Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:7][CH:6]([NH2:8])[C:5]1([CH3:10])[CH3:9])[CH3:2].Cl[C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)(C)(C)C.ClCCCl>[CH2:1]([O:3][CH:4]1[CH2:7][CH:6]([NH:8][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=2)[C:5]1([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC1CC(N)C1(C)C
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC1CC(Nc2nc(SC)ncc2C#N)C1(C)C
Temperature: 70 °C
Yield: 100 %

Procedure:
A solution of 3-ethoxy-2,2-dimethylcyclobutanamine (1.0 equiv.) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.1 equiv.) in tert-butanol/1,2-dichloroethane (0.5 M) was treated with potassium carbonate powder (3.0 equiv.). The resulting reaction mixture was then heated at 70° C. under nitrogen for 3 h. After cooling, ethyl acetate was added and the mixture was vigorously stirred. The solid was removed by vacuum-filtration. The filtrate was concentrated and further dried to give (100% yield) of waxy, yellow solid, which was used in the next step without further purification. MS (ESI) m/z 293.0 [M+1]+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])([O-:8])=[O:7]>>[CH3:15][C:10]1[CH:11]=[CH:12][C:13]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1[N+](=O)[O-]
Product: Cc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
Placed chlorosulfonic acid (128 mL, 1.91 mmol) in a 500 mL four necked round bottomed flask. Then added 2-nitro toluene (65 mL, 0.547 mmol) drop wise, under stirring in 25 minutes at 25° C. The reaction mass was heated at 85° C. for 3 hours. Quenched the reaction mass into ice cold water and extracted with ethylacetate (4×250 mL), the combined organic layer was washed with brine solution (1×100 mL), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to obtain syrupy product. Yield: 109.5 grams.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[N:14][C:15]=2[NH2:17])[N:10]=[CH:9]1)([CH3:4])[CH3:3].[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O.C(OCC)(=O)C>CS(C)=O>[C:29]([O:28][C:26]([N:20]1[CH2:25][CH2:24][N:23]([C:13]2[N:12]=[C:11]3[C:16]([N:8]([CH2:7][C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:19])[CH:9]=[N:10]3)=[C:15]([NH2:17])[N:14]=2)[CH2:22][CH2:21]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)Cn1cnc2nc(Cl)nc(N)c21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cn1cnc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)nc(N)c21
Reaction time: 14 h

Procedure:
To a stirred mixture of (6-amino-2-chloro-purin-7-yl)-acetic acid 1,1-dimethylethyl ester, 3 (5 g, 17.6 mmol) in dimethylsulfoxide (50 ml) was added tert-butyl piperazine-1-carboxylate (10 g, 53.8 mmol) at 120° C. After the addition, the mixture was stirred for about 14 h. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction mixture. The organic layers was then washed with H2O several times, dried with Na2SO4 and concentrated to give crude product 4-(6-amino-7-tert-butoxycarbonylmethyl-7H-purin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester, 4 (7 g) which was not purified and used for the next reaction directly.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][C:4]#[CH:5].Br[C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:11]=[CH:12][CH:13]=1>>[F:20][C:19]([F:21])([F:22])[C:18]([NH:17][CH2:16][CH2:15][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]#[C:4][CH2:3][CH:2]([OH:6])[CH3:1])[CH:9]=1)=[O:23]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CCC(C)O
Product: CC(O)CC#Cc1cccc(CCCNC(=O)C(F)(F)F)c1

Procedure:
Coupling of pent-4-yn-2-ol with bromide 10 following the method used in Example 13 except the reaction was conducted at room temperature gave 2,2,2-trifluoro-N-(3-(3-(4-hydroxypent-1-ynyl)phenyl)propyl)acetamide as a pale yellow oil. Yield (0.95 g, 63%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (br s, 1H), 7.14-7.26 (m, 4H), 4.80 (s, 1H), 3.81 (q, J=5.6 Hz, 1H), 3.16 (q, J=6.8 Hz, 2H), 2.54 (t, J=5.6 Hz, 2H), 2.39 (dd, J=16.8, 6.8 Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.17 (d, J=5.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Fc1cccc(CBr)c1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1F

