Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[I:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[CH2:14][CH2:15]Br.C(N(CC)CC)C.Cl.[CH3:29][N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>C(O)C>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[CH2:14][CH2:15][N:9]1[C:6]2[CH:7]=[CH:8][C:3]([I:2])=[CH:4][C:5]=2[C:32]2[CH2:31][N:30]([CH3:29])[CH2:35][CH2:34][C:33]1=2
Reactant: NNc1ccc(I)cc1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1ccccc1CCBr
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCc2c(c3cc(I)ccc3n2CCc2ccccc2F)C1
Yield: 0.5 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. 4-Iodophenylhydrazine hydrochloride (500 mg, 2.1 mmol), 2-fluorophenethylbromide (0.3 ml, 2.1 mmol), triethyl amine (0.8 ml, 6.3 mmol) and N-methyl-4-piperidone hydrochloride (312 mg, 2.1 mmol) were taken in ethanol (10 ml) to obtain 5 mg of 5-(2-fluorophenethyl)-2,3,4,5-tetrahydro-8-iodo-2-methyl-1H-pyrido[4,3-b]indole as a trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[C:14]2=O.[C:20]1([O:26]C(C)=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O.S(=O)(=O)(O)O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:14]2([C:23]3[CH:24]=[CH:25][C:20]([OH:26])=[CH:21][CH:22]=3)[C:13]3[C:17](=[C:9]([CH3:8])[CH:10]=[CH:11][CH:12]=3)[NH:16][C:15]2=[O:18])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)Oc1ccccc1
Reactant: Cc1cccc2c1NC(=O)C2=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: Cc1cccc2c1NC(=O)C2(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 60 °C
Yield: 58.7 %

Procedure:
38.2 g of pure phenol were mixed with 0.4 g of concentrated sulphuric acid, with stirring and heating to 60° C. 28.5 g (0.177 mole) of 7-methylisatin were added in portions. At the end of the addition, the temperature was raised to 85° C. and 21 g of PhOAc were gradually added dropwise over a period of 5 hours. Finally, the temperature of the stirred mixture was raised to 120° C. for 30 minutes. It was then allowed to cool, filtered and washed with abundant water to remove the PhOAc. The resulting solid was dried and gave 50 g. It was dissolved in acetone and precipitated with chloroform, allowed to cool and filtered. The solid formed was dried to yield 30 g of 3,3-bis-(4-hydroxyphenyl)-7-methyl-2 -indolinone, m.p. 272°-4° C. Yield: 52%.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[NH:7][N:6]=1.Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([C:19]2[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[N:6]=1
Reactant: Fc1ccccc1Cc1n[nH]c2cccnc12
Reactant: Nc1nc(N)nc(Cl)n1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1nc(N)nc(-n2nc(Cc3ccccc3F)c3ncccc32)n1

Procedure:
A solution of 100 mg (0.44 mmol) of 3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridine from example 4A, 64 mg (0.44 mmol) of 6-chloro-1,3,5-triazine-2,4-diamine, 8.1 mg (0.009 mmol) of tris(di-benzylideneacetone)dipalladium, 13 mg (0.026 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) and 201 mg (0.62 mmol) of cesium carbonate in 3 ml of degassed toluene is heated at 90° C. for 20 h. It is then diluted with ethyl acetate and methanol, filtered and concentrated in vacuo. The residue is crystallized from methanol to result in 42 mg (28% of theory) of the title compound as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:34]([F:37])([F:36])[F:35])[O:13][N:12]([CH3:14])[C:11]([C:15]3[CH:32]=[CH:31][C:18]([CH2:19][N:20]4C(=O)C5C(=CC=CC=5)C4=O)=[C:17]([CH3:33])[CH:16]=3)=[CH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.NN>C(O)C.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:34]([F:36])([F:35])[F:37])[O:13][N:12]([CH3:14])[C:11]([C:15]3[CH:32]=[CH:31][C:18]([CH2:19][NH2:20])=[C:17]([CH3:33])[CH:16]=3)=[CH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CN
Yield: 65 %

Procedure:
837 mg of 2-{4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzyl}-isoindole-1,3-dione (Example I14) and 500 mg hydrazine hydrate in 25 ml ethanol were heated at reflux for 2 hours under stirring. The mixture was cooled and diluted with diethyl ether. The solid was filtered off and the filtrate was evaporated. The residue was dissolved in 100 ml of ether and washed with water. The organic phase was dried and evaporated. The residue was purified on silica gel (eluent dichloromethane/methanol 4:1) affording 4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzylamine as a resin in 65% yield. 1H-NMR (CDCl3, δ in ppm): 7.44 (s, 2H), 7.37 (m, 2H), 7.28 (m, 2H), 5.33 (s, 1H), 3.88 (s, 2H), 2.99 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=1)[N:6]=[CH:5]2.[K+].[Br-].[CH:23](Cl)(Cl)Cl.CO>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]3[O:18][CH2:23][CH2:19][O:20][C:14]=3[CH:13]=1)[N:6]=[CH:5]2
Reactant: Nc1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Reactant: ClC(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: Nc1ccc2nc(-c3ccc4c(c3)OCCO4)ncc2c1
Yield: 67 %

