Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].C(N(CC)CC)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH2:33][SH:34])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:34][CH2:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1cccc(CS)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSCc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
2-Bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and triethylamine were combined in CH2Cl2. (3-trifluoromethyl-phenyl)-methanethiol was added, and the reaction was stirred at room temperature for at least 1 hour. After workup, the crude material was purified by silica gel chromatography.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[Br:15])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>CN(C)C=O>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[Br:15])[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
Place (2-bromo-5-fluoro-phenyl)-carbamic acid tert-butyl ester (2.00 g, 6.90 mmol) and dimethylformamide (40 mL) in a round bottom flask. Cool the solution to 0° C., add sodium hydride (60% dispersion in mineral oil) (0.303 g, 7.59 mmol), remove the ice bath and stir this suspension for 25 minutes allowing it to warm slowly towards ambient temperature. Cool the resulting mixture to 0° C. once again, and add iodomethane (0.56 mL, 8.96 mmol). Stir the resulting mixture overnight, allowing it to warm to ambient temperature. Quench the reaction with brine and extract the resulting mixture into ethyl acetate. Combine the extracts and wash with brine; then dry (sodium sulfate) and concentrate in vacuo. Purify the resulting material by flash chromatography (silica gel; 35%-50% dichloromethane gradient in hexanes) to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.[H-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][O:9][CH2:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=2)[CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COc1ccc(Br)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1COCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
0.8 g of 5-bromo-2-methoxyphenyl methanol was dissolved in 30 ml tetrahydrofuran. 2.6 g of 4-(trifluoromethyl)benzyl bromide and 0.22 g of sodium hydride (60% oily) were added thereto, followed by stirring at room temperature for 16 hours. Water was added to the reaction solution, followed by extracting with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 1.4 g of 4-bromo-1-methoxy-2-({[4-(trifluoromethyl)benzyl]oxy}methyl)benzene from fractions eluted with hexane-ethyl acetate (9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]5)[CH2:16]3)[CH2:22]4)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].[O:34]=[C:35]1[NH:39][C:38](=[O:40])[CH:37]([CH2:41][C:42]2[CH:52]=[CH:51][C:45]([O:46][CH2:47][C:48](O)=[O:49])=[CH:44][CH:43]=2)[S:36]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:34]=[C:35]1[NH:39][C:38](=[O:40])[CH:37]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:46][CH2:47][C:48]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]56[CH2:24][CH:19]7[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]7)[CH2:22]5)[CH2:16]6)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:49])=[CH:51][CH:52]=2)[S:36]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 86.1 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[4-(1-adamantyl)phenoxy]phenyl}-N-methylcarbamate (1.34 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.83 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[F-].[Cs+].Cl[C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)[CH:21]=[N:20][CH:19]=1.O>CS(C)=O>[N:26]1[N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[C:24]([C:22]2[N:23]=[C:18]([NH:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)[CH:19]=[N:20][CH:21]=2)[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1cncc(-c2cnn3ccccc23)n1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Temperature: 100 °C
Reaction time: 22 h
Yield: 34 %

Procedure:
Tert-Butyl (3R)-3-aminopiperidine-1-carboxylate (0.51 g, 2.54 mmol) and cesium fluoride (0.83 g, 5.46 mmol) were added to a stirred solution of 3-(6-chloropyrazin-2-yl)pyrazolo[1,5-a]pyridine (Preparation 27b, 0.42 g, 1.82 mmol) in dimethylsulfoxide (20 mL). The resulting mixture was stirred at 100° C. for 22 h before being poured onto 50 mL of water. The resultant suspension was extracted with ethyl acetate (×2) and the combined organic layers were dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified by flash chromatography (3:7 to 7:3 ethyl acetate/hexane) to give the title compound (0.244 g, 34%) as a yellowish foam.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(#N)C.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)=C2Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc2c(Br)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 1 h

