Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N+:14]([O-])=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: [O-][n+]1cc2ccccc2cc1CCCCOCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(CCCCOCc2ccccc2)cc2ccccc12

Procedure:
3-(4-Benzyloxybutyl)isoquinoline-2-oxide (2.0 g) and phosphorous oxychloride (5 ml) were reacted at 110° C. for 2 hr. The reaction solution was evaporated, to the resulting residue were added ethyl acetate and aqueous solution of saturated sodium bicarbonate, and the resulting organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate followed by evaporating the solvent. The resulting 1-chloro-3-(4-benzyloxybutyl)isoquinoline obtained as a yellow oil was reacted with N-ethylpiperazine (5 ml) and potassium carbonate (0.5 g) at 120° C. for 5 hr. The reaction solution was then cooled and then partitioned by adding ethyl acetate and water thereto. The resulting organic layer was washe with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system) to give 1.32 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(O)(C)C.[CH2:17]([O:29][CH2:30][CH:31]1[O:33][CH2:32]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[ClH:34]>O>[ClH:34].[OH:33][CH:31]([CH2:30][O:29][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:32][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CCCCCCCCCCCCOCC1CO1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCOCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Yield: 33.1 %

Procedure:
L-arginine (17.4 g, 0.1 mols) was dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 24.2 g (0.1 mols) of dodecylglycidyl ether (made by Sakamoto Yakuhin Kogyo Co., Ltd.) were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that dodecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60 made by Merck & Co., Inc., eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 15.0 g of N-(2-hydroxy-3-dodecyloxypropyl)-L-arginine hydrochloride (yield 36.0%).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.Cl.[CH3:16][NH:17][CH:18]1[CH2:21][NH:20][CH2:19]1.[C:22]([C:26]1[O:27][C:28]2[C:29](=[C:31]([C:43]#[N:44])[C:32]([CH3:42])=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:34]=2F)[N:30]=1)([CH3:25])([CH3:24])[CH3:23].O.C(=O)(O)[O-].[Na+]>[Cl-].[Na+].O.CS(C)=O>[C:22]([C:26]1[O:27][C:28]2[C:29](=[C:31]([C:43]#[N:44])[C:32]([CH3:42])=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:34]=2[N:20]2[CH2:21][CH:18]([NH:17][CH3:16])[CH2:19]2)[N:30]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)C)nc2c1C#N
Reactant: CNC1CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CNC1CN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(C)(C)C)oc23)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Triethylamine (316 μl, 2.27 mmol) and 3-methylaminoazetidine hydrochloride trifluoroacetate (140 mg, 590 μmol) were added to a dimethyl sulfoxide (3.5 ml) solution of 2-tert-butyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-72) (140 mg, 454 μmol), followed by stirring overnight at 90° C., then 3-methylaminoazetidine hydrochloride trifluoroacetate (53.7 mg, 227 μmol) and triethylamine (63.3 μl, 454 μmol) were added, followed by stirring at 90° C. for 8 hours. After cooling, saturated sodium bicarbonate water and saturated brine were added to the reaction liquid, and this was extracted with ethyl acetate and chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol-100:1) to obtain the entitled compound (118 mg, 69%) as a pale yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:23]([F:24])=[C:22]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[F:33])C1C=CC=CC=1>[C].[Pd].C1COCC1>[F:24][C:23]1[C:17]2[O:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:33])[CH:11]=3)=[N:19][C:18]=2[CH:20]=[CH:21][C:22]=1[O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2c1F
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
A mixture of N-((2S)-1-((2-(4-(benzyloxy)-3-fluorophenyl)-7-fluoro-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (1.05 g), 10% palladium-carbon (containing water (50%), 1.00 g) and THF (10 mL) was stirred at room temperature for 30 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure to give the title compound (810 mg).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>N1C=CC=CC=1>[C:1]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.3 %

