Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nccc(O)c2cc1OC
Product: COc1cc2nccc(Cl)c2cc1OC
Temperature: 85 °C

Procedure:
6,7-Dimethoxy-4-hydroxyquinoline (Step A, 7.8 g) was dissolved in POCl3 (45 mL) and heated at 85° C. for 3 h. The mixture was cooled down to RT, POCl3 was evaporated and the resulting oil was quenched by adding ice at 0° C. The aqueous phase was basified to pH 8 and a solid precipitated. The solid was filtered and dried under vacuum to give 4-chloro-6,7-dimethoxyquinoline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2].O[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 506 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (2 g, 6.79 mmol) prepared in Preparation Example 2 was dissolved in THF/benzene (270 mL/90 mL) solution, and 2-hydroxyethylmorpholine (5.83 g, 44.45 mmol) and triphenylphosphine (11.66 g, 44.45 mmol) were added thereto and kept at 0° C. Diisopropyl azodicarboxylate (8.99 g, 44.45 mmol) was added dropwise to the mixture, followed by stirring for 2 hrs at room temperature. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 14 g of the titled compound (yield: 93%) as a red solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Br:11][CH2:12][CH2:13][CH2:14]Br>CO>[Br:11][CH2:12][CH2:13][CH2:14][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCBr)cc1
Temperature: 70 °C
Yield: 23.4 %

Procedure:
To a solution of hydroquinone (3.0 g, 27 mmol) in MeOH (30 mL), KOH (1.5 g, 27 mmol) was added. Then, 1,3-dibromopropane (3.3 mL, 32 mmol) was added dropwise over 10 minutes. After the addition was complete, the mixture was refluxed for 12 hours at 70° C. The reaction mixture was concentrated and quenched with water (100 mL), and then the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was with washed water, thetn brine, and dried over Na2SO4. The solvent was evaporated and the product was purified by column chromatography to isolate the intermediate 10a (1.46 g, 6.31 mmol, 23% yield) as a pinkish solid. 1H NMR (CDCl3, 400 MHz) δ 6.81 (m, 4H), 5.93 (broad s, 1H), 4.06 (t, 2H), 3.61 (t, 2H), 2.30 (m, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[C:22]([NH:24][C:25]([NH:27][CH2:28][CH:29]=[CH2:30])=[O:26])[S:23][C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[CH2:28]([NH:27][C:25]([NH:24][C:22]1[S:23][C:17]2[CH2:16][NH:15][CH2:20][CH2:19][C:18]=2[N:21]=1)=[O:26])[CH:29]=[CH2:30]
Reactant: C=CCNC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C=CCNC(=O)Nc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
10% TFA in 60 ml chloroform was added to 2.5 g 2-(3-allyl-ureido)-6,7-dihydro-4H-thiazolo (5,4-c) pyridine-5-carboxylic acid tert-butyl ester in 28 ml chloroform and stirred for 2 h at RT. The mixture was concentrated, the residue was diluted with chloroform and basified with 2.5 M aqueous potassium carbonate solution and extracted with chloroform. The organic layer was concentrated. The residue was washed with a mixture 50% ethyl acetate and 50% hexane to yield 1.7 g of the desired product. (M+H)+: 239
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16]([NH:18][CH2:19][C:20]([O:22]C)=O)=[O:17])=[C:4]2[CH:3]=[CH:2]1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C[Al](C)C.O>O1CCCC1>[CH2:24]([NH:31][C:20]([CH2:19][NH:18][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12)=[O:17])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: NCc1ccccc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a solution of methyl ({[3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)thiophen-2-yl]carbonyl}amino)acetate (50 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added a pre-mixed solution of benzylamine (25 uL, 0.23 mmol) and trimethylaluminum (2.0 M toluene, 91 uL, 0.18 mmol). The solution was stirred at room temperature for 10 minutes then water was added resulting in precipitation. The precipitate was collected by filtration and dried under vacuum to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (benzylcarbamoyl-methyl)-amide (55 mg, 90%) (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.31 (1H, s) 8.46 (1H, t, J=6.08 Hz) 8.39 (1H, t, J=5.69 Hz) 8.03 (1H, d, J=5.37 Hz) 7.81 (1H, d, J=5.42 Hz) 7.51 (1H, d, J=5.42 Hz) 7.33 (1H, dd, J=3.20, 2.71 Hz) 7.28 (4H, d, J=0.05 Hz) 7.16-7.25 (1H, m) 6.85 (1H, d, J=5.47 Hz) 6.44 (1H, dd, J=3.47, 1.90 Hz) 4.30 (2H, d, J=5.95 Hz) 3.89 (2H, d, J=5.71 Hz)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5].[C:16]([O:20][C:21](=[O:33])[NH:22][C@H:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1)[CH3:24])([CH3:19])([CH3:18])[CH3:17].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:2][O:3][C:4]([C:6]1[C:7]2[CH2:8][CH2:9][N:10]([CH2:31][C:28]3[CH:27]=[CH:26][C:25]([C@@H:23]([NH:22][C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:33])[CH3:24])=[CH:30][CH:29]=3)[CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5]
Reactant: COC(=O)c1cccc2c1CCNC2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1CCN(Cc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 600 mg (2.64 mmol) 1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester hydrochloride and 657 mg (2.64 mmol) [(S)-1-(4-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (example II) in 5 mL THF are added 452 μL (7.91 mmol) AcOH and the mixture is stirred at r.t. for 10 min. After that time, the resulting mixture is cooled to 0° C., 838 mg (3.95 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. The reaction is quenched by the addition of 500 μl water and purified by HPLC (ACN/H2O/NH3).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH:18]([F:20])[F:19])[N:13]([CH:15]2[CH2:17][CH2:16]2)[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:15]1([N:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:21])[CH:11]=[C:12]2[CH:18]([F:20])[F:19])[CH2:16][CH2:17]1
Reactant: O=c1cc(C(F)F)n(C2CC2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1cc(C(F)F)n(C2CC2)cc1O
Yield: 77.7 %

