Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]([NH2:18])=O)=[N:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([C:16]#[N:18])=[N:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])[CH:7]=1
Reactant: COc1cn(COCC[Si](C)(C)C)nc1C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cn(COCC[Si](C)(C)C)nc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
To a solution of 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamide (compound 280.5, 1.08 g, 4.0 mmol) in toluene (25 mL) was added POCl3 (1.86 mL, 20.0 mmol) dropwise at 0° C. The mixture was stirred for 2 h at 50° C., then quenched with 30 mL of sodium bicarbonate (sat.). The aqueous phase was extracted with 2×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:6) as the eluent to yield 500 mg (49%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][CH2:55][N:54]([C:57](=[O:62])[CH2:58][N:59]([CH3:61])[CH3:60])[CH2:53][CH2:52]2)=[CH:47][CH:46]=1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([CH:51]4[CH2:52][CH2:53][N:54]([C:57](=[O:62])[CH2:58][N:59]([CH3:60])[CH3:61])[CH2:55][CH2:56]4)=[CH:47][CH:46]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN(C)CC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(C4CCN(C(=O)CN(C)C)CC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20.5 mg, 0.050 mmol) and 1-[4-(4-amino-phenyl)-piperidin-1-yl]-2-dimethylamino-ethanone di-TFA salt (24 mg g, 0.050 mmol) were combined in i-PrOH (1 mL) and TEA (10.6 mg, 0.11 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/1120 gradient over 10 min) and lyophilized to provide 24 mg (80%) of 2-{4-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.31 (s, 1H), 9.10 (br s, 1H), 8.48 (s, 1H), 7.51 (d, 2H, J=8.1 Hz), 7.22-7.34 (2H), 7.13-7.16 (m 3H), 4.38 (q, 2H, J=7.0 Hz), 3.09 (br s, 2H), 2.95-3.02 (m, 6H), 2.71-2.80 (m, 2H), 2.39 (s, 6H), 2.11-2.22 (m, 2H), 1.55-1.93 (m, 4H), 1.39 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([S:21]([N:24](CC2C=CC(OC)=CC=2OC)[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([S:21]([NH:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3ccnn3C)c(Cl)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1Cl
Yield: 77 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (314 mg, 0.51 mmol) prepared in Example 79b, triethylsilane (0.50 mL), trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (183 mg, 77%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](F)[CH:5]=[C:4]([CH2:9][F:10])[N:3]=1.[CH3:11][SH:12].O1CCCC1.[Na]>CO>[NH2:1][C:2]1[N:3]=[C:4]([CH2:9][F:10])[CH:5]=[C:6]([S:12][CH3:11])[N:7]=1
Reactant: CS
Reactant: Nc1nc(F)cc(CF)n1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CSc1cc(CF)nc(N)n1
Reaction time: 1 h

Procedure:
A mixture of 1.0 part of 2-amino-4-fluoro-6-fluoromethylpyrimidine, 3.0 parts of methanethiol and 50 parts of dry tetrahydrofuran was stirred at 5° C. whilst a solution of 0.16 parts of sodium in 20 parts of dry methanol was added dropwise. The temperature was kept below 10° C. with ice-bath cooling. When the addition was complete, stirring was continued for 1 hour. The resulting solution was evaporated and the residue was diluted with water and extracted three times with 50 parts of ether. The ethereal solutions were combined and dried (MgSO4). The solvent was evaporated and the crude product was purified by recrystallisation from carbon tetrachloride to give 2-amino-4-fluoromethyl-6-methylthiopyrimidine m.p. 95°-97° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:26]([CH3:27])=[CH:25][S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:26]([CH3:27])=[CH:25][S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccno3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([C:16]([CH3:36])([CH3:35])[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH3:34])=[CH:24][CH:25]=1)=[O:18])C(=O)[O-])(C)C>ClCCl>[CH2:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C:16]([CH3:36])([CH3:35])[NH2:12])=[CH:25][CH:24]=1)[CH3:34]
