Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH3:22])=[N:10][C:9]=1[OH:23].[C:29](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.CCOCC>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH3:22])=[N:10][C:9]=1[O:23][CH3:29]
Reactant: COc1ccc(Cc2c(O)nc(C)c3cc(OC)c(OC)cc23)cc1OC
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COc1ccc(Cc2c(OC)nc(C)c3cc(OC)c(OC)cc23)cc1OC
Temperature: 90 °C
Reaction time: 0.37 h
Yield: 53.1 %

Procedure:
A mixture of 4-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol (compound 2 free base, 60 mg, 162 μmol), cesium carbonate (70 mg, 215 μmol) and iodomethane (13 μL, 208 μmol) in dry DMF (2 mL) in a 5 mL microwave vial equipped with a magnetic stirrer was stirred at 90° C. for 22 min under microwave irradiation. After cooling to RT, the mixture was diluted with Et2O (50 mL) before washing with water (10 mL) then with brine (10 mL), drying over Na2SO4, filtration and concentration at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) gave 4-(3,4-dimethoxybenzyl)-3,6,7-trimethoxy-1-methylisoquinoline as a colorless oil (33 mg). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.15 M HCl solution in MeOH (1.5 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum. The solid was then washed with Et2O to afford, after drying, 4-(3,4-dimethoxybenzyl)-3,6,7-trimethoxy-1-methylisoquinoline hydrochloride 3 as a pale brown solid (23 mg, 34% yield).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>ClC1C=CC=CC=1Cl>[Cl:3][C:2]1[N:4]=[C:5]([C:22]2[CH:23]=[CH:24][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[N:7]=[C:8]([C:22]2[CH:23]=[CH:24][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)c1ccc(-c2nc(Cl)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring mixture of 1 eq of cyanuric chloride and 3 eq of aluminum chloride in o-dichlorobenzene at ice bath temperature was added concentrated HCl (13 wt % based on cyanuric chloride). After 10 minutes, 1.95 eq of tert-butylbenzene was added and the reaction was stirred at ice bath temperature for 10 minutes. The cooling bath was removed, the reaction mixture was allowed to warm to room temperature, and stirred. After 2 h, HPLC analysis indicated 62% cyanuric chloride conversion to 2-chloro-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine as the major product (>78%). The reaction mixture was stirred at room temperature for an additional 24 h HPLC analysis showed 83% cyanuric chloride conversion to 2-chloro-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine as the major product (>72%), with the isomer.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8][C:7]=2[CH:6]=[CH:5][C:4]=1[S:16](Cl)(=[O:18])=[O:17]>S1(CCCC1)(=O)=O.O>[CH3:1][NH:2][S:16]([C:4]1[CH:5]=[CH:6][C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]=2[CH:3]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccc2sc3ccccc3c2c1
Reactant: CN
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CNS(=O)(=O)c1ccc2sc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A large excess of aqueous methylamine was added to a suspension of dibenzo[b,d]thiophene-2-sulfonyl chloride (2.83 g) in sulfolane (15 ml) and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with water, and the precipitate was recovered, washed with water, dried and purified by silica gel chromatography eluting with a gradient of ethyl acetate:DCM of 0:100 to 10:90 to give the title compound (1.79 g, 64%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.C([O:12][C:13](=O)/[CH:14]=[CH:15]\[O-])C.[Na+]>CCO.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]3[N:9]=[CH:15][CH:14]=[C:13]([OH:12])[N:7]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C\[O-]
Reactant: Nc1cc(C2CC2)[nH]n1
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Oc1ccnc2cc(C3CC3)nn12
Temperature: 80 °C

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (415 mg, 3.37 mmol) and sodium (Z)-3-ethoxy-3-oxoprop-1-en-1-olate (0.791 g, 5.73 mmol) in EtOH (3 mL) and toluene (1 mL) was heated to 80° C. in a resealable tube. After 16 hrs the solvent was removed in vacuo. The resulting residue was dissolved in a minimal amount of warm water and triturated with 1 N HCl with cooling (0° C.) until the pH ˜1. The resulting solid was filtered and washed with water to afford 2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ol as an off-white solid that was advanced without further purification. M+H+ found=176.2.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4]1.[C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24](F)=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1)#[CH:10]>C1COCC1>[C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:8][C@H:5]4[CH2:6][CH2:7][O:3][CH2:4]4)=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1)#[CH:10]
Reactant: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Reactant: O[C@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#Cc1cccc(Nc2ncnc3cc(O[C@H]4CCOC4)c([N+](=O)[O-])cc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48370.9 %

