Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].[F:25][C:26]1[CH:27]=[C:28]([C:40]#[N:41])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=2)=[CH:30][CH:31]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:38][C:35]3[CH:36]=[CH:37][C:32]([C:29]4[C:28]([C:40]#[N:41])=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)=[CH:33][CH:34]=3)[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: N#Cc1cc(F)ccc1-c1ccc(CO)cc1
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccc(F)cc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4-fluoro-4′-(hydroxymethyl)biphenyl-2-carbonitrile (1.4 g), 1,1′-(azodicarbonyl)dipiperidine (2.2 g), tributylphosphine (2.2 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (2 g, 86%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[CH:20](OC)(OC)OC>>[C:1]1([S:7]([CH2:10][C:11]2[O:12][CH:20]=[N:14][N:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)CS(=O)(=O)c1ccccc1
Reactant: COC(OC)OC
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cc1nnco1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To 1.73 g (8.07 mmol) of benzenesulfonyl-acetic acid hydrazide were added 20 mL of trimethyl orthoformate and 1.26 g (8.07 mmol, 1 eq) of phosphorous oxychloride. The reaction mixture was stirred one hour at RT, and concentrated under reduced pressure. Column chromatography on silica gel with EtOAc/hexane 2:1 yielded 930 mg (52%) of 2-benzenesulfonylmethyl-[1,3,4]oxadiazole as a white solid, MS: 225 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][CH2:12][C:13]([O:15]C)=O>C1COCC1.C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)([OH:15])[CH2:12][O:11][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)OC
Reactant: Clc1cccc([Mg]Br)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: COCC(O)(c1cccc(Cl)c1)c1cccc(Cl)c1

Procedure:
A solution of 1,1-bis(3-chlorophenyl)-2-methoxyethanol (47 g) (obtained by the reaction of 3-chlorophenylmagnesium bromide with methyl 2-methoxyacetate in THF) in formic acid (44 cc) is heated to reflux for 5 hours, cooled and poured into a mixture of saturated sodium carbonate solution (500 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×250 cc) and with saturated sodium chloride solution (200 cc), then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis(3-chlorophenyl)acetaldehyde (36.9 g) in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15].[C:16]([N:23]1[CH2:31][CH2:30][CH2:29][C@@H:25]([C:26](O)=[O:27])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:26]([C@@H:25]2[CH2:29][CH2:30][CH2:31][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)=[O:27])=[C:3]([NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: COCCCNc1cc(C#N)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COCCCNc1cc(C#N)ccc1NC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
4-Amino-3-(3-methoxypropylamino)benzonitrile (41B) (3.50 mmol, 718 mg) in DMF (25 mL) was added (R)-(−)—N-Boc-Nipecotic acid (4.55 mmol, 1.04 g) and N-methylmotpholine (10.50 mmol, 1.15 mL). The reaction mixture was stirred at rt for 5 min and then added HATU (5.25 mmol, 2.00 g) and kept stirring at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, NaHCO3, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel EtOAc-hexane: 1:2) to afford (R)-tert-butyl 3-(4-cyano-2-(3-methoxypropylamino)phenylcarbamoyl)piperidine-1-carboxylate (41C) (2.40 mmol, 1.01 g, three-step yield: 68.6%). ESI-MS: m/z 417.5 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:10]=1.S(=O)(=O)(O)[OH:25].[OH-].[Na+]>CO>[NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:9][CH:10]=1
Reactant: C[C@H](CCc1ccc(C#CCCCC2CCCCC2)s1)C(N)O
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](CCc1ccc(C(=O)CCCCC2CCCCC2)s1)C(N)O
Yield: 91 %

Procedure:
(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol (126 mg, 0.41 mmol) obtained in Example 1 was dissolved in methanol (2 ml), and 6N sulfuric acid (2 ml) was added thereto followed by heating under reflux for 4 hours. After the reaction solution was made alkaline with a 1N aqueous sodium hydroxide solution, the resulting solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (130 mg, 91% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(=O)C.[O:11]=[P:12]1([CH2:26][OH:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13]1>C(N(CC)CC)C>[O:11]=[P:12]1([CH:26]=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13]1
Reactant: O=P1(CO)Oc2ccccc2-c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CP1(=O)Oc2ccccc2-c2ccccc21
Reaction time: 0.17 h

