Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:6]=1[C:7](=[O:16])[NH:8][S:9]2(=[O:11])=[O:10])([CH3:4])[CH3:3].[C:17]1([S:23][CH2:24]Cl)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:17]1([S:23][CH2:24][N:8]2[C:7](=[O:16])[C:6]3[C:12](=[CH:13][CH:14]=[CH:15][C:5]=3[C:2]([CH3:1])([CH3:3])[CH3:4])[S:9]2(=[O:11])=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)c1cccc2c1C(=O)NS2(=O)=O
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cccc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Temperature: 25 °C
Yield: 96.8 %

Procedure:
The 4-(1,1-dimethylethyl) saccharin (0.025 g 1.0 mmol) was mixed with chloromethyl phenyl sulfide (0.25 g, 1.5 mmol) and tetrabutyl ammonium bromide (0.2 g, 0.6 mmol) in toluene (25 mL) and refluxed under nitrogen for 16 hr. The resulting mixture was cooled to room temperature, evaporated to dryness and purified by chromatography on silica gel (80%) MDC in hexanes) to give 0.35 g (98%) of 2-phenylthiomethyl-4-(1,1-dimethylethyl]saccharin, which was treated with sulfuryl chloride (0.25 g, 1.8 mmol) in MDC to give 0.21g (75%) of 2-chloromethyl-4-(1,1-dimethylethyl]saccharin.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[OH-].[Na+].Cl[CH2:9][C@@H:10]1[CH2:12][O:11]1.Cl>O>[O:11]1[CH2:12][C@@H:10]1[CH2:9][NH:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: ClC[C@@H]1CO1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)NC[C@H]1CO1
Reaction time: 2 h
Yield: 15.7 %

Procedure:
To a cold solution of methanesulfonamide (10 g, 0.105 mol) in water (100 mL) in an ice bath was added sodium hydroxide as pellets (8.4 g, 0.21 mol) and then (S)-2-chloromethyloxirane (12.4 g, 0.158 mol). The mixture was stirred at the same temperature for 2 h, and at room temperature for 12 h and then concentrated hydrochloric acid (18 mL) was added. The product was isolated by extracting the aqueous layer with dichloromethane (2×300 mL). The organic layer was dried over MgSO4 and then evaporated to dryness, yielding a colorless liquid (2.5 g), which was used directly in the next step.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH2:14]O)([CH3:3])[CH3:2].C1C=CC(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:30]([CH2:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To 8B (190 mg, 0.89 mmol) in THF (5 mL) at 0° C. was added DPPA (300 mg, 1.1 mmol) in THF (1 mL) and DBU (170 mg, 1.9 mmol). The cold bath was removed and the reaction was stirred at rt overnight. The reaction was then concentrated and purified via silica gel chromatography (0-15% ethyl acetate/hexane) to provide 8C (160 mg, 90%) and starting material (8B) (30 mg). 8C: LC-MS: 237.16 (M+H)+.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:9][C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:34])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:2]([O:6][C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:9][C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:34])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])[CH:20]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (4.4 mmol, 3.3 eq) of 1-iodobutane and 530 mg (1.33 mmol, 1 eq) of methyl 3-[2-hydroxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 2.7 eq) of potassium carbonate at 80° C. for 16 hours, methyl 3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([O:9][CH2:8][C:6]1[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=[C:2]([Cl:1])[N:7]=1)(=[O:45])[CH3:44]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(COC(C)=O)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (Intermediate 35B, 342 mg, 0.750 mmol) was dissolved in DCM (4.0 ml). The reaction mixture was charged with DIEA (0.197 ml, 1.125 mmol) followed by acetyl chloride (0.064 ml, 0.900 mmol) and allowed to stir at rt for 15 minutes. The reaction was concentrated in vacuo to provide (6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (41B). The products were carried forward without purification. MS: [M+H]+ m/z 498.
Reaction SMILES: [ClH:1].Cl.Cl.Cl.[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:21][C:22]1[N:23]=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)[CH:11]1[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH:48]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[ClH:1].[C:27]1([N:25]2[CH:26]=[C:22]([CH2:21][N:10]([CH:11]3[C:20]4[N:19]=[CH:18][CH:17]=[CH:16][C:15]=4[CH2:14][CH2:13][CH2:12]3)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:48][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][N:42]=3)[N:23]=[N:24]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1ccccn1
Reactant: NCCCCN(Cc1cn(-c2ccccc2)nn1)C1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1ccc(-n2cc(CN(CCCCNCc3ccccn3)C3CCCc4cccnc43)nn2)cc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A solution of N-(4-aminobutyl)-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-5,6,7,8-tetrahydro-quinolin-8-amine tetrahydrochloride, Z, (0.20 g, 0.38 mmol) in 1,2-dichloroethane (10 mL) was treated with Hünigs base (0.08 mL, 0.42 mmol), 2-pyridine carboxaldehyde (0.04 mL, 0.42 mmol), sodium triacetoxyborohydride (0.12 g, 0.57 mmol) and a catalytic amount of acetic acid (2 drops). The resulting mixture was warmed to 65° C. and stirred for 18 h. The reaction mixture was cooled to room temperature. A saturated aqueous solution of sodium bicarbonate was added. The product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-15% methanol/CH2Cl2) to afford 0.08 g (45% yield) of the desired product AB: 1H NMR (400 MHz, CDCl3) δ 8.54-8.34 (m, 2H), 8.15 (bs, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.60-7.52 (m, 1H), 7.45 (t, J=7.2 Hz, 2H), 7.39-7.32 (m, 1H), 7.32-7.22 (m, 2H), 7.14-7.04 (m, 1H), 7.02-6.84 (m, 1H), 4.15-4.04 (m, 1H), 3.92-3.70 (m, 4H), 2.82-2.50 (m, 6H), 2.15-2.04 (m, 1H), 2.04-1.82 (m, 1H), 1.82-1.78 (m, 1H), 1.70-1.40 (m, 5H); ESI+ MS: m/z (rel intensity) 468.3 (100, [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: C1CCNC1
Reactant: C=Cc1ccc([N+](=O)[O-])c(OC)c1
Solvent: CO
Product: COc1cc(CCN2CCCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 75 %