Procedure:
In an ice bath, NaH (1.87 g, 60%, 0.046 mol) was carefully added into a solution of (S)-tetrahydrofuran-3-ol (3.43 g, 0.039 mmol) in 100 mL anhydrous THF, and stirred for 2 hours at room temperature. Then N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine (10 g, 0.032 mol) was added and stirred for at 60° C. overnight. The solution was quenched with 1 mL H2O and concentrated, the residue was purified by silica gel column to give (S)—N-(3-ethynylphenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine as yellow solid 7.1 g (58.1% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.Br[CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: CCCSCCCBr
Reactant: N#Cc1ccc(OCCCNCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCCSCCCN(CCO)CCCOc1ccc(C#N)cc1

Procedure:
A mixture of 4-[3-[(2-hydroxyethyl)amino]propoxy]benzonitrile (3 g), 1-bromo-3-(propylthio)propane (2.7 g) and potassium carbonate (3.7 g) in 2-propanol (50 ml) was refluxed for 28 hours. The solvent was evaporated and the residue dissolved in aqueous HCl (2 M) and extracted with diethylether. The aqueous layer was basified with sodium hydroxide (10 M) and extracted with methylene chloride followed by drying over sodium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography. Yield 2.6 g of the title compound as an oil.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:16]=[C:15]([Si](C)(C)C)[C:13]=2[N:14]=1>C(#N)C.O>[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19][C:20]([F:23])([F:21])[F:22])[CH:16]=[C:15]([N+:7]([O-:8])=[O:6])[C:13]=2[N:14]=1
Reactant: O=[N+]=O
Reactant: C[Si](C)(C)c1cc(OC(F)(F)F)cc2sc(N)nc12
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: Nc1nc2c([N+](=O)[O-])cc(OC(F)(F)F)cc2s1
Temperature: 0 °C
Reaction time: 12 h
Yield: 43.3 %

Procedure:
0.68 g of nitronium tetrafluoroborate are added in small portions to a solution of 0.76 g of 2-amino-4-trimethylsilyl-6-trifluoromethoxybenzothiazole in 20 cm3 of acetonitrile cooled to 0° C. Stirring is continued for 12 hours at a temperature close to 20° C. The solution is then diluted with 50 cm3 of water and extracted with 2 times 50 cm3 of ethyl acetate. The organic phases are combined, dried over sodium sulphate and concentrated in vacuum. The residue is purified by flash chromatography on silica gel with a cyclohexane-ethyl acetate mixture (7-3 by volume) as eluent. After recrystallization from a cyclohexane-ethyl acetate mixture (3-2 by volume), 0.3 g of 2-amino-4-nitro-6-trifluoromethoxybenzothiazole melting at 260° C. is obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]([CH3:27])[CH3:26])=[N:10][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[S:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]([CH3:27])[CH3:26])=[N:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CN(C)c1ccccc1CSc1nccn1-c1ccc(N)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(-n2ccnc2SCc2ccccc2N(C)C)nc1
Reaction time: 2 h

