Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:30][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: N#Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(Cc3ccc(C#N)cc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide (0.20 g, 0.63 mmol) in anhydrous N,N-dimethylformamide (8 mL) was added potassium carbonate (0.10 g, 0.69 mmol), followed by the addition of 4-(chloromethyl)benzonitrile (0.11 g, 0.69 mmol). The reaction mixture was stirred at 80° C. for 4 hours. The solvent was concentrated in vacuo to one-fourth, then diluted with ethyl acetate (150 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane to afford the title compound as a colorless solid in 40% yield (0.11 g): mp 176-178° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.65-7.63 (m, 2H), 7.40-7.24 (m, 7H), 5.88 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.51 (s, 2H), 4.13-4.07 (m, 2H), 3.50-3.44 (m, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 157.0, 155.5, 152.8, 141.1, 137.8, 132.7, 129.0, 128.8, 128.7, 127.8, 118.3, 117.6, 112.1, 47.7, 44.1, 42.0, 17.2; MS (ES+) m/z 432.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1CCNCC1.C([O-])([O-])=[O:23].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:23])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: C1CNCCN1
Agent: [K+]
Solvent: CCC(C)=O
Product: OC(c1ccccc1)c1ccc(Cl)cc1
Yield: 57 %

Procedure:
A mixture of 1-chloro-4-(chloro-phenyl-methyl)-benzene (4.12 g, 17.4 mmol) in butanone (20 ml), anhydrous piperazine (5.98 g, 69.6 mmol), anhydrous K2CO3 (2.40 g, 17.4 mmol) and KI (2.88 g, 17.4 mmol) was refluxed under nitrogen for 18 hours. The mixture was then cooled and filtered and the solvent removed in vacuo. The residue was dissolved in CH2Cl2 (100 ml) and washed with water (30 ml). Drying and removal of the solvent followed by chromatography (CH2Cl2:CH3OH:NH4OH 90:10:0.5) afforded desired product in 57% yield. D. Synthesis of 1-{4-[(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one
Reaction SMILES: [N:1]1[C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[S:3][C:2]=1[NH2:14])=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].O>N1C=CC=CC=1>[N:1]1[C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[S:3][C:2]=1[NH:14][C:15](=[O:18])[CH2:16][CH3:17])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCC(=O)Cl
Reactant: Nc1nc2c(s1)CCc1ccccc1-2
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1nc2c(s1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Under ice-cooling, to a solution of 4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (1.50 g, 7.4 mmol) in pyridine (20 mL) was added propionyl chloride (1.03 g, 11 mmol), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (1.75 g, yield 91%) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=O)[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[CH3:30][O:31][NH2:32]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=[N:32][O:31][CH3:30])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CON
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCC(CC(C(=O)Nc2cnccn2)c2ccc(S(C)(=O)=O)c(Cl)c2)C1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 45, 73.5 mg, 0.17 mmol) and methoxyamine hydrochloride (21.8 mg, 0.26 mmol) in methanol (512 μL) and pyridine (512 μL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were washed with a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 70% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-methoxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (61.2 mg, 78%) as a white foam: mp 85-87° C.; (ES)+-HRMS m/e calcd for C20H23ClN4O4S (M+H)+ 451.1202. found 451.1207.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:16][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2[N+](=O)[O-])n1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1nccc(Nc2cc(Br)ccc2N)n1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of 4-N-(5-bromo-2-nitrophenyl)pyrimidine-2,4-diamine (5.06 g, 16.32 mmol) in ethanol (110 mL) was added tin(II) chloride dihydrate (12.89 g, 57.11 mmol). The reaction mixture was stirred at 65° C. for 2 hr. The reaction mixture was evaporated to dryness and ice-water added. The pH of the mixture was adjusted to 10 using saturated aqueous Na2CO3 solution. EtOAc was added followed by saturated aqueous Rochelles salt (potassium sodium tartrate). The resulting mixture was stirred until separate layers were observed. The organic layer was extracted and the extraction repeated (2×) with EtOAc and DCM. Combined organic layer were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a pale yellow solid: 1H NMR (250 MHz, DMSO) δ 5.05 (2H, br. s), 5.79 (1H, d, J=5.79 Hz), 6.08 (2H, br. s), 6.68 (1H, d, J=8.53 Hz), 7.02 (1H, dd, J=8.60, 2.36 Hz), 7.36 (1H, d, J=2.28 Hz), 7.75 (1H, d, J=5.63 Hz), 8.15 (1H, s); LC-MS: m/z=+279.9, 281.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20]Br.Cl.[CH3:24][NH:25][CH3:26].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20][N:25]([CH3:26])[CH3:24]
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: CNC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1CN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.102 g (0.273 mmol) of the above (example 45A]) prepared 2-bromomethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester was dissolved in 1.5 ml of acetonitrile and treated with 0.027 g (0.331 mmol) of dimethylamine hydrochloride and 0.080 ml (2 eq.) of triethylamine. After stirring for 2 h at ambient temperature, the reaction mixture was poured onto crashed ice/KHSO4-solution and extracted twice with AcOEt. Washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, AcOEt/MeOH/NEt3=9/1/0.05), produced 0.047 g of pure title compound as off-white crystals.
