Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:22]=[C:16]2[CH:17]=[N+:18]([O-])[CH:19]=[CH:20][C:15]2=[N:14]1.P(Cl)(Cl)([Cl:25])=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:25][C:17]1[C:16]2=[CH:22][N:13]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:5][C:4]=3[Cl:12])[N:14]=[C:15]2[CH:20]=[CH:19][N:18]=1
Reactant: CS(=O)(=O)c1cc(Cl)c(-n2cc3c[n+]([O-])ccc3n2)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: CS(=O)(=O)c1cc(Cl)c(-n2cc3c(Cl)nccc3n2)c(Cl)c1
Temperature: 85 °C
Yield: 35 %

Procedure:
2-(2,6-Dichloro-4-methanesulfonylphenyl)-2H-pyrazolo[4,3-c]pyridine-5-oxide (640 mg, 1.79 mmol) was added to a solution of tetrabutylammonium chloride (497 mg, 1.79 mmol) in phosphorous oxychloride (5 mL) and the reaction mixture was heated at 85° C. for 4 hours. The reaction mixture was cooled and partitioned between ethyl acetate and sodium hydrogen carbonate (sat. aq.). The organic phase was washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography (40% ethyl acetate in cyclohexane) to afford the title compound as a white solid (238 mg, 35% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.35 (d, J=1.0 Hz, 1H), 8.36 (s, 2H), 8.14 (d, J=6.3 Hz, 1H), 7.76 (dd, J=6.3, 1.0 Hz, 1H), 3.49 (s, 3H). LCMS (Method D): RT=3.19 min, m/z: 376 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]3[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccc2nc(N)sc2c1
Product: CCOC(=O)c1cn2c(n1)sc1cc(C)ccc12
Yield: 57.6 %

Procedure:
Ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from 6-methyl-2-amino benzothiazole (3.2 g, 20 mmol) and ethyl bromopyruvate (4.0 g, 20.4 mmol), 3.0 g (57% Yield) of ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as brown solid. (M+H) 261.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([S:28]([C:24]5[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=5)(=[O:30])=[O:29])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1nc(C2CC2)cnc1O[C@H]1C[C@H]2CNCCN2C1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 49B (200 mg, 0.674 mmol)) in dichloromethane (3 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (198 mg, 0.809 mmol) followed by triethylamine (0.3 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by flash chromatography (ethyl acetate/hexane=1:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.38 (m, 1H), 2.04-2.20 (m, 4H), 2.42 (m, 3H), 3.00 (m, 2H), 3.66 (m, 1H), 3.82 (m, 1H), 5.20 (m, 1H), 7.92 (m, 1H), 7.98 (m, 1H), 8.03 (m, 1H), 8.11 (m, 3H); MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl.N1C=CC=CC=1>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([Br:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cccc(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(Br)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc(Br)c1
Yield: 55.8 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3-bromoaniline (1.98 g, 11.6 mmol) in 16 mL of pyridine. The crude product was recrystallized from ethyl acetate-hexanes to yield 1.99 g of the title compound, mp 194°-196° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[CH2:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH:14]=O)[CH:10]=[CH2:11]>O.CO>[CH2:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH:14]=[N:7][OH:8])[CH:10]=[CH2:11]
Reactant: NO
Reactant: C=CCc1cccc(Cl)c1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCc1cccc(Cl)c1C=NO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.58 g of sodium bicarbonate were added to a solution of 4.62 g of hydroxylamine hydrochloride in 50 ml of water, and the mixture was cooled to 0° C. A solution of 9.7 g (44.32 mmol) of 2-allyl-6-chlorobenzaldehyde in 50 ml of methanol was then added dropwise, and the mixture was stirred at room temperature overnight. The methanol was subsequently removed under reduced pressure and the residue was stirred into 300 ml of water. The aqueous phase was extracted with diethyl ether and the combined organic phases were washed with saturated ammonium chloride solution and dried, and the solvent was removed. This gave 8.7 g (quantitative) of 2-allyl-6-chlorobenzaldehyde oxime in the form of a viscous oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[H-].[Na+].O>CN(C)C=O>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(CN(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
