Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][N+:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>CO>[CH3:12][N:9]1[CH2:8][CH:7]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: COC(=O)c1cc[n+](C)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A suspension of 1.385 kg of 4-methoxycarbonyl-1-methylpyridinium iodide in 25 liters of dry methanol was stirred and cooled to 5° C. and 700 g of sodium borohydride were added thereto in portions over 1 hour with the temperature held at 5°-10° C. When the addition was complete, the resultant solution was stirred at room temperature for another hour and was then concentrated to 5 to 7 liters. 25 liters of water were added thereto followed by addition of 2 kg of solid sodium carbonate. The solution thus obtained was extracted 3 times with 2.5 liters of chloroform and the organic phase was dried over Na2SO4 and was evaporated to dryness. The residual oil was distilled to obtain 583 g of methyl 1,2,3,6-tetrahydro-1-methylisonicotinate (67.1% yield) boiling at 78° C. at 1 mm Hg.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1.Cl>>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[N:12]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=4)[C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3=O
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(C#N)cc1)C3=O

Procedure:
Using procedure 48, 6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione (93, 0.12 g, 0.4 mmol) was treated with alpha-bromo-p-tolunitrile (0.08 mL, 0.4 mmol). Purification using silica gel, eluting with 3:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 97 as a white solid (m.p. 263-264° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
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: COCCOC
Product: COc1cccnc1N
Temperature: 100 °C

Procedure:
A mixture 4,5-dibromo-2-(4-(trifluoromethyl)phenyl)-1-((2-trimethylsilyl)ethoxy)methyl-1H-imidazole (730 mg, 1.5 mmol) and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (400 mg, 1.6 mmol; Example 17, Step 3), and 2.0 M aqueous Na2CO3 solution (3 mL, 6.0 mmol) in DME (10 mL) was purged with Ar for 3 min. Pd(PPh3)4 (65 mg, 0.055 mmol) was added the reaction was heated to 100° C. by for 20 h. The reaction was allowed to cool to rt and phases partitioned. The organic portion was separated and concentrated. The resulting residue crude was purified by flash chromatography (SiO2; 80:20-0:100 hexanes-EtOAc) to furnish 640 mg (1.2 mmol, 80%) of 5-(5-bromo-2-(4-trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine: LCMS (m/z): 545.0 (MH+), tR=1.02 min.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(Cl)CCl>[C:12]1([C:7]2[NH:8][C:9]3[C:5]([C:6]=2[C:16]([C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]([OH:18])=[O:23])=[O:17])=[CH:4][CH:3]=[CH:11][CH:10]=3)[CH:5]=[CH:4][CH:3]=[CH:11][CH:10]=1
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 5.0 g (0.03 mole) of 5-methoxy-2-methylindole and 4.6 g (0.03 mole) of phthalic anhydride in 25 ml of ethylene dichloride was refluxed for ten hours, cooled to room temperature and the separated solid was collected by filtration and dried to obtain 2-[(2-methyl-5-methoxy-3-indolyl)carbonyl]benzoic acid (Formula VIII: R°=R1 =R2 =R3 =R6 =H; R5 =CH3 ; Y1 =OCH3), as a pale pink-colored solid which decomposed at 203°-204° C. The nuclear magnetic resonance and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][CH:20]([CH3:39])[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38])O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH:21]([C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=4)=[N:25][C:24]=3[CH3:38])[CH:20]([CH3:39])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2c(O)cccc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(Oc1cccc2c1ccn2CC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 14 h
Yield: 12 %

Procedure:
To an ice cold solution of (4-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (49 mg, 0.2 mmol), [rac]-2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol [62 mg, 0.2 mmol; PCT Int. Appl. (2002), WO 02/062774 A1] and tributylphosphine (70 μl, 0.3 mmol) in tetrahydrofuran (3 ml) was added N,N,N′,N′-tetramethyl azodicarboxamide (51 mg, 0.3 mmol) under an argon atmosphere. The cooling bath was removed and stirring continued for 14 h. Filtration over celite and evaporation of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 13 mg (24 μmol, 12%) of the title compound as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C@@H:13]3[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=O)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.Cl.[CH3:31][NH:32][CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:31][N:32]([CH3:33])[C:18]([C@@H:15]1[CH2:14][C@H:13]([N:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH:4]=3)[CH:9]=[N:10]2)[CH2:17][NH:16]1)=[O:20]
Reactant: Nc1ncc(-c2cnn([C@@H]3CN[C@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1C[C@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CN1
Reaction time: 0.02 h

