Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([C:18]([Cl:21])=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2.[CH3:23][O:24][C:25]([CH2:27][CH2:28][C:29](Cl)=[O:30])=[O:26].C(=O)([O-])O.[Na+]>O.C(N(CC)CC)C.ClCCl>[Cl:22][C:3]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][C:25]([O:24][CH3:23])=[O:26])=[CH:20][CH:19]=[C:18]([Cl:21])[C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N)c3Cl)c2n1
Reactant: COC(=O)CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC(=O)Nc1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-2-methylquinoline (1.67 g), triethylamine (0.9 ml) and anhydrous dichloromethane (84 ml) was added 3-methoxycarbonylpropionyl chloride (0.7 ml). After stirring at ambient temperature for 9 hours, triethylamine (1.8 ml) and 3-methoxycarbonylpropionyl chloride (1.4 ml) were added thereto and the mixture was stirred for additional 30 minutes. The reaction mixture was washedwith water and saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluted with chloroform to give 8-[2,6-dichloro-3-(3-methoxycarbonylpropionylamino)benzyloxy]-2-methylquinoline (2.04 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>C(O)C>[ClH:1].[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(N)cc1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: COc1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Product: Cl
Yield: 25.7 %

Procedure:
5 ml of ethanol were added to a mixture of 4.8 g of 4,7-dichloroquinazoline and 3.0 g of p-anisidine. The resulting mixture was heated, whereupon the solids dissolved and the reaction mixture immediately then solidified. After cooling, the solidified product was collected and washed with ethanol and the resulting crystals were recrystallized from ethanol, giving 2.0 g (yield 62%) of the desired Compound No. 10 in the form of a fine pale yellow powder having a melting point of 276°-279° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.[CH3:20][O-:21].[Na+].O>CO>[CH3:20][O:21][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc2nc(Cl)cc(CCNC(C)=O)c2c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2nc(OC)cc(CCNC(C)=O)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
A mixture of N-[2-(2-chloro-6-methoxyquinolin-4-yl)ethyl]acetamide (0.9 g, 3.2 mmol) and sodium methoxide (30 g, 28% methanol solution) in methanol (20 ml) was stirred at 60° C. overnight. The reaction mixture was poured into water, and the organic layer was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate) and recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the title compound (0.46 g, 52%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[C:21]1([C@H:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:29][C@@H:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:28])=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: C[C@@H](N)c1ccccc1
Product: CCCN(CC(=O)N[C@H](C)c1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and (1R)-1-phenylethanamine: MS (APCI) m/z 390 (M+1).
Reaction SMILES: O=S(Cl)Cl.[CH:5]1([NH:9][C:10]2([CH2:15]Cl)[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6]1.ClCCN.[CH3:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[N:31]=[C:32]=[O:33]>>[CH:5]1([N:9]2[C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:15][O:33][C:32]2=[N:31][C:23]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=2[CH3:21])[CH2:8][CH2:7][CH2:6]1
Reactant: ClCC1(NC2CCC2)CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Agent: NCCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OCC2(CCCC2)N1C1CCC1

Procedure:
1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. The 2-hydroxyethylamine was reacted with cyclobutanone according to Method B4a, Step 1 to give 5-aza-12-oxadispiro[3.1.4.2]dodecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1-(cyclobutylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to 1-(cyclobutylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclobutyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH2:31]>O1CCCC1>[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH:31][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: COC(CN)OC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(CNC(=O)C(CSC(C)=O)CC(C)C)OC
