Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][CH:33]=[O:34])[N:27]=[CH:26]3)=[O:12])[N:7]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][CH2:33][OH:34])[N:27]=[CH:26]3)=[O:12])[N:7]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CC=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
1-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-((5-fluoro-2-(1-(2-oxoethyl)-1H-indazol-5-yloxy)phenyl)methyl)urea (2.179 g, 3.929 mmol) was suspended in MeOH (40 mL) and treated with sodium borohydride (0.7432 g, 19.64 mmol) portionwise at room temperature. The reaction mixture was stirred at room temperature until complete conversion of the starting material to product was observed by HPLC analysis. The reaction mixture was concentrated under reduced pressure and then diluted with saturated aqueous NH4Cl and extracted into dichloromethane. The organics were dried (MgSO4) and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant 2-6% iPrOH/DCM) to provide 1.21 g (55%) of the desired compound. MS (APCI+) m/z 557 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.68 (d, 1H, J=9.1 Hz), 7.35 (s, 1H), 6.85-7.4 (m, 8H), 6.24 (s, 1H), 4.87 (t, 1H, J=5.4 Hz), 4.43 (t, 1H, J=5.6 Hz), 4.28 (d, 1H, J=5.9 Hz), 3.80 (q, 1H, J=5.5 Hz), 2.35 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[C:20]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][C@H:33]([O:36][CH3:37])[C:32]([CH3:39])([CH3:38])[CH2:31]2)[C:27]2[C:26](=O)[N:25]([C:41]3[CH:46]=[C:45]([CH:47]([CH3:49])[CH3:48])[CH:44]=[CH:43][C:42]=3[CH3:50])[CH2:24][CH2:23][C:22]=2[N:21]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[C:20]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][C@H:33]([O:36][CH3:37])[C:32]([CH3:39])([CH3:38])[CH2:31]2)[C:27]2[CH2:26][N:25]([C:41]3[CH:46]=[C:45]([CH:47]([CH3:48])[CH3:49])[CH:44]=[CH:43][C:42]=3[CH3:50])[CH2:24][CH2:23][C:22]=2[N:21]=1
Reactant: CO[C@H]1CCN(c2cc(-c3c(C)cccc3C)nc3c2C(=O)N(c2cc(C(C)C)ccc2C)CC3)CC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CO[C@H]1CCN(c2cc(-c3c(C)cccc3C)nc3c2CN(c2cc(C(C)C)ccc2C)CC3)CC1(C)C
Temperature: 55 °C

Procedure:
A 1.0 M solution of lithium aluminum hydride in THF (23.0 mL, 3.00 mmol) was added to a vessel containing (S)-2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (63 mg, 0.120 mmol). The reaction flask was then capped and the pink reaction mixture was heated to 55° C. and stirred at that temperature. After 1.5 h the oil bath was removed, the reaction mixture was diluted with 6 mL of THF, and the reaction flask cooled to 0° C. Then 0.9 mL of a 9:1 THF/H2O mixture was added dropwise, followed by 3 mL of THF, and 0.3 mL of 2 N NaOH was slowly added. After stirring for 5 min, the ice bath was removed and 600 μL of H2O and 6 mL of THF were added. The mixture was stirred for 10 min, then 900 mg of magnesium sulfate were added and the mixture further stirred. The mixture was then filtered over Celite® and the filter cake washed with EtOAc. The filtrate was concentrated and the residue was purified by FCC (0-50% EtOAc/heptanes) to provide (S)-2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.14-7.19 (m, 1 H) 7.06-7.12 (m, 3 H) 6.94 (d, J=1.5 Hz, 1 H) 6.83 (dd, J=7.8, 1.5 Hz, 1 H) 6.68 (s, 1 H) 4.10-4.22 (m, 2 H) 3.28 (s, 3 H) 3.07-3.18 (m, 1 H) 2.73-3.04 (m, 6 H) 2.23 (s, 3 H) 2.00 (s, 6 H) 1.91-2.03 (m, 2 H) 1.58 (d, J=9.3 Hz, 1 H) 1.20-1.28 (m, 1 H) 1.16 (d, J=6.8 Hz, 6 H) 1.01 (d, J=10.4 Hz, 6 H); MS (ESI+) m/z 512.4 (M+H)+.