Procedure:
Combine 1-bromo-2-(4-methanesulfonylphenyl)-3,4-dihydro-6-methoxynaphthalene and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.8 equiv.) in 10 volumes acetonitrile and 5 volumes of THF. Under nitrogen atmosphere, heat reaction contents to 73-75° C. Monitor reaction progress by GC analysis until reaction completion. Additional DDQ (0.2-0.3 equiv.) may be required for reaction completion. Cool contents to ambient temperature and add 10 volumes 1 N sodium hydroxide. Stir for approximately 1 hour and filter. Rinse filter cake with 2 volumes water, 3×5 volumes 50% acetonitrile/water and finally 3 volumes methanol. Vacuum dry the filter cake at 65° C. to give the title compound.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:26]=[C:25]([N:27]5[CH:31]=[CH:30][CH:29]=[CH:28]5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:11]=2)[O:8][CH:9]=1)=[O:4].[OH:33][CH2:34][CH2:35][NH:36][CH2:37][CH2:38][OH:39]>>[OH:33][CH2:34][CH2:35][N:36]([CH2:37][CH2:38][OH:39])[C:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:26]=[C:25]([N:27]5[CH:28]=[CH:29][CH:30]=[CH:31]5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:11]=2)[O:8][CH:9]=1)=[O:4]
Reactant: OCCNCCO
Reactant: COC(=O)c1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Product: O=C1CC(c2cccc(-c3nc(C(=O)N(CCO)CCO)co3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
A solution of 2-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-oxazole-4-carboxylic acid methyl ester (Example 25)(88 mg) in 2-(2-hydroxy-ethylamino)-ethanol (2 mL) was stirred at 50° C. for 6 h. The mixture was partitioned between H2O and EtOAc. The organic layer was dried and evaporated in vacuum, and the residue was triturated with EtOAc to give the title compound (32 mg) as light-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Br:17]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(=O)c3ccccc3oc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c2ccccc2oc2cc(CBr)ccc12
Yield: 98.2 %

Procedure:
A mixture of 3-methyl-9H-xanthen-9-one (1.62 g, 7.71 mmol), N-bromosuccinic acid imide (1.37 g, 7.71 mmol), benzoyl peroxide (93 mg, 0.39 mmol) and carbon tetrachloride (15 ml) was heated under reflux for 15 hours. The insoluble matter was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to give 3-bromomethyl-9H-xanthen-9-one (2.19 g, 7.57 mmol, 98%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Pd](Cl)Cl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCCCCCCCOc1ccc([Mg]Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 92 %

Procedure:
4-octyloxyphenylmagnesium bromide (124 g, 25% solution in tetrahydrofuran) is added dropwise over ten hours to a refluxing solution of 4-bromobenzonitrile (17 g), palladium (II) chloride (0.68 g) and triphenylphosphine (2.0 g) in tetrahydrofuran (100 ml). [HPLC: yield 92-94%]. After cooling to room temperature tetrahydrofuran is removed under vacuum. Water (20 ml) and toluene (150 ml) are added and the mixture filtered hot (80-85 C.). The aqueous phase is separated off, and the solvent removed by distillation. The crude product is recrystallised from ethanol/n-hexane to give 4'-octyloxybiphenyl-4-carbonitrile as a solid. 1H NMR (CDCl3): 0.89(t,3H), 1.29-1.50(m,10H), 1.81(quint.2H), 4.00(t,2H), 6.99(d,2H), 7.52(d,2H), 7.63(d,2H), 7.68(d,2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:33][CH2:32]1)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:4]=1[C:5]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:34]2[CH2:35][CH2:36][CH:31]([NH:30][C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:32][CH2:33]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:7]
Reactant: COc1ccc(S(C)=O)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(S(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-methylsulfinylbenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12
Reactant: Oc1ncnc2[nH]ncc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2[nH]ncc12

Procedure:
31.1 g. of 4-hydroxypyrazolo[3,4-d]pyrimidine are heated at reflux with 200 ml. of phosphorous oxychloride for 12 hours. The excess phosphorous oxychloride is distilled off and the residue is boiled with benzene. After distilling off the benzene and trituration with petroleum ether, there remain 15.8 g. of 4-chloropyrazolo[3,4-d]pyrimidine as light yellow crystals, m.p. 94°-96°. This product is pure enough for further use.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1
Reactant: N#Cc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C#N)c1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 1H-Imidazole-4-carbonitrile (300 mg, 3.22 mmol) and 4-Fluoro-3-methoxynitrobenzene (552 mg, 3.22 mmol) in DMF (Volume: 6446 μl) was added K2CO3 (891 mg, 6.45 mmol). The resulting mixture was brought to 120° C. and stirred overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo to give 1-(2-methoxy-4-nitrophenyl)-1H-imidazole-4-carbonitrile (698 mg, 2.86 mmol, 89% yield). LC-MS (M+H)+=245.0. 1H NMR (500 MHz, MeOD) δ ppm 8.30-8.34 (1H), 8.19-8.23 (1H), 8.09-8.12 (1H), 8.00-8.05 (1H), 7.71-7.79 (1H), 4.02-4.10 (3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([OH:15])[CH2:6][O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH3:2].C(N(CC)CC)C.[CH3:23][S:24]([CH2:27][CH2:28][C:29](Cl)=[O:30])(=[O:26])=[O:25]>ClCCl>[CH2:1]([O:3][CH2:4][CH:5]([OH:15])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:29](=[O:30])[CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CS(=O)(=O)CCC(=O)Cl
Reactant: CCOCC(O)COc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(O)COc1ccc(NC(=O)CCS(C)(=O)=O)cc1
Yield: 94.2 %

