Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:14]([CH:15]([F:17])[F:16])=[CH:13][C:12]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:11][C:10]=12)=[O:5])C.[OH-].[K+].S(=O)(=O)(O)O>O.CO>[F:17][CH:15]([F:16])[C:14]1[N:9]2[CH:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]2[N:11]=[C:12]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH:13]=1
Reactant: CCOC(=O)c1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
A mixture of 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (6.0 g, 15.6 mmol), potassium hydroxide 14 g (0.25 mmol) in water (62.5 ml) and methanol (125 ml) was stirred at room temperature for 2 h and at 60° C. for 1 h, cooled (ice-water), and 3N sulfuric acid (90 ml) was added. The formed precipitate (4.32 g) was collected by filtration, acetic acid (65 ml) was added and the stirred solution was heated under reflux conditions for 1 h. The reaction mixture was evaporated, ethyl acetate (30 ml) was added and the mixture was stirred for 30 min at 0° C. The precipitate was collected by filtration and dried to yield 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid (2.15 g, 39%) as a yellow solid. MS (ISN) 356.0 [(M−H)−]; mp 238° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[Cl-].[NH4+]>C1COCC1>[S:25]([O:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:10]=1)([CH3:24])(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Temperature: -50 °C
Yield: 109.5 %

Procedure:
1-[3-[(tert-Butoxycarbonyl)amino]phenyl]methanol (10 g, 44.8 mmoles) (Ref.: F. J. Brown, P. R. Bernstein, L. A. Cronk, D. L. Dosset, K. C. Hebbel. T. P. Maduskuie, Jr., H. S. Shapiro, E. P. Vacek, Y. K. Lee, A. K. Willard, R. D. Krell and D. W. Snyder, J. Med. Chem., 32, 1989, 807-826) and triethylamine (13 g, 17.9 mL, 138.4 mmoles) were dissolved in anhydrous THF (169 mL) and the solution was stirred and cooled to −50° C. Methanesulfonyl chloride (10.26 g, 7.02 mL, 89.6 mmoles) in anhydrous THF (85 mL) was added dropwise over a period of 20 min at −50° C. under an argon atmosphere. The mixture was stirred at −50° C. for an additional 20 min. A saturated aqueous solution of ammonium chloride (12.9 g) was added and the mixture was warmed to 25° C. The mixture was filtered and the filtrate was extracted twice with ethyl acetate. The ethyl acetate was washed with brine, water, dried (MgSO4), filtered and evaporated to dryness to give the title compound (14.78 g). The material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[C:11]([O:18][C:19]([F:22])([F:21])[F:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:24]1[N:29]=[N:28][C:27]([N:30]([CH3:41])[CH:31]2[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]2[N:29]=[N:28][C:27]([N:30]([CH3:41])[CH:31]3[CH2:36][C:35]([CH3:37])([CH3:38])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]3)=[CH:26][CH:25]=2)=[C:11]([O:18][C:19]([F:22])([F:21])[F:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1OC(F)(F)F
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: CN(c1ccc(-c2ccc(OCc3ccccc3)cc2OC(F)(F)F)nn1)C1CC(C)(C)NC(C)(C)C1

Procedure:
(4-(Benzyloxy)-2-(trifluoromethoxy)phenyl)boronic acid (1.2 g, 61% pure, 2.307 mmol) and Intermediate 1-1 (246 mg, 0.871 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. Compound 6-(4-(benzyloxy)-2-(trifluoromethoxy)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine was obtained as a beige solid (405 mg, 90% yield) after flash column chromatography purification. MS (M+1)=515.5.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[Si]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](=O)[CH:43](OCC)[O:44]CC)=[CH:37][CH:36]=1)(C(C)(C)C)(C)C.Cl.CCCCCC>O1CCOCC1>[OH:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]2[C:43](=[O:44])[N:19]3[CH:20]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[NH:16][C:17]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[C:18]3[N:21]=2)=[CH:39][CH:40]=1
