Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH:15]1[CH:16]=[CH:17][N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[NH:21][CH2:20][C:19]=12.C(N(C(C)C)CC)(C)C>ClCCl>[N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([N:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[CH2:24][N:18]4[CH:17]=[CH:16][CH:15]=[C:19]4[CH2:20]3)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(Cl)c1ccc(-n2cccn2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-n2cccn2)cc1)N1Cc2cccn2Cc2ccccc21
Reaction time: 18 h
Yield: 76.7 %

Procedure:
The 4-(pyrazol-1-yl)benzoyl chloride (0.75 g) was added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.61 g) and diisopropylethylamine (0.47 g) in dichloromethane (25 ml). After 18 hours at room temperature, the reaction mixture was washed with water and a saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.90 g), m.p. 179-181° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:29]2[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:9][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: OB(O)c1cccnc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Temperature: 85 °C

Procedure:
A 500 mL RBF was charged with (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (20.00 g, 54.8 mmol), 2-fluoropyridin-3-ylboronic acid (13.89 g, 99 mmol) and sodium carbonate (23.22 g, 219 mmol). DMF (130 mL) was added and the mixture was stirred for 1 minute before tetrakis(triphenylphosphine) palladium (4.43 g, 3.83 mmol) and water (52.2 mL) were added. The mixture was capped with argon, equipped with a reflux condenser and heated at 85° C. for 16 hrs. The mixture was cooled to RT and the resulting yellow precipitate was filtered. The filtrate was diluted with water (200 mL) and saturated ammonium chloride (200 mL), leading to the formation of a white precipitate and a brown semisolid. The precipitate was filtered and the semisolid was triturated with water (˜200 mL) to provide a brown solid which was also filtered and washed with water. The combined solids were washed excessively with water and dried overnight under a stream of air to afford (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as tan solid which was used without further purification. MS m/z=382.0 [M+H].
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C:12]3[C:25]([C:26](=O)[C:27]=2[CH:28]=1)=[CH:24][C:23]1[CH2:22][C:21]2[C:16](=[CH:17][C:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:19][CH:20]=2)[C:15](=O)[C:14]=1[CH:13]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>COCCOCCOC>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[C:27](=[CH:26][C:25]3[C:12]([CH:11]=2)=[CH:13][C:14]2[C:23](=[CH:22][C:21]4[C:16]([CH:15]=2)=[CH:17][C:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:19][CH:20]=4)[CH:24]=3)[CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc2c(c1)C(=O)c1cc3c(cc1C2)C(=O)c1cc(CCCCCC)ccc1C3
Solvent: COCCOCCOC
Product: CCCCCCc1ccc2cc3cc4cc5cc(CCCCCC)ccc5cc4cc3cc2c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 20 grams of 3,10-dihexyl-7,14-dihydropentacene-5,12-dione and 200 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 15 minutes. To this was added 13.4 grams of sodium borohydride, and stirring was continued at room temperature overnight. To the resulting mixture was added 126 mL of methanol over 1.25 hours. The temperature increased to 40° C. and was maintained at 40° C. during the addition by intermittent application of a cold water bath. When addition was complete stirring was continued at room temperature. After stirring for 2 hours at room temperature an additional 50 mL of 2-methoxyethyl ether was added. After stirring with methanol for a total of 3.5 hours, 300 mL of acetic acid was added, and the resulting mixture was heated to 60° C. for 1.5 hours. To the mixture was added 100 mL of concentrated hydrochloric acid and heating at 60° C. was continued for one hour. The mixture was cooled to room temperature and the resulting solid was collected by filtration and washed with 500 mL of water. The solid was washed with 500 mL of acetone and then 60 mL of tetrahydrofuran. The solid was washed with an additional one liter of acetone and dried to give 2,9-dihexylpentacene.
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:42])[O:33][C@@H:34]1[C@H:41]2[C@H:37]([O:38][CH2:39][CH2:40]2)[O:36][CH2:35]1)[C@H:9]([OH:30])[CH2:10][N:11]([O:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:11]([O:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:10][C@@H:9]([OH:30])[C@@H:8]([NH:31][C:32](=[O:42])[O:33][C@@H:34]2[C@H:41]3[C@H:37]([O:38][CH2:39][CH2:40]3)[O:36][CH2:35]2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(N)cc1
Reaction time: 16 h
Yield: 71 %

