Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]=O)=[N:4][CH:5]=[C:6]([N:8]([CH3:12])[CH:9]([CH3:11])[CH3:10])[N:7]=1.[CH2:15]([NH:22][CH2:23][C@@H:24]([OH:28])[CH2:25][O:26][CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:15]([N:22]([CH2:13][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH3:12])[CH:9]([CH3:10])[CH3:11])=[CH:5][N:4]=1)[CH2:23][C@@H:24]([OH:28])[CH2:25][O:26][CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)N(C)c1cnc(C=O)c(Cl)n1
Reactant: COC[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC[C@H](O)CN(Cc1ccccc1)Cc1ncc(N(C)C(C)C)nc1Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 62.7 %

Procedure:
To a solution of 3-chloro-5-[methyl(1-methylethyl)amino]pyrazine-2-carbaldehyde (321 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (351 mg) and acetic acid (258 μL) in acetonitrile (5 mL) was added sodium triacetoxyborohydride (477 mg), and the mixture was stirred at room temperature for 5.5 hr. To the reaction mixture was added dropwise saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (370 mg, 70%).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Cl.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[CH3:23][O:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][C:15]1[C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=[CH:2][CH:16]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccccc1OCCCCl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: COc1ccccc1OCCCc1cccc2onc(C3CCNCC3)c12
Temperature: 90 °C

Procedure:
A stirred mixture of 6-fluoro-(4-piperidinyl)-1,2-benzisoxazole (2.45 g; 11.1 mmol), K2CO3 (2.0 g), and 3-(2-methoxyphenoxy)propyl chloride (3.5 g, 17.4 mmol) in acetonitrile (40 ml) was heated at 90° C. for 4 hours. At the end of the reaction, the solvent was removed, and the solids were dissolved into dichloromethane (100 ml). The solution was washed with water and brine, then dried over MgSO4. The crude material from the solution was combined with 1.2 g of crude material prepared in the same fashion (using 0.5 g of starting material). The combined material was purified by flash chromatography on a silica gel column (49 g, eluted with 0.5% diethylamine: 1% methanol:98.5% dichloromethane, 1 L). The fractions containing the pure product were pooled and concentrated down to a light oil (3.68 g). This oil was treated with fumaric acid (1.14 g, 9.8 mmol) in ethanol (13 ml). The 6fluoro-3-[1-[3-(2-methoxyphenoxy)propyl[-4piperidinyl]-1,2-benzisoxazole fumarate crystals obtained weighed 4.01 g (60%), m.p.=169-170° C.
Reaction SMILES: C(OC([N:11]1[C@H:33]([CH2:34][OH:35])[C@@H:24]([O:25]CC2C=CC=CC=2)[C@H:22]([OH:23])[C@@H:13]([O:14]CC2C=CC=CC=2)[CH2:12]1)=O)C1C=CC=CC=1.C(OCC)C>C(O)(=O)C.[Pd]>[NH:11]1[C@H:33]([CH2:34][OH:35])[C@@H:24]([OH:25])[C@H:22]([OH:23])[C@@H:13]([OH:14])[CH2:12]1
Reactant: O=C(OCc1ccccc1)N1C[C@H](OCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1CO
Agent: [Pd]
Solvent: CCOCC
Solvent: CC(=O)O
Product: OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O
Yield: 96 %

