Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][CH:34]2[C:38]3=[N:39][CH:40]=[CH:41][CH:42]=[C:37]3[CH2:36][CH:35]2[CH2:43][CH3:44])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][CH:34]2[C:38]3=[N:39][CH:40]=[CH:41][CH:42]=[C:37]3[CH2:36][CH:35]2[CH2:43][CH3:44])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2c3ncccc3CC2CC)n1
Product: CCc1nc(NC2c3ncccc3CC2CC)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.43, 7.62, 7.19, 5.37, 5.28, 3.11, 3.08, 2.87–2.69, 1.41–1.26, 0.86; HRMS (FAB) calcd for C18H23BrN4+H 375.1185, found 375.1189.
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6][O:7]CC.[CH3:10][N:11]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][S:20][C:14]=2[CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1.O.[OH-].[Na+].[Cl:30]CCl>C(OC(=O)C)(=O)C.C(O)C>[ClH:30].[C:6]([C:19]1[S:20][C:14]2[CH:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][N:11]([CH3:10])[CH2:17][CH2:16][C:15]=2[CH:18]=1)(=[O:7])[CH3:5]
Reactant: ClCCl
Reactant: CCOCC
Reactant: CN1CCc2ccsc2C(c2ccccc2)C1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc2c(s1)C(c1ccccc1)CN(C)CC2
Product: Cl
Reaction time: 16 h

Procedure:
Boron trifluoride etherate (0.69 ml) was added dropwise to a stirred solution of 6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (0.46 g) in acetic anhydride (5 ml) at room temperature. After 16 hours, water (30 ml) and dichloromethane (30 ml) were added and the stirred mixture basified to pH~10 with 2M sodium hydroxide. This was extracted with dichloromethane (2×30 ml) and the extracts were dried, filtered and evaporated to a brown oil. Chromatography on silica eluting with 2% methanol in dichloromethane gave a yellow oil. This was dissolved in ethanol and ethanolic hydrogen chloride, evaporated and the title product recrystallised from ethanoldiethylethyl (m.p. 170°-176° C.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH:14]([F:16])[F:15])[C:10]#[N:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH:14]([F:16])[F:15])[C:10]#[N:11]
Reactant: Cc1ccc(C)c(O)c1
Reactant: N#CC(=NOC(F)F)c1ccccc1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NOC(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 7.0 g of 2-(2-bromomethylphenyl)-2-difluoromethoxyimino-acetonitrile, 5.4 g of 2,5-dimethylphenol, 16.1 g of pulverized potash and 0.38 g of 18-crown-6 in 35 ml of acetonitrile is stirred at room temperature for 24 hours. For working up, water is added and exhaustive extraction with ethyl acetate is carried out. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate (9:1) yields 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-difluoromethoxyiminoacetonitrile in the form of a sticky crystalline mass which, when treated with hexane, yields a fine crystal powder of m.p. 104°-108° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:35])[CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]([OH:35])[CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2nc(-c3ccc(S(C)(=O)=O)cc3)ncc2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(-c3ccc(S(C)(=O)=O)cc3)ncc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (50 mg) is added to an ice-cooled solution of 4-{2-[5-chloro-2-(4-methanesulfonyl-phenyl)-pyrimidin-4-yl]acetyl}-piperidine-1-carboxylic acid tert-butyl ester (280 mg) in a mixture of tetrahydrofuran (10 mL) and water (2 mL). The ice bath is removed after 5 min and the reaction mixture is stirred for 0.5 h at room temperature. 