Procedure:
To a solution of (2S,4S)-4-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-pyrrolidine-2-carboxylic acid (5.00 mg, 0.00969 mmol) in DMF (2 mL) at rt were added dimethylamine hydrochloride (20 mg, 0.25 mmol) and DIPEA (0.1 mL, 0.6 mmol), and the mixture was stirred for 1 min. TBTU (6.22 mg, 0.0194 mmol) was then added, and the solution was stirred for 10 min. The material was transferred to a separatory funnel. The organic layer was washed with water, and concentrated in vacuo. The material was loaded onto a prep TLC plate, eluting with 6% (7N NH3 in MeOH)/DCM. The band containing the product was collected and filtered off with 1:1 MeOH/DCM. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.15-2.21 (m, 1H), 2.82-2.91 (m, 1H), 3.00 (s, 3H), 3.12 (s, 3H), 3.23 (dd, J=12.4, 6.3 Hz, 1H), 3.49 (dd, J=12.0, 3.4 Hz, 1H), 4.15 (t, J=8.3 Hz, 1H), 4.98-5.05 (m, 1H), 7.42-7.47 (m, 1H), 7.53 (td, J=7.7, 1.3 Hz, 1H), 7.85 (s, 1H), 8.02 (dd, J=11.6, 7.8 Hz, 2H), 8.13 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H). MS (ES+): m/z=434.14 (100) [MH+]. HPLC: tR=2.12 min (ZQ2, polar—5 min).
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH2:11][CH:12]=[CH2:13])[CH:3]([CH3:9])[C:4]([O:6]CC)=[O:5]>[OH-].[K+].CO>[OH:1][CH:2]([CH2:10][CH2:11][CH:12]=[CH2:13])[CH:3]([CH3:9])[C:4]([OH:6])=[O:5]
Reactant: C=CCCC(O)C(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCCC(O)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
Ethyl 3-hydroxy-2-methylhept-6-enoate (6.11 g, 32.8 mmol) was dissolved in a 2 N potassium hydroxide-methanol solution (100 mL), and the mixture was stirred at room temperature for 2 hours and then left overnight. The methanol was distilled off under reduced pressure, and the residue was diluted with water, then washed with methylene chloride, and then neutralized with dilute hydrochloric acid. The aqueous layer was subjected to extraction with ethyl acetate, and the extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil (5.46 g).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([C:18](=[NH:21])[NH:19]O)=[CH:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:3]1.C(OC(=O)C)(=O)C>C(O)(=O)C.[Pd]>[C:18]([C:15]1[S:14][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:17][CH:16]=1)(=[NH:19])[NH2:21]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=N)NO)s3)cc(C)c21
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=N)N)s3)cc(C)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude ethyl 2-(1-hydroxy-6-(5-(N-hydroxycarbamimidoyl)thiazol-2-yloxy)-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (6.2 g crude) in 30 ml of acetic acid was added 400 ul of acetic anhydride. After the mixture was stirred at room temperature for one and half hour, it was treated with palladium (10% wet on charcoal, 1.8 g) and then hydrogenation on Parr-shaker for five hours. The mixture was filtered through a Celite pad and the filtrate was concentrated and dried under hi-Vac to give the crude product. The crude was used in subsequent steps without further purification.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[N:5]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1nn(CC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(3-acetyl-1H-indazol-1-yl)acetate (4 g, 12.4 mmol) in CH2Cl2 (45 mL) was added TFA (15 mL, 195.0 mmol), and the reaction mixture was stirred at RT overnight. Then was then diluted with CH2Cl2 and MeOH, and volatiles were evaporated under reduced pressure to afford the title compound: MS: 219 [M+H]+; tR (HPLC conditions d): 2.78 min.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH2:18][CH:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][CH:17]2[O:16][N:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH2:18]2)[CH2:32][CH2:31]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=CCCC1CC(c2cccc(Oc3ccccc3)c2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccccc1N1CCN(CCCC2CC(c3cccc(Oc4ccccc4)c3)=NO2)CC1
Yield: 69.6 %