In an argon atmosphere, diphenylamine (338 mg, 2.00 mmol) and 4-bromobenzyl bromide (500 mg, 2.00 mmol) were dissolved in dimethylformamide (8 mL), and to the solution was added sodium hydride (88 mg, 2.2 mmol) under ice -cooling, followed by stirring at room temperature for 4 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (14:1 hexane/acetone) to obtain N-(4-bromobenzyl)diphenylamine (478 mg, 71%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[N:4][C:3]1=[O:19].S(Cl)([Cl:23])(=O)=O.N>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]2[S:8][C:9]([Cl:23])=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[N:4][C:3]1=[O:19]
Reactant: Cc1csc2c1c(-c1ccccc1Cl)nc(=O)n2C
Reactant: O=S(=O)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)sc2c1c(-c1ccccc1Cl)nc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5 g of 1-methyl-4-(o-chlorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 30 ml of chloroform is added dropwise 1.62 g of sulfuryl chloride in 6 ml of chloroform. After stirring the reaction mixture for 2 hours at room temperature, the reaction mixture is neutralized with aqueous ammonia, then extracted with chloroform. The chloroform extracts are washed with water, dried, evaporated under reduced pressure to a residue to give crystals of 1-methyl-4-(o-chlorophenyl)-5-methyl-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one, which are recrystallized from ethanol to give 1.252 g of crystals having a melting point of 199.5° - 200.5°C; yield 74.5 %.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH2:11][CH2:10]1
Reactant: CCCC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1CCN(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1 eq 1-(pyridin-2-ylmethyl)piperazine hydrochloride in dry dichloromethane are added 1.5 eq butanoyl chloride and 2.5 eq triethylamine. After stirring for 6 hours at room temperature the solvent is removed in vacuo and the residue re-dissolved in ethyl acetate. The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, ethyl acetate is removed in vacuo and the crude product is purified by column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([O:15][CH3:16])([CH2:12][O:13][CH3:14])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1>>[CH3:16][O:15][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH:3]=1)([CH2:12][O:13][CH3:14])[CH2:9][CH2:10][OH:11]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COCC(CCO)(OC)c1cccc(O)c1
Product: COCC(CCO)(OC)c1cccc(OCc2ccc3ccccc3c2)c1
Yield: 87 %

Procedure:
Using the procedure described in Example 12, 3-(3-hydroxyphenyl)-3,4-dimethoxybutan-1-ol was reacted with 2-bromomethylnaphthalene to give 3,4-dimethoxy-3-[3-(naphth-2-ylmethoxy)phenyl]butan-1-ol in 87% yield, m.p. 64°-65° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:16]=[CH:15][C:6]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[C:5](C)[CH:4]=1.