Procedure:
A 2.11 g quantity of 4-(3-ethoxy-2-hydroxypropoxy)aniline and 1.53 g of triethylamine were dissolved in 50 ml of dichloromethane. To the solution was added 1.71 g of 3-(methylsulfonyl)propionyl chloride with ice cooling. The same subsequent procedure as in Example 2 was repeated and recrystallization from benzene was performed, giving 3.25 g of N-[4-(3-ethoxy-2-hydroxypropoxy)phenyl]-3-(methylsulfonyl)propionamide in a yield of 94.2 %. M.p. 111° to 112° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH2:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[C:13](=[O:15])[NH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:35]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[Cl:35][C:9]1[C:10]2[NH:14][C:13](=[O:15])[N:12]([CH2:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[C:11]=2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(CC)c1cccc2[nH]c(=O)n(CC(=O)OC(C)C)c12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCC(CC)c1ccc(Cl)c2[nH]c(=O)n(CC(=O)OC(C)C)c12
Temperature: 70 °C
Reaction time: 84 h
Yield: 75.3 %

Procedure:
To a solution of isopropyl [7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate (17.9 g, 58.8 mmol) and 2,2′-azobisisobutyronitrile (966 mg, 5.88 mmol) in chlorobenzene (170 mL) was added portionwise N-chlorosuccinimide (7.85 g, 58.8 mmol) at 65° C., and the mixture was stirred at 70° C. for 3.5 days. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate (200 mL), and the aqueous layer was separated and extracted with ethyl acetate (200 mL). The combined organic layer was washed with aqueous sodium chloride (200 mL) and brine (150 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 15-25% ethyl acetate/n-hexane gradient mixture to give the title compound (15.0 g, 44.3 mmol, 75.3%) as a solid.
Reaction SMILES: C(C1C([C:9]2[N:14]=[C:13]([CH3:15])[C:12]([C:16]([C:18]3[C:19]([CH3:32])=[N:20][C:21](C4C(CC)=NC=NC=4)=[N:22][CH:23]=3)=[O:17])=[CH:11][N:10]=2)=CN=CN=1)C.[BH4-].[Na+].[CH3:35]COC(C)=O>CCO>[CH2:32]([C:19]1[C:18]([CH:16]([C:12]2[C:13]([CH3:15])=[N:14][CH:9]=[N:10][CH:11]=2)[OH:17])=[CH:23][N:22]=[CH:21][N:20]=1)[CH3:35]
Reactant: CCOC(C)=O
Reactant: CCc1ncncc1-c1ncc(C(=O)c2cnc(-c3cncnc3CC)nc2C)c(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ncncc1C(O)c1cncnc1C
Reaction time: 0.5 h

Procedure:
To a solution of 63 mg of (4-ethylpyrimidin-5-yl)-4-methylpyrimidin-5-yl ketone in 1 ml EtOH chilled in an ice bath was added 7.4 mg of sodium borohydride. After stirring the solution for 30 minutes, 1 ml of EtOAc was added followed by 1 ml NaH2PO4 (pH=3.0). The mixture was stirred vigorously and the aqueous extracted with EtOAc (3 times). The organic layers were combined, dried (MgSO4) and filtered through silica gel with EtOAc. The solvent was evaporated to yield 52 mg of pure 1-(4-ethylpyrimidin-5-yl)-1-(4-methylpyrimidin-5-yl)methanol.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@@H:10]1[CH3:19])C1C=CC=CC=1>CO.[H][H].[Pd]>[NH2:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@@H:10]1[CH3:19]
Reactant: COC(=O)N1CC[C@@H](NCc2ccccc2)[C@@H](C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)N1CC[C@@H](N)[C@@H](C)C1
Yield: 101.6 %

