Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([Br:13])=[CH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1.[CH2:14]([C:17]1([CH2:21][OH:22])[CH2:20][O:19][CH2:18]1)[CH2:15][CH3:16].N1C=CC=CC=1>ClCCl>[Br:1][C:2]([Br:13])=[CH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:22][CH2:21][C:17]2([CH2:14][CH2:15][CH3:16])[CH2:20][O:19][CH2:18]2)=[O:11])[CH2:6][CH2:5]1
Reactant: O=C(Cl)C1CCC(C=C(Br)Br)CC1
Reactant: CCCC1(CO)COC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(COC(=O)C2CCC(C=C(Br)Br)CC2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
4-(2,2-Dibromovinyl)cyclohexanecarbonyl chloride (0.91 g) in dry dichloromethane (5 ml) was added to a cooled (0° C.) solution of 3-propyl-3-hydroxymethyloxetane (0.406 g) and pyridine (0.64 ml) in dry dichloromethane (10 ml) under a stream of nitrogen. The reaction mixture was allowed to warm to room temperature and to stir overnight. Further dichloromethane was added. The organic phase was then washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine before drying over anhydrous magnesium sulphate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel, pre-eluted with hexane containing 1% triethylamine. Elution with hexane/ether (3:1) gave 3-propyloxetan-3-ylmethyl 4-(2,2-dibromovinyl)cyclohexanecarboxylate (0.6 g) as a mixture of cis- and trans-isomers.
Reaction SMILES: N#N.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:10]1[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=1.[NH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[N:18]1([C:10]2[C:11]([C:16]#[N:17])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: N#Cc1ncccc1Br
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1ncccc1N1CCCc2ccccc21
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
A 250 mL round bottom flask was fitted with a magnetic stirrer and a reflux condenser (with a septum and N2 inlet on top). Cs2CO3 (13.04 g, 40 mmol), 3-bromopyridine-2-carbonitrile (2.66 g, 20 mmol), toluene (100 mL), 1,2,3,4-tetrahydroquinoline (2.76 mL, 22 mmol), and 4,5-bis-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthene (174 mg, 1.5% mol) were added in sequence. The mixture was degassed at room temperature by bubbling N2 through the suspension with stirring for 5 minutes. Pd2(dba)3 (90 mg, 0.5% mol) was added and the mixture was degassed again for 1 h at room temperature. The mixture was heated to 120° C. (bath) and refluxed under N2 in the dark. After two days, the mixture was cooled to room temperature. Another batch of 1,2,3,4-tetrahydroquinoline (2 mL), and Pd2(dba)3 (90 mg) were added. The system was degassed again for 1 h, and the heating was resumed. After another two days, the reaction mixture was cooled to room temperature and was concentrated by rotary evaporation under high vacuum. The residue was absorbed onto silica gel (50 mL) and loaded to a dry-packed silica gel column (200 mL silica). The column was eluted with 20% AcOEt/hexanes to afford a mixture of product and 3-bromo-2-cyanopyridine. The mixture was recrystallized from hexanes-AcOEt to give the product, 3-(3,4-dihydro-2H-quinoline-1-yl)pyridine-2-carbonitrile, as yellow crystals, 2.90 g (61.4%). 1H NMR (CDCl3) δ 2.06 (tt, 2H, J=5.7, 6.6 Hz), 2.91 (t, 2H, J=6.6 Hz), 3.76 (t, 2H, J=5.7 Hz), 6.56 (d, 1H, J=8.1 Hz), 6.85 (dd, 1H, J=0.9, 7.5 Hz), 6.98 (br, t, 1H, J=7.5 Hz), 7.10 (br, d, 1H, J=7.5 Hz), 7.42 (dd, 1H, J=4.5, 8.4 Hz), 7.72 (dd, 1H, J=1.2, 8.4 Hz), 8.42 (dd, 1H, J=1.5, 4.5 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:22])[CH2:15][S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:22])[CH2:15][S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSCC(F)(F)F
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CSCC(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(2,2,2-trifluoro-ethylsulfanyl)-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)=[CH:4][CH:3]=1.C=O.[C:20](=O)([O-])[O-:21].[K+].[K+].C(O)(C)C>O.CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9]([CH2:20][OH:21])=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(-c2nc(-c3cccnc3)c[nH]2)s1
Agent: C=O
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CN(C)C=O
Product: OCc1[nH]c(-c2ccc(Cl)s2)nc1-c1cccnc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A mixture of 2-(5-chlorothiophen-2-yl)-4-(3-pyridyl) imidazole (1.07 g), 35% formalin aqueous solution (35 ml), potassium carbonate (1.70 g), isopropanol (30 ml) and N,N-dimethyl-formamide (10 ml) was stirred at 90° C. for 2 hours. After cooling, water was added to the mixture and precipitated solid was collected by filtration. The solid was dissolved in methanol and, after removing insolubles by filtration, the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate to obtain 2-(5-chlorothiophen-2-yl)-5-hydroxymethyl-4-(3-pyridyl)imidazole (519 mg) as colorless powder.