Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (35.7 g) in dichloromethane (350 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (19.8 g) in dichloromethane (200 ml) at −78° C. Dimethylsulfide (10 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water, and the organic layer was washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate), which was recrystallized from diisopropyl ether-ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (30.5 g) (Compound 371) as yellow crystals.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([CH:16]([CH3:19])[CH:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:20][C:21]([CH:23]=[CH:24][CH3:25])=[CH2:22]>C1(C)C=CC=CC=1>[CH3:20][C:21]1[CH2:22][CH:17]([CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:19])[O:18][CH:24]([CH3:25])[CH:23]=1
Reactant: C=C(C)C=CC
Reactant: CC(C=O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1=CC(C)OC(C(C)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
A 5-L reaction flask equipped with a reflux condenser was charged with toluene (1 L) and borontrifluride etherate (C4H10BF3O) (16 g, 0.012 mol). The reaction flask was cooled to 0° C. and 2-phenylpropanal (300 g, 2.23 mol) was added over 15 minutes. 2-Methyl-1,3-pentadiene (1.22 Kg, 4.92 mol) was added over 1 hour. During the feed, the reaction exothermed to 10° C. The reaction mixture was aged overnight and then quenched with aqueous sodium hydroxide (50%, 1 L). Vacuum distillation of the resulting mixture afforded 4,6-dimethyl-2-(1-phenyl-ethyl)-3,6-dihydro-2H-pyran (120 g) having a boiling point of 118-120° C. at 3 mmHg.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@@H:9]1[CH3:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([NH2:26])C1C=CC=CC=1>>[C:1]([N:8]1[CH2:12][C@@H:11]([NH2:26])[CH2:10][C@@H:9]1[CH3:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: NCc1ccccc1
Reactant: C[C@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Product: C[C@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 81.5 %

Procedure:
To a 90 g (0.322 mol) sample of (2S,4R)-1BOC-4-methanesulfonyloxy-2-methylpyrrolidine, prepared as described in U.S. Pat. No. 4,962,112, was added 345 g (3.22 mol) of benzylamine, and the solution was heated at 100° C. under N2 for 8 hours. The solution was cooled to room temperature and the excess benzylamine removed under vacuum. The residue was dissolved in ethyl acetate and washed with water. The product was then extracted into 1.0M citric acid, which was then adjusted to pH 11.5 with conc. ammonium hydroxide solution. The product was extracted into ethyl acetate, which was dried over Na2SO4, filtered, and concentrated. After drying, 76.2 g (81.5% yield) of the title product was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]([CH3:18])[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[N:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1>>[NH:19]1[C:27]2[C:22](=[C:23]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([N:12]([CH3:18])[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: CN(C)CCN(C)c1nc(Cl)nc2c1cnn2C
Product: CN(C)CCN(C)c1nc(-c2cccc3[nH]ncc23)nc2c1cnn2C

Procedure:
N-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N,N′,N′-trimethyl-ethane-1,2-diamine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica yielded 131. NMR: (CDCl3): 2.38 (s, 6H, 2×CH3), 2.73 (t, 2H, CH2, J=7.17 Hz), 3.54 (s, 311, CH3), 4.08 (m, 2H, CH2), 4.17 (s, 3H, CH3), 7.52 (t, H, ArH, J=7.77 Hz), 7.60 (d, H, ArH, J=8.27 Hz), 8.01 (s, H, ArH), 8.42 (d, H, ArH, J=7.23 Hz), 9.19 (s, H, ArH), 10.35 (sbr, H, NH). MS: (ESI+) MH+=351.18
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:26]3[CH:27]=[CH:28][N:29]=[C:24]([Cl:23])[N:25]=3)[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(Oc3ccnc(Cl)n3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (3′-hydroxy-biphenyl-4-ylmethyl)-carbamic acid tert-butyl ester (435 mg), 2,4-dichloropyrimidine (221 mg) and potassium carbonate (295 mg) in DMF (10 ml) is stirred at rt for 20 h. This mixture is quenched with brine and extracted twice with EtOAc. The combined organic phases are dried over sodium sulfate, the solvent is evaporated and the resulting crude product is purified on silica (90 g) with cyclohexane/EtOAc 80/20 to afford pure [3′-(2-chloro-pyrimidin-4-yloxy)-biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]1.O=CCCCNC(=O)C1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[O:19])[CH2:13][CH2:14]1
Reactant: OCCCCN1CCN(c2cccc(Cl)c2Cl)CC1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCCCN1CCN(c2cccc(Cl)c2Cl)CC1

