise. The mixture was stirred at the same temperature for 1.5 h and saturated aqueous ammonium chloride solution (120 ml) was added to stop the reaction. The solvent was evaporated under reduced pressure and an ethanol-soluble material was extracted from the resulting residue and the solvent was evaporated again. The residue was purified by flash silica gel column chromatography (eluent, chloroform/methanol containing ammonia (7%), 19/1→9/1). The eluate was recrystallized from methanol to give the title compound (3.36 g) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)[CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-tert-Butylphenol (7.52 g, 50 mmol) in anhydrous DMF (40 mL) was added dropwise to NaH (2.2 g, 55 mmol, 60% w/w in mineral oil) at 0° C. under an atmosphere of nitrogen. After five min, ethyl 2-bromopropionate (6.49 mL, 50 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir for 18 h, gradually warming to ambient temperature. The reaction mixture was diluted with ethyl acetate (300 mL) and extracted twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[C:20]1([O:10][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a solution of the 4-methanesulfonyl-benzoic acid (20 g, 99.9 mmol) in CH2Cl2 (150 mL), was oxalyl chloride (13.1 mL, 149.9 mmol) added. The reaction mixture was cooled to 0° C. and treated with DMF (2 mL). The reaction was warmed to room temperature and maintained for 10 h. The reaction was concentrated under vacuum and dissolved with CH2Cl2 (200 mL). The reaction was treated with phenol (10.5 mL, 120 mmol) followed by Et3N (16.7 mL, 120 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 7 hr. The reaction was extracted with CH2Cl2 (500 mL), dried and concentrated under vacuum. The desired compound, 4-methanesulfonyl-benzoic acid phenyl ester, was obtained by recrystallization from methanol (200 mL) as a white crystal in 78% yield (21.5 g). 1H NMR (400 Mz, DMSO-d6) δ 8.41 (d, J=7.1, 2H), 8.39 (d, J=7.1, 2H), 7.55˜7.51 (m, 2H), 7.37˜7.35 (m, 3H), 3.35 (s, 3H). LCMS 277.0 [M+H].
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:27].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[ClH:21].[OH:8][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:27])[CH2:11][CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: COc1ccc(C(=O)CCCCCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Product: Cl

Procedure:
A mixture of 41.5 g (0.15 mole) of α,α-diphenyl-4-piperidinemethanol, 38.6 g (0.17 mole) of 5-chloro-4'-methoxyvalerophenone, 30 g of potassium bicarbonate, and 0.19 g of potassium iodide in 500 ml of toluene and 70 ml of water is stirred and refluxed for 136 hours. The organic layer is separated and combined with toluene extracts of the aqueous layer. The combined organic material is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate is diluted with ether and made acidic with ethereal HCl. The resulting precipitate is recrystallized from methanol-butanone to give 5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]-4'-methoxyvalerophenone hydrochloride, M.P. 211°-213°C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=2)(=[O:16])=[O:15])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH3:13]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(CC)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CC)CC2)cc1

Procedure:
1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (.7.94 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.5 g (88%); white solid; mp 162° C.; MS: 370 (M+H)+
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:18])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (53 mg, 0.280 mmol) in tetrahydrofuran (2.0 mL) were added oxalyl chloride (35 μL, 0.42 mmol) and N,N-dimethylformamide (about 20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)benzoyl chloride as a pale-brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:11][C:10]=2[N+:28]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[NH2:28][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)[CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1Sc1ccc(O)cc1
Yield: 97.6 %

