Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:11][C:10]([C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH:5]=[CH:6][N:1]=1)=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Reactant: OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)c1ccnc(C(=O)OCc2ccccc2)c1

Procedure:
30g of pyridine-2,4-dicarboxylic acid are converted into the acid chloride using 30 ml of thionyl chloride analogously to Example 1 and the acid chloride is reacted with 43.8 g of benzyl alcohol. The product is recrystallized from diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:29].[Mg+2].O>C(O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:29])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: [Mg+2]
Solvent: CCO
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 4 h
Yield: 165.8 %

Procedure:
1.0 g (2.8 mmol) of 2-([3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl)thio-1H-benzimidazole was dissolved in 20 Ml of 95% ethanol, and cooled to −20˜−10° C. 1.0 g (1.6 mmol) of 80% MMPP (magnesium monoperoxyphthalate) was added thereto, and the resulting mixture was stirred for 4 hours at the same temperature. Completion of the reaction was confirmed by TLC and HPLC, and 10 Ml of water was added to the reaction mixture, which was then stirred for 1 hour under ice-cooling. The reaction mixture was filtered to separate crystal, and thus separated crystal was washed with ice-cooled isopropanol-water mixture (1:1), and dried under reduced pressure, to give 0.98 g (Yield 95%) of Lansoprazole as white solid.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[Br:27][C:28]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][C:28]=4[Br:27])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)c1ccc([N+](=O)[O-])cc1Br)c1ccnc2cc3c(cc12)OCO3

Procedure:
To a solution of compound 7 (259 mg, 1.0 mmol) and triethylamine (0.5 mL) in dry CH2Cl2 (20 mL) was added a solution of 2-bromo-4-nitrobenzoic acid chloride in 20 mL of CH2Cl2 (which was prepared by refluxing of 295 mg, 1.2 mmol of 2-bromo-4-nitrobenzoic acid in 10 mL of thionyl chloride for 4 h). The reaction mixture was heated to reflux for 6 h. The reaction mixture was allowed to cool and was then washed with saturated NaHCO3 solution, water and brine and dried over anhydrous Na2SO4. The solvent was then removed in vacuo to give a yellow solid; yield 345 mg (70.8%); mp 111–112° C.; 1H NMR (CDCl3) δ (2.29, S, 6H), 2.60 (t, 2H, J=6.2), 3.62–3.72 (m, 1H), 4.49–4.62 (m, 1H), 6.19 (d, 2H, J=5.6), 7.12 (d, 1H, J=8.2), 7.37 (s, 3H), 7.75 (d, 1H, J=8) 8.26 (s, 1H), 8.5 (d, 1H, J=4.6); 13C NMR(CDCl3) δ 45.4, 46.6, 56.4, 97.8, 102.4, 106.7, 119.5, 120.6, 121.7, 122.7, 127.6, 128.1, 143.6, 144.4, 147.9, 148.2, 148.5, 149.5, 151.4, 166.8.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH3:11])[NH:6][C:5]1=[O:12])[CH2:2][CH3:3].OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>O>[CH3:11][C:7]1[NH:6][C:5](=[O:12])[N:4]([CH2:1][CH2:2][CH3:3])[C:9](=[O:10])[C:8]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CCCn1c(=O)cc(C)[nH]c1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCn1c(=O)[nH]c(C)c([N+](=O)[O-])c1=O
Reaction time: 2 h