Procedure:
4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butyraldehyde (37B) is prepared from 37A as described for 1E.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C@@H:24]([OH:25])[CH2:23][CH2:22][C@@:21]2([CH3:26])[C@H:3]1[CH2:4][CH2:5][C:6]1[C:7]3[C@:17]([CH3:27])([CH2:18][CH2:19][C:20]=12)[C@@H:10]([C@H:11]([CH3:16])[CH2:12][CH2:13][CH2:14][OH:15])[CH2:9][CH:8]=3>C1C=CC=CC=1>[OH:25][C@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:26])[C@@H:3]([CH2:4][CH2:5][C:6]3[C:7]4[C@:17]([CH3:27])([CH2:18][CH2:19][C:20]=32)[C@@H:10]([C@H:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[O:15])[CH2:9][CH:8]=4)[C:2]1([CH3:1])[CH3:28]
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Solvent: c1ccccc1
Product: C[C@H](CCC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.8 %

Procedure:
4,4-Dimethyl-5α-chola-8,14-dien-3β,24-diol (0.21 g) is dissolved in benzene (21 ml). Tris(triphenylphosphine)ruthenium(II)chloride (1.04 g) is added and the mixture is stirred at room temperature for 20 hours. Purification by column chromatography gives the title compound (129 mg). 1H-NMR (CDCl3, 300 MHz): δ=9.79 (1H, s); 5.36 (1H, s); 1.05 (3H, s), 1.01 (3H, s); 0.95 (3H, d); 0.82 (3H, s); 0.80 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:21])[S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:22]1[S:23][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25][N:26]=1)=[CH:5]2.C(P(CCCC)CCCC)CCC.[CH3:47][O:48][CH2:49][C@H:50](O)[CH3:51].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:47][O:48][CH2:49][C@H:50]([CH3:51])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:21])[S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:22]1[S:23][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)[CH2:25][N:26]=1)=[CH:5]2
Reactant: CN(c1cc(O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: COC[C@@H](C)O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of N-{5-hydroxy-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (145 mg) in toluene (2 mL) and tetrahydrofuran (1 mL) were added tributylphosphine (0.22 mL), (2R)-1-methoxypropan-2-ol (0.057 mL) and 1,1′-(azodicarbonyl)dipiperidine (220 mg), and the mixture was stirred at 80° C. for 3 hr, and concentrated. The residue was diluted with ethyl acetate, and subjected to basic silica gel column chromatography (eluate: ethyl acetate), and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:2) to give the title compound (80 mg, yield 48%) as a colorless powder.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:34]=[C:35]4[CH2:40][CH2:39][CH2:38][CH2:37][N:36]4[C:41]=3[Cl:42])[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:34]=[C:35]4[CH2:40][CH2:39][CH2:38][CH2:37][N:36]4[C:41]=3[Cl:42])[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(-c3nc4n(c3Cl)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(C)cc(-c3nc4n(c3Cl)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 208 from tert.butyl 4'-[(2-ethyl-4-methyl-6-(3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-:20]>S(Cl)(Cl)=O>[N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]=[C:10]([Cl:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [Cl-]
Reactant: O=C(NCc1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1ccc(CN=C(Cl)c2ccccc2)cc1
Yield: 85 %

Procedure:
A solution of 3.7 mmol of N-(p-nitrobenzyl)-benzamide in thionyl chloride was refluxed under an inert atmosphere for 30 minutes and after cooling, the excess thionyl chloride was removed under vacuum to leave a solid residue. The residue was crystallized from dry cyclohexane under dry nitrogen (Note: the subsequent filtration had to be done under dry nitrogen also to obtain an 85% yield of the purified imidoyl--chloride melting at 71° to 73° C. (Lit. m.pt. 73-4Huisgen et al--Loc. cit) which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)[NH:16][CH:17]=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:42]=2)C=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[CH:17][N:20]3[CH:21]=[CH:22][N:23]=[C:24]([NH2:42])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CNC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCC1
Product: Nc1nccn2cnc(-c3cccc(OCc4ccccc4)c3)c12

