Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][CH3:26])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:21](OC)=[O:22])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:27][CH2:28][CH2:29][CH2:30][NH2:31]>CO>[OH:27][CH2:28][CH2:29][CH2:30][NH:31][C:21]([C@@H:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:25][CH3:26])=[O:22]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OC
Reactant: NCCCO
Solvent: CO
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)NCCCO
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Methyl 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)indoline-2(S)-carboxylate (0.36 g, 1 mmol) was dissolved in methanol (10 ml) and treated, under nitrogen and at 50° C., with 3-hydroxypropylamine (10 ml). The mixture was stirred at 50° C. for 3 h and the solvent was evaporated off. The residue was dissolved in methylene chloride (30 ml) and washed with 1M KHSO4. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by column chromatography in order to give the product.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[C:6](#[N:9])[CH:7]=[CH2:8]>CO>[CH:1]1([NH:5][CH2:8][CH2:7][C:6]#[N:9])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: C=CC#N
Solvent: CO
Product: N#CCCNC1CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, cyclobutylamine (5.90 mL, 59.8 mmol) was added dropwise, over 15 mins, to a solution of acrylonitrile (4.76 g, 89.7 mmol) in methanol (7 mL). The mixture was stirred at room temperature for 30 mins and at reflux for 1 hr, cooled to room temperature, concentrated under reduced pressure. The desired product was obtained by distillation under vacuum to provide a clear liquid (7.7 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 3.29-3.21 (m, 1H), 2.88-2.83 (t, 2H, J=6.6 Hz), 2.50-2.46 (t, 2H, J=6.6 Hz), 2.26-2.20 (m, 2H), 1.76-1.63 (m, 4H), 1.30 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:5].C(N(CC)CC)C.[CH2:22]([O:29][CH2:30][C:31](Cl)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:9][CH:8]=1)[CH3:5]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)C(C)Oc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Oc1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a mixture of 2-(4-aminophenoxy)-propionic acid methyl ester 10 (20 grams, 102.5 mmol) and triethylamine (23 ml, 165 mmol) in acetone (120 ml) at 0° C. was added dropwise benzyloxy acetyl chloride (28 g, 152 mmol) followed by stirring at room temp for 12 hours. The solids were filtered off, acetone distilled off, and water (100 ml) added. Crude 51 was extracted into chloroform, washed with 5% sodium bicarbonate (2×100 ml) and water (200 ml), then dried over sodium sulphate and distilled. Crude 51 was purified by column chromatography on silica gel using benzene as eluant to get pure 51 (21 g, 59.8%) as a light brown powder with an m.p. between 67-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SCCC.BrCC1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](C3C=CC=CC=3OC)[CH:36]=2)[NH:31]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+]>C(S)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])([CH3:20])[CH:13]=[C:12]2[CH2:21][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-propylsulfanylmethyl-1,2-dihydroquinoline 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 20 μL of 1-propanethiol reacted to give 13 mg of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([NH2:25])[CH:24]=1)[CH2:20][OH:21]>>[CH:4]1[C:3]2[C:8](=[N:9][C:10]3[C:15]([C:2]=2[NH:16][C:17]2[CH:24]=[C:23]([CH:22]=[C:19]([CH2:20][OH:21])[CH:18]=2)[NH2:25])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: Nc1cc(N)cc(CO)c1
Product: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1

Procedure:
The contacting in step (a) comprises the condensation of 9-chloroacridine and 3,5-diaminobenzyl alcohol to form 3-(9-acridinylamino)-5-hydroxymethylaniline.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[N:13]1([C:9]2[CH2:8][CH2:7][C:6]3[C:11]([CH:10]=2)=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cccc(Br)c2C1
Reactant: C1CCNC1
Product: C1=C(N2CCCC2)CCc2ccccc21

Procedure:
When R2 in the compounds of Formula I is methyl, the methyl-substituted 8-bromo-2-tetralone can be prepared from the corresponding unsubstituted 8-bromo-2-tetralone. The 8-bromo-2-tetralone first is treated with pyrrolidine to produce the corresponding 1,2-dihydro- 3-pyrrolidinyl-naphthalene. The latter, upon treatment with methyl iodide and acid hydrolysis, gives the desired 8-bromo-1-methyl-2-tetralone.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:17])=[CH:9][C:10]=1[CH2:11][C:12]([O:14]CC)=[O:13])=[O:5])C.[Li+].[OH-].Cl>CO.O>[C:12]([CH2:11][C:10]1[CH:9]=[C:8]([CH3:17])[NH:7][C:6]=1[C:4]([OH:5])=[O:3])([OH:14])=[O:13]
Reactant: CCOC(=O)Cc1cc(C)[nH]c1C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(CC(=O)O)c(C(=O)O)[nH]1
Yield: 87.1 %

