Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:12]([NH2:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(O)C>[CH2:12]([NH:30][CH:11]1[O:4][C@@H:3]([CH3:2])[C@@H:5]([OH:6])[C@@H:7]([OH:8])[C@@H:9]1[OH:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCNC1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O

Procedure:
3.26 g of L-fucose and 5.38 g of stearylamine were heated at 70° C. in 20 ml of ethanol, with stirring, until a clear solution had formed. The solution was allowed to cool and, when crystallization had ended, the solid was filtered off with suction and washed with ethanol and ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:21]#[N:22])([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].C(O)C.N>[Ni].O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:7][C:8](=[O:9])[NH:22][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CNC(=O)C1

Procedure:
Combine 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (6.7 kg, wet cake containing isopropanol, about 3% L.O.D.) and 3C ethanol (52 kg) in a pressure reactor. Add Raney nickel in water (17.5 kg, about 11 kg of active catalyst) and an aqueous concentrated ammonia solution (8.7 kg). Hydrogenate at 200 psi and 35° C. When the reaction is complete, cool, vent the reactor, and purge with nitrogen. Filter through a filter bag, rinse with ethanol, and then filter through a 0.2 micron cartridge filter, and rinse the solids with ethanol. Evaporate the filtrate in vacuo to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:10]1[CH:14]=[C:13]([B:15]2[O:23][C:20]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[O:16]2)[CH:12]=[N:11]1>C(#N)C>[N:5]1([C:3](=[O:4])[CH2:2][N:11]2[CH:12]=[C:13]([B:15]3[O:16][C:17]([CH3:19])([CH3:18])[C:20]([CH3:22])([CH3:21])[O:23]3)[CH:14]=[N:10]2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(CBr)N1CCCC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CC(=O)N3CCCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A solution of 1-(bromoacetyl)pyrrolidine (Chemical Diversity Labs; 3.0 g, 15.6 mmol, 1.2 eq.) in acetonitrile (15 mL) was slowly added over a suspension of pyrazole-4-boronic acid pinacol ester (2.5 g, 12.9 mmol, 1 eq.) in acetonitrile and stirred overnight at RT. The reaction mixture was filtered and the filtrate was diluted with DCM and washed with water then brine. Separated organic phase was dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow oil (2.72 g, 100%).
Reaction SMILES: [Li+].[OH-].[C:3]1([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O.O1CCCC1>[C:3]1([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:22])=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(C(=O)N2CCCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C(=O)N2CCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of LiOH (495 mg, 11.79 mmol) in water (8 ml) was added to a stirred solution of methyl 2-[(phenylmethyl)oxy]-5-(1-pyrrolidinylcarbonyl)benzoate (may be prepared as described in Description 54; 400 mg, 1.18 mmol) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was acidified by HCl (6 mol/l). The precipitate was collected and dried to yield the title compound as a white solid. 300 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14].O.[C:17]([OH:21])(=[O:20])[CH:18]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])/[CH:14]=[CH:18]/[C:17]([OH:21])=[O:20]
Reactant: O=CC(=O)O
Reactant: COc1ccc(/C=C/C(C)=O)c(OC)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)c(OC)c1