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
A solution of 2-[(acetylthio)methyl]-4-methylpentanoic acid (2.0 g) and triethyl amine (1.0 g) in 50 ml of tetrahydrofuran (THF) is cooled to -5° C. Ethyl chloroformate (1.1 g) in 5 ml of THF is added dropwise and the reaction mixture is stirred at -5° C. for 30 minutes. Amino acetaldehyde dimethyl acetal (1.1 g) in 20 ml of THF is added dropwise to the mixed anhydride solution at -5° C. After addition, it is stirred at 10°-20° C. for 2 hours and stored at 0° C. for about 16 hours. Triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. The residue (2.1 g) is dissolved in 3 ml of ether. Silica gel (5 g) is added and ether is evaporated off. This is placed on top of 40 g of dry silica gel and washed through with pentane, 1:1 pentane:ether and finally ether. Product elutes with ether to yield 1.3 g of product which solidifies to give a low melting waxy solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:37])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C@@H:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:16]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:38][C:39]1[CH:44]=[C:43]([CH2:45][O:46][CH3:47])[CH:42]=[C:41]([F:48])[C:40]=1[C:49]1[N:54]=[C:53]([C:55](O)=[O:56])[CH:52]=[CH:51][C:50]=1[F:58].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:37][C:55]([C:53]3[CH:52]=[CH:51][C:50]([F:58])=[C:49]([C:40]4[C:39]([F:38])=[CH:44][C:43]([CH2:45][O:46][CH3:47])=[CH:42][C:41]=4[F:48])[N:54]=3)=[O:56])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C@@H:17]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:24])[CH3:23])[C@H:16]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: COCc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (324 mg, 0.606 mmol), 6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (180 mg, 0.606 mmol) and HATU (0.460 g, 1.21 mmol) in DMF (3.0 mL) and DIPEA (0.316 mL, 1.82 mmol) was stirred at room temperature for 2 h. After quenching the reaction with water, the mixture was extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to give an amide intermediate, 4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[S:18][C:17]([Br:19])=[CH:16][C:14]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]=O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][C:10]2=[N:15][C:14]3[CH:16]=[C:17]([Br:19])[S:18][C:13]=3[C:12](=[O:20])[N:11]2[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(CNCc2ccccc2)nc2cc(Br)sc12
Reactant: C=O
Solvent: C1CCOC1
Product: O=c1c2sc(Br)cc2nc2n1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of a crude product (185 mg) of 2-[(benzylamino)methyl]-6-bromothieno[3,2-d]pyrimidin-4(3H)-one, 37% aqueous formaldehyde solution (1 mL) and tetrahydrofuran (2 mL) was stirred at room temperature for 1 hr. The precipitate was collected by filtration, and washed successively with water and ethyl acetate to give a crude product (104 mg) of the title compound as a pale-yellow solid.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=34)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.Cl.Cl.[CH3:31][N:32]1[CH2:39][CH2:38][CH2:37][C:33]21[CH2:36][NH:35][CH2:34]2.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:28][O:27][C:4]1[CH:3]=[C:2]([N:35]2[CH2:36][C:33]3([N:32]([CH3:31])[CH2:39][CH2:38][CH2:37]3)[CH2:34]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=23)[CH:15]=[CH:14][N:13]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: CN1CCCC12CNC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 83.9 %

Procedure:
N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 300 mg, 0.78 mmol), 8-methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 118 mg, 0.94 mmol) and DIPEA (0.162 mL, 0.94 mmol) were heated at 100° C. in DMA (4 mL) for 1.75 h. The mixture was then absorbed onto an SCX column, then the column was washed with CH3OH and then eluted with 1:1 7M methanolic ammonia in CH2Cl2. Fractions that contained the desired product were combined and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (321 mg, 84%) as an orange foam; 1H NMR: 1.62-1.74 (2H, m), 1.74-1.85 (2H, m), 1.91-2.00 (2H, m), 2.00-2.06 (2H, m), 2.38 (3H, s), 2.65 (2H, t), 3.03 (2H, t), 3.71 (2H, d), 3.95 (3H, s), 4.04-4.15 (4H, m), 6.27 (1H, s), 7.01 (1H, d), 8.01 (1H, s), 8.09 (1H, s), 8.33 (1H, d), 8.54 (1H, s); m/z: ES′ MH+ 491.6.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][C@@H:7]([O:20]C(=O)C)[C@@H:6]1[NH:24][C:25](=[O:27])[CH3:26])(=O)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[OH:20][CH:7]1[O:8][C@H:9]([CH2:15][OH:16])[C@H:10]([OH:11])[C@H:5]([OH:4])[C@H:6]1[NH:24][C:25]([CH3:26])=[O:27]