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C1COCC1>[S:19]1[CH2:20][CH2:21][N:17]([C:15]([C@H:9]2[NH:8][CH2:12][C@@H:11]([CH2:13][NH:14][S:32]([C:35]3[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:42][CH:43]=3)(=[O:34])=[O:33])[CH2:10]2)=[O:16])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(S(=O)(=O)NC[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (32 mg, 0.1 mmol) in anhydrous THF (5 mL) was added N,N-diisopropylethylamine (0.035 mL, 0.2 mmol) followed by 4-chlorosulfonyl-benzoic acid (20.92 mg, 0.12 mmol). The mixture was stirred for 8 hours at room temperature and concentrated under reduced pressure. The residue was taken up in anhydrous dichloromethane (3 mL) and trifluoroacetic acid (0.075 mL) in dichloromethane (0.075 mL) was added and the mixture was allowed to stir for 5 hours at room temperature. The mixture was concentrated under reduced pressure and purified using RP-HPLC to provide the titled compound. MS (ESI) m/e 400 (M+H)+, 398 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 1.78 (m, 1 H) 2.65 (m, 1 H) 3.00 (m, 2 H) 3.08 (m, 1 H) 3.14 (m, 1 H) 3.20 (m, 1 H) 3.49 (m, 1 H) 3.60 (m, 1 H) 3.73 (m, 1H) 3.88 (m, 1 H) 4.50 (m, 1 H) 4.66 (m, 2 H) 7.95 (d, 2 H) 8.19 (d, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].ClC1C=C(C=CC=1)C(OO)=[O:35]>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25]([CH2:26][CH2:27][CH2:28][OH:29])=[O:35])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCSCCCO)ccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCS(=O)CCCO)ccc1Cl
Yield: 56.3 %

Procedure:
Prepared according to the method of Example 14 using 2-chloro-5-[2-(3-hydroxypropylthio)ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 15, 0.12 g) and 3-chloroperoxybenzoic acid (0.07 g, 70%) to give the title compound (0.07 g).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[CH:3]=1.[ClH:26]>ClCCl.O1CCOCC1>[ClH:26].[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[CH:3]=1.[ClH:26]
Reactant: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 4-(4-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate D4 (0.072 mmol, 25 mg) was dissolved in dichloromethane (5 ml) and was treated with HCl (3 ml of a 4M solution in 1,4-dioxane) at room temperature; the mixture was stirred at room temperature for two hours. Solvent was evaporated to afford the title compound, mono hydrochloride salt, M++H=250.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[Cl:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[C:17](Cl)=[N:16][N:15]=1>O>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:6][CH2:5][CH2:4][CH2:3][OH:7])=[N:16][N:15]=[C:14]2[NH:13][CH2:12][C:11]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:9]([Cl:8])[CH:10]=1
Reactant: OCCCO
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(Cl)cc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(CNc2nnc(OCCCO)c3ccc(Cl)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60% Sodium hydride (0.12 g, 3.0 mmol) was added to 8 ml of 1,3-propanediol. The obtained mixture was stirred at room temperature for one hour, followed by the addition of 1.0 g (2.7 mmol) of the compound prepared in Example 27. The obtained mixture was stirred at 150° C. for one hour, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by distillation. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1)] and recrystallized from aqueous ethanol to give 0.58 g of the title compound as white needles.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:9](=O)[CH:10]([CH3:12])[CH3:11]>>[CH:9](=[C:8]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]1[CH2:2][NH2:1])[CH:10]([CH3:12])[CH3:11]
Reactant: NCc1ccccn1
Reactant: CC(C)C=O
Product: CC(C)C=C1C=CC=NC1CN
Yield: 85.5 %

Procedure:
The procedure is carried out as described in Example 1(a) but with the use of 216 g (2 mols) of 2-aminomethylpyridine and 144 g (2 mols) isobutyraldehyde. After a reaction time of 2 hours at 35°-40° C., subsequent distillation leaves 277 g (1.71 mols) of isobutylidene-2-aminomethylpyridine; yield 85.5% of theory; b.p. 69° C./200 Pa.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[O:13][CH3:14])=[O:4].[CH3:15][NH:16][CH3:17]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:16]([CH3:17])[CH3:15]
Reactant: CNC
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c(C(=O)CN(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-bromo-1-(2,5-dimethoxyphenyl)-ethanone (10.0 g) is added dropwise to a solution of dimethylamine (6.1 g) in toluene (450 ml). The mixture is stirred overnight at room temperature and extracted with a 1-N water solution of hydrochloric acid (3×250 ml). The mixed aqueous phases are alcalinized with a 25% water solution of sodium hydroxide (200 ml) and extracted with dichloromethane (4×250 ml). The mixed organic phases are washed with water (3×200 ml) and dried over magnesium sulphate. The solvent is distilled in vacuo and the residue is dried in vacuo to constant weight to give 1-(2,5-dimethoxyphenyl)-2-dimethylamino-ethanone which is a liquid, b.p. 250°-255°.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:16]([O:24][CH2:25][CH:26]1[O:28][CH2:27]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:27][CH:26]([OH:28])[CH2:25][O:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Reactant: CC(C)CCCCCOCC1CO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC(C)CCCCCOCC(O)COc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 68.9 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (2.3 g, 10 mmol), isooctylglycidyl ether (1.9 g, 10 mmol) and ethyltriphenylphosphonium bromide (0.2 g) are reacted and purified as described for compound 102 to afford a light yellow liquid 2.85 g (69%).