Procedure:
3-[3-(3-Phenoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (38.0 mg, 0.122 mmol), 1-(2-fluorophenyl)piperazine (20.0 mg, 0.111 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (70.5 mg, 0.333 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 35.5 mg (70.1 %) of the target compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)=[O:4].C(=O)([O-])O.[Na+].Cl[CH2:18][CH:19]=O>CO.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:18]=[CH:19][N:11]=[C:7]2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccn2ccnc2c1
Yield: 38 %

Procedure:
A solution of crude 2-aminopyridin-4-ylcarboxylic acid methyl ester (13.0 g) in methanol (150 ml) was treated with sodium hydrogencarbonate (14.3 g, 0.171 mol) and chloroacetaldehyde (8 ml of a 45 wt % solution in water) then heated at reflux for 16 h. The reaction was cooled and pre-adsorbed directly on to silica gel. Purification by flash chromatography eluting with dichloromethane (+1% conc. ammonia) on a gradient of methanol (1%-4%) gave a solid which was triturated with 5% ether in isohexane to afford imidazo[1,2-α]pyridine-7-carboxylic acid methyl ester (8.0 g, 38% from pyridine N-oxide) as a tan solid. 1H NMR (400 MHz, CDCl3) δH 3.97 (3H, s), 7.37-7.43 (2H, m), 7.70 (1H, s), 7.80 (1H, s), 8.18 (1H, dd, J 1 and 7), 8.38 (1H, s).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25]([OH:34])(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].ON1C(=O)CCC1=O.CC(N=C=NC(C)C)C>CS(C)=O>[CH2:27]([CH:26]([CH2:1][CH2:2][CH2:3][CH2:7][CH2:8][CH3:9])[C:25]([OH:34])=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11]
Reactant: CCCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CS(C)=O
Solvent: OCC(O)CO
Product: CCCCCCC(CCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous DMSO (50 mL). Octanoic acid (15.12 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) and N-hydroxysuccinimide (0.183 g, 1.59 mmol) were both dissolved in the solution. When the catalysts were fully dissolved, N,N-diisopropylcarbodiimide (15.0 mL, 97.03 mmol) was pipetted into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was dialyzed in SpectraPor7 MWCO 1000 dialysis tubing to remove the DMSO and unreacted monomer. The polymer crashed out in water into a thick white liquid. After 3 days of dialysis, the solution was placed into a reparatory funnel and the organic portion was dissolved into chloroform. The water layer was removed and the organic layer was dried with sodium sulfate. The solvent was stripped via rotoevaporation to leave a clear thick liquid product. NMR analysis supported full conversion of hydroxyl groups to the octanoic esters.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[C:23]([OH:27])(=[O:26])[CH:24]=[CH2:25]>C(Cl)Cl>[C:11]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:8]([O:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:25][CH2:24][C:23]([OH:27])=[O:26])[CH2:6][CH2:5]1)=[O:22]
Reactant: C=CC(=O)O
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Solvent: ClCCl
Product: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 75 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
A stirred solution of biphenyl-2-ylcarbamic acid piperidin-4-yl ester (50.0 g, 168.7 mmol) (see, e.g., U.S. Patent Publication No. 2006/0035931 A1, published Feb. 16, 2006) and acrylic acid (15.1 mL, 219.3 mmol) in DCM (500 mL) was heated at 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (600 mL). The resulting solution was heated at 75° C. for 2 h and then allowed to stand at room temperature for about 48 h. The resulting solid was collected by filtration, washed with MeOH, and dried to give the title compound (61.5 g, 99% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O1CCCC1>[CH2:1]([O:8][CH2:9][CH:10]([OH:11])[CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: Cl[Mg]CCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: OC(CCc1ccccc1)COCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Benzyloxy-acetaldehyde (3.0 g, 20 mmol) is dissolved in tetrahydrofuran (200 mL), cooled to −78° C. This solution is treated with phenylethylmagnesium chloride (1.0 M in tetrahydrofuran, 24 mL, 24 mmol), and stirred for one hour. The mixture is allowed to warm to room temperature and stirred for 4 h. The mixture is treated with hydrochloric acid (1 M, 40 mL) and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over sodium sulfate, and filtered. The filtrate is concentrated in vacuo to provide the title compound, 4.0 g (80%), as a colorless liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]>>[CH3:28][S:29]([C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.6) (0.404 g, 1.0 mmol) and commercially available 3-methanesulfonyl-phenylboronic acid (0.22 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.4 g, 77%). MS (ISP) 524.0 [(M+H)+]; mp 238.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.[CH3:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[CH3:33][O:32][C:30]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([S:11][CH2:12][CH2:13][N:7]4[C@H:6]4[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]34)[CH:10]=2)=[C:26]([CH3:25])[CH:31]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CCS3)c(C)c1
Yield: 54.6 %

Procedure:
The tert-butyl(6bR,10aS)-5-(4-methoxy-2-methylphenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (420 mg, 55%) was prepared via coupling of tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (700 mg, 1.70 mmol) with 2-methyl-4-methoxyphenyl boronic acid (424 mg, 2.55 mmol) using the procedure described in Example 450 Step A.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]#[N:14])=[CH:7][C:6]=1[F:15].[BH4-].[Li+]>O1CCCC1>[F:15][C:6]1[C:5]([CH2:4][CH2:3][OH:2])=[CH:10][C:9]([O:11][CH3:12])=[C:8]([CH:7]=1)[C:13]#[N:14]
Reactant: COC(=O)Cc1cc(OC)c(C#N)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CCO)c(F)cc1C#N
Temperature: 25 °C

Procedure:
To a solution of methyl(4-cyano-2-fluoro-5-methoxyphenyl)acetate (212 mg, 0.95 mmol) in tetrahydrofuran (4 mL) at 0° C. was added lithium borohydride (2.0 M solution in tetrahydrofuran, 0.62 mL). The mixture warmed slowly to room temperature and was quenched with saturated sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate (2×). The combined organics were washed with water and brine, then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (MPLC, 5-60% Ethyl Acetate:Hexanes) to provide 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile. 1H-NMR (500 MHz, CD3OD) δ ppm 7.22 (m, 1H), 6.92 (m, 1H), 3.93 (s, 3H), 3.88 (m, 2H), 2.95 (m, 2H), 2.29 (br s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:45]=[C:46]([N+:48]([O-])=O)[CH:47]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:44])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:43])([F:42])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8])([O-])=O>CN(C)C=O.O.[Zn]>[NH2:48][C:46]1[CH:45]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:47]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:44])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:42])([F:43])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N)cc(C(=O)OCCCCCCOC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 83.1 %

Procedure:
5.95 g (8.38 mmol) of 6-[((2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)-prop-2-enoyl)oxy]-hexyl 3,5-dinitrobenzoate are dissolved in a mixture of 54 mL of N,N-di-methylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate is added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 4.53 g of 6-[((2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenyl]-methoxy}-phenyl)-prop-2-enoyl)oxy]hexyl 3,5-diaminobenzoate as yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C@H:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)=O)(C)(C)C.[ClH:29]>CCOC(C)=O>[ClH:29].[CH3:20][C:16]1[CH:15]=[C:14]([C@@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCc2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc([C@@H]2CCNC[C@H]2OCc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of trans-N-t butoxycarbonyl-4-(3-methylphenyl)-3-benzyloxy piperidine, (0.137 g, 3.60 mmol) in EtOAc (50 ml) at 0° C. was bubbled HCl gas until saturated. The reaction was strirred at 0° C. for 10 min and then the solvent evaporated in vacuo to afford the product as a white foam.