Procedure:
A solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (237 mg, 0.390 mmol) in absolute methanol (5 mL) was combined with Palladium on carbon (10 wt %, 50 mg) and reduced under a Hydrogen atmosphere over 16 hours. The reaction was filtered and evaporated in vacuo. The residue was purified on silica gel eluting with 50-60% ethyl acetate in hexane. Fractions containing the product were combined and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate (160 mg, 71%) as a white solid. H1-NMR (chloroform-D3): 0.90 (m, 6H), 1.58 (m, 7H), 2.95 (m, 5H), 3.69 (m, 2H), 3.91 (m, 4H), 4.13 (m, 1H), 4.26 (b, 2H), 4.80 (d, 1H), 5.00 (m, 1H), 5.63 (d, 1H), 6.67 (d, 2H), 7.22 (m, 5H), 7.58 (d, 2H).). MS(ESI): 600(M+Na).
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:37][CH2:38][O:39][CH3:40].C(N(CC)C(C)C)(C)C>CN(C=O)C.[I-].[K+]>[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[N:6]([CH2:37][CH2:38][O:39][CH3:40])[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1
Reactant: COCCBr
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c(CC2CCCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (300 mg, 0.64 mmol) was added slowly to an ice-cooled slurry of sodium hydride (51 mg, 1.3 mmol, 60% dispersion in mineral oil) in DMF (10 ml). After stirring for 0.5 h 1-bromo-2-methoxy-ethane (139 mg, 10 mmol), N,N-diisopropylethylamine (0.3 ml) and potassium iodide (5 mg) was added. The mixture was stirred at room temperature for 0.5 h then 100° C. for 16 h. The volatiles were removed in vacuo from the cooled reaction mixture. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organics were dried (Na2SO4) and the solvent removed in vacuo. The residue was triturated with ethyl acetate to afford the title compound as a solid (306 mg, 65%). Mass spectrum (Electrospray LC/MS) Found 529 (MH+). C27H27F3N4O2S requires 528. The product was dissolved in methanol and treated with 1M HCl in diethyl ether (excess). The volatiles were removed in vacuo and the residue triturated with methanol-ethyl acetate to afford the hydrochloride salt of the title compound as a white solid (66 mg).
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.[BH3-]C#N.[Na+]>CO>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:40][C:36]2[S:35][CH:39]=[CH:38][N:37]=2)[CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: O=Cc1nccs1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3nccs3)C3CCCc4cccnc43)cc2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
To a stirred solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.295 g, 0.643 mmol) in anhydrous methanol (6.5 mL), at room temperature, was added thiazole-2-carboxaldehyde (0.33 mL, 3.76 mmol) followed by NaBH3CN (0.131 g, 2.09 mmol) and the resultant solution was stirred at room temperature. After 2 days, an additional amount of NaBH3CN (0.134 g, 2.10 mmol) was added and the solution was stirred at room temperature for an additional 4 days. The solvent was removed under reduced pressure and CH2Cl2 (20 mL) and water (10 mL) were added to the residue. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (2 mm plate, 40:1 CH2Cl2-MeOH containing 1% NH4OH) afforded 0.164 g of the protected amine as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([CH:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19][C:18]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:17]1=2)=O)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([CH:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19][C:18]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:17]1=2)=[S:41])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(C(=S)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Yield: 96.3 %

Procedure:
After 1.09 g of Compound 4 obtained in Example 4 was dissolved in 10 ml of toluene, 1.07 g of Lawesson's reagent was added to the solution. The mixture was heated under reflux for an hour. The reaction mixture was allowed to stand at room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: hexane-ethyl acetate (2:1 )]to obtain 1.46 g of a crude product. The crude product was recrystallized from ethyl acetate-hexane to obtain 1.09 g of Compound 36.
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1>CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]#[N:2])=[C:6]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH:7]=1
Reactant: Fc1ccc(Br)c(-n2cccn2)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-n1cccn1
Temperature: 110 °C
Yield: 72.4 %