Procedure:
Trityl chloride (18.8 g, 67.4 mmol) was added to an ice cold (0° C.) stirring solution of 14a (9.9 g, 67.4 mmol) in 80 mL of pyridine. The reaction mixture was warmed to room temperature and stirred under argon for 2 days, during which time a white byproduct formed. The solvent was removed under reduced pressure, and the resulting material was redissolved in ice cold THF. The insoluble byproduct was removed by filtration, and the filtrate was dried under reduced pressure to obtain 22.6 g (86%) of an orange oil 15a. 1H-NMR (400 MHz, CDCl3, δH ppm): 7.43 (6H, m, p-Ar), 7.29 (6, m, m-Ar), 7.22 (3H, m, o-Ar), 3.65 (3H, s, CO2CH3), 3.05 (2H, t, 3JH—H=6.6 Hz, HO—CH2), 2.29 (2H, t, 3JH—H=7.5 Hz, CH2CO2), 1.54-1.71 (4H, m, 2CH2), 1.33-1.45 (m, 2H, CH2). HRMS (EI): m/z calcd 388.2038 (C26H28O3), found 388.2039 [M]+.
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[CH:14]=[CH:15][N:16]2[C:21]=1[C:20](=[O:22])[N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([C@@H:29]([NH:31]C(=O)OC(C)(C)C)[CH3:30])=[N:17]2.Cl.O1CCOCC1>>[NH2:31][C@H:29]([C:18]1[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:22])[C:21]2=[C:13]([S:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:39])[CH:14]=[CH:15][N:16]2[N:17]=1)[CH3:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Sc3ccccc3NCCN(C)C)c2c(=O)n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1nn2ccc(Sc3ccccc3NCCN(C)C)c2c(=O)n1-c1ccccc1
Yield: 63 %

Procedure:
(S)-tert-Butyl (1-(5-((2-((2-(dimethylamino)ethyl)amino)phenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (432 mg, 0.79 mmol) was treated with a solution of hydrochloric acid in dioxane (4M, 3.9 mL, 15.76 mmol) according to the method described in Preparation 1 to obtain 267 mg (90% purity, 63% yield) of the title compound as a hydrochloride salt that was used in the following step without further purification.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].Br[C:9]1[C:10](=O)[CH2:11][CH2:12][C:13]=1[O:14]C.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O>[CH3:2][CH:3]([C:4]1[NH:5][C:10]2[CH2:11][CH2:12][C:13](=[O:14])[C:9]=2[N:6]=1)[CH3:7]
Reactant: COC1=C(Br)C(=O)CC1
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1nc2c([nH]1)CCC2=O
Temperature: 100 °C
Yield: 61.8 %

Procedure:
A mixture of 2-methylpropanimidamide hydrochloride (0.770 g), 2-bromo-3-(methyloxy)-2-cyclopenten-1-one (1 g) and potassium carbonate (2.17 g) in N,N-dimethylformamide (15 mL) were heated at 100° C. for 4.5 hr and then heated at 110° C. for 1 hour. The reaction mixture was cooled down to room temperature and dichloromethane was added. The white suspension (potassium carbonate) was filtered off and the filtrate concentrated under vacuum. The residue was purified by reverse phase chromatography using an acetonitrile—0.1% NH3:water—with an ammonium carbonate buffer modifier using a 5%-95% gradient. The desired fractions were combined and concentrated under vacuum to yield the title compound (531 mg). LC/MS MH+ 165, Rt 0.36 min (2 minute run).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([S:32](=[O:38])(=[O:37])[NH:33][CH:34]2[CH2:36][CH2:35]2)=[CH:28][C:22]=1[C:23]([N:25]=[C:26]=[O:27])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([S:32]([NH:33][CH:34]2[CH2:36][CH2:35]2)(=[O:38])=[O:37])=[CH:28][C:22]=1[C:23]1[NH:25][C:26](=[O:27])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Reactant: O=C=NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2cc(S(=O)(=O)NC3CC3)ccc2Cl)nn1-c1ccc(C(F)(F)F)cc1
Yield: 60.5 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 0.050 g, 0.18 mmol), 2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl isocyanate (step-4 of Intermediate-40, 0.108 g, 0.36 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.050 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 0.40-0.42 (m, 2H), 0.50-0.54 (m, 2H), 2.17-2.21 (m, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.92-7.98 (m, 2H), 8.15-8.21 (m, 4H), 12.84 (s, 1H); MS (m/z): 457.15 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5](=[C:7]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[C:8]1=O)[O-])C.[K+].[O:16]=[S:17]1(=[O:24])[CH2:21][CH2:20][CH:19]([NH:22][NH2:23])[CH2:18]1>>[O:16]=[S:17]1(=[O:24])[CH2:21][CH2:20][CH:19]([N:22]2[C:8]3[C@@H:9]4[CH2:10][C@@H:11]4[CH2:12][C:7]=3[C:5]([C:4]([OH:3])=[O:14])=[N:23]2)[CH2:18]1
Reactant: CCOC(=O)C([O-])=C1C[C@H]2C[C@H]2C1=O
Reactant: NNC1CCS(=O)(=O)C1
Agent: [K+]
Product: O=C(O)c1nn(C2CCS(=O)(=O)C2)c2c1C[C@H]1C[C@@H]21

