Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]12[CH2:21][C:20]([OH:26])([C:22]([O:24][CH3:25])=[O:23])[N:19]3[C:9]4=[C:10]([C:13]5[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:11][CH2:12][N:7]([CH:8]14)[CH2:6][CH2:5][CH2:4]2.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>CO>[CH3:1][CH2:2][C@:3]12[CH2:21][C@:20]([OH:26])([C:22]([O:24][CH3:25])=[O:23])[N:19]3[C:9]4=[C:10]([CH2:11][CH2:12][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=13
Reactant: CCC12CCCN3CCc4c(n(c5ccccc45)C(O)(C(=O)OC)C1)C32
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Reaction time: 5 h
Yield: 36 %

Procedure:
If the isomerisation of 16-epivincamine described in Example 4 is repeated but using 177 mg. (0.5 millimole) of 16-epivincamine in 20 ml. of methanol and 130 mg. (0.2 millimole) of a 40% aqueous solution of tetrabutylammonium hydroxide (formula (I)b), and the mixture is allowed to stand for 5 hours at 25°C. 64 mg. of vincamine are obtained (yield 36%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16]CC)=O)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH2:19])=[O:16])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1ccc(Cc2ccccc2)cn1
Product: NC(=O)c1ccc(Cc2ccccc2)cn1
Reaction time: 24 h

Procedure:
To one gram of ethyl 5-benzylpicolinate, 10 ml. of 28% aqueous ammonia were added. After allowing the mixture to stand at room temperature for 24 hours, crystals formed were collected by filtration and recrystallized from ethanol to obtain 0.6 g of 5-benzylpicolinic acid amide as colorless crystals of a melting point of 193°~196° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[S:24]1(=[O:34])=[O:33]>>[O:33]=[S:24]1(=[O:34])[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=c1ccc2ccccc2n1C1CCNCC1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCC(n2c(=O)ccc3ccccc32)CC1

Procedure:
From the hydrochloride salt of 1-(4-piperidyl)-2(1H)-quinolinone was prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: 1H NMR (300 MHz, CDCl3) 8.08 (d, J=6.73 Hz, 1H), 7.90 (m, 3H), 7.7 (d, J=9.5 Hz, 1H), 7.6 (d, J=9.2 Hz, 1H), 7.56 (d, J=7.62 Hz, 1H), 7.26 (m, 2H), 6.71 (d, J=9.47 Hz, 1H), 3.85 (br m, 3H), 3.45 (br m, 1H), 3.25 (br m, 3H), 3.14 (br m, 6H), 1.95 (br s, 4H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[CH:22]=2)[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].CCN(C(C)C)C(C)C.Cl[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34]>ClCCl>[NH2:7][C:6]1[CH:8]=[CH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]([C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[CH2:17][C:16]=3[CH:22]=2)=[CH:11][C:5]=1[N+:2]([O-:4])=[O:3]
Reactant: C=CCOC(=O)Cl
Reactant: Nc1ccc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
2-nitro-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)aniline hydrochloride salt (3.61 g, 11.2 mmol) and DIPEA (5.2 mL, 30 mmol) were taken into dichloromethane (50 mL) followed by dropwise addition of allyl chloroformate (1.23 mL, 11.2 mmol) over 5 minutes. The mixture was allowed to stir 30 minutes at room temperature then concentrated. The residue was partitioned with ethyl acetate and 10% aqueous citric acid and the organic solution washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to give prop-2-en-1-yl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (4.2 g, 100% yield) as a red amorphous residue. MS (EI) for C19H19N3O5: 370 (MH1).
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH:24]([NH:29][CH3:30])[C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[F:33][CH:2]([F:1])[C:3]([NH:5][C@H:9]([CH2:10][F:11])[C@H:8]([OH:7])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([CH:24]([NH:29][CH3:30])[C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)=[O:4]
Reactant: CNC(c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
To a solution of 2,2-Difluoro-1-((4S,5R)-4-fluoromethyl-2,2-dimethyl-5-{4-[6-(2,2,2-trifluoro-1-methylamino-ethyl)-pyridin-3-yl]-phenyl}-oxazolidin-3-yl) ethanone (0.12 g, 0.235 mmol) in CH2Cl2 (2 mL) is added trifluoroacetic acid (0.5 mL) at 0° C. then is stirred to room temperature for 2 hours. Reaction solvent evaporated in vacuo then diluted with sodium bicarbonate solution and extract with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combiflash eluting in 5% Methanol in CH2Cl2 to afford the title compound (0.028 g). 1H-NMR (400 MHz, DMSO) δ: 2.25 (d, J=5.84 Hz, 3H), 3.00-3.04 (m, 1H), 4.31-4.35 (m, 1.5H), 4.41-4.46 (m, 1.5H), 4.55-4.56 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.90 (m, 1H), 5.93 (d, J=4.36 Hz, 1H), 6.19 (d, J=53.72 Hz, 1H), 7.46 (d, J=8.32 Hz, 2H), 7.95-7.98 (dd, J1=1.96 HzHz, J2=8.32 Hz, 1H), 8.03 (d, J=8.32 Hz, 1H), 8.06 (d, J=8.48 Hz, 2H), 8.71 (d, J=1.88 Hz, 1H), 8.84 (d, J=8.72 Hz, 1H). LC-MS (m/z): [M+H]=436.0.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([N:14]=CC2C=CC=CC=2)[C:6](=[O:22])[C:5]=1C(OCC)=O>O1CCOCC1>[NH2:14][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([OH:3])=[CH:5][C:6]1=[O:22]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(N=Cc2ccccc2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nn1c(=O)cc(O)c2ccccc21
Yield: 91 %

