Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1.[S:29]1[CH:33]=[N:32][N:31]=[C:30]1[NH2:34]>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:34][C:30]3[S:29][CH:33]=[N:32][N:31]=3)=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Reactant: Nc1nncs1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3nncs3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Yield: 100 %

Procedure:
The product of Example 162b (300 mg, 0.6197 mmol) and [1,3,4]Thiadiazol-2-ylamine (62 mg, 0.6197 mmol) in toluene (10 mL) were reacted as in Example 162c to yield the title compound (340 mg, 100% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:5].FC(F)(F)C(O)=O>[Pt].C(O)C>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH2:12][CH2:11][CH2:10]2)=[O:5]
Reactant: CC(C)(C)CC(=O)Nc1ccc2ncccc2c1
Agent: [Pt]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)CCCN2
Reaction time: 48 h
Yield: 86.1 %

Procedure:
A mixture of 3,3-dimethyl-N-quinolin-6-ylbutanamide (2.4 g), 5% platinum on carbon (0.15 g), trifluoroacetic acid (2.0 mL) and ethanol (50 mL) was hydrogenated at 45 PSI on a Parr shaker for 48 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was dissolved in ethyl acetate and washed carefully with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4) and concentrated. The resulting oil was dissolved in ether and 4 N HCl was added. The solid was collected by filtration to yield 3,3-dimethyl-N-1,2,3,4-tetrahydroquinolin-6-ylbutanamide (2.1 g) as its HCl salt. MS (ES) m/z 247.2.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[N:9]=[C:10]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:5]=[CH:4][C:3]=1[N+:28]([O-:30])=[O:29].S(=O)(=O)(O)[OH:32].N([O-])=O.[Na+]>CS(C)=O.O>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:12]1[NH:11][C:10]([C:21]([CH3:26])([CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[N:9][C:8]=1[C:6]1[CH:5]=[CH:4][C:3]([N+:28]([O-:30])=[O:29])=[C:2]([OH:32])[N:7]=1
Reactant: O=S(=O)(O)O
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(N)n2)c(-c2ccc(F)cc2F)[nH]1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a solution of methyl 2-[4-(6-amino-5-nitro-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]-2-methyl-propanoate (56 g, 134.17 mmol) in dimethyl sulfoxide (DMSO, 400 mL) and water (320 mL), is added sulfuric acid 95-97% (80 mL) dropwise. Then the mixture is cooled to 0° C. To the above mixture a solution of sodium nitrite (18.70 g, 268.35 mmol) in water (80 mL) is added dropwise over 15 min at 0° C. The reaction mixture is stirred for 20 min at that temperature and then the cooling bath is removed and the temperature is allowed to rise to RT. To the reaction mixture is added a 0.8 M aqueous solution of buffered sodium phosphate monobasic (1200 mL, pH=6). A yellow suspension appears. This suspension is stirred at RT for 1 h. The solid is filtered, washed with water, and dried in the oven to afford the title compound as an orange solid (49.5 g, 88%). LC-ES/MS m/z 419 (M+1).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[C:13]2[O:14][CH2:15][CH2:16][O:17][C:12]=2[CH:11]=[C:10]([CH:18]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:19]([NH2:21])=[S:20])[CH:9]=1.[C:35](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:35][S:20][C:19](=[NH:21])[CH:18]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:13]2[O:14][CH2:15][CH2:16][O:17][C:12]=2[CH:11]=1)[NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc2c1OCCO2
Reactant: O=C([O-])O
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 750 mg of Me3O+BF4− to a solution of 1.92 g of 2-(8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 20 ml of acetonitrile, the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:10]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH2:1]([N:10]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
6 mL benzyl bromide was added to 5 g azepane-4-one hydrochloride and 18.5 g potassium carbonate in 50 mL THF and 25 mL water. The mixture was stirred 5 h at 50° C., evaporated, diluted with water and extracted with ethyl acetate. The organic layer was evaporated. The residue was purified by chromatographie on silica gel (petrolether/ethyl acetate:8/2) to give 5 g of the desired product. Rf: 0.40 (hexane/ethyl acetate=1/1), (M+H)+=204
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1[O:10][C:9](/[CH:15]=[CH:16]/[CH:17]2[CH2:19][CH2:18]2)([C:11]([F:14])([F:13])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[N:6](CC2C=CC(OC)=CC=2)[C:5]1=[O:34].O>C(#N)C>[Br:1][CH2:2][CH2:3][C@@H:4]1[O:10][C@:9](/[CH:15]=[CH:16]/[CH:17]2[CH2:18][CH2:19]2)([C:11]([F:13])([F:14])[F:12])[C:8]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:7]=2[NH:6][C:5]1=[O:34]
Reactant: COc1ccc(CN2C(=O)C(CCBr)OC(/C=C/C3CC3)(C(F)(F)F)c3cc(Cl)ccc32)cc1
Solvent: CC#N
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2[C@@](/C=C/C2CC2)(C(F)(F)F)O[C@H]1CCBr
Reaction time: 0.33 h