Reaction SMILES: [BH4-].[Na+].C(O)C.[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:19]=[CH:18][N:17]([CH2:20][C@@H:21]([NH:23][C:24]([C:26]3[N:27]=[C:28]([C:31](OCC)=[O:32])[S:29][CH:30]=3)=[O:25])[CH3:22])[N:16]=2)[CH:10]=[CH:11][C:12]=1[C:13]#[N:14]>O>[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:19]=[CH:18][N:17]([CH2:20][C@@H:21]([NH:23][C:24]([C:26]3[N:27]=[C:28]([CH2:31][OH:32])[S:29][CH:30]=3)=[O:25])[CH3:22])[N:16]=2)[CH:10]=[CH:11][C:12]=1[C:13]#[N:14]
Reactant: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(CO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
Sodium borohydride (86 mg, 2.262 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (S)-ethyl 4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylate (502 mg, 1.131 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., water was added dropwise, the pH was adjusted to 7 and the mixture was evaporated. DCM and a few drops of methanol were added and the crude product was washed with 1M Na2CO3 and with water. Yield 58.6%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 4.31 (dd, 1H), 4.40 (dd, 1H), 4.43-4.51 (m, 1H), 4.79 (d, 2H), 6.20 (t, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.96 (dd, 1H), 7.98 (dd, 1H), 8.08 (dd, 1H), 8.13 (s, 1H), 8.50 (d, 1H).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH:13](=O)[CH3:14].C(O)C.S(=O)(=O)(O)O>CCOCC>[CH:13](=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[CH3:14]
Reactant: CC=O
Reactant: NNC1=NCCc2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: CC=NNC1=NCCc2ccccc21

Procedure:
A mixture of 1-ethoxy-3,4-dihydroisoquinoline (1.0 g.), hydrazine monohydrochloride (0.4 g.) and absolute ethanol (15 ml.) was heated under reflux (for 40 min.). The solution was cooled, filtered and concentrated and the residue was recrystallized from ethanol-ether, affording 1-hydrazino-3,4-dihydroisoquinoline hydrochloride (0.9 g., m.p. 205°-207° C.). C. A mixture of 1-hydrazino-3,4-dihydroisoquinoline (8.0 g.), acetaldehyde (20 ml.) and ethanol (20 ml.) was allowed to stand at room temperature (for 45 min). Ethanolic sulfuric acid was added until the solution was distinctly acidic. Ether was added. The resulting oil crystallized and the crystals were recrystallized from ethanol-ether, affording 1-(2-ethylidenehydrazino)-3,4-dihydroisoquinoline (I: X=CH3, X'=Y=Y'=Z=Z'=H) sulfate in two crops (8.3 g., m.p. 152°-154° C.; 0.5 g., m.p. 152°-155° C.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]12([NH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C>ClCCl.CS(C)=O.[Cl-].[Na+].O>[C:7]12([NH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH:22]=[O:23])[CH2:16][CH:11]3[CH2:10][CH:9]([CH2:15][CH:13]([CH2:12]3)[CH2:14]1)[CH2:8]2
Reactant: O=C(CCCCO)NC12CC3CC(CC(C3)C1)C2
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=CCCCC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
A solution of 1.11 mL (12.8 mmol) oxalyl chloride in 35 mL of dichloromethane is cooled to −80° C. under argon atmosphere. 2.33 mL (32.7 mmol) of dimethylsulfoxide in 9.33 mL of dichloromethane is introduced dropwise over 10 minutes. After 5 minutes a solution of 1.76 g (7 mmol) N-adamantyl-5-hydroxypentanamide in 8 mL dichloromethane and 2 mL dimethylsulfoxide is added over the course of 10 minutes. The reaction mixture is stirred for another hour at −80° C. before 5 mL of triethylamine is added and the mixture is allowed to warm up to room temperature. 50 mL of saturated brine solution is added for hydrolysis. The organic phase is separated, extracted three times with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[O:16][CH3:17].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl>[CH3:8][C:9]1[CH:14]=[C:13]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH:12]=[C:11]([CH3:15])[C:10]=1[O:16][CH3:17]
Reactant: O=C1CCC(=O)O1
Reactant: COc1c(C)cccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1c(C)cc(C(=O)CCC(=O)O)cc1C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Succinic anhydride (22.06 gm) was added to a mixture of 2,6-dimethylanisole (30 g) and anhydrous aluminium trichloride (59 g) in 1,2-dichloroethane (200 ml) at 0° C. The mixture was stirred for 0.5 hr at 0° C. and at room temperature for 4 hr. The mixture was poured onto ice-concentrated hydrochloric acid. After stirring vigorously for 5 min, the mixture was extracted with ethyl acetate. The dried (MgSO4) organic fraction was evaporated to give 4-(3,5-dimethyl-4-methoxyphenyl)-4-oxobutyric acid as white crystals, mp 108° C.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:16][S:17](O)(=[O:19])=[O:18].CN(C=O)C.S(Cl)(Cl)=O>ClCCl.O>[Cl:16][S:17]([C:13]1[CH:12]=[CH:11][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0.75 °C
Reaction time: 0.5 h

Procedure:
Cool a solution of the ethyl 2-methyl-2-phenoxypropanoate, (1.0 wt, 1.0 eq), in dichloromethane (7.5 vols) to 0° C. with stirring under a nitrogen atmosphere. Slowly add neat chlorosulfonic acid (0.78 wt, 1.4 eq) to the reaction mixture at a rate such that the reaction temperature never rises above 5.0° C. The addition typically takes 30 minutes to complete. Following the completion of the addition, stir the reaction mixture at 0–1° C. Follow the course of the reaction by HPLC. The reaction is typically complete after 30 minutes. At this point, slowly treat the reaction mixture with DMF (1.75 L) (1.40 wt, 4.0 eq). The addition of DMF to the reaction mixture is very exothermic. Adjust the rate of addition so that the reaction temperature never rises above 10.0° C. The addition of DMF to the reaction mixture takes approximately 30 minutes. Following the completion of the DMF addition, re-cool the reaction mixture to 0.5 to 1° C. Treat the cooled reaction mixture with neat thionyl chloride (619 mL, 1.01 kg) (0.86 wt, 1.5 eq). Adjust the rate of addition so that the process temperature never reaches 5.0° C. The addition of thionyl chloride to the reaction mixture is not very exothermic at all. Hence, the addition of thionyl chloride is typically complete in 5 minutes. Following the completion of the DMF addition, warm the reaction mixture to 20° C. with stirring. Follow the course of the reaction via HPLC. After 2.0 h, the reaction is typically complete. At this point, cool the reaction mixture to 0–1° C. and carefully treat the reaction mixture with water (8.8 L) (7.5 vols). [Note: The addition of water may be somewhat exothermic depending upon how much unreacted thionyl chloride is left in the reaction mixture.] Separate the organic layer and wash the organic layer with aqueous 0.1N HCl solution (2×7.5 vols). Separate the organic layer, concentrate the organic layer to a minimum stir volume, treat the organic layer with isopropyl acetate (1×5.0 vols) and then concentrate the resulting solution via vacuum distillation to afford the titled compound as a translucent bronze colored oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1([O:18][CH3:19])B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C(O)C.C(=O)([O-])[O-].[K+].[K+].Br[C:32]1[CH:33]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:35]=[CH:36][CH:37]=1.Cl>C(OCC)C.COCCOC.[Pd].ClC1[C-](P)C(C2C=CC=CC=2)=C(C2C=CC=CC=2)C=1Cl.[CH-]1C=CC=C1.[Fe+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:36]2[CH:37]=[CH:32][CH:33]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:35]=2)[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: COC1(B(O)O)C=CC=CC1OCc1ccccc1
Agent: [Fe+2]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: COCCOC
Solvent: CC(O)CO
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
1.753 g of 2-Benzyloxy-1-methoxybenzeneboronic acid was suspended in 50 ml of diethyl ether, and 0.49 ml of propylene glycol was added thereto. The mixture was stirred at room temperature for 1 hour, and the solvent was removed to give 2-(3-benzyloxy-4-methoxyphenyl)-[1,3,2]dioxaborynane. This product was dissolved in 30 ml of 1,2-dimethoxyethane, then 1.5 g of potassium carbonate, 1.9 g of methyl 3-bromophenylacetate and 270 mg of dichlorodiphenyl phosphinoferrocene palladium were added thereto, and the mixture was stirred at 80° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 1.356 g of the title compound in the 6:1→4:1 fraction.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=1.[Br:12]N1C(=O)CCC1=O>C1COCC1>[Br:12][C:3]1[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][NH:6][C:2]=1[NH2:1]