Procedure:
To a solution of 25% by weight aqueous potassium hydroxide (200 mL) and 1,4-dioxane (50 mL) heated to 90-100° C. was added portion wise the product of Example 226C (6.72 g, 20.0 mmol). The reaction mixture was heated at reflux for 90 minutes allowing distillation to occur and additional water and dioxane (30 mL each) were added to the reaction vessel to reach the original volume. The mixture was refluxed for an additional 90 minutes with distillation, cooled, washed with 200 mL of 1:1 diethyl ether/ethyl acetate, acidified with concentrated hydrochloric acid to pH 2 and the resulting solid was collected by filtration, washed with water and dried to constant mass to give the title compound as a tan sold (3.22 g, 91% yield). MS (DCI) m/z 177 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 5.56 (s, 2 H) 5.94 (s, 1 H) 7.20 (t, J=7.54 Hz, 1 H) 7.62 (m, 1 H) 7.85 (m, 2 H) 11.33 (s, 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:8]([Mg]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCOCC1
Reactant: Cl[Mg]Cc1ccccc1
Product: OC1(Cc2ccccc2)CCOCC1
Yield: 87.5 %

Procedure:
Tetrahydropyran-4-one (4.34 g, 43.4 mmol) is treated with benzylmagnesium chloride (2 M in THF, 32.5 mL, 65.0 mmol) according to general procedure A. The crude product is filtered through silica gel, first with CH2Cl2, then with 1:1 hexane/EtOAc, to give alcohol 17 as a colorless oil (7.3 g, 87%) . 1H NMR (CDCl3) 7.40-7.15(m,5), 3.80-3.65(m,4), 2.77(s,2), 1.81(s,1), 1.80-1.70(m,2), 1.50-1.40(m,2); 3C NMR(CDCl3) 135.90, 130.53, 128.32, 126.74, 68.55, 63.65, 49.42, 37.46; MS(MW=192.3, CI/CH4, eE=70eV) m/z 193 (M+H)+, 191, 176, 175(base peak), 157, 145, 129, 119, 101, 92, 83, 71.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[N+:8]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(C)=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]

Procedure:
5-Bromo-2-methyl-2-pentene (15 g, 0.092 mol) was added to a slurry of 2-nitroimidazole (10.4 g, 0.092 mol) and potassium carbonate (12.7 g, 0.092 mol) and refluxed for 24 hrs. Acetone was removed on a rotary evaporator and the residue was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](COC)[C:12]2[C:13]([C:19]([C:21]3[C:22]4[CH:29]=[N:28][NH:27][C:23]=4[N:24]=[CH:25][CH:26]=3)=[O:20])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[C:22]4[CH:29]=[N:28][NH:27][C:23]=4[N:24]=[CH:25][CH:26]=3)=[O:20])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:33]([F:35])([F:34])[F:36]
Reactant: COCN(c1cc(C)cnc1C(=O)c1ccnc2[nH]ncc12)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(C(=O)c2ccnc3[nH]ncc23)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A mixture of 4-chloro-N-methoxymethyl-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (50 mg, 0.092 mmol) in 4M HCl in dioxane (4 mL) and water (1 mL) was stirred at 70° C. for overnight. Reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified by flash chromatography (SiO2, 70% EtOAc-hexanes) to afford 4-chloro-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (28.9 mg) as yellow solid (after lyophilization) in 63% yield. 1H NMR (400 MHz, CDCl3) δ10.75 (s, 1H), 8.65 (d, 1H), 8.24 (m, 1H), 8.14 (d, 1H), 8.08 (s, 1H), 7.94-7.99 (m, 2H), 7.59 (d, 1H), 7.58 (d, 1H), 2.48 (s, 3H); ESMS m/z (relative intensity): 496 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[CH:10]=[CH:11][N:12]=[C:4]2[CH:3]=1.[OH-:13].[K+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([OH:13])[N:5]2[CH:10]=[CH:11][N:12]=[C:4]2[CH:3]=1
Reactant: CSc1nc(Cl)cc2nccn12
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: Oc1nc(Cl)cc2nccn12