Procedure:
A solution of 19 g (92 mmol) of (E)-4-(2,4-dimethoxyphenyl)but-3-en-2-one and 8.4 g (92 mmol) of glyoxylic acid monohydrate in 24 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether/hexane yielded (E,E)-6-(2,4-dimethoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 195°-200°.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:28]=[C:29]([O:33][CH3:34])[CH:30]=[CH:31][CH:32]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4c(F)ccnc4F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12j and 3-bromoanisole
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32]([NH2:34])[CH3:33])=[CH:27][CH:26]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:34][CH:32]([CH3:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CC(N)Cc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Product: CC(Cc1ccc(Cl)cc1)NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid was coupled with (±)-2-(4-chlorophenyl)-1-methylethylamine as in EXAMPLE 1, Part C. HPLC: RT=10.50 min. MS (ESI−): mass calcd. for C22H18BrClN4O3S2, 563.97; m/z found, 563/565 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.61 (s, 1H), 8.37 (dd, J=7.0, 1.2, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.88 (d, J=1.8, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.32-7.25 (m, 2H), 7.13-7.05 (m, 2H), 7.07 (dd, J=8.4, 1.8, 1H), 7.01 (d, J=8.4, 1H), 5.74 (br d, J=7.8, 1H), 4.40-4.28 (m, 1H), 2.88 (dd, J=13.6, 5.6, 1H), 2.75 (dd, J=13.6, 7.1, 1H), 1.17 (d, J=6.7, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:16][C:4]=2[CH2:3]1.NC1C=CC(C(C)C(O)=[O:31])=CC=1CC(O)=O.C1(S)C=CC=CC=1>>[C:2]([CH2:3][C:4]1[CH:16]=[C:15]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:14]=[CH:13][C:5]=1[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:1])=[O:31]
Reactant: CC(C(=O)O)c1ccc(N)c(CC(=O)O)c1
Reactant: CC(C(=O)O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Agent: Sc1ccccc1
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1

Procedure:
A process for preparing 2-(10,11-dihydro-10-oxodibenzo [b,f] thiepin-2-yl)propionic acid which comprises subjecting 2-(4-amino-3-carboxymethylphenyl)propionic acid or its salt to diazotization and subsequent reaction with thiophenol to produce 2-(3-carboxymethyl-4-phenylthiophenyl)propionic acid or its salt, and subjecting the product to cyclization reaction.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]12[O:11][C:8]([CH2:12][O:13][CH3:14])([CH:9]=[CH:10]1)[CH2:7][C:6](OS(C(F)(F)F)(=O)=O)=[CH:5]2.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)O1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]12[O:11][C:8]([CH2:12][O:13][CH3:14])([CH:9]=[CH:10]1)[CH2:7][C:6]([C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)=[CH:5]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COCC12C=CC(COC)(CC(OS(=O)(=O)C(F)(F)F)=C1)O2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCC12C=CC(COC)(CC(c3ccc(N)cc3)=C1)O2
Yield: 81 %

Procedure:
The title compound was prepared by the procedure of Example 4, step (b) using trifluoromethanesulfonic acid 1,5-bis-methoxymethyl-8-oxa-bicyclo[3.2.1]octa-2,6-dien-3-yl ester (as prepared in the previous step, 3.25 g, 9.45 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (2.28 g, 10.4 mmol). Silica gel chromatography (5-10% EtOAc/DCM) afforded the title compound (2.19 g, 81%) as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C17H21NO3, 288.2 (M+H), found 288.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[OH:8].C(N(CC)C(C)C)(C)C.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30]Cl>ClCCl.Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[O:8][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]
Reactant: COCCOCCl
Reactant: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1c(Br)cc(CC(=O)OC)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5-L round-bottom flask was added methyl (3-bromo-5-formyl-4-hydroxy-phenyl)acetate (210 g, 769 mmol, prepared in Reference A above), dichloromethane (2 L), and N,N-diisopropylethylamine (161 mL, 119 g, 923 mmol). A solution of 2-methoxyethoxymethyl chloride (MEM chloride, obtained from TCI America; 106 mL; 923 mmol) in dichloromethane (500 mL) was added dropwise via an addition funnel over 2 h. The reaction was allowed to stir at ambient temperature for overnight, after which time HPLC analysis showed that the reaction was complete. The reaction mixture was diluted with 0.5 N aqueous HCl (1 L) and the solution was allowed to stir at ambient temperature for 0.25 h, then the layers were separated. The organic layer was washed with additional 0.5 N aqueous HCl, followed by saturated aqueous sodium chloride (1 L). The organic layer was concentrated under vacuum to give an oil, which later solidified upon standing. The solid could be crystallized from ethyl acetate and hexane to yield methyl [3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)phenyl]-acetate (237 g) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][OH:13])[CH2:9][N:8]3[CH:14]=[C:15]([C:17]([NH2:19])=[O:18])[N:16]=[C:7]3[C:6]=2[CH:20]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:23]=1>>[OH:31][C:27]([C:24]1[CH:23]=[C:22]([CH3:21])[O:26][N:25]=1)([CH3:28])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][OH:13])[CH2:9][N:8]3[CH:14]=[C:15]([C:17]([NH2:19])=[O:18])[N:16]=[C:7]3[C:6]=2[CH:20]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(CO)C2
Reactant: C#CC(C)(O)c1cc(C)on1
Product: Cc1cc(C(C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CC(CO)O3)no1
Yield: 40 %

