Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)COC(=O)C(C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(C#N)c(Cl)c1

Procedure:
Following General Procedure AP above and using 2-chloro-4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared. The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as the eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.CN(C)CCN(C)C.C([N-]CC)C.[K+].[C:25](=[O:27])=[O:26]>C(N(CC)CC)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:25]([OH:27])=[O:26]
Reactant: O=C=O
Reactant: COc1cccc(OC)c1
Agent: CC[N-]CC
Agent: CN(C)CCN(C)C
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of 1,3-dimethoxybenzene (12.06 g.) and tetramethylethylenediamine (15 ml.) in triethylamine (20 ml.) was added to the potassium diethylamide reaction mixture and stirred for two hours. The entire mixture, a gray suspension, was poured into a 1-liter beaker containing crushed dry ice (456 g.) with the aid of 35 ml of added triethylamine and was allowed to warm to room temperature. The contents of the beaker were transferred into a 1-liter flask with the aid of some water. All volatile components were removed by a rotary evaporator. The solid remaining in the flask was partitioned between diethyl ether (30 ml.) and water, which was extracted with diethyl ether (four times, 30 ml.). The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 1. The resultant precipitate was collected by filtration, water-washed and air dried to give 10.99 g. (69% yield) of 2,6-dimethoxybenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:24]([O:28][C:29]([NH:31][CH:32]([CH2:36][S:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:41]([O:40][C:38](=[O:39])[S:37][CH2:36][CH:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[C:33]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC(CSC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)C(CSC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
Using General Procedure G: To a solution of COMPOUND 249 (0.1233 g, 0.40 mmol) in DMF (5 mL) were added 2-tert-butoxycarbonylamino-3-tert-butoxycarbonylsulfanyl-propionic acid (0.1414 g, 0.44 mmol), DIPEA (0.14 mL, 0.80 mmol), EDCI (0.0920 g, 0.48 mmol), and HOBT (0.0649 g, 0.48 mmol), and stirred at room temperature for 16 hours. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1652 g (67%) of thiocarbonic acid S-(3-{4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-2-tert-butoxycarbonylamino-3-oxo-propyl) ester O-tert-butyl ester as a white solid. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.47 (s, 9H), 1.67 (s, 5H), 2.08 (d, 6H, J=6.0 Hz), 2.39-2.43 (m, 1H), 2.75-3.14 (m, 3H), 3.80-3.83 (m, 4H), 4.13 (d, 1H, J=15.0 Hz), 4.65 (d, 1H, J=15.0 Hz), 4.88-4.89 (m, 1H), 5.52-5.55 (m, 1H), 7.07-7.11 (m, 2H), 7.37 (d, 2H, J=6.0 Hz), 8.34 (d, 2H, J=3.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[CH3:34][N:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:18]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20]
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Reactant: CNCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Yield: 64.8 %

Procedure:
Operations are carried out as for Example 7, starting from 2.83 g of 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.56 g of N-methyl benzylamine in 100 ml of chloroform. 2.5 g of N-methyl N-phenylmethyl 1-(2-chloro phenyl) isoquinoline 3-carboxamide, melting at 128° C., are obtained.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH2:31][CH2:30][N:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]4)=[CH:17][C:18]=3[CH:19]=[C:11]2[C:10]1=[O:32])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:6][CH2:7][CH2:8][N:9]1[CH2:31][CH2:30][N:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:20][CH:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:25][CH2:26]4)=[CH:17][C:18]=3[CH:19]=[C:11]2[C:10]1=[O:32]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CCO[Si](C)(C)C(C)(C)C)C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CCO)C2=O)CC1
Yield: 88 %