Reactant: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl[2-({6-[(2-ethylphenyl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 77, 88.6 mg) was dissolved in dichloromethane (2 mL) to give a yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 minutes, the solvent was evaporated under vacuum affording a yellow oil that was charged on a 5 g SCX cartridge and was then flushed with mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (67.1 mg).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:35]=[CH:36][C:37]([O:39][CH3:40])=[O:38])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Yield: 93.3 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylvinyl)indol-1-ylmethyl]-3-methoxybenzoate (1.11 g) in methanol (10 ml) was treated with 10% (w/w) palladium on carbon (0.28 g) and shaken under 3.45 bars of hydrogen for 24 hours. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was evaporated to give t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoate (1.04 g, 94%) as a grey foam, mp 58°-60°.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[CH:14]=[N:15][CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[C:14]([N+:6]([O-:9])=[O:7])=[N:15][CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Nc1cncc(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Nc1cc(Br)cnc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
To a mixture of concentrated H2SO4 (60 mL, 1126 mmol) and fuming HNO3 (40 mL, 895 mmol), ethyl (5-bromopyridin-3-yl)carbamate (21.5 g, 88 mmol) was added portionwise at 0° C. After stirring at 0° C. for 5 min, the mixture was stirred at rt overnight and poured onto ice water. A crash out formed and was filtered off and washed thoroughly with water and dried. Ethyl (5-bromo-2-nitropyridin-3-yl)carbamate (21.26 g, 84%) was thus obtained as a white solid. LCMS (m/z): 290.1 (MH+), 0.76 min. 1H NMR (400 MHz, CDCl3) δ ppm 9.63 (br. s., 1H) 9.33 (d, J=2.0 Hz, 1H) 8.28 (d, J=2.0 Hz, 1H) 4.32 (q, J=7.3 Hz, 3H) 1.68 (br. s., 2H) 1.38 (t, J=7.0 Hz, 4H).
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.Cl[C:17]1[N:22]=[C:21]([C:23]2[C:24]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[CH:33][CH:32]=3)=[C:25]3[CH2:30][CH2:29][CH2:28][N:26]3[N:27]=2)[CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([C:17]1[N:22]=[C:21]([C:23]2[C:24]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[CH:33][CH:32]=3)=[C:25]3[CH2:30][CH2:29][CH2:28][N:26]3[N:27]=2)[CH:20]=[CH:19][CH:18]=1)=[CH2:2]
Reactant: Clc1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3)n1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3)n1
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Add tributylvinyltin (0.059 mL, 0.19 mmol) to a solution of 4-[2-(6-chloro-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline, EXAMPLE 101, (59 mg, 0.17 mmol) in toluene (0.7 mL) at RT. Bubble nitrogen into the reaction mixture for 5 min and add tetrakis-(triphenylphosphine) palladium (0) (10 mg, 0.0085 mmol). Bubble nitrogen into the solution for an additional 2 min and heat the reaction to 110° C. for 18 h. Concentrate the reaction in vacuo and purify by flash column chromatography (SiO2, 20-40% acetone/hexanes) to provide the title compound (35 mg, 62%) as a white solid.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:43])[N:30](COC(=O)C(C)(C)C)[CH:31]=[N:32]2)=[C:27]([OH:44])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O[CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:43])[NH:30][CH:31]=[N:32]2)=[C:27]([O:44][CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)C(=O)OCn1cnc2cc(OCc3ccccc3)cc(O)c2c1=O
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: O=c1[nH]cnc2cc(OCc3ccccc3)cc(OC3CCOCC3)c12
Temperature: 5 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Di-tert-butyl azodicarboxylate (16.3 g) was added portionwise to a stirred mixture of 7-benzyloxy-5-hydroxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (17 g), 4-hydroxytetrahydropyran (5.4 g) and methylene chloride (200 ml) that had been cooled to 5° C. The mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The mixture was evaporated and the residue was dissolved in a saturated methanolic ammonia solution. The resultant mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was dried under vacuum to give 7-benzyloxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (12.5 g); NMR Spectrum: (DMSOd6) 1.6–1.7 (m, 2H), 1.85–1.95 (m, 2H), 3.5 (m, 2H), 3.9 (m, 2H), 4.75 (m, 1H), 5.22 (s, 2H), 6.7 (d, 1H), 6.8 (d, 1H), 7.3–7.5 (m, 5H), 7.9 (s, 1H); Mass Spectrum: M+H+ 353.