Reactant: CC(=O)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 0 °C
Yield: 179.1 %

Procedure:
Commercially available acetic acid (2S,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yl ester (10.0 g, 26 mmol) was dissolved in 116 mL of abs. CH2Cl2 and treated with trimethylsilyl triflate (14.27 g, 64 mmol). The reaction was allowed to proceed over night at 45° C. After cooling to 0° C., triethylamine (4.88 mL, 35 mmol) was added, the mixture diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent yielded 10.3 g of the title compound as brownish oil which was used without further purification for the next step, MS (ISP): 330.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)#[CH:12]>C(N(CC)CC)C.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>[F:19][C:15]1[CH:14]=[C:13]([C:11]#[C:12][C:2]2[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1cccc(F)c1
Reactant: Cc1cc(C)c(N)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(N)c(C#Cc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of Cul (41 mg, 0.2 mmol) in triethylamine (12 ml) were added 2-bromo-4,6-dimethyl-pyridin-3-ylamine (870 mg, 4.33 mmol), (PPh3)2PdCl2 (152 mg, 0.22 mmol), and 1-ethynyl-3-fluorobenzene (500 μl, 4.33 mmol). The reaction mixture was stirred for 30 min. at room temperature and for 3 h under reflux. The solvent was evaporated and the crude residue was purified by flash chromatography (cyclohexane/ethyl acetate 4:1) to yield 745 mg (3.10 mmol, 72%) of (2-(3-fluoro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][NH:23][C@@H:24]([CH2:35][CH2:36][C:37]2[NH:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:41]=2)[C:25](OCC2C=CC=CC=2)=[O:26])=[CH:14]1.C(N(CC)CC)C>C1COCC1>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:23]2[C@@H:24]([CH2:35][CH2:36][C:37]3[NH:38][CH:39]=[C:40]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:41]=3)[C:25](=[O:26])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:11]2=[S:12])=[CH:14]1
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1[C@H](CCc2nc(-c3ccccc3)c[nH]2)N(Cc2c[nH]c3ccccc23)C(=S)N1c1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (93 mg; 1 eq.) in THF (2 ml). The mixture is stirred for 2 hours at approximately 20° C. then diluted with 4 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine). Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound (90 mg; 84% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([CH:20]=[N:21][CH:22]=4)[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:23].FC1C=CC(C2C(C3C=NC(CN)=CC=3)=CC=CN=2)=CC=1C.C(O)=[O:47]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[N:18][C:17]([CH2:22][NH:21][CH:20]=[O:47])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(-c2ncccc2-c2ccc3cncn3c2)ccc1F
Reactant: O=CO
Agent: Cc1cc(-c2ncccc2-c2ccc(CN)nc2)ccc1F
Product: Cc1cc(-c2ncccc2-c2ccc(CNC=O)nc2)ccc1F
Temperature: 100 °C
Reaction time: 72 h

Procedure:
6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine (Compound 269) can be prepared via the reactions shown in the first two steps of Scheme 20: (2′-(4-Fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine (2.18 g) and formic acid (15 mL) were stirred and heated under nitrogen atmosphere at 100° C. After 72 h, the reaction mixture was concentrated and partitioned between CH2Cl2/aq. NaHCO3. Usual work-up and purification by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 50-100% EtOAC/hexanes as elutant) provided 630 mg of N-((2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)formamide as an off white solid. N-((2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)formamide (630 mg) and POCl3 (3 mL) were stirred and heated in benzene (20 mL) overnight