Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[O:15][CH3:16].[OH-].[Na+]>CO.O>[F:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16]
Reactant: COC(=O)c1ccc(OCC(C)(C)F)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCC(C)(C)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(2-fluoro-2-methyl-propoxy)-3-methoxy-benzoate (450 mg, 1.76 mmol) in MeOH (3.6 mL) and water (900 μL) was added NaOH (210 mg, 5.27 mmol) and the mixture was stirred at 40° C. for 1 hour. The MeOH was evaporated and the pH of the solution was adjusted to 3 with 1N HCl. The precipitate was filtered, washed with water, and desiccated to give 4-(2-fluoro-2-methylpropoxy)-3-methoxybenzoic acid. ESI-MS m/z calc. 242.2, found 243.7 (M+1)+; Retention time: 1.25 minutes (3 min run).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:12]=[C:13]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17].CN(C(ON1N=NC2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(OC(N1CCNCC1)=O)(C)(C)C>>[NH:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]=[C:3]1[C:11]1[CH:12]=[C:13]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([N:41]3[CH2:40][CH2:39][CH2:38][CH2:36]3)=[O:25])[CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: O=C(O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C([C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)C1)N1CCCC1
Temperature: 35 °C
Yield: 52.4 %

Procedure:
Method B—Step a To a vial with (R)-1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidine-3-carboxylic acid hydrochloride (obtained as described in general method 2, step e) (0.10 g, 0.28 mmol) (obtained as described in general method 2), HATU (0.11 g, 0.30 mmol), triethylamine (TEA) (0.09 mL, 0.66 mmol) and tert-Butyl-1-piperazinecarboxylate (0.08 g, 0.62 mmol) dichloromethane (2 L) was added and the reaction mixture was heated at 35° C. overnight. Reaction was cooled to room temperature, solvent removed and the crude purified by preparative HPLC and NH2 column filtration, to obtain 0.06 g of the title compound (55%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[S:9][C:10](Br)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].O>C(N(CC)CC)C.[Cu]I>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[S:9][C:10]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(C#C[Si](C)(C)C)s1
Temperature: 80 °C
Yield: 79.1 %

Procedure:
(5-Bromo-thiazol-2-yl)-carbamic acid tert-butyl ester (2.0 g, 7.164 mmol) was taken in triethylamine (20 ml). To this solution was added CuI (0.041 g, 0.215 mmol), PdCl2 (PPh3)2 (0.050 g, 0.071 mmol) followed by the addition of trimethylsilylacetylene (1.055 g, 10.741 mmol). The reaction was heated at 80° C. overnight. Reaction mixture was cooled to room temperature and poured into water (50 ml), extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with 1N HCl followed by brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by column chromatography over silica gel using 6% ethyl acetate hexane as eluent to provide pure (5-trimethylsilanylethynyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.679 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:37]=[C:36]([C:47]([O:50][CH3:51])([CH3:49])[CH3:48])[CH:35]=2)=[CH:30][CH:29]=1)(C)(C)C>C1COCC1>[CH3:51][O:50][C:47]([C:36]1[CH:35]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][OH:24])=[CH:29][CH:30]=2)[N:38]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[N:37]=1)([CH3:49])[CH3:48]
Reactant: COc1ccc(-n2nc(C(C)(C)OC)cc2-c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)(C)OC)cc2-c2ccc(OCCO)cc2)cc1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A 1M solution of tetra-n-butylammonium fluoride in THF (0.24 mg) was added to a solution of 5-[4-(2-{ [tert-butyl-(dimethyl)silyl]oxy}ethoxy)phenyl]-3-(1-methoxy-1-methylethyl)-1-(4-methoxyphenyl)-1H-pyrazole (98 mg) in THF (2 ml) under ice bath cooling. The reaction mixture was stirred at same temperature for 1 hour. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by 50% AcOEt/n-hexane. The seaparated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 2-{4-[3-(1-methoxy-1-methylethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanol (66 mg) as an oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C@H:18]1[CH2:20][O:19]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[O:30])=[C:24]([F:39])[CH:23]=1)#[N:5]>O1CCCC1>[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C@H:18]([OH:19])[CH2:20][N:2]([CH3:3])[CH3:1])[N:12]=[CH:11][CH:10]=[C:9]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[O:30])=[C:24]([F:39])[CH:23]=1)#[N:5]
Reactant: CNC
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OC[C@H]1CO1
Solvent: C1CCOC1
Product: CN(C)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N

Procedure:
After adding tetrahydrofuran (0.5 ml) and a dimethylamine-2N tetrahydrofuran solution (Aldrich, 0.2 ml) to N-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(4-fluorophenyl)urea (40 mg), the mixture was stirred overnight at room temperature. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (45 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:19]C(C)([O-])C.[K+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]([CH3:19])[C:13](=[O:18])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(-c2cc(=O)[nH]c(C)n2)cc1OC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc(-c2cc(=O)n(C)c(C)n2)cc1OC
Temperature: 25 °C
Yield: 65.3 %

Procedure:
To a suspension of 3,4-dihydro-6-(3,4 dimethoxyphenyl)-2-methylpyrimidin-4-one (2.0 g) in N,N-dimethylformamide (20 ml) were added potassium tert.butoxide (1.08 g) and methyl iodide (1.0 ml), and stirred at ambient temperature for an hour. Resulting mixture was poured into water, and extracted with ethyl acetate. The organic layer was chromatographed on silica gel eluting with chloroform to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2,3-dimethylpyrimidin-4-one (1.38 g).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[N:13]1[C:20](Cl)=[N:19][C:17](Cl)=[N:16][C:14]=1Cl.Cl>C1(C)C(C)=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][N:13]2[CH2:20][N:19]([NH:1][C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:17][N:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)[CH2:14]2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccc(NN2CN(Nc3ccc(C(=O)OCC)cc3)CN(Nc3ccc(C(=O)OCC)cc3)C2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
82.6 g of ethyl p-aminobenzoate and 30.75 g of cyanuric chloride in 1,500 ml of xylene were refluxed for 8 hours, hydrogen chloride escaping during this procedure. Thereafter, 1 liter of xylene was added, and the suspension, at 80°-90° C., was washed neutral with saturated sodium bicarbonate solution and then cooled to room temperature, and the product was filtered off over a glass suction filter. The white crystals obtained were washed with ethanol and dried. Mp: 218°-223° C.; yield: 97% of 1,3,5-tris-(p-ethoxycarbonylanilino)-s-triazine; ultraviolet (in ethanol): E1 cm1% =2,080 at 313 nm, E1 cm1% =699 at 218 nm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH2:24][C:25]1([C:38]([OH:40])=[O:39])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][C:25]([NH:24][CH2:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[O:18][CH3:19])[N:9]=[CH:8][N:7]=[C:6]3[NH:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[C:3]=2[F:23])([C:38]([OH:40])=[O:39])[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)O)CC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 4-amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid using an analogous method to that described for the equivalent step in Example 1 to give 1-(tert-butoxycarbonyl)-4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-4-carboxylic acid; 1H NMR Spectrum: (DMSO d6) 1.39 (s, 9H); 1.70 (m, 2H); 1.86 (m, 2H); 3.43 (m, 4H); 3.76 (s, 2H); 3.96 (s, 3H); 7.19 (s, 1H); 7.28 (t, 1H); 7.48 (t, 1H); 7.55 (t, 1H); 8.37 (s, 1H); 8.43 (s, 1H); 9.78 (s, 1H); Mass Spectrum: (M+H)+ 560.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:20])[C:7](=[O:19])[NH:8][N:9]=1.O=[C:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1.C([BH3-])#N.[Na+]>CCO.CC(O)=O>[C:29]([O:28][C:26]([N:24]1[CH2:25][CH:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[CH:16]2[CH2:17][CH2:18]2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:20])[C:7](=[O:19])[NH:8][N:9]=2)[CH2:23]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC1C(=O)NN=C2COc3cc(C4CC4)c(N)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A solution of 6-amino-7-cyclopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.860 g, 3.16 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (2.703 g, 15.79 mmol) in EtOH (25 mL) and HOAc (2.5 mL) was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and sodium cyanoborohydride (0.073 g, 1.159 mmol) was added. The reaction mixture was stirred overnight and concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 3) to give 3-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.560 g, 41%). The racemic product was separated by chiral SFC (Table 2, Method 6) to give 3-(7-cyclopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 12) Rt=6.01 min., 0.300 g, 22%) and 3-[7-(2,4-dichloro-phenyl)-4(S)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 12) Rt=8.89 min., 0.280 g, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:34].[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:25])=[O:34])=[CH:20][CH:19]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:27][CH:28]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(SC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(S(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 146.9 %

