Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH3:14])[C@@H:9]2[C:15]([NH2:17])=O)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH3:14])[C@@H:9]2[CH2:15][NH2:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2CCC[C@H](C)[C@@H]2C(N)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCC[C@H](C)[C@@H]2CN)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
rac-cis-1-(4-Methoxybenzyl)-3-methylpiperidine-2-carboxamide (0.61 g, 2.33 mmol) was added portionwise to a suspension of LiAlH4 (0.30 g, 7.50 mmol) and THF (12 mL) and heated to reflux for 14 h. The reaction mixture was then cooled to 0° C. and quenched with water and NaOH (aq.). The resulting mixture was stirred at rt for 1 h, filtered and the filtrated was concentrated in vacuo to provide rac-cis-(1-(4-methoxybenzyl)-3-methylpiperidin-2-yl)methanamine as a colorless oil, used as-is without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[N:11]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>C(#N)CCC.C(OCC)(=O)C>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[N:11]=2)[CH2:5][CH2:4]1
Reactant: CCN(CC)c1nc(Cl)c2ccccc2n1
Reactant: NCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCC#N
Product: CCN(CC)c1nc(N2CCC(CN)CC2)c2ccccc2n1

Procedure:
A mixture of 4-(aminomethyl)-piperidine (1.2 g, 11 mmol), 4-chloro-2-diethylaminoquinazoline (1.2 g, 5.1 mmol) and Hunig's base (2.8 ml, 16 mmol) in 10 ml of butyronitrile was reacted for 12 hours at 100° C. After cooling, ethyl acetate (50 ml) and 50 ml of sodium hydroxide (10%) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×25 ml). The combined organic phases were dried (Na2SO4), concentrated on a rotary evaporator and purified by chromatography on silica gel (eluent: methylene chloride/ethanol/ammonia, 50/10/1) to give the free base as a solid.
Reaction SMILES: C(OC(N1C(C)C2C(O[C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=NC=NC=2C1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][CH:19]=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1
Reactant: CC1c2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 5-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester in DCM (20 mL), TFA (20 ml, 134 mmol) is added at 0° C. After 30 min the reaction is warmed to rt. At this point, the reaction is evaporated and the crude product is dissolved in EtOAc. A Few drops of NH4OH are added to freebase the amine and the whole mixture is then evaporated. The crude product is added to a silica gel column and is eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1) to give racemic 545-Methyl-6,7-dihydro-5H-pyrrolo[3,4-a]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 454.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1 H) 8.33 (s, 1 H) 8.06 (s, 1 H) 7.94 (br. S., 2 H) 7.57 (s, 1 H) 7.42 (br. S., 2 H) 7.12 (d, J=9.09 Hz, 1 H) 6.75 (d, J=3.03 Hz, 1 H) 4.70 (br. S., 1 H) 4.10-4.22 (m, 2 H) 1.60 (d, J=6.57 Hz, 3 H). Racemate is then separated using chiral HPLC (IA column; 40% heptane, 60% Ethanol) to give the corresponding enantiomers D-1 and D-2.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]1>C1(C)C=CC=CC=1>[OH:19][CH:16]1[CH2:17][CH2:18][N:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: OC1CCNC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N2CCC(O)C2)c2ccccc12

Procedure:
1-Cyano-4-fluoronaphthalene (86 mg, 0.5 mmol) was transferred to a Pyrex tube and 3-pyrrolidinol (162 μL, 2.0 mmol) was added followed by toluene (0.5 mL). The tube was capped and the reaction tube was exposed to microwave irradiation (180° C., 5 min). The reaction mixture was concentrated and purified by re-crystallization with EtOH. Yield: 51 mg (43%).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:16]([CH2:15][C:14]1[CH:30]=[CH:31][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1)[C:17]1[CH:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:22]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc(/C=C/C(=O)OCC)cc2)cc1
Product: CCCCCCCCC#Cc1ccc(CN(C(C)=O)c2ccc(/C=C/C(=O)OCC)cc2)cc1