Reaction SMILES: CNS(N(S(NC)(=O)=O)C(=O)C1C=CC=CC=1)(=O)=O.[C:20]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[O:38][C:37](=[O:39])[C:36]3[CH:40]=[C:41]([S:44]([N:47]([CH3:49])[CH3:48])(=[O:46])=[O:45])[CH:42]=[CH:43][C:35]=3[N:34]=2)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][N:52]=1>>[C:20]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([NH:34][C:35]2[CH:43]=[CH:42][C:41]([S:44]([N:47]([CH3:48])[CH3:49])(=[O:45])=[O:46])=[CH:40][C:36]=2[C:37]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][N:52]=2)=[O:39])=[O:38])[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: Nc1ccc(Cl)cn1
Reactant: CN(C)S(=O)(=O)c1ccc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)oc(=O)c2c1
Agent: CNS(=O)(=O)N(C(=O)c1ccccc1)S(=O)(=O)NC
Product: CN(C)S(=O)(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using methods substantially equivalent to those described in Example 51-D, 2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonylbenzamide (0.912 g, 85%) was prepared from 2-(1-Boc-piperidin-4-yl)-6-(N,N-dimethylaminosulfonyl)-4H-3,1-benzoxazin-4-one and 2-amino-5-chloropyridine.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:4]=1)=[CH2:2].[OH-:25].[Na+].OO.Cl>C1COCC1.O>[OH:25][CH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:4]=1)[CH3:2]
Reactant: C=Cc1cc(C(=O)OC)cc2cc(OCc3ccccc3)ccc12
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(C)O)c2ccc(OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.3 g (0.9 mmol) of 1-vinyl-3-carbomethoxy-6benzyloxynaphthalene and 0.9 ml (0.9 mmol) of 1.0M BH3.THF complex in 15 ml of THF is stirred at 25° C. for 2 hours. To this is added 1 ml of H2O, 1 ml of 1N NaOH and 1 ml of 30% H2O2 which is then stirred at 25° C. for 2 hours. The mixture is acidified to pH ~1 using 1N HCl and extracted with ethyl acetate. The organics are dried (MgSO4) and concentrated in vacuo. Purification by flash silica gel chromatography using 15% ethyl acetate in hexanes as an eluent affords 0.08 g of 1-hydroxyethyl-3-carbomethoxy-6-benzyloxynaphthalene in the form a yellow oil which is used directly in the next step.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][CH:29]=2)[N:11]2[CH2:14][C:13](=[C:15]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12]2)=[CH:6][CH:5]=1.O>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][OH:35])=[CH:32][CH:33]=2)[N:11]2[CH2:12][C:13](=[C:15]([C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(C=O)cc2)C1)c1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(CO)cc2)C1)c1cc(F)cc(F)c1
Reaction time: 1 h
Yield: 57.8 %

Procedure:
0.020 g of sodium borohydride is added to a solution of 0.50 g of (RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine in 15 cm3 of methanol at 0° C. After 1 hour at 0° C. , 40 cm3 of water are added and the product extracted with 100 cm3 of dichloromethane. The organic phase is washed twice with 40 cm3 of water and then 40 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 14 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 by volume) and collecting 20 cm3 fractions. Fractions 20 to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of (RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz): 3.02 (3H, s, SCH3), 3.90 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.42 (2H, d, J=5 Hz, OCH2), 4.75 (1H, s, NCH), 5.10 (1H, t, J=5 Hz, OH), between 7.10 and 7.50 (11H, m, 11CH arom.)].
