Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:8][CH2:7][O:6][CH2:5]1.[F:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13].O>O1CCCC1>[F:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:3][CH:4]2[CH2:8][CH2:7][O:6][CH2:5]2)[C:11]=1[C:12]#[N:13]
Reactant: OC1CCOC1
Reactant: COc1cc(F)c(C#N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(C#N)c(OC2CCOC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.83 g, 21 mmol) was added portionwise to 3-hydroxytetrahydrofuran (1.82 g, 21 mmol) in tetrahydrofuran (40 ml) at 0° C. under a nitrogen atmosphere. The suspension was warmed to room temperature and was stirred for 1 hour. The mixture formed was added over 30 minutes to 2,6-difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (3.5 g, 21 mmol) in tetrahydrofuran (50 ml) and the resulting solution was held at room temperature for 16 hours. Water (75 ml) was added and the aqueous mixture was extracted with ethyl acetate (3×200 ml) The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The material obtained was dried under vacuum to give the title compound as a brown solid (5.1 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21]2[C:22]([C:23](=[O:24])[NH2:25])=[CH:26][CH:27]=[CH:28][N:29]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
Dissolve [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (Example 377, Part A) (0.500 g, 2.11 mmol) in DMF (10.5 mL). Add NaH (80% in mineral oil) (0.070 g, 2.32 mmol). Stir at room temperature for 30 minutes. Add 2-chloronicotinamide (0.330 g, 2.11 mmol) and heat to 100° C. Remove DMF as an azeotrope with xylenes after 18¾ hours. Take the solid up with ethyl acetate (150 mL) and 1.0 N NaOH (75 mL). Separate the two layers. Extract the aqueous layer with ethyl acetate (1×150 mL). Wash the combined organic layers with brine (1×50 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 35-45% ethyl acetate in dichloromethane to give the title compound (0.538 g, 71.4%): MS ES+ 358.3 (M+H)+, base peak ES+ 302.1 (M+2H—C(CH3)3)+, MS ES− 356.4 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 50-99% over 19 min], tR=12.9 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c(C)c1
Yield: 56.7 %

Procedure:
As described in Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.303 g (1.8 mmol) of 2,4-dimethylbenzoyl chloride in 10 ml of dichloromethane. The product is recrystallized from hexane-dichloromethane to give 0.38 g of crystals, m.p. 197°-199° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]1[CH3:18].[Na].[H-].[Na+].[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>CN(C)C=O>[CH2:22]([O:24][C:25](=[O:30])[C:26]([CH3:28])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([CH3:18])=[C:4]2[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:27])[CH3:23]
Reactant: Cc1c(-c2ccccc2)c2cc(O)ccc2n1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccc1)c(C)n2C

Procedure:
One gram (42 m mole) of 1,2-dimethyl-3-phenyl-1H-indole-5-ol was converted to the sodium salt in 10 of absolute dimethylformamide in the presence of 223 mg (5 m mole) of 55% sodium hydride immersion in oil, and the sodium salt was mixed at room temperature with 990 mg (5 m mole) of 2-bromo-2-methyl-propanoic acid ethylester. After a reaction time of six hours, the solvent was distilled off in vacuo and the reaction product was purified by chromatography on a silicagel column (eluant: toluene/ethyl acetate (9:1)). The evaporation residue of the combined fractions, which contained the purified ester, was treated with petroleum ether.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na]>C(O)C>[CH2:11]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH2:10])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NC(=O)c1ccccc1O
Reactant: CCCCCCCCCCBr
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCOc1ccccc1C(N)=O
Reaction time: 2.25 h

Procedure:
Salicylamide (27.4 g.) and decyl bromide (48.3 ml.) were added to a solution of sodium (4.6 g.) in ethanol (175 ml.) and the mixture was heated to reflux with stirring for 2.25 hours. Most of the ethanol was removed by evaporation in vacuo and the residue was poured into water (350 ml.). The oil which separated solidified, and was filtered off and triturated with 2N sodium hydroxide (150 ml.). The solid was filtered off, washed with water (100 ml.), dried over phosphoric oxide, and recrystallised from light petroleum (b.p. 40°-60° C.) to give 2-decyloxybenzamide (40.5 g.), m.p. 58°-59° C.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH3:29][C:30]1[N:31]=[C:32]([CH2:35]O)[S:33][CH:34]=1>C1(C)C=CC=CC=1>[N:15]([CH2:35][C:32]1[S:33][CH:34]=[C:30]([CH3:29])[N:31]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1csc(CO)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1csc(CN=[N+]=[N-])n1
Reaction time: 8 h