2 N Citric acid is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with aqueous NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 40:60→0:100) to give the title compound. LC (method 7): tR=1.48 min; Mass spectrum (ESI−): m/z=494 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:25]([O:14][C:12]1[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)nc1OCc1ccccc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (500 mg, 1.47 mmol) from Step D in DMF (6 mL) was added benzyl bromide (0.22 mL, 1.91 mmol) and then cesium carbonate (622 mg, 1.91 mmol). The reaction was stirred at 55° C. for 4 h and was then diluted with water and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a 4:1 mixture of the crude products. The products were separated by flash column chromatography on silica gel eluted with a gradient of 5 to 10% ethyl acetate in hexanes to first yield the desired higher Rf O-alkylation title product. HPLC/MS: 430 (M+1); Rt=4.9 min;
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:5](=[O:14])[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[N:23]=[C:22]1[NH:30][CH:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[C:38](=[O:41])([O-:40])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[C:5]([OH:14])(=[O:6])[C:38]([OH:40])=[O:41].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[N:23]=[C:22]1[NH:30][CH:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:2][CH2:3][C:4]2[C:5](=[O:14])[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[CH:9]=2)[CH2:33][CH2:32]1
Reactant: c1coc(Cn2c(NC3CCCNCC3)nc3cccnc32)c1
Reactant: O=C([O-])[O-]
Reactant: O=c1oc2ccccc2cc1CCBr
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)C(=O)O
Product: O=c1oc2ccccc2cc1CCN1CCCC(Nc2nc3cccnc3n2Cc2ccco2)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
A mixture of 3.8 parts of 3-(2-bromoethyl)-2H-1-benzopyran-2-one, 4.7 parts of 3-(2-furanylmethyl)-N-(hexahydro-1H-azepin-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, 1.5 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred for 48 hours at 80° C. After cooling, the reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in ethanol. The salt was filtered off and dried, yielding 1 part (10%) of 3-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]-amino]hexahydro-1H-azepin-1-yl]ethyl]-2H-1-benzopyran-2-one ethanedioate(1:2); mp. 179.7° C. (compound 109).
Reaction SMILES: [Cl:1][C:2]1[CH:3]([OH:20])[CH:4]2[CH2:19][C:7]3([C:18]=1[C:17]1[CH:16]=[CH:15][C:14]4[NH:13][N:12]=[CH:11][C:10]=4[C:9]=1[CH2:8]3)[CH2:6][CH2:5]2>C(O)C.CO>[Cl:1][C:2]1[C@H:3]([OH:20])[C@H:4]2[CH2:19][C@@:7]3([C:18]=1[C:17]1[CH:16]=[CH:15][C:14]4[NH:13][N:12]=[CH:11][C:10]=4[C:9]=1[CH2:8]3)[CH2:6][CH2:5]2
Reactant: OC1C(Cl)=C2c3ccc4[nH]ncc4c3CC23CCC1C3
Solvent: CCO
Solvent: CO
Product: O[C@H]1C(Cl)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3

Procedure:
Racemic (7R,8R,10aS)-6-chloro-3,7,8,9,10,11-hexahydro-8,10a-methanoazuleno-[2,1-e]indazol-7-ol (318 mg) was dissolved in 4/1 ethanol/methanol (25 mL) and resolved by chiral HPLC on a 2.0×25 cm Daicel Chiralcel OJ column (3-4 mL injections, elution with 35% EtOH:Heptane at 7.5 mL/min, fractions monitored at 254 nm). The fractions containing the first enantiomer to elute (enantiomer A) were combined and concentrated to a clear oil which had a negative rotation. The pure fractions containing the second enantiomer to elute (enantiomer B) were combined, concentrated, and lyophilized from benzene to give a white solid which had a positive rotation.
Reaction SMILES: [S:1]([O-:4])([O-])=[O:2].[Na+].[Na+].[Na].[N+]([C:11]1C=C(S(Cl)(=O)=O)C=CC=1C(Cl)=O)([O-])=O.ClCC(O)=O.[N+:29]([C:32]1[CH2:40][C:39](=S=O)[CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=[O:35])([O-:31])=[O:30]>O>[N+:29]([C:32]1[CH:40]=[C:39]([S:1]([CH3:11])(=[O:4])=[O:2])[CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=[O:35])([O-:31])=[O:30]
Reactant: O=S=C1C=CC(C(=O)O)=C([N+](=O)[O-])C1
Reactant: O=S([O-])[O-]
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Agent: O=C(O)CCl
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 15 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A 100 mL round bottom flask equipped with a reflux condenser, thermometer and magnetic stirrer was charged with 1.9 g (15 mmol) of sodium sulfite, 5.1 g (60 mmol) of sodium bicarbona+and 20 mL of water. The resulting slurry was cooled to 15° C. and 4.0 g (14 mmol) of 2-nitro-4(chlorosulfonyl)benzoyl chloride was added over 5 minutes. The reaction mixture was stirred at 15° C. for three hours and then at ambient temperature overnight. After warming to 40° C., 3.1 g (27 mmol) of the sodium salt of chloroacetic acid was added to the aqueous solution of 2 nitro-4-sulfinylbenzoic acid and the reaction mixture heated to reflux. After heating for 7 hours, the reaction mixture was allowed to cool to ambient temperature, diluted with 30 mL of water and washed with 50 mL of ethyl acetate. The aqueous layer was acidified with concentrated HCl and extracted with 75 mL of ethyl acetate. The organic solution was concentrated to afford 3.0 g (87% yield) of 2-nitro-4-(methylsulfonyl)benzoic acid as a pale yellow solid.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:10][CH:9]([OH:11])[CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22].C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH:1]1([S:4]([N:7]2[CH2:8][CH:9]([O:11][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:10]2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=S(=O)(C1CC1)N1CC(O)C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)OC1CN(S(=O)(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
To a solution of 1-(cyclopropylsulfonyl)azetidin-3-ol (1.04 g, 5.87 mmol) and triethylamine (3.11 mL, 22.3 mmol) in tetrahydrofuran (20 mL) was added 4-dimethylaminopyridine (0.090 g, 0.73 mmol) followed by chlorotriethylsilane (1.00 M in THF, 8.0 mL, 8.0 mmol). The reaction was stirred at room temperature for 16 hours. To the reaction was added saturated sodium bicarbonate solution and the product was extracted with a 1:1 mix of ethyl acetate:hexanes three times. The combined organic extracts were washed with dilute HCl and brine, then dried over sodium sulfate, decanted and concentrated. Flash column chromatography, eluting with a gradient of 0-50% ethyl acetate in hexanes afforded desired product (1.0 g, 58%).
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]1([F:17])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][OH:16])=[CH:14][C:8]=2[O:7]1>[O-2].[O-2].[Mn+4].O1CCCC1>[F:17][C:6]1([F:5])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH:15]=[O:16])=[CH:14][C:8]=2[O:7]1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 20 mL of chloroform containing 930 mg of (2,2-difluorobenzo[1,3]dioxol-5-yl)methanol and 20 mL of a tetrahydrofuran solution, 2.20 g of manganese dioxide was added, and the mixture was stirred at room temperature for 3 days. The insoluble material filtered off, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate:hexane 1:2] to obtain 687 mg of a yellow oily substance, 2,2-difluorobenzo[1,3]dioxol-5-carbaldehyde.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:3]([NH:5][CH3:6])=[O:4].Cl[C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.[CH3:22][C:23]1([CH3:32])[CH2:28][CH:27]([NH2:29])[CH2:26][C:25]([CH3:31])([CH3:30])[NH:24]1>>[CH3:1][C:2]([CH3:13])([CH2:7][C:8]1[S:9][C:10]([C:17]2[CH:18]=[CH:19][N:20]=[C:15]([NH:29][CH:27]3[CH2:28][C:23]([CH3:32])([CH3:22])[NH:24][C:25]([CH3:31])([CH3:30])[CH2:26]3)[N:16]=2)=[CH:11][CH:12]=1)[C:3]([NH:5][CH3:6])=[O:4]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNC(=O)C(C)(C)Cc1cccs1
Product: CNC(=O)C(C)(C)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Steps B and C of Method A, starting from 2,2,N-trimethyl-3-thiophen-2-yl-propionamide, 2,4-dichloro-pyrimidine and 2,2,6,6-tetramethyl-piperidin-4-ylamine.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.ClC(OCC(C)C)=O.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]1)=[O:29]>O1CCCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]1)=[O:29])=[O:10]
Reactant: O=C(O)CN1CCCC1=O
Reactant: NCC(=O)N1CCC(C(N)=O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(C(=O)CNC(=O)CN2CCCC2=O)CC1
Reaction time: 0.25 h

Procedure:
27.8 g of (2-oxo-1-pyrrolidinyl)acetic acid was suspended in 450 ml of tetrahydrofuran, to which 27.8 g of isobutyl chloroformate at -15° C. and 20.3 g of triethylamine at -15° to -5° C. were added. After stirring at -10° to -5° C. for 15 minutes, 36.0 g of 1-glycyl-4-piperidinecarboxamide was added at -10° to -5° C. and then the reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours. The insoluble matter was filtered off and suspended in 500 ml of chloroform. The suspension was filtered off to obtain the crude crystal. The crude crystal was recrystallized from methanol to obtain the titled compound.
Reaction SMILES: C([NH:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[O:13][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C.C(=O)([O-])O.O1CCOCC1.O.C(=O)(O)[O-].[Na+]>CO>[NH2:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([CH3:16])([CH3:17])[CH3:15])[O:13][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(NC(C)=O)c2cc(C(C)(C)C)oc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2)c(N)c2cc(C(C)(C)C)oc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
A methanol (60 ml) solution of methyl 4-acetylamino-2-tert-butyl-5-phenyl-1-benzofuran-7-carboxylate (I-253) (2.28 g, 6.24 mmol) and 4 N hydrogen carbonate/1,4-dioxane solution (15.6 ml, 62.4 mmol) were stirred overnight at room temperature, then heated up to 50° C. and stirred for 5 hours. The reaction liquid was put into saturated sodium bicarbonate water (300 ml), followed by extraction with ethyl acetate (200 ml). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→1:1) to obtain the entitled compound (972 mg, 48%) as a yellow white solid. Starting material recovery, 1.10 g (48%).
Reaction SMILES: C(O[C:5](=[O:11])[C@H:6]([CH:8]([CH3:10])[CH3:9])[NH2:7])C=C.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1.O1C[CH2:22][CH2:21][CH2:20]1>O1CCOCC1.CO>[CH:8]([C@H:6]([NH:7][CH2:13][CH2:12][CH2:18][S:15]([OH:14])(=[O:17])=[O:16])[C:5](=[O:11])[CH2:22][CH:21]=[CH2:20])([CH3:9])[CH3:10]
Reactant: C1CCOC1
Reactant: C=CCOC(=O)[C@@H](N)C(C)C
Reactant: O=S1(=O)CCCO1
Solvent: CO
Solvent: C1COCCO1
Product: C=CCC(=O)[C@@H](NCCCS(=O)(=O)O)C(C)C
Temperature: 25 °C
Yield: 26 %

Procedure:
To a solution of L-valine allylester (1.30 g, 8.3 mmol) in tetrahydrofuran (6 mL), 1,4-dioxane (6 mL) and MeOH (0.5 mL) was added 1,3-propanesultone (910 mg, 7.5 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solvent was evaporated under reduced pressure. The sticky paste was suspended in 20% acetone/ether. The solid was filtered and dissolved EtOH (75 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated to dryness under reduced pressure, affording the title compound (605 mg, 26%). 1H NMR (D2O, 500 MHz) δ ppm 5.84 (m, 1H), 5.27 (d, 1H, J=17.1 Hz), 5.19 (m, 1H, J=10.3 Hz), 3.91 (d, 1H, J=3.9 Hz), 3.10 (t, 2H, J=7.3 Hz), 2.85 (t, 2H, J=7.3 Hz), 2.22 (m, 1H), 2.03 (m, 2H), 0.93 (d, 3H, J=6.8 Hz), 0.85 (d, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 168.55, 130.90, 120.31, 67.58, 65.82, 48.09, 46.57, 29.53, 21.29, 18.25, 16.57. [α]D=+5.0° (c=0.0011 in water), ES-MS 278 (M−1).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C[CH2:20][N:21](CC)CC.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([CH2:20][NH:21][S:30]([CH2:29][CH2:28][CH2:27][Cl:26])(=[O:32])=[O:31])=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)CCCCl
Reactant: c1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Solvent: ClCCl
Product: O=S(=O)(CCCCl)NCc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
To a solution of 5-aminomethyl-[2-(4-cyclopropylpiperazin-1-yl)benzooxazole (500 mg, 1.84 mmol) in CH2Cl2 (15 mL) was added Et3N (929 mg, 9.2 mmol). The mixture was stirred at 0° C. for 5 min and then 3-chloropropane-1-sulfonyl chloride (326 mg, 1.84 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h and brought gradually to rt. Then the mixture was stirred for another 1 h. The volatiles were removed and the residue was extracted with CH2Cl2. The resulting residue was purified by column chromatography on silica gel (elute: 5% CH2Cl2 in methanol) to give 3-chloropropane-1-sulfonic acid [2-(4-cyclopropyl-piperazin-1-yl)benzooxazol-5-ylmethyl]amide (315 mg, 42%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:23])[CH2:21][CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCCN
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCCNc1c(C(=O)OCC)cnc2c(N)cccc12
Yield: 87 %

Procedure:
The compound prepared in Example 3 was reacted with propyl amine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3C)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C>ClCCl.N>[CH3:1][O:2][C:3]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][NH:12]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@H]1[C@H]2CCCN1C
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc2c1CC[C@@H]1NCCC[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
cis-7-Methoxy-1,2,3,4,4a5,6,10b-octahydrobenzo[f]quinoline 1-Chloroethylchloroformate (4.62 ml, 42.8 mmol) was added with stirring to an ice cooled solution of cis-and trans-7-methoxy-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (4.3 g, 18.6 mmol) in dichloromethane (140 ml). The mixture was allowed to warm to room temperature and stirred for a further 2 h. Diisopropylethylamine (4.9 ml, 28 mmol) was added and the mixture heated at reflux for 1 h. The mixture was cooled and concentrated in vacuo before dissolving in methanol (100 ml) and refluxing for 1 h. After cooling, the solvent was removed and the residue partitioned between saturated aqueous K2CO3 (50 ml) and dichloromethane (3×50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4) and the solvent evaporated to afford a yellow oil. Chromatography on silica using 10% methanol-dichloromethane and 6.6 ml/L 0.880 ammonia as eluent gave trans 7-methoxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (0.6 g, 30%) as the first eluting isomer.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9](O[C@@H](C)CC)=[N:10][C:11]=2[NH2:17].FC(F)(F)C(O)=O.[CH3:30][C@@H:31]([NH:35]C1NC2C(N=C(OC)N=2)=C(N)N=1)[CH2:32][CH2:33][CH3:34].BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:35][C@H:31]([CH3:30])[CH2:32][CH2:33][CH3:34])=[N:10][C:11]=2[NH2:17]
Reactant: CCC[C@@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from N2-[(1R)-1-methylbutyl]-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:14])[CH2:10][SiH:11]([Cl:13])[Cl:12])[CH3:2].[CH2:15]=[CH:16][CH2:17][CH2:18][CH:19]=[CH2:20]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:14])[CH2:10][Si:11]([CH:15]([Si:11]([Cl:12])([Cl:13])[CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([Cl:13])[Cl:12])[CH3:2]
Reactant: CCc1ccccc1C(C)C[SiH](Cl)Cl
Reactant: C=CCCC=C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCCCCC([Si](Cl)(Cl)CC(C)c1ccccc1CC)[Si](Cl)(Cl)CC(C)c1ccccc1CC
Yield: 69.9 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 37.5 g (0.153 mole) of 3-(ethylphenyl)-1,1-dichloro-1-silabutane and 100 μl of 1% chloroplatinic acid solution in isopropanol were placed and then 5 g (0.061 mole) of 1,5-hexadiene was added dropwise for 5 min. The solution was reacted for 14 hours at reflux under the dry nitrogen atmosphere. Vacuum distillation gave 24.6 g (190°-192° C./0.03 mmHg) of bis[{2-(ethylphenyl)propyl}dichlorosilyl]hexane in 69.8% yield.