Procedure:
(1aR,5aR)-2-(1,1-Dioxo-tetrahydrothiophen-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid was prepared in a manner similar to that described in Method C and D using potassium 2-ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate and (1,1-dioxo-tetrahydrothiophen-3-yl)hydrazine.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([CH3:30])([CH3:29])[C:22]([O:24]CCCC)=[O:23])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.O[Li].O>C1COCC1.O.CO>[OH:1][C:2]([CH3:37])([CH3:38])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([CH3:30])([CH3:29])[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CCCCOC(=O)C(C)(C)C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H](c1ccc(C#CC(C)(C)C(=O)O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
To a stirred solution of butyl 4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2,2-dimethylbut-3-ynoate (11.3 mg, 0.022 mmol) in 1:1:2 THF/H2O/MeOH (2 mL) was added LiOH.H2O (60 mg, 1.4 mmol). The mixture was stirred at rt for 1 day and concentrated. The residue was purified by prep HPLC to afford 4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2,2-dimethylbut-3-ynoic acid (7 mg, 72%) as a solid. LC-MS Method 1 tR=1.58 min, m/z=464, 406; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.51 (d, 3H), 1.58 (s, 6H), 2.10-2.40 (5H), 2.90 (m, 1H), 5.67 (q, 1H), 6.86 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:25][CH:26]=[CH:27][C:28]=1B(O)O)(=[O:20])[CH3:19].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:20])[CH3:19]
Reactant: Cc1nccc(Nc2cc(Cl)nn(C)c2=O)n1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccnc(C)n3)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 33 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 225a (200 mg, 0.80 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (318 mg, 0.80 mmol), PdCl2(dppf) (65.3 mg, 0.080 mmol), K3PO4 (624 mg, 2.4 mmol), sodium acetate (200 mg, 2.4 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 225b as a red solid (150 mg, 47%). MS-ESI: [M+H]+ 569.3
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[O:16]1CCC[CH2:17]1>>[CH3:10][O:9][C:6]1[C:7]2[NH:8][C:17](=[O:16])[NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=1
Reactant: C1CCOC1
Reactant: COc1ccc(CCN(C)C)c(N)c1N
Product: COc1ccc(CCN(C)C)c2[nH]c(=O)[nH]c12

Procedure:
500 mg of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dimethylamine is heated under reflux for 3 hours with 40 ml of tetrahydrofuran and 500 mg of N,N'-carbonyldiimidazole. After concentration, the residue is combined with methanol and water. The mixture is again concentrated and dried over phosphorus pentoxide, thus obtaining 410 mg of 7-methoxy-4-[2-(N,N-dimethylamino)ethyl]-2,3-dihydro-2-benzimidazolone, mp 197°-199° C.
Reaction SMILES: [CH2:1](O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:33]1[CH:37]2[CH2:38][NH:39][CH2:40][CH:36]2[CH2:35][N:34]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C=O.[OH-].[Na+]>ClCCCl>[CH3:1][N:39]1[CH2:38][CH:37]2[CH2:33][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH:36]2[CH2:40]1
Reactant: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
Step BI (1): Sodium triacetoxyborohydride (666 mg, 3.14 mmol) was added to a magnetically stirred solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (165 mg, 0.777 mmol) and 37% formaldehyde (144 mg, 1.77 mmol) in 1,2-dichloroethane (10 mL). The resulting mixture was allowed to stir at rt for 16 h. Sodium hydroxide solution (2 mL of a 1 N solution) was added with vigorous stirring. Stirring was stopped and the layers were allowed to separate. The organic layer was removed and concentrated in vacuo with heating. Acetone was added to the residue, and the solution was decanted. The decanted portion was concentrated in vacuo to afford 80 mg (46% yield) of tert-butyl 5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate as a colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([Cl:31])(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[ClH:31].[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)NCCCSc1ccncc1
Yield: 79.2 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 830 mg (4.98 mmol) of cinnamoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 1.10 g of the desired compound (free base) (88.8%, colorless powder), mp: 116.0°-11.7.0° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[CH:6]=1)=O.[BH4-].[Li+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:2][CH2:3][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]2)[CH:6]=1
Reactant: COC(=O)c1ccnc(N2CCN(C(=O)OCC(C)(C)C)CC2)c1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)COC(=O)N1CCN(c2cc(CO)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.3 %