Procedure:
To a stirred suspension of CuCN (358 mg, 4.0 mmol, Aldrich) in DMF (2 mL, Sure Seal) was added a solution of 1-(2-Bromo-5-fluoro-phenyl)-1H-pyrazole (964 mg, 4.0 mmol) in DMF (2 mL) and the resulting clear solution was stirred in an oil bath heated at 110° C. under nitrogen for 1.5 h. After cooling, the mixture was concentrated in vacuo and the residue mixed with 14% aqueous NH4OH (10 mL) was stirred at room temperature for 0.5 h. To this was added EtOAc (15 mL) and the mixture stirred for additional 0.5 h. The EtOAc extract was washed with dil. NH4OH and then with brine, dried (Na2SO4), filtered, and concentrated. The residual oil was purified by column chromatography (SiO2, 0-10% EtOAc/CH2Cl2) to obtain 542 mg of the title compound as a white crystalline solid: TLC Rf 0.42 (CH2Cl2); HPLC rt=1.94 min. LC/MS m/z 188 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 6.55 (1H, dd, J=2.6, 1.7 Hz, 9-CH), 7.10-7.13 (1H, m, 5-CH), 7.59 (1H, dd, J=9.5, 2.5 Hz, 3-CH), 7.76 (1H, dd, J=8.7, 5.5 Hz, 6-CH), 7.80 (1H, d, J=−1.2 Hz, 10-CH), 8.25 (1H, d, J=2.7 Hz, 8-CH); 13C NMR (CDCl3, 125.8 Hz) δ ppm 100.5 (d, J=3.8 Hz, 1-C), 109.1 (9-CH), 111.9 (d, J=27 Hz, 3-CH), 114.9 (d, J=23 Hz, 5-CH), 116.6 (7-CN), 129.5 (8-CH), 136.7 (d, J=10 Hz, 6-CH), 142.8 (10-CH), 144.2 (d, J=12 Hz, 2-C), 165.5 (d, J=258 Hz, 4-CF); HRMS (ESI) calcd for C10H7FN3 (M+H) 189.0576, found 189.0568 (δ-4.5 ppm); UV (MeOH) λ max 224 nm (ε2.54×104), 261 nm (ε1.20×104); Anal. calcd for C10H7FN3: C, 64.16; H, 3.24; N, 22.45; found C, 64.02; H, 3.16; N, 22.68.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]([C:18]1[CH:19]=[N:20][C:21]([NH:24][C:25]3[N:26]=[CH:27][C:28]4[CH:33]=[C:32]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[N:31]([CH:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[C:29]=4[N:30]=3)=[CH:22][CH:23]=1)=[O:17])[CH2:12]2)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:36][N:35]([CH3:37])[C:34]([C:32]1[N:31]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:29]2[N:30]=[C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([C:16]([N:11]4[CH2:10][CH:9]5[NH:8][CH:13]([CH2:14][CH2:15]5)[CH2:12]4)=[O:17])=[CH:19][N:20]=3)[N:26]=[CH:27][C:28]=2[CH:33]=1)=[O:38]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 150.7 %

Procedure:
To a stirring solution of 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.232 g, 1. mmol) in CH2Cl2 (4 mL) was added a solution of 4M HCl in dioxane (2.54 mL, 10.14 mmol, 10 eq) at 25° C. After 4 hours stirring at 25° C. the reaction mixture was filtered and washed with CH2Cl2 (5 mL). The residue was collected and taken up in water then basified with 1M NaOH and extracted with CH2Cl2 (2×15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to a tan solid. The crude was purified using Column Chromatography (MeOH/CH2Cl2) giving the desired product as a white solid (0.290 g, 0.594 mmol, 59%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[C:9]1[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.[OH:27]P([O-])(O)=O.[K+].Cl([O-])=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([OH:27])=[O:18])=[C:9]1[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C=O)c2ccccc2n1Cc1ccccc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: CC(C)c1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 1-benzyl-2-isopropyl-1H-indole-3-carbaldehyde (Compound 40, 545 mg, 2.0 mmol) in acetonitrile (6 ml), tert-butanol (6 ml) and H2O (12 ml) was added 2-methyl-2-butene (8 ml), potassium phosphate monobasic (5.4 g, 40 mmol), sodium chlorite (80%, 2.3 g, 40 mmol). The mixture was stirred at room temperature for 16 h, more potassium phosphate monobasic (5.4 g, 40 mmol) and sodium chlorite (80%, 2.3 g, 40 mmol) were added and the mixture was stirred at room temperature for an additional 24 h, at which time more potassium phosphate monobasic (5.4 g, 40 mmol), sodium chlorite (80%, 2.3 g, 40 mmol), H2O (8 ml), and 2-methyl-2-butene (8 ml) were added and the mixture was stirred for another 48 h. The solvent was removed in vacuo and the residual solid was washed with CHCl3 (×3) and filtered. The filtrate was concentrated and was purified by flash chromatography on silica gel eluting with 0-20% EtOAc-hexanes to yield 1-benzyl-2-isopropyl-1H-indole-3-carboxylic acid (Compound 41) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH2:13]([O:20][N:21]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: NOCc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(=NOCc1ccccc1)C(=O)OCC
Temperature: 75 °C
Yield: 99 %

Procedure:
Di-ethylketomalonate (60 g) was added at 20° C. to a stirred suspension of O-benzylhydroxylamine (57.8 g) in IMS (500 ml) containing pyridine (30 ml). The reaction was heated at 75° C. for 4 hr. The reaction was cooled and solvents removed under reduced pressure. The residue was partitioned between EtOAc (500 ml) and water (300 ml) and the organic layer separated, washed with water (250 ml) and dried over MgSO4. Solvents were evaporated to give the title compound 95.3 g, as a colourless oil (99% th, ca 3% w/w residual EtOAc) which was used without further purification.
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][C@@H:26]([O:29][CH3:30])[CH2:25][C:24]4=[O:31])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:32])[O:11]1)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[OH:1][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][C@@H:26]([O:29][CH3:30])[CH2:25][C:24]4=[O:31])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:32])[O:11]1
Reactant: CO[C@@H]1CCN(c2ccc3c(c2)OC[C@H]2[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)N32)C(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: CO[C@@H]1CCN(c2ccc3c(c2)OC[C@H]2[C@H](CO)OC(=O)N32)C(=O)C1
Yield: 75.3 %

Procedure:
Using compound (3R,3aS)-3-((t-butyldimethylsiloxy)methyl)-7-((R)-4-methoxyl-2-oxopiperidin-1-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (1.5 g, 3.24 mmol), and TBAF (1.27 g, 4.86 mmol) as starting materials, DCM as solvent, preparation following the method as described in Example 1 (b) afforded white solid 0.85 g, yield 75.0%.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]C)=[O:21])([CH2:7][OH:8])[CH2:5][OH:6]>>[ClH:1].[NH2:3][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:7][OH:8])[CH2:5][OH:6]
Reactant: COC(=O)CCCCCCCCCCCC(N)(CO)CO
Agent: Cl
Product: NC(CO)(CO)CCCCCCCCCCCC(=O)O
Temperature: 90 °C

Procedure:
2N Hydrochloric acid (0.5 ml) was added to 10 mg of 2-amino-2-(11-methoxycarbonylundecyl)-1,3-propanediol hydrochloride and the mixture was heated at 90° C. for 1 hour. The solvent was distilled away under reduced pressure to give 10 mg of the subject compound.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH3:17][C:18]1[C:26]2[C:25](=[O:27])[NH:24][C:23]([C:28]([O:30]CC)=O)=[N:22][C:21]=2[S:20][CH:19]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:76]2[CH:80]=[N:79][C:78]([O:81][CH2:82][CH2:83][O:84][C:85]3[CH:86]=[C:87]([CH2:91][NH2:92])[CH:88]=[CH:89][CH:90]=3)=[N:77]2)C=CC=CC=1>>[CH3:17][C:18]1[C:26]2[C:25](=[O:27])[NH:24][C:23]([C:28]([NH:92][CH2:91][C:87]3[CH:88]=[CH:89][CH:90]=[C:85]([O:84][CH2:83][CH2:82][O:81][C:78]4[N:79]=[CH:80][NH:76][N:77]=4)[CH:86]=3)=[O:30])=[N:22][C:21]=2[S:20][CH:19]=1
Reactant: CCOC(=O)c1nc2scc(C)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: Cc1csc2nc(C(=O)NCc3cccc(OCCOc4nc[nH]n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained according to the method described in U.S. Pat. No. 4,054,656 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (126 mg, 79%).
Reaction SMILES: C([O:8][C:9](=[O:21])[CH2:10][N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[N:13]=[CH:12]1)C1C=CC=CC=1>CCO>[CH3:20][N:16]1[CH2:17][CH2:18][C:19]2[N:11]([CH2:10][C:9]([OH:21])=[O:8])[CH:12]=[N:13][C:14]=2[CH2:15]1
Reactant: CN1CCc2c(ncn2CC(=O)OCc2ccccc2)C1
Solvent: CCO
Product: CN1CCc2c(ncn2CC(=O)O)C1

Procedure:
The final compound was prepared using a method analogous to that of Example 14 step 14.2, (5-methyl-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)acetic acid benzyl ester replacing intermediate 14.1 and using EtOH instead of MeOH/AcOH. LC-MS (B): tR=0.13 min; [M+H]+: 196.31.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[S:31]([OH:35])([CH3:34])(=[O:33])=[O:32]>C(Cl)Cl>[S:31]([OH:35])(=[O:33])(=[O:32])[CH3:34].[S:31]([OH:35])(=[O:33])(=[O:32])[CH3:34].[NH2:10][CH2:9][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][CH:25]=[CH:24]2)=[O:19]
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: NC[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (S)-tert-butyl 2-(4-chlorophenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (29, 7.8 g) was added CH2Cl2 and MsOH and the solution was stirred overnight at room temperature. The solvents were evaporated and the crude 30 was dried on the high vacuum. Recrystallization (isopropanol) and drying on the high vacuum gave pure (S)-3-amino-2-(4-chlorophenyl)-N-(isoquinolin-6-yl)propanamide dimesylate salt (30, 7.2 g, 77%, >99% S-enantiomer).