Procedure:
A mixture of 5-benzyloxy-1-cyclopropyl-2-difluoromethyl-1H-pyridin-4-one (3.0 g, 10.3 mmol) and 10% Pd/C (340 mg) in methanol (60 mL) was subjected to hydrogenation in a Parr apparatus under a 15 psi hydrogen pressure for 22 min. The mixture was diluted with 300 mL of methanol, sonicated for 20 min, and then filtered through a pad of CELITE™ (pre-treated with HCl and washed to neutral with deionized water). The volume of the filtrate was reduced in vacuo until a solid precipitated out. The solid was collected by suction filtration. The recrystallization was repeated on the filtrate to obtain a second crop of solid. The combined solids were dried to constant weight in a vacuum oven thereby affording the title product (1.61 g) in 77% yield. HPLC purity (peak area percent) of product is 99.5% at λ=280 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6+D2O) δ (ppm): 7.54 (s, 1H), 7.33 (t, J=53.0 Hz, 1H, CF2H), 6.51 (s, 1H), 3.53-3.57 (m, 1H, N—CH), 1.07-1.10 (m, 4H, 2CH2); MS-ESI (m/z): 202.5 [M+1]+, 142.3 (100%); Anal. Calcd. for C9H9F2NO2: C, 53.73; H, 4.51; N, 6.96%. Found: C, 53.75; H, 4.80; N, 6.89%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[CH:17]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=3[CH:17]=2)[CH2:31][CH2:30]1
Reactant: O=C1CCCc2cc(OCCCCl)ccc2N1
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2cc(OCCCN3CCN(Cc4ccc5ccccc5n4)CC3)ccc2N1
Temperature: 150 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A mixture consisting of 7-(3-chloropropoxy)-2,3,4,5-tetrahydro-1H-benzoazepin-2-one (0.304 g, 1.2 mmol) and 1-(2-quinolylmethyl)piperazine (1.091 g, 4.8 mmol) was stirred for 4 hours at a bath temperature of 150° C. under an argon gas stream. The reaction mixture was dissolved in chloroform. The thus-obtained solution was rendered basic with a dilute aqueous solution of sodium hydroxide, washed with water, and then dried over magnesium sulfate. After the resulting solution was purified by subjecting it to chromatography on a silica gel column (developer: chloroform/methanol=40/1), recrystallization was conducted from acetone. The title compound (0.270 g) was obtained as yellow prisms (yield: 50.6%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccccc1I
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 88 %

Procedure:
Under an atmosphere of argon, 2-bromoiodobenzene (7.9 g, 25 mmole), biphenylboronic acid (5.0 g, 25 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (60 ml). To the obtained solution, an aqueous solution of sodium carbonate (8.0 g, 75 mmole, 3 eq/40 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+5% dichloromethane, successively) and white needle crystals (6.8 g, 88%) were obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:29]([C:32]1[CH:33]=[C:34]([NH:38][CH:39]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][OH:51])=[C:45]([CH2:52][CH3:53])[CH:44]=2)[C:40](O)=[O:41])[CH:35]=[CH:36][CH:37]=1)(=[O:31])[NH2:30].[CH:54]([S:57][C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][C:59]=1[CH2:65][NH:66][CH3:67])([CH3:56])[CH3:55]>CCOC(C)=O>[NH2:62][C:61]1[CH:63]=[CH:64][C:58]([S:57][CH:54]([CH3:56])[CH3:55])=[C:59]([CH:60]=1)[CH2:65][N:66]([CH3:67])[C:40](=[O:41])[CH:39]([NH:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[C:29]([NH2:30])=[O:31])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][OH:51])=[C:45]([CH2:52][CH3:53])[CH:44]=1
Reactant: CCc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1CCO
Reactant: CNCc1cc(N)ccc1SC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)N(C)Cc2cc(N)ccc2SC(C)C)ccc1CCO
Temperature: 50 °C
Reaction time: 4 h

Procedure:
EDCI (67 mg, 0.35 mmol), HOAt (80 mg, 0.58 mmol) and triethylamine (0.79 mL, 0.58 mmol) were added to a solution of 46C (100 mg, 0.3 mmol) and 16D (67 mg, 0.3 mmol) and stirred at 50° C. for 4 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude oil was purified by flash chromatography (0% to 20% MeOH in CH2Cl2) to yield 46D as a yellow solid. MS (ESI) m/z 535.4 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=2)=[C:20]([C:36]([F:39])([F:37])[F:38])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: Cc1cc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)ccc1F
Agent: Cl
Solvent: CCO
Product: Cc1cc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)ccc1F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 44-5 (800 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.
Reaction SMILES: CO.[F:3][C:4]1[C:11]([F:12])=[C:10]([CH2:13]Br)[C:9]([F:15])=[C:8]([F:16])[C:5]=1[CH2:6][OH:7]>[Pd].O>[F:3][C:4]1[C:11]([F:12])=[C:10]([CH3:13])[C:9]([F:15])=[C:8]([F:16])[C:5]=1[CH2:6][OH:7]
Reactant: OCc1c(F)c(F)c(CBr)c(F)c1F
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Cc1c(F)c(F)c(CO)c(F)c1F
Yield: 89.3 %

Procedure:
The following procedures were carried out in a 1 litre glass autoclave (working volume 350-500 mls) fitted with a dispersion agitator (1000 rpm). H2 gas was fed through a dip-pipe via a Buchi gas controller (Type 6002). The increase/decrease of the temperature is controlled by a Jelabo FP40 external heating/cooling bath. Methanol (362 g, water (6 g, 2,3,5,6-tetrafluoro-4-(bromomethyl)benzyl alcohol (95.1 g 100% wt.), MgO (18.1 g and 5% palladium/carbon catalyst (0.8 g, 100 wt %; Type 58, provided by Johnson Matthey) were charged to the autoclave. The lid was sealed and the autoclave was initially purged with nitrogen to remove residual oxygen (nearly 0), then pressurized to 2.5 bar with hydrogen, and stirred. The pressure was maintained at 2.5 bar by the Buchi controller. The reaction temperature was controlled at 50° C. throughout the reaction by means of the external heating/cooling bath. The reaction was continued until the consumption of hydrogen ceased (typically 60 to 90 minutes). The residual pressure was released and the autoclave purged with nitrogen. The contents of the autoclave were discharged, followed by a small methanol (30 g wash. The spent catalyst and inorganic salts were removed and recovered by filtration. The filter cake was washed with a small amount of methanol (2×30 g. The filtrates and filter-cake washes were combined. On analysis, the reaction had produced 60.4 g of 2,3,5,6-tetrafluoro-4-methylbenzyl alcohol with a yield of 89.4%.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C[C@H]1Cc1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@H](NCCc2ccccc2)C[C@H]1Cc1ccccc1
Yield: 59.3 %

Procedure:
1 g (3.44 mmol) of (2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-4-piperidinamine is reacted in analogy to Example 11a with 1 ml (4.48 mmol) of phenylacetaldehyde, 0.433 g (6.89 mmol) of sodium cyanoborohydride, 0.791 g (9.64 mmol) of sodium acetate and 434 μl of acetic acid to give the title compound (805 mg, 60%). TLC:methylene chloride/methanol/cone. ammonia (700:50:1) Rf =0.35, FD-MS:M+ =394.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([OH:25])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]=[C:10]([NH:33][C:34](C3OC=CC=3)=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=C=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([OH:25])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]=[C:10]([NH:33][C:34]([NH:41][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)c3ccco3)cc(-c3cccc(Cl)c3)c2c1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)Nc3ccccc3)cc(-c3cccc(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
A mixture of (±)-2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.000210 mol) (see Example B8) and isocyanato-benzene (0.000630 mol; 3 equiv) in THF (1 ml) was stirred for 5 hours at 60° C. Water (a few drops) was added. The solvent was evaporated. The residue was HPLC purified. The product fractions were collected and the solvent was evaporated, yielding 0.071 g (56.77%) of (±)-N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinolinyl]-N′-phenylurea, MS (ESI) m/z: 594 596 598.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[CH:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[CH:19]=1
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 64.8 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (8 mg, 0.033 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (8.9 mg, 0.0367 mmol) in DMF (1 mL) at rt was added TEA (5.1 μL, 0.0367 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (9.5 mg; yield 64%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.26 (s, 1 H), 7.66-7.85 (m, 6 H), 4.32-4.96 (m, 2 H), 1.51 (s,6 H) ppm; MS: m/z=444 (M+1, ESI+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:14][CH:13]2[C:37]([NH2:39])=[O:38])=[CH:4][CH:3]=1.O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:37]([NH2:39])=[O:38])=[CH:4][CH:3]=1
Reactant: NC(=O)C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)C1CNCCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
33.1 g (53.8 mmol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-tritylpiperazine-2-carboxamide were dissolved in 180 ml of glacial acetic acid, 180 ml of water were added dropwise in the course of 15 minutes, the mixture was subsequently stirred for 90 minutes, the oily precipitate was decanted, 720 ml of H2O and a Little Celite®, a product from Johns-Mannville Corporation, New York, were added, the mixture was filtered and the filtrate was brought to pH 10 with concentrated NaOH and extracted with methylene chloride. The organic phase was dried and concentrated in vacuo.
Reaction SMILES: Cl.N1C=CC=CC=1.[Cl:8][C:9]1[C:10]([O:28]CC(O)=O)=[CH:11][C:12]2[CH2:13][CH2:14][C:15]3([CH2:25][CH2:26][CH3:27])[C:20]([C:21]=2[C:22]=1[Cl:23])=[CH:19][C:18](=[O:24])[CH2:17][CH2:16]3>>[Cl:8][C:9]1[C:10]([OH:28])=[CH:11][C:12]2[CH2:13][CH2:14][C:15]3([CH2:25][CH2:26][CH3:27])[C:20]([C:21]=2[C:22]=1[Cl:23])=[CH:19][C:18](=[O:24])[CH2:17][CH2:16]3
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)CC2
Agent: Cl
Solvent: c1ccncc1
Product: CCCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)CC2
Temperature: 190 °C
Reaction time: 0.25 h

Procedure:
Pyridine hydrochloride (20 g, 173 mmole) is melted and heated to 190° C. and then (-) [(3,4-dichloro-6,7,8,8a,9,10-hexahydro-6-oxo-8a-propyl-2-phenanthrenyl)oxy]acetic acid (Example 3) (325 mg, 1 mmole) is added and stirred for 15 minutes at 190°. The mixture is poured into crushed ice (200 g) and the product extracted with ether. The organic extract is washed with water, then with brine and dried over MgSO4. Evaporation of the solvent gave (-)3,4-dichloro-6,7,8,8a,9,10-hexahydro-2-hydroxy-6-oxo-8a-propylphenanthrene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=S.[OH-].[Na+]>C1COCC1.O>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[N:7]=[C:5]1[NH:4][CH2:3][CH2:2][NH:1]1
Reactant: NCCNC(=S)Nc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cccc(Cl)c1N=C1NCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
1-(2-Aminoethyl)-3-(2,6-dichlorophenyl)thiourea (200 mg) was dissolved under argon in THF (4 ml), admixed with a solution of sodium hydroxide (102 mg) in water (2 ml) and then a slurry of polystyrene-bound toluenesulfonyl chloride (457 mg, 2.9 mmol/g) in THF (4 ml) was added dropwise within five minutes. After stirring at room temperature for 2 h, further polystyrene-bound toluenesulfonyl chloride (65 mg in 2 ml of THF) was added, followed, after a further hour, by further acid chloride (124 mg in 2 ml of THF). After standing overnight, the reaction mixture was filtered, the resin was slurried twice in dichloromethane and the combined phases were concentrated to dryness. The residue was taken up in water/dichloromethane, the phases were separated and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, and the solvent was removed under reduced pressure and the residue subsequently dried under high vacuum. 104 mg of the title compound were obtained.