Procedure:
The title compound was prepared following the procedure E using ethyl (2E)-3-{4-[(4-dec-1-ynylbenzyl)amino]phenyl}acrylate and acetyl chloride as a yellow oil (97%). M+ (ESI): 460.2. HPLC, Rt: 6.0 min (purity: 98.8%).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)=[O:19])=[C:15]([NH:28][C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]3)=[O:30])[C:14]=2[CH:40]=1)=[O:7])(C)(C)C.C(O)(C)C>Cl>[ClH:27].[C:6]([CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)=[O:19])=[C:15]([NH:28][C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]([CH3:38])[CH3:39])[CH2:33][CH2:32]3)=[O:30])[C:14]=2[CH:40]=1)([OH:7])=[O:5]
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(OCC(=O)OC(C)(C)C)cc23)CC1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(OCC(=O)O)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans-5-t-butoxycarbonylmethoxy-3-[4-(dimethylamino)-cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (1.92 g) obtained in Example 31 is dissolved in 6N hydrochloric acid (40 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added isopropanol (100 ml), and the precipitated solid is collected by filtration, washed with isopropanol and diethyl ether, and dried under reduced pressure to give the title compound (1.86 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH2:12]([O:19][C@@H:20]1[CH2:23][C@H:22]([NH2:24])[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>CC#N>[CH2:12]([O:19][C@@H:20]1[CH2:23][C@H:22]([NH:24][C:2]2[C:3]([NH2:9])=[CH:4][CH:5]=[C:6]([F:8])[CH:7]=2)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1C[C@@H](OCc2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ccc(F)cc1N[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.92 mL, 8.36 mmol) in CH3CN (60 mL) were added cis-3-benzyloxycyclobutylamine (1.48 g, 8.36 mmol) and DIPEA (1.46 mL, 8.36 mmol). The reaction mixture was stirred at RT for 18 h then concentrated in vacuo to afford the title compound as yellow oil (3.2 g, quantitative). To a solution of the product thus obtained (1.6 g, 5.03 mmol) in MeOH (20 mL) was added Iron powder (1.13 g, 20.12 mmol), NH4Cl (1.56 g, 30.18 mmol) and H2O (8 mL) and the reaction mixture stirred at 90° C. for 2 h under a nitrogen atmosphere. The resulting dark green mixture was filtered through a pad of Celite® and the filtrate concentrated in vacuo giving a dark brown solid. The crude material was partitioned between EtOAc (50 mL) and water (30 mL). Aqueous layer extracted with EtOAc (2×30 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to afford the title compound as a dark brown gum (1.13 g, 78%). 1H NMR (CDCl3, 300 MHz): δ 7.25-7.30 (5H, m), 6.6 (1H, dd, J=14.0, 2.8 Hz), 6.35-6.26 (1H, m), 6.26-6.18 (1H, m), 4.43 (2H, s), 3.95-3.83 (1H, m), 3.50-3.37 (1H, m), 2.90-2.78 (2H, m), 1.92-1.79 (2H, m). NMR: 328138. LCMS (Method B): RT 2.87 min [M+H]+ 287.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[Li]CCCC.CN([CH:19]=[O:20])C.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH:19]=[O:20])[S:7][C:6]=2[CH:10]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc2ccsc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1cc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-chlorobenzo[b]thiophene (1.0 g, 5.93 mmol) in THF (60 mL) at −78° C. is added a 1.6 M solution of n-BuLi in THF (3.9 mL, 6.23 mmol). After 10 minutes, 0.5 mL of DMF is added. The solution is stirred for 0.5 hours, then allowed to warm to ambient temperature. The solution is poured into a solution of saturated NH4Cl. The solution is diluted with ether and the layers are separated. The organic layer is washed with H2O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The title compound is obtained as a white solid. MS (EI): m/z 196 (M+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[C:6]=1[Br:15])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COc1c(C)cc(NC(C)=O)cc1C
Solvent: CC(=O)O
Product: COc1c(C)cc(NC(C)=O)c(Br)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
4-Acetamido-2,6-dimethylanisole (7, 8.6 g, 44.3 mmol) and acetic acid (30 mL) were placed in a round-bottom flask under an argon atmosphere. Bromine (2.7 mL, 44.3 mmol) was added dropwise to the solution, after which the reaction mixture was stirred at room temperature for about 3 h, and then concentrated. The residue was diluted with methylene chloride and carefully washed sequentially with saturated aq. sodium bicarbonate and brine, and dried (MgSO4). Removal of solvents gave a brown-colored solid which was recrystallized from methylene chloride-hexanes to yield 4-acetamido-3-bromo-2,6-dimethylanisole (10.3 g, 85% yield) as an off-white solid, mp 152°-153° C. Spectral data: 1H NMR: δ 2.18 (s, 3H), 2.24 (s, 3H), 2.35 (s, 3H), 3.66 (s, 3H), 7.55 (br s, 1H), 7.9 (s, 1H); 13C NMR: δ 16.1, 16.8, 24.6, 60.1, 114.5, 122.0, 130.5, 131.3, 131.5, 153.6, 168.1; CI-HRMS: calcd. for C11H15BrNO2 (M+H+) 272.0286, fnd. 272.0284.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].Br.C[N:13]1[CH2:18][CH2:17][C:16]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=3)[S:19]2)[CH2:15][CH2:14]1>ClCCl>[CH3:33][C:29]1[CH:28]=[C:27]([CH:20]2[S:19][C:16]3([CH2:17][CH2:18][N:13]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:14][CH2:15]3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=3)[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cccc(C2SC3(CCN(C)CC3)c3ccccc32)c1
Agent: Br
Solvent: ClCCl
Product: Cc1cccc(C2SC3(CCN(C(=O)Oc4ccccc4)CC3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To 1.81 g of phenyl chloroformate in 40 ml of dichloromethane is added a solution of 2.98 g of the free base 1,3-dihydro-1'-methyl-3-(3-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine] of Example 41 in 35 ml of dichloromethane over 5 minutes. The reaction is stirred at ambient temperature for 21 hours The reactionn is then diluted with 100 ml of dichloromethane; washed with two 150 ml portions of 5% aqueous sodium hydroxide solution, two 100 ml portions of water and one 50 ml portion of brine; and dried over magnesium sulfate to an oil. The oil is chromatographed on silica gel with dichloromethane to yield 1,3-dihydro-3-(3-methylphenyl)-1'-phenoxycarbonylspiro[benzo(c)-thiophene-1,4'-piperidine], m.p. 154°-157° C. A portion is recrystallized from toluene-hexane, m.p. 157°-160° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1(=[O:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][NH:10]1>C(#N)C>[Cl:1][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:19])[NH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1[nH]ccc2ccccc12
Solvent: CC#N
Product: O=c1[nH]cc(Cl)c2ccccc12
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of N-chlorosuccinimide (9.66 g, 72 mmol) in acetonitrile (MeCN) (80 mL) was added dropwise to a stirred solution of 1-(2H)-isoquinolone (10 g, 69 mmol) in MeCN (250 mL) which was being heated under reflux. The mixture was heated under reflux for an additional 1.5 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 4-chloro-1(2H)-isoquinolone (11.3 g, 62.9 mmol) as a pale pink solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1.[C:22](Cl)(=O)[C:23](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CN(C=O)C>[O:20]=[C:19]1[CH2:18][C:14]2[CH:13]=[C:12]([N:3]3[C:2](=[O:1])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])[CH:17]=[CH:16][C:15]=2[CH2:23][CH2:22]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(N2C(=O)c3ccccc3C2=O)c1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2ccc(N3C(=O)c4ccccc4C3=O)cc2C1
Temperature: 25 °C