Procedure:
A solution of the product of Example 255B (0.660 g, 1.52 mmol), iron powder (0.339 g, 6.07 mmol) and ammonium chloride (0.099 g, 1.82 mmol), tetrahydrofuran (18 mL), and water (6 mL) solution was heated to reflux for 3 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was diluted with water (50 mL) and extracted with dichloromethane (2×100 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.60 g, 97%).
Reaction SMILES: C(O[C:4](=[O:36])[CH:5]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][N:15]=[C:16]([C:19]3[C:24](C)=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])[CH:17]=2)[N:12]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH:11]=1)[CH2:6][CH2:7][CH3:8])C.[CH3:37][CH:38](C[AlH]CC(C)C)C.[C@H:46](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>>[CH2:23]([C:24]1[CH:38]=[CH:37][CH:21]=[C:20]([CH2:26][CH3:46])[C:19]=1[C:16]1[CH:17]=[C:18]2[C:10]([CH2:9][CH:5]([CH2:6][CH2:7][CH3:8])[CH2:4][OH:36])=[CH:11][N:12]([C:27]3[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=3)[C:13]2=[CH:14][N:15]=1)[CH3:22]
Reactant: CCCC(Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(C)cccc3C)cc12)C(=O)OCC
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Product: CCCC(CO)Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[5-(2,6-dimethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-pentanoic acid ethyl ester (120 mg, 0.23 mmol) at −78° C., DIBAL (1M sol in toluene, 1.0 mL, 1.0 mmol) is added, and the mixture is stirred for 3 h at −78° C. The temperature of the mixture is allowed to gradually warm up to room temperature. To the mixture, a saturated aqueous Rochelle's salt solution (10 mL) is added, and the resultant suspension is stirred for 2 h at room temperature. The organic phase is separated, and the aqueous portion is extracted with DCM. The combined organic extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure, and the residue purified by chromatography on silica gel (hexane-EtOAc, 1:1) to afford 2-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-pentan-1-ol as colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([NH2:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])C.C([CH2:33][C:34](=[NH:36])[S-])C1C=CC=CC=1.Br>N1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:7]=[C:6]3[C:4]([OH:5])=[N:36][C:34]([CH3:33])=[N:11][C:10]=23)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Reactant: N=C([S-])CCc1ccccc1
Agent: Br
Solvent: c1ccncc1
Product: Cc1nc(O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
A mixture of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-2A-1a (21.4 g, 57 mmol) and benzylthioacetimidate.HBr (12.6 g, 51 mmol) in pyridine was heated at 115° C. (see Yuan et al., Bioorg. & Med. Chem. Lett., 12, 2133-2136 (2002)). Additional benzylthioacetimidate.HBr (12.6 g) was added after 0.5 h and 1.5 h. The reaction mixture was stirred for an additional 1 h at 115° C. After cooling to room temperature, a yellow solid precipitated out of solution. The reaction mixture was poured over ice water and acidified with conc. HCl (210 ml). Additional ice was added to keep the reaction mixture cool. The yellow solid was collected by filtration and washed with H2O to give the desired product, I-4A-1a (24 g).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10](=[O:14])[NH:11]2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=O)C>C(O)C>[NH2:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10](=[O:14])[NH:11]2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(CC(C)C)C(=O)N2
Solvent: CCO
Product: CC(C)CC1C(=O)Nc2cc(N)c([N+](=O)[O-])cc21

Procedure:
A solution of 2.9 g. (0.01 mol) 6-acetamido-3-(2-methylpropyl)-5-nitroindolin-2-one in 50 ml. ethanol is heated under reflux for about 30 minutes with 3 ml. concentrated hydrochloric acid, evaporated and the residue purified on silica gel (elution agent: methylene chloride/ammonia-saturated methanol 20:1 v/v). Yield: 1.5 g. (60% of theory).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:51]4[CH2:52][CH2:53][CH2:54][N:48]([CH3:47])[CH2:49][CH2:50]4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CN1CCCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with 1-methyl-[1,4]diazepane (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C42H55Cl2N6O3 [(M+H)+] 761.3707, observed 761.3707.
Reaction SMILES: [Si]([O:8][CH:9]1CCCC(=O)CC[CH2:10]1)(C(C)(C)C)(C)C.N.C(B1OC(C)(C)C(C)(C)O1)C=C.[CH2:31]([C:34]1([NH2:41])[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)[CH:32]=[CH2:33]>CO>[CH2:31]([C:34]1([NH2:41])[CH2:39][CH2:38][CH2:37][CH:9]([OH:8])[CH2:10][CH2:36][CH2:35]1)[CH:32]=[CH2:33]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(=O)CCC1
Reactant: C=CCC1(N)CCC(O)CC1
Agent: C=CCB1OC(C)(C)C(C)(C)O1
Agent: N
Solvent: CO
Product: C=CCC1(N)CCCC(O)CCC1

Procedure:
0.89 g of 5-Allyl-5-amino-cyclooctanol (30) were synthesized as a diastereomeric mixture starting from 1.50 g (5.85 mmol) of 5-(tert-butyldimethylsilyloxy)cyclooctanone, 8.4 mL (58.5 mmol) of 7N ammonia in methanol, and 1.7 mL (9.36 mmol) of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, following the protocol described for 4-allyl-4-amino-cyclohexanol (16). Rt=0.44 min, 0.49 min (Method C). Detected mass: 184.3 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:20][C:19]=2[Cl:30])[N:16]=[CH:15][C:14]=1[C:31]#[N:32]>C(Cl)(Cl)Cl>[C:1]([NH:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([S:25][C:26]([F:27])([F:28])[F:29])=[CH:20][C:19]=2[Cl:30])[N:16]=[CH:15][C:14]=1[C:31]#[N:32])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: N#Cc1cnn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c1N
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1c(C#N)cnn1-c1c(Cl)cc(SC(F)(F)F)cc1Cl
Reaction time: 20 h
Yield: 83.1 %

