Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:6]=[CH:7][N:8]=1.[F-:13].[Cs+].Cl>CS(C)=O>[F:13][CH2:2][C:3]1[C:4]([C:9]([O:11][CH3:12])=[O:10])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: COC(=O)c1nccnc1CCl
Reactant: [F-]
Agent: Cl
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1nccnc1CF
Temperature: 140 °C
Yield: 9.2 %

Procedure:
Methyl 3-chloromethylpyrazine-2-carboxylate (1.55 g, 8.3 mmol) was dissolved in DMSO (30 ml), followed by adding cesium fluoride (2.52 g, 16.6 mmol) and hexamethyl triamidophosphate (0.3 ml) and heated at 140° C. for 40 minutes while stirring. The reaction solution was cooled, followed by pouring into a diluted HCl solution, extracting with ethyl acetate, and washing with water. The solution was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 0.13 g of the desired compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:24])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CN(C=O)C>[CH3:22][N:21]([CH3:23])[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:4]2[C:5](=[O:13])[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[C:3]2=[O:24])=[CH:16][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: CN(C)c1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3ccc(N(C)C)cc3)C2=O)cc1
Temperature: 150 °C
Yield: 12.9 %

Procedure:
3-Chloro-1-[4-(dimethylamino)benzyl]-4-phenyl-1H-pyrrole-2,5-dione (0.20 mmol, 68 mg) and 4-methoxyaniline (0.48 mmol, 59 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 11 mg (13%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.38-7.34 (m, 2H), 7.15 (bs, 1H), 7.13-7.04 (m, 3H), 6.97 (m, 2H), 6.70 (d, 2H), 6.60-6.51 (m, 4H), 4.67 (s, 2H), 3.69 (s, 3H), 2.93 (s, 6H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:2][CH2:3][CH2:4][C:5]2[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(CCN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
A suspension of 11.5 g. (50 mMol) ethyl 4-(2-aminoethyl)-benzoate hydrochloride (J.A.C.S., 65, 2281, 2284/1943) and 12.65 g. (125 mMol) triethylamine in 150 ml. methylene chloride is stirred for 30 minutes at ambient temperature, cooled to 0° C. and a solution of 11.55 g. (50 mMol) 4-chlorobenzenesulphonic acid chloride in 50 ml. methylene chloride slowly added dropwise thereto. After ending of the reaction, the reaction mixture is extracted twice with dilute hydrochloric acid, washed with water and the organic phase then dried over anhydrous sodium sulphate. After evaporation of the solvent, there are obtained 11.4 g. (62% of theory) of colourless crystals; m.p. 88° C., after recrystallisation from ethanol.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]=[C:21]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH2:25][O:24][C:23]4[CH:33]=[CH:34][CH:35]=[CH:36][C:22]3=4)[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].[Cl:39]CCl.Cl>C(O)C>[ClH:39].[CH:29]1[C:28]2[C:21](=[CH:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:7]4[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:17][CH2:16]3)[C:22]3[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=3[O:24][CH2:25][O:26][C:27]=2[CH:32]=[CH:31][CH:30]=1
Reactant: ClCCl
Reactant: CCOC(=O)c1cccnc1N1CCN(CCC=C2c3ccccc3OCOc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccnc1N1CCN(CCC=C2c3ccccc3OCOc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A mixture of the above ester (0.99 g, 2 mmol) and 20% sodium hydroxide (1.5 ml) in ethanol (13 ml) was stirred at room temperature for 4 h. The mixture was poured into dichloromethane (100 ml), acidified with 2 N hydrochloric acid and washed with water (10 ml). The organic solution was dried (MgSO4) and activated charcoal was added. The mixture was stirred for 10 minutes, filtered and the solvent was removed in vacuo. The residue was triturated with acetone and the solid product was overlaid with ethyl acetate, stirred for 15 minutes, filtered off and washed with ethyl acetate. After drying, the title compound (0.80 g, 74%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[CH2:14](O)[CH2:15][CH2:16]O.C(P(CCCC)CCCC)CCC>COCCOC.[Ru](Cl)(Cl)Cl>[CH3:12][C:7]1([CH3:13])[O:8][C:9]2=[CH:10][C:11]3[CH:14]=[CH:15][CH:16]=[N:1][C:2]=3[CH:3]=[C:4]2[CH:5]=[CH:6]1
Reactant: CC1(C)C=Cc2cc(N)ccc2O1
Reactant: OCCCO
Agent: Cl[Ru](Cl)Cl
Agent: CCCCP(CCCC)CCCC
Solvent: COCCOC
Product: CC1(C)C=Cc2cc3ncccc3cc2O1
