Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>CN(C=O)C>[F:11][C:5]1[CH:4]=[C:3]([CH2:2][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(CBr)cc1F
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromomethyl-2-fluoro-benzonitrile, as described in Step D above, (3.44 g, 16.0 mmol) and imidazole (5.47 g, 80.3 mmol) were dissolved in DMF (40 mL) and stirred at ambient temperature for 2 h. The DMF was removed in vacuo and the residue was partitioned between EtOAc (300 mL) and aqueous saturated NaHCO3 solution. The organic layer was separated, washed with NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography (silica gel, 1-2% CH3OH/CH2Cl2).
Reaction SMILES: OCC(CO)O.C([O:11][C:12](=[O:26])[CH:13]1CCCC[CH:14]1[C:15]([O:17]CC1OC1)=[O:16])C1OC1>>[C:15]([OH:17])(=[O:16])[CH2:14][CH2:13][C:12]([OH:26])=[O:11].[CH2:15]([OH:16])[CH2:14][CH2:13][CH2:12][OH:11]
Reactant: O=C(OCC1CO1)C1CCCCC1C(=O)OCC1CO1
Solvent: OCC(O)CO
Product: O=C(O)CCC(=O)O
Product: OCCCCO

Procedure:
0.1 equivalent of an acid polyester obtained from 11 mols of adipic acid and 10 mols of hexanediol (equivalent weight=1,080), 0.1 equivalent of a branched acid polyester obtained from 17 mols of succinic acid, 14 mols of butane-1,4-diol and 1 mol of glycerol (equivalent weight=1,460) and 0.2 equivalent of a hexahydrophthalic acid diglycidyl ester with an epoxide equivalent weight of 160 are warmed and mixed well. After adding 0.3%=0.9 g of 1-methylimidazole, the mixture is evacuated and poured into aluminium tubes. After heating to 140° for 16 hours, crystalline, crosslinked mouldings with the following characteristics are obtained:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][O:18][CH3:19].Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[N:17]([O:18][CH3:19])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)C1CCCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from (RS)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (14.8 g) and N,O-dimethylhydroxylamine.HCl (7.37 g) according to a procedure similar to that for Example 4.
Reaction SMILES: B(F)(F)F.CCOCC.Br[CH2:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1)=O.[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29](=[O:31])[NH2:30]>C1COCC1>[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[O:31][CH:11]=[C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:30]=1
Reactant: COc1cccnc1C(=O)CBr
Reactant: COC(=O)CCCCC(N)=O
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CCCCc1nc(-c2ncccc2OC)co1
Temperature: 80 °C
Yield: 33.4 %

Procedure:
Add boron trifluoride etherate (0.30 mL, 1.00 mmol) to a sealed tube containing 2-bromo-1-(3-methoxy-pyridin-2-yl)-ethanone (231 mg, 1.00 mmol), 5-carbamoyl-pentanoic acid methyl ester (222 mg, 1.39 mmol), and THF (anhydrous, 3 mL). Flush with N2, seal, heat at 80° C. overnight. Partition between saturated aqueous NaHCO3 solution and 20% i-PrOH/CHCl3, separate layers. Extract from aqueous layer with 20% i-PrOH/CHCl3 (×3), dry combined organic layers with MgSO4 and concentrate. Adsorb on SiO2 and purify by flash chromatography on silica gel eluting with 1-3% methanol/CHCl3 to afford the title compound (97 mg, 33%). MS (IS) 291 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[O:13])=[S:10])=[C:4]([CH:38]([CH3:40])[CH3:39])[CH:3]=1.[C:41]([O-])(=[O:43])[CH3:42].[Na+].BrCC(OC)=O.C(#N)C>[Cl-].[Na+].O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:41](=[O:43])[CH2:42][S:10]/[C:9]/2=[N:11]\[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[O:13])=[C:4]([CH:38]([CH3:40])[CH3:39])[CH:3]=1
Reactant: CC(C)c1cc(F)ccc1NC(=S)NC(=O)NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)[O-]
Agent: COC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)c1cc(F)ccc1N1C(=O)CS/C1=N\C(=O)NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 65 °C
Yield: 59.2 %