Procedure:
A solution of 73.25 g (366.87 mmol) of 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine are dissolved in 732 ml of methanol, and 1275 ml of a 2 molar aqueous potassium hydroxide solution are added. The mixture is heated under reflux for 3 h. After the reaction is complete, the methanol is removed in vacuo, the mixture is neutralized with half-concentrated hydrochloric acid, and the crystals which have separated out are filtered off with suction. They are washed with methanol and water and then dried under high vacuum. 40.0 g (64% of theory) of the product are obtained.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5]([O:12][CH:13]([C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[CH:17][C:16]=1[C:23]1[CH:24]=[N:25][C:26]2N[CH2:28][CH2:29][CH2:30][C:31]=2[CH:32]=1)[CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:5]([O:12][CH:13]([C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[CH:17][C:16]=1[C:23]1[CH:32]=[C:31]2[C:26](=[N:25][CH:24]=1)[N:1]([C:2]([NH2:4])=[O:3])[CH2:28][CH2:29][CH2:30]2)[CH3:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(OCc1ccccc1)c1c(C#N)cncc1-c1cnc2c(c1)CCCN2
Reactant: NC(N)=O
Product: CC(OCc1ccccc1)c1c(C#N)cncc1-c1cnc2c(c1)CCCN2C(N)=O

Procedure:
The titled product is synthesized according to the procedure of Urea Formation Method II using 4-(1-benzyloxy-ethyl)-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-nicotinonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[N:26]=2)=[N:10]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH:35]1[C:40]([OH:42])=[O:41]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[N:26]=2)[NH:12][C:13]([CH2:20][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH:35]2[C:40]([OH:42])=[O:41])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)NC(C)C)cs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nc(CC(=O)NC(C)C)cs2)=NC1c1ccc(F)cc1Br
Yield: 49 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2-(isopropylamino)-2-oxo ethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.2 g, 2 mmol) was reacted with morpholine-3-carboxylic acid (0.39 g, 3 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.64 g, 49%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: C1CCNCC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCCCC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and piperidine. Yellow solid. MS (m/e): 339.1 ({37Cl}M+H+, 29%), 337.1 ({35Cl}M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:12]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:22])[S@:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H](c1cc(Cl)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a solution of (S)-N-((R)-1-(3-chloro-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.5 g, 4.6 mmol) in anhydrous THF (20 mL) under N2 atmosphere was dropwise added LHMDS (9.2 mL, 1 M in THF, 9.2 mmol) at −60° C. The reaction was stirred for 30 min at −60° C., followed by addition of MeI (1.04 g, 6.9 mmol). The reaction was stirred at room temperature for another 3 h and quenched with water at 0° C. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (1.2 g, yield: 76.5%); m/z (ES+): 342 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:22]([C:26](Cl)=[O:27])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]1=[O:29].[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:22]([C:26]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([F:30])=[C:32]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)=[O:27])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]1=[O:29]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COc1cc2nccc(CN3CCc4c(C(=O)Cl)cccc4C3=O)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2nccc(CN3CCc4c(C(=O)Nc5ccc(F)c(C(F)(F)F)c5)cccc4C3=O)c2cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.5 %