Temperature: 180 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Under nitrogen atmosphere, to a solution of 6-amino-2,2-dimethylchromene (3.88 g, 22.1 mmol) and ruthenium trichloride (55.0 mg, 0.265 mmol) in dimethylene glycol dimethyl ether (8 mL), 1,3-propanediol (0.639 mL, 8.84 mmol) and tri-n-butyl phosphine (0.132 mL, 0.530 mmol) were added at room temperature, and the resulting mixture was stirred at 180° C. for 5 hours. Upon the completion of the reaction, ruthenium complex was removed by florisil column, and solvent was distilled off. The residue was purified by medium pressure column chromatography (hexane/ethyl acetate=5/1) and the aimed product was obtained (yield: 59%).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH:25]=O>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH2:25][NH:6][CH3:5]
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: Cn1cc(C=O)c2cc(Cl)ccc21
Product: CNCc1cn(C)c2ccc(Cl)cc12
Yield: 93 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 5-chloro-1-methyl-1H-indole-3-carboxaldehyde for the ,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.1 g, 93%) was obtained as an amber oil: MS (ES) m/e 209.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C@H:11]([CH2:19][C:20]#[CH:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([O:33][CH2:34][CH2:35][N:36]=[N+:37]=[N-:38])(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C>O1CCCC1.[Cu]I>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C@H:11]([CH2:19][C:20]1[N:38]=[N:37][N:36]([CH2:35][CH2:34][O:33][S:30]([CH3:29])(=[O:32])=[O:31])[CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Reactant: C#CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCOS(C)(=O)=O)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-prop-2-yn-1-yl-L-glutamate (60 mg, 151 μmol) and 2-azidoethyl methanesulfonate (37.4 mg, 226 μmol) were dissolved in tetrahydrofuran (4 ml). To the solution, copper(I) iodide (2.9 mg, 15 μmol) and N,N-diisopropylethylamine (32 μl, 181 μmol) were added and the mixture was stirred for 18 h at room temperature. The mixture was then concentrated in vacuo and the residue was purified by preparative reversed phase HPLC. The product fractions were collected, lyophilized, and purified again by silicagel chromatography to yield 50 mg (47%) of the product.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=2)[CH:4]=1.[S:27]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])(=[O:29])[NH2:28]>>[S:27]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:34]=[CH:35][CH:36]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(F)c4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-fluoro-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.16) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 528.0 [(M−H)−]; mp 262° C.
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:36])(=[O:35])[NH:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH:32]1([CH2:31][NH:30][S:29]([C:26]2[CH:27]=[CH:28][C:20]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:21]([CH:25]=2)[C:22]([OH:24])=[O:23])(=[O:36])=[O:35])[CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1Cl
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1N1CCOCC1
Yield: 33 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(cyclopropylmethyl-sulfamoyl)-benzoic acid and morpholine and obtained in 33% yield.
Reaction SMILES: C([O:4][CH:5]([CH3:32])[C:6]([NH:8][C:9]1[C:10]([I:31])=[C:11]([C:17]([I:30])=[C:18]([NH:21][C:22](=[O:29])[CH:23]([O:25]C(=O)C)[CH3:24])[C:19]=1[I:20])[CH2:12]CC([O-])=O)=[O:7])(=O)C.[OH-:33].[Na+].Cl>CO.O>[OH:4][CH:5]([CH3:32])[C:6]([NH:8][C:9]1[C:10]([I:31])=[C:11]([C:17]([I:30])=[C:18]([NH:21][C:22](=[O:29])[CH:23]([OH:25])[CH3:24])[C:19]=1[I:20])[CH2:12][OH:33])=[O:7]
Reactant: CC(=O)OC(C)C(=O)Nc1c(I)c(CCC(=O)[O-])c(I)c(NC(=O)C(C)OC(C)=O)c1I
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)C(=O)Nc1c(I)c(CO)c(I)c(NC(=O)C(C)O)c1I
Reaction time: 15 h
Yield: 46 %

Procedure:
N,N'-Bis(2-acetoxypropionyl)-3,5-diamino-2,4,6-triiodobenzylacetate (0.16 g, 0.2 mmol) was dissolved in a mixture of methanol (5 ml) and water (5 ml) and the pH was adjusted to 12 using a 1M aqueous solution of NaOH. After stirring for 15 h, the solution was neutralized with 1M HCl and the solvents were removed by evaporation. Purification by preparative HPLC gave 61 mg (46%) of the pure product.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[N+:18]([C:21]1[CH:31]=[CH:30][C:24]([CH2:25][O:26][C:27](Cl)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][O:26][C:27]([N:4]([CH:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]2)[CH2:1][CH2:2][CH3:3])=[O:28])=[CH:30][CH:31]=1)([O-:20])=[O:19]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCCNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCNCC1