Procedure:
3.07 g (17.17 mmol) of the product prepared in step 24.1 and 7.13 mL (85.84 mL) of pyrrolidine in 60 mL of anhydrous methanol are placed in a sealed tube. The mixture is heated under pressure at 100°C. for 4 hours. After cooling to room temperature, it is evaporated to dryness. The residue obtained is purified by chromatography on a column of silica, eluting with a dichloromethane/methanol gradient (100/0 to 90/10). 3.22 g of the expected product are obtained in the form of a yellow solid. Yield=75%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:14][CH:15]([F:27])N1C=C2C(C=C(N)C=C2C)=N1>>[F:14][CH:15]([F:27])[N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([NH2:11])[CH:8]=2)[CH:4]=[N:5]1
Reactant: Cc1cc(N)cc2nn(C(F)F)cc12
Reactant: Cc1cc([N+](=O)[O-])cc2[nH]ncc12
Product: Cc1cc(N)cc2c1cnn2C(F)F

Procedure:
In accordance with Example 24 (Steps 1 and 2), 4-methyl-6-nitro-1H-indazole (934 mg) was used instead of 6-nitro-1H-indazole to obtain 1-(difluoromethyl)-4-methyl-1H-indazol-6-amine (112 mg) and 2-(difluoromethyl)-4-methyl-2H-indazol-6-amine.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.[N:24]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]=O)[CH:25]=1.C[O-].[Na+].CO.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.O.C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:23])[N:11]2[CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][CH:3]([NH:2][CH2:34][C:26]3[CH:25]=[N:24][C:33]4[C:28]([CH:27]=3)=[N:29][CH:30]=[CH:31][CH:32]=4)[CH2:8][CH2:7]2)=[N:16][CH:17]=1
Reactant: O=Cc1cnc2cccnc2c1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cnc5cccnc5c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.9 %