Procedure:
This compound was synthesized in 67% yield, according to the procedure described in example 3 for 6-amino-2-(3,4-methylendioxy-phenyl)-quinazoline. C16H13N3O2, MW: 279.30. mp 179.4-181.6° C.; 1H NMR (DMSO-d6) 9.24 (s, 1H), 7.92-7.98 (m, 2H), 7.72 (d, 1H), 7.38 (dd, 1H), 6.89-6.99 (m, 2H), 5.91 (s, 2H), 4.31 (s, 4H); IR (KBr) 1555, 1507, 1286; TLC (CHCl3/MeOH 9/1) Rf=0.65.
Reaction SMILES: [CH:1]([N:4]([CH:10]([CH3:12])[CH3:11])[C:5](=[O:9])[O:6][CH2:7]Cl)([CH3:3])[CH3:2].[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O-:35])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CN(C)C(=O)C>[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O:35][CH2:7][O:6][C:5]([N:4]([CH:10]([CH3:12])[CH3:11])[CH:1]([CH3:3])[CH3:2])=[O:9])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)N(C(=O)OCCl)C(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)C
Temperature: 30 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
Chloromethyl N,N-diisopropylcarbamate (2.81 g) and 2.76 g of triethyl benzyl ammonium chloride were added to 50 ml of a solution of 4.89 g of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate in N,N-dimethylacetamide, and the mixture was stirred at 30° C. for 5 hr. The reaction solution was washed twice with 180 ml of heptane. Thereafter, 125 ml of ethyl acetate and 125 ml of 20% brine were added thereto, followed by separation. The organic layer was washed three times with 125 ml of 10% brine, was dried over anhydrous magnesium sulfate, and was filtered, and ethyl acetate was removed by distillation under the reduced pressure to give 6.01 g of the title compound.
Reaction SMILES: O.NN.[CH3:4][C:5]1[C:9]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:8]([N:15]2C(=O)C3C(=CC=CC=3)C2=O)[S:7][N:6]=1>CCO>[CH3:4][C:5]1[C:9]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:8]([NH2:15])[S:7][N:6]=1
Reactant: Cc1nsc(N2C(=O)c3ccccc3C2=O)c1N1CCCC1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nsc(N)c1N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Hydrazine hydrate (25.56 mg, 25.03 μL, 0.5106 mmol) was added to a solution of 2-(3-methyl-4-pyrrolidin-1-yl-isothiazol-5-yl)isoindoline-1,3-dione (160 mg, 0.5106 mmol) in EtOH (5 mL) and the mixture was stirred at RT for 10 min. The mixture was heated for 15 min at 120° C. in a microwave, then was concentrated in vacuo. The residue was purified by fractionlynx. The clean fractions were concentrated in vacuo and dried by azeotropic distillation with toluene (×2) to yield 3-methyl-4-(pyrrolidin-1-yl)isothiazol-5-amine as pale yellow solid. (61.7 mg, 59.9% over two steps). MS (ES+) 184.1.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:22]=[O:23].[OH-].[Na+]>C(O)(=O)C>[CH:6]([NH2:5])([CH3:19])[CH3:7].[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH2:22][OH:23])=[CH:8][CH:7]=1
Reactant: CN(C)CCNc1cccc2sc3ccccc3c(=O)c12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)N
Product: CN(C)CCNc1ccc(CO)c2sc3ccccc3c(=O)c12
Temperature: 100 °C
Yield: 64 %