Procedure:
To a solution of N1-(4-Methoxybenzoyl)-N2-[4-(methylthio)benzoyl]-1,2-benzenediamine (417 mg, 0.60 mmol) in chloroform (20 mL), cooled to 0° C. was added m-chloroperoxybenzoic acid (346 mg, 1.16 mmol). After 30 min, the reaction mixture was warmed to room temperature and calcium hydroxide (123 mg, 1.66 mmol) was added. After 15 min, the reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was chromatographed (silica gel, 50% ethyl acetate/50% hexanes to 80% ethyl acetate/20% hexanes) to give 360 mg (83%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35](=[N:37]O)[NH2:36]>>[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35]1[N:36]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:37]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(Cc1ccc(F)cc1Cl)=NO
Product: CCc1ccc(C2CC(c3nc(Cc4ccc(F)cc4Cl)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 45 mg (0.22 mmol, 1.1 eq.) of 2-(2-chloro-4-fluorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 59 mg (57% of theory)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[I:18][C:19]1[C:20]([C:29](OCC)=[O:30])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.IC1C(C(OCCC(C)C)=O)=NC2C(C=1)=CC=CC=2.[BH4-].[Na+]>C1COCC1.CCO.O>[I:18][C:19]1[C:20]([CH2:29][OH:30])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: CCOC(=O)c1nc2ccccc2cc1I
Agent: CC(C)CCOC(=O)c1nc2ccccc2cc1I
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: OCc1nc2ccccc2cc1I
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of diisobutyl aluminum hydride in toluene (1M, 652 μL, 0.652 mmol) was added to a stirred solution of a 3:1 mixture of ethyl 3-iodoquinoline-2-carboxylate and 3-methylbutyl 3-iodoquinoline-2-carboxylate (100 mg, 0.297 mmol) in dry THF (3 mL) at 0° C. under N2. The reaction was stirred for 4 h at 0° C. The reaction was quenched with saturated NH4Cl (5 mL) and water (5 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. Sodium borohydride was added to a stirred solution of the crude product in EtOH (3 mL) and the reaction was stirred at room temperature for 20 min. The reaction was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-50% EtOAc in hexanes gradient) to afford (3-iodoquinolin-2-yl)methanol, as a colorless solid. Rf=0.88 (50% EtOAc/hexanes). LCMS calc.=286.0; found=286.0 (M+1)+. 1H NMR (500 MHz, CDCl3): δ 8.56 (s, 1H); 8.03 (d, J=8.4 Hz, 1H); 7.74-7.71 (m, 1H); 7.70 (d, J=8.1 Hz, 1H); 7.54 (t, J=7.1 Hz, 1H); 4.90 (br s, 1H); 4.78 (s, 2H).
Reaction SMILES: [Br-].[CH2:2]1[CH2:29][O:28][C:4]([CH3:27])([CH2:5][CH2:6][CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:3]1.C([Li])CCC.CCCCCC.C([O:43][CH:44](OCC)[C:45](=O)[CH2:46][CH2:47][CH:48]=[C:49]([CH3:51])[CH3:50])C.CCCCCC>O1CCCC1.C(O)(=O)C>[CH2:29]1[CH2:2][O:3][C:4]([CH2:5][CH2:6][CH:7]=[C:45]([CH:44]=[O:43])[CH2:46][CH2:47][CH:48]=[C:49]([CH3:51])[CH3:50])([CH3:27])[O:28]1
Reactant: CC1(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)OCCO1
Reactant: CCOC(OCC)C(=O)CCC=C(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=CCCC(C=O)=CCCC1(C)OCCO1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
In 160 ml of anhydrous tetrahydrofuran was suspended 38.5 g of 4,4-ethylenedioxypentan-1-yltriphenylphosphonium bromide, and to this was added the equimolar amount of a n-butyl-lithium-hexane solution at -20° C in a stream of nitrogen. The reaction mixture was stirred for 1 hour and cooled to -60° C. To this was added 14.5 g of 1,1-diethoxy-6-methyl-5-hepten-2-one, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was, after addition of ice-water, extracted with n-hexane and from the extract was obtained an oil. The oil was suspended in 250 ml of 50 % acetic acid and stirred at room temperature for one hour. 2,2-Ethylenedioxy-6-formyl-10-methyl-5,9-undecadiene obtained by the n-hexane extraction, not purified, was reduced in 100 ml of ethanol by using 500 mg of sodium borohydride. The product thus obtained was chromatographed on the silica gel (100 g) column to yield 7.3 g of 2,2-ethylenedioxy-6-hydroxymethyl-10-methyl-5,9-undecadien.