Procedure:
To a 20 mL vial was added 1-[(4-fluoro-2-isopropyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea (PC3) (0.092 g, 0.16 mmol), sodium acetate (0.040 g, 0.48 mmol), methyl 2-bromoacetate (0.084 mL, 0.80 mmol) and acetonitrile (2.0 mL). The vial was sealed and the reaction was heated overnight at 65° C. The reaction mixture was diluted with brine solution and dichloromethane and passed through a phase separator. The organic layer was concentrated and the resulting residue was purified by flash column chromatography using 10-80% ethyl acetate/hexanes as eluent providing the title compound as a white solid (0.058 g, 58%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared staing from 1-butyl-4-[4-(4chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (3.3 g, 6.9 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.08 g (67%); white solid; mp 201° C.; MS: 451.9 (M+H)+
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][C@H:15]([C:19](O)([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17].[C:23]([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:14][C@H:15]([C:19]([CH3:21])([CH3:23])[CH3:20])[C:16]([OH:18])=[O:17])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Temperature: 85 °C
Reaction time: 96 h
Yield: 98.4 %

Procedure:
4-fluoro-2-(trifluoromethyl)benzonitrile (7.10 g, 37.55 mmol) was mixed together with (R)-2-amino-3-hydroxy-3-methylbutanoic acid (5 g, 37.55 mmol) in DMSO (220 mL). K2CO3 (15.57 g, 112.65 mmol) was added to the reaction mixture and the reaction mixture stirred at 85° C. for 96 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (40 mL) and extracted with EtOAc (2×80 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×80 mL). The later organic extracts were combined, washed with H2O (2×30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a pale yellow solid (11.1 g, 98%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.57 (d, J=9 Hz, 1H), 6.98 (d, J=2 Hz, 1H), 6.80 (dd, J=9 and 2 Hz, 1H), 5.52 (br s, 1H), 3.96 (d, J=7 Hz, 1H), 1.42 (s, 3H), and 1.36 (s, 3H).
Reaction SMILES: Cl[CH:2]([O:10][CH2:11][CH3:12])[CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:13]([O-:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].C(Cl)Cl>CN(C)C=O.CCOCC>[C:13]([O:21][CH:2]([O:10][CH2:11][CH3:12])[CH:3]([O:4][CH2:5][CH3:6])[O:7][CH2:8][CH3:9])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(Cl)C(OCC)OCC
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(OCC)C(OCC)OC(=O)c1ccccc1
Reaction time: 21 h
Yield: 83 %

Procedure:
A mixture of 178 mg (0.905 mmole) of 1-chloro-1,2,2-triethoxyethane (produced in accordance with Example IV) and 206 mg (1.43 mmoles) of sodium benzoate in 3.00 mL of N,N-dimethylformamide, spectrophotometric-grade, commercially available from Aldrich Chemical Co., Milwaukee, Wis., was stirred, while being protected from exposure to atmospheric moisture, at room temperature for 21 hours. The mixture was diluted with 20 mL of 3:1 (volume/volume) ether:methylene chloride; and the organic layer was washed five times with 25 mL portions of I0% aqueous sodium chloride to ensure removal of dimethylformamide. The washed organic layer was subsequently dried over anhydrous sodium sulfate and filtered. Removal of the volatile organic material under reduced pressure afforded 212 mg (83% yield) of the title compound, the identity and purity of which were ascertained by proton NMR analysis [two doublets (J=5.5 Hz), one at δ4.63 (CH3CH2OCHOCH2CH3), the other at δ6.07 (CHOC(=O)C6H5)]. The title compound was subsequently saponified by use of potassium carbonate (2 equivalents) in 4:1 (volume/volume) methanol:water at 0° C. for 5 hours to afford glyoxal mono(diethyl acetal) and the corresponding hydrate (CH3CH2O)2CHCH(OH)2 and hemiacetal ##STR10## in high yield. Heating the latter mixture in toluene as described in Example XVIII affords glyoxal mono(diethyl acetal) as methanol and water are distilled out of the mixture.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([NH:9][CH3:10])=[O:8])[CH2:20][CH2:19]1
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: OCCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-fluoro-N-methyl-2-nitrobenzamide, 1-(2-hydroxyethyl)piperazine, and Hunig's base in 20 mL of DMF was stirred at room temperature over the weekend. The resulting mixture was rotavaped to dryness, and the residue was purified by flash column SF40-150 at 2%-10% MeOH/CH2Cl2. Product came out at 7% MeOH/CH2Cl2. MS (ES) m/e 309 [M+H].
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:22].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:31]O.O>C(O)C>[N:31](=[C:18]1[CH2:17][CH2:16][C:9]2([C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH:7]([C:15]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:8]2)[CH2:20][CH2:19]1)[OH:22]
Reactant: NO
Reactant: O=C1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Yield: 92.3 %