at 75° C. The reaction mixture was cooled to room temperature and concentrated. Subsequently, ice/water solution was added to the crude residue followed by CH2Cl2 and aq. NaHCO3. Upon allowing the solution warm to room temperature, organic layer was separated, stirred over Na2SO4, filtered and concentrated. Purification of the crude residue by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 2-8% MeOH/CH2Cl2 as an eluting solvent) provided 320 mg of 6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine as an off-white solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14](=[O:39])[CH2:15][CH2:16][CH2:17][CH:18](Br)[CH:19]1[O:37][C@H:22]2[CH2:23][C@@H:24]([OH:36])[C@H:25](/[CH:26]=[CH:27]/[C@@H:28]([OH:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])[C@H:21]2[CH2:20]1.Cl.P([O-])([O-])([O-])=O>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14](=[O:39])[CH2:15][CH2:16][CH2:17]/[CH:18]=[C:19]1/[CH2:20][C@@H:21]2[C@@H:25](/[CH:26]=[CH:27]/[C@@H:28]([OH:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])[C@H:24]([OH:36])[CH2:23][C@@H:22]2[O:37]/1
Reactant: COC(=O)CCCC(Br)C1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCCCl)[C@H](O)C[C@@H]2O1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCC/C=C1/C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCCCl)[C@H](O)C[C@@H]2O1
Temperature: 50 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
Under an atmosphere of nitrogen, 0.1 ml of DBU was added to a solution of 50 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-bromo-6,9-epoxy-11,15-dihydroxy-20-chloroprost-13-enoic acid methyl ester (prepared as described in Example 3) in 0.2 ml of toluene. The mixture was stirred at 50° C. for 1 hour, then at 70° C. for 1.5 hours and then cooled to 0° C. To the reaction mixture were added 0.5 ml of 1 N hydrochloric acid and 0.5 ml of phosphate buffer solution (pH 6.86) with cooling to 0° C. The reaction mixture was extracted quickly with diethyl ether. The extract was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on Florisil using a mixture of ethyl acetate and n-hexane (1:1) containing 0.1% of triethylamine as eluent to give 15 mg of the title compound having the following physical characteristics:
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClC(Cl)C.C1C=CC=CC=1.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: CC(Cl)Cl
Solvent: c1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (1.0 g) in dichloroethane (10 ml) was added rhodium(II) octanoate (10 mg) under refluxing. After refluxing for 30 minutes, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in benzene (5 ml) and then evaporated in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: C1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CN2CCCCCC2)cn1
Temperature: 80 °C
Yield: 58.4 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (419 mg, 2.59 mmole) in 5 mL of dry acetonitrile is 512 mg (5.18 mmol) of azacycloheptane followed by 358 mg (2.59 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 340 mg (59% yield) of 1-(6-Chloro-pyridin-3-ylmethyl)-azepane. Diagnostic 1H NMR (400 MHz, CDCl3) 1.40–1.70 (m, 8H), 2.50–2.65 (m, 4H), 3.65 (s, 2H), 7.28 (d, 1H, J=8.3 Hz), 7.65–7.70 (m, 1H), 8.30 (d, 1H, J=2.1 Hz); MS 225.3 (M+H).
Reaction SMILES: [CH2:1]([C@@H:3]([CH2:6][CH2:7][CH3:8])[CH2:4][OH:5])[CH3:2].CCN(CC)CC.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH2:1]([C@@H:3]([CH2:6][CH2:7][CH3:8])[CH2:4][O:5][S:17]([CH3:16])(=[O:19])=[O:18])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC[C@H](CC)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@H](CC)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a −10° C. stirred solution of (S)-2-ethyl-pentan-1-ol (1.30 g, 11.2 mmol) in dry CH2Cl2 (35 mL) was added Et3N (2.33 mL, 16.8 mmol). The reaction was stirred at this temperature for 15 minutes and methansulfonyl chloride (0.952 mL, 12.3 mmol) was added. The reaction was allowed to warm to room temperature overnight with good stirring. The reaction was washed with 1N HCl (3×30 mL), sat. NaHCO3 (3×30 mL), and brine (2×30 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a quantitative yield of crude product.