Procedure:
To a suspension of 86 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 4 mL of methanol, 33 mg of 1,5-naphthyridine-3-carbaldehyde, 0.12 g of a 28% sodium methoxide/methanol solution and 12 μL of acetic acid were added. Then, 26 mg of sodium cyanoborohydride was added thereto, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, chloroform, a saturated aqueous sodium hydrogen carbonate solution and water were added. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol=87:13 to 85:15 to obtain 11 mg of 7-methoxy-1-(2-(4-((1,5-naphthyridin-3-ylmethyl)amino)piperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one as a light yellow oily substance.
Reaction SMILES: C([Li])CCC.[Si:6]([O:13][CH2:14][C:15]1[N:20]=[C:19]([N:21]=[C:22]2[N:26]([CH2:27][O:28][CH3:29])[CH:25]=[CH:24][S:23]2)[CH:18]=[CH:17][CH:16]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:40])(=O)=O)=CC=1.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[Si:6]([O:13][CH2:14][C:15]1[N:20]=[C:19]([N:21]=[C:22]2[N:26]([CH2:27][O:28][CH3:29])[CH:25]=[C:24]([F:40])[S:23]2)[CH:18]=[CH:17][CH:16]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COCn1ccsc1=Nc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCn1cc(F)sc1=Nc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5 ml of tetrahydrofuran was cooled to −78° C., and then 1.05 ml of butyllithium (1.6 M, hexane solution) was dropped thereinto. Into the resulting reaction solution was dropped a solution of 280 mg of 6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-(3-(methoxymethyl)thiazol-2(3H)-ylidene)pyridin-2-amine in 5 ml of tetrahydrofuran, followed by stirring at −78° C. for 30 minutes. A solution of N-fluorobenzenesulfonimide in 5 ml of tetrahydrofuran was dropped thereinto. After having the temperature of the resulting reaction solution allowed to −30° C., 230 μl of acetic acid was dropped thereinto. The resulting reaction solution was diluted with ethyl acetate, and then washed with water and brine. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=3/1) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8].[CH:14](O)=[O:15]>O>[CH:14]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8])=[O:15]
Reactant: O=CO
Reactant: COC(=O)C=Cc1cccc(N)c1
Solvent: O
Product: COC(=O)C=Cc1cccc(NC=O)c1

Procedure:
193 g of methyl 3-aminocinnamate and 900 ml of formic acid were mixed and heated under reflux for 2 hours. The reaction solution was poured into water and the crystals (methyl 3-formamidocinnamate) obtained were collected by filtration. Yield: 127 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:6][C@H:5]([C:7](=[O:29])[CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:4]([CH:30]=[CH2:31])[O:3]1.[CH:33]([Mg]Br)=[CH2:34]>O1CCCC1>[CH3:1][C:2]1([CH3:32])[O:6][C@H:5]([C@@:7]([OH:29])([CH:33]=[CH2:34])[CH2:8][O:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:4]([CH:30]=[CH2:31])[O:3]1
Reactant: C=C[C@@H]1OC(C)(C)O[C@@H]1C(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=C[C@@H]1OC(C)(C)O[C@@H]1[C@@](O)(C=C)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 4 (14.66 g, 34.22 mmol) in tetrahydrofuran (150 ml) was added dropwise vinylmagnesium bromide (68.44 ml, 68.44 mmol, 1.0 M solution in tetrahydrofuran) at −78° C., and the reaction mixture was stirred for 1 hour at the same temperature. The reaction mixture was quenched by saturated ammonium chloride solution and brine, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated. The resulting oil was purified by column chromatography (hexane:ethyl acetate=9:1) to give 5 (15.62 g, 100%) as a white semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.43-7.22 (m, 15H), 6.16 (dd, J=17.2, 10.8 Hz, 1H), 6.01-5.93 (m, 1H), 5.42 (dd, J=17.2, 1.2 Hz, 1H), 5.27 (dd, J=10.8, 1.2 Hz, 1H), 4.99 (d, J=16.0 Hz, 1H), 4.98 (d, J=11.2 Hz, 1H), 4.54-4.47 (m, 2H), 3.33 (d, J=8.8 Hz, 1H), 3.05 (d, J=8.4 Hz, 1H), 2.54 (bs, 1H), 1.46 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.CCOC(C)=O>C1COCC1.O>[C:21]([O:20][C:18](=[O:17])[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([Br:2])=[CH:4][CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reaction time: 12 h
Yield: 90.9 %

Procedure:
A solution of 4-bromobenzylamine hydrochloride 116 (2.225 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol, 1.5 equiv) in THF (20 mL) and water (5 mL) was treated with BOC2O (2.40 g, 11.0 mmol, 1.1 equiv) at room temperature and stirred for 12 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was treated with water (10 mL) and EtOAc (40 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (4-bromo-benzyl)-carbamic acid tert-butyl ester 117-(2.60 g, 90.9% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10](=[C:11]3[C:16]=1[CH:15]=[C:14]([F:17])[CH:13]=[CH:12]3)[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2].[BH4-].[Na+].FC(F)(F)C(O)=O.C1C=CC2C3C=CC=CC=3NCC=2C=1.C(N(CC)CC)C.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1>O1CCCC1.ClCCl>[CH:14]1[CH:13]=[CH:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:4][CH2:3][C:16]=2[CH:15]=1.[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:56]([C:53]1[CH:52]=[CH:51][C:50]([O:49][CH3:48])=[CH:55][CH:54]=1)(=[O:58])=[O:57])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1nc2ccccc2c2ccc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2c(c1)CNc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)cc1