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18]([O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][N:34]2[C:35](=[O:36])[C:16]3[C:15]([OH:14])=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[N:23]4)=[C:18]([O:25][S:26]([C:29]([F:30])([F:31])[F:32])(=[O:28])=[O:27])[C:17]=3[CH2:33]2)=[CH:43][CH:42]=1
Reactant: O=C1c2c(c(OS(=O)(=O)C(F)(F)F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(c(OS(=O)(=O)C(F)(F)F)c3cccnc3c2O)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 46 (28 mg, 0.045 mmol) dissolved in dichloromethane (2 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford trifluoro-methanesulfonic acid 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 274, (13.7 mg, 0.03 mmol, 67%) as a yellow solid: 1H NMR (CDCl3) δ 9.0 (d, 1H), 8.4 (d, 1H), 7.7 (dd, 1H), 7.3 (dd, 2H), 7.1 (t, 2H), 4.8 (s, 2H), 4.6 (s, 2H); MS: 457 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH3:7][O:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:12]([O:17][CH3:18])[CH:11]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(OC)c1
Yield: 85.2 %

Procedure:
Potassium carbonate (3.45 g; 25 mmol) was added to a solution of 4-hydroxy-3-methoxy benzoic acid methyl ester (3.6 g; 20 mmol) and benzyl bromide (3.42 g; 20 mmol) in acetone (100 ml). The reaction mixture was refluxed for 12 hrs. After the removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was washed with water (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 4.64 g of 4-benzyloxy-3-methoxy benzoic acid methyl ester (Yield=86.6%)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C1C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)(O)[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1>O>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:30][CH:31]=1
Reactant: CCOC(=O)C(C)C(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(C)=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
4.10 ml of phosphorus oxychloride were dropped at from 5° to 10° C. onto 140 ml of a benzene solution containing 7.02 g of ethyl 3,3-bis(4-methoxyphenyl)-3-hydroxy-2-methylpropionate (prepared as described in Preparation 106) on an ice bath. The reaction solution was then stirred for 3 hours at room temperature, after which it was poured into water and then extracted with diethyl ether three times. The combined ethereal extracts were washed with a saturated aqueous solution of sodium bicarbonate, with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure. The residue (6.72 g) was subjected to flash column chromatography through 100 g of silica gel. 6.04 g of the title compound were obtained as an oily substance from those fractions eluted with a 95:5 by volume mixture of hexane and ethyl acetate.
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][CH:15]([F:19])[C:16](F)=[O:17].C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:14][CH:15]([F:19])[C:16](=[O:17])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C=CN1CCCCC1
Reactant: O=C(F)C(F)F
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
Ethyl 3-piperidin-1-ylacrylate (94%, 9.4 g, 48 mmol) was initially charged in toluene (100 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (5.0 g, 51 mmol) was introduced. Tributylamine (9.5 g, 51 mmol) was then added to the reaction mixture. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (50 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml) and the solvent was then removed under reduced pressure. This gave ethyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 12.7 g; purity according to GC: 82.15%; yield: 82.8%).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([CH3:26])[C:14]=1[C:15](O)=[O:16]>>[CH3:26][C:18]1[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=[C:13]([CH3:12])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: Cc1cc(C(F)(F)F)cc(C)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: Cc1cc(C(F)(F)F)cc(C)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, light yellow oil, MS: m/e=355.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,6-dimethyl-4-trifluoromethyl-benzoic acid (intermediate AQ).