Reaction SMILES: C[Mg]Br.[C:4]([O:8][C:9]([NH:11][C:12]1[S:16][C:15]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:14][C:13]=1[C:25]([NH:27][C:28]1[C:29]([N:38]2[CH2:43][CH2:42][CH2:41][C@H:40]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:39]2)=[C:30]2[CH2:36][CH2:35][C:34](=[O:37])[C:31]2=[N:32][CH:33]=1)=[O:26])=[O:10])([CH3:7])([CH3:6])[CH3:5].[CH3:52]COC(C)=O.Cl>C1COCC1>[C:4]([O:8][C:9]([NH:11][C:12]1[S:16][C:15]([C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[N:14][C:13]=1[C:25]([NH:27][C:28]1[C:29]([N:38]2[CH2:43][CH2:42][CH2:41][C@H:40]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:39]2)=[C:30]2[CH2:36][CH2:35][C:34]([OH:37])([CH3:52])[C:31]2=[N:32][CH:33]=1)=[O:26])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCC2=O
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCC2(C)O
Temperature: 25 °C

Procedure:
Methylmagnesium bromide in THF (3.0 M, 5.8 μL, 0.018 mmol) was added to a solution of tert-butyl {(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (3.0 mg, 0.0044 mmol) in THF (0.068 mL), which was stirred under N2 and cooled in an ice bath. The reaction mixture was slowly allowed to warmed to room temperature over a period of 1 h. EtOAc was added to the reaction mixture, then 1 M HCl was slowly added to adjust the pH to 7. The aqueous layer was extracted twice with EtOAc. The organic extracts were combined, dried over Na2SO4, then filtered and concentrated under reduced pressure to give the sub-title compound. LCMS calc. for C34H43F2N6O6S (M+H)+: m/z=701.3. Found: 701.1.
Reaction SMILES: C([O:8][C:9]1[C:10]([F:30])=[C:11]([F:29])[CH:12]=[C:13]2[C:18]=1[N:17]([NH:19][CH2:20][CH:21]=[O:22])[CH:16]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]2=[O:28])C1C=CC=CC=1>C(Cl)(Cl)Cl.CO.[Pd]>[F:29][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([OH:8])[C:10]=1[F:30])[N:17]([NH:19][CH2:20][CH:21]=[O:22])[CH:16]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]2=[O:28]
Reactant: CCOC(=O)c1cn(NCC=O)c2c(OCc3ccccc3)c(F)c(F)cc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(NCC=O)c2c(O)c(F)c(F)cc2c1=O
Yield: 92.4 %

Procedure:
Ethyl 8-benzyloxy-6,7-difluoro-1-(formylmethylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (330 mg) was hydrogenated over 5% Pd/C (50 mg) in chloroform (14 ml) for 4 hours. The reaction mixture was diluted with methanol (14 ml) and filtered. The filtered cake was washed with chloroform/methanol (1:1). The combined filtrate was evaporated and the residue was recrystallized from ethanol to give 239 mg of ethyl 6,7-difluoro-1-(formylmethylamino)-8-hydroxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate, mp 221°-225° C. (dec.); MS m/z 326 (M+).