Procedure:
2-((6,7-dimethoxyquinolin-4-yl)methyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carbonyl chloride (75 mg, 0.168 mmol) was suspended in dichloromethane (1 mL) then added a solution of 4-fluoro-3-trifluoromethylaniline (36 mg, 0.201 mmol) in dichloromethane (0.5 mL) and N,N-diisopropylethylamine (65 mg, 0.504 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was purified directly by silica gel chromatography (3% methanol/dichloromethane) to afford 2-((6,7-dimethoxyquinolin-4-yl)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (46 mg) as a pale yellow solid. MS (ESI, pos. ion) m/z: 554.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-n3ccnc3)c(F)c21
Temperature: 100 °C
Reaction time: 1.25 h
Yield: 48.1 %

Procedure:
To 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (13.6 g) and imidazole (10.2 g) is added dimethylformamide (80 ml), and the mixture is stirred at 100° C. for 1.25 hour. The reaction mixture is cooled to room temperature, and the precipitated crystals are separated by filtration and washed with ethanol. The crude crystals thus obtained are recrystallized from dimethylformaide to give the title compound (7.7 g) as colorless needles. Melting point: 283°-288° C. (decomp. with foam), being gradually colored from about 245° C. IR (KBr, νC=O): near 1720 cm-1.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:20][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][C:9]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(-c2ccncc2)nc(-c2ccccc2)[nH]1
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(-c2ccccc2)nc(-c2ccncc2)c1Br
Temperature: 90 °C
Yield: 92.1 %

Procedure:
2-Phenyl-6-(4-pyridyl)pyrimidin-4-one (0.61 g) obtained in Example 12 was dissolved in 3 ml of acetic acid, and then the mixture was added with 0.48 g of N-bromosuccinimide and heated at 90° C. for 1 hour. Water was added to the reaction mixture, and solid mass was separated by filtration. The solid was washed with water, acetone, and ethyl acetate, and dried to obtain 0.74 g of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:28])[CH2:8][CH2:7]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O>N1C=CC=CC=1>[C:32]([O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:28])[CH2:10][CH2:11]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2cccc(O)c2)CC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To a solution of 207 mg (0.5 mmol) of 3-[1-(3-hydroxybenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)quinazolinone in 3 mL of pyridine was added 61 mg (0.6 mmol) of acetic anhydride, and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer separated was washed with water and then with brine, dried on sodium sulfate and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 187 mg (0.41 mmol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[O:7][CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:44]
Reactant: Cn1ncc(N)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1OC1CCNCC1
Yield: 9 %

Procedure:
Following the procedures as described in Example 113, tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yloxy)piperidine-1-carboxylate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 120 as a white solid (20 mg, 9.0%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.64-7.40 (m, 3H), 7.27 (t, J=8.7, 2H), 4.39-4.11 (m, 1H), 3.60 (s, 3H), 2.94 (dt, J=12.5, 3.9, 2H), 2.50-2.40 (m, 2H), 2.03-1.81 (m, 2H), 1.53 (td, J=13.2, 4.0, 2H). ESIMS m/z=435.1 (M+1).
Reaction SMILES: [CH:1]1([Li])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:12][CH2:13]Br>C1COCC1>[CH:1]1([CH:7]([CH:6]2[C:12]3[C:13](=[CH:9][CH:1]=[CH:2][CH:3]=3)[CH:4]=[CH:5]2)[CH3:8])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: BrCCBr
Reactant: [Li]C1C=Cc2ccccc21
Solvent: C1CCOC1
Product: CC(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Reaction time: 4 h

Procedure:
Am. Chem. Soc., 109 (1987) 6544-6545, to J. A. Ewen et al. discloses a process similar to the one of Collins wherein, as described in the supplementary material to the article, two equivalents of indenyllithium are reacted with 1,2-dibromoethane dissolved in THF by warming the reaction mixture from −91° C. to 25° C. and stirring for 4 h. Bisindenylethane was obtained in a crude yield of 60%. The product was recrystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].CO[C:18](OC)([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>FC(F)(F)C(O)=O>[CH3:23][C:18]1([C:19]([O:21][CH3:22])=[O:20])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1
Reactant: COC(=O)C(C)(OC)OC
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.044 g, 0.20 mmol) in methyl 2,2-dimethoxypropanoate (0.3 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 1 h. Then, the reaction mixture was concentrated, and the obtained residue was dissolved in methanol (10 mL), and the solution was concentrated with NaHCO3 (0.5 g) and silica gel (2 mL), and the residue was purified by flash chromatography (Combiflash, silica gel, dichloromethane to 90:10 dichloromethane/methanol) to give a crude product. Trituration with hexanes/ethyl acetate gave the title compound (0.026 g, 42%) as a yellow solid: