Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.S(Cl)([Cl:16])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:16][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-n2nccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(-n2nccn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50.58 g (289 mmol) of (4-[1,2,3]triazol-2-yl-phenyl)-methanol in 2000 ml of CH2Cl2, 31.59 ml (433 mmol) of thionyl chloride is added dropwise at 0-5° C. and the reaction mixture is allowed to warm to r.t. After stirring for 16 h, the reaction mixture is basified with sat. NaHCO3 at 0-5° C. and extracted with CH2Cl2. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C[O:23][CH:24]1[CH:28]([CH:29]=O)[CH2:27][CH:26](OC)O1.O>C(O)(=O)C>[CH:24]([C:28]1[CH:27]=[CH:26][N:1]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:17])[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]3)=[CH:4][C:3]=2[C:18]([F:21])([F:20])[F:19])[CH:29]=1)=[O:23]
Reactant: COC1CC(C=O)C(OC)O1
Reactant: CCOC(=O)C1Nc2cc(N)c(C(F)(F)F)cc2NC1=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1Nc2cc(-n3ccc(C=O)c3)c(C(F)(F)F)cc2NC1=O
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
To a solution of ethyl 7-amino-3-oxo-1,2,3,4-tetrahydro-6-trifluoromethylquinoxaline-2-carboxylate (3.60 g, 11.9 mmol) in acetic acid (60 ml) was added dropwise 2,5-dimethoxytetrahydrofuran-3-aldehyde (2.01 ml, 14.2 mmol) at 50° C., and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was poured into water (300 ml), which was extracted with ethyl acetate. After dried over anhydrous sodium sulfate, solvent was distilled off. Methylene chloride was added to the residue obtained and the crystals were collected by filtration. These were washed with methylene chloride and then air-dried to obtain 2.57 g of the title compound as yellow powder. The filtrate and the washings were combined, concentrated under reduced pressure, and purified by means of silica gel column chromatography [ethyl acetate-hexane=2:1] to obtain further 973 mg. Total yield by weight 3.54 g. Yield 78%.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([Br:8])[CH2:5][CH2:6][Br:7].[CH3:10][NH2:11]>>[CH3:10][NH:11][C:3](=[O:2])[CH:4]([Br:8])[CH2:5][CH2:6][Br:7]
Reactant: COC(=O)C(Br)CCBr
Reactant: CN
Product: CNC(=O)C(Br)CCBr

Procedure:
In a second step of the reaction, the methyl-2,4-dibromobutyrate is reacted with methylamine in an aqueous solution at a temperature of below ambient in order to form N-methyl-2,4-dibromobutyramide. Then butyramide is then recovered and purified to obtain the solid intermediate product.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[C:11]([CH3:16])[CH:12]=2)[C:7]1=[O:18])[CH3:4].[C:19]1([N:25]2[C:29]3([CH2:34]CNC[CH2:30]3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([N:25]2[C:29]3([CH2:30][CH2:2][N:3]([CH2:5][CH:6]4[CH2:15][CH2:14][C:13]5[C:8](=[CH:9][C:10]([CH3:17])=[C:11]([CH3:16])[CH:12]=5)[C:7]4=[O:18])[CH2:4][CH2:34]3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: Cc1cc2c(cc1C)C(=O)C(CN(C)C)CC2
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(cc1C)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Reaction time: 14 h
Yield: 80.6 %

Procedure:
A mixture of 14.0 g of 2-[(dimethylamino)methyl]-3,4-dihydro-6,7-dimethyl-1(2H)-naphthalenone, hydrochloride, 13.1 g of 92% 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one and 250 ml of absolute ethanol is warmed on a steam bath for 1 hour and then stirred vigorously for 14 hours. The resulting precipitates are collected and washed with absolute ethanol to give 17.6 g of the title compound, melting point 182°-183° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH:17]1([CH2:20][C:21]2[C:26]([CH2:27]O)=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=[C:23]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=3)[N:22]=2)[CH2:19][CH2:18]1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:27][C:26]3[C:21]([CH2:20][CH:17]4[CH2:19][CH2:18]4)=[N:22][C:23]([C:33]4[CH:34]=[CH:35][C:36]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=4)=[CH:24][C:25]=3[C:29]([F:30])([F:32])[F:31])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCc1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1CC1CC1
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc3CC3CC3)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [2-cyclopropylmethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[NH3:13]>>[NH2:13][C:6]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: COc1cc(F)c(C#N)c(F)c1
Reactant: N
Product: COc1cc(N)c(C#N)c(F)c1
Temperature: 140 °C