Procedure:
The diol (17) (580 mg, 1.2 mmol) was stirred in glacial acetic acid (30 ml) in the presence of palladium black (100 mg) under hydrogen for 3 days, by which time no starting material (Rf 0.2) remained by t.l.c. (diethyl ether). Filtration and removal of the solvent then gave a gum which was purified by ion exchange chromatography with Dowex 50(H+) followed by Amberlite CG-400(Cl-) resins to give 1,5-dideoxy-1,5-imino-D-glucitol (3) (188 mg, 95%), which was crystallized as its hydrochloride salt. m.p. 204°-205° C. (lit.* 203°-206° C.). All spectroscopic data were identical to that of authentic material. --C NMR (D2O) free base δ: 79.0, 72.1, 71.1 (3d, C-2, C-3, C-4), 61.9 (t, C-6), 61.0 (d, C-5), 49.2 (t, C-1). Hydrogen chloride salt δ: 77.1, 68.6, 67.8 (3d, C-2, C-3, C-4), 60.8 (d, C-5), 58.5 (t, C-6), 46.7 (t, C-1). [*Fleet et al., Tetrahedron 43, 979 (1987)].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:19])[C:11]3[C:16]([CH:17]=2)=[C:15]([CH3:18])[CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20]#[N:21])=[CH:3][CH:4]=1)[NH:9][C:10]2=[O:19]
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(Br)cc3)cc12
Reactant: CN(C)C=O
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: Cc1cccc2c(=O)[nH]c(-c3ccc(C#N)cc3)cc12
Yield: 79 %

Procedure:
3-(4-Bromo-phenyl)-5-methyl-2H-isoquinolin-1-one (200 mg, 0.64 mmol), zinc cyanide (90 mg, 0.76 mmol) and tetrakis(triphenylphosphine)palladium(0) (74 mg, 0.064 mmol) were stirred in DMF (2.1 mL) and degassed with N2. The reaction mixtures were irradiated using a microwave (300 W, 180° C., 30 min). The reaction mixtures were combined and the resulting precipitate was filtered, washed with DMF and water and dried to give 4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzonitrile as a yellowish solid (718 mg, 79%) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:26])([CH3:25])[CH2:20][S:21](O)(=[O:23])=[O:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)([Cl:29])=O>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]([CH3:26])([CH3:25])[CH2:20][S:21]([Cl:29])(=[O:23])=[O:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(CS(=O)(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: CC(C)(CS(=O)(=O)Cl)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
(2-Chlorosulfonyl-1,1-dimethyl-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester was prepared by an analogous procedure as described in example 26v) starting from 457 mg (1.2 mmol) 2-(9H-fluoren-9-ylmethoxycarbonylamino)-2-methyl-propane-1-sulfonic acid and 2.3 ml (3.6 equiv.) phosgene (20% in toluene). (2-Chlorosulfonyl-1,1-dimethyl-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester was obtained in crude form as a colorless oil. Yield: 503 mg
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:3]1.[NH4+].[OH-]>[Rh].CCO>[NH2:11][CH2:10][C:9]1[CH:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]2)[CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cccc(N2CC[C@@H](O)C2)c1
Agent: [Rh]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCc1cccc(N2CC[C@@H](O)C2)c1
Reaction time: 48 h
Yield: 871.6 %