Procedure:
A solution of 3-ethoxycarbonylmethyl-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (7 g, 29.26 mmol), LiOH (7 g, 10 eq.) in methanol (90 mL) and water (30 mL) was heated in a 70° C. oil bath for 3 hours. The cooled reaction was adjusted to pH 3 with 3N HCl, the resulted precipitate was collected by filtration, washed with water and dried to give 4.67 g (87%) of 3-carboxymethyl-5-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][CH:11]([CH2:24][N:25](CC1C=CC=CC=1)[CH3:26])[CH2:12][CH2:13][CH2:14][N:15](CC1C=CC=CC=1)[CH3:16])C1C=CC=CC=1.[H][H]>[Pd]>[CH3:1][NH:8][CH2:9][CH2:10][CH:11]([CH2:24][NH:25][CH3:26])[CH2:12][CH2:13][CH2:14][NH:15][CH3:16]
Reactant: [H][H]
Reactant: CN(CCCC(CCN(C)Cc1ccccc1)CN(C)Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Product: CNCCCC(CCNC)CNC
Reaction time: 48 h
Yield: 90 %

Procedure:
To a methanolic solution of N1,N6-Dibenzyl-3-[(benzyl-methyl-amino)-methyl]-N1,N6-dimethylhexane-1,6-diamine (1 g, 0.002 mol) was added 1 g of Pd/C. The solution was exposed to 2 bar of hydrogen and left to shake for 48 hours at ambient temperature. The reaction mixture was filtered through celite and concentrated at reduced pressure to yield a viscous oil. The structure was confirmed by NMR, yield ˜90%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:15].N#N.N1C=CC=CC=1.[F:39][C:40]([F:46])([F:45])[S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=1)=[C:2]([O:1][S:41]([C:40]([F:46])([F:45])[F:39])(=[O:43])=[O:42])[CH:11]=[CH:10]2
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(O)ccc2c1
Agent: N#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reaction time: 0.25 h

Procedure:
Dissolve (2-hydroxy-6-methoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone in CH2Cl2 (10 volumes) in a three neck round bottom flask equipped with a stir bar and N2 source and chill to 0° C. in an ice/brine bath. Add pyridine (1.3 equivalents). Add trifluoromethane sulfonyl chloride (1.2 equivalents) via syringe over 15 minutes. After 15 minutes, quench the reaction with H2O (10 volumes), wash with 1 N HCl (5 volumes), wash with 1.0 N NaHCO3, and dry over Na2SO4. Concentrate to give the title compound in quantitative yield. Use the product without further purification.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=[O:14].[C:16]1([CH3:45])[CH:21]=[CH:20][C:19]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]3([CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:25][CH2:24]2)=[CH:18][CH:17]=1>C(Cl)Cl>[O:42]1[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][C:31]2([CH2:30][CH2:29][N:26]3[CH2:27][CH2:28][CH:23]([N:22]([C:19]4[CH:20]=[CH:21][C:16]([CH3:45])=[CH:17][CH:18]=4)[C:13]([C:9]4[O:8][CH:12]=[CH:11][CH:10]=4)=[O:14])[CH2:24][CH2:25]3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:40][CH2:41]1
Reactant: Cc1ccc(NC2CCN(CCC3(CCN4CCOCC4)CCCCC3)CC2)cc1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN4CCOCC4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
After adding triethylamine (0.21 mL, 1.50 mmol) and 2-furoyl chloride (0.10 mL, 1.00 mmol) in that order to a solution of 4-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]morpholine (319 mg, 0.77 mmol) in methylene chloride (5 mL) while cooling on ice, the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (20 g Merck Art 9385, chloroform:methanol=20:1-chloroform:methanol:ammonia water=10:1:0.1) to obtain the title compound as a colorless oil (283 mg) (72% yield).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([N:6]1[CH2:17][CH2:16][CH2:15][C@H:7]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])[CH3:3].[H][H].C(Cl)(Cl)Cl.CO>CO.[Pd]>[NH2:1][C@H:2]([C:4]([N:6]1[CH2:17][CH2:16][CH2:15][C@H:7]1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
9.36 g of Z-Ala-Pro-OtBu are hydrogenated in 100 ml of methanol in the presence of 500 mg of Pd on charcoal (10%) at room temperature. The hydrogen uptake has ended after 90 minutes. The solution is freed of catalyst by filtration and evaporated in a waterpump vacuum at 30° C. to give an oil. This proves to be homogeneous in a thin layer chromatogram on silica gel. Rf = 0.35 in the system chloroform-methanol (1:1).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([NH2:16])=[S:15])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C1COCC1.[CH3:24][N:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](=O)[CH2:31]Br>CCOC(C)=O>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]3[S:15][C:30]([C:26]4[N:25]([CH3:24])[CH:29]=[CH:28][CH:27]=4)=[CH:31][N:16]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CC(N)=S)cc1
Reactant: Cn1cccc1C(=O)CBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cccc1-c1cnc(Cc2cncn2Cc2ccc(C#N)cc2)s1
Temperature: 50 °C