Procedure:
Similar to as described in General Procedure G, racemic 10-bromo-6-(hydroxymethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with racemic 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as a yellow solid (mixture of diasteromers, 98 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[NH:19]1[CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:19]2[CH2:22][CH2:21][CH2:20]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: C1CNC1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 97.8 %

Procedure:
A solution of 1.07 g (4.0 mmol) of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester and 0.461 ml (6.8 mmol) of azetidine in 10 ml of tetrahydrofuran is heated at reflux for 90 minutes. After evaporation of the tetrahydrofuran the residue is distributed between water and ethyl acetate, the organic phase separated and washed with water and brine, dried over Na2SO4 and concentrated yielding 1.19 g of 5-azetidin-1-yl-2-nitro-4-trifluoromethyl-benzoic acid methyl ester as yellow powder, m.p. 127-136° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37]>>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:37][CH2:36][C:35]4[CH:38]=[CH:39][CH:40]=[C:33]([CH3:32])[CH:34]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:27][CH:26]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: Cc1cccc(CN)c1
Product: Cc1cccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)COc2ccc(Cl)cc2)C3)c1

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and 3-methylbenzylamine (2.2 eq.) in the manner of Example 68, m.p. 130-131° C. MS [(+)ESI, m/z]: 500 [M+H]+ Anal. Calcd for C29H26CIN3O3: C, 69.66; H, 5.24; N, 8.40. Found: C, 69.80; H, 5.30; N, 8.42.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:29])[C@H:26]([CH3:28])[NH2:27])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:29])[CH:26]([NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH3:28])[CH3:23]
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(C)NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[N:3]1[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:14]([C:13]4[CH:12]=[CH:11][C:10]([CH2:9][N:3]5[C@H:2]([CH3:1])[CH2:6][CH2:5][S:4]5(=[O:7])=[O:8])=[CH:19][CH:18]=4)=[O:16])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc(CN2[C@H](C)CCS2(=O)=O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3[C@H](C)CCS3(=O)=O)cc2)CC1
Yield: 79.6 %

Procedure:
Using methyl (R)-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoate (79 mg) described in Preparation Example 42 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (61 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (104 mg) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH3:20][N:21]([CH3:35])[C:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>C1COCC1>[S:1]1[C:5]([C:25]2([OH:28])[CH2:26][CH2:27][C:22]([N:21]([CH3:20])[CH3:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:24]2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(O)(c2cc3ccccc3s2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
A solution of benzo[b]thiophene (400 mg, 2.98 mmol) in dry THF (20 ml) was cooled to −5° C. under a stream of argon. Tert-butyllithium (3.58 mmol, 2.11 ml of a 1.7 molar pentane solution) was carefully added dropwise, to avoid exceeding a reaction temperature of 0° C. Once all the substance had been added, the reaction mixture was stirred for 2 hours at 0° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (648 mg, 2.98 mmol) in dry THF (5 ml) was then added dropwise at 0° C. The mixture was stirred for 15 minutes at 0° C. and then 6 hours at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (20 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed under vacuum. Purification was carried out by flash chromatography over silica gel with cyclohexane/ethylacetate (V:V=1:1). 345 mg 1-benzo[b]thiophen-2-yl-4-dimethylamino-4-phenylcyclohexanol with a melting point of 183–185° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=O.N.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:15][C:3]1[C:4](=[O:14])[NH:5][C:6](=[O:13])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:2]=1[NH2:1]
Reactant: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCn1c(N)c(N)c(=O)[nH]c1=O
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
To a mixture of 6-amino-5-nitroso-1-pentylpyrimidine-2,4(1H,3H)-dione (1.9 g, 8.3 mmol) and a solution of ammonia in water (20 M, 20 mL) at 70° C. was added sodium dithionite (3.1 g, 18 mmol) slowly. After stirring for 20 minutes, the reaction mixture was concentrated to a volume of about 10 mL and cooled in an ice bath. The greenish solid was collected by filtration and dried on high vacuum for 4 h to provide the desire product (1.5 g, 85% yield). LCMS calculated for C9H17N4O2(M+H): 213.1; found: 213.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:16](=[O:18])[CH3:17])=[O:5])C.[Li+].[OH-].Cl>C1COCC1.O>[C:16]([C:7]1[N:8]([CH3:15])[C:9](=[O:14])[C:10]([CH3:13])=[C:11]([Cl:12])[C:6]=1[C:4]([OH:5])=[O:3])(=[O:18])[CH3:17]
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1c(C(=O)O)c(Cl)c(C)c(=O)n1C
Reaction time: 0.5 h

Procedure:
To a solution of 2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent) in THF:water (4:1) is added 1 M aqueous LiOH solution (2.05 equivalents). After 30 minutes, the reaction mixture is acidified to pH 1 with 1 N HCl solution and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give the desired product which is used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:9]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:7][CH2:6][N:5]2[CH:16]=1.CN(C)[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[O:20]>>[C:24]1([CH3:27])[CH:25]=[CH:26][C:21]([C:19]([C:16]2[N:5]3[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[C:4]3=[CH:3][C:2]=2[CH3:1])=[O:20])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C(=O)N(C)C)cc1
Reactant: Cc1cc2n(c1)CCCC2C(=O)OC(C)C
Product: Cc1ccc(C(=O)c2c(C)cc3n2CCCC3C(=O)OC(C)C)cc1

Procedure:
In accordance with the method of Example 8, isopropyl 2-methyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate is condensed with N,N-dimethyl-p-toluamide, to produce isopropyl 3-p-toluoyl-2-methyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate (XI, R=CH3, L=p-CH3, R2 =iC3H7, n=1).
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26]>>[F:12][C:11]([F:14])([F:13])[C:10]1[C:5]2[N:6]([C:2]([C:26]#[C:25][C:27]3[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=3)=[CH:3][N:4]=2)[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3n2)cc1
Reactant: C#Cc1cnc(N)nc1
Product: Nc1ncc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nn23)cn1

Procedure:
The title compound was prepared from 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazine (example C.26 step 11) (457 mg, 1 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2) (155 mg, 1.3 mmol) according to general procedure II. Obtained as a light yellow solid (50 mg, 11%). MS (ISP) 449.2 [(M+H)+]; mp 220-221° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example J21) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) according to the general procedure M. Obtained as a light brown solid (262 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][CH2:3][CH:4]([Br:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COCC(Br)c1ccccc1
Yield: 84.2 %

Procedure:
A solution of methylphenethylether (1.0 g, 7.34 mmol), NBS (1.96 g, 11.01 mmol) and AIBN (240 mg, 1.47 mmol) in carbon tetrachloride (30 ml) was heated under reflux for 2 hours. After cooling, the reaction mixture was diluted with saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a crude 2-methoxy-1-phenylbromoethane (1.33 g, 84%) as brown liquid.