Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[F:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[Na+]>C(O)CCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:2][C:3]2[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=2[F:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: Fc1ccc(F)c(CBr)c1
Agent: [Na+]
Solvent: CCCCO
Product: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1

Procedure:
Process 3: After addition of 2-bromomethyl-1,4-difluorobenzene (12.3 ml, 95.5 mmol) to a suspension of sodium 4-chlorobenzenesulfinate (19.0 g, 95.5 mmol) in butanol (200 ml), the mixture was heated under reflux for 5 hours. The solid thus precipitated was collected by filtration and dissolved in methylene chloride. The resulting solution was washed with brine, dried over MgSO4, and concentrated. The solid thus obtained was recrystallized from hexane, whereby the title compound (12.3 g, 43%) was obtained as colorless needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O.[Cl-].[Na+].O>[CH2:19]([N:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:11]1=[O:12])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)C(=O)NCCC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCCc2ccc(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A solution of 8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (10.0 g 0.052 mol) in N,N-dimethylformamide (30 mL) and allylbromide (23 mL, 0.260 mL) was treated with NaH (60% by wt. dispersion in oil, 2.50 g, 0.063 mol) and the resulting grey suspension stirred at room temperature under an atmosphere of argon. Gas evolution was noted. After 15 minutes, the solution was diluted with brine and partitioned between ethyl acetate and brine. The combined organic layers were concentrated in vacuo and purified by chromatography over silica gel eluting with a gradient of hexane to 1:1 ethyl acetate/hexane to yield 8 g (83%) of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil: 1H NMR(CDCl3) d7.23(m, 1H), 7.03(d, J=9 Hz, 1H), 6.90(dd, J=3, 9 Hz, 1H), 5.91(m, 1H), 5.23(m, 2H), 4.20(d, J=6 Hz, 2H), 3.82(s, 3H), 3.18(t, J=6 Hz, 2H), 2.72(t, J=6 Hz, 2H), 1.96(pentet, J=6 Hz, 2H); 13C NMR(CDCl3) d170.59(CO), 158.42(NCO), 136.88, 133.81, 129.43, 129.35, 129.33, 117.56, 117.54, 112.98, 55.26, 49.43, 45.37, 29.57, 29.22; MS(FAB) m/z=232.1(MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19](=[O:31])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH2:14][CH2:13]3)[C:7]=1[C:8]#[N:9].[CH3:32][NH:33][NH2:34]>C(O)C>[CH3:32][N:33]1[C:2]2=[CH:3][N:4]=[CH:5][C:6]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([C:19](=[O:31])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:14][CH2:13]4)=[C:7]2[C:8]([NH2:9])=[N:34]1
Reactant: CNN
Reactant: N#Cc1c(Cl)cncc1-c1ccc2c(c1)CCN2C(=O)Cc1cccc(C(F)(F)F)c1
Solvent: CCO
Product: Cn1nc(N)c2c(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)cncc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To 3-chloro-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-4-pyridinecarbonitrile (80 mg, 0.181 mmol) was added Methyl hydrazine (0.286 mL, 5.43 mmol) to a 5 mL sealable vial with Ethanol (3 mL). The reaction was then capped and heated at 100° C. overnight. Observed incomplete conversion. Additional Methyl hydrazine (0.286 mL, 5.43 mmol) was added and heating was continued overnight. The reaction was concentrated, dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 17% ACN/H2O, 0.1% TFA to 42% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and the mixture was extracted with EtOAc (3×15 mL). The organics were combined, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was transferred into a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 1-methyl-4-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-c]pyridin-3-amine (34 mg, 41.6% yield) as a light yellow solid. LC/MS (ES) m/z=452.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.17 (d, J=8.34 Hz, 1H), 7.94 (s, 1H), 7.69 (s, 1H), 7.56-7.66 (m, 3H), 7.43 (s, 1H), 7.32 (d, J=8.08 Hz, 1H), 4.67 (br. s., 2H), 4.30 (t, J=8.46 Hz, 2H), 4.05 (s, 2H), 3.92 (s, 3H), 3.29 (t, 2H).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-(trifluoromethyl)phenyl boronic acid. The title compound was obtained in 52% yield as yellow foam. MS (m/e): 550.2 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:26]1([CH:29]=[CH:30]B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:30]=[CH:29][CH:26]2[CH2:28][CH2:27]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(C=CC2CC2)OC1(C)C
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=CC2CC2)Cc2ccccc2C1
Yield: 47.9 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (600 mg, 1.34 mmol) and 2-(2-cyclopropyl-vinyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.11 mL, 5.36 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0), (4.84% Pd, 285 mg, 0.13 mmol) and 2M aqueous solution of K2SO4 (2.68 mL, 5.36 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (137) as white solid (250 mg, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([OH:22])=[N:10]2)=[CH:5][CH:4]=1.Cl.Cl[CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([O:22][CH2:25][C:26]3[N:27]=[CH:28][S:29][CH:30]=3)=[N:10]2)=[CH:7][CH:8]=1
Reactant: ClCc1cscn1
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Agent: Cl
Product: COc1ccc(-c2nc(OCc3cscn3)nn2-c2ccc(OC)cc2)cc1
Yield: 49.7 %