Procedure:
The title compound is prepared in analogy to Example 20a) from 3-fluoro-4-nitrophenol and 3-fluoro benzyl bromide. Yield: 100% of a colorless solid. MS: m/e=265.0 (M+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[C:24]([F:27])[C:25]=1[F:26].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8](=[O:11])[C:22]1[CH:21]=[C:20]([F:19])[C:25]([F:26])=[C:24]([F:27])[CH:23]=1)[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 4.1 g) in THF (100 mL), 3,4,5-trifluorophenylmagnesium bromide (0.35 M solution in diethyl ether; 55 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. for five hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the solution. The reaction solution was heated to room temperature, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=1:1) to obtain 4.8 g of ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate. A solution of 4 N hydrochloric acid in ethyl acetate (30 mL) was added to a solution of the resulting ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate in ethyl acetate (30 mL), and the solution was stirred for 16 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 10% palladium-carbon (100 mg) was added to a solution of the residue in ethyl acetate (50 mL), and the reaction solution was stirred in a hydrogen atmosphere at 1 atm for six hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 2.91 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([CH3:15])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:16])[C:10]([CH3:15])=[C:11]([CH3:14])[CH:12]2[OH:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C)C(=O)N(c2cccc(C)c2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1=C(C)C(O)N(c2cccc(C)c2)C1=O
Yield: 9.2 %

Procedure:
To 20 g (0.93 mole) of the resulting N-(3-methylphenyl)dimethyl-maleimide in 180 ml of methanol is added at 20° 7.2 g (0.185 mole) of sodium borohydride in portions so small that the temperature does not exceed 40°. An intense evolution of gas is observed. The reaction mixture is initially a clear colourless solution, but soon becomes a white suspension, which is poured after one hour into water. The white substance which has precipitated out is filtered off, washed well with methanol and dried under reduced pressure to obtain 18.6 g of white crystals (92.1% of theory), which melt at 170°-172° (compound No. 9, Table I).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[Br:18]Br>C(Cl)Cl>[Br:18][C:11]1[CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)CCC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Br)c2c(c1)CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.4 %

Procedure:
5-Acetylindane (6.3 g, 39 mmol) was dissolved in CH2Cl2 (150 mL) whereupon aluminium chloride (13.0 g, 97 mmol) was added during one minute and a vigorous generation of HCl gas was observed, which was conducted away by means of a tube. The mixture was stirred at room temperature for 5 min and then bromine (9.0 g, 56 mmol), dissolved in CH2Cl2 (50 mL) was added during 2 min. Additional stirring at room temperature for 2 h was followed by pouring the reaction mixture over ice (200 g). The flask was washed with additional CH2Cl2 (100 mL). The organic solution was washed twice with brine, dried and then the solvent was evaporated. There was obtained 8.8 g (93%) of 1-(7-bromo-2,3-dihydro-1H-inden-5-yl)ethanone as a solid material. 1H NMR (300 MHz, CDCl3): 2.1-2.2 (q, 2H), 2.6 (s, 3H), 2.9 (t, 2H), 3.1 (t, 2H), 7.7 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].[CH:12](=O)[CH:13]=[CH:14][CH:15]=[CH:16][CH3:17].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][CH3:17])[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: CC=CC=CC=O
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC=CC=CC=C1SC(=S)N(CC(=O)O)C1=O
Yield: 72.5 %

Procedure:
4 Grams (0.021 mole) of 3-carboxymethylrhodanine was dissolved into 30 ml of acetic acid. To the solution were added 2 g (0.021 mole) of hexa-2,4-dienal and 3.8 g (0.046 mole) of sodium acetate, and the resultant was stirred under mild reflux for 5 hours. The obtained black reaction mixture was concentrated to about one-half its initial volume under reduced pressure. The residual mixture was poured into water to form precipitate. The precipitate was extracted with ethyl acetate and the extract was recrystallized from a mixed solvent of methylene chloride and ethyl acetate to give 4.1 g of 3-carboxymethyl-5-(2,4-hexadienylidene)rhodanine in the form of yellow prism (yield: 73%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])([O:20][CH3:21])=[O:19]>ClCCl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:24](=[O:25])[CH2:23][CH2:22][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a stirred suspension of anhydrous aluminum chloride (3.45 g, 0.026 mol) in dichloromethane (20 mL) at 5° C. was added dropwise a solution of 4-bromobiphenyl (2.3 g, 0.010 mol) in dichloromethane (11 mL) followed by the dropwise addition of 3-carbomethoxypropionyl chloride (1.35 mL, 0.011 mol) in dichloromethane (15 mL), and the mixture stirred. After 2 hours at 5° C., the mixture was allowed to warm to room temperature. After 1 day, the reaction was cooled to 5° C. and quenched by the dropwise addition of water (50 mL). The layers were separated, and the organic layer washed with water and brine, dried (MgSO4), and rotary evaporated. The residue was dissolved (CH2Cl2) and purified by column chromatography on silica gel, eluting with dichloromethane to give 2.68 g of 4-(4′-bromo-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 115.0-116.5° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CC(C)=O.C1(C)C=CC=CC=1>[O:18]1[CH2:17][CH:16]1[CH2:14][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCC1CO1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(OCC2CO2)cc1
Yield: 59.9 %