Procedure:
First 10 ml (0.11 mole) of propionyl chloride and then 1.8 ml (0.02 mole) of pyridine in 15 ml of chloroform are added to a suspension of 3.5 g (0.01 mole) of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylthio-phenyl)pyrazole in 30 ml of chloroform at 0° C., with stirring. A clear solution is obtained, and, when the addition has ended, stirring is continued at room temperature for 20 hours. The solution thus obtained is evaporated to dryness. For working up, the residue is taken up in 50 ml of ethanol, aqueous ammonia is added until the reaction is alkaline, the mixture is heated under reflux for 10 minutes, the volatile constituents are removed in vacuo, the residue is taken up in 100 ml of chloroform, the mixture is washed with water, then with 2N aqueous hydrochloric acid and again with water and dried over sodium sulphate and the solvent is removed in vacuo. 3.4 g (83% of theory) of 5-propionylamino-4-cyano-1-(2,6-dichloro-4-trifluoromethylthio-phenyl)-pyrazole of melting point 153° C. to 156° C. are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:25])(=[O:3])[CH3:2].[CH2:26]([Br:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Br-:33].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:25])(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1C(C)=O)CC2
Reactant: BrCc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+](Cc3ccccc3)cc1C(C)=O)CC2
Product: [Br-]

Procedure:
The title compound 132 is prepared according to the procedure reported in Example 38.1 with compound 104 (93 mg, 0.27 mmol) and benzyl bromide (66 μL, 0.54 mmol) as reactants. White solid. (Yield 117.1 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[C:22]=[O:23]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:22]([NH:21][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[O:23])=[CH:16][CH:15]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COP(=O)(OC)c1cnc(N)c(-c2ccc(N)cc2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COP(=O)(OC)c1cnc(N)c(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c1
Temperature: 25 °C

Procedure:
The reaction mixture of dimethyl (6-amino-5-(4-aminophenyl)pyridin-3-yl)phosphonate (30 mg, 0.10 mmol, 1 eq) and 1-isocyanato-3-(trifluoromethyl)benzene (0.018 mL, 1.2 eq) in anhydrous DMF (0.5 mL) under anhydrous nitrogen atmosphere was stirred at room temperature for an hour. It was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (EtOAc-Hex 2:1 to MeOH-EtOAc 1:20) to yield dimethyl (6-amino-5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)pyridin-3-yl)phosphonate as a white solid in amount of 41 mg.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[Al].O>COCCOCCOC>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: [Al]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 15 ml of diglyme (bis (2-methoxyethyl) ether) was dissolved 1.0 g of N-(cyclohexylmethoxycarbonyl)-tyrosine. To the solution were added 570 mg of sodium borohydride and 50 ml of diglyme solution containing 7g of anhydrous aluminium chyloride. The mixture was stirred at room temperature for two hours. After addition of 150 ml of water, the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give N-(cyclohexylmethoxycarbonyl)-tyrosinol.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:12])[NH:9][CH:10](O)[C:6]=2[C:5]([F:13])=[C:4]([Cl:14])[N:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(OC)(C)(C)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:12])[NH:9][CH2:10][C:6]=2[C:5]([F:13])=[C:4]([Cl:14])[N:3]=1
Reactant: O=C1NC(O)c2c(F)c(Cl)nc(Cl)c21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: O=C1NCc2c(F)c(Cl)nc(Cl)c21
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A 22-L 3-neck RBF equipped with overhead stirrer, refluxing condenser, and N2 inlet/outlet, and having all glass or PTFE-coated parts, was sequentially charged with 4,6-dichloro-7-fluoro-1-hydroxy-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (908 g), DCM (4.55 L), and TFA (3.46 L, 11.76 eq). Agitation was started and Et3SiH (3.05 L, 4.97 eq) was added. The cloudy mixture was heated to reflux, resulting in a clear solution that was stirred at refluxing conditions for 24 h. The mixture was cooled to RT and stirred overnight. The orange solution was cooled to <10° C. using an ice bath. Methyl tert-butyl ether (14.0 L) was added via a peristaltic pump within a 1 h period. The resultant slurry was stirred at <10° C. for 1 h and then filtered through a coarse fitted glass funnel. The filter cake was washed with MTBE (2×4 L). The solid was dried under high vacuum at RT for 19 h to afford the title compound (802 g, 94%). 1H NMR (500 MHz, DMSO-d6) δ ppm 4.55 (s, 2 H), 9.15 (s, 1 H). [M+H] calc'd for C7H3Cl2FN2O, 221; found, 221.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][C@@H:32]([CH3:35])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: C[C@@H](CO)CCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 46.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide (45 mg) was prepared by following General Procedure F starting 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (80 mg), (R)-4-amino-2-methyl-butan-1-ol (25 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 493.6.