Procedure:
N-[(3-Benzyloxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-formamide: Prepared according to the procedures for Cyclobutanecarboxylic Acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]Amide, White solid, 1H NMR (CDCl3, 400 MHz) δ 5.03 (s, 2H), 6.62 (d, 1H, J=8.0 Hz), 6.88-6.97 (m, 3H), 7.22-7.24 (m, 1H), 7.32-7.41 (m, 5H), 8.29 (bs, 1H), 8.35 (d, 1H, J=2.4 Hz), 8.51 (d, 1H, J=2.0 Hz).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC1C=CC(S(O[CH2:22][CH2:23][CH:24]=[C:25]([F:27])[F:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:26][C:25]([F:27])=[CH:24][CH2:23][CH2:22][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC=C(F)F)cc1
Reactant: Sc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)=CCCSc1nc2ccccc2o1
Yield: 120.6 %

Procedure:
2-Mercaptobenzoxazole (4.79 g) was added to a solution of 1,1-difluorobut-1-en-4-yl 4-methylbenzenesulphonate (6.4 g) in acetone (200 cm3) containing potassium carbonate (5.06 g). The mixture was heated to reflux overnight (17 hr) and gc used to confirm that the 1,1-difluorobut-1-en-4-yl 4-methylbenzenesulphonate had been consumed and the product had formed. The reaction mass was allowed to cool and was filtered through a plug of High-Flo filter aid to remove insoluble inorganic material. The solid material was washed with ethyl acetate and the combined organic portions evaporated under reduced pressure to give 7.1 g of a brown oily residue. This material was fractionated by eluting through a bed of silica using hexane/ethyl acetate (40:1 by volume) as solvent to give the required product as a colourless oil (5.4 g, 92% based on the sulphonate); M+ =241;
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccccc3C)c(=O)n(C3CCCC3)c12
Yield: 59.8 %

Procedure:
1-Cyclopentyl-7-methoxy-3-o-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (24 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-2-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 402 [M+1]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:25]([S:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1)[CH3:26]>C(OCC)C>[CH2:18]([O:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=1[CH:32]([C:31]1[CH:34]=[CH:35][C:28]([S:27][CH2:25][CH3:26])=[CH:29][CH:30]=1)[OH:33])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)c(Br)c1
Reactant: CCSc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCSc1ccc(C(O)c2cc(C(F)(F)F)ccc2OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
A solution of butyl lithium (1.6M in hexane, 1.03 ml) was added to a stirred solution of the product from step (i) (0.5 g) in diethylether (20 ml) at −78° C. After 1 h, 4-ethylsulfanyl-benzaldehyde (0.25 g) was added and stirred for a further 1 h. The reaction was quenched with water, extracted with diethylether and the organic layer dried, then evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 50% diethylether/isohexane. Yield 0.7 g
Reaction SMILES: [C:1]([C:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4][NH:5][NH:6][C:7]1[C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=[C:9]2[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:8]=12)#[N:2].O>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:21]([N:18]1[C:9]2[N:10]=[CH:11][C:12]3[C:13](=[O:14])[NH:2][C:1]4[N:6]([N:5]=[CH:4][C:3]=4[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]=3[C:8]=2[CH:20]=[N:19]1)[CH3:22]
Reactant: CCOC(=O)C(C#N)=CNNc1c(C(=O)OCC)cnc2c1cnn2CC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c1[nH]c(=O)c1cnc3c(cnn3CC)c12

Procedure:
351 g of 4-[2-(2-cyano-3-ethoxy-3-oxo-1-propenyl)-hydrazino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester are heated in 2 liters of acetic acid containing 50 g of zinc chloride for 24 hours. After this time, the solution is cooled and 2 liters of cold water are added. The precipitated 8-ethyl-5,8-dihydro-5-oxo-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester is filtered off and purified by dissolving in the theoretical amount of sodium hydroxide in water and precipitating the compound with acetic acid, yield 256 g (83%); m.p. 263°-265°.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N+:16]([O-])=[CH:15][CH:14]=[CH:13]2)=[O:9]>C(OCC)(=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([Cl:3])[CH:14]=[CH:13]2)=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(ccc[n+]2[O-])c1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2nc(Cl)ccc2c1
Temperature: 25 °C
Yield: 28 %

Procedure:
Phosphorus oxychloride (10 mL) was added to quinoline-6-carboxylic acid methyl ester N-oxide (1.5 g, 7.6 mmol), and the solution was refluxed for 2 hours. The reaction solution was poured onto an ice, and warmed gradually to room temperature. Ethyl acetate was added to the reaction solution, which was then extracted, and sequentially washed with an aqueous solution of saturated sodium bicarbonate and brine. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), and the title compound (0.47 g, 2.1 mmol, 28%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH:15]=[CH2:16])[CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: C=CCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O

Procedure:
A solution of 3-(3-allyl-4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester(330 mg, 0.97 mmol) in absolute ethanol (5 mL) was treated with 5% Pd/C and then the mixture was evacuated thee times with N2. The reaction mixture was hydrogenated at 1 atm with an H2-filled balloon for 24 h before filtering the mixture over celite and rinsing with ethanol. The product was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.22 (t, J=7.6 Hz, 2H), 7.99–6.95 (m, 3H), 6.82 (m, 2H), 6.68 (d, J=8.0 Hz, 1H), 4.20 (q, J=6.8 Hz, 2H), 3.24 (A of AB, J=13.6 Hz, 1H), 3.08 (B of AB, J=13.6 Hz, 1H), 2.55 (t, J=7.6 Hz, 2h), 1.62 (sextet, J=7.6 Hz, 2H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz, 3H), 0.96 (t, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3([OH:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3([OH:18])[CH2:16][CH2:15][CH:14]([N:19]4[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=5)=[O:25])[CH2:20]4)[CH2:13][CH2:12]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(O)(c2ccc3c(c2)OCCO3)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc4c(c3)OCCO4)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4-hydroxy-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:6]=1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([Cl:15])[CH:8]=1.[Cu][C:23]#[N:24]>CN(C)C=O>[Cl:15][C:9]1[CH:8]=[C:7]([C:6]2[N:5]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:4]=[CH:3][C:2]=2[C:23]#[N:24])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1ccc(-c2c(Br)cnn2C2CCCCO2)cc1Cl
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2c(C#N)cnn2C2CCCCO2)cc1Cl
Temperature: 190 °C
Reaction time: 0.5 h

Procedure:
4-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-chlorobenzonitrile (3 g, 8.18 mmol), copper(I) cyanide (0.733 g, 8.18 mmol) and N,N-dimethyl formamide (15 ml) were loaded in a microwave reactor tube. The mixture was heated 190° C. for 5 h. The reaction was quenched by pouring the mixture into 200 ml of 12% ammonia solution and stirred for 30 min. The precipitate was filtered, washed with water and dried in vacuum at 40° C. The product was used in the next step without further purification. LC-MS: [M+1]=313.75.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[CH3:15][N:16]([CH:18]=O)[CH3:17].CN(C(OC)OC)C>C(OC(=O)C)C>[CH3:15][N:16]([CH3:18])[CH:17]=[N:14][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:10][CH:9]=1)(=[O:12])=[O:13]
Reactant: CN(C)C=O
Reactant: CCC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a stirred solution of 4-propionylbenzenesulfonamide (prepared according to the procedure reported in Bioorganic Chemistry 1994, 22, 387-394), 2.2 g (10.3 mmol) in ethylacetate (20 ml) was added DMF (2.0 ml) followed by the addition of N,N-dimethylformamidedimethyl acetal (1.36 g, 1.51 ml, 11.36 mmol) in a dropwise manner at room temperature. The resulting mixture was stirred at room temperature for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain a solid product, which was washed with diisopropylether to obtain the title compound (2.6 g, 94%).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[O:7](C(OC(C)(C)C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O>ClCCl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:8](=[O:7])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCCBr
Agent: Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCBr

Procedure:
was prepared from 3-bromopropylamine hydrobromide and BOC2O in the presence of base in dichloromethane.