Procedure:
To 3-[(3R)-3-hydroxypyrrolidin-1-yl]benzonitrile (0.070 g, 0.37 mmol) and 5% rhodium on alumina (15 mg) in abs EtOH (5 mL) was added NH4OH (26%, 1 mL). The resulting mixture was stirred under H2 over night. A second portion of 5% rhodium on alumina (30 mg) was added and the stirring under H2 continued for 2 days. The mixture was filtered through Celite and concentrated to give 0.62 g (69%) of the title compound (purity ˜80%). 1H NMR (400 MHz, CD3OD) δ 7.10 (dd, 1H, J=8.1, 7.6 Hz), 6.56 (d, 1H, J=7.6 Hz), 6.51 (s, 1H), 6.42 (dd, 1H, J=8.1, 2.0 Hz), 4.47 (m, 1H), 3.69 (s, 1H), 3.47-3.36 (m, 2H), 3.32-3.24 (m, 1H), 3.17 (bd, 1H, J=9-7 Hz), 2.15-1.93 (m, 2H). 13C NMR (MeOH-d4) δ 149.7, 143.4, 130.3, 115.8, 111.8, 111.7, 71.7, 57.0, 46.9, 46.7, 34.9.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][C:8]([CH2:10][CH:3]1[CH2:4][CH2:5]2)=[O:9].ClC(O[CH2:15][CH2:16]Cl)=O.O>C(Cl)(Cl)Cl>[CH2:1]([N:2]1[CH:6]2[CH2:5][CH2:4][CH:3]1[CH2:10][C:8](=[O:9])[CH2:7]2)[C:16]1[CH:15]=[CH:5][CH:4]=[CH:3][CH:10]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: O=C(Cl)OCCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
25 g of tropinone was dissolved in 100 mL of chloroform, and 50 mL of chloroethyl chloroformate was added thereto and stirred at room temperature for 6 hours. The reaction liquid was concentrated, 100 mL of methanol was added thereto, and heated overnight under reflux. The reaction liquid was cooled to room temperature and concentrated, and the resulting crude product was dissolved in 80 mL of N-methylpyrrolidone. 43 mL of benzyl bromide and 99 g of potassium carbonate were added thereto and stirred overnight at room temperature. The reaction liquid was poured into water, and extracted three times with ethyl acetate. The organic layer was washed with water and saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure to obtain 29.5 g of the entitled compound as a pale yellow liquid.
Reaction SMILES: [CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]2[CH2:18][C:17]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:16]=2[Cl:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC1(C)NN(C2CCCCCC2)C1=O
Reactant: Clc1ccc(Cl)c(CBr)c1
Product: CC1(C)C(=O)N(C2CCCCCC2)N1Cc1cc(Cl)ccc1Cl

Procedure:
2-Cycloheptyl-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[CH:8]=[C:7]([NH2:23])[C:6]=1[NH2:24].[NH:30]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[N:31]1>>[F:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[C:6]2[N:24]=[C:35]([C:32]3[CH:33]=[CH:34][NH:30][N:31]=3)[NH:23][C:7]=2[CH:8]=[C:9]([O:11][C:12]2[CH:13]=[N:14][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[CH:10]=1
Reactant: O=Cc1cc[nH]n1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(N)c(N)c(Oc3c(F)cccc3F)c2)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Oc3c(F)cccc3F)c3nc(-c4cc[nH]n4)[nH]c3c2)cn1

Procedure:
The entitled compound was obtained in the same method as in Example 202 or in accordance with the method or by combining it with an ordinary method but using 3-(2,6-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 268 and 1H-pyrazole-3-carboxaldehyde.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[S].[OH-].[Na+].[SH2:23]>>[CH2:10]([C:18]1[C:13]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[S:23][C:14]2([OH:19])[CH:15]=[CH:16][CH:17]=1)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:13][CH3:14]
Reactant: S
Reactant: CCCCCCCCCCCCc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Agent: [S]
Product: CCCCCCCCCCCCC1=CC=CC2(O)SC12CCCCCCCCCCCC

Procedure:
A mixture of dodecyl phenol (1.0m., 262g.), sulphur (1.0m., 32g.) and caustic soda (8g.) was heated, with stirring, under nitrogen, at 160° C until the evolution of hydrogen sulphide ceased (42 hrs.). The caustic soda was neutralized with 10 ml. of phosphoric acid (SG = 1.75) and the mixture was then filtered. %S of Product = 5.85 (calc. = 5.8).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:30][CH3:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:17]=[C:16]([N:35]3[CH2:36][CH2:37][N:32]([CH2:29][CH2:30][CH3:31])[CH2:33][CH2:34]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(Cl)n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCCN1CCN(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)CC1