Reactant: CCOC(OCC)C(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cccs3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=c1c(Cc2ccc(O)cc2)nc2c(-c3cccs3)[nH]c(-c3ccc(O)cc3)cn1-2
Temperature: 25 °C
Yield: 22.8 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thiophen-2-yl)pyrazin-2-amine (7f) (276 mg, 720 μmol) and 3-[4-(tert-butyldimethylsilyloxy)phenyl]-1,1-diethoxypropan-2-one (8) (381 mg, 1.08 mmol) dissolved in 1,4-dioxane (2 mL) was added 4 M hydrochloric acid (780 μL) at 0° C. and the mixture was heated to reflux for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography in an argon flow (acidic silica gel 20 g, n-hexane/ethyl acetate=1/2→ethyl acetate→ethyl acetate/methanol=20/1). To the suspension obtained during the concentration under reduced pressure was added n-hexane. The precipitates were collected by filtration and dried in vacuo to give Compound 3f (TMD-278) (68.2 mg, 164 μmol, 22.8%) as a brown solid. Rf=0.67 (ethyl acetate/methanol=20/1); HPLC retention time 9.5 min; 1H NMR (400 MHz, CD3OD) δ 4.22 (s, 2H), 6.72-6.78 (AA′BB′, 2H), 6.90-6.97 (AA′BB′, 2H), 7.11-7.18 (AA′BB′, 2H), 7.32 (dd, 1H, J=3.8, 5.2 Hz), 7.87 (dd, 1H, J=1.1, 5.2 Hz), 7.91-7.97 (AA′BB′, 2H), 8.12 (dd, 1H, J=1.1, 3.8 Hz), 8.48 (s, 1H); IR (KBr, cm−1) 521, 581, 629, 721, 777, 841, 881, 966, 1109, 1172, 1261, 1341, 1429, 1508, 1533, 1609, 1653, 2822, 3107; HRMS (ESI+) m/z 416.1075 ([M+H]+, C23H18N3O3S+ requires 416.1063).
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)O1.[H-].[Na+].[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>>[C:16]1([C:4]2[C:6]3[C:5]4[C:25](=[CH:24][CH:28]=[CH:16][CH:4]=4)[CH2:26][C:2]=3[C:7]([C:8]#[N:9])=[C:6]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)oc1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 2-oxo-6-phenyl-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (280 mg), indanone-2 (132 mg) and NaH (44 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 140-141° C.; ESIMS 351 (M++1); IR (KBr) 2219 cm−1 (CN); 13C NMR (75.53 MHz, CDCl3): δ 22.89, 24.96, 36.00, 52.15, 100.45, 116.08, 117.93, 120.78, 123.54, 125.06, 125.34, 126.97, 127.35, 127.42, 131.32, 138.85, 139.20, 140.94, 141.01, 149.06, 153.62.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:14]Br>[Fe].II>[CH3:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: BrBr
Reactant: CC1(c2ccccc2)CCCCC1
Agent: [Fe]
Agent: II
Product: CC1(c2ccc(Br)cc2)CCCCC1
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To 20.0 g (115 mmol) of the 1-methylcyclohexylbenzene obtained in the above-mentioned (1) were added 279 mg (5.00 mmol) of iron and 198 mg (0.78 mmol) of iodine, and 17.8 g (111 mmol) of bromine was slowly added dropwise at 0° C. spending 1.5 hours, followed by stirring at the same temperature for 1.5 hours and then at room temperature for 20 hours. The reaction solution was cooled and then quenched with 30 ml of saturated sodium sulfite aqueous solution and extracted three times with 50 ml of hexane. The combined organic layers were washed with 30 ml of sodium sulfite aqueous solution and 30 ml of water and dried with anhydrous sodium sulfate. After filtration of the desiccant, the solvent was recovered under a reduced pressure to obtain 27.9 g of crude bromide. By purifying the thus obtained crude bromide by distillation under a reduced pressure (from 117 to 120° C./2 mmHg), the specified substance was obtained with a yield of 80.3%.