Procedure:
To a solution of [3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]acetic acid (0.75 g, 2.7 mmol) in DCM (25 mL) was added oxalyl chloride (0.28 mL, 3.2 mmol) and a drop of DMF. The mixture was allowed to stir at RT until all solids disappeared. At that point, the solution was cooled to to 0° C. with an ice bath, and aluminum chloride (1.1 g, 8.0 mmol) was added into the reaction slowly. After stirring the mixture for another 10 minutes, ethylene was bubbled through the reaction via a long needle. TLC showed complete reaction within 30 minutes. The reaction was poured into ice water, neutralized with sodium carbonate, extracted with DCM, dried, concentrated, and purified by MPLC (Hexane/EtOAc). LC-MS (IE, m/z): 292 [M+1]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.C[C:13](=O)[C:14](=[O:16])C.O=O>C(O)(=O)C>[C:14]([C:7]12[CH2:9][CH:3]3[CH2:4][CH:5]([CH2:10][CH:1]([C:2]3=[O:11])[CH2:8]1)[CH2:6]2)(=[O:16])[CH3:13]
Reactant: CC(=O)C(C)=O
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: O=O
Solvent: CC(=O)O
Product: CC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In a flask were placed 2-adamantanone (100 mmol), acetylacetonatocobalt [Co(acac)2] (50 mmol), 2,3-butanedione (600 mmol), and acetic acid (100 g). A condenser and an oxygen balloon were attached to the flask, and the mixture in the flask was vigorously stirred at 80° C. for 4 hours. After the completion of the reaction, the reaction mixture was concentrated, was diluted with toluene and washing with water. The resulting organic layer was concentrated, the concentrate was subjected to silica gel column chromatography and thereby yielded the title compound 1-acetyladamantan-4-one in a yield of 21%.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]2)=[CH:7][CH:6]=1)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:23][C:20]([F:21])([F:22])[C:13]1[CH:14]=[C:15]([C:16]([F:17])([F:18])[F:19])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=2)[N:12]=1
Reactant: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A stirred solution of 4-(3,5-bis-trifluoromethyl-pyrazol-1-yl)-benzoic acid ethyl ester (2.4 g, 6.8 mmol) in dry toluene (20 mL) was treated with 1 M solution of DIBAL-H in toluene (10.2 mL, 10.2 mmol) at room temperature. The mixture was stirred for 1 hour and quenched with saturated aqueous NH4Cl (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×30 mL). The organics were washed with water (30 mL), dried (anhydrous Na2SO4) and the solvent removed under reduced pressure. Purification by flash chromatography (SiO2, 4:1 hexane/EtOAc) gave [4-(3, 5-bis-trifluoromethyl-pyrazol-1-yl)-phenyl]-methanol (2 g, 94.8% yield) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14](C)C)=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:8]=1)#[N:2].[CH3:17][O:18][C:19](=[O:35])[C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:22](N)[CH:21]=1.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.O>[CH3:17][O:18][C:19](=[O:35])[C:20]1[CH:21]=[CH:22][C:23]([S:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:24]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH:9]([CH3:10])[CH3:11])=[N:5][C:4]=3[N:12]=[CH:13][N:14]=2)[CH:25]=1
Reactant: COC(=O)c1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Temperature: 120 °C
Yield: 81.3 %