Procedure:
A mixture of 9.4 gm (0.1 mole) of phenol, 28 gm (0.2 mole) of potassium carbonate and 30 mL (0.4 mole) of epichlorohydrin in 250 mL acetone was heated to reflux for 12 hours. The reaction medium was then filtered and evaporated leaving an oil which was taken up in toluene and successively washed with 100 mL water, 2×100 mL 1.0 N sodium hydroxide and 2×100 mL water. The toluene phase was dried with magnesium sulfate and evaporated to provide a clear oil which was chromatographed on a Prep-500 silica gel column employing hexane: ethyl acetate (9:1) as the mobile phase. Collection of the major peak and evaporation of solvent provided 9 gm (60%) of a clear oil whose NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].Cl.Cl.CC1(C)C2C(=NC=CC=2)N(C2CCNCC2)C1=O.Cl[C:41]1[N:50]=[CH:49][C:48]2[C:43](=[CH:44][C:45]([Cl:51])=[CH:46][CH:47]=2)[N:42]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:51][C:45]1[CH:44]=[C:43]2[C:48]([CH:49]=[N:50][C:41]([N:15]3[CH2:16][CH2:17][CH:12]([N:5]4[C:6]5=[N:7][CH:8]=[CH:9][N:10]=[C:11]5[C:3]([CH3:19])([CH3:2])[C:4]4=[O:18])[CH2:13][CH2:14]3)=[N:42]2)=[CH:47][CH:46]=1
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Reactant: Clc1ccc2cnc(Cl)nc2c1
Agent: CC1(C)C(=O)N(C2CCNCC2)c2ncccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)C(=O)N(C2CCN(c3ncc4ccc(Cl)cc4n3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 76.1 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.150 g, 0.530 mmol, Intermediate 57), 2,7-dichloroquinazoline (0.127 g, 0.637 mmol), and potassium carbonate (0.257 g, 1.857 mmol) in DMSO (3 mL) was heated at 110° C. in 2 h. The reaction mixture was cooled, H2O was added, and the solid was collected, purified by ISCO (30% EtOAc/Hexanes) to give the title compound (165 mg, 76%). MS (M+1): 409. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.25 (1 H, s), 8.08 (1 H, d, J=3.1 Hz), 8.12 (1 H, d, J=3.1 Hz), 7.89 (1 H, d, J=8.6 Hz), 7.54 (1 H, d, J=1.8 Hz), 7.29 (1 H, dd, J=8.6, 2.0 Hz), 5.02 (2 H, d, J=13.3 Hz), 4.60 (1 H, tt, J=12.2, 4.0 Hz), 2.92-3.15 (2 H, m), 2.42 (2 H, qd, J=12.6, 4.4 Hz), 1.82 (2 H, d, J=9.8 Hz), 1.32 (6 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][C:3]=1[O:20]C.B(Br)(Br)Br.CC[O:28]C(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:17]([C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]([OH:28])=[O:19])=[O:18])=[CH:4][C:3]=1[OH:20]
Reactant: CCOC(C)=O
Reactant: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)NCc1ccc(Cl)c(O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
2-{[4-Chloro-3-(methyloxy)phenyl]methyl}-1H-isoindole-1,3(2H)-dione (7.0 g, 23 mmol) was dissolved in CH2Cl2 (25 mL) and cooled to 0° C. Boron tribromide (1.0 M sol., 46 mL) was added slowly then the solution was warmed to RT and stirred for 4 h. The reaction was cooled to 0° C. and ice water (100 mL) and EtOAc (200 mL) were added. The aqueous layer was separated and extracted with EtOAc (2×200 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. The solid was dissolved in EtOAc and washed with 1N NaOH. The aqueous layers were combined, acidified with 10% citric acid and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (3.0 g, 42%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.87 (br. s., 1H), 10.06 (s, 1H), 8.82 (t, 1H), 7.74 (d, 1H), 7.56 (dd, 1H), 7.47-7.54 (m, 1H), 7.45 (d, 1H), 7.23 (d, 1H), 6.94 (d, 1H), 6.80 (dd, 1H), 4.30 (d, 2H). MS: m/z 306.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Yield: 99.8 %

Procedure:
To a solution of 19.89 g of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid, ethyl ester in 200 ml of 3A ethanol was added 12.5 ml of 10N sodium hydroxide. This mixture was refluxed on a steam bath for 3 hours and then allowed to evaporate. The residue was taken up in water and treated with 10.4 ml of concentrated hydrochloric acid. The resulting solid was collected and dried, giving 18.11 g of the desired product, mp 311°-317° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[N:10]1([CH2:15][CH:16]([N:18]2[C:31]3[CH:30]=[C:29]([C:32](=[S:34])N)[CH:28]=[CH:27][C:26]=3[S:25][C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.S>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:32]([C:29]1[CH:28]=[CH:27][C:26]2[S:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:16]([CH3:17])[CH2:15][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:31]=2[CH:30]=1)=[S:34]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: Cc1ccccc1CN
Agent: S
Solvent: CCO
Product: Cc1ccccc1CNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 20 h