Procedure:
3-propyl-6-methyl-1,3-dihydropyrimidine-2,4-dione (3 g), as prepared in Example 3, was added to a solution of concentrated H2SO4 (12 ml) and HNO3 (9.6 ml) at 0° C. The reaction mixture was allowed to come to room temperature and continued stirring for another 2 h. The reaction mixture was then poured into water and extracted with ethyl acetate (3×50 mL). The organic layer was washed with water, brine and dried over Na2SO4. Removal of the solvent and recrystallization of the residue with ethylacetate/hexane mixture furnished the 6-methyl-5-nitro-3-propyl-1,3-dihydropyrimidine-2,4-dione(1.56 g).
Reaction SMILES: Cl.[NH:2]=[C:3]1[S:6][CH2:5][S:4]1.Cl[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].C([O-])(=O)C.[Na+]>C1C=CC=CC=1>[CH:11]([O:10][C:8]([N:2]=[C:3]1[S:6][CH2:5][S:4]1)=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)OC(=O)Cl
Reactant: N=C1SCS1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)OC(=O)N=C1SCS1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a well-stirred mixture of 2.8 g. of 2-imino-1,3-dithietane hydrochloride and 24.5 g. of isopropyl chloroformate was added 3.3 g. of powdered sodium acetate in small portions. After stirring for about one hour, the mixture was diluted with 50 ml. of benzene and stirred another hour. An ice-water mixture was added and mixing continued for two hours. The benzene phase was separated and the water extracted with fresh benzene. After combining and drying the benzene extracts, evaporation left 5.4 g. of off-white crude product. Recrystallization from hexane afforded 2.5 g. of white solid, m.p. 72.0°-73.0° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.Cl.Cl[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1.[OH-].[Na+]>O>[CH3:26][O:25][C:22]1[C:21]([CH3:27])=[CH:20][N:19]=[C:18]([CH2:17][S:10][C:8]2[NH:9][C:5]3[CH:4]=[C:3]([C:2]([F:13])([F:1])[F:14])[CH:12]=[CH:11][C:6]=3[N:7]=2)[C:23]=1[CH3:24]
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c1C

Procedure:
21.8 g of 5-(trifluoromethyl)-2-benzimidazolethiol are suspended in 400 ml of alcohol and treated with 22.2 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride while cooling with ice. Thereafter, a solution of 8.0 g of sodium hydroxide in 300 ml of water is added dropwise thereto, the mixture is left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue is dissolved in 1.5 l of methylene chloride. The solution is washed firstly with 200 ml of 1.5N sodium hydroxide solution and then 3 x with 700 ml of water, dried over sodium sulphate and evaporated in vacuo. The crude product is purified on 360 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gives 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole of melting point 164°-166°.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH2:8]([NH:10][C:11]1[C:16]([C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=O)=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:9].O>O1CCCC1>[CH2:8]([N:10]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[N:5][C:6]1=[O:7])[CH3:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCNc1ncccc1C(=O)c1cccs1
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)nc(-c2cccs2)c2cccnc21
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
Chlorosulfonyl isocyanate (0.5 ml, 5.6 mmol) was added to a solution of 2-ethylamino-3-(2-thiophenecarbonyl)pyridine (1.01 g, 4.35 mmol) in tetrahydrofuran (50 ml) under ice-cooling, followed by stirring for 30 minutes. The reaction solution was mixed with water and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the resulting filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-ethyl acetate) and recrystallized from ethyl acetate to give 1-ethyl-4-(2-thienyl)pyrido[2,3-d]pyrimidin-2(1H)-one (613 mg, 2.38 mmol, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]([C:34]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]([C:34]2([OH:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)=[CH:26][CH2:27][N:28]2[CH2:29][CH2:30][N:31]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:32][CH2:33]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(C(=CCN2CCNCC2)C2(O)CCCCC2)c1
Reactant: COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(CN2CCN(CC=C(c3cccc(OC)c3)C3(O)CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxybenzyl chloride (1.28 g, 7.5 mol) and Cs2CO3 (5.9 g, 18 mmole) were added to a solution of 1-[1-(3-methoxyphenyl)-3-(1-piperazinyl)-1-propenyl]cyclohexanol (2.0 g, 6 mmole) in DMF (50 mL) and the mixture stirred at room temperature for one hour. Triethylamine (0.25 mL) was then added and the reaction mixture stirred overnight. The solvent was evaporated and the residue dissolved in chloroform. The solution was washed with water and the water back-extracted with chloroform. The combined organic solution was washed with brine, dried over magnesium sulfate and evaporated. The product was purified using column chromatography with chloroform as eluent and the purified title compound was converted to the hydrochloride. Yield 530 mg, m.p. 169°-171° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[S:23][C:22]2[C:21]3[C:24]([CH3:27])=[N:25][O:26][C:20]=3[C@H:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:18][C:17](=[O:36])[C:16]=2[C:15]=1[CH3:37].IC>C1COCC1>[CH3:13][C:14]1[S:23][C:22]2[C:21]3[C:24]([CH3:27])=[N:25][O:26][C:20]=3[C@H:19]([C@@H:28]([CH3:1])[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[NH:18][C:17](=[O:36])[C:16]=2[C:15]=1[CH3:37]
Reactant: CC(C)NC(C)C
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(=O)N[C@H]2CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1noc2c1-c1sc(C)c(C)c1C(=O)N[C@H]2[C@@H](C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 16.6 %