Procedure:
2,2-Dimethylpropyl 4-[4-(methoxycarbonyl)pyridin-2-yl]-1-piperazinecarboxylate (365 mg) obtained in Example 5 was dissolved in tetrahydrofuran (5 mL), and lithium tetrahydroborate (30 mg) was added thereto, stirred at room temperature for 30 minutes, and then 1 N sodium hydroxide was added thereto and stirred at room temperature for 30 minutes. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 11 mg of the entitled compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCOC(C)=O.O=[Pt]=O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:11]=1
Reactant: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2cccnc2)c1
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of 3-(3-nitrophenyl)pyridine (0.22 g, 1.1 mmol) in EtOAc (10 mL) was added PtO2 (0.025 g, 10% mol) and the mixture was stirred for 4 h under H2 (1 atm). It was filtered through Celite® and the combined filtrates were concentrated to yield 3-(pyridin-3-yl)benzenamine (0.175 g, 94%) as a semi solid which was used without further purification. 1H NMR (DMSO-d6): 8.77 (d, J=2.0 Hz, 1H), 8.53 (dd, J=8.8 Hz, 1.6 Hz, 1H), 7.57-7.52 (m, 1H), 7.46-7.43 (m, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.86-6.80 (m, 2H), 6.63-6.60 (m, 1H), 5.23 (s, 2H); Exact mass: 170.0, Found: 171.0 (M+1)+.
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6]1)([CH3:3])[CH3:2].[F:23][C:24]([F:39])([F:38])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:37])[CH2:33][C:34](O)=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:34](=[O:35])[CH2:33][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([F:38])([F:23])[F:39])=[O:37])[C@H:7]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(F)(F)F
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CC(=O)Nc2ccccc2C(F)(F)F)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 14 h

Procedure:
A solution of (1R*,3R*,4S*)-N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)cyclohexane-1,4-diamine (47.4 mg, 0.11 mmol, see example 25b) in DMF (2 mL) was charged sequentially with N-(2-trifluoromethyl-phenyl)-malonamic acid (29.5 mg, 0.12 mmol), BOP (72 mg, 0.16 mmol), and N-methyl morpholine (60 uL, 0.54 mmol). The solution was stirred for 14 h and the reaction was partitioned between water and EtOAc. The organic phase was washed with sat. NH4Cl, water, and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by RP-HPLC to afford the desired product as a white powder (presumed mono-TFA salt). MS found: (M+H)+=554.32.
Reaction SMILES: [Br-].[C:2]([CH2:7][S+](C)C)([O:4][CH2:5][CH3:6])=[O:3].N12CCCN=C1CCCCC2.[C:22]1(=[O:27])[CH2:26][CH2:25][CH:24]=[CH:23]1.Cl.[Cl-].[Na+]>C1(C)C=CC=CC=1>[O:27]=[C:22]1[CH2:26][CH2:25][CH:24]2[CH:23]1[CH:7]2[C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: O=C1C=CCC1
Reactant: CCOC(=O)C[S+](C)C
Agent: Cl
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1C2CCC(=O)C21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A suspension of carboethoxymethyl dimethylsulfonium bromide (45.5 g, 198.6 mmol) in toluene (350 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (30.2 g, 198.4 mmol). The resulting mixture was stirred at room temperature. After one hour, the reaction mixture was treated with 2-cyclopenten-1-one (19.57 g, 238.4 mmol). After an additional 18 hours, the reaction mixture was added to a 1 N hydrochloric acid/sodium chloride solution. The resulting mixture was extracted with diethyl ether. The combined ether extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica-gel chromatography, eluting with a linear gradient of 10% ethyl acetate/hexanes to 50% ethyl acetate/hexanes, to give 22.81 g (68%) of the title compound. Melting point: 36-38° C.