Reaction SMILES: II.[CH3:3][C:4]([CH3:6])=O.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=1Cl)([O-:9])=[O:8]>C(OCC)(=O)C.[Cu]>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=1[C:4]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:15][CH:10]=[CH:11][C:3]=1[N+:16]([O-:18])=[O:17])([O-:9])=[O:8]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: [Cu]
Agent: II
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1-c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
Pre-treatment of copper powder: The copper powder (5.0 g, 78 mmol) was weighted and added into to a 20 mL of 2% iodine/acetone solution. The mixture was stirred for 10 minutes, and filtered in vacuum. The resultant was added into 20 mL of mixed solution of acetone:hydrochloric acid=1:1. The resultant mixture was stirred for 10 minutes, filtered, and dried in vacuum. The 2,6-dinitrochlorobenzene (3.04 g, 15 mmol) and copper powder (2.88 g, 45 mmol) were added into a 250 mL round flask, and were mixed homogeneously. Under the protection of nitrogen gas, the mixture was heated at 180° C. under stirring in an oil bath for two hours. Upon completion of the reaction, the solid in the flask was grounded, and dissolved in 20 mL of ethyl acetate. The solid was filtered off, and the filtration was collected and rotary evaporated. The residue was recrystallized from a mixed solution of ethyl acetate: petroleum ether=10:1, to precipitate a pale yellow needle-like crystal. The crystal was filtered in vacuum, to afford the product in a yield of 63.9%.
Reaction SMILES: CO[C:3](=[O:26])[CH:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[S:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([N:8]3[C:3](=[O:26])[CH:4]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:5][C:6]3=[S:7])[S:10][C:11]=2[CH:17]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nc2ccc(F)cc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C(Cc2ccccc2)NC(=S)N1c1nc2ccc(F)cc2s1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A solution of N-[[(6-fluoro-2-benzothiazolyl)amino]thioxomethyl]-DL-phenylalanine methyl ester (0.90 g, 2.31 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 48 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 251 mg (31%) of the titled product:
Reaction SMILES: Cl([O-])(=O)(=O)=[O:2].[Cl:6][C:7]([C:13]([C:18]#N)=[CH:14][N:15](C)C)=[N:8][CH:9]=[N+:10]([CH3:12])[CH3:11]>C(#N)C.O>[Cl:6][C:7]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[C:13]([CH:18]=[O:2])[C:14]#[N:15]
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: CN(C)C=C(C#N)C(Cl)=NC=[N+](C)C
Solvent: O
Solvent: CC#N
Product: CN(C)C=NC(Cl)=C(C#N)C=O
Reaction time: 6 h
Yield: 60.7 %

Procedure:
100 g of N-(3-chloro-4-cyano-5-dimethylamino-2-aza-2,4-pentadienylidene)N,N-dimethylammonium perchlorate are dissolved in a mixture of 400 ml of acetonitrile and 400 ml of water. Stirring is carried out for 6 hours at 20° to 22°C and is followed by double extraction with two 400 ml portions of trichloromethane. Following this the combined trichloromethane phases are extracted twice with two 1000 ml portions of water. The organic phase is dried with Na2SO4 or MgSO4 and reduced in volume by distilling off of the solvent at 30° to 35°C to a quarter of the original volume. After allowing the resultant to stand for one hour in an ice-box at about 0°C, the precipitate is vacuum filtered to yield yellowish crystals. 36 g (61%) of 3-chloro-5-dimethylamino-2-formyl-4-aza-2,4-pentadienenitrile, with a melting point of 144°C (with decomposition), are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5](F)=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8].Cl[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][C:30]=1F)[C:21](NS(C)(=O)=O)=[O:22]>>[C:20]12([CH2:21][O:22][C:3]3[CH:4]=[CH:5][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[CH:14][C:2]=3[Cl:1])[CH2:28][CH:29]3[CH2:5][CH:6]([CH2:14][CH:18]([CH2:30]3)[CH2:19]1)[CH2:7]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CS(=O)(=O)NC(=O)c1ccc(F)c(Cl)c1
Product: CS(=O)(=O)NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 3-chloro-4-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.34 g, 52%): 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.04-7.94 (m, 2H), 7.25 (d, J=8.5 Hz, 1H), 3.72 (s, 2H), 3.36 (s, 3H), 1.99 (br, 3H), 1.71-1.66 (m, 12H); MS (ES−) m/z 396.1, 398.1 (M−1).