Procedure:
To a room temperature solution of 750 mg of trans-3-(2-bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-1-(4-methoxybenzyl)-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 35 mL of acetonitrile was added 18 mL of water and 3.78 g of ceric ammonium nitrate. After 20 min, the reaction mixture was partitioned between eater and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. This produced two diastereomeric products which were separated by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes). The first diastereomer eluted (162 mg) was the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 78.6 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.056 g (78%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([C@H:27]4[CH2:32][CH2:31][C@H:30](O)[CH2:29][CH2:28]4)=[N:25][CH:26]=[C:18]1[C:17](=[O:34])[NH:16]3)=[O:12])[CH2:6][CH2:5]2.ClCCl.C(N(S(F)(F)F)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([CH:27]4[CH2:32][CH2:31][CH:30]=[CH:29][CH2:28]4)=[N:25][CH:26]=[C:18]1[C:17](=[O:34])[NH:16]3)=[O:12])[CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1cnc([C@H]3CC[C@H](O)CC3)n12
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1cnc(C3CC=CCC3)n12
Reaction time: 2 h
Yield: 8.4 %

Procedure:
A mixed solution of 87 mg of 7-[(5-chloro-2,3-dihydro-1H-indol -1-yl)carbonyl]-1-(trans-4-hydroxycyclohexyl)-8-methylimidazo[1,5-a]quinoxalin-4(5H)-one and 2.8 mL of dichloromethane was cooled to −70° C., and 48 μL of N,N-diethylaminosulfur trifluoride was added thereto, followed by stirring at the same temperature for 2 hours. To the mixed reaction liquid were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, followed by extraction with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3). To the obtained solid was added 1.5 mL of methanol to give a mixture, and then warmed. A precipitate was collected by filtration and dried under reduced pressure to obtain 7 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-(cyclohex-3-en-1-yl)-8-methylimidazo[1,5-a]quinoxalin-4(5H)-one as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8]O)[CH:7]=1.P(Br)(Br)[Br:14].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:14][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: BrP(Br)Br
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
5-methyl-2-nitrobenzoic acid (10.0 g, 55.2 mmol) were dissolved in THF (100 mL) followed by dropping 2.0 M borane dimethisulfide comples (110 mL, 221.1 mmol) and heating at 80° C. After 1.5 hours, 100 ml of 1 M HCl were dropped into this reaction system while cooling with ice and stirring. The system was extracted with ethyl acetate, and then was dried with Na2SO4 followed by concentration under reduced pressure and drying to obtain benzylic alcohol (9.1 g, 99% yield) as viscous colorless oil. (5-methyl-2-nitrophenyl) methanol (9.1 g, 54.5 mmol) were dissolved in dry CH2Cl2 (100 mL) followed by the addition of phosphorous tribromide (7.4 g, 27.3 mmol) and stirring at room temperature. After 30 minutes, saturated NaHCO3(aq. 100 mL) were added followed by stirring for 10 minutes and extracting with CH2Cl2 (200 ml×2). The organic phase was then concentrated under reduced pressure and dried to obtain the benzyl bromide analogue, 49, (11.9 g, 95% yield) as a white solid: mp 51-52° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=C(C)C=1.[CH:35]([N:37]1[C:45](=[O:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]1=[O:47])=[CH2:36]>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[NH2:5][C:4]1[CH:3]=[C:2](/[CH:36]=[CH:35]/[N:37]2[C:38](=[O:47])[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:45]2=[O:46])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cccc(P(c2ccccc2C)c2ccccc2C)c1
Solvent: CC#N
Product: Nc1cc(/C=C/N2C(=O)c3ccccc3C2=O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a degassed solution of 3-bromo-5-(trifluoromethyl)aniline (1.00 g, 4.17 mmol) and ACN (40 mL) was added Pd(OAc)2 (0.46 g, 0.20 mmol), bis(2-methylphenyl)(3-methylphenyl)phosphine (0.13 g, 0.40 mmol), and TEA (1.15 mL, 8.25 mmol). After stirring for 1 h, 2-vinyl-1H-isoindole-1,3(2H)-dione (0.72 g, 4.17 mmol) was added. The solution was heated at reflux for 20 h and then allowed to cool to rt and filtered through Celite. The filtrate was washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to yield the title compound as a yellow solid (0.90 g, 62%). LCMS: (FA) ES+ 333.2 (M+1).
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([C:5](=S)[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:5]1[CH:4]2[CH2:3][CH2:2][CH2:1][CH:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: S=C1Nc2ccccc2C2CCCC12
Reactant: CN
Product: CNC1=Nc2ccccc2C2CCCC12