Procedure:
1,5-bis(4-methoxyphenyl)-3-(1,3-thiazol-4-ylmethoxy)-1H-1,2,4-triazole (132 mg, 49.7% yield) was prepared from 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol and 4-(chloromethyl)-1,3-thiazole hydrochloride by the similar manner described for Example 18.
Reaction SMILES: [CH3:1][CH:2]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:20]=O>C(O)=O>[CH3:20][N:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)NCCCCc1ccccc1
Reactant: C=O
Solvent: O=CO
Product: CCCCCCC(C)N(C)CCCCc1ccccc1

Procedure:
4-Phenylbutyryl chloride was reacted with 1-methylheptylamine to provide N-(1-methylheptyl)-4-phenylbutyramide, which, when reduced by reaction with diborane in tetrahydrofuran, provided N-(1-methylheptyl)-4-phenylbutylamine. The amine so formed was reacted with formic acid and formaldehyde to give N-methyl-N-(1-methylheptyl)-4-phenylbutylamine.
Reaction SMILES: BrC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([NH:43][C:44]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[C:27]([F:33])[CH:28]=1)=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccccc1Br
Agent: O=C(N=C=S)c1ccccc1Br
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Br)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
2-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 83%).
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:17][CH3:18])[C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19]C(N)=S>CN(C)C=O>[C:2]1([C:1]2[O:9][C:10]([CH2:17][CH3:18])=[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(OC(=O)c1ccccc1)C(=O)C(C)(C)C
Reactant: NC(N)=S
Solvent: CN(C)C=O
Product: CCc1oc(-c2ccccc2)nc1C(C)(C)C
Temperature: 160 °C

Procedure:
0.31 g of 1-ethyl-3,3-dimethyl-2-oxobutyl benzoate is dissolved in 8 ml of dimethylformamide in a reactor. 0.75 g of thiourea (5 eq.) is subsequently added and the reaction mixture is left to react at reflux (160° C.) for 6 hours. The reaction mixture is extracted with dichloromethane and then washed 3 times with water, dried over anhydrous sodium sulphate, filtered and finally brought to dryness under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccc(OC)cc4nc3OC)CC2)c1
Yield: 86 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 86%). MS(ESI) m/z 454 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:12](O)=O>>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Reactant: O=CO
Product: Cc1ccc2c(=O)[nH]cnc2c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 2-amino-4-methylbenzamide (20 g, 133 mmol) and formic acid (120 ml, 3129 mmol) was heated to 100° C. After 6 hours, the reaction was cooled down to RT and the volatiles were removed under reduced pressure. The residue was then washed carefully with aqueous saturated sodium bicarbonate and then with water. The tan solid was then dried in a vacuum oven at 45° C. overnight to give 7-methylquinazolin-4(3H)-one. MS (M+H)+ 161.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]2[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O)#[N:2].C(=O)([O-])[O-].[K+].[K+].O.[NH2:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[NH2:33][C:34]1[CH:39]=[C:38]([C:8]2[CH:7]=[CH:6][C:5]([C:17]3[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=3)=[CH:4][C:3]=2[C:1]#[N:2])[CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)s1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(-c3cccc(N)c3)c(C#N)c2)s1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A toluene (0.5 ml) suspension of 20 mg of methyl 5-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)thiophene-2-carboxylate and 10 mg of potassium carbonate was added to 15 mg of 3-aminobenzeneboronic acid monohydrate, and in an argon atmosphere, 8 mg of tetrakis(triphenylphosphine)palladium was added thereto. The mixture was stirred overnight at 100° C., then cooled to room temperature, and filtered through Celite. The solvent was evaporated under reduced pressure to obtain methyl 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:8]1([C:6]2[N:5]=[C:4]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[C:2]([S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)CNc1cc(Cl)nc(-c2ccccc2)n1
Product: CCOC(=O)CNc1cc(Sc2ccccc2)nc(-c2ccccc2)n1

Procedure:
A mixture of the above prepared N-(6-chloro-2-phenyl-4-pyrimidinyl)-glycine, ethyl ester is reacted with thiophenol, as in Example X, to afford N-(2-phenyl-6-phenylthio-4-pyrimidinyl)-glycine, ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:15])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2Cl)=[O:4].[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([OH:26])=[CH:21][CH:20]=2.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:15])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2[O:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:16])=[CH:25]2)=[O:4]
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COC(=O)c1cn2ncnc(Cl)c2c1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cn2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.7 %

