Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[NH:6])=[NH:3].CO[C:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]=1>C(O)C>[NH2:6][C:5]1[N:4]=[C:2]([NH2:1])[N:3]=[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:10][NH2:11])[N:7]=1
Reactant: N=C(N)NC(=N)N
Reactant: COC1=NCCCCC1
Solvent: CCO
Product: NCCCCCc1nc(N)nc(N)n1

Procedure:
A mixture of biguanide (1.05 g.), 4,5,6,7-tetrahydro-2-methoxy-3H-azepine (1.27 g.) and ethanol (50 ml.) was heated under reflux for 18 hours, cooled and the solid that crystallised was collected to give 2,4-diamino-6-(5-aminopentyl)-1,3,5-triazine which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[I-:24].[Na+]>CC(CC)=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][I:24])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CCCCCCCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(CCCCCCCI)cc1
Yield: 90.1 %

Procedure:
1.32 g of 4-chloro-4'-(7-chloroheptyl)benzophenone and 0.85 g of sodium iodide were heated under reflux in 20 ml of ethyl methyl ketone. After 24 hours the reaction mixture was evaporated. The residue was suspended in 50 ml of water, whereupon the suspension was extracted three times with 50 ml of ethyl acetate each time, the combined organic phases were washed with 50 ml of a saturated sodium chloride solution, dried over magnesium sulphate and evaporated. There were obtained 1.5 g (90%) of crude 4-chloro-4'-(7-iodoheptyl)benzophenone as a yellowish oil which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:10]=[CH:9][C:8]=2[CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.O.[NH2:44][C:45]1[NH:49][N:48]=[N:47][N:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O.CC#N.O.C(Cl)CCl>[CH:1]1([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:22])[F:21])=[CH:16][CH:17]=3)[N:10]=[CH:9][C:8]=2[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:44][C:45]3[NH:49][N:48]=[N:47][N:46]=3)=[O:30])=[CH:31][CH:32]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc(Cc2cnn(-c3ccc(OC(F)(F)F)cc3)c2C2CCCCC2)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(Nc1nnn[nH]1)c1ccc(Cc2cnn(-c3ccc(OC(F)(F)F)cc3)c2C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 66.7 mg product from Step F above, 71.9 mg EDC, 30.4 mg HOBt and 23.2 mg aminotetrazole monohydrate was dissolved in 1 mL DMF. DIEA (92 μL) was added immediately and the resulting solution was stirred at room temperature for 17 hours. The reaction mixture was diluted with a mixture of DMSO, MeCN, and water and purified on preparative HPLC using 65˜80% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA. The title compound was obtained as a white solid following lyophilization. 1H NMR (DMSO-d6, 500 MHz) δ 8.045 (d, J=8.2 Hz, 2H), 7.50˜7.54 (m, 4H), 7.41 (d, J=8.2 Hz, 2H), 7.33 (s, 1H), 4.06 (s, 2H), 2.64 (tt, J=3.0 & 12.2 Hz, 1H), 1.62˜1.72 (m, 4H), 1.48˜1.48 (m, 3H), 1.05˜1.15 (m, 3H). LC-MS: 1.97 min. (M+H=512.2).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]([OH:32])=[C:28]([CH2:30][CH3:31])[CH:29]=1)[C:24](Cl)=[O:25].C(N(CC)CC)C>ClC(Cl)Cl>[Cl:20][C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]([OH:32])=[C:28]([CH2:30][CH3:31])[CH:29]=1)[C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11](=[O:12])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:4][C@H:3]1[O:18][CH3:19])=[O:25]
Reactant: CCc1cc(Cl)c(OC)c(C(=O)Cl)c1O
Reactant: CO[C@@H]1CN(CCCC(=O)N2CCCC2)CC[C@@H]1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cc(Cl)c(OC)c(C(=O)N[C@H]2CCN(CCCC(=O)N3CCCC3)C[C@H]2OC)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To a stirred solution of 4.04 parts of cis-1-[4-(4-amino-3-methoxy-1-piperidinyl)-1-oxobutyl]pyrrolidine in 225 parts of trichloromethane was added a solution of 4.15 parts of 3-chloro-5-ethyl-6-hydroxy-2-methoxybenzoyl chloride in trichloromethane. After stirring for 15 minutes at room temperature, 1.9 parts of N,N-diethylethanamine were added and the whole was stirred overnight at room temperature. The reaction mixture was washed with water, saturated with ammonia and twice with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 5.2 parts (71.9%) of cis-3-chloro-5-ethyl-6-hydroxy-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(1-pyrrolidinyl)butyl]-4-piperidinyl]benzamide; mp. 90.8° C. (compound 67).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:19][C:11]1[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]2[N:7]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[O:35][N:34]=[C:33]([CH3:36])[CH:32]=4)[CH:26]=3)[CH2:22][C:21](=[O:37])[NH:20][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(F)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCCC5)c(F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-fluoro-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example M48) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a brown solid (86 mg).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:10][CH3:11]>ClCCl>[CH2:9]([N:12]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH3:15])[CH2:10][CH3:11]
Reactant: O=Cc1ccccc1
Reactant: CCCNCCC
Solvent: ClCCl
Product: CCCN(CCC)Cc1ccccc1
Reaction time: 3 h