Procedure:
Diphenylphosphoryl azide (DPPA) (1.2 eq) and 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) (1.2 eq) were added to a stirred solution of (4-methylthiazol-2-yl)methanol (1 eq) in 7 ml anh. toluene under Ar. After stirring overnight, the solvent was removed in vacuo. Purification via flash chromatography yielded 2-(azidomethyl)-4-methylthiazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](O)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.O=P(Cl)(Cl)[Cl:18]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([Cl:18])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)O)sc2ccc(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Temperature: 60 °C
Yield: 93 %

Procedure:
A mixture of 5-fluoro-3-methylbenzothiophene-2-sulfonic acid (230 mg, 0.93 mmol) in POCl3 (5 mL) was heated at 60° C. over night. The POCl3 was evaporated and the crude product was dissolved in CH2Cl2 and washed with water. The organic phase was dried and evaporated to give 0.23 g (93%) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][CH2:10]Br.[Br:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:14]=1[OH:21]>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:14]=1[O:21][CH2:10][CH2:9][O:8][CH3:7]
Reactant: COCCBr
Reactant: CCc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(OCCOC)c(Br)c1
Reaction time: 20 h
Yield: 89.3 %

Procedure:
Potassium carbonate (8.25 g, 60 mol) followed by 2-bromoethyl methyl ether (1.87 mL, 20 mmol) were added to a solution of 2-bromo-4-ethyl-phenol (4 g, 20 mmol, from step 1 of Example B(98)) in DMF (25 mL). The mixture was stirred for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the desired product (4.63 g, 90%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3H), 2.57 (q, J=7.6 Hz, 2H), 3.48 (s, 3H), 3.79 (t, J=5.1 Hz, 2H), 4.15 (t, J=4.8 Hz, 2H), 0.6.85 (d, J=8.3 Hz, 1H), 7.06 (dd, J=8.3, 2.3 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H).
Reaction SMILES: O1CCCC1.[I:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([I:6])=[CH:8][CH:9]=2)=[O:12])[CH2:28][CH2:29]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
To tetrahydrofuran (60 mL) were added 4-iodobenzoyl chloride (5 g), 1-(2,4-dimethylphenyl)piperazine (3.6 g) and 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added and the mixture was partitioned. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](I)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=Cc1ccncc1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: O=[N+]([O-])c1cccc(C=Cc2ccncc2)c1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
A mixture of 3.0 g (20 mmol) of 3-nitroiodobenzene, 3.5 mL (25 mmol) of TEA, 0.045 g (0.20 mmol) of palladium(II) acetate and 2.77 g (25.0 mmol) of 4-vinylpyridine was suspended in 4 mL of dry acetonitrle in a pyrex sealed tube and heated to 100° C. for 48 h. The mixture was cooled to rt and was quenched with 200 mL of 10% hydrochloric acid. The resulting yellow solid was isolated by filtration and partitioned between 250 mL of EtOAc and 250 mL of 1 N aqueous sodium hydroxide. The organic phase was dried over MgSO4 and concentrated to give 3.0 g (66%) of 4-[2-(3-nitrophenyl)ethenyl]-pyridine as a yellow solid: 1H NMR (DMSO-d6): δ 3.0-4.6 (br s, 1H), 7.71-7.78 (m, 2H), 8.07 (d, J=15.8 Hz, 1H), 8.13-8.16 (m, 3H), 8.24 (d, J=8.0 Hz, 1H), 8.56 (s, 1H), 8,84 (d, J=5.7 Hz, 2H); ESI−MS m/z 227 (M+1)+. A portion (1.3 g, 7.1 mmol) of this solid was dissolved in 100 mL of EtOAc, and 0.5 g of 10% palladium on charcoal was added. The mixture was hydrogenated on a Parr apparatus at 40 psi for 1.5 h. Another 0.5 g batch of 10% palladium on charcoal was added and the mixture was subjected to further hydrogenation for 1 h. The palladium catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated to give 1.13 g (100%) of 3-(4-pyridinyl)ethylaniline: 1H NMR (DMSO-d6): δ 2.69 (m, 2H), 2.80 (m, 2H), 4.9 (bs, 2H), 6.33 (d, J=7.7 Hz, 2H), 6.38 (s, 1H), 6.86 (t, J=7.7 Hz, 1H), 7.20 (d, J=5.8 Hz, 2H), 8.41 (d, J=5.8 Hz, 2H). Conversion of 3-[2-(4-pyridinyl)ethyl]-aniline to 4-2-pyridin-4-yl-ethyl)-1H-indole-2,3-dione was accomplished according to Procedure A in 24% overall yield: 1H NMR (DMSO-d6): δ 2.80 (m, 2H), 3.10 (m, 2H), 6.70 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 7.24 (m, 2H), 7.40 (t, J=8.0 Hz, 1H), 8.42 (bs, 2H), 11.00 (s, 1H). Conversion of 4-(2-pyridin-4-yl-ethyl)-1H-indole-2,3dione to the title compound was accomplished according to Procedure G in 40% overall yield: 1H NMR (DMSO-d6): δ 2.98 (t, J=7.9 Hz, 2H), 3.30 (m, 2H, underneath water peak), 6.78 (d, J=7.7 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.25 (s, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 8.47 (d, J=6.0 Hz, 2H), 11.13 (s, 1H), 12.98 (s, 1H); APCI−MS m/z 420 (M−1)−. Anal. Calcd for C21H19N5O3S.0.15 HCl: C, 55.93, H, 4.43; N, 15.53; S, 7.11. Found C, 56.05, H, 4.36; N, 15.38; S, 7.18.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)=O.[Cl:18][C:19]1[N:24]=[N:23][C:22]([NH2:25])=[CH:21][CH:20]=1>CCO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=3)[N:25]=2)[N:24]=1
Reactant: CS(=O)(=O)Nc1cc(C#N)cc(C(=O)CBr)c1
Reactant: Nc1ccc(Cl)nn1
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(C#N)cc(-c2cn3nc(Cl)ccc3n2)c1
Yield: 50 %