Procedure:
The intermediate dihydrophenanthridine was prepared from 6-ethyl-8-fluorophenanthridine (1.10 g, 4.88 mmol) by treatment with sodium borohydride (1.11 g, 29.3 mmol) and trifluoroacetic acid (1.50 mL, 19.5 mmol) in tetrahydrofuran (18 mL). In a separate, second step, the dihydrophenanthridine was treated with triethylamine (4.1 mL, 29.3 mmol) and 4-methoxybenzenesulfonyl chloride (1.11 g, 5.37 mmol) in dichloromethane (5 mL) according to the procedure and in the same manner as described in Example 32, Method A, Step d. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 3:7 gradient), to yield 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine as a homogeneous, white, crystalline, solid (1.67 g, 87%), m.p. 153-156° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][C:8]([N:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:11])=[O:9].[N:30]#[C:31]Br>C(O)C>[NH2:30][C:31]1[N:5]([CH2:6][CH2:7][C:8]([N:10]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH3:11])=[O:9])[CH2:4][C:3]2[C:2](=[CH:21][CH:20]=[C:19]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=2)[N:1]=1
Reactant: N#CBr
Reactant: CN(C(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N)C1CCCCC1
Solvent: CCO
Product: CN(C(=O)CCN1Cc2cc(C(=O)c3ccccc3)ccc2N=C1N)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 3-(2-amino-5-benzoyl-benzylamino)-N-cyclohexyl-N-methyl-propionamide (0.017) prepared as described in Example 3 in ethanol (250 mL) was stirred at room temperature and cyanogen bromide (0.027 mol) was added. The reaction mixture was stirred and refluxed for 3 hours, then cooled. The solvent was evaporated and the residue was crystallized from CH3CN. The precipitate was filtered off and dried to yield the title compound as a residue.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:17][CH3:18])=[CH:9][C:3]=1[C:4](OCC)=[O:5].Cl.[CH:20](N)=[NH:21]>C(N)=O>[CH2:17]([O:16][C:10]1[CH:9]=[C:3]2[C:2](=[CH:12][C:11]=1[O:13][CH2:14][CH3:15])[N:1]=[CH:20][NH:21][C:4]2=[O:5])[CH3:18]
Reactant: N=CN
Reactant: CCOC(=O)c1cc(OCC)c(OCC)cc1N
Agent: Cl
Solvent: NC=O
Product: CCOc1cc2nc[nH]c(=O)c2cc1OCC
Temperature: 140 °C
Yield: 72.7 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of ethyl 2-amino-4,5-diethoxybenzoate (2.53 g, 10 mmol) and formamidine hydrochloride (0.966 g, 12 mmol) in formamide (10 mL) was heated at 140° C. for 5 hours, to afford 6,7-diethoxyquinazolin-4(3H)-one as a white solid (1.702 g, 73%). 1H NMR (300 MHz, CDCl3) δ 10.49 (br, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.14 (s, 1H), 4.24 (m, 4H), 1.54 (m, 6H); LC-MS (ESI) m/z 235 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([O:14]CC)=[O:13])[N:5]([CH3:17])[N:4]=1.[OH-].[Na+]>CO>[F:18][CH:2]([F:1])[C:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([OH:14])=[O:13])[N:5]([CH3:17])[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)c(C(F)F)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(F)F)c(C(F)(F)F)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 600 mg (2.20 mmol) of ethyl 3-(difluoromethyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate in 10 ml of methanol is admixed with 331 mg (3.31 mmol) of 40% strength sodium hydroxide solution and stirred for three hours at room temperature. The reaction mixture is concentrated by evaporation, admixed with water and extracted with diethyl ether. The aqueous phase is acidified with dilute hydrochloric acid and extracted twice with diethyl acetate. The organic phase is dried over sodium sulphate and, after filtration, is concentrated by evaporation. This gives 452 mg of 3-(difluoromethyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (84%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:38]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:30][C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1CBr
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1cccc(C)c1COc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-(3-Benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 2-Bromomethyl-1,3-dimethyl-benzene following the procedure of Example 478: MS m/z 498; HRMS: calcd for C32H26F3NO+H+, 498.20392; found (ESI, [M+H]+), 498.2038.