Procedure:
A warm solution of 8.35 g of 3'-phenylspiro[cyclohexane-1,1'(3'H)-isobenzofuran]-4-one in 300 ml of ethanol is mixed with a solution of 8.16 g of sodium acetate trihydrate, 4.17 g of hydroxylamine hydrochloride, and 60 ml of water. The solution is refluxed for 120 minutes. The solvent is removed in vacuo and the residue stirred with 300 ml of water. The precipitate is suction filtered, washed with water and dried to give 92.3% of product, mp: 172°-175° C.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:28](=[O:35])[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH2:27])[CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:13][CH:12]=1)=[O:7])(C)(C)C.C(O)(=O)C.[CH:40]1[C:52]2[CH:51]([CH2:53]OC(ON3C(=O)CCC3=O)=O)[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1>O.O1CCOCC1>[CH:40]1[C:52]2[CH:51]([CH2:53][O:5][C:6]([NH:8][C@H:9]([C:28](=[O:35])[N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17](=[CH2:27])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=3)=[O:7])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: C=C(CCC(=O)OC(C)(C)C)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: C=C(CCC(=O)O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (S)-4-(4-(2-((tert-butoxycarbonyl)amino)-3-oxo-3-(piperidin-1-yl)propyl)phenyl)pent-4-enoate (Compound SP415) (0.50 g, 1.03 mmol) was suspended in acetic acid (7.0 ml, 122.28 mmol) and water (7.0 ml), and the suspension was stirred with heating at reflux for 8 hours. The same reaction was additionally carried out four times. The reaction solutions were combined and concentrated under reduced pressure, and the resulting residue was suspended in a 10% aqueous sodium carbonate solution (38 ml). A solution of N-(9-fluorenylmethoxycarbonyloxy)-succinimide (1.65 g, 4.89 mmol) in 1,4-dioxane (19.0 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with diethyl ether, made acidic by adding acetic acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate=100:0-40:60) to afford the title compound SP416 (1.60 g, 56.3%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([C:9](O)=[O:10])[C:4]([CH3:12])=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH3:33]>CN(C)C=O.O1CCCC1>[CH2:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][NH:25][C:9]([C:5]1[C:4]([CH3:12])=[N:3][N:2]([CH3:1])[C:6]=1[O:7][CH3:8])=[O:10])[CH3:33]
Reactant: COc1c(C(=O)O)c(C)nn1C
Reactant: CCN1CCCC1CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN1CCCC1CNC(=O)c1c(C)nn(C)c1OC
Reaction time: 1 h
Yield: 90 %

Procedure:
3.1 g (0.0178 mole) of 1,3-dimethyl-5-methoxy-4-pyrazole carboxylic acid was dissolved in 15 ml of dry N,N-dimethylformamide. Then 3.18 g (0.0196 mole) of 1,1'-carbonyl-diimidazole was added. The reaction mixture was stirred for one hour. A solution of 2.28 g (0.0178 mole) of 2-(aminomethyl)-1-ethylpyrrolidine in 10 ml of dry tetrahydrofuran was added dropwise with stirring over 1/2 hour. The reaction was then stirred overnight at room temperature and the solvent evaporated under vacuum (1 mm) and a water bath (60° C.). The resultant oil was then taken up in chloroform, washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated. 4.5 g of amber colored oil (90% yield) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:49])[N:21]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:22]=[C:23]([NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[CH:32]=2)=[O:27])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:51][CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:55]3[CH2:56][CH2:57][CH:52]([F:51])[CH2:53][CH2:54]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:49])[N:21]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:22]=[C:23]([NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[CH:32]=2)=[O:27])[CH:24]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC1CCNCC1
Reactant: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(C=O)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(CN6CCC(F)CC6)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of intermediate (8f), 5-Formyl-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester, (150 mg, 0.22 mmol) in dichloromethane (10 mL) was added 4-fluoropiperidine hydrochloride (61 mg, 0.44 mmol), sodium triacetoxyborohydride (140 mg, 0.66 mmol) and acetic acid (1 drop). The reaction mixture was stirred at ambient temperature for 3 hours and then diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 with hexane—ethyl acetate (gradient) and then ion exchange using an SCX-2 column to afford the title compound as a yellow solid, 96 mg, 57%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[O:3].[CH2:14]=O.[ClH:16].[CH3:17][NH:18][CH3:19].Cl>CCO>[ClH:16].[CH3:17][N:18]([CH3:14])[CH2:19][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: C=O
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
4-(Trifluoromethyl) acetophenone (4.97 g, 26.4 mmol), paraformaldehyde (1.586 g, 2 eq.), dimethylamine hydrochloride (3.231 g, 1.5 eq.) were mixed together in 7 ml of EtOH, treated with 0.08 ml of 37% HCl, and heated to reflux for 5 h. Cooling down to ambient temperature, filtration and washing with tiny amounts of cold EtOH delivered 4.59 g of the title compound as white crystals of mp. 128-142° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.CO.C1COCC1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=S(=O)(NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=S(=O)(NC1Cc2cc(-c3ccc(F)cc3)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 78.7 %