Procedure:
To a cooled solution of 0.145 g (0.30 mmol) 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one in 3 mL dichloromethane, 1 mL (1.49 g, 13 mmol) trifluoroacetic acid was added and the cooling bath was removed. The solution was evaporated and the residue was taken up in ethyl acetate and was washed with 1M aqueous sodium hydroxide solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica gel with dichloromethane: methanol:ammonia (9:1:0.1 v/v) to give the desired compound as a white foam (88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[OH:29])[CH:9]([CH3:26])[CH2:10][C:11]1[CH:25]=[CH:24][C:14]2[O:15][C:16]([C:21]([OH:23])=[O:22])([C:18]([OH:20])=[O:19])[O:17][C:13]=2[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:38]([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:42]([O:41][C:39]([CH:38]([O:19][C:18]([C:16]1([C:21]([O:23][CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:44])=[O:22])[O:15][C:14]2[CH:24]=[CH:25][C:11]([CH2:10][CH:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[CH3:26])=[CH:12][C:13]=2[O:17]1)=[O:20])[CH3:44])=[O:40])[CH3:43]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)N(CC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)OC(=O)C1(C(=O)OC(C)C(=O)OCC)Oc2ccc(CC(C)N(CC(O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and ethyl 2-bromopropionate according to the procedure of Example 24, Step 3 as a colorless oil; 1H NMR (300 MHz, CDCl3): δ 1.15-1.30 (complex m, 9H), 1.40 (brs, 9H), 1.52-1.69 (m, 6H), 2.47-2.58 (m, 1H), 2.58-2.70 (m, 1H), 3.05-3.16 (m, 1H), 3.42-3.54 (m, 1H), 4.05-4.30 (complexm, 5H), 4.77 (m, 1H), 5.19-5.30 (m, 2H), 5.49 (brs, 1H), 6.57-6.67 (m, 1H), 6.71-6.80 (m, 1H), 6.82-6.91 (m, 2H), 7.20-7.35 (m, 2H), 7.41 (brs, 1H); MS (ES) m/z (relative intensity): 722 (M+, 100).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[CH:18][CH:19]=[C:13]2[N:12]=1.[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:20][C:19]1[CH:18]=[N:17][N:14]2[CH:15]=[CH:16][C:11]([NH:10][CH2:9][CH2:8][O:7][CH3:6])=[N:12][C:13]=12
Reactant: COCCNc1ccn2nccc2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCNc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
Sodium acetate [127-09-3] (457.6 mg, 5.6 mmol) was added to a solution of N-(2-methoxyethyl)pyrazolo[1,5-a]pyrimidin-5-amine (706.4 mg, 3.7 mmol) in glacial acetic acid (40 mL) and allowed to stir at ambient temperature until all of the solid had dissolved. Bromine [7726-95-6] (0.2 mL, 3.7 mmol) was added into the ambient temperature, buffered acetic acid reaction solution over 2 minutes, then the reaction solution was slowly poured into stirring water (1 L). The pH was increased by the addition of solid sodium bicarbonate until the pH of the supernatant was determined to be approximately 8 by pH paper. Precipitated product was isolated by filtration, the filter cake washed with water, and allowed to dry to afford 819.6 mg of white powder. LRMS (ESI) m/z 271.0/273.0 [(M+H)]+, calc'd for C9H11BrN4O: 271.12.
Reaction SMILES: [Br:1][CH:2]([CH2:12][O:13][CH3:14])[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]#[C:8][CH3:9])=[O:4].Cl.NC(C)(C)C#C[CH2:20][O:21]C>>[Br:1][CH:2]([CH2:12][O:13][CH3:14])[C:3]([NH:5][C:6]([CH3:10])([CH3:11])[C:7]#[C:8][CH2:9][O:21][CH3:20])=[O:4]
Reactant: COCC#CC(C)(C)N
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Agent: Cl
Product: COCC#CC(C)(C)NC(=O)C(Br)COC