Procedure:
2-Methylbenzylamine (6.0 cc) is added to a solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (3.70 g) in absolute ethanol (50 cc). The mixture is saturated with hydrogen sulphide and brought to 110° C. for 20 hours. After cooling to 20° C., the mixture is concentrated to dryness under reduced pressure (30 mm Hg, 4 kPa) at 40° C. and the residue is purified by chromatography on a column (height: 22 cm; diameter: 4.2 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with pure ethyl acetate (400 cc) and then with a 90:10 (by volume) mixture (400 cc) of ethyl acetate and methanol and collecting 80-cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give N-(2-methylbenzyl)-10- [(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2.6 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: COC1N=C2C(=CC=1)N[C@@H](C)C[C@H]2NC(=O)C.[CH3:18][C@H:19]1[CH2:28][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[N:25]=2)[NH:20]1.Cl[C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH:41]([O:40][C:38]([N:20]1[C:21]2[C:26](=[N:25][C:24]([C:33]([F:34])([F:36])[F:35])=[CH:23][CH:22]=2)[C@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH2:28][C@@H:19]1[CH3:18])=[O:39])([CH3:43])[CH3:42]
Reactant: CC(=O)N[C@@H]1C[C@H](C)Nc2ccc(C(F)(F)F)nc21
Reactant: CC(C)OC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Yield: 68 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 46, Step 2, by replacing (+/−)-cis-N-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide, with (+/−)-cis-N-(2-methyl-6-trifluoromethyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide (0.140.g, 0.512 mmol), and using isopropyl chloroformate, pyridine, and dimethylaminopyridine. Purify using silica gel column chromatography (gradient eluent, 0-5% MeOH in ethyl acetate) to provide the title compound (0.123 g, 68%). MS (ES+): 360 (M+H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.N12CCN(CC1)CC2.[NH2:15][C:16]1[C:25](I)=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:27])[N:17]=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[C:25]2[CH:4]=[C:2]([C:1]([OH:6])=[O:5])[NH:15][C:16]2=[N:17][C:18]=1[CH3:27])=[O:21]
Reactant: COC(=O)c1cc(I)c(N)nc1C
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(C(=O)O)[nH]c2nc1C
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
Under argon, pyruvic acid (6.90 ml, 100.1 mmol) and 1,4-diazabicyclo[2.2.2]octane (11.2 g, 100.1 mmol) were added to a solution of methyl 6-amino-5-iodo-2-methylnicotinate (9.00 g, 30.8 mmol) in N,N-dimethylformamide (88 ml), and the flask was evacuated and flushed with argon. Argon was subsequently passed through the solution for 5 min, palladium(II) acetate (0.345 g, 1.54 mmol) was then added and the mixture was heated at 100° C. for 2 h. The cooled solution was filtered through Celite and the dimethylformamide was distilled off. The residue was then taken up in water and acidified with hydrochloric acid, giving a solid (6.3 g, 86% of theory). HPLC-MS: log P=1.26; mass (m/z): 235.0 (M+H)+; 1H-NMR (DMSO) 2.79 (s, 3H), 3.85 (s, 3H), 7.19 (s, 1H), 8.62 (s, 1H), 12.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:24].N1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:15]([F:21])[C:3]=1[C:4]1[S:24][C:7]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:6]=2[N:5]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(F)c(C(Cl)=Nc2ccnc(Cl)c2F)c(Cl)c1
Reactant: NC(N)=S
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: c1ccncc1
Product: N#Cc1cc(F)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A mixture of 2-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-4-cyano-6-fluorobenzimidoyl chloride (0.713 g, 2.05 mmol), thiourea (0.623 g, 8.2 mmol) and pyridine (538 μL, 6.66 mmol) in isopropanol (7 mL) was heated under reflux for 3 hours. The reaction mixture was allowed to cool to ambient temperature before adding triethylamine (1.7 mL, 12.3 mmol). The resulting mixture was heated under reflux for a further 3 hours and allowed to cool. The mixture was concentrated under reduced pressure and the residue was partitioned between DCM and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (0-10% EtOAc in pentane) to give the desired compound as an off-white solid (0.356 g, 53% yield). 1H NMR (300 MHz, CDCl3): δ 8.55 (d, J=5.6 Hz, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.72 (t, J=1.4 Hz, 1H), 7.52 (dd, J=8.3, 1.5 Hz, 1H). LCMS (Method D): RT=3.86 min, m/z: 324 [M+H+].