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]I.[SH:11][C:12]1[NH:16][N:15]=[N:14][CH:13]=1>C(O)C>[N:14]1[CH:13]=[C:12]([S:11][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:11][C:12]2[NH:16][N:15]=[N:14][CH:13]=2)[NH:16][N:15]=1
Reactant: Sc1cnn[nH]1
Reactant: ICCOCCOCCI
Solvent: CCO
Product: c1nn[nH]c1SCCOCCOCCSc1cnn[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
10 ml of 1,2-bis(2-iodoethoxy)-ethane was dropped into the solution of 20 mmole 5-mercapto-1H-1,2,3-triazole (sodium salt) in 20 ml ethanol, and stirred for 24 hours at room temperature. After the solvent was evaporated in vacuum, the residual was separated with silica gel column. Elution with hexane/ethylacetate (1/3) first, and then with pure ethyl acetate gave 2.70 g product as viscous solid. Yield: 88%. 1H NMR (CDCl3): δ(ppm) 7.72 (2H, s), 3.74 (4H, t, JH-H=6.19), 3.65 (4H, s), 3.07 (4H, t, JH-H=6.19).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: C1COCCN1
Solvent: ClCCl
Product: Cc1nc(Cl)cc(N2CCOCC2)n1
Temperature: -78 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
The crude 2-methyl-4,6-dichloropyrimidine (41.8 g.; 256 mmol) was dissolved in dichloromethane (200 mL) and chilled to −78° C. in an inert atmosphere. Morpholine (48 g.; 550 mol) dissolved in dichloromethane (100 mL) was added slowly. The reaction was allowed to warm to room temperature while stirring overnight. The organic layer was washed with saturated ammonium chloride (2×100 mL), dried with sodium sulfate, and evaporated to give 2-methyl-4-chloro-6-morpholino-pyrimidine (48.5 g.; 227 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[C:15]([CH2:18]Br)[CH:14]=[C:13]([Br:20])[C:12]=2[Br:21])[CH:9]=1)[C:5]#[N:6].[NH3:22].CO>ClCCl>[NH2:22][CH2:18][C:15]1[C:16]([F:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:12]([Br:21])=[C:13]([Br:20])[CH:14]=1
Reactant: N
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)c(CBr)cc(Br)c2Br)c1
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(F)c(CN)cc(Br)c2Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A mixture of 3-chloro-5-{[2,3-dibromo-5-(bromomethyl)-6-fluorophenyl]oxy}benzonitrile (0.185 g, 0.371 mmol) and 7M ammonia in methanol (5 mL, 35.0 mmol) in dichloromethane (5 mL) was stirred at RT overnight. The solvent was evaporated and the residue was purified by chromatography (MeOH:dichloromethane) to give the desired product (37 mg, 19.5%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 7.80 (d, 1H), 7.52 (t, 1H), 7.25 (t, 1H), 7.20 (d, 1H), 3.82 (s, 2H).
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4]1.[C:13]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:13][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4]1
Reactant: [BH3-]C#N
Reactant: OCCCC1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC(CCCO)CC1
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
Formalin (6.33 g, 211 mmol) is added to a stirred solution of 3-(piperidin-4-yl)-propan-1-ol (3.02 g, 21.1 mmol) in acetonitrile (30 mL) at ambient temperature. The solution is allowed to stir for 20 minutes. Sodium cyanoborohydride (3.31 g, 52.7 mmol) and acetic acid (3 mL) are sequentially added to the reaction mixture and the resultant mixture is stirred for another 2 hours. After concentration, the crude product is dissolved in dichloromethane (150 mL), washed with saturated aqueous NaHCO3 (60 mL×2), dried and concentrated. The crude product is subjected to chromatography on silica gel and eluted with 2 M NH3/CH3OH in dichloromethane 0-15% to give the title compound as an oil (2.70 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 100 g of 4-bromophenylacetic acid in 1.5 l of methanol is mixed with 232 g of Amberlyst 15, and the suspension is stirred for 48 hours at room temperature. The reaction mixture is suctioned off on diatomaceous earth, the filter residue is washed with dichloromethane, and the filtrate is concentrated by evaporation. The residue is taken up in ethyl acetate, washed with 10% sodium bicarbonate solution and saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. 106 g of 4-bromophenylacetic acid methyl ester is obtained as oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH3:15])[C:9]([CH3:16])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH2:14]([O:13][C:10]1[C:9]([CH3:16])=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[C:11]=1[CH3:12])[CH3:15]
Reactant: CCOc1c(C)cnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(C)cnc(CO)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
32.9 g of (4-ethoxy-3,5-dimethyl-2-pyridyl)methyl acetate were dissolved in 190 ml of ethanol. 95 ml of 3N sodium hydroxide solution were then added dropwise thereto at 0° and the mixture was stirred at room temperature for a further 3 hours. The ethanol was subsequently removed in vacuo and the residual aqueous solution was extracted three times with 200 ml of methylene chloride. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue crystallized from petroleum ether and there was obtained 4-ethoxy-3,5-dimethyl-2-pyridylmethanol of melting point 58-59° .