Procedure:
To a round bottomed flask was added THF (50 mL) and diisopropylamine (1.29 mL, 9.10 mmol) before the solution was cooled to 0° C. To this solution was added n-BuLi (3.62 mL, 8.69 mmol) and the reaction was stirred at 0° C. for 10 min before cooling to −78° C. and addition of tert-butyl 2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)acetate (1.5 g, 4.14 mmol), a form of intermediate 17, prepared according to Example 14. The solution was stirred at −78° C. for 1 h before addition of iodomethane (0.285 mL, 4.55 mmol) and warming to room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl solution and then diluted with water and brine. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (MTBE/hexanes) to afford the titled product (0.259 g, 0.688 mmol).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:70][C:71]1[CH:77]=[CH:76][C:74]([NH2:75])=[CH:73][CH:72]=1>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:75][C:74]2[CH:76]=[CH:77][C:71]([F:70])=[CH:72][CH:73]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3ccc(F)cc3)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and 4-fluoroaniline (9.6 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 46%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:39])[O:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:39])[O:35][CH:36]([CH3:37])[CH3:38])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)OC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 144 was prepared from diphenylacetyl chloride and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.25–7.12 (m, 12H), 7.09–7.06 (m, 1H), 7.00–6.94 (m, 1H), 6.79 (d, 1H, J=7.6 Hz), 6.60 (s, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.79 (s, 1H), 4.04 (q, 1H, J=6.4 Hz), 3.30 (q, 2H, J=5.8 Hz), 2.91–2.83 (m, 2H), 2.42–2.30 (m, 3H), 1.91 (t, 2H, J=11.4 Hz), 1.74–1.67 (m, 2H), 1.65–1.51 (m, 3H), 1.21 (d, 6H, J=6.2 Hz); ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=O)=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3 carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (93.6 mg, 74%).
Reaction SMILES: [NH2:1][CH:2]1[C:7]2=[N:8][C:9]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:10][C:11](=[O:12])[N:6]2[CH2:5][CH2:4][CH2:3]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[O:12]=[C:11]1[N:6]2[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])[C:7]2=[N:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:10]1
Reactant: NC1CCCn2c1nc(-c1ccncc1)cc2=O
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC1CCCn2c1nc(-c1ccncc1)cc2=O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.07 g (0.29 mmol) of (+/−) 9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one dissolved in 1 mL of dichloromethane at 10° C. was added 0.034 g (0.29 mmol) of phenylisocyanate dissolved in 1 mL at 10° C. The resulting mixture was stirred at 10° C. for 30 min. The mixture was stirred at room temperature for 1 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[NH:10][C:9]([CH3:11])=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[N:10]([CH3:19])[C:9]([CH3:11])=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13]
Reactant: Cc1nc(C(C)C)c(Cc2cc(Cl)cc(Cl)c2)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1nc(C(C)C)c(Cc2cc(Cl)cc(Cl)c2)n1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.2 %

Procedure:
In 20 ml of dry acetone was dissolved 930 mg (3.3 mmol) of 5-(3,5-dichlorobenzyl)-4-isopropyl-2-methyl-1H-imidazole (54), followed by addition of 1.4 g (10.1 mmol)of anhydrous potassium carbonate, and the mixture was stirred at room temperature. After 5 minutes, 225 μl (3.6 mmol)of methyl iodide was added at room temperature, and the mixture was heated to 80° C. After 5 hours, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water, and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate)to give 218 mg of the target compound (Compound I-100)(yield 22%).
Reaction SMILES: [NH3:1].Cl[C:3]([C:5]([F:16])([F:15])[CH:6]([O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[CH2:7][CH3:8])=[O:4]>>[NH2:1][C:3]([C:5]([F:16])([F:15])[CH:6]([O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[CH2:7][CH3:8])=[O:4]
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)Cl
Reactant: N
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(N)=O
Yield: 90.9 %

