Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[N:9][N:8]=2)[NH2:6])[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C>ClCCl>[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:6][CH:5]([C:7]1[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[N:9][N:8]=1)[CH2:4][CH:1]1[CH2:2][CH2:3]1)=[O:22]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cn1c(SCC2CC2)nnc1C(N)CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(SCC2CC2)nnc1C(CC1CC1)NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the amine obtained in step e in dichloromethane (3 mL) was added 2,4-dichlorobenzoyl chloride (210 μL, 1.5 mmol) and triethylamine (500 μL, 3.6 mmol). The reaction mixture was stirred at room temperature for 6 h. Following aqueous work-up, the residue was purified by chromatography on silica eluting with 40 to 50% ethyl acetate in hexanes to give the title compound. m/z (ES+) 427 (M+H), 425 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH:18]([F:20])[F:19])[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:52]=[CH:51][C:34]([C:35](Cl)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>ClCCl>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([C:35]([NH:17][C:10]2[CH2:11][S:12](=[O:16])(=[O:15])[CH2:13][CH2:14][C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:21])([CH:18]([F:19])[F:20])[N:9]=2)([C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)CCS(=O)(=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@@](c3cc(Br)ccc3F)(C(F)F)CCS(=O)(=O)C2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.3 %

Procedure:
A solution of (S)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-ylamine (318 mg, 826 μmol) and triethylamine (167 mg, 1.65 mmol) in dichloromethane (15 ml) was treated at 0° C. with 4,4′-dimethoxytritylchloride (336 mg, 991 μmol). The green reaction mixture was stirred at room temperature for 6 hours. Thereafter, the reaction mixture was evaporated, and the crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate 100:0 to 50:50 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(S)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-yl]-amine (365 mg, 63% yield) was obtained as a grey foam. MS (ISP): m/z=687.0 [M+H]+and 689.3 [M+2+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[CH2:6]=[O:7]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCO
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COCCOCOCCOC
Yield: 71.4 %

Procedure:
1045 g of 2-methoxyethanol (Mr =76,1), 194 g of paraformaldehyde (Mr =30.03 based on formaldehyde) and 16 g of p-toluenesulfonic acid (Mr =172.2) are reacted for 2 hours at 90° C. The water of reaction is then removed by distillation. The reaction mixture is distilled under reduced pressure (c. 20 mbar), affording 758 g of bis(2-methoxyethoxy)methane (Mr =164.21) in c. 99% purity, yield: 67% of theory. The remainder (33%) consists almost completely of the educt, which can be recycled, so that total yields of over 97% result.
Reaction SMILES: [OH-].[K+].Br[CH2:4][CH:5]([CH3:7])[CH3:6].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1.O>CS(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][CH2:4][CH:5]([CH3:7])[CH3:6])=[CH:11][CH:10]=1
Reactant: CC(C)CBr
Reactant: OCCc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Potassium hydroxide (1.32 g) and 1-bromo-2-methylpropane (1.04 mL) were added to a solution of 2-(4-bromophenyl)ethylalcohol (140 μL) in dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give the title compound as a colorless oil (180 mg, 70%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1cccc(C(F)(F)F)c1
Product: O=C(O)c1ccncc1NCc1cccc(C(F)(F)F)c1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 3-trifluoromethyl-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.47 (br s, 1H), 8.12 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.74 (s, 1H), 7.57-7.69 (m, 4H), 4.67 (s, 2H). [M+H] calc'd for C14H11F3N2O2, 297. Found 297.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C1COCC1>[S:23]([O:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=1)(=[O:25])(=[O:24])[CH3:26]
Reactant: CCCCCc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 3-(4-pentylphenyl)propanol (30.8 g, 149 mmol) and triethylamine (22 ml, 155 mmol) in THF (300 ml) was added mesyl chloride (11.6 ml, 150 mmol) at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate anhydride, and the organic layer was concentrated to give the object compound as an oily substance. 42.4 g, (yield 100%)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][CH3:14])[C@H:9]1[C:15](=[O:17])[NH2:16])=O)(C)(C)C.CO.[ClH:20]>>[ClH:20].[CH3:14][O:13][C@H:10]1[CH2:11][CH2:12][NH:8][C@@H:9]1[C:15]([NH2:16])=[O:17]
Reactant: CO[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(N)=O
Agent: Cl
Solvent: CO
Product: CO[C@H]1CCN[C@@H]1C(N)=O
Yield: 38 %

Procedure:
(2S,3S)-2-Carbamoyl-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 0.49 mmol) was stirred in hydrochloric acid (5 mL, 3M in methanol) and methanol for 4 h. The reaction mixture was concentrated in vacuo and the residue triturated in diethyl ether and methanol to give (2S,3S)-3-Methoxy-pyrrolidine-2-carboxylic acid amide hydrochloride salt as a white solid (69 mg, 38%). 1H NMR 400 MHz (DMSO-d6) δ: 8.28 (1 H, br, s), 7.82 (1 H, br, s), 4.23 (1 H, m), 4.11-4.10 (1 H, m), 3.37 (1 H, m), 3.35 (3 H, s), 3.19-3.16 (1 H, m), 2.07 (1 H, m), 1.84-1.83 (1 H, m)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=3[F:27])[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:28].[I-].N.CCO>>[NH2:28][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=3[F:27])[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(c3cccc(F)c3F)Oc3ccc(Br)cc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3cccc(F)c3F)Oc3ccc(Br)cc32)N=C1N
Yield: 59.2 %

Procedure:
A solution of 6-bromo-2-(2,3-difluorophenyl)-1′-methyl-2′-(methylthio) spiro[chroman-4,4′-imidazol]-5′(1′H)-one (63 mg, 0.14 mmol), NH4I (60.6 mg, 0.42 mmol) in a solution of NH3/EtOH (3 mL, 1.5 N) was heated at 110° C. in a tube under microwave reactor for 3 hrs. After cooling, the mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(2,3-difluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (35 mg, 60%). 1H-NMR (CDCl3): 2.31 (d, 1H), 2.45 (t, 1H), 3.27 (s, 3H), 6.12 (d, 1H), 6.87 (m, 1H), 7.09 (m, 3H), 7.34 (m, 2H), 7.45 (m, 1H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=2)[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4]([Br:33])[N:3]=1.[NH3:34].CO>C1COCC1>[NH2:34][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][P:25]([O:27][CH2:28][CH3:29])([O:30][CH2:31][CH3:32])=[O:26])=[CH:22][CH:23]=2)[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4]([Br:33])[N:3]=1
Reactant: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
To a solution of ethyl (2,6-dibromo-3-nitropyridin-4-yl)(4-((diethoxyphosphoryl)methyl)benzyl)carbamate (1 equiv.) in THF (0.40 M) was added a 7 M solution of ammonia in methanol (5 equiv.). The reaction mixture was then allowed to stir at room temperature for 48 h. At this point the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (68%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].COCCOC.[H-].[Na+].[CH3:21][S:22][CH2:23]Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:21][S:22][CH3:23])[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CSCCl
Reactant: CNC(=O)Nc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)N(CSC)c1ccccc1F
Reaction time: 0.25 h

Procedure:
A solution of 16.8 g. (0.1 mol) of N-(2-fluorophenyl)-N'-methyl urea in 250 ml. of 1,2-dimethoxyethane was cooled to 0°C. Then 4.8 g. (0.1 mol) of a 50% dispersion of sodium hydride in mineral oil was added slowly. After addition was complete, the solution was stirred for 15 minutes. This solution was added slowly to a stirred solution of 9.7 g. (0.1 mol) of chloromethyl methyl sulfide in 100 ml. of 1,2-dimethoxyethane. The resulting mixture was stirred at room temperature for 65 hours. At the end of this time, the precipitate was removed by filtration and the resulting filtrate was evaporated to give an oil which solidified upon adding water. The solid was isolated by filtration, washed with hexane and dried. Recrystallization from a hexene-benzene mixture gave 12 g. crystalline solid, melting point 102.5°-103°C. An infrared spectrum showed sharp, strong adsorptions at 3.0, 6.1, 13.05 and 13.2μ .
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1.[CH3:11][NH:12][CH3:13]>C(O)C>[CH3:11][N:12]([CH3:13])[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Chloro[1,2,4]triazolo[1,5-b]pyridazine (0.9 g) is dissolved in 10 ml of ethanol, to which 10 ml of a 7.2% solution of dimethylamine in ethanol is added. The mixture is stirred at room temperature for 24 hours. After the solvent is evaporated off under reduced pressure, the residue is dissolved in methylene chloride, washed with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent is evaporated off under reduced pressure to give 0.82 g of the titled compound as a white crystal.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:36][C:37](O)=[O:38])=[N:28]1>>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:36][C:37]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:38])=[N:28]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)Cc1noc2ccccc12
Agent: Cl
Product: O=C(Cc1noc2ccccc12)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (107 mg, 88%), MS (ISP) m/z=488.4 [(M+H)+], mp 214° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2-benzo[d]isoxazol-3-yl-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]2[O:10][C:9]([C:11]([CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH2:12])=[CH:8][C:7]=2[CH:24]=1.[CH3:27]O>[Pd]>[CH3:1][O:2][C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]2[O:10][C:9]([CH:11]([CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])[CH2:12][CH3:27])=[CH:8][C:7]=2[CH:24]=1
Reactant: C=C(CC/C=C(\C)CCC=C(C)C)c1cc2cc(OC)c(OC)cc2o1
Reactant: CO
Agent: [Pd]
Product: CCC(CC/C=C(\C)CCC=C(C)C)c1cc2cc(OC)c(OC)cc2o1
Reaction time: 0.5 h

Procedure:
To a solution of compound A4 (0.7 g 1.9 mmol) in MeOH was added 10 Mol % Pd/C and reaction was shacked at 40 psi pressure for 0.5 hrs. After completion of the reaction (monitored by TLC) filtered the reaction mixture and evaporated the methanol completely. Chromatography of the residue on silica gel (3% EtOAc/Hexanes) afforded the compound A5 (0.633 g) in 90% yield colorless liquid: 1H NMR (500 MHz, CDCl3) δ 7.04 (s, 1H), 6.98 (s, 1H), 6.294 (s, 1H), 5.15-5.12 (m, 4H), 3.940 (s, 6H), 2.94-2.91 (m, 1H), 2.10-1.98 (m, 4H), 1.87-1.82 (m, 2H), 1.74 (s, 3H), 1.634 (s, 3H), 1.59 (s, 3H), 1.34-1.32 (d, 3H), ppm. Mass: ESI [M+Na]+: 356.24; Elemental anal. calcd. for C23H32O3; C, 77.49; H, 9.05. found C, 77.49; H, 9.05.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][C:26]#[N:27]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][C:26]#[N:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.5 %

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50 mmol), K2CO3 (8.5 g, 74 mmol) and 3-bromopropionitrile (8.2 g, 1.2 eq) in acetonitrile (300 ml) was heated at reflux for 24 hours. The mixture was cooled and the insolubles were filtered. The solvent was removed on a rotary evaporator and the crude product was purified by flash chromatography over a silica gel column (SiO2, 120 g). The product thus purified weighed 8.94 g. Recrystallization from ethanol yielded the nitrile as white crystals 4.3 g, m.p. 100-101° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6](Br)[C:7]=1[CH3:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH3:27])=[C:19]([C:22]([F:24])([F:25])[F:23])[CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[C:7]=1[CH3:8]
Reactant: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(Br)c(C)c(Br)c1)CC2
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(Br)c(C)c(-c3cccnc3)c1)CC2
Yield: 27.7 %