Procedure:
2-Bromo-N-(1-methoxy-4-methylpent-2-yn-4-yl)-3-methoxypropionamide was prepared from 2-bromo-1-methoxypropionic acid in a similar manner to 2-bromo-N-(4-methylpent-2-yn-4-yl)-3-methoxypropionamide described in Example 3, Stage 1, Step 2 using 4-amino-1-methoxy-4-methylpent-2-yne hydrochloride in place of 4-amino-4-methylpent-2-yne hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.Cl.[CH3:34][O:35][C:36](=[O:45])[C@H:37]([CH2:39][C:40]1[N:44]=[CH:43][NH:42][CH:41]=1)[NH2:38]>C(Cl)Cl>[CH3:34][O:35][C:36](=[O:45])[C@H:37]([CH2:39][C:40]1[N:44]=[CH:43][NH:42][CH:41]=1)[NH:38][C:14](=[O:16])[C@H:9]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)OC
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
23.3 of t-butoxycarbonylisoleucine is dissolved in 200 ml of methylene chloride. 33.3 ml of N-methylmorpholine is added to the solution. The solution is cooled to -70° C. 13.1 ml of isobutylchloroformate is then added. The reaction mixture is warmed up to -15° C. and stirred for 5 minutes. The reaction mixture is again cooled to -70° C. 26.0 g of histidine methyl ester dihydrochloride is added to the reaction mixture. The reaction mixture is allowed to warm to room temperature, and then is stirred for 16 hours. The reaction mixture is extracted three times with 0.5 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of of solvent. The residue is dissolved in 200 ml of ethyl ether. The ether solution is added to cold rapidly stirring Skellysolve B. The white precipitate is filtered and dried to afford the product t-butoxycarbonylisoleucylhistidine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[Cl:24])=[CH:8]2)=[O:4].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:17]([Cl:24])=[CH:18][C:19]([NH:23][S:33]([C:27]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])(=[O:35])=[O:34])=[CH:20][C:21]=1[Cl:22])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Yield: 44.5 %

Procedure:
A solution of 3-(4-Amino-2,6-dichloro-phenoxy)-quinoline-6-carboxylic acid methyl ester (312) (0.93 mmol) and 2,4-dichlorobenzenesulfonyl chloride (250 mg, 1.02 mmol) in Pyridine (0.13 ml, 1.53 mmol)-CH2Cl2 (3.7 ml) was stirred at room temperature for 12 hr. Sat NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated. Crude residue was purified by column chromatography (Hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 181 (237 mg, 41%, in 3 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH3:34])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: COc1ccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)n(-c3ccccc3)c2c1
Product: COc1ccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3C)n(-c3ccccc3)c2c1

Procedure:
From the compound of step 4, the title compound was prepared analogously as described in example 1, step 2, using 2-methylphenol. Yield: 480 mg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: FC(F)(F)c1cccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-trifluoromethyl-phenylboronic acid to give (1H-pyrazol-3-yl)-[1-(3-trifluoromethyl-phenyl)-isoquinolin-3-yl]-amine. LC-MS m/e 355(MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][C@:9]3([CH3:49])[O:12][CH:13]=[CH:14][C@H:15]([O:47][CH3:48])[C@@H:16]([CH3:46])[C@@H:17]([O:42][C:43]([CH3:45])=[O:44])[C@H:18]([CH3:41])[C@H:19]([OH:40])[C@H:20]([CH3:39])[C@@H:21]([OH:38])[C@@H:22]([CH3:37])[CH:23]=[CH:24][CH:25]=[C:26]([CH3:36])[C:27]([NH:29][C:30]4[C:34](=[O:35])[C:4](=[C:5]([C:32](=[O:33])[CH:31]=4)[C:6]=2[C:10]3=[O:11])[C:3]=1[OH:50])=[O:28].[CH3:51][CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>O1CCOCC1.O>[CH3:37][C@@H:22]1[C@H:21]([OH:38])[C@@H:20]([CH3:39])[C@@H:19]([OH:40])[C@@H:18]([CH3:41])[C@H:17]([O:42][C:43]([CH3:45])=[O:44])[C@H:16]([CH3:46])[C@@H:15]([O:47][CH3:48])[CH:14]=[CH:13][O:12][C@:9]2([CH3:49])[C:10](=[O:11])[C:6]3=[C:7]([O:8]2)[C:2]([CH3:1])=[C:3]([OH:50])[C:4]2=[C:5]3[C:32]([OH:33])=[C:31]([N:55]3[CH2:56][CH2:57][CH:52]([CH3:51])[CH2:53][CH2:54]3)[C:30](=[C:34]2[OH:35])[NH:29][C:27](=[O:28])[C:26]([CH3:36])=[CH:25][CH:24]=[CH:23]1
Reactant: CC1CCNCC1
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(N5CCC(C)CC5)c(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Solvent: O
Solvent: C1COCCO1
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(N5CCC(C)CC5)c(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C