Procedure:
1,2,3,3a,5,9b-Hexahydrocyclopenta[c]quinoline-4-thione (90 mg, 0.44 mmol) is stirred in 2 M methanolic methylamine solution (15 ml) for 24 hours at room temperature. After concentration by evaporation, the residue is purified on silica gel with dichloromethane-methanol: 90 mg (99%).
Reaction SMILES: [OH:1][C:2]1[C:19]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](OC)=[O:36].O>CN(C=O)C>[O:36]=[C:35]1[CH2:34][O:1][C:2]2[C:19](=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)[N:20]1[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c(NC3CCOCC3)cc2CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(C1CCOCC1)C(=O)CO3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 215 mg of t-butyl 7-hydroxy-8-(tetrahydro-2H-pyran-4-ylamino)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 4 ml of DMF were added 98 mg of potassium carbonate and 0.062 ml of methyl bromoacetate, followed by stirring at room temperature for 6 hours. To the reaction mixture was added water, followed by extraction with EtOAc twice. The combined organic layer was washed with saturated brine three times, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. To a solution of 259 mg of the resulting residue in 7 ml of EtOH was added 1.2 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 50° C. overnight. Further, 1.2 ml of a 1 M aqueous hydrochloric acid solution was added thereto under ice-cooling, followed by extraction with chloroform twice, and the combined organic layer was dried over anhydrous sodium sulfate and then filtered. The solvent was evaporated under reduced pressure. To a solution of 239 mg of the resulting residue in 4 ml of DMF were added 120 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 84 mg of HOBt at room temperature, followed by stirring at room temperature overnight. Water was added thereto, followed by extraction with EtOAc twice. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 153 mg of t-butyl 3-oxo-4-(tetrahydro-2H-pyran-4-yl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a white solid.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:28]([OH:30])=[O:29])[CH2:20][NH:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.[Cl:37][C:38]1[CH:46]=[C:45]([C:47]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([OH:57])[CH:52]=2)=[O:48])[CH:44]=[CH:43][C:39]=1[C:40]([OH:42])=O.C1C=NC2N(O)N=NC=2C=1>CN1CCCC1=O>[Cl:37][C:38]1[CH:46]=[C:45]([C:47]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([OH:57])[CH:52]=2)=[O:48])[CH:44]=[CH:43][C:39]=1[C:40]([NH:18][C@H:19]([C:28]([OH:30])=[O:29])[CH2:20][NH:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[O:42]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C=CCOC(=O)NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Solvent: C1CCNCC1
Product: C=CCOC(=O)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A150 mL cylidrical glass vessel equipped with a coarse glass frit was charged with N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-[(2-propenyloxy)carbonyl]amino-L-alanine resin (Example 64; 5 g) and 25% piperidine in N-methylpyrrolidinone (50 mL). The mixture was agitated at room temperature for 30 min. The resin was filtered and treated again with fresh 25% piperidine in N-methylpyrrolidinone (50 mL) at room temperature for 30 min. After filtration, the resin was washed with dichloromethane and methanol. To the resin was added a solution prepared from 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 26; 2.5 g, 8.2 mmol), HOAT (3.7 g, 27.2 mmol) and DICI (4.3 mL, 27.5 mmol) in N-methylpyrrolidinone (50 mL). The reaction mixture was agitated at room temperature for 1 h, and then filtered. The resin was washed with dichloromethane and methanol, and dried under vacuum to afford resin-bound N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(2-propenyioxy) carbonyl]amino-L-alanine.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18]O>>[C:1]([O:12][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:20])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCCCO
Product: CCCCCCC/C=C/C(=O)OCCCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 4-dimethylamino-1-butanol as starting materials to give the aimed compound.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:24](OC)(OC)(OC)[CH2:25][CH2:26][CH3:27]>>[CH3:1][C:2]([CH3:23])([CH2:16][C:17]1([CH3:22])[O:21][CH2:20][CH2:19][O:18]1)[CH2:3][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:24]1[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(OC)(OC)OC
Reactant: CC(C)(CNc1c(N)cnc2ccccc12)CC1(C)OCCO1
Product: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Yield: 29.2 %