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][OH:21])[CH:16]=[C:15]([Cl:22])[C:14]=2[Cl:23])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:27]>C1COCC1>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][O:21][CH3:27])[CH:16]=[C:15]([Cl:22])[C:14]=2[Cl:23])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[CH2:3][CH2:2]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCO)cc(Cl)c1Cl)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1cc(Cl)c(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1,1-Dimethylethyl cyclopropyl{[2,3-dichloro-5-(2-hydroxyethyl)phenyl]-methyl}carbamate (1 eq.) was taken up in THF (0.3 M). To this solution was then added sodium hydride (60% w/w dispersion in oil, 1 eq.) and the resulting suspension was stirred at RT for 5 min. Finally, iodomethane (10 eq.) was added and the now pale yellow solution was stirred in darkness at RT for another 10 h. The volatiles were then removed in vacuo and the resulting residue partitioned between ether and 1 N aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed further with 1 N aq. NaOH, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to give the title compound (contaminated with oil) as a pale yellow oil.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:22]([C:26]1[N:27]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[S:55](=[O:58])(=[O:57])[NH2:56])=[CH:45][CH:44]=2)[C:28](=[O:41])[N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])[N:30]=1)[CH2:23][CH2:24][CH3:25].N12CCCN=C1CCCCC2>C1COCC1>[C:1]([NH:56][S:55]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:27]2[C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:30][N:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:38])[F:39])[C:28]2=[O:41])=[CH:44][CH:45]=1)(=[O:58])=[O:57])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of 145 mg (1.18 mmole) of benzoic acid and 192 mg (1.18 mmole) of 1,1'-carbonyldiimidazole in 1 mL of THF was stirred under N2 at 55° C. for 2 hours. Then a solution of 157 mg (0.296 mmole) of 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) and 133 mL (135 mg, 0.888 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 1 mL of THF was added dropwise. After being stirred overnight at 55° C., the mixture was partitioned between ethyl acetate and 5% citric acid (aqueous). The organic layer was washed with H2O and then with saturated NaCl solution. The ethyl acetate phase was then dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue as in Example 16, Step D, gave 159 mg (85%) of the title compound, homogeneous by TLC in 98:2 CH2Cl2 --MeOH and comparable in physical properties to the product made according to Example 16, Step D.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8]CC(Cl)(Cl)Cl)[C@H:3]1[C:15]([O:17][C@H:18]([CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].C(O)(=O)C.O>C(Cl)Cl.[Zn]>[CH3:1][C:2]1([CH3:33])[C@@H:4]([C:5]#[C:6][C:7](=[O:8])[OH:14])[C@H:3]1[C:15]([O:17][C@H:18]([CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:16]
Reactant: C[C@@H](OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1
Agent: [Zn]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A solution of 4.16 g of the product of Step A in 4 ml of methylene chloride was admixed with 45 ml of acetic acid containing 10% of water and 0.53 g of zinc powder and the mixture was stirred for 30 minutes at room temperature, then another 0.53 g of zinc powder were added 4 times until The reaction was complete and after 3 hours contact, the mixture was filtered. The filtrate was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness by azeotropic distillation with toluene to obtain 3.05 g of (R)α-methyl-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:16]1[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:35]>CS(C)=O.ClCCl.C(OCC)C>[ClH:35].[N+:26]([C:19]1[CH:18]=[CH:17][C:16]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:21][C:20]=1[C:22]([F:23])([F:24])[F:25])([O-:28])=[O:27].[ClH:35]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2.2 g; 11.0 mmol), 5-fluoro-2-nitrobenzotrifluoride (2.5 g; 11.9 mmol) and potassium carbonate (3.0 g; 22.0 mmol) in dimethylsulfoxide (25 mL) is heated over night at 100° C. The mixture is then diluted with dichloromethane (200 mL) and is washed with water (25 mL), aq. sat. ammonium chloride (25 mL) and twice with water (25 mL). The organic layer is then filtered and the filtrate is evaporated under reduced pressure. The product is dissolved in a 1 to 1 mixture of dichloromethane and trifluoroacetic acid (16 mL) and the resulting solution is stirred at room temperature until complete conversion is observed (about 30 minutes). After concentration under reduced pressure, the residue obtained is co-evaporated with dichloromethane (3×30 mL). The crude product is diluted in diethylether (25 mL) and a molar solution of hydrochloric acid in diethylether (15 mL) is added under stirring. The solid obtained is finally filtered and is dried under high vacuum to yield the desired product as hydrochloride (1.86 g; 5.7 mmol).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[C:13]([Cl:19])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].CCOCC>C(O)(C(F)(F)F)=O.CC(C)=O>[ClH:19].[C:13]([C:3]([CH2:9][C:10](=[O:11])[O-:12])([CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])[OH:2])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
1.98 g (0.01 moles) of carnitine hydrochloride are dissolved in 3 mls of CF3COOH, and to the solution an excess (7 mls) of pivalic acid chloride is added. The solution is kept under stirring at room temperature for about 48 hours. At the end of this period of time, the mixture is diluted with 20 mls of acetone and some ether is slowly added till complete precipitation. The mixture is filtered and the precipitate which has the tendency to become hygroscopic is quickly washed with ether and dried under vacuum at the temperature of about 50° C. 1.70 g are obtained with a yield of 60% of a product having the following characteristics: