Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][P:9]2(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][P:9]2(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(CP2(=O)CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CP2(=O)CCCCC2)cc1
Reaction time: 24 h
Yield: 75.6 %

Procedure:
A mixture of 1-(4-nitrobenzyl)phosphorinane-1-oxide (2.25 g) and 10% Pd-C (0.2 g) in ethanol (30 ml) was vigorously stirred under hydrogen atmosphere for 24 hours. The catalyst was filtered off, and the filtrate was concentrated recrystallized from ethanol-diethylether to give 1-(4-aminobenzyl)-phosphorinane-1-oxide (1.5 g) as pale yellow crystals.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:30])([CH3:29])[CH2:21][N:22]([CH2:27][CH3:28])[C:23]2=[O:26])=[CH:18][CH:17]=1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O)(=O)C>ClCCl>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([CH3:29])([CH3:30])[CH2:21][N:22]([CH2:27][CH3:28])[C:23]3=[O:26])=[CH:18][CH:17]=2)=[CH:34][CH:33]=1
Reactant: CCN1CC(C)(C)c2ccc(N)cc2C1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CC(C)(C)c2ccc(NCc3ccc(Cl)cc3)cc2C1=O
Reaction time: 8 h
Yield: 32.4 %

Procedure:
Sodium triacetoxyborohydride (77 mg, 0.36 mmol) was added to a stirred solution of 7-amino-2-ethyl-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (40 mg, 0.18 mmol), 4-chlorobenzaldehyde (31 mg, 0.22 mmol) and acetic acid (11 μl, 0.18 mmol) in anhydrous dichloromethane (6 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by preparative tlc (20% ethyl acetate in petroleum ether) to afford the title compound as a colourless solid (20 mg, 32%). HPLC retention time 4.78 min. Mass spectrum (ES+) m/z 343 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[C:10]([NH:18][C:19]([NH:5][C:4]1[CH:3]=[C:2]([I:1])[CH:8]=[C:7]([I:9])[CH:6]=1)=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(I)cc(I)c1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(I)cc(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125 %

Procedure:
To the solution of 3,5-diiodoaniline (5.0 g, 0.01 mol) in anhydrous acetone (150 mL) was added benzoylisothiocyanate (2.81 g, 0.012 mol) and the reaction mixture was stirred at room temperature for 30 min. Acetone was distilled off and the crude residue was washed with hexane to obtain desired compound as a yellow solid (6.35 g, 91%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[OH:22])(=[O:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].C>CN(C=O)C.C1(C)C=CC=CC=1>[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C(C)=O)c(OCc2ccccc2)c1
Reaction time: 18 h
Yield: 52.6 %

Procedure:
Benzyl bromide (4.84 mL, 6.97 g, 40.76 mmol) was added dropwise over 5 minutes to a mixture of give N-(4-acetyl-3-hydroxy-phenyl)-acetamide (7.50 g, 38.82 mmol) and Cs2CO3 (25.30 g, 77.64 mmol) in DMF (175 mL) at room temperature. After stirring for 18 hours, the solvent was removed in vacuo, and the residue stirred vigourously with water (200 mL) and DCM (200 mL) until dissolution was complete. The layers were separated, and the aqueous further extractede with DCM (2×200 mL). The combined organic layers were dried (MgSO4) and the solvents removed in vacuo. The residue was taken up in PhMe (150 mL) and evaporated to dryness, whereupon crystals started to form. The mixture was re-suspended in PhMe (100 mL) and refluxed for 1 hr with activated charcoal (5 g). The hot solution was filtered and allowed to cool. The product was collected by filtration to give N-(4-acetyl-3-benzyloxy-phenyl)-acetamide (5.79 g, 53%) as colourless crystals; δH (CDCl3) 7.83 (1H, m), 7.76 (1H, d, J=8.5 Hz), 7.58 (1H, br s), 7.45-7.32 (6H, m), 6.74 (1H, dd, J=8.5, 1.9 Hz), 5.15 (2H, s), 2.56 (3H, s), 2.19 (3H, s); LCMS retention time 2.33 min, M+H+ 284.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[C:19]([N:20]=2)=[C:18]2[N:21]([C:25]4[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=4)[C:22](=[O:24])[NH:23][C:17]2=[CH:16][N:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].I[CH3:35]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[C:19]([N:20]=2)=[C:18]2[N:21]([C:25]4[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=4)[C:22](=[O:24])[N:23]([CH3:35])[C:17]2=[CH:16][N:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc3ncc4[nH]c(=O)n(-c5cn(C)nc5C)c4c3n2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3ncc4c(c3n2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 8-(3,4-dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one (Example 249, 50 mg, 0.120 mmol) and NaH 55% (8 mg, 0.183 mmol) in DMF (1.2 ml) was stirred at rt for 20 min. Then iodomethane (0.011 ml, 0.180 mmol) was added and the RM was stirred at rt for 2.25 h. After that, the RM was quenched with saturated aqueous NaHCO3, the suspension was then filtered, the cake was washed with water and dried in the vacuum oven to give the title compound as an off-white solid. (HPLC: tR 2.67 min (Method A); M+H=431 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.38 (d, 1H), 8.24 (d, 1H), 7.96 (s, 1H), 7.62-7.54 (m, 1H), 7.42-7.38 (m, 1H), 7.02 (d, 1H), 3.85 (s, 6H), 3.81 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](O)(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].P(Cl)(Cl)(Cl)(Cl)[Cl:21]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:21])(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)O)ccc1F
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Temperature: 25 °C
Yield: 81.7 %

Procedure:
To 2-fluoronitrobenzene (2.33 g) was added fuming sulfuric acid (20 mL), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice and potassium chloride (10 g), and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g). To phosphoryl chloride (85 mL) were added 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g) and phosphorus pentachloride (2.82 g) under ice-cooling, and the mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue was added ice water, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/1) to give the title compound (2.65 g).
Reaction SMILES: C1([C:7]2[N:8]=[C:9]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C=CC=CC=1.[CH3:31][O:32]C1C=CC=CC=1C(=O)C=O>>[CH3:31][O:32][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:11]1[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[C:9]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[N:8][CH:7]=1
Reactant: COc1ccccc1C(=O)C=O
Reactant: C[Si](C)(C)CCOCn1c(CCC(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Product: COc1ccccc1-c1cnc(CCC(=O)O)n1COCC[Si](C)(C)C

Procedure:
Prepared in analogy to the methods described for 3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propionic acid replacing benzil with (2-methoxy-phenyl)-oxo-acetaldehyde.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10](O)[C:11]=1[C:12]#[N:13].N1C=CC=CC=1>O1CCCC1>[NH2:6][C:7]1[S:8][CH:9]=[C:10]([Cl:3])[C:11]=1[C:12]#[N:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(O)csc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1c(Cl)csc1N
Reaction time: 8 h
Yield: 60 %