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11]OS(C)(=O)=O)[CH2:7][CH2:6]1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[H-].[Na+]>CN(C)C=O>[N:30]1([CH2:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][CH2:3][N:2]([CH3:1])[S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:6][CH2:7]2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC[C@H]1CC[C@H](Cn2ccnc2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 25.1, trans-methanesulfonic acid 4-{2-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-ethyl}-cyclohexylmethyl ester (example 13.2) was reacted with imidazole in N,N-dimethylformamide in the presence of sodium hydride to yield trans-N-[2-(4-imidazol-1-ylmethyl-cyclohexyl)-ethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 430 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:15])[CH2:8]2.[N+:16]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:15])([O-:18])=[O:17]
Reactant: COc1ccc2c(c1OC)CCC(=O)C2
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Product: COc1cc(C=C2C(=O)CCc3c2ccc(OC)c3OC)c([N+](=O)[O-])cc1OC

Procedure:
Prepared from 5,6-dimethoxy-2-tetralone and 2-nitro-4,5-dimethoxybenzaldehyde; mp 70-72° C.; IR (Nujol): 1715, 1550; 1H NMR: δ2.59 (2H, t), 3.06 (2H, t), 3.78 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 3.92 (3H, s), 6.47 (1H, s), 6.77 (1H, d, J=8.2), 7.41 (1H, d, J=8.2), 7.67 (1H, s); 13C NMR: δ19.7, 32.0, 56.3, 56.7, 56.8, 56.85, 108.1, 121.9, 125.6, 126.1, 128.0, 129.2, 132.1, 132.9, 133.7, 140.3, 141.4, 149.3, 152.9, 153.5, 200.9; Anal. (C21H21NO7) C, H, N.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[BH4-].[Na+]>O1CCCC1>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:4]([C:9]([N:11]2[CH2:12][C:13]([C:16]([CH3:21])([CH3:20])[CH2:17][OH:18])([OH:15])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C(=O)O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CO)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To solution of 2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoic acid (300 mg, 0.56 mmol) in tetrahydrofuran (5 mL) was added triethylamine (80 μL, 0.56 mmol), followed by PyBOP (295 mg, 0.56 mmol) and finally sodium borohydride (64 mg, 1.68 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding 20% aqueous citric acid, and then partitioned with ethyl acetate. The organic portion was washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a white solid which was purified by column chromatography. Eluting with 60% ethyl acetate in hexanes, the isolated product was concentrated in vacuo to afford 238 mg, 0.46 mmol (82%) of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxy-1,1-dimethylethyl)azetidin-3-ol as a white solid. 1H NMR (400 MHz, DMSO): 8.53 (s, 1H), 7.57 (d, 1H), 7.38-7.28 (m, 2H), 7.22-7.15 (m, 1H), 6.70-6.64 (m, 1H), 5.61 (s, 1H), 4.57 (br s, 1H), 4.30-4.27 (m, 1H), 4.18-4.15 (m, 1H), 3.80-3.77 (m, 1H), 3.68-3.64 (m, 1H), 3.25 (s, 2H), 0.76 (d, 6H); MS (EI) for C20H20F3IN2O3: 521 (MH+).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([O:27]CC)=O)[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].[CH3:30][NH2:31]>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:31][CH3:30])=[O:27])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CN
Product: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate (46.4 g) and methylamine (40% in water, 600 ml) was stirred at ambient temperature for about 4 hours, following the progress of the reaction by HPLC analysis. The majority of the excess methylamine was removed under reduced pressure, and the remaining mixture cooled at 0° C. for 2 hours. The solid material was filtered off, washed with ice-cold 200 proof ethanol, and dried under reduced pressure, to provide (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide as its monohydrate, 36.6 g, purity 99.6%.