Procedure:
Heat a solution of 4-[2-chloro-6-(3-chloro-4-fluoro-phenyl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 5.9 mmol), N-propylpiperazine (5.9 mmol) and DIEA (11.7 mmol) in DMA at 100° C. for 16 h. Cool, partition between 10% NaOH and EtOAc and wash the organic layer with additional NaOH solution (3×). Dry the organic layer (Na2SO4) and concentrate under reduced pressure to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])=O.[K]>>[F:18][C:15]1[CH:14]=[C:3]([CH2:4][C:6]2[C:7]([F:13])=[CH:8][CH:9]=[CH:10][C:11]=2[F:12])[C:2](=[CH:17][CH:16]=1)[NH2:1]
Reactant: Nc1ccc(F)cc1C(=O)c1c(F)cccc1F
Agent: [K]
Product: Nc1ccc(F)cc1Cc1c(F)cccc1F

Procedure:
In the manner given in Preparation 11, 2-amino-2',5,6'-trifluorobenzophenone is refluxed with potassium hydroxidein diethylene glycol to give 4-fluoro-α-(2,6-difluorophenyl)-o-toluidene.
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH2:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]1=2)(=[O:3])[CH3:2].[CH3:24][CH:25]([C:29]([NH:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[O:30])[C:26](O)=[O:27]>>[C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:26](=[O:27])[CH:25]([CH3:24])[C:29]([NH:31][CH2:32][C:33]([F:38])([F:39])[C:34]([F:35])([F:36])[F:37])=[O:30])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@H](N)C(=O)N(Cc2ccccc2)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CC(=O)N1C[C@H](NC(=O)C(C)C(=O)NCC(F)(F)C(F)(F)F)C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-1-benzyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a white solid; MS: m/e=539 (M−H)−.
Reaction SMILES: [C:1]1(=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[ClH:41]>ClC(Cl)C.C(OCC)C>[ClH:41].[CH2:33]([NH:40][CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCCc2c1[nH]c1ccccc21
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: c1ccc(CNC2CCCc3c2[nH]c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution of 2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.52 mmol) in dichloroethane (5 mL) was added sodium triacetoxyborohydride (0.17 g, 0.80 mmol), acetic acid (0.046 mL, 0.80 mmol) and benzyl amine (0.087 mL, 0.80 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched by adding saturated NaHCO3 (5 mL) and EtOAc (5 mL) and stirred for 30 minutes. The layers were separated, the aqueous layer extracted with EtOAc (2×5 mL), the organic layers combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by silica gel chromatography with hexanes/ethyl acetate as the eluant to afford yellowish oil. The compound was dissolved in diethyl ether and a solution of HCl in diethyl ethyl ether was added to yield a white precipitate was upon evaporation. Recrystallization from methanol/diethyl ether afforded a white solid (42 mg, 35%). 1H-NMR (DMSO-ds): δ 11.2 (s, 1H), 9.70 (s, 1H), 9.58 (s, 1H), 7.64 (d, 2H), 7.43 (m, 5H), 7.14 (t, 1H), 7.02 (t, 1H), 4.67 (s, 1H), 4.29 (s, 2H), 2.71 (m, 2H), 2.22 (m, 2H), 2.08 (m, 1H), 1.82(m, 1H); 13C-NMR (CDCl3): δ 140.7, 136.2, 135.7, 128.5, 128.1, 127.5, 127.1, 121.5, 119.0, 118.3, 111.2, 110.8, 51.9, 50.4, 30.5, 21.8, 21.0; MS m/z 277 (M).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:29]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
5 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 3.7 g of 4-methoxyphenylhydrazine hydrochloride and 3 ml of triethylamine are boiled under reflux for 2 h in 75 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 179-181° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 40 mg, 1.0 mmol) in 2.0 mL of DMF at room temperature was added 1-amino-2-(isopropylsulphonyl)benzene (0.20 g, 1.0 mmol) as a solid in 3 portions. After 30 minutes of stirring at room temperature, 2,4-dichloropyrimidine (0.15 g, 1.0 mmol) was added as a solution in 1.0 mL DMF. The reaction mixture stirred for 3 h at room temperature. The reaction was quenched with saturated sodium bicarbonate solution and the solution extracted ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-30% ethyl acetate:heptane) to afford the desired compound as an off-white solid (53 mg, 17% yield). MS/ES+: m/z=312.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][S:17]([O-:20])(=[O:19])=[O:18].[C:21]1([I+]C2C=CC=CC=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1.ClC1C=CC=CC=1>[CH3:15][O:16][S:17]([O-:20])(=[O:19])=[O:18].[C:21]1([S+:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: c1ccc2c(c1)Oc1ccccc1S2
Agent: [Cu+2]
Agent: COS(=O)(=O)[O-]
Agent: O=C([O-])c1ccccc1
Solvent: Clc1ccccc1
Product: c1ccc([S+]2c3ccccc3Oc3ccccc32)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of 20 g of phenoxathiin, 43.1 g of diphenyliodonium methylsulfate, 0.9 g of copper(II) benzoate, and 210 g of chlorobenzene was heated and stirred at 120° C. for 3 hours. The reaction solution was cooled to room temperature and combined with 20 g of diisopropyl ether for crystallization. The solid was dried under reduced pressure, obtaining the target compound, 10-phenyl-10-phenoxathiinium methylsulfate. Amount 24.7 g, yield 63%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]([C@@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CCOC(C)=O.CCCCCC.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C@H:20]1[CH2:21][CH2:22][C@H:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:18][CH2:19]1)[CH:6]=[CH:5]2
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: Oc1ccc2cc(Br)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3n2)CC1