Procedure:
15.3 parts of phosphoryl trichloride are added to a mixture of 14 parts of 2-amino-3-cyano-4-hydroxythiophene, 7.9 parts of pyridine and 70 parts of tetrahydrofuran, and the mixture is then heated at the boil for 1 hour. After cooling, the mixture is poured onto water and left to stand overnight, and the precipitate is filtered off under suction, washed with water and dried. 9.4 parts (60% of theory) of 2-amino-4-chloro-3-cyanothiophene are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH2:25][OH:26]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH2:25][O:26][C:2]1[CH:3]=[C:4]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1ccc(F)cc1F
Reactant: CC(C)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC(C)N1c2cc(OCc3ccc(F)cc3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1-isopropyl-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,4-difluorophenyl)methanol.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:30])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(CCl)Nc1ccccc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(=O)Nc3ccccc3)C2=O)CC1
Yield: 14 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-chloro-N-phenylacetamide, to give the desired product as a white solid (14%).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](F)[CH:12]=2)[C:7](=[O:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]1)[CH:2]=[CH2:3].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O.CO>[CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:12]=2)[C:7](=[O:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C1CNCCN1
Reactant: C=CCn1cc(C(=O)OCC)c(=O)c2ccc(F)cc21
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCn1cc(C(=O)OCC)c(=O)c2ccc(N3CCNCC3)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
A solution of ethyl 1-allyl-7-fluoro-4-quinolone-3-carboxylate (390 mg, 1.41 mmol) and piperazine (1.22 g, 14.1 mmol) in dry N,N-dimethylformamide was heated for 7 hours at 110° C., then stirred at room temperature for 2 days. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel using dichloromethane:methanol (gradient from 98:2 to 85:15) as eluent affording 300 mg (62% yield) of ethyl 1-allyl-4-oxo-7-(4-piperazinyl)quinoline-3-carboxylate.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10]Br)C.[OH:12][C:13]1[CH:18]=[CH:17][N:16]([C:19]2[S:20][C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[N:23]=2)[C:15](=[O:30])[CH:14]=1>>[F:9][C:7]1[CH:8]=[CH:3][C:4]([CH2:10][O:12][C:13]2[CH:18]=[CH:17][N:16]([C:19]3[S:20][C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([CH3:24])[N:23]=3)[C:15](=[O:30])[CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1sc(-n2ccc(O)cc2=O)nc1C
Reactant: CCc1cc(F)ccc1CBr
Product: CCOC(=O)c1sc(-n2ccc(OCc3ccc(F)cc3)cc2=O)nc1C
Yield: 70 %

Procedure:
Following the procedure as described in Example 17, making variations only as required to use ethyl 1-(bromomethyl)-4-fluorobenzene in place of 2-(bromomethyl)-5-(trifluoromethyl)furan to react with ethyl 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 70% yield: mp 214-217° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J=8.1 Hz, 1H), 7.42-7.34 (m, 2H), 7.12-7.04 (m, 2H), 6.20 (dd, J=8.1, 2.7 Hz, 1H), 6.07 (d, J=2.7 Hz, 1H), 5.01 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.68 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.1, 164.5, 162.8, 161.2, 156.5, 155.6, 131.5, 130.4, 129.8, 119.8, 115.9, 103.9, 97.4, 70.1, 61.9, 17.3, 14.3; MS (ES+) m/z 389.2 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:35](=[O:44])[C:36]2=[CH:43][CH:42]=[CH:41][CH:40]=[C:37]2[C:38]1=[O:39])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(Br)CCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 25.3 %

Procedure:
In 100 ml of acetonitrile are dissolved 2 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 7.4 g of ethyl 2-bromo-7-phthalimidoheptanoate, and 0.85 g of triethylamine is added to the solution. After the mixture is heated at 80°-100° C. for 2 days, the mixture is concentrated under reduced pressure, diluted with 100 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give from the first fraction 1.0 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]34[CH2:19][CH2:18][C:17]([CH2:22][C:23]([O:25][CH2:26][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:24])([CH2:20][CH2:21]3)[O:16][CH2:15]4)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cc4)cc3)(CC1)CO2
Reactant: OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccc(C34CCC(CC(=O)OCc5ccccc5)(CC3)OC4)cc2)cc1
Temperature: 120 °C
Yield: 68.8 %

Procedure:
To a mixture of methyl 2-(4-(4′-amino-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (0.323 g, 0.918 mmol) in toluene (35 ml) was added benzyl alcohol (2.377 ml, 22.95 mmol), titanium(IV) isopropoxide (0.807 ml, 2.75 mmol) and 4 A molecular sieves (5 g, 0.918 mmol). The reaction mixture was heated at 120° C. for 48 hours. The resulting mixture was taken up in EtOAc and filtered. The filtrate was subsequently washed with water, then brine. The organic portion dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10 to 50% EtOAc/Heptane) to give the title compound after drying (270 mg, yield 68.8% yield). LC/MS, ESI-MS(+) m/z 428.1, RT 1.59 (Condition R).
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]1[CH2:8][C@H:7]([CH3:9])[CH2:6][NH:5]1.[C:10](#[N:13])[CH:11]=[CH2:12]>>[OH:2][CH2:3][C@H:4]1[CH2:8][C@H:7]([CH3:9])[CH2:6][N:5]1[CH2:12][CH2:11][C:10]#[N:13]
Reactant: C=CC#N
Reactant: C[C@@H]1CN[C@@H](CO)C1
Agent: Cl
Product: C[C@H]1C[C@H](CO)N(CCC#N)C1