Procedure:
A mixture of 1-[[2-(dimethylamino)ethyl]amino]thioxanthen-9-one (13 g, 0.044 mol) , 37% formalin (390 mL) and 5N acetic acid (6.5 mL) was heated to 100° C. for 8.5 hours, allowed to stand over the weekend and then was heated at 100° C. for several more hours. The mixture was poured into ice water, basified with 35% NaOH and extracted with chloroform. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica eluting in succession with; 25% CHCL3 /hexane; 50% CHCl3 /hexane; 75% CHCl3 /hexane; 100% CHCl3 ; 0.5% isopropylamine/chloroform; 1% isopropylamine/chloroform; 2% isopropylamine/chloroform; then 2% isopropylamine/2% MeOH/CHCl3 to afford 9.2 g (64%) of 1-[[2-(dimethylamino) ethyl]amino]-4-(hydroxymethyl)thioxanthen-9-one.
Reaction SMILES: B#B.[F:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:6][CH:5]=1>O1CCCC1>[F:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[CH2:10][OH:11])=[CH:6][CH:5]=1
Reactant: CC(Oc1ccc(F)cc1)C(=O)O
Agent: B#B
Solvent: C1CCOC1
Product: CC(CO)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 95 ml. of diborane in 95 ml. of tetrahydrofuran was added 10.2 g. of 2-(4-fluorophenoxy)propionic acid in 100 ml. of tetrahydrofuran. The reaction mixture was stirred at room temperature for 20 hours. The solution was gradually poured onto 600 g. of ice and extracted (3×-250 ml each) with chloroform. The combined organic layer was extracted with water (3×-50 ml each) and dried. The solvent was removed under vacuum giving a clear liquid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([Cl:28])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:11]([CH:25]([F:27])[F:26])=[CH:10]2)(=O)=O.[CH3:31][N:32](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:28][C:8]1[C:7]([C:31]#[N:32])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([CH:25]([F:26])[F:27])[N:12]2[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])=[O:18]
Reactant: CN(C)C=O
Reactant: O=S(=O)(c1ccccc1)n1c(C(F)F)cc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(cc(C(F)F)n2S(=O)(=O)c2ccccc2)c1Cl
Temperature: 120 °C
Yield: 62 %

Procedure:
To a solution of 4-chloro-2-(difluoromethyl)-1-(phenylsulfonyl)-1H-indol-5-yl trifluoromethanesulfonate (0.75 g, 1.53 mmol) in anhydrous DMF (10 mL) under N2, was added Zn(CN)2 (0.093 g, 0.80 mmol) and Pd(PPh3)4 (0.088 g, 0.077 mmol) and the resulting mixture was heated at 120° C. for 2 h. Upon cooling, the mixture was partitioned between Et2O and water. The organic phase was washed with water. The combined aqueous phases were reextracted with Et2O. The combined organic phases were washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-40% EtOAc-hexanes gradient) to afford 4-chloro-2-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-5-carbonitrile (0.35 g, 62% yield) 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.8 Hz, 1H), 7.94 (d, J=7.8 Hz, 2H), 7.67-7.63 (m, 2H), 7.52 (t, J=7.8 Hz, 2H), 7.35 (t, J=54 Hz, 1H), 7.25 (s, 1H, overlapping CHCl3 signal); MS (ES) m/z 365 (M−1)) and 2-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-4,5-dicarbonitrile (0.054 g, 10% yield) (1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=8.8 Hz, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.8 Hz, 2H), 7.38 (t, J=54 Hz, 1H), 7.35 (s, 1H); MS (ES) m/z 356 (M−1)).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][CH:12]([OH:15])[CH2:13][NH2:14].C(N(CC)CC)C>C(O)C>[N+:8]([C:7]1[C:2]([NH:14][CH2:13][CH:12]([OH:15])[CH3:11])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(O)CN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(O)CNc1ncccc1[N+](=O)[O-]
Yield: 95.8 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (10.0 g, 0.063 mole), DL-1-amino-2-propanol (7.1 g, 0.095 mole), and triethylamine (8.75 ml, 0.063 mole) in absolute ethanol was heated at reflux for 11/2 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between water and methylene chloride. The water layer was separated and extracted with methylene chloride (2×). The combined methylene chloride layers were extracted with water and dried over sodium sulfate. The filtrate was evaporated to a yellow oil. The oil was purified on a silica gel column (200 g) eluting first with methylene chloride, followed by 5%, 10%, 25% (500 ml each), and finally 50% ethyl acetate/methylene chloride. The appropriate fractions (TLC using ethyl acetate) were combined and evaporated to an oil. A sample of the oil was dried at 50°-60° C., then at 70° C. for 6 hours to give 11.9 g (96%) of a yellow oil.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:14][S:15]([N:18]1[CH2:23][CH2:22][CH:21](OS(C)(=O)=O)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C(O)C.CO>[CH3:14][S:15]([N:18]1[CH2:23][CH2:22][CH:21]([S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)OC1CCN(S(C)(=O)=O)CC1
Reactant: Sc1cccc2nccn12
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)N1CCC(Sc2cccc3nccn23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (1.50 g, 10 moles) in ethanol (100 ml) was added a solution of 4.1M sodium methylate (2.44 ml, 10 mmoles) in methanol and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 1-methylsulfonyl-4-methylsulfonyloxypiperidine (2.83 g, 11 mmoles) at room temperature and the mixture was heated under reflux for 14 hours. After the solvent was distilled off, the residue was dissolved in chloroform, which was washed in turn with an aqueous 1N sodium hydroxide solution and water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent:ethyl acetate/ethanol (10:1)] to obtain 1.27 g of the desired product (40.8%, light brown solid).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[N:19]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])[N:19]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cccc(C(CC(=O)O)C4CC4)c3)nc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.3 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methoxy)phenyl)propanoate (131 mg) in THF (2.0 mL) and methanol (1.0 ml) was added 1N aqueous sodium hydroxide solution (2.0 ml), and the mixture was stirred at room temperature for 14 hr. 1N Hydrochloric acid (2.0 ml) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (124 mg) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([OH:14])=O.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[O:8][CH2:7][CH2:6]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: O=C(O)C1CCOc2ccc(F)cc21
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCOc3ccc(F)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 67.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-fluorochroman-4-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-6-fluoro-N-(4-isopropylphenyl)chroman-4-carboxamide (0.42 g) was obtained.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[Cu:5]>O.[Cl-].C([N+](CC)(CC)CC)C.CO>[C:1]([O-:4])(=[O:3])[CH3:2].[Cu+2:5].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: [Cu]
Reactant: CC(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(=O)[O-]
Product: [Cu+2]
Yield: 33.6 %