Procedure:
In a 25-mL glass flask with a dropping funnel, 5.0 g (82.2 mmol/4.0 eq) of 28% aqueous ammonia solution was added and stirred. Subsequently, 5.0 g (purity: 98%, 20.4 mmol) of methacrylic acid 1-chlorocarbonyl-1,1-difluoro-2-butyl ester was dropped into the glass flask. The resulting solution was stirred for 10 minutes at room temperature. The completion of the reaction was confirmed by 19F NMR. After that, the solution was separated into an organic layer and an aqueous layer with the addition of 5 mL of water and 5 mL of diisopropyl ether. The thus-obtained aqueous layer was concentrated under a reduced pressure. With this, 4.1 g of methacrylic acid 1-aminocarbonyl-1,1-difluoro-2-butyl ester was obtained as a white crystalline substance (yield: 86%, purity: 96%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:8])[CH3:7])[CH2:2]1.Br[CH2:10][CH2:11][O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[CH:25][C:26]=3[O:31][CH3:32])[N:21]=2)=[CH:15][C:14]=1[CH3:35].C(N(CC)CC)C>CN(C=O)C>[CH3:32][O:31][C:26]1[CH:25]=[C:24]([O:33][CH3:34])[CH:23]=[C:22]2[C:27]=1[C:28](=[O:30])[NH:29][C:20]([C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([O:12][CH2:11][CH2:10][N:1]3[CH2:4][CH:3]([NH:5][C:6](=[O:8])[CH3:7])[CH2:2]3)=[C:14]([CH3:35])[CH:15]=1)=[N:21]2
Reactant: CC(=O)NC1CNC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CC(NC(C)=O)C4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of N-azetidin-3-yl-acetamide (0.30 g crude, 1.99 mmol) and 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.43 g, 1.00 mmol) in anhydrous DMF (10 mL) was added triethylamine (3 mL). The reaction mixture was stirred at room temperature for 3 days under nitrogen. Solvent was evaporated under reduced pressure, water (50 mL) was added, and the precipitated solid was filtered. The aqueous phase was extracted with ethyl acetate (2×100 mL). The organic phase was dried over anhydrous Na2SO4. Solvent was evaporated, and crude compound was purified by the Simpliflash system (0-5% 7 N ammonia in methanol and CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.30 g (63%). MP 111.8-113.6° C. 1H NMR (400 MHz, CDCl3): δ 9.60 (br s, 1H), 7.69 (s, 2H), 6.82 (d, J=2.34 Hz, 1H), 6.46 (d, J=2.34 Hz, 1H), 6.10 (d, J=7.81 Hz, 1H), 4.71-4.44 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.85-3.67 (m, 4H), 3.26-3.13 (m, 2H), 2.90 (t, J=5.46 Hz, 2H), 2.36 (s, 6H), 2.01 (s, 3H). MS (ES+) m/z: 467.20 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.N1CCCC1>CO>[Cl:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:1]/[C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccc(Cl)cc2)s1
Yield: 67 %

Procedure:
A solution (1.74 M) of methyl 5-methyl-4-nitrothiophene-2-carboxylate (prepared as described in example 1, step 1) in MeOH, was treated with 4-chlorobenzaldehyde (1.5 eq.). The reaction mixture was heated to reflux and when it became a clear solution, a catalytic amount of pyrrolidine (0.10 eq.) was added. The reaction mixture was heated to reflux overnight. After cooling down, evaporation of the solvent gave a residue that was triturated with petroleum ether/Et2O and filtered to afford the title compound title compound (67%) as a solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][C@H:3]1[CH:16]([CH3:18])[CH3:17].[NH:19]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:20][C:21](O)=[O:22].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:27]([O:26][C:24]([NH:19][CH2:20][C:21]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4][C@H:3]1[CH:16]([CH3:18])[CH3:17])=[O:22])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
Tert-butyl(1R,3S,4S)-4-amino-3-isopropylcyclohexylcarbamate (780 mg) dissolved in DMF (10 mL) and cooled to 0° C. prior to the addition of N-Cbz-Gly-OH (1.14 g), 4-methylmorpholine (1.2 mL), and BOP (2.42 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3S,4S)-4-(2-benzyloxycarbonylaminoacetamido)-3-isopropylcyclohexylcarbamate (790 mg). MS found: (M+H)+=448.4.