[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Br:28])[CH:22]=1)=O>O1CCCC1.BrCCBr>[Br:28][C:23]1[CH:22]=[C:21]([C:19]([C:3]2[CH:4]=[CH:5][C:6]([O:7][Si:8]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10])=[CH:15][CH:16]=2)=[CH2:18])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: Cc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=C(c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a mixture of magnesium turnings (1.5 g, 0.06 mol, 1.2 eq) in dry tetrahydrofuran (10 mL), was added a portion (⅕) of (4-bromo-2-methyl-phenoxy)-tert-butyl-dimethyl-silane (16.0 g. 0.05 mol, 1.1 eq) in dry tetrahydrofuran (50 mL) and 1,2-dibromoethane (0.5 mL). The resulting solution was refluxed and the other (⅘) portion of the above solution was added and the resulting solution was refluxed for 2 h. After cooled at 0° C. a solution of 3-bromo-4-fluoroacetophenone (11.5 g, 0.05 mol, 1 eq) in dry tetrahydrofuran (40 mL) was added dropwise and the reaction was stirred for 3 h at room temperature. The mixture was quenched with saturated ammonium chloride solution (20 mL). The aqueous phase was extracted with dichloromethane (3×20 mL), dried (sodium sulfate) and the solvent removed in vacuo. The crude latter was dissolved in toluene (200 mL) and a catalytic amount (30 mg) of p-toluenesulfonic acid was added and refluxed for 3 h. The solvent was removed and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colourless oil (18.5 g, 39%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=3)[C:11]([CH3:20])([CH3:19])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[C:26](=[O:28])=[O:27]>C1COCC1>[CH3:19][C:11]1([CH3:20])[CH2:10][CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:17]2[CH:16]=[C:15]([C:26]([OH:28])=[O:27])[CH:14]=[CH:13][C:12]1=2
Reactant: O=C=O
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)O)cc32)cc1
Temperature: 25 °C

Procedure:
A solution of 3,4-dihydro-1-(4-methylphenyl)-4,4-dimethyl-7-bromonaphthalene (Compound D) (250.0 mg, 0.764 mmol) in 2.0 ml of THF was cooled to −78° C. and 1.0 ml of t-butyllithium (1.68 mmol, 1.7 M solution in pentane) was added slowly. After stirring for 1 hour at −78° C. gaseous CO2 (generated by evaporation of Dry-Ice, and passed though a drying tube) was bubbled through the reaction for 1 hour. The solution was then allowed to warm to room temperature and the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc was followed by washing the combined organic layers with H2O and saturated aqueous NaCl, and drying over MgSO4. Removal of the solvents under reduced pressure and washing of the solid with hexanes afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.94 (1H, dd, J=1.8, 8.1 Hz), 7.76 (1H, d, J=1.8 Hz), 7.45 (1H, d, J=8.1 Hz), 7.24 (4H, m), 6.01 (1H, t, J=4.7 Hz), 2.40 (3H, s), 2.36 (2H, d, J=3. 4.7 Hz), 1.35 (6H, s).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:22](=[O:23])[N:21]2[CH:17]([CH2:18][CH:19]([O:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][N:26]=3)[CH2:20]2)[C:16](=[O:35])[NH:15][C:14]2([C:36]([NH:38][S:39]([CH:42]3[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[O:37])[CH:12]([CH2:13]2)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:55]([O:57][CH:58]1[CH2:62][CH2:61][O:60][CH2:59]1)=[O:56]>C(Cl)Cl>[O:60]1[CH2:61][CH2:62][CH:58]([O:57][C:55](=[O:56])[NH:3][CH:4]2[C:22](=[O:23])[N:21]3[CH:17]([CH2:18][CH:19]([O:24][C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][N:26]=4)[CH2:20]3)[C:16](=[O:35])[NH:15][C:14]3([C:36]([NH:38][S:39]([CH:42]4[CH2:43][CH2:44]4)(=[O:40])=[O:41])=[O:37])[CH:12]([CH2:13]3)[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:59]1
Reactant: O=C(Cl)OC1CCOC1
Reactant: NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O)OC1CCOC1
Yield: 52.6 %

Procedure:
Prepared from cyclopropanesulfonic acid [14-amino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carbonyl]-amide bis hydrochloride (50 mg, 0.075 mmol), 44 μL (0.25 mmol) of DIPEA and 0.10 mL (0.1 mmol) of tetrahydro-furan-3-yl chloroformate (prepared by treating tetrahydrofuran-3-ol with phosgene) in DCM as described in the procedure above to give 28 mg (52%) of a white solid. Preparative HPLC condition: YMC ODS-A, S5, 30×50 mm, gradient: 50% B to 85% B, 8 min, hold 2 min, flow rate 45 ml/min. LC-MS (Method A, retention time: 3.05 min), MS m/z 710 (M++1).