Procedure:
The title compound was prepared by the reaction of 4-(N-(prop-1-yl)amino)-1-tert-butoxycarbonylpiperidine (from Example 17, Step A) with (4-nitrobenzyl)chloroformate, followed by treatment of the product with 50% TFA in CH2Cl2 to remove the tert-butoxycarbonyl group, affording the title compound. ESI-MS: 322.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]=[C:8]=[S:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19].COC1C=C(C=CC=1)CNC(N)=S>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][NH:7][C:8]([NH:19][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH3:13])[CH:16]=1)=[S:9]
Reactant: COc1cccc(CN=C=S)c1
Reactant: COc1cccc(CN)c1
Agent: COc1cccc(CNC(N)=S)c1
Solvent: CCO
Product: COc1cccc(CNC(=S)NCc2cccc(OC)c2)c1
Temperature: 40 °C

Procedure:
The reaction of 3-methoxybenzyl isothiocyanate with 3-methoxybenzyl amine in ethanol was repeated doubling the reaction volume and reactants and heating for 2 h at 40° C. Crystallization at −10° C., followed by evaporation of the supernatant to 20 ml and a second crystallization gave 98.4% of the theoretical yield for the two crystallizations combined. Calculated elemental analysis of 3-methoxybenzyl thiourea: C, 64.53; H, 6.37; N, 8.85; S, 10.13. Found: C, 64.30; H, 6.46; N, 8.85; S, 10.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][N:9]=[C:8]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:23]=1.C(Cl)Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][N:9]=[C:8]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:23]=1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CN=C2C#Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)N(C)C(=O)CN=C2CCc1ccccc1
Yield: 5 %

Procedure:
Stir a mixture of 80 mg (0.24 mmol) of 7,8-dimethoxy-1-methyl-5-(2-phenylethynyl)-1,3-dihydro-1,4-benzodiazepin-2-one 132, 15 mg of 10% Pd/C by weight in 5 ml of MeOH and 5 ml of CH2Cl2 under 70 psi of H2 for 48 hours. Filter the suspension on celite, rinse three times with 10 ml of MeOH. Evaporate to dryness and purify by silica chromatography (AcOEt 1/hexane 1, then AcOEt). Yield: 5%. M: 112–115° C. 1H-NMR (CDCl3, 300 MHz): d 2.95–3.07 (m, 4H, CH2CH2), 3.28 (s, 3H, NCH3), 3.87 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.10 (AB system, ? d=0.96, JAB=10.2, 2H, CH2), 6.67 (s, 1H Ar), 6.78 (s, 1H Ar), 7.15–7.25 (m, 5H Ar). Mass: (M+H)+=339.15
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[CH3:11][O:12][CH2:13][CH2:14]Cl>>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][O:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1ccc(O)cc1Br
Reactant: COCCCl
Product: CCOCOc1ccc(CC)c(Br)c1