Procedure:
0.26 ml of acetyl chloride is added to a mixture of 0.98 g of 1-(5-amino-2-pyridyl)-2-[2-(dimethylamino)benzylthio]imidazole, 1 ml of triethylamine and 30 ml of methylene chloride under ice-cooling. The mixture is stirred at the same temperature for 2 hours, washed with water and a saturated aqueous sodium bicarbonate solution, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=30:1), and crystallized with isopropyl ether. The crystals are collected by filtration, whereby 0.82 g of 1-(5-acetylamino-2-pyridyl)-2-[2-(dimethylamino)benzylthio]imidazole is obtained.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](Cl)(=[O:11])[CH3:10]>N1C=CC=CC=1.Cl>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: Nc1ccccc1I
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Iodoaniline (1.00 g, 4.56 mmol) was dissolved in pyridine (5 mL) and cooled to 0° C. After acetyl chloride (314 μL, 5.94 mmol) was added, the reaction was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The reaction was diluted with 1 N HCl and extracted with ether. The organic layer was dried (MgSO4) and concentrated to give the desired acetamide (assumed quantitative), which was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:21][CH3:22])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH:19]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28][NH2:29].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][NH:29][CH2:19][C:9]1[CH:10]=[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH3:18])[C:12]2=[N:13][C:8]=1[N:7]([CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:21][CH3:22]
Reactant: CCN(CC1CCCC1)c1nc2c(cc1C=O)c(C)nn2C
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A mixture of 6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (5.3 g, 17.0 mmol) and 3,5-bis-trifluoromethylbenzylamine (4.7 g, 0.019 mol) in MeOH and acetic acid (2 drops) was stirred at RT for 30 min. After cooling to 0° C., sodium cyanoborohydride (2.2 g, 35.0 mmol) was added slowly over a period of about 10 min. After stirring at RT for 30 min, the reaction mixture was concentrated in vacuo. Water (50 mL) was added to the residue and stirred for 30 min. The solid was filtered off, washed with water followed by petroleum ether, and dried in vacuo to yield colorless solid (72%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH:19]([CH3:26])[CH2:20][O:21][N:22]=[C:23]([CH3:25])[CH3:24]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH:19]([CH3:26])[CH2:20][O:21][N:22]=[C:23]([CH3:25])[CH3:24])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=NOCC(C)O
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: CC(C)=NOCC(C)OC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and acetone (2-hydroxypropyl) oxime, there is obtained 2-[(isopropylideneamino)oxy]-1-methylethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 351 (12), 295 (4), 237 (81), 194 (100), 114 (35), 56 (78);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:24][C:25]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([Br:37])=[CH:29][CH:28]=1)=[O:26]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:24][C:25]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([Br:37])=[CH:29][CH:28]=1)=[O:26])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccc(Br)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc(Br)c2ccccc12
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (4.85 g) was dissolved in acetonitrile (65 mL), and triethylamine (3.09 mL) was added. A solution of 2-bromo-1-(4-bromonaphthalen-1-yl)-ethanone (6.60 g) in acetonitrile (35 mL) was added. Reaction mixture was stirred 90 minutes and evaporated under vacuum. Oil was dissolved in DCM (50 mL), extracted once with water (20 mL) and once with NaHCO3 solution (20 mL), and evaporated under vacuum to a concentrated liquid. Solution was purified by chromatography (0-50% ethyl acetate:hexane) and evaporated under vacuum, giving pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromonaphthalen-1-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (8.95 g, 95%) as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]/[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]/[CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of tert-butyl (E)-4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)allyl]piperidine-1-carboxylate (0.0313 g, 0.0807 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0118 g, 0.0807 mmol) and piperidine (0.0800 mL, 0.810 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((E)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperidine-1-carboxylate (0.0308 g, 74%).
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].O.[NH2:11][NH2:12]>C1COCC1>[C:4]1([CH:2]([NH:11][NH2:12])[CH3:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: CC(Br)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(NN)c1ccccc1

Procedure:
1-bromoethylbenzene Compound 3a (8.0 mL, 58.0 mMol) was added to a solution of hydrazine hydrate Compound 3b (20 mL) in THF (80 mL) which was then heated to reflux for 8 hrs. The solvent was removed in vacito and Et2O (100 mL) was added. The organic layer was washed with brine, separated and dried over Na2SO4. The solvent was removed in vacuo to yield (1-phenyl-ethyl)-hydrazine Compound 3c as a pale yellow oil (5.8 g), used in the next step without purification. MS m/z 137 (M+H, 70%), 105 (M-NHNH2, 100%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8](=O)[CH3:9])(=[O:3])[CH3:2].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1C=CC=CC=1>[NH:11]1[CH2:16][CH2:15][CH:14]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH:7]=[CH:8][CH3:9])[CH2:13][CH2:12]1
Reactant: CC(=O)CCCOC(C)=O
Reactant: C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: CC=CCC(OC(C)=O)C1CCNCC1