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514-522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{2-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[C:18]3=[O:34])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:37])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[C:18]3=[O:34])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:37])=[O:8]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(=O)O)cc4Cl)CC3)C2=O)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(=O)Cl)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 203.8 %

Procedure:
To a solution of (S)-5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinic acid (0.40 g, 0.38 mmol) in DCM (20 mL) was added sulfurous dichloride (0.28 g, 2.3 mmol) and DMF (1 drop) and the reaction was stirred at ambient temperature for 3 hours. The reaction was concentrated under vacuum to give (S)-5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinoyl chloride (0.41 g, 100%). The material was used directly in the next step without purification.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]([CH2:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)([CH2:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)[N+:13]([O-:15])=[O:14])=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH2:27][CH2:28][CH2:29][NH2:30])([CH2:16][CH2:17][CH2:18][NH2:19])[N+:13]([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCC(CCCNC(=O)OC(C)(C)C)(CCCNC(=O)OC(C)(C)C)[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCC(CCCN)(CCCN)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of tris(3-(tert-butoxycarbonylamino)propyl)nitromethane 1c (10 g, 18.8 mmol) in trifluoroacetic acid (20 ml) and dichloromethane (50 ml) was stirred at room temperature for 4 h. The reaction was then concentrated under high vacuum to afford the title compound 10c (10.8 g, 18.8 mmol. 100%) as a gum.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[N:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:7]=[CH:8][N:9]=1)=[O:4].[CH3:28]C1C=CC2N(C(CN3C(C(OC)=O)=NC=N3)=C(C3C=CC(C)=CC=3)N=2)C=1.CNC>>[CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:6]([CH2:10][C:11]2[N:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:7]=[CH:8][N:9]=1)=[O:4]
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: CNC
Product: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ncnc2C(=O)N(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and dimethylamine. m/e 375 for C21H23N6O [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.35 (s, 2H), 7.87 (d, J=2.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 2H), 7.54 (d, J=9.0 Hz, 1H), 7.26 (d, J=7.8 Hz, 2H), 7.10 (d, J=9.0 Hz, 1H), 6.00 (s, 1H), 3.06 (s, 3H), 3.00 (s, 3H), 2.40 (s, 3H), 2.35 (s, 3H) ppm; 13C-NMR (75 MHz, CDCl3, δ) 158.440, 150.213, 147.869, 146.313, 144.771, 138.154, 131.236, 131.236, 129.600, 128.812, 128.725, 122.609, 116.939, 113.480, 43.481, 38.888, 35.781, 21.585, 18.727 ppm.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH2:17][CH2:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C@H:26]2[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]2)[CH2:22][CH2:21]1.[C:35](O)(=[O:38])[CH:36]=[CH2:37]>CN(C)C1C=CN=CC=1.ClCCl>[C:35]([O:16][CH2:17][CH2:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C@H:26]2[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)(=[O:38])[CH:36]=[CH2:37]
Reactant: C=CC(=O)O
Reactant: O=C(O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCCO)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Reaction time: 8 h

Procedure:
4.2 g of N,N'-dicyclohexylcarbodiimide were added within 5 minutes while stirring to a solution of 5.2 g of trans-4-(trans-4-[3-hydroxypropyl]cyclohexyl)cyclohexanecarboxylic acid, 1.2 g of acrylic acid and 0.2 g 4-(dimethylamino)pyridine in 25 ml of dichloromethane. The reaction mixture was stirred overnight, filtered and then concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 8:2) and recrystallization from ethyl alcohol of the fractions which were pure according to thin-layer chromatography gave 4.2 g of trans-4-(trans-4-[3-acryloyloxypropyl]cyclohexyl)cyclohexanecarboxylic acid.