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].IC.[CH3:32]COCC>CN(C=O)C>[CH3:32][N:22]1[C:23]2[C:19](=[CH:18][C:17]([S:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@H:9]3[CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:16])=[O:15])=[CH:25][CH:24]=2)[C:20](=[O:27])[C:21]1=[O:26]
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a solution of 10 (193 mg, 0.5 mmol) in DMF (3 mL) was added 60% NaH (30 mg, 0.75 mmol) at room temperature. The mixture was stirred 15 min, then iodomethane (0.5 mL) was added. The mixture was stirred overnight at ambient temperature, then ether (75 mL) was added, washed with water (30 mL) and saturated NaCl (30 mL), and dried over Na2SO4. After evaporation of the solvent, the crude product was purified with ether to afford 85 mg (43%) of 11a as a yellow solid, mp 160.1-160.9° C. 1H NMR (300 MHz, CDCl3) δ 8.07 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 8.01 (s, 11H), 7.25 (t, J=8.4 Hz, 2H), 6.92 (m, 3H), 6.81 (d, J=7.8 Hz, 2H), 4.15 (dd, J=9.0 Hz, J=2.7 Hz, 1H), 4.00 (m, 1H), 3.92 (m, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 3.26 (s, 3H), 2.04 (m, 2H), 1.81 (m, 2H). Anal. Calcd for C20H20N2O5S: C, 59.99, H, 5.03; N, 7.00. Found: C, 59.80, H, 5.03; N, 6.91.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([Cl:16])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
trans-4-Trifluoromethyl-cyclohexanecarboxylic acid (2.0 g, 10.2 mmol) is stirred in thionyl chloride (30 mL) for 1 h at reflux. The reaction mixture is concentrated and used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14](O)=O>>[CH3:10][O:11][C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14]1[NH:9][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)[N:8]=1
Reactant: COc1cc(OCc2ccccc2)ccc1C(=O)O
Reactant: Nc1cnc(Cl)nc1N
Product: COc1cc(OCc2ccccc2)ccc1-c1nc2nc(Cl)ncc2[nH]1

Procedure:
Prepared analogously to Example 5 from 2-chloro-4,5-diaminopyrimidine and 2-methoxy-4-benzyloxy benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([C:17]2[CH:22]=[C:21]([C:23](=O)[C:24]#[CH:25])[CH:20]=[CH:19][C:18]=2[CH3:27])[C:5]([CH3:16])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1.Cl.[OH:30][C:31]([CH3:36])([CH3:35])[C:32]([NH2:34])=[NH:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][N:34]=[C:32]([C:31]([OH:30])([CH3:36])[CH3:35])[N:33]=3)[CH:20]=[CH:19][C:18]=2[CH3:27])[C:5]([CH3:16])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Cl)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)cs1
Temperature: 75 °C
Yield: 11.5 %

Procedure:
To a solution of 5-chloro-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-6-(2-methyl-thiazol-4-ylmethoxy)-3H-pyrimidin-4-one from Step C (87 mg, 0.21 mmol) in acetonitrile (2 mL) was added 2-hydroxy-2-methylpropionamidine HCl (44 mg, 0.32 mmol) and potassium carbonate (87 mg, 0.63 mmol) and the slurry was heated at 75° C. for two hours and at ambient temperature for eighteen hours. The reaction was filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (12 mg, 11% yield). MS (M+H): 499; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.17 (s, 3H), 2.21 (s, 3H), 2.77 (s, 3H), 5.59-5.68 (m, 2H), 7.26 (s, 1H), 7.55-7.59 (m, 2H), 7.93 (s, 1H), 8.14 (d, J=8.60, 1H), 8.78 (d, J=5.08, 1H).