Procedure:
2,6-Difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (200 mg, 1.18 mmol) was dissolved in ethanolic ammonia (2M solution, 10 ml) and the mixture was heated at 140° C. in an autoclave for 16 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate in pentane as eluant (20:80) to give the title compound as a white solid (165 mg). LRMS: m/z (ES+) 189 [MNa+]
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[C:39]([CH2:41]O)[CH:38]=[CH:37][N:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[NH2:34][C:35]1[CH:40]=[C:39]([CH2:41][O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:38]=[CH:37][N:36]=1
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Reactant: Nc1cc(CO)ccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 4-nitronaphthol (5.17 g, 27.3 mmol), triphenylphosphine (10.75 g, 41.0 mmol) and 2-aminopyridine-4-methanol (2) (5.09 g, 41.0 mmol) in THF (50 mL), at −15° C., was added dropwise diisopropyl azodicarboxylate (DIAD) (8.07 mL, 41.0 mmol). The mixture was stirred overnight at RT and the volatiles then removed in vacuo. The crude product was triturated from EtOAc (150 mL), filtered off and washed with EtOAc (100 mL). A second trituration from MeOH (100 mL) gave 2-amino-4-[(4-nitronaphthalen-1-yloxy)methyl]pyridine (3) (4.54 g, 56%) as a yellow solid: m/z 296 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:11]=[C:10](Br)[S:9][C:8]=1[O:13][CH3:14].CI>C1COCC1>[Br:6][C:7]1[CH:11]=[C:10]([CH3:1])[S:9][C:8]=1[O:13][CH3:14]
Reactant: [Li]CCCC
Reactant: COc1sc(Br)cc1Br
Solvent: CI
Solvent: C1CCOC1
Product: COc1sc(C)cc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (2.0M in pentane, 0.97 mL, 1.93 mmol) was added to a stirred solution of 3,5-dibromo-2-methoxythiophene (Step A, 500 mg, 1.84 mmol) in THF (5 mL) at −78° C. under an atmosphere of N2. The reaction stirred at −78° C. for 1 h prior to addition of methyl iodide (114 μL, 1.84 mmol). The reaction was allowed to warm to room temperature and stirred for 20 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (15 mL0 and H2O (15 mL). The aqueous layer was re-extracted with ether (2×15 mL) and the combined organic layers were washed with H2O (15 mL) and brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (hexanes) to afford 3-bromo-2-methoxy-5-methylthiophene as a yellow oil. 1H NMR (CDCl3, 500 MHz): δ 6.44 (s, 1 H), 3.95 (s, 3 H), 2.41 (s, 3 H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(Cl)Cl>O>[CH:1]([C:4]1[CH:10]=[CH:9][C:7](/[N:8]=[CH:17]/[C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:21])[F:22])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)c1ccc(N)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)c1ccc(/N=C/c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
4-Isopropylaniline (5.5 ml, 40.2 mmol) was added to a vigorously stirred mixture of 4-(trifluoromethyl)benzaldehyde (5.5 ml, 40.2 mmol) in H2O (60 ml) at room temperature. After 2 hours, DCM (100 ml) was added and the mixture was stirred for 20 minutes. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated to give the imine (11.6 g, 99%) as a beige solid. 1H NMR (360 MHz, CDCl3) δ: 1.28 (6H, d, J 6.9), 2.95 (1H, septet, J 6.9), 7.18-7.21 (2H, m), 7.25-7.29 (2H, m), 7.71-7.73 (2H, m), 8.00-8.02 (2H, m), 8.52 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([NH:21][CH2:34][C:30]3[O:29][CH:33]=[CH:32][CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1ccco1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(N)ccc2F)COC1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(NCc3ccco3)ccc2F)COC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of [5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (77.5 mg, 0.240 mmol) and NaOAc (59.0 mg, 0.719 mmol) in MeOH (1 ml) was added 2-furaldehyde (0.020 ml, 23.0 mg, 0.240 mmol). The reaction mixture was degassed with Ar and stirred for 15 min at 100° C. in a microwave. After cooling to 0° C., NaBH4 (10.02 mg, 0.252 mmol) was added portionwise and stirring was continued at rt for 1 h. The reaction mixture was quenched with water and diluted with EtOAc. The phases were separated and the aq. layer was twice reextracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting title compound was purified by FC (cyclohexane:EtOAc 100:0 to 80:20).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:3][N:1]=[C:4]3[CH:5]=[CH:6][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:8][C:9]=23)=[CH:25][CH:24]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(F)cc4)c3c2)cc1

Procedure:
The title compound, light grey solid (50 mg, 38%), MS (ISP) m/z=370.2 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1 p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:16])=O)=[CH:10]2)[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCCC1>[CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14](=[S:37])[NH2:16])=[CH:10]2)[CH3:3]
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=S)[nH]c12
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 117.6 %