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1.CI.O>C1COCC1>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH2:16][CH3:2])[CH:8]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CCc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Yield: 46 %

Procedure:
To a yellow solution of 2,2,6,6-TMPH (5.45 g, 38.69 mmol) in THF (6 mL) was added n-BuLi (16 mL) slowly at −78° C. under protection of nitrogen, thereto, the mixture was warmed up to room temperature, stirred at this temperature for an hour, and then cooled to −78° C. again, a solution of 4-chloro-2-methylbenzoic acid (3.0 g, 17.58 mmol) in THF (30 mL) was added slowly, kept stirring at this temperature for an hour, added MeI (5.49 g, 38.69 mmol) solution (in 20 mL THF), the mixture above was then stirred overnight at room temperature. LCMS showed the completion of the reaction, added water, the mixture was then washed with ethyl acetate, the aqueous phase was acidified to pH=1, extracted with ethyl acetate twice, and concentrated the organic phase, washed the residue with PE/EA=1/1 to give 1.5 g of the title compound (46%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([OH:17])[N:14]=[C:13]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:12]=1)[CH3:8].COC(=O)[C:27](Cl)([F:29])[F:28]>CC(=O)CC>[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([O:17][CH:27]([F:29])[F:28])[N:14]=[C:13]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:12]=1)[CH3:8]
Reactant: CCOC(=O)c1cc(O)nc(N[C@@H](C)CC)c1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc(N[C@@H](C)CC)nc(OC(F)F)c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
Add cesium carbonate (0.352 g, 1.08 mmol) to (S)-2-sec-butylamino-6-hydroxy-isonicotinic acid ethyl ester (0.172 g, 0.72 mmol) in butan-2-one (10 mL) ((Bioorg. Med. Chem. Lett., 12, 2149-2152 (2002)). Heat at 70° C. for 30 min and add chlorodifluoroacetic acid methyl ester (0.24 mL, 2.16 mmol) in three equal portions over 3 h. Heat for 3 days at 70° C. Add again chlorodifluoroacetic acid methyl ester (0.24 mL, 2.16 mmol) in three equal portions over 3 h and stir at room temperature for 24 h. Concentrate and dissolve the crude mixture in ethyl acetate and filter. Purify (silica gel chromatography, eluting with 2:98 to 6:92 ethyl acetate:hexanes) to give the title compound (0.135 g, 65%). MS (ES): m/z=289 [M+H].
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=[O:5])#[N:2].[NH2:9][C:10]([NH2:12])=[S:11].C[O-].[Na+]>>[NH2:2][C:1]1[CH:3]=[C:4]([OH:5])[N:12]=[C:10]([SH:11])[N:9]=1
Reactant: CCOC(=O)CC#N
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Product: Nc1cc(O)nc(S)n1

Procedure:
According to a method described by Baker, Joseph, and Schaub, J. Org. Chem. 19, p. 631 (1954) ethyl cyanoacetate is reacted with thiourea in the presence of sodium methoxide to give 4-amino-6-hydroxy-2-mercaptopyrimidine which is methylated in situ to obtain 4-amino-6-hydroxy-2-(methylthio)pyrimidine. Chlorination of the latter compound with phosphorus oxychloride in dimethylaniline gives the desired 4-amino-6-chloro-2-(methylthio)pyrimidine. Yields using this method are uncertain.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[C@@H:7]([O:19]C(=O)C2C=CC=CC=2)[CH2:6][C@@H:5]1[CH3:28])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[C@@H:7]([OH:19])[CH2:6][C@@H:5]1[CH3:28])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)[C@@H](OC(=O)c1ccccc1)C[C@H](C)N2C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)[C@@H](O)C[C@H](C)N2C(C)=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
[Step 3] 1.02 g of ethyl (2S,4S)-1-acetyl-4-benzoyloxy-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate was dissolved in 10 mL of ethanol, and 1.11 g of potassium carbonate was slowly added to the solution. The mixture was stirred for 18 hours at 50° C., subsequently solids were filtered off, and the filtrate was washed two times with chloroform. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by using silica gel chromatography (hexane:ethyl acetate=2:1→1:2). Thus, 346 mg (38.2%, 2 steps) of ethyl (2S,4S)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate was obtained as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24]Cl)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[I-].[Na+]>COCCOC>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCl
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCN1CCOCC1
Temperature: 135 °C

Procedure:
A mixture of 0.8 g (1.83 mmol) of 4-(4-chloro-2-fluoro-5-hydroxy-phenylamino)-7-(2-chloro-ethoxy)-6-methoxy-quinoline-3-carbonitrile, 2.4 g (27.5 mmol) of morpholine, and 0.11 g of sodium iodide in 15 ml ethylene glycol dimethyl ether heated in a sealed tube at 135° C. for 12 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate-methanol-triethylamine 70:30:1 giving 0.43 g of the title compound as a tan solid: mass spectrum (electrospray, m/e) M+H 470.0; (M+2H)+2 237.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:21]([C:24]3[CH:29]=[CH:28][C:27](F)=[C:26]([Cl:31])[CH:25]=3)(=[O:23])=[O:22])[CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:19]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:40][C:37]4[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=4)=[C:26]([Cl:31])[CH:25]=3)(=[O:23])=[O:22])[CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1ccc(F)c(Cl)c1
Product: CN([C@@H]1CCCc2c(OCC(=O)OC(C)(C)C)cccc21)S(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Yield: 75 %

Procedure:
Starting with {(R)-5-[(3-chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester (100 mg, 0.207 mmol) and 4-chlorophenol (315 mg, 2.45 mmol), using the method analogous to the one described for example 2-2, method D, 2nd step, ((R)-5-{[3-chloro-4-(4-chlorophenoxy)-benzenesulfonyl]-methyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (92 mg, 75%) was obtained as a white powder. MS cald. For C29H31Cl2NO6S 591, obsd. 592 (ESI+) [(M+H)+].
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(OC)(OC)OC.C([BH3-])#N.[N-]=C=O>COCCOC.CN(C)C(=O)C.C(O)(=O)C>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1sc(-c2ccc(C=O)cc2)cc1C(N)=O
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [N-]=C=O
Solvent: CC(=O)N(C)C
Solvent: COCCOC
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(-c3cc(C(N)=O)c(NC(N)=O)s3)cc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
2-[(Aminocarbonyl)amino]-5-(4-formylphenyl)-3-thiophenecarboxamide (100 mg) was stirred in a mixture of 1,2-dimethoxyethane (10 ml) and N,N-dimethylacetamide (5 ml). 1-Methyl piperazine (0.16 g) was added, followed by trimethyl orthoformate (5 ml) and acetic acid (0.5 ml). The reaction was stirred at 80° C. for 20 minutes, and then polymer-supported cyanoborohydride (0.45 g) was added. The reaction was stirred at 80° C. for a further 2 h, and then polymer-supported isocyanate (0.5 g) was added. The resins were removed by filtration, and the filtrate was then passed through a 5 g SCX column, washing with methanol (25 ml). The product was eluted using 1M methanolic ammonia (45 ml), and this solution was then evaporated to dryness under reduced pressure and the residue purified by chromatography on silica, eluting with dichloromethane/methanol (9:1), to give the product as an off-white solid (16 mg).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]([CH2:47][CH2:48][CH2:49][CH3:50])[CH3:46])=[O:44])=[C:41]([S:53]([CH:56]([CH3:58])[CH3:57])(=[O:55])=[O:54])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]([CH2:47][CH2:48][CH2:49][CH3:50])[CH3:46])=[O:44])=[C:41]([S:53]([CH:56]([CH3:57])[CH3:58])(=[O:54])=[O:55])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCCN(C)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CCCCN(C)C(=O)c1ccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1S(=O)(=O)C(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-N-butyl-2-(isopropylsulfonyl)-N-methylbenzamide (Intermediate 253), the title compound was obtained.