Procedure:
A mixture of 1-(3,5-dibromo-4-methylphenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline (D25, 0.51 g, 1 mmol), 3-pyridylboronic acid (0.12 g, 1 mmol), tetrakis (triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) and sodium carbonate (0.41 g, 4 mmol) in dimethoxyethane (30 mL) and water (3 mL) was heated under reflux, under argon, for 18 h. The mixture was cooled and poured into water. The precipitate was filtered off, washed with water and dried. The crude product was chromatographed on silica gel, eluted with ethyl acetate, and the eluted material was triturated with ether to give the title compound (0.14 g, 28%), m.p. 216-8° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.Cl>C1COCC1>[CH:20]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1)=[O:21]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)O
Reaction time: 3 h
Yield: 41.4 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (10.7 g, 50 mmol) in THF (250 mL) at −78° C. was added n-BuLi (60 mL, 2.5 M in hexane). The mixture was stirred for 3 h and to it was added DMF (9.6 mL, 125 mmol). The reaction mixture was stirred for 1.5 h, acidified with 1N HCl and extracted with EA (200 mL). The organic solution was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude yellow solid was washed with PE to afford 4-formyl-2-methylbenzoic acid (3.4 g; yield 41%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].C([O-])(O)=O.[Na+].[NH2:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21]>CO>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:18][CH2:19][C:20]([OH:22])([CH3:23])[CH3:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(O)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(O)CNS(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-formyl-benzene sulfonyl chloride (1.0 g) in MeOH was added NaHCO3 (0.425 g), followed by 1-amino-2-methylpropan-2-ol (0.566 g). The reaction mixture was stirred for 1 h at RT, then filtered through Celite and the solvent removed under reduced pressure to provide 4-formyl-N-(2-hydroxy-2-methylpropyl)-benzene sulfonamide.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[CH3:24][NH:25][CH3:26]>[OH-].[Na+]>[CH3:24][N:25]([CH3:26])[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: CNC
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1ccccc1-c1nc2nc(N(C)C)nnc2c(=O)[nH]1

Procedure:
3-Methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (0.6 g) was treated with a solution of dimethylamine in industrial methylated spirit (33%, 20 ml) at 100° C. in a pressure vessel for 24 hours. The cooled reaction mixture was evaporated under reduced pressure to afford a yellow solid residue which was dissolved in dilute aqueous sodium hydroxide and filtered. The filtrate was acidified with a few drops of concentrated hydrochloric acid to afford a yellow precipitate which was collected, washed with water and recrystallised from methanol to afford the title compound, 0.44 g, m.p. 257.5°-259° C.
Reaction SMILES: [O:1]=[C:2](O)[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C([NH:21][NH2:22])(OC(C)(C)C)=O>CO>[O:1]=[C:2]([NH:21][NH2:22])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Product: NNC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Five grams of gluconic acid were suspended in 15 ml of warm MeOH. After the complete dissolution 4 grams of monoBOC-hydrazine were added to the reaction vessel. The solution was refluxed for 36 h. After the addition of monoBOC-hydrazine the suspension disappeared. At the end, the reaction showed a white precipitate which contained most of the product. The solvent was removed under vacuum and the solid product was extracted in a mixture of NaOH sol. 0.1 N/chloroform. The organic phase was removed while the aqueous phase was passed through anionic exchanger resin and lyophilized. Finally, product was dissolved in cold MeOH and deprotected from the BOC-function by bubbling HCl gas into the solution over 30′. The purity of the protected and the deprotected product was checked by TLC, HPLC and the identity was confirmed by ESI-MS.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7](SC)[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].O.[NH2:30][NH2:31]>C(O)CCC>[CH2:1]([C:5]1[N:6]=[C:7]([NH:30][NH2:31])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(SC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CCCCc1nc(NN)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
A mixture of 4′-{[4-butyl-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (3.5 g), hydrazine hydrate (10 mL) and n-butanol (100 mL) was stirred at 120° C. for 6 hr. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration. The obtained solid was washed with methanol to give the title compound as a colorless solid (2.6 g, 77%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(OCC(O)CO)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: OCC(O)COc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine and 4-(2,3-dihydroxypropoxy)aniline were reacted to produce N2-[4-(2,3-dihydroxypropoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.09 (s, 1H), 8.95 (s, 1H), 7.98 (d, 1H, J=3.5 Hz), 7.51 (d, 2H, J=8.8 Hz), 7.32 (d, 1H, J=2.3 Hz), 7.17 (dd, 1H, J=2.3 and 8.8 Hz), 6.77 (dd, 3H, J=8.8 Hz), 4.90 (d, 1H, J=5.3 Hz), 4.64 (t, 1H, J=5.8 Hz), 4.23-4.19 (m, 4H), 3.91-3.89 (m, 1H), 3.80-3.73 (m, 2H), 3.41 (t, 2H, J=5.3 Hz); LCMS: ret. time: 15.04 min.; purity: 96%; MS (m/e): 429 (MH+).