Procedure:
To a stirred solution of 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (0.5 g, 2.22 mmol) and 2-methyl-5-hydroxyindole (424 mg, 2.9 mmol) under argon in acetonitrile (10.0 mL) was added triethylamine (6.65 mmol, 0.93 mL). After stirring the mixture at room temperature for 17 h. solvent was removed under vacuum and the residue was chromatographed on silica gel eluting with 20-30% ethyl acetate (gradient) in hexanes. The solvent was removed in vacuo to obtain 5-methyl-4-(2-methyl-1H-indol-5-yloxy)-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester as a white solid (0.58 g, 85%). LC/MS; (M+H)+=337.2
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1I
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1I
Temperature: 80 °C
Yield: 99 %

Procedure:
2-(2-Iodophenyl)acetic acid (5.00 g, 19.1 mmol) was placed into a reaction flask and dissolved in MeOH (150 mL). Sulfuric acid (250 μL) was added and reaction mixture was stirred and heated at 80° C. under nitrogen for 16 hours. The resulting mixture was cooled to room temperature and the volatiles removed by evaporation under reduced pressure. The residue was taken up in ethyl acetate (100 mL), washed with 10% NaHCO3 (100 mL), dried (MgSO4) and evaporated under reduced pressure to give the title compound (I9) (5.20 g, 99%) as a clear liquid; 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J=7.9, 1.0 Hz, 1H), 7.35-7.27 (m, 2H), 6.97 (ddd, J=7.9, 7.0, 2.1 Hz, 1H), 3.81 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][N:9]=[C:10]2[CH2:17][CH:16]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I.O>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[N:9]=[C:10]2[CH2:17][CH:16]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CC(=NNc1cccc(Br)n1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(N=C1CC2CCCC(C1)N2C(=O)OC(C)(C)C)c1cccc(Br)n1
Reaction time: 0.5 h
Yield: 103.8 %

Procedure:
tert-Butyl 3-(2-(6-bromopyridin-2-yl)hydrazono)-9-azabicyclo[3.3.1]nonane-9-carboxylate (609 mg, 1.49 mmol) was dissolved in DMF, and NaH (60%, 65 mg, 1.63 mmol) was added. After 30 min, MeI (232 mg, 1.63 mmol, 102 μL) was added, and stirring continued for 30 min. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was concentrated to provide the crude product (655 mg, >100%) as a red oil: ESI MS m/z 423 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH3:5].[CH2:17]([OH:20])[CH2:18][OH:19]>O>[CH3:1][O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:19][CH2:18][CH2:17][OH:20])=[O:15])=[CH:9][CH:8]=1)[CH3:5]
Reactant: OCCO
Reactant: COC(=O)C(C)Oc1ccc(N=C=O)cc1
Solvent: O
Product: COC(=O)C(C)Oc1ccc(NC(=O)OCCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Isocyanatophenoxy)-propionic acid methyl ester 11 (20 g, 90.49 mmol) was added to ethylene glycol (40 ml) at room temperature. The reaction was exothermic and the temperature rose to 58° C. This was followed by stirring at room temperature for 16 hours. Water (150 ml) was added and crude 12 was extracted in to chloroform, washed with water (2×50 ml), dried over sodium sulphate and distilled. Crude 12 was purified by column chromatography on silica gel using chloroform as eluant to get pure 12 (13 g; 50.76%) as a syrup which crystallized in 48 hours as a white powder with an m.p between 90.5-92.8° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>C(O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cccc(CN)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Solvent: CCO
Product: COc1cccc(CNc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.1 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methoxybenzylamine (37 μl, 0.290 mmol) in 10 ml of ethanol was stirred at room temperature for 48 h. The mixture was rotary evaporated to dryness and purified by preparative TLC with hexane:ethyl acetate (3:1) to give a yellow solid (14 mg, 20%). 1H NMR (CDCl3): 9.60-9.59 (m, 1H), 8.70-8.66 (m, 2H), 7.40-7.32 (m, 1H), 7.30 (d, J 7.8 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.91 (s, 1H), 6.85 (dd, J=2.7, 8.4 Hz, 1H), 6.62 (s, 1H), 5.75 (bs, 1H), 4.73 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CO>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 40.2 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 6.49 g, 39.5 mmol) and tert-butyl-dimethyl-[(R)-2-oxiranyl-ethoxy]-silane (first eluting compound of step P.i of Preparation P; 8.0 g, 39.5 mmol) in EtOH/H2O 9-1 (240 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate containing the product was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (5.82 g, 40% yield).
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20]Cl)[CH:5]=1)(=[O:3])[CH3:2].[CH3:22][SH:23].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20][S:23][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(CCl)c(OCCCCCCC#N)cc1O
Reactant: CS
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1cc(C(C)=O)c(O)cc1OCCCCCCC#N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 600 mg of the compound from Example 127 was dissolved in 50 ml of methylene chloride and cooled to 0° C. Fifteen grams of methanethiol were added followed by the addition of 2 ml of triethylamine. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and an acidic sodium chloride solution. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 40% ethyl acetate in hexane providing 200 mg of the desired title product, m.p.=78° C.