Procedure:
A mixture of N-(3-(2-bromoacetyl)-5-cyanophenyl)methanesulfonamide (0.8 mmol) and 6-chloropyridazin-3-amine (0.8 mmol) in EtOH (8 mL) was refluxed for 4 hours. After cooling, the resulting mixture was filtrated to give N-(3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-5-cyanophenyl)methanesulfonamide in 50% yield. 10% Pd/C (20 mg) was added to the solution of N-(3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-5-cyanophenyl)methanesulfonamide (0.3 mmol) in THF (25 mL. Then it was stirred at room temperature for 4 hours. After filtration, it was concentrated to give N-(3-cyano-5-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanesulfonamide in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([OH:21])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[NH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:19]([NH:22][N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)=[CH:6][CH:7]=1
Reactant: NN1CCC(O)CC1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(NN1CCC(O)CC1)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAN 1018782-76-7) and 1-amino-4-piperidinol (CAN 79414-82-7) as starting materials; MS (EI) 402.4 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:19]1[C:30]2[C:29]3[CH2:28][CH2:27][CH2:26][C:25]=3[S:24][C:23]=2[N:22]=[CH:21][N:20]=1>O1CCCC1>[C:30]12[C:19]([O:1][CH:2]3[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]3)=[N:20][CH:21]=[N:22][C:23]=1[S:24][C:25]1[CH2:26][CH2:27][CH2:28][C:29]2=1
Reactant: Clc1ncnc2sc3c(c12)CCC3
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (194 mg, 0.90 mmol, 1.40 equiv) in anhydrous tetrahydrofuran (5 mL) was added sodium hydride (60% dispersion in mineral oil, 77 mg, 1.92 mmol, 3.00 equiv) at 0° C. under nitrogen. After stirred at room temperature for 1 h, 12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraene (200 mg, 0.95 mmol, 1.00 equiv) was added and the resulting solution was stirred overnight at ambient temperature for additional 5 h. The reaction was then quenched with water and extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give the resulted ter t-butyl N-(4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexyl)carbamate (308 mg, 83%) as a yellow solid. MS (ES, m/z): 390 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[N:28][CH:27]=[CH:26]3)=[O:21])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C(Cl)CCl.[CH3:37][C:38]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:37][C:38]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:39]=1[C:40]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][N:11]([C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH3:19])[C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[N:28][CH:27]=[CH:26]3)=[O:21])=[CH:7][CH:8]=1)=[O:41]
Reactant: CN(CC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OCc2ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropyl(methyl)carbamate (E205-1) in pyridine was added was added EDC, DMAP, and 2,4-dimethylbenzoic acid, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2 gradient) gave pure 4-(3-(tert-butoxycarbonyl(methyl)amino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E205-2).
Reaction SMILES: [O:1]=[C:2]1[CH:7](OS(C)(=O)=O)[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH:7]3[CH2:6][CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Reactant: CS(=O)(=O)OC1CCCNC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)C2CCN(C3CCCNC3=O)CC2)cc1
Temperature: 85 °C
Yield: 31.6 %