Procedure:
To a solution of 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (700 mg) in tetrahydrofuran (40 mL) was added Lawesson's reagent (729 mg) and the mixture was stirred at 60° C. for 40 min. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95 to 50/50, volume ratio) to give the title compound (857 mg, 100%) as a yellow amorphous solid. MS 405 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][C:9]=2[O:19][CH3:20])=[CH:6][CH:7]=1.[Si:21]([O:28][C@H:29]([C@H:31]1[NH:36][C:35]([CH3:38])([CH3:37])[CH2:34][CH:33]([OH:39])[CH2:32]1)[CH3:30])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CC(C)([O-])C.[K+]>CN(C=O)C>[Si:21]([O:28][C@H:29]([C@H:31]1[NH:36][C:35]([CH3:38])([CH3:37])[CH2:34][CH:33]([O:39][C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[N:15]4)=[CH:10][C:9]=3[O:19][CH3:20])=[CH:6][CH:7]=2)[CH2:32]1)[CH3:30])([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22]
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CC(O)CC(C)(C)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-n2cccn2)ccc1-c1ccc(OC2C[C@@H]([C@H](C)O[Si](C)(C)C(C)(C)C)NC(C)(C)C2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 3-chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate 2-1 (32 mg, 0.11 mmol) and (6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-ol (Intermediate 4-1, 32 mg, 0.11 mmol) in DMF (1 mL) was added potassium tert-butoxide (1 M in THF, 0.45 mL, 0.45 mmol) at 0° C. The reaction mixture was stirred for 1 h at RT. The mixture was then quenched with saturated ammonium chloride solution (10 mL) and extracted with 10% MeOH in dichloromethane (20 mL). The extract was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to afford 56 mg (94%) of 3-((6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-yloxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine: LCMS (m/z, MH+): 538.5; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.05 (d, J=8.1 Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 6.94 (d, J=9.1 Hz, 1H), 6.54-6.47 (m, 1H), 5.79-5.87 (m, 1H), 3.96 (s, 3H), 3.83-3.93 (m, 1H), 3.07-3.17 (m, 1H), 2.13-2.22 (m, 1H), 2.05-2.12 (m, 1H), 1.43-1.57 (m, 2H), 1.27 (s, 3H), 1.16 (d, J=6.6 Hz, 3H), 1.14 (s, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[H][H]>CO>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]([OH:11])[CH2:3][CH2:2]1
Reactant: O=C1CCOc2ccccc21
Reactant: [H][H]
Solvent: CO
Product: O[C@@H]1CCOc2ccccc21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
In a 50-ml autoclave, 3.3 mg (0.005 mmol, S/C=1000) of RuCl(R,R)—O-HT-Tsdpen) was placed, and the autoclave was purged with nitrogen. Subsequently, 0.74 g (5.0 mmol) of 4-chromanone and 4.4 ml of methanol were added thereto, and the pressure was raised with hydrogen up to 3.0 MPa. Subsequently, the mixture was stirred for 18 hours at 60° C. The reaction liquid was subjected to a GC analysis, and as a result, (R)-4-chromanol was obtained at a conversion rate of 98.6% with an optical purity of 99.1% ee.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][S:9][C:8]=2[CH:20]=1)([O-])=O.O.NN>CO.[Ni]>[N:15]1([CH2:14][CH2:13][N:12]2[CH2:11][CH2:10][S:9][C:8]3[CH:20]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCN1CCCC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)SCCN2CCN1CCCC1
Temperature: 25 °C
Yield: 106.6 %

Procedure:
To a solution of 7-nitro-4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.637 g, 2.172 mmol) in MeOH (30 mL) was added Raney-Nickel (slurry in water) (˜30 mg, 2.172 mmol) followed by hydrazine hydrate (1.056 mL, 21.72 mmol), and the mixture was immersed in a preheated oil bath and refluxed for 1 hour. The solution was cooled to room temperature, filtered through a pad of Celite, and washed with 100 mL of MeOH. The crude material was filtered through a silica plug (3.5-10% 2M NH3 in MeOH/CH2Cl2). The solvent was evaporated to give the title product as a dark brown oil (0.61 g, quantitative). 1H NMR (DMSO-d6) δ 6.49 (d, J=8.7 Hz, 1H), 6.26-6.23 (m, 2H), 4.42 (brs, 2H), 3.38-3.35 (m, 2H), 3.21 (t, J=7.2 Hz, 2H), 2.97-2.94 (m, 2H), 2.55 (t, J=7.2 Hz, 2H), 2.45 (brs, 4H), 1.66 (brs, 4H); ESI-MS (m/z, %): 266, 264 (MH+, 100), 98 (34).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:11][C:7]=2[C:6]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccccc2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccccc1
Product: COc1ccc(Oc2ccccc2)c2sc(NC(=O)c3ccccc3)nc12