Reactant: Nc1cc(-c2cccs2)n[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Nc1[nH]nc(-c2cccs2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a stirring solution of 5-amino-3-(2-thienyl)pyrazole (500 mg, 3.03 mmol) in THF (10 mL) was added N-bromosuccinimide (592 mg, 3.33 mmol) in one portion. The reaction mixture was stirred at room temperature for 3 h, then the solvent was evaporated and the residue was taken up in ethyl acetate. The organic layer was washed successively with 1M aqueous sodium thiosulfate, twice with a saturated aqueous solution of sodium bicarbonate, and brine, then it was dried over sodium sulfate, filtered, and adsorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 686 mg (93%) of 4-bromo-5-thiophen-2-yl-2H-pyrazol-3-ylamine as a dark foam. 1H-NMR (d6-DMSO) δ: 11.9 and 12.4 (2 broad s, 1H, NH+tautomer), 7.4-7.65 (m, 2H), 7.05-7.2 (m, 1H), 4.8 and 5.3 (2 broad s, 2H, NH2+tautomer).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH3:13].C1COCC1.[H+].[B-](F)(F)(F)[F:21].N([O-])=O.[Na+]>O.F[B-](F)(F)F.C([N+]1C=CN(C)C=1)C.CCOCC>[F:21][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH3:13]
Reactant: F[B-](F)(F)F
Reactant: COc1cccc2c(N)cccc12
Agent: CC[n+]1ccn(C)c1
Agent: O=N[O-]
Agent: [H+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c(F)cccc12
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
A stirred mixture of 6.8 g of 5-amino-1-methoxynaphthalene, 57 ml THF and 74 ml of 48-50% HBF4 was cooled in an ice/salt bath. To the stirred suspension was added dropwise a solution of 3.00 g of sodium nitrite in 6 ml of water. The mixture was stirred at 0-5° C. for 30 minutes after which 300 ml of ether was added. The mixture was stirred at 0-5° C. for 45 minutes after which it was filtered and the residue washed three times with dry ether. The resulting dark red solid was air dried overnight to yield 12.2 g. The material was dissolved in 70 ml of 1-ethyl-3-methylimidazolium tetrafluoroborate and heated at 70-80° C. for 2 h (gas evolution was observed). The mixture was allowed to cool to room temperature, extracted twice with ether, washed with brine, dried (magnesium sulphate), filtered and concentrated to an oil. The material was dissolved in dichloromethane and flash chromatographed on silica gel, eluting with ethyl acetate/heptane to provide 2.08 g (30%) of 5-fluoro-1-methoxynaphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](OC)[CH:11]=1)[N:8]=[C:7]([Cl:14])[N:6]=[CH:5]2.NC1C=CC(Br)=C([F:25])C=1C#N>>[Br:1][C:2]1[C:3]([F:25])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:14])[N:6]=[CH:5]2
Reactant: N#Cc1c(N)ccc(Br)c1F
Reactant: COc1cc(Br)cc2cnc(Cl)nc12
Product: Fc1c(Br)ccc2nc(Cl)ncc12

Procedure:
6-bromo-2-chloro-5-fluoro-quinazoline is prepared analogously to WO 2007/117607 or to the above-mentioned synthesis of 6-bromo-2-chloro-8-methoxy-quinazoline starting from 2-amino-5-bromo-6-fluoro-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[S:20])[C:3]([F:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1F
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)cnc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 3-amino-5-bromo-2-fluoropyridine (1.0 g, 5.23 mmol) in acetone (15.0 mL) was added benzoylisothiocyanate (0.85 mL, 6.25 mmol) and the resulting reaction mixture was stirred at room temperature for 30 min. After the completion of the reaction (TLC monitoring), acetone was removed under reduced pressure and the residue was washed with hexane and filtered to obtain the desired product (1.68 g, 91%). 1H NMR (400 MHz, DMSO-d6): δ 7.55 (t, J=7.60 Hz, 2H), 7.68 (t, J=7.60 Hz, 1H), 8.0 (d, J=7.60 Hz, 2H), 8.31 (s, 1H), 8.84 (dd, J=2.0 and 8.40 Hz, 1H), 12.03 (br s, 1H) and 12.60 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]=[CH2:20]>CC(C)=O>[CH2:20]([O:10][C:8]1[CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=[CH:6][CH:7]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To solution of 3-hydroxyacetophenone (2.140 g, 15.72 mmol) in acetone (100 mL) was added potassium carbonate (4.344 g, 31.43 mmol), and 3-bromo-propene (2.282 g, 18.86 mmol) and the reaction was stirred at room temperature for 16 h. The solvent was removed in vacuo and water (25 mL) was added to the reaction mixture and then extracted with ethyl acetate (3×60 mL). The organic extracts were washed with brine (15 mL), dried (Na2SO4) and concentrated to give the title compound which was used as is in the next step.
Reaction SMILES: [NH2:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Yield: 87 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-phenyl-3-(4-(trifluoromethyl)phenyl)-1-propanol (500 mg, 1.69 mmol) in ethyl acetate (15 ml) were added 3-phenylpropionyl chloride; (377 ml, 2.54 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (628 mg, 87%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>[H-].[Na+].O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: Oc1cccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Oc1cccnc1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A 6 g. sample of 4-(8-cyclohexyloctylamino)benzoic acid and 2.7 g. 1,1'-carbonyldiimidazole in 50 ml. dry tetrahydrofuran is stirred for 2 hours. Then, 1.58 g. 3-hydroxypyridine and a trace of sodium hydride catalyst is added and the reaction is refluxed for 3 hours. The solution is cooled, filtered, and evaporated. The product is crystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:30])[C:11]([C:17]1[C:18]([F:29])=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:30])[C:11]([C:17]1[C:18]([F:29])=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)([OH:16])[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc(C(C)C(O)(c2cc3c(cc2F)OCC(=O)N3C)C(F)(F)F)c(Cl)c1
Agent: BrB(Br)Br
Product: CC(c1ccc(O)cc1Cl)C(O)(c1cc2c(cc1F)OCC(=O)N2C)C(F)(F)F

Procedure:
In analogy to Example 1, step 4, 6-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with BBr3 to give the title compound as a colorless foam. MS (m/e, ISP neg. ion)=432.1 [M−H+].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)C=O.[CH:11]([Cl:14])(Cl)Cl.C[C:16]1[CH:25]=[C:24](C)[CH:23]=[C:22]2[C:17]=1[CH2:18][CH2:19][CH2:20][C:21]2=[O:27]>O>[Cl:14][C:11]1[C:22]2[C:17](=[CH:16][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19][C:20]=1[CH:21]=[O:27]
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Reactant: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1=C(Cl)c2ccccc2CC1
Reaction time: 0.5 h

Procedure:
1.3 mL of phosphorus oxychloride was added dropwise to 1.6 mL of dimethylformamide under ice cooling, after which the system was brought up to room temperature and stirred for 30 minutes. To this was added at room temperature a 50 mL chloroform solution of 1.8 g of 5,7-dimethyltetralone, and the system was refluxed under heating overnight. After the reaction, water was added and the system was stirred for 30 minutes, after which the organic layer was washed first with a saturated sodium hydrogencarbonate aqueous solution and then with saturated brine, dried with magnesium sulfate, and then subjected to reduced-pressure solvent distillation, and the residue was refined by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 2.0 g of 1-chloro-2-formyl-3,4-dihydronaphthalene in the form of a brown solid.
Reaction SMILES: C=O.[CH3:3][CH:4]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([CH:11]([CH3:13])[CH3:12])[CH2:6][CH2:5]1.[Cl:14][CH:15](Cl)CCl>Cl>[Cl:14][CH2:15][O:10][CH:8]1[CH:7]([CH:11]([CH3:13])[CH3:12])[CH2:6][CH2:5][CH:4]([CH3:3])[CH2:9]1
Reactant: ClCC(Cl)Cl
Reactant: CC1CC[C@H](C(C)C)[C@@H](O)C1
Agent: C=O
Agent: Cl
Product: CC1CCC(C(C)C)C(OCCl)C1
Reaction time: 2 h

Procedure:
3.0 g (0.1 mole) of paraformaldehyde were stirred at 0°-5° C. with 15.6 g (0.1 mole) of (+) Menthol in 1,1,2-trichloroethane and HCl gas was passed for 2 hours. The product was further diluted to 1M concentration.