Procedure:
Benzaldehyde (0.404 cm3, 4.0 mmol), di-n-propylamine (0.548 cm3, 4.0 mmol) and [Ir(COD)(dppb)][PF6] (0.070 g, 2 mol %) in dichloromethane were treated as stated above under approx 1 bar H2 at approx. 20° C. for 3 hrs. The yield of N,N-di-n-propylbenzylamine obtained was 39.6%.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[C:16]([C:17]#[N:18])=[CH:15][N:14]=[CH:13][C:12]=1Br)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]3[C:35](=[N:36][CH:37]=2)[NH:34][CH2:33][CH2:32][CH2:31]3)O1>>[CH2:1]([O:8][CH:9]([C:11]1[C:16]([C:17]#[N:18])=[CH:15][N:14]=[CH:13][C:12]=1[C:32]1[CH:33]=[N:34][C:35]2[NH:36][CH2:37][CH2:28][CH2:29][C:30]=2[CH:31]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3)OC1(C)C
Reactant: CC(OCc1ccccc1)c1c(Br)cncc1C#N
Product: CC(OCc1ccccc1)c1c(C#N)cncc1-c1cnc2c(c1)CCCN2

Procedure:
4-(1-Benzyloxy-ethyl)-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-nicotinonitrile is synthesized according to the procedure of Suzuki Coupling Method VI using 4-(1-benzyloxy-ethyl)-5-bromo-nicotinonitrile and crude 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (which is prepared according to Step 4 of Example 105).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([S:12][CH3:13])[CH:6]=[C:5]([CH3:14])[N:4]=1.[H][H].CN(C)C1C=CC=CC=1>CO.O1CCOCC1.[Ni].C(Cl)(Cl)Cl>[NH2:9][C:8]1[C:3]([S:2][CH3:1])=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[S:12][CH3:13]
Reactant: CSc1cc(C)nc(SC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CSc1cc(C)nc(SC)c1N

Procedure:
With reference to Example 238 described in Japanese Patent Publication (kokoku) No. 25974/1996, 2,4-bis(methylthio)-3-nitro-6-methylpyridine was obtained, and the thus-obtained nitro compound was dissolved in a mixture of methanol and dioxane, followed by reduction in the presence of Raney nickel in a hydrogen atmosphere. Subsequently, N,N-dimethylaniline (0.85 g, 7 mmol) was added to a suspension of the obtained crude 3-amino-2,4-bis(methylthio)-6-methylpyridine (1.0 g, 5 mmol) in chloroform (15 mL). Under cooling with ice, a solution of bromoacetyl chloride (1.21 g, 6 mmol) in chloroform (3 mL) was added dropwise thereto, and the resultant mixture was stirred at room temperature for 2 hours. Subsequently, TLC was performed to confirm that starting materials had been completely consumed. Thereafter, water (65 mL) was added to the reaction mixture, and the resultant mixture was stirred overnight. The crystals that precipitated were collected through filtration, followed by recrystallization from ethanol and drying through air blow, to thereby yield primary crystals of N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-bromoacetamide (818 mg, yield: 50.9%, HPLC: 97.2%).
Reaction SMILES: C1(OC([N:10]2[CH2:14][CH2:13][CH:12]([C:15]([C:28]#[N:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=O)C=CC=CC=1.[OH-:30].[Na+]>S(=O)(=O)(O)O>[C:16]1([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:12]2[CH2:13][CH2:14][NH:10][CH2:11]2)[C:28]([NH2:29])=[O:30])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [OH-]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCN(C(=O)Oc2ccccc2)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Yield: 65 %

Procedure:
A solution of 3.0 g (0.008 mole) of 3-(cyanodiphenylmethyl)-1-pyrrolidinecarboxylic acid phenyl ester in 100 ml of 90% sulfuric acid was stirred at 70° C. for 20 hr. The reaction mixture was cooled, poured over ice and basified by adding, alternately, 50% sodium hydroxide and ice. The mixture was extracted with chloroform. The chloroform extract was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized in ethyl acetate. Recrystallization from ethyl acetate-ethanol gave 1.4 g (65%) of title product, molecular ion at 281 by mass spectrometer analysis.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.N#N.[F:15][C:16]1[N:30]=[CH:29][CH:28]=[CH:27][C:17]=1[C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19].CN([CH:34]=[O:35])C>C1COCC1>[F:15][C:16]1[N:30]=[CH:29][CH:28]=[C:27]([CH:34]=[O:35])[C:17]=1[C:18]([N:20]([CH:21]([CH3:22])[CH3:23])[CH:24]([CH3:25])[CH3:26])=[O:19]
Reactant: CC(C)N(C(=O)c1cccnc1F)C(C)C
Reactant: CN(C)C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)N(C(=O)c1c(C=O)ccnc1F)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (1.7 mL, 12.2 mmol) in THF (50 mL) at −78° C. was added n-BuLi (6.1 mL, 2.0 M hexanes) dropwise under N2. The reaction was stirred for 30 min and 2-fluoro-N,N-diisopropyl-nicotinamide (2.75 g, 12.2 mmol) was added dropwise in a solution of THF (15 mL). The reaction was stir for 1 h, then DMF (3 mL, 36 mmol, 3 eq) was added in one portion. The reaction was stirred at −78° C. for 5 min then warmed to RT over 1 h. The reaction was quenched with NH4Cl (saturated, 100 mL), and extracted with EtOAc (2×100 mL). The combined organics were washed with brine (saturated, 200 mL), dried with Na2SO4, and purified by passing through a plug of SiO2to give pure title compound as a white solid. MS (ES+): 253.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccnn2Cc2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Reaction time: 5 h

Procedure:
A mixture of 5 mmol of 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine in 25 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[CH:14]=2)=[CH:4][C:3]=1[NH:24]C(=O)OC(C)(C)C>FC(F)(F)C(O)=O>[NH2:24][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([N:15]=[C:16]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[N:17]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Trifluoroacetic acid (30 mL) was added to tert-butyl [2-chloro-5-({2-[(cyclopropylcarbonyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}oxy)phenyl]carbamate (5.59 g, 12.6 mmol), and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give the title compound (3.58 g, 83%) as a white solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH:14]=1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 3-iodo-1H-indazole-6-carbaldehyde (50 mg, 0.18 mmol), pyridin-3-ylboronic acid (27 mg, 0.22 mmol), PdCl2(PPh3)2 (13 mg, 0.018 mmol) and 2M Na2CO3 (0.10 mL, 0.18 mmol) in DME/H2O/EtOH (1.4 mL/0.4 mL/0.2 mL) was degassed by evacuation and refilling with Ar. The reaction mixture was sealed and heated with stirring under microwave irradiation at 125° C. for 60 min. The crude reaction mixture was concentrated under reduced pressure. Ethyl acetate (5 mL) was added and the solution was washed with brine (2×20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using MeOH (5%) in DCM as the eluent to provide the title compound a pale yellow solid (24 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (s, 1H), 8.88 (d, J=2.3 Hz, 1H), 8.69 (d, J=4.8 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.45 (dd, J=8.0, 5.0 Hz, 1H); MS ESI 224.0 (100) [M+H]+, calcd for [C13H9N3O+H]+ 224.07.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=1)[CH2:15][N:16]1[C:22](=[O:23])[C@H:21]2[CH2:24][CH2:25][CH2:26][C@H:20]2[NH:19][C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]1=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1(=[O:48])[N:38]([CH2:39][C:40](Cl)=[O:41])[C:37](=[O:43])[C:36]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:35]12.C([O-])(O)=O.[Na+]>ClCCCl.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][CH:33]=1)[CH2:15][N:16]1[C:22](=[O:23])[C@H:21]2[CH2:24][CH2:25][CH2:26][C@H:20]2[N:19]([C:40](=[O:41])[CH2:39][N:38]2[C:37](=[O:43])[C:36]3=[CH:44][CH:45]=[CH:46][CH:47]=[C:35]3[C:34]2=[O:48])[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]1=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: O=C(Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)c1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: O=C(Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)c1)OCc1ccccc1
Yield: 55.5 %

Procedure:
To a solution of (3aR*,10aS*)-9-[3-(benzyloxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (1.9 g, 4.3 mmol) in 1,2-dichloroethane (50 mL) was added phthalimidoacetyl chloride (1.1 g, 4.7 mmol) at room temperature and the mixture was refluxed for 17 hours. After cooling, saturated aqueous NaHCO3 solution (30 mL) was added and the mixture was diluted with water and extracted with 2 portions of chloroform. The pooled organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to provide 1.5 g (yield 55%) of the title compound. m.p. 224°-225° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[S:15](N)([NH2:18])(=[O:17])=[O:16]>C(COC)OC>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][S:15]([NH2:18])(=[O:17])=[O:16])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: NS(N)(=O)=O
Solvent: COCCOC
Product: NS(=O)(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 105.7 %

Procedure:
To a solution of 3.0 g of 4-amino-1-benzylpiperidine in dimethoxyethane (20 ml) was added 1.35 g of sulfamide. The resulting mixture was stirred at 100° C. for 10 minutes and then reacted at 130° C. for 1 hour. After distilling off the solvent under reduced pressure, 4.0 g of the title compound was obtained as a brown oily substance.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[C@@H:7]1[CH2:17][C@H:10]2[CH2:9][CH2:8]1)C=C.[C:18]1(C)[CH:23]=C(C)C=C(C)[CH:19]=1>>[CH2:23]([C:14]1[CH:13]=[C:12]([O:15][CH3:16])[C:11]2[C@H:10]3[CH2:17][C@H:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]=1[OH:4])[CH:18]=[CH2:19]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1ccc(OC)c2c1[C@H]1CC[C@@H]2C1
Product: C=CCc1cc(OC)c2c(c1O)[C@H]1CC[C@@H]2C1
Yield: 80 %

Procedure:
Treatment of (1R*,4S*)-5-(allyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalene (15.8 g, 0.069 mol) in refluxing mesitylene generally according to the procedure described for Intermediate 1 gave 12.58 g (80%) of (1R*,4S*)-6-allyl-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-ol as a colorless oil. Anal. calcd. for C20H22O.0.2H2O: C, 77.02; H, 7.93. Found: C, 76.68; H, 7.88.
Reaction SMILES: COC1C=[C:5]([CH:10]=[C:11]([O:14][CH3:15])C=1O)[C:6](OC)=O.Br[CH2:17][CH2:18][CH2:19]C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH2:15]([O:14][CH2:11][CH2:10][CH2:5][CH3:6])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCBr
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOCCCC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3,5-dimethoxy-4-hydroxybenzoate represented by Formula 87 (5 g, 23.56 mmol), 1-bromobutane (2.80 mL, 25.92 mmol), potassium carbonate (3.58 mg, 25.92 mmol) and potassium iodide (547.60 mg, 3.30 mmol) in DMF (50 mL) was agitated at 80° C. for 24 hours. After decreasing a temperature of the reaction mixture to room temperature, removing solids through filtration and adding ethyl acetate to the remaining filtrate, the filtrate was consecutively washed with water and a 5N-hydrochloric acid solution. After separating an organic layer and drying the same with magnesium sulfate, the solvent was removed under reduced pressure to form a concentrate mixture, which in turn, was subjected to separation and purification through column chromatography (ethyl acetate/hexane, 1:5) using silica gel (SiO2), resulting in an n-butylether compound represented by Formula 92 as a desired product (6.20 g, 94%). Analysis data of the product is provided as follows:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][S:8][CH:7]2[CH2:10][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12](=[O:13])[N:6]12)=O.[NH3:22].CO>>[C:18]([O:17][C:15](=[O:16])[NH:14][CH:11]1[C:12](=[O:13])[N:6]2[CH:7]([S:8][CH2:9][CH:5]2[C:3](=[O:2])[NH2:22])[CH2:10]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1CSC2CC(NC(=O)OC(C)(C)C)C(=O)N21
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC2SCC(C(N)=O)N2C1=O
Reaction time: 8 h

Procedure:
Compound 4 (0.5 g, 1.58 mmol) was treated with NH3/MeOH (20 mL) at room temperature and stirred overnight. The crude product was obtained by evaporation and used directly in the next step.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[O:11])(=O)=O.C(N(CC)C(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:35]=1[CH2:36][NH:37][C:38]1[C:39]2[CH:46]=[CH:45][N:44]([C@H:47]3[C@H:54]4[C@H:50]([O:51][C:52]([CH3:56])([CH3:55])[O:53]4)[C@@H:49]([CH2:57][NH:58][CH3:59])[O:48]3)[C:40]=2[N:41]=[CH:42][N:43]=1.C(#N)C.S([O-])(=O)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C(OCC)C>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:58]([CH2:57][C@@H:49]2[C@@H:50]3[C@@H:54]([O:53][C:52]([CH3:56])([CH3:55])[O:51]3)[C@H:47]([N:44]3[C:40]4[N:41]=[CH:42][N:43]=[C:38]([NH:37][CH2:36][C:35]5[CH:60]=[CH:61][C:62]([O:64][CH3:65])=[CH:63][C:34]=5[O:33][CH3:32])[C:39]=4[CH:46]=[CH:45]3)[O:48]2)[CH3:59])=[O:11])=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(NC(=O)NCCCOS(C)(=O)=O)cc1
Reactant: CNC[C@H]1O[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)CCCNC(=O)Nc3ccc(C(C)(C)C)cc3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 65 °C
Reaction time: 16.5 h
Yield: 61.8 %

Procedure:
A mixture of 3-(3-(4-(tert-butyl)phenyl)ureido)propyl methanesulfonate (224 mg, 0.682 mmol), tetra-n-butylammonium iodide (252 mg, 0.682 mmol) and N,N-diisopropylethylamine (120 μL, 0.67 mmol) was treated with N-(2,4-dimethoxybenzyl)-7-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methylamino)methyl)tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (320 mg, 0.68 mmol) in acetonitrile (7.8 mL, 150 mmol) and the solution was heated at 65° C. After 16.5 h at 65° C., HPLC indicated the reaction was about 78-85% complete. An additional 60 mg of mesylate (in 0.4 mL CH3CN) and 67 mg of TBAI were added and continued heating for 7 h. The reaction mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography (60 g silica gel, 3-7% 7N NH3 in CH3OH/CH2Cl2) to yield the product contaminated with TBAI. The material was dissolved in 20 mL 1/1 ethyl acetate/ethyl ether and washed with three 10 mL portions of H2O. The organic phase was dried over Na2SO4, filtered and concentrated to yield the title compound (295 mg, 62%) as a foam: MS (ESI+) for C38H51N7O6 m/z 702.2 (M+H)+: (ESI−) for C38H51N7O6 m/z 700.3 (M−H)−; HPLC purity 96% (ret. time, 3.69 min).