Procedure:
In a manner similar to that of Example 1(e), by reacting 13 g (65 mmol) of 3-bromo-4-ethylphenol with 6.7 ml (72 mmol) of methoxyethyl chloride, and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (90/10), 12 g (76%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]([O:38]CC)=[CH2:37])=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C(=O)N([Br:50])C(=O)C1>C1COCC1.O>[N+:1]([C:4]1[CH:42]=[CH:41][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36](=[O:37])[CH2:38][Br:50])=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1cc(C#N)nc2cc(Cn3cc([C@](CC)(OC(=O)c4ccc([N+](=O)[O-])cc4)C(F)(F)F)nn3)ccc12
Solvent: O
Solvent: C1CCOC1
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(C(=O)CBr)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-1-(1-{[2-cyano-4-(1-ethoxyvinyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (593 mg, 1.05 mmol) in THF (4 ml) and water (0.25 ml) was added NBS (205 mg, 1.16 mmol). The mixture was stirred at room temperature for 30 min. The solution was then evaporated to dryness and purified by flash chromatography (eluting solvent: 3% acetone in dichloromethane) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.55 (s, 1H), 8.50 (s, 1H), 8.40 (d, 2H), 8.37 (d, 1H), 8.30 (d, 2H), 8.07 (s, 1H), 7.85 (d, 1H), 6.05 (s, 2H), 5.05 (s, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 1.15 (t, 3H).
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)[CH2:10][NH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:27][O:28][C:29]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:27][O:28][C:29]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:30]=1[C:31]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][NH:9][C:8]2=[O:17])[CH2:5][CH2:6]1)=[O:32]
Reactant: O=C1NCc2ccccc2N1C1CCNCC1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2CCC(N3C(=O)NCc4ccccc43)CC2)c(OC)c1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one (680 mg, 1.40 mmol) from Step 5 in DCM (15 mL) was added DIEA (0.366 mL, 2.1 mmol) followed by 2,4-dimethoxybenzoyl chloride (309 mg, 1.54 mmol). The reaction was stirred for 2 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 5% aqueous citric acid (50 mL) and saturated aqueous NaHCO3 (2×50 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography eluting first with 95:5 EtOAc:CHCl3 and then with 95:3:2 EtOAc:CHCl3 :MeOH. The title compound was obtained as a white solid (77% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16](=[O:23])[C:17]3[NH:18][CH:19]=[N:20][C:21]=3[N:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[NH:15][C:16](=[O:23])[C:17]3[N:18]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:19]=[N:20][C:21]=3[N:22]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3nc[nH]c3c(=O)[nH]2)CC1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(6-oxo-6,7-dihydro-1H-purin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester, 3 (1 g), potassium carbonate and dimethylforamide was stirred at room temperature for 2 h, then the solution of ClCH2COOEt (0.38 g/5 mL dimethylforamide) was added drop-wise into the reaction mixture, After stirring for 15 h, the solution was then partitioned between ethyl acetate and water. The ethyl acetate solution was washed with water, then it was dried over sodium sulfate and filtered, evaporated under reduced pressure, and purification of the residue by use of column chromatography to give 4.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].[NH2:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][C:27]([F:30])([F:29])[F:28])[N:19]=1>ClCCCl>[CH3:25][O:24][C:22]1[N:21]=[C:20]([O:26][C:27]([F:30])([F:28])[F:29])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:12])=[O:13])=[O:16])[N:23]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(OC(F)(F)F)n1
Solvent: ClCCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC(F)(F)F)n1
Temperature: 22 °C
Reaction time: 12 h

Procedure:
3.6 g (0.015 mol) of 2-carbomethoxybenzenesulfonyl isocyanate in 4 ml of 1,2-dichloroethane were added over the course of 5 minutes to a stirred mixture of 3.15 g (0.015 mol) of 2-amino-4-methoxy-6-trifluoromethoxy-1,3,5-triazine and 150 ml of 1,2-dichloroethane at 22° C., and the mixture was stirred at 22° C. for 12 hours. It was then concentrated under reduced pressure and crystallized using 1:1 methyl tert-butyl ether/petroleum ether, and the product was filtered off with suction and washed with petroleum ether to yield 5.1 g (75.4% of theory) of the title compound of melting point 149° C. (decomposition).
Reaction SMILES: C1(NC(N)=S)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[CH3:29])=[S:20])=[C:14]([OH:30])[C:13]=1[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32].[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].N1C=CN=C1>>[CH3:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([S:31]([N:34]([CH3:35])[CH3:36])(=[O:32])=[O:33])[C:14]=1[O:30][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[S:20]
Reactant: Cc1c(F)cccc1NC(=S)Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: NC(=S)Nc1ccccc1
Agent: c1c[nH]cn1
Product: Cc1c(F)cccc1NC(=S)Nc1ccc(Cl)c(S(=O)(=O)N(C)C)c1O[Si](C)(C)C(C)(C)C
Yield: 49 %

Procedure:
Following the general procedure for protected phenyl thiourea formation outlined in example 12, N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-methyl-3-fluorophenyl)thiourea (530 mg, 1.27 mmol), tert-butyldimethylsilyl chloride (951 mg, 6.35 mmol) and imidazole (173 mg, 2.54 mmol) were reacted to form the desired product (331 mg, 49%). EI-MS m/z 532.2 (M+).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[CH:37]=[CH:36][C:27]([C:28]([NH:30][C:31]([CH2:34][CH3:35])([CH3:33])[CH3:32])=[O:29])=[CH:26][N:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:25]([O-:9])=[CH:26][C:27]([C:28]([NH:30][C:31]([CH3:33])([CH3:32])[CH2:34][CH3:35])=[O:29])=[CH:36][CH:37]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: CCC(C)(C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC(C)(C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(tert-pentyl)nicotinamide (Intermediate 32, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylpropyl)-3-pyridinecarboxamide 1-oxide as a white solid.