Procedure:
Methyl (3S,4R)-4-(benzylamino)-3-methylpiperidine-1-carboxylate (8.0 g, 0.02 mol) was dissolved in methanol (200 mL) and hydrogenated at room temperature, under 50 psi of hydrogen pressure, in the presence of palladium (2.5 g) on carbon for 2 h. The solution was then filtered and concentrated under reduced pressure to yield 3.5 g (92%) Methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate as liquid.
Reaction SMILES: [CH3:1][CH:2]1[S:26][C:5]2[C:6]([CH3:25])([CH3:24])[O:7][C:8]3[CH:13]=[C:12]([CH:14]([CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:15])[CH:11]=[C:10]([OH:23])[C:9]=3[C:4]=2[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:42].[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][CH2:51][C:52](O)=[O:53])[CH2:45][CH2:44]1>C(Cl)Cl>[ClH:42].[CH3:1][CH:2]1[S:26][C:5]2[C:6]([CH3:25])([CH3:24])[O:7][C:8]3[CH:13]=[C:12]([CH:14]([CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:15])[CH:11]=[C:10]([O:23][C:52](=[O:53])[CH2:51][CH2:50][CH2:49][N:46]4[CH2:45][CH2:44][O:43][CH2:48][CH2:47]4)[C:9]=3[C:4]=2[CH2:3]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)S1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CC(C)S1
Temperature: 25 °C

Procedure:
1,2-Dihydro-2,4,4-trimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno-[2,3-c][1]benzopyran, dicyclohexylcarbodiimide and γ-morpholinobutyric acid hydrochloride are combined in methylene chloride and stirred at room temperature. The insoluble dicyclohexylurea is removed by filtration and the methylene chloride is removed on a rotary evaporator. The residue is crystallized from ether to give 1,2-dihydro-2,4,4-trimethyl-9-[4-(morpholino)butyryloxy]-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran hydrochloride.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[C:7]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH2:21]([N:28]([CH2:32][Si](C)(C)C)[CH2:29]OC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:21]([N:28]1[CH2:32][CH2:10][C:9]([C:7]2[CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:4]=[C:5]([C:15]([F:18])([F:16])[F:17])[CH:6]=2)([C:11]([F:14])([F:13])[F:12])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
To the solution of 2,6-bis(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (1.25 g) and N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (5.0 g) in dichloromethane was added dropwise the solution of trifluoroacetic acid (0.038 g) in dichloromethane while cooling with ice. On completion of the dropwise addition, the mixture was warmed to room temperature and stirred over night. The mixture was washed with saturated sodium bicarbonate water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed under reduced pressure, and the residue was then purified by silica gel chromatography to yield 4-[1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl]-2,6-bis(trifluoromethyl)pyridine (1.52 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][C:19]([CH3:20])=[C:6]12)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1CCCCC1.C(OCC)(=O)C>[CH3:3][N:5]([CH2:11][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][N:21]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][C:19]([CH3:20])=[C:6]12)=[O:4])[CH3:6]
Reactant: C1CCNCC1
Reactant: Cc1scc2c1N(C(=O)CCl)c1ccccc1NC2=O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Cc1scc2c1N(C(=O)CN1CCCCC1CN(C)C)c1ccccc1NC2=O

Procedure:
The title compound is prepared analogously to Example 2 from 4-(chloroacetyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-(dimethylamino)methyl]piperidine to give colorless crystals, mp. 172°-173° C. (cyclohexane/ethyl acetate 4:1 v/v).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.Cl[CH2:28][CH:29]([OH:31])[CH3:30]>>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:22][CH2:23][N:24]([CH2:28][CH:29]([OH:31])[CH3:30])[CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)s1
Reactant: CC(O)CCl
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCN(CC(C)O)CC4)cc3)n2)s1

Procedure:
By treatment of [4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-piperazin-1-yl-phenyl)-amine with 1-chloro-2-propanol. 1H-NMR (CDCl3) δ: 1.10 (d, 3H, J=6.0 Hz, CH3), 2.26-2.33 (m, 2H, CH2), 2.49-2.53 (m, 2H, CH2), 2.61 (s, 3H, CH3), 2.63 (s, 3H, CH3), 2.76-2.80 (m, 2H, CH2), 3.07-3.13 (m, 4H, CH2), 3.83 (m, 1H, CH), 6.81 (d, 1H, J=4.4 Hz, pyrimidinyl-H), 6.88 (d, 2H, J=8.8 Hz, Ph-H), 7.02 (brs, 1H, OH), 7.44 (d, 2H, J=8.8 Hz, Ph-H), 8.30 (d, 1H, J=4.4 Hz, pyrimidinyl-H).