Procedure:
A mixture of 0.5 moles of 1-acetoxypentan-4-one and 0.5 moles of piperidine in benzene is refluxed using a water separator until no more water distills from the reaction mixture. The reaction mixture is then cooled, washed and dried to afford the 4-piperidyl-1-acetoxypent-3-ene (XIX). A mixture of 5 g. of XIX in 100 ml. of dioxane is treated with an excess of methyl iodide at 20°C for 18 hours and then heated at 70°C for 6 hours. The reaction mixture is concentrated to a small volume, diluted with water and 1-acetoxy-3-methylpentan-4-one isolated by extraction with ethyl acetate. A mixture of 0.5 g. of this ketone, 100 mg. of p-toluenesulfonic acid, 3 ml. of ethyleneglycol and 100 ml. of benzene is refluxed using a water separator for 24 hours. The reaction mixture is cooled and then 100 ml. of ethanol and 2 g. of potassium hydroxide are added. This mixture is refluxed for 6 hours, cooled, diluted with water and the corresponding ethylene ketal is isolated by extraction with ethyl acetate. A solution of 0.1 moles of the ketal in 50 ml. of dimethylformamide containing 0.1 moles of triphenylphosphine is reacted with 0.1 moles of carbon tetrabromide at room temperature for 18 hours. The mixture is diluted with water and extracted with ether. The ether extracts are combined, washed with water, dried and evaporated. The residue is chromatographed on 400 g. of alumina eluting with hexane-benzene and benzene to give the ethylene ketal of 1-bromo-3-methylpentan-4-one. ##EQU16##
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)([O-])=O.C1COCC1.[H][H]>[Pd].[C].C(O)C>[NH2:1][C:4]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: Cc1ccccc1NC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)c1ccc(Oc2ccc(N)cc2N)cc1
Reaction time: 15 h
Yield: 96.9 %

Procedure:
1.55 g (3.90 mmol) of 4-(2,4-dinitrophenoxy)-2′-methylbenzanilide was dissolved into the solvent mixture with 70 ml THF and 30 ml of ethanol, and 0.166 g of 5% Pd-carbon powder was added into this solution. The solution was thoroughly deaerated under the reduced pressure at −78° C., and then stirred for 15 hours after the system was replaced with hydrogen gas and temperature was brought back to room temperature. The solution was concentrated after removing catalyst with Celite to yield 1.26 g of 4-(2,4-diaminophenoxy)-2′-methylbenzanilide shown in the structural formula (V) above in light brown solid (Yield: 96.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[C:11](=O)[CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.O.Cl>C1(C)C=CC=CC=1.[Zn]>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CCCC(=O)C(=O)Cc2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CCCCCCc2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
With stirring, 212.2 g (0.65 mole) of 1,6-bis(4-methoxyphenyl)hexanedione in 500 ml of toluene are heated to 80° C. Then 520 g of amalgamated zinc filings as well as 150 ml of water and 500 ml of hydrochloric acid are added, whereupon evolution of H2 gas commences. After the evolution of gas has subsided, the reaction solution is gently refluxed overnight. After filtration, the aqueous phase which has been separated from the organic phase is extracted with 200 ml of toluene. The organic phases are combined and subjected to fractional distillation, affording 412.6 g (69.1% of theory) of almost colourless crystals of 1,6-bis(4-methoxyphenyl)hexane.
Reaction SMILES: [F:1][C:2]1([F:40])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]4[CH2:32][O:31]C(C)(C)[O:29]4)[C:21]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[F:40][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]([OH:29])[CH2:32][OH:31])[C:21]([C:35]([CH3:38])([CH3:39])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)CO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1C[C@@H](O)CO
Temperature: 80 °C

Procedure:
(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (3.0 g, 5.4 mmol) was dissolved in methanol (52 mL). Water (5.2 mL) was added followed by p-TsOH.H2O (204 mg, 1.1 mmol). The reaction was heated at 80° C. for 45 minutes. The solution was concentrated and then partitioned between ethyl acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100% ethyl acetate-hexanes) to yield the product as a cream colored foamy solid. (1.3 g, 47%, ee>98% by SFC). ESI-MS m/z calc. 520.5, found 521.7 (M+1)+. Retention time 1.69 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42-7.38 (m, 2H), 7.33-7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J=5.2 Hz, 1H), 4.90 (t, J=5.5 Hz, 1H), 4.75 (t, J=5.8 Hz, 1H), 4.40 (dd, J=2.6, 15.1 Hz, 1H), 4.10 (dd, J=8.7, 15.1 Hz, 1H), 3.90 (s, 1H), 3.65-3.54 (m, 2H), 3.48-3.33 (m, 2H), 1.48-1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14-1.11 (m, 2H) ppm.