Procedure:
A solution of 25 g (0.036 mol) of rifamycin S in 50 ml of dioxane is mixed with 20 ml (0.2 mol) of 4-methylpiperidine and left to stand at 20° C until the reaction mixture, which is initially deep violet in colour has assumed an orange-yellow colour. The reaction mixture is now diluted with water, acidified to pH 5 and extracted with chloroform. After drying and evaporating the chloroform extract, the evaporation residue is dissolved in methanol and mixed dropwise with concentrated ascorbic acid solution. After standing for some time yellow crystals separate out and are filtered off and twice recrystallised from 80 % strength aqueous methanol. 3-(4-methylpiperidino)-rifamycin SV is thus obtained in crystals of melting point 185°-186° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[CH3:36][S:37]([CH3:39])=O.C(OC(=O)C)(=O)C>O>[CH3:36][S:37][CH2:39][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CS(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCSC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.0 g), dimethyl sulfoxide (30 mL) and acetic anhydride (10 mL) was stirred at room temperature for 14 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1cccc(Cl)c1
Yield: 97.6 %

Procedure:
Step AP (1): 2-(3-Chlorophenyl)acetic acid (5 g, 29.3 mmol) was deprotonated with NaHMDS (2.0 M in THF, 29.3 mL, 58.6 mmol) and reacted with 1-chloro-4-iodobutane (3.59 mL, 29.3 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(3-chlorophenyl)hexanoic acid (7.47 g, 98% yield). LC-MS (M−H)− 259.1. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>CS(C)=O.O>[S:19]1[C:14]2=[CH:15][N:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[C:11]1[C:8]1[N:6]2[N:7]=[C:2]([NH:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2ncc(-c3cc4ccncc4s3)n2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(-c4cc5ccncc5s4)n3n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(thieno[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.174 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (25 mg, 0.174 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.870 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 42 mg of the yellow solid, 67%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:19][CH2:20][CH:21]([O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22]Br)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:11]([O:19][CH2:20][CH:21]([O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OCC(CBr)OC(=O)c1ccccc1)c1ccccc1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCC(Cn1ccc2ncnc(Cl)c21)OC(=O)c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg), 3-bromopropane-1,2-diyl dibenzoate (1.77 g), cesium carbonate (1.59 g) and N,N-dimethylformamide (6.5 mL) was stirred at 80° C. for 4 hrs. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→40/60) to give the title compound (401 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[CH2:36][C@@H:35]([CH3:37])[NH:34][C:33]2=[O:38])=[CH:29][CH:28]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C@H:35]([CH3:37])[CH2:36][N:32]([CH2:31][C:30]5[CH:39]=[CH:40][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:33]4=[O:38])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: COc1ccc(CN2C[C@@H](C)NC2=O)cc1
Product: COc1ccc(CN2C[C@@H](C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1
Yield: 81.3 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and (R)-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 202 and by the reaction and treatment in the same manner as in Example 1, (R)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (173 mg) was obtained. Using the obtained (R)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (173 mg) and by the reaction and treatment in the same manner as in Example 421, the title compound (106 mg) was obtained.