Procedure:
Purified dichloro methane anhydride 100 ml is cooled using dry ice and acetone. When the cooling is completed, oxalyl chloride 42.5 ml (0.05 mol) and dimethyl sulfur oxide 5.76 ml (0.08 mol) are added. Thereafter, they are stirred for 10 minutes. Then, (10-oxo-10H-9-oxa-10-phosphaphenanthrene-10-yl)-methanol (compound F) 10 g (0.04 mol) is added thereto. Thereafter, they are stirred for 1 hour. Then, triethylamine 22 ml is slowly added thereto. Thereafter, they are stirred at a normal temperature for 12 hours. When the reaction is completed, distilled water 100 ml is added thereto. Thereafter, solution is extracted using dichloro methane. The extracted solution is processed using 1N-hydrochloric acid water, saturated sodium bicarbonate solution, saturated brine water, or the like, and is dried using magnesium sulfate anhydride. The dried solution is filtered under reduced pressure and evaporated under reduced pressure to obtain brown solution. The obtained product is used for reaction in immediately subsequent step.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH3:3][C@H:2]([C@@H:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCCCCC=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: CCCCC[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
Was prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with hexanal.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:17][CH3:18])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH:15][OH:16])=[NH:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].CO[C:21](OC)(N(C)C)[CH3:22]>>[CH2:1]([C:3]1[C:4]([O:17][CH3:18])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]3[N:14]=[C:21]([CH3:22])[O:16][N:15]=3)[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: COC(C)(OC)N(C)C
Reactant: CCc1c(OC)nc2nc(C(=N)NO)cn2c1C
Product: CCc1c(OC)nc2nc(-c3noc(C)n3)cn2c1C
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 1.70 g of 6-ethyl-N-hydroxy-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxamidine and 3.5 ml of dimethylacetamide dimethyl acetal was heated at 100° C. for 15 minutes and the resulting mixture was evaporated to dryness and purified by flash chromatography. The resulting solid was crystallized from aqueous methanol to give 1.76 g of 6-ethyl-7-methoxy-5-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)imidazol[1,2-a]pyrimidine (95% yield) as a white crystalline solid melting at 176°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]([C@H:36]([CH2:41][OH:42])[CH2:37][CH2:38][CH2:39][NH2:40])[CH2:32][CH:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7](=[O:9])[NH:40][CH2:39][CH2:38][CH2:37][C@H:36]([N:31]([S:28]([C:25]1[CH:24]=[CH:23][C:22]([NH2:21])=[CH:27][CH:26]=1)(=[O:30])=[O:29])[CH2:32][CH:33]([CH3:34])[CH3:35])[CH2:41][OH:42])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)O
Reactant: CC(C)CN([C@H](CO)CCCN)S(=O)(=O)c1ccc(N)cc1
Product: COC(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from general procedure A using (2S)-2-methoxycarbonylamino-3-naphthalen-1-yl-propionic acid and amine intermediate VII. The final product was obtained in 76% yield. Rf=0.57, EtOAc 100%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([O:18][CH2:25][CH:24]=[CH2:23])[CH2:15][CH:16]=[CH2:17])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC(O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(CC=C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48 %