Procedure:
A suspension of N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine (0.75 g, 3.5 mmol) and 3-amino-4-(4-hydroxy-phenylsulfanyl)-benzoic acid methyl ester (0.96 g, 3.5 mmol) in AcOH (15 mL) was heated at 120° C. for 10 minutes under N2. The reaction mixture was portioned between AcOEt (10 mL) and H2O (150 mL) and made basic to pH 9 with K2CO3 under stirring. The resulting solid was collected by filtration, washed with H2O and AcOEt, and dried at 50° C. overnight under reduced pressure to give the title compound as pale brown crystal (1.27 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.CI.[C:27](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[N:17]([CH3:27])[C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C(C)(C)C1=O
Temperature: 80 °C

Procedure:
A mixture of 204 mg (0.50 mmol) of 1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione, 0.0411 ml (0.66 mmol) of methyl iodide and 244 mg (0.750 mmol) of Cesium Carbonate in 5.0 ml of N,N-Dimethylformamide was heated at 80° C. for 2 hours. The mixture was filtered, the filtrate concentrated in high vacuum, the residue partitioned between ethyl acetate and water. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated to give 1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2,4-dione. Weight 0.205 (97%). MS (ESI+): 421.9
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][C:44](=[O:62])[C@H:45]([NH2:61])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([C:59]#[N:60])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:20])[NH:61][C@@H:45]([C:44]([O:43][CH3:42])=[O:62])[CH2:46][C:47]2[CH:48]=[CH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:59]#[N:60])=[CH:55][CH:54]=3)=[CH:51][CH:52]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: COC(=O)[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 81.1 %

Procedure:
(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (75 mg) was coupled with (R)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (43 mg) according to General Procedure L to give (S)-8-[(R)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (88 mg). This intermediate was deprotected according to General Procedure C to give (R)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride. This compound (100 mg) was further reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to give (R)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure E. This product (69 mg) was deacylated followed by hydrolysis according to General Procedures N and B to give the title compound. LCMS (m/z): 910.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=2)[CH:3]=1.[Mg].[CH:16]([C:18]1[N:19]=[CH:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1)=[O:17].[Cl-].[NH4+]>C1COCC1.CI.O>[CH2:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:16]([C:18]1[N:19]=[CH:20][N:21]([C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:22]=1)[OH:17])[CH:11]=[CH:10]2)[CH3:14]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOc1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Yield: 59.6 %

Procedure:
2-Bromo-6-ethoxynaphthalene (5.3 g) was dissolved in THF (40 ml) and magnesium (0.515 g) and methyl iodide (one drop) were added and the mixture was vigorously stirred to dissolve magnesium. The reaction mixture was ice-cooled and a solution of 4-formyl-1-tritylimidazole (7 g) in THF (80 ml) was added dropwise over 30 min. The mixture was stirred at room temperature for 1 h. To the reaction mixture were added saturated aqueous solution (40 ml) of ammonium chloride and water (40 ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated. The residue was washed with ethyl acetate to give (6-ethoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol (6.3 g) as a colorless powder. This product (6.3 g) was dissolved in dichloromethane (120 ml) and manganese dioxide (6 g) was added. The mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was crystallized from THF-ethyl acetate to give the title compound (5.5 g) as a colorless powder.