Procedure:
To a solution of methanesulfonic acid 2-oxo-piperidin-3-yl ester (250 mg, 1/294 mmol, 1.0 eq) and (4-methoxy-phenyl)-piperidin-4-yl-methanone (312 mg, 1.423 mmol, 1.1 eq) in acetonitrile (2.5 mL) was added diisopropylethylamine (351 mg, 0.475 mL, 2.1 eq) and the reaction was heated at 85° C. for 3 hours. The reaction was cooled to room temperature and the solvent evaporated in vacuo. The resulting oily residue was purified by silica gel column chromatography (MeOH/CH2Cl2) to give the title compound as a clear oil (142 mg, 0.449 mmol, 34.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (d, J=9.09 Hz, 2H) 7.39-7.43 (br. s, 1H) 7.04 (d, J=8.59 Hz, 2H) 3.84 (s, 3H) 3.23-3.33 (m, 2H) 2.97-3.14 (m, 4H) 2.74-2.85 (m, 2H) 1.75-1.91 (m, 2H) 1.57-1.75 (m, 4H) 1.47-1.54 (m, 2H). MS (m/z, MH+): 316.8
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:20][C:21]([OH:23])=[O:22]
Reactant: COc1c(C=O)cccc1Oc1ccccc1C
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1c(C=CC(=O)O)cccc1Oc1ccccc1C
Yield: 53.3 %

Procedure:
2-Methoxy-3-(o-tolyloxy)benzaldehyde (28 g), malonic acid (24 g), pyridine (200 ml) and piperidine (2 ml) were treated in a similar manner to that of Example 4-(4), and the resultant crude product was crystallized with a mixture of benzene and n-hexane to give 3-[2-methoxy-3-(o-tolyloxy)phenyl]acrylic acid (17.5 g). mp 143°-146° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:8][C:7]([C:13]([O:15][CH3:16])=[O:14])([C:9]([O:11][CH3:12])=[O:10])[CH2:6]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:3][CH2:4][CH:5]1[CH2:6][C:7]([C:9]([O:11][CH3:12])=[O:10])([C:13]([O:15][CH3:16])=[O:14])[CH2:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1(C(=O)OC)CC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)OC)CC(COCc2ccccc2)C1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% oil dispersion, 2.1 g, 53 mmol) is added in portions to a solution of dimethyl 3-(hydroxymethyl)cyclobutane-1,1-dicarboxylate (51), benzyl bromide, and n-tetrabutylammonium iodide in dry DMF at 25° C. (Step 47). The mixture is stirred for 1 hr at 65° C., poured onto ice and then extracted with ether (2×50 mL). The combined ether extract is washed with water (3×50 mL) and dried over MgSO4. Chromatography on silica gel.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([Br:15])[C:12]([F:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].O>C1COCC1>[Br:15][C:11]1[C:12]([F:14])=[CH:13][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2cc(F)c(Br)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(F)c(Br)cc2s1
Yield: 9.1 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 25 for the preparation of I-25b above, 6-bromo-5-fluoro-benzo[b]thiophene-2-carboxylic acid methyl ester (I-27b: 0.3 g, 10 mmol) in THF (10 mL) was hydrolyzed with LiOH (87 mg, 2.04 mmol) and water (2 mL) to afford 250 mg of the product (yield 88%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([CH:14]=O)[CH2:13][C:7]=3[C:6]=2[CH:16]=1.[CH3:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]3[O:31][CH2:30][C@H:29]([CH2:32][NH2:33])[O:28][C:24]3=2)[N:19]=1.[BH3-]C#N.[Na+].CC(O)=O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([CH2:14][NH:33][CH2:32][C@@H:29]4[O:28][C:24]5=[C:25]6[C:20](=[CH:21][CH:22]=[C:23]5[O:31][CH2:30]4)[N:19]=[C:18]([CH3:17])[CH:27]=[CH:26]6)[CH2:13][C:7]=3[C:6]=2[CH:16]=1
Reactant: O=CC1CCc2oc3ccc(F)cc3c2C1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CN)O3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CNCC1CCc2oc4ccc(F)cc4c2C1)O3
Reaction time: 3 h

Procedure:
8-fluoro-1,2,3,4-tetrahydrodibenzo[b,d]furan-2-carbaldehyde (0.040 g, 0.18 mmol), [(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methylamine (0.042 g, 0.18 mmol), and NaBH3CN (0.023 g, 0.38 mmol) were stirred together in MeOH (1.2 mL) under a N2 atmosphere. To this mixture was added AcOH (0.023 mL) and reaction was allowed to stir for 3 h. The reaction mixture was concentrated and the resulting oil was purified by flash chromatography on silica gel to afford title compound as a mixture of two diastereomers (0.068 g, 88%). The diastereomers were separated by HPLC on a Chiracel AD column (2×25 cm), eluting with 100% ethanol; MS (ES) m/z=433.1 [M+H]+.