Procedure:
(S)-4-(2-Hydroxy-pent-4-enyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.54 g, 8.91 mmol) was dissolved in dry tetrahydrofuran (60 mL). Sodium hydride (60% suspension in mineral oil, 360 mg) was added. The mixture was stirred at 0° C. for 5 min. Then allylbromide (1.60 mL) was added. The mixture was stirred at room temperature for 18 h. Solvents were evaporated and the residue was extracted with diethyl ether and citric acid solution. The organic layer was washed with saturated sodium chloride solution and concentrated. The crude material was purified through flash column chromatography (silica gel, 5-30% ethyl acetate/hexanes) to afford (S)-4-(2-allyloxy-pent-4-enyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (1.38 g, 48% yield for two steps) as an oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 12H), 1.56, 1.60 (2×s, 3H), 1.64-1.77 (m, 1H), 1.80-2.07 (m, 1H), 2.32 (br. s., 2H), 3.48 (br. s., 1H), 3.79-4.23 (m, 5H), 4.98-5.19 (m, 3H), 5.26 (d, J=17.2 Hz, 1H), 5.72-5.98 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([I:11])=[C:6]([NH2:12])[CH:5]=1.[CH2:14](I)[CH3:15].CC(C)([O-])C.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH2:14][CH3:15])[C:7]([I:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: COC(=O)c1cc(N)c(I)c(O)c1
Reactant: CCI
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc(N)c1I
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 3-amino-5-hydroxy-4-iodo-benzoic acid methyl ester (0.25 g, 0.85 mmol, 1.0 equiv) in DMF (3 mL) and ethyl iodide (0.10 mL, 0.146 g, 0.94 mmol, 1.1 equiv) at 0° C. was added sodium tert-butoxide (0.11 g, 0.94 mmol, 1.1 equiv) in small portions over a time period of 10 min. After stirring for 1 h, the cooling bath was removed and the the reaction mixture stirred at rt for an additional 18 h. The solution was concentrated by evaporation under reduced pressure and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (2:1) yielding 0.19 g (69%) of the title compound. 1H NMR (250 MHz, CDCl3): δ 1.49 (t, J=7.0 Hz, 3H), 3.89 (s, 3H), 4.11 (q, J=7.0 Hz, 2H), 4.33 (br s, 2H), 6.82 (d, J=2.7 Hz, 1H), 7.07 (d, J=2.7 Hz, 1H). MS (EI): 321.0 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.3 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.075 g, 0.34 mmol) in N-methyl 2-pyrolidone (0.5 mL) was added powdered potassium hydroxide (0.095 g, 1.7 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.102 g, 0.85 mmol) was added and stirred for further at 80 deg C. 3 h. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC to get the desired compound as yellow oil (0.020 g, 13% yield). 8-Chloro-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.020 g, 0.06 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.008 g, 0.06 mmol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.008 g, 32% yield).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:33][C:34]1[S:35][C:36]([S:40](Cl)(=[O:42])=[O:41])=[C:37]([CH3:39])[N:38]=1>ClCCl>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([S:40]([C:36]5[S:35][C:34]([CH3:33])=[N:38][C:37]=5[CH3:39])(=[O:42])=[O:41])[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(n3ncc(COc4ccc(-n5cnnn5)nc4)n3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-((2-(piperidin-4-yl)-2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine hydrochloride (Intermediate 15, 0.050 g, 0.153 mmol), dichloromethane (1.5 mL), and triethyl amine (0.043 mL, 0.306 mmol) was added 2,4-dimethyl-thiazole-5-sulfonyl chloride (0.049 g, 0.229 mmol) and the reaction stirred at room temperature for 2 hours. The solution was concentrated and purified by flash column chromatography on silica gel eluting with 0-100% ethyl acetate in hexanes to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[O:13])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)c(I)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetic acid (280 mg, 0.83 mmol) and tert-butyl piperazine-1-carboxylate (185 mg, 0.99 mmol) in DMF (10 mL) at room temperature, BOP (550 mg, 1.25 mmol) and DIEA (321 mg, 2.4 9 mmol) were added and the resulting mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=3:1) to afford the desired product (350 mg, 68.7% yield). ESI-MS m/z: 510.3[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24](=O)[CH3:25]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][CH2:24][CH3:25])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CC=O
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCNc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC

Procedure:
5-Ethyl-2-(4-ethylamino-1H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (100 mg, 0.32 mmol) and acetaldehyde (30 μl, 0.53 mmol). The title compound was obtained as light grey powder (23 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:37][C:38]([C@@H:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][N:41]2C(OC(C)(C)C)=O)=[O:39])[C:10](=[O:36])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][S:24]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])(=[O:26])=[O:25])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:37][C:38]([C@@H:40]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][NH:41]2)=[O:39])[C:10](=[O:36])[N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][S:24]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])(=[O:26])=[O:25])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)[C@@H]3Cc4ccccc4CN3C(=O)OC(C)(C)C)CC2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccccc2C2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)[C@@H]3Cc4ccccc4CN3)CC2)c(C)c1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-(N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}phenyl) piperidyl]ethyl)carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step a) (146 mg, 0.18 mmol) and 50% TFA in CH2Cl2 (10 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min) provided the title compound (TFA salt) as a white foam (81 mg). MS (ESI, pos. ion) m/z: 699 (M+1); (ESI, neg. ion) m/z: 697 (M−1). Calc'd for C30H43ClN4O4S: 698.27.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[OH:11].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[S:1]1
Reactant: OC1CCc2ccccc2S1
Reactant: ClCC1CO1
Product: c1ccc2c(c1)CCC(OCC1CO1)S2
Yield: 65 %

Procedure:
The procedure of Step A of Example 1 is followed, starting from 1.72 g (10.34 mmol) of thiochromanol and 7.653 g (82.72 mmol) of epichlorohydrin. 1.5 g (6.721 mmol) of 2,3-epoxypropoxythiochroman are obtained.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:23])[C:4]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5].[H-].[Na+].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C=O)C>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:12]([C@H:9]2[CH2:10][CH2:11][C@@H:6]([C:4](=[O:5])[N:3]([O:2][CH3:1])[CH3:23])[CH2:7][CH2:8]2)[C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:29][CH:28]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H]1CC[C@@H](N(Cc2ccc(Cl)cc2)C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of benzyl cis-4-(methoxy(methyl)carbamoyl)cyclohexylcarbamate in DMF (12 mL) under an atmosphere of nitrogen was cooled to 0° C., followed by treatment with sodium hydride (150 mg of 60 wt % NaH in oil, 3.75 mmol). After stirring at room temperature for 30 min, the reaction mixture was cooled to 0° C. and charged with 4-chlorobenzyl bromide (793 g, 3.75 mmol). The resulting solution was warmed slowly to room temperature and stirred for another 16 hr prior to partitioning of the solution between saturated aqueous NaHCO3 and ethyl acetate. The aqueous layer was further extracted with additional ethyl acetate. After separating the organic layer, the combined organic layer was washed with saturated aqueous sodium chloride, dried using MgSO4, filtered, and concentrated to give benzyl 4-chlorobenzyl(cis-4-(methoxy(methyl)carbamoyl)cyclohexyl)carbamate as a colorless oil (1.19 g, 2.67 mmol, 86.0%). 1H NMR (CDCl3, 300 MHz) δ 7.45-7.05 (m, 9H), 5.09 (bs, 2H), 4.41 (bs, 2H), 4.30-4.04 (m, 1H), 3.65 (s, 3H), 3.14 (s, 3H), 2.91 (m, 1H), 2.02-1.84 (m, 4H), 1.70-1.47 (m, 4H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].ClC[C:22]([O:24][CH2:25]OC)=C.C(N(CC)CC)C>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:22][O:24][CH2:25][O:1][C@@H:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCCCCCCCCC[C@H](O)CC(=O)OCC
Reactant: C=C(CCl)OCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC[C@@H](CC(=O)OCC)OCOC
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.2 %

Procedure:
Ethyl (S)-3-hydroxytetradecanoate (2.00 g, 7.3 mmol) and 2-(chloromethyl)-3,5-dioxahexa-1-ene (manufactured by Tokyo Kasei Co., Ltd., 1.20 g, 8.8 mmol) were dissolved in THF (10 mL), p-toluenesulfonic acid (p-TsOH, 10 mg) was added, and the mixture was stirred at room temperature for 15 hr. Triethylamine (1 mL) was poured into the reaction mixture and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate (0.5 g) and filtered. The solvent was evaporated to give the corresponding ethyl (S)-3-methoxymethoxytetradecanoate (2.20 g, yield 95%).