Procedure:
To a 25 mL round bottomed flask with a stirring bar reflux condenser and an argon inlet is added 1-(4-cyanobenzyl)-5-(aminothiocarbonyl)methyl-1H-imidazole (0.12 g, 0.468 mmol), dry THF (10 mL), and N-methyl-a-bromoacetylpyrrole (0.098 g, 0.491 mmol). This mixture is heated at 50° C. for 7 hours. The cooled reaction mixture is diluted with EtOAc and washed sucessively with aq. NaHCO3, water, and brine. The organic extract is dried, (MgSO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH:22][CH2:23]CC4C=CC=CC=4)=[CH:16][CH:17]=3)[C:12](=[O:31])[C:11]([CH3:33])([CH3:32])[CH2:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH:22][CH3:23])=[CH:16][CH:17]=3)[C:12](=[O:31])[C:11]([CH3:33])([CH3:32])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(OCCNCCc3ccccc3)cc2C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1

Procedure:
A solution of 4-(4-chlorophenyl)-7-(2-benzylmethylaminoethoxy)-2,2-dimethyl-1-tetralone hydrochloride (4.3 g) in ethanol (100 ml) was hydrogenated in the presence of 10% palladium on charcoal (0.43 g) until hydrogen uptake was complete. After filtration the solvent was removed in vacuo to give 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-methylaminoethoxy)-1-tetralone hydrochloride. Recrystallisation from ether-ethyl acetate gave white crystals m.p. 150°-3° (2.6 g, 74%).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:7])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([NH:5][C:6](=[O:7])[C:8]2[CH:27]=[CH:26][CH:25]=[C:10]([CH2:11][N:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NC3CCC3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCC1)c1cccc(CN2CCNCC2)c1
Reaction time: 24 h
Yield: 99.3 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(cyclobutylcarbamoyl)benzyl)piperazine-1-carboxylate (8.84 mmol, 3.3 g) in dichloromethane (10 mL) was added trifluoroacetic acid (5 ml). The reaction mixture was stirred for 24 hours then concentrated under reduced pressure. Purification by strong cation exchange column chromatography gave the title compound (2.4 g). MS (ESI) m/z 274.5 [M+H]+
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:22]1([CH:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.05 g, 3.27 mmol) in N,N-dimethylformamide (15 mL) were serially added 2,2-diphenylethyl iodide (1.11 g, 3.60 mmol) and potassium carbonate (500 mg, 3.60 mmol) and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl [[2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate (1.11 g). To a solution of this compound (1.00 g, 1.99 mmol) in ethanol (45 mL)-water (5 mL) was added sodium periodate (0.51 g, 2.39 mmol) and the mixture was refluxed for 3 hours. To this reaction mixture were added ethyl acetate and water, and the resulting two layers were separated. The aqueous layer was extracted with ethyl acetate and the pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:8) and recrystallized from ethyl acetate to provide 0.64 g of the title compound. Yield 42%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1.C(=O)([O-])[O-:25].[K+].[K+].OO.Cl>O.CS(C)=O>[CH3:23][S:22][C:4]1[NH:3][C:2](=[O:25])[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)[N:5]=1
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(Nc2cccc(S(C)(=O)=O)c2)c(C(N)=O)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a mixture of 4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide (Preparation Example 298) (1.95 g) and DMSO (30 mL), potassium carbonate (1.81 g) and 30% hydrogen peroxide solution (2.65 mL) were added and stirred at 50° C. for 1.5 hours. The reaction liquid was ice-cooled, and 1M hydrochloric acid (25 mL) and thereafter water (150 mL) were added and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with water to give 2-(methylsulfanyl)-4-{[3-(methylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (1.40 g) as a light yellow solid.
Reaction SMILES: Br[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C.Cl>[O:18]1[CH2:19][CH2:20][N:15]([CH:2]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: CCOC(=O)C(Br)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)N1CCOCC1
Yield: 39.1 %