Procedure:
The mixture of 6-bromo-quinolin-2-ol (1.00 g, 0.00446 mol), cis-4-tert-butylcyclohexanol (0.837 g, 0.00536 mol), and triphenylphosphine (1.405 g, 0.005356 mol) in toluene (9.508 mL, 0.08926 mol) was heated to reflux, and diisopropyl azodicarboxylate (1.054 mL, 0.005356 mol) was added dropwise and was stirred at reflux for 6 hours. The mixture was taken up into methylene chloride and subjected to chromatography with EtOAc/hexane (0:100 to 40:60) to give 6-bromo-2-(trans-4-tert-butylcyclohexyloxy)quinoline as a white solid (0.581 g, 36%). LCMS: Rf=2.82 min (362.38, [M]+, 100%).
Reaction SMILES: [SiH3]O[SiH3].[CH:4]1([O:7][C:8]2[CH:9]=[C:10]([CH2:18][O:19][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:6][CH2:5]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:4]1([O:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[CH2:18][OH:19])[CH2:5][CH2:6]1
Reactant: CC(C)[Si](OCc1ccc(OC(F)F)c(OC2CC2)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [SiH3]O[SiH3]
Solvent: C1CCOC1
Product: OCc1ccc(OC(F)F)c(OC2CC2)c1
Reaction time: 17 h

Procedure:
To a solution of the silyl ether, 3-Cyclopropyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene, from Step 4 (70 g, 179 mmol) in TBF (700 mL) at room temperature was added TBAF (215 mL of a 1M solution in THF, 215 mmol) and the resulting mixture was stirred for 17 h. The mixture was partitioned between 25% aq. NH4OAc (500 mL) and ethyl acetate (1 L) and the aqueous layer was extracted with ethyl acetate (2×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 3:2 to 1:1) provided the 3-Cyclopropyloxy-4-difluoromethoxybenzyl alcohol compound (41 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([OH:18])[CH3:17])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: CC(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 79.7 %

Procedure:
In dry MC, dissolved was 1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]ethanol (24 g, 93 mmol), and PCC (pyridinium chlorochromate) (30 g, 139 mmol) was added thereto. The resultant mixture was heated under reflux. The reaction mixture was filtered through Celite, and the filtrate was extracted with EA, washed twice with brine, dried over MgSO4 and filtered. After removing the solvent by evaporation under reduced pressure, the mixture was purified via column chromatography (n-hexane/MC=7/1) to obtain 1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]ethanone (19 g, 91%).