Procedure:
The same procedure was repeated in this reaction except that 9.0 g (0.150 mole) of acetic acid, 60 g methanol and 0.30 g of tetraethylammonium chloride hydrate were used. Copper foil was used as the anode and a graphite rod as the cathode. After passing 15.984 coulombs of electricity, 4.80 g (0.076 mole) of copper was consumed. The reaction solution was filtered to remove the metallic particles and the solvent was removed at reduced pressure. This gave a blue-greenish solid of copper acetate containing 33.6% copper.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:16]=[CH:17][C@H:18]([OH:29])[C@@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][CH2:17][C@H:18]([OH:29])[C@@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[OH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][CH2:17][C@H:18]([OH:29])[C@@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH3:20]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)C=Cc1ccc(F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1ccc(F)cc1O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1ccc(F)cc1OCc1ccccc1
Reaction time: 0.22 h
Yield: 45.5 %
Yield: 51.3 %

Procedure:
A mixture of (3S,4S)-1-(2-benzyloxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-1-penten-3-ol (2.62 g) and 10% Pd—C (0.52 g) in EtOAc (65 ml) was stirred under hydrogen atmosphere at atmospheric pressure for 13 min. Pd—C was removed by filtration and the filtrate was evaporated. The residual oil (2.38 g) was chromatographed over silica gel (30 g) eluting with a mixture of hexane and EtOAc (50:1 to 2:1) to give a colorless oil of (3S,4S)-1-(2-benzyloxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-3-pentanol (1.35 g, 51.3%) and (3S,4S)-1-(2-hydroxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-3-pentanol (0.94 g, 45.5%).
Reaction SMILES: Cl.N[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:11]3[C:12]4[CH2:13][C@H:14]([CH2:23][C:24]([NH2:26])=[O:25])[CH2:15][CH2:16][C:17]=4[S:18][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:5][CH2:4]1.C=O.[CH3:29]C(O)=O.[BH3-][C:34]#[N:35].[Na+]>CO>[CH3:29][N:35]([CH3:34])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:11]3[C:12]4[CH2:13][C@H:14]([CH2:23][C:24]([NH2:26])=[O:25])[CH2:15][CH2:16][C:17]=4[S:18][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)O
Reactant: NC(=O)C[C@@H]1CCc2sc3ncnc(OC4CCC(N)CC4)c3c2C1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)C[C@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl N-(4-[[(12R)-12-(carbamoylmethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (72 mg, 0.16 mmol, 1.00 equiv) in 5 mL of dichloromethane (5 mL) was added 6 M aqueous hydrochloric acid (0.5 mL) at 0° C. and the resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum to give 62 mg (crude) of 2-[(12R)-3-[(4-aminocyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetamide hydrochloride as a yellow solid. The crude hydrochloride in 4 mL of MeOH was added HCHO (37%, 1 mL) and 0.5 mL of HOAc at room temperature. Then NaCNBH3 (31 mg, 0.49 mmol, 2.54 equiv) was added and the resulting solution was stirred for 4 h at ambient temperature. The resulting mixture was filtered through a thin silica column and further purified by preparative HPLC under the following conditions (Waters): column: Xbridge Prep C18 5 um, 19*150 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (5.0% CH3CN up to 41.0% in 9 min, up to 95.0% in 2 min, down to 5.0% in 2 min); flow rate: 20 mL/min; UV detection at 220/254 nm. The product-containing fractions were collected and evaporated under reduced pressure to give the desired 2-[(12R)-3-[[4-(dimethylamino)cyclohexyl]oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetamide (13.8 mg) as a white solid. MS: 389 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.51 (s, 1H), 5.46-5.40 (m, 1H), 5.24-5.21 (m, 1H), 3.30-3.24 (m, 1H), 2.91 (m, 2H), 2.62-2.59 (m, 1H), 2.56-2.32 (m, 11H), 2.15-2.11 (m, 1H), 2.02-2.00 (m, 3H), 1.74-1.49 (m, 6H).