Procedure:
Using 4-Methoxy-7-phenoxy-benzothiazol-2-ylamine and benzoyl chloride the title compound was obtained crude, which was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/EtOAc (1:1), to afford the pure title compound as a white solid (72% yield), MS: m/e=376.1 (M+).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>O1CCCC1.[OH-].[Na+]>[CH2:21]([O:28][C:29]([NH:4][C:2]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)=[NH:3])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCCOc1ccc(C(=N)N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCOc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 5-(4-amidinophenoxy)valerate hydrochloride (14.6 g) in a mixture of tetrahydrofuran (150 ml) and 1N sodium hydroxide solution was added benzyloxycarbonyl chloride (10.4 ml) under cooling with ice-water for 1 hour. The mixture was stirred for 2 hours at 10° C. maintaining pH≈10 with 1N sodium hydroxide solution. The reaction mixture was poured into ethyl acetate (300 ml), and separated organic layer was washed with aqueous solution of sodium chloride, and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the resulting precipitate was washed with diethyl ether to give ethyl 5-[4-(N-benzyloxycarbonylamidino)phenoxy]valerate (171.48 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12]>>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCCN
Reactant: Clc1cnccn1
Product: NCCCNc1cnccn1

Procedure:
Reacting 2-chloropyrazine with 1,3-diaminopropane by the procedure of Example 93 gives 2-(3-aminopropylamino)-pyrazine and reacting this intermediate with methyl isothiocyanate gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C>[Si:22]([O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=3)[O:9][C:10]=2[CH:16]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(-c2nc3ccc(O)cc3o2)cn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2nc(-c3ccc(N)nc3)oc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 345.6 %

Procedure:
To a solution of 2-(6-aminopyridin-3-yl)-1,3-benzoxazol-6-ol (0.95 mmol) in DMF (25 mL) was added tert-butylchlorodimethylsilane (1.05 mmol) and imidazole (2.38 mmol), the resulting mixture was stirred at room temperature for 3 hours. LCMS showed no conversion. Additional tert-butylchlorodimethylsilane (1.05 mmol) and imidazole (2.38 mmol) was added to the reaction mixture, then stirred at room temperature overnight. The reaction mixture was then partitioned between EtOAc (100 mL) and water (250 mL), and the aqueous layer was extracted twice with EtOAc (100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered and evaporated to give 1.121 g of a yellow solid. Purified by flash column chromatography (SiO2, Heptane:EtOAc 0→100%), to give the title compound (322.5 mg) as an ivory-white solid. 1H NMR δ ppm 8.67 (d, 1H) 8.01 (dd, 1H) 7.54 (d, 1H) 7.18 (d, 1H) 6.85 (dd, 1H) 6.77 (s, 2H) 6.57 (d, 1H) 0.97 (s, 9H) 0.22 (s, 6H); MS m/z 342 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[CH2:10]([NH2:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(OCC)(=O)C>[OH:6][CH2:7][CH2:8][N:4]1[CH2:3][CH2:2][N:18]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]1=[O:9]
Reactant: O=C1OCCN1CCCl
Reactant: CCCCCCCCN
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CCN(CCO)C1=O
Reaction time: 8 h
Yield: 83 %

Procedure:
7.1 g of 3-(2-chloroethyl)oxazolidin-2-one was treated with 12.271 g of octyl amine. The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and brine. The organic solution was dried and concentrated to give 9.55 g (83%) of product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].CS(O[CH2:23][CH2:24][CH:25]=[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH2:29][C:28]2[CH:37]=[CH:38][CH:39]=[CH:40][C:27]1=2)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:12]2[CH2:13][CH2:14][N:15]([CH2:23][CH2:24][CH:25]=[C:26]3[C:27]4[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=4[CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]3=4)[CH2:16][CH2:17]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)OCCC=C1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)c1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1N1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A mixture of 2-(1-piperazinyl)-3-pyridinecarboxylic acid ethyl ester (4.6 g, 0.019 mol), 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl methanesulfonate (5.0 g, 0.015 mol) and potassium carbonate (4.8 g) in N,N-dimethylformamide (50 ml) was heated to 60° C. for 5 h. After standing overnight, the solid was filtered off and washed with benzene. The filtrate was diluted with benzene (200 ml) and washed with water (4×100 ml). The organic solution was dried (MgSO4) and the solvent evaporated in vacuo. The residue (7.8 g) was purified by column chromatography on silica gel using benzene and a benzene-ethyl acetate mixture as eluents, affording 2-(4-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-1-piperazinyl)-3-pyridinecarboxylic acid ethyl ester (3.4 g, 48%) as an oil.