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[CH2:12][CH2:13][CH2:14][OH:15])(=[O:8])=[O:7])C.Cl[C:19]1[C:20]([CH3:28])=[CH:21][C:22]2[N:23]([N:25]=[CH:26][N:27]=2)[N:24]=1>>[CH3:17][C:11]([CH3:16])([CH2:10][CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:12][CH2:13][CH2:14][O:15][C:19]1[C:20]([CH3:28])=[CH:21][C:22]2[N:23]([N:25]=[CH:26][N:27]=2)[N:24]=1
Reactant: CN(C)C=NS(=O)(=O)CCC(C)(C)CCCO
Reactant: Cc1cc2ncnn2nc1Cl
Product: Cc1cc2ncnn2nc1OCCCC(C)(C)CCS(N)(=O)=O

Procedure:
Using 6-(N,N-dimethylaminomethylene)aminosulfonyl-4,4-dimethyl-1-hexanol and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 154°-155° C.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:20][NH:21][C:22]([C:24]3[S:25][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]4[NH:34][CH2:35][CH2:36][CH2:37][N:38]=4)=[CH:27][CH:28]=3)=[O:23])[C:17]([OH:19])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)(Cl)=O.[CH:44](O)([CH3:46])[CH3:45]>>[CH:44]([O:18][C:17](=[O:19])[C@@H:16]([NH:15][C:13]([O:12][CH2:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:14])[CH2:20][NH:21][C:22]([C:24]1[S:25][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:34][CH2:35][CH2:36][CH2:37][N:38]=2)=[CH:27][CH:28]=1)=[O:23])([CH3:46])[CH3:45]
Reactant: CC(C)O
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)O)s1)NC1=NCCCN1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.559 g (1 mmol) of (2S)-2-(1-adamantylmethoxycarbonylamino)-3-((5-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-thiophene-2-carbonyl)-amino)-propionic acid (example 15) were dissolved in 10 ml of isopropanol. Under an inert gas atmosphere and under external cooling 0.26 ml of thionyl chloride were cautiously addded. After stirring for 8 hours at 50° C. the reaction was complete. The solvents were removed in vacuo to give a colourless foam which was purified by chromatography (silica gel; isopropanol/ethyl acetate/water (4/3/1; v/v/v)). The fractions containing the title compound were lyopholized to give 0.27 g of a colourless fluffy material.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])=[N:14][CH:13]=[C:12]([NH2:25])[N:11]=1>CS(C)=O.O>[Br:1][C:13]1[N:14]=[C:15]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])[C:10]([NH2:9])=[N:11][C:12]=1[NH2:25]
Reactant: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1Br
Temperature: 15 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (0.194 g, 1.09×10−3 mole) was added over 20 min to a mixture of 2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine (0.3 g, 1.04×10−3 mole) in dimethylsulfoxide (10 ml) and water (0.25 ml) below 15° C. The resulting reaction mixture was stirred at 15° C. for 1 hr, poured onto ice water (150 ml) and extracted with ethyl acetate (2×75 ml). The extract was then washed with 2 M sodium carbonate solution (50 ml) and water (100 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by ‘flash chromatography’ using 5-13% ethyl acetate in cyclohexane as the eluent. Yield 0.183 g (48%), M.p. 222-224° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[C:6]([O:14]CC2C=CC=CC=2)[CH:5]=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[C:6]([OH:14])[CH:5]=1
Reactant: COC(=O)c1cc(CC(C)C)cc(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cc(O)cc(CC(C)C)c1
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a solution of 3-benzyloxy-5-isobutylbenzoic acid methyl ester (388 mg, 1.30 mmol) in ethanol (20 mL) was added palladium hydroxide (80 mg, 20 wt % on carbon). After shaking on Parr hydrogenation apparatus for 3 h at 45 psi, the catalyst was filtered through a pad of Celite and the solvent evaporated to afford 271 mg (100%) of 3-hydroxy-5-isobutylbenzoic acid methyl ester. 1H NMR (300 MHz. DMSO-d6) δ 0.850 (d, 6H, J=6 Hz), 1.77-1.84 (m, 1H), 2.42 (d, 2H, J=7 Hz). 3.81 (s, 3H), 6.81-6.82 (m, 1H), 7.17-7.19 (m, 2H), 9.70 (s, 1H).