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[Cl:13].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:2][N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCN(C)CC2)c(Cl)c1
Yield: 95.5 %

Procedure:
Methyl 4-(bromomethyl)-3-chlorobenzoate (400 mg, 1.5 mmol), 1-methylpiperazine (100 mg, 1.0 mmol), and potassium carbonate (276 mg, 2.0 mmol) in N,N-dimethylformamide (2.5 mL) were stirred at room temperature overnight. The mixture was concentrated and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and concentrated to give product (270 mg, 58%). LCMS (ESI): RT (min)=0.934, M+H+=282.8, method=B.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.Cl[C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=O)[C:18](=O)N2>>[C:16]1([CH:17]([C:18]2[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=2)[N:6]2[C:7]3[C:3](=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[CH3:11])[C:4](=[O:13])[C:5]2=[O:12])[CH:20]=[CH:21][CH:22]=[CH:23][CH:15]=1
Reactant: Cc1ccc(F)c2c1NC(=O)C2=O
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Product: Cc1ccc(F)c2c1N(C(c1ccccc1)c1ccccc1)C(=O)C2=O

Procedure:
Following the procedure as described in PREPARATION 4A, and making non-critical variations using 4-fluoro-7-methyl-1H-indole-2,3-dione (Cassebaum, J. Prakt. Chem. (1960) 12:91-92) to replace 4-chloro-1H-indole-2,3-dione, 1-(diphenylmethyl)-4-fluoro-7-methyl-1H-indole-2,3-dione was obtained (45%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ7.38-7.27 (m, 11H), 6.81 (s, 1H), 6.71 (dd, J=8.3, 8.3 Hz, 1H), 2.27 (s, 3H); MS (ES+) m/z 367.7 (M+23).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:24]([O-])=O)=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[F:12])[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].CO>[Ni].O1CCOCC1>[NH2:24][C:3]1[C:2]([F:1])=[C:11]([F:12])[C:10]([CH3:13])=[C:9]2[C:4]=1[C:5](=[O:23])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][N:8]2[C@@H:14]1[CH2:16][C@@H:15]1[F:17]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(F)c(N)c2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A 3.91 g (37.6 mmol) portion of ethyl 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate was suspended in 1 liter of a 1:1 mixture of methanol and 1,4-dioxane. This was mixed with 200 ml of Raney nickel and stirred for 10 minutes at room temperature. After completion of the reaction, the reaction solution was filtered and the resulting filtrate was concentrated. The resulting residue was dissolved in 300 ml of chloroform and filtered through celite. By concentrating the filtrate, 12.5 g (98%) of the title compound was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.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.[CH2:47]([O:49][C:50]([C:52]1[C:60]2[N:59]=[C:58]([NH2:61])[NH:57][C:56]=2[CH:55]=[C:54]([S:62][CH2:63][CH3:64])[CH:53]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[C:60]2[NH:59][C:58]([NH:61][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:57][C:56]=2[CH:55]=[C:54]([S:62][CH2:63][CH3:64])[CH:53]=1)=[O:51])[CH3:48]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: CCOC(=O)c1cc(SCC)cc2[nH]c(N)nc12
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: CCOC(=O)c1cc(SCC)cc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Yield: 83 %

Procedure:
0.4 g (2.0 mmol) of isoquinoline-3-carboxylic acid and 800 mg (2.1 mmol) HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.26 g (1.0 mmol) of 2-amino-6-ethylsulfanyl-1H-benzoimidazole-4-carboxylic acid ethyl ester as described in general procedure A to produce 0.35 g (0.83 mmol, 83%) of 6-ethylsulfanyl-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 421 (M+1)+.