Procedure:
A solution of 2.0 g ethyl 2-bromo-3-phenylpropionate and 2.8 g morpholine in 5 mL DMF was stirred overnight at RT. The mixture was diluted with 75 mL 1% HCl and washed 3×50 mL ether. The aqueous phase was made basic and extracted 3×100 mL EtOAc. The combined extracts were dried over MgSO4, filtered and concentrated. The residue was chromatographed (35% EtOAc:Hex) to afford 0.8 g pure product. NMR (300 MHz, CDCl3) delta 1.12 (t, J=7 Hz, 3H), 3.36 (m, 1H), 4.04 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:12]=1[C:13](O)=O>>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[C:2](=[N:3][CH:4]=[N:5][CH:6]=2)[N:1]=1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Reactant: Nc1cncnc1N
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ncncc2[nH]1

Procedure:
Prepared analogously to Example 14 from 4,5-diaminopyrimidine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.C[Mg]Cl.CC1(C)CCCC(C(=O)C)C1.[C:27]([O:31][CH2:32][C:33](O)=[O:34])(=[O:30])[CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:27]([O:31][CH2:32][C:33]([O:11][C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:12])([CH3:1])[CH2:3]1)([CH3:10])[CH3:9])=[O:34])(=[O:30])[CH2:28][CH3:29]
Reactant: CC1(C)CCCC(C(C)(C)O)C1
Reactant: CCC(=O)OCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)C1CCCC(C)(C)C1
Agent: C[Mg]Cl
Solvent: ClCCl
Product: CCC(=O)OCC(=O)OC(C)(C)C1CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
4-dimethyl-aminopyridine (122 mg, 1.0 mmol) and 2-(3,3-dimethylcyclohexyl)-2-propanol (2.6 g, 15 mmol), [which is obtainable from methylmagnesium chloride and 1-(3,3-dimethylcyclohexyl)-ethanone by a Grignard reaction] are added successively to a solution of 81% (propionyloxy) acetic acid (2.7 g, 16.5 mmol) in CH2Cl2 (15 ml). The reaction solution is now cooled to 0° C. and dicyclohexylcarbodiimide (3.4 g, 16.5 mmol), dissolved in CH2Cl2 (5 ml) is added. After 1 h at 0° C., the cooling is removed, and the reaction mixture is stirred for a further 16 h at room temperature. The precipitate that has precipitated is, then, filtered off, and the filtrate is freed from solvent in a rotary evaporator. The resulting crude product is taken up in n-pentane (20 ml) and the precipitate that forms is again filtered off. The filtrate is also washed twice with 0.5 M HCl and twice with saturated NaHCO3 solution, and the organic phase is then dried over Na2SO4, filtered off, and concentrated in a rotary evaporator. After purification by flash chromatography (cyclohexane/EtOAc=10:1, Rf=0.23) and subsequent bulb tube distillation (BTD: 221° C., 1.3 mbar), 3.1 g (73%) 2-[1-(3,3-dimethylcyclohexyl)-1-methylethoxy]-2-oxoethyl propionate is obtained as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.ClC1N=C(Cl)N=C(Cl)N=1>CN(C=O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]#[N:7]
Reactant: COc1c(Br)ccc(F)c1C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: COc1c(Br)ccc(F)c1C#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-bromo-6-fluoro-2-methoxybenzamide (14 g, 61 mmol) in 100 mL of DMF was added 2,4,6-trichloro-[1,3,5]triazine (12.3 g, 67.0 mmol) portionwise at 0° C. and stirred for 2 hours before poured to ice/water. The white solid was collected by filtration and was washed with water, dissolved in DCM, dried over anhydrous Na2SO4 and concentrated to afford 3-bromo-6-fluoro-2-methoxybenzonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][O:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1.C=C1CCOC(C2C=CC=CC=2)C1.C(=O)C1C=CC=CC=1.CC(CCO)=C>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:7][CH2:6][O:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CC1=CC(c2ccccc2)OCC1
Agent: [Pd]
Agent: C=C(C)CCO
Agent: C=C1CCOC(c2ccccc2)C1
Solvent: CCO
Solvent: O=Cc1ccccc1
Product: CC1CCOC(c2ccccc2)C1

Procedure:
In an autoclave, 10 g of a mixture of 5,6-dihydro-4-methyl-2-phenyl-2H-pyran and tetrahydro-4-methylene-2-phenyl-2H-pyran (prepared from benzaldehyde and isoprenol as described in Swiss Pat. No. 655 932) in 50 ml of ethyl alcohol were hydrogenated in the presence of 0.1 g of 10% Pd on charcoal to yield 9.7 g of pure tetrahydro-4-methyl-2-phenyl-2H-pyran.