Procedure:
The general method described in Step 6 of Example 22 was used to cyclize N4-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]quinoline-3,4-diamine (9.1 g, 28.9 mmol) by reaction with trimethyl orthobutyrate (4.4 g, 30 mmol) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-propyl-1H-imidazo[4,5-c]quinoline (3.10 g) as a solid after chromatography on silica gel (elution with a solution of 7% methanol in dichloromethane that contained about 5 mL of ammonium hydroxide solution per liter of eluent).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)[C:13]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:22][C:17]1[CH:16]=[C:15]([N:14]2[C:13]3[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Yield: 100.4 %

Procedure:
A solution of {(S)-1-[1-(3,5-difluorophenyl)-6-fluoro-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (668 mg, 1.7 mmol) in TFA (4 mL) and DCM (12 mL) was stirred for 1 h at RT. The reaction solution was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow oil (497 mg, 99%). Marfey's test: 97% de. LCMS (Method C): RT 1.96 min [M+H]+ 292. 1H NMR (CDCl3, 400 MHz): δ 7.70 (1H, dd, J=9.0, 5.0 Hz), 7.08-7.00 (2H, m), 6.97-6.93 (2H, m), 6.80 (1H, dd, J=8.0, 2.5 Hz), 6.19 (2H, bs), 4.51 (1H, q, 7.0 Hz), 1.55 (3H, d, J=7.0 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])([O:11][CH2:12][CH2:13][O:14][CH3:15])[O:6][CH2:7][CH2:8][O:9][CH3:10].[N-:21]=[N+:22]=[N-:23].[Na+]>C(#N)C>[N:21]([CH2:2][CH2:3][CH2:4][Si:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])([O:11][CH2:12][CH2:13][O:14][CH3:15])[O:6][CH2:7][CH2:8][O:9][CH3:10])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: COCCO[Si](CCCCl)(OCCOC)OCCOC
Agent: [Na+]
Solvent: CC#N
Product: COCCO[Si](CCCN=[N+]=[N-])(OCCOC)OCCOC

Procedure:
1.0 mole of 3-chloropropyltris(methoxyethoxy)-silane and 1.1 moles of sodium azide in 500 ml of acetonitrile were heated in the presence of 5 mole percent of the catalyst described in Example 1 (a) for eight hours under reflux and stirring. After separation of the salt the subsequent distillation under reduced pressure gave the 3-azidopropyltris(methoxyethoxy)silane in a yield of 84 weight percent with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[CH:17](O)=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH:16][CH:17]=[O:18])[CH:3]=1
Reactant: O=CO
Reactant: CN(c1ccccc1)c1ccc(Cl)cc1N
Product: CN(c1ccccc1)c1ccc(Cl)cc1NC=O
Reaction time: 2 h
Yield: 100 %

Procedure:
4-Chloro-N1-methyl-N1-phenylbenzene-1,2-diamine (9.3 g, 40.1 mmol) was dissolved in formic acid (60 mL) and heated to reflux. After 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL) and washed with aq. NaHCO3 (5%, 500 mL). The organic layer was dried, filtered and concentrated under reduced pressure. The residual oil was chromatographed over silica (cyclohexane/CH2Cl2, 9/1, v/v) to give pure title compound (10.4 g, 100% yield). Data: Rf 0.25 (heptane/ethyl acetate, 3/1, v/v). (m/z)=261 (M+H)+.