Procedure:
To a solution of 87B (3.648 g, 8.0 mmol) and 4-fluorobenzene boronic acid (2.24 g, 16.0 mmol) in a mixed solvent of MeOH-THF (80 mL, 1:1 ratio) was added K2CO3 (4.423 g, 32.0 mmol), followed by PXPd (215 mg, 0.40 mmol). The resulting suspension was vigorously stirred in a 70° oil bath for 35 min. After cooling down to RT, the dark brown solution was diluted with water (200 mL), and extracted with EtOAc (200 mL×2). The combined EtOAc extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc/hexane (0-30%) to afford the title compound (2.977 g, 79%) as a light brown solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[CH3:18][C:19]([C:22]1[C:27]([OH:28])=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:24]([C:33](N(OC)C)=[O:34])[N:23]=1)([CH3:21])[CH3:20]>O1CCCC1.C1CCCCC1>[CH3:21][C:19]([C:22]1[C:27]([OH:28])=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:24]([C:33]([C:14]2[S:13][CH:17]=[CH:16][N:15]=2)=[O:34])[N:23]=1)([CH3:18])[CH3:20]
Reactant: c1cscn1
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)c1nc(C(=O)c2nccs2)nc(C(C)(C)C)c1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a solution of diisopropylamine (0.39 mL, 4.2 mmol) in tetrahydrofuran (8 mL) at -78° C. under nitrogen atmosphere is added a 2.1M solution of n-butyllithium (2.0 mL, 4.2 mmol) in cyclohexane. This mixture is stirred at -78° C. for 1 hour and thiazole (0.3 mL, 4.2 mmol) added. After stirring 1 hour at -78° C., the reaction mixture is warmed to ~0° C. and stirred 0.5 hours. The mixture is cooled to -78° and 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide (0.50 g, 1.7 mmol) in a mixture of tetrahydrofuran (5 mL) and N,N,N'N'-tetramethylethylenediamine (2 mL). After stirring 1 hour at 78° C., the resulting mixture is warmed to room temperature and stirred 16 hours. The mixture is then quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts are washed with water and brine. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The organic residue is purified by flash chromatography (SiO2, 10% methanol/dichloromethane) followed by recrystallization from ethyl acetate and hexane to give 0.30 g (53%) of the title compound, mp 181°-184° C.
Reaction SMILES: [CH:1]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)(Cl)=[S:9].C1CCCCC1.[NH2:18][OH:19]>C(Cl)Cl.O>[CH:4]12[CH2:5][CH2:6][C:7](=[CH:2][CH2:3]1)[CH2:1][C:8](=[N:18][OH:19])[S:9]2
Reactant: NO
Reactant: S=C(Cl)Cl
Reactant: C1=CCCCC=C1
Solvent: O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: ON=C1CC2=CCC(CC2)S1

Procedure:
A solution of 29 g (0.3 m) of 1,3-cycloheptadiene, 46 g (0.4 m) of thiophosgene, and 25 ml of cyclohexane was heated under reflux for 24 hours, then stripped of volatiles under reduced pressure. The oily residue was taken up in 150 ml of methylene chloride and stirred with 1.5 m of hydroxylamine in 200 ml of water at room temperature for three days. The separated organic layer was dried over magnesium sulfate and stripped to yield 26.7 g of viscous oil. Purification by dry column chromatography using silica gel an 1:4::ether:hexane as eluent. There was obtained 14 g of yellow solid. Recrystallization of 2 g portion from 1:1 ether-hexane yielded 1.4 g of the title compound as white crystals, m. 130°-132° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].[I:12]I.[OH-].[NH4+]>CN(C=O)C.O>[I:12][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: II
Reactant: c1cc2[nH]ccc2cn1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ccncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 1H-pyrrolo[3,2-c]pyridine (20 g, 170 mmol) in DMF (100 mL) was added KOH (33.2 g, 593 mmol) and the mixture was stirred for 10 minutes. A solution of iodine (47.3 g, 186 mmol) in DMF (100 mL) was added at 0° C., and the reaction allowed to warm to room temperature over 1.5 hours. The reaction was poured onto an aqueous solution of Na2S2O5 (17.2 g) and ammonium hydroxide (35%, 170 mL) in water (2.5 L). The resulting precipitate was filtered, washed with water and dried to afford the title compound (33.5 g, 81%).