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[CH2:13]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Ic1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a stirred suspension of 4-iodo-1H-pyrazole (1.50 g, 7.73 mmol) and potassium carbonate (2.67 g, 19.3 mmol) in acetone was added benzyl bromide (0.96 mL, 8.07 mmol) and the reaction was refluxed for 3 h. After cooling to room temperature the mixture was concentrated onto silica gel in vacuo and eluted through a short silica plug (sequential elution-hexane, 10% diethyl ether in hexanes) to provide the title compound as a white solid (2.12 g, 97% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>CN(C=O)C>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:32]1[C:27]([CH3:26])=[N:28][CH:29]=[CH:30][CH:31]=1)[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: Cc1ncccc1B(O)O
Solvent: CN(C)C=O
Product: Cc1ncccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-methylpyridine-3-boronic acid (CAS RN 899436-71-6) and using DMF as solvent for the reaction. Yellow sticky liquid (11%). MS (ESI): m/z=439.8 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:9](OC)(OC)[O:10][CH3:11].C(OC(=O)C)(=O)C>>[CH3:9][O:10][CH:11]=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: COC(OC)OC
Solvent: CC(=O)OC(C)=O
Product: COC=CC(=O)CC(=O)OC

Procedure:
From methyl acetoacetate (30.2 g, 0.26 mol), trimethyl orthoformate (26.7 g, 0.18 mol) and acetic anhydride (53 g., 0.52 mol): 4.3 g, 15%; bp=100°-105° C. at 0.5 mm Hg (lit.1 80°-84° C. at 0.15 mm Hg); NMR (CDCl3) δ 2.4 (d, 3H), 3.8 (d, 3H), 4.1 (s, 3H), 7.6 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Br[C:20]1[C:21]2[C:22]3[CH:36]=[CH:35][S:34][C:23]=3[C:24](=[O:33])[NH:25][C:26]=2[C:27]([CH3:32])=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:31][O:30][C:29]1[CH:28]=[C:27]([CH3:32])[C:26]2[NH:25][C:24](=[O:33])[C:23]3[S:34][CH:35]=[CH:36][C:22]=3[C:21]=2[C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Br)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Yield: 79.1 %

Procedure:
Following General Procedure E, tert-butyl 2-(4-bromophenyl)propan-2-ylcarbamate (0.44 g, 1.4 mmol) was reacted with 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (0.45 g, 1.4 mmol) to afford the desired product (0.53 g, 79%) as a brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1O.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cc1ccc(O)c(Cl)c1)Oc1cc(Cl)c(Cl)cc1Cl
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A solution of 4 g (21.6 mmol) of 3-chloro-4-hydroxyphenylacetic acid in 130 mL of ethyl acetate is slowly added to a solution of 4.7 g (23.6 mmol) of 2,4,5-trichlorophenol and 4.9 g (23.6 mmol) of DCC in 22 mL of dichloromethane and the reaction mixture is stirred overnight. The precipitate formed is separated by filtration and the solution is chilled to precipitate the rest of N,N-dicyclohexylurea. After a second filtration, the filtrate is washed three times with a solution of sodium bicarbonate, dried over MgSO4 and evaporated to dryness in a rotary evaporator. The resulting oil is chromatographed through silica gel eluting with hexanes and increasing amounts of dichloromethane. The desired product appears in the fraction eluted with 50% dichloromethane. After elimination of the solvent 2.8 g of product are isolated (34% yield), with the following analytical data: mp=77° C. Rf=0.33 (AcOEt/hexanes 3:7).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([F:15])(F)[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[F-].CO[CH2:21][N:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:23][Si](C)(C)C>C(#N)C>[CH2:1]([N:8]1[C:9](=[O:16])[C@:10]2([F:15])[C@@H:11]([CH2:21][N:22]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23]2)[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(F)(F)C(=O)N1Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: [F-]
Agent: [Li+]
Solvent: CC#N
Product: O=C1[C@@H]2CN(Cc3ccccc3)C[C@]2(F)C(=O)N1Cc1ccccc1

Procedure:
To a solution of 1-benzyl-3,3-difluoropyrrolidine-2,5-dione (325 mg, 1.44 mmol) in acetonitrile (3.6 mL), LiF (56 mg, 1.50 eq) and a stir bar were added. The reaction mixture was sonicated for 2.5 hr at rt. N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.4 mL, 1.59 mmol, 1.10 eq) and LiF (37 mg, 1.44 mmol, 1 eq) were added and continued to sonicate for 0.5 hr. The reaction mixture was concentrated and the salt was removed by filtration. The crude residue was purified by column chromatography and eluted with 2 to 20% EtOAc/heptane and purified further with 2 to 10% EtOAc/heptane. The desired fractions were faintly ultraviolet active but were visualized with KMNO4 stain. The title compound was isolated as a yellow oil (196 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.10-7.43 (m, 10 H) 4.57-4.75 (m, 2 H) 3.63 (s, 2 H) 3.56-3.65 (m, 1 H) 3.33-3.41 (m, 1 H) 3.13 (d, J=9.29 Hz, 1 H) 2.74 (dd, J=9.35, 7.03 Hz, 1 H) 2.57-2.70 (m, 1 H). m/z (APCI+) for C20H20FN2O2 339.20 (M+H)+.