Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[CH3:30]O>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([O:28][CH3:30])=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (30.0 mg, 0.079 mmol) was added 1.25M hydrogen chloride in methanol (1.907 mL, 2.384 mmol). The reaction was stirred at room temperature for 4 h. The mixture was concentrated and purified by HPLC to give the title compound. LCMS m/z=392.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.9 Hz, 0.3H), 1.46 (d, J=6.5 Hz, 2.7H), 1.67-1.84 (m, 5H), 2.01-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.59-2.67 (m, 1H), 3.05-3.21 (m, 4H), 3.36-3.47 (m, 1H), 3.51-3.58 (m, 1H), 3.61 (s, 3H), 3.73-3.84 (m, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=2)[CH2:2][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])=[N:8][CH:9]=1
Reactant: CCOP(OCC)OCC
Reactant: Cc1ccc(Oc2cccc(CCl)c2)nc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cccc(Oc2ccc(C)cn2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 59.3 %

Procedure:
2-(3-(Chloromethyl)phenoxy)-5-methylpyridine (2.0 g, 8.8 mmol) was treated neat with triethylphosphite (1.89 mL, 11 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (10-75%, EtOAc:CH2Cl2) to afford the title compound (1.75 g, 59% yield) as a thick oil.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].Cl.[NH2:23][CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl.Cl.NCC1(O)CCCCC1>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:23][CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[N:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: NCC1(O)CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cccnc2c1NCC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Triethylamine (8.38 mL, 60.1 mmol) was added over 10 min to a stirred mixture of 4-chloro-3-nitro-1,5-naphthyridine (6.00 g, 28.6 mmol) and 1-aminomethyl-1-cyclohexanol hydrochloride (5.00 g, 30.1 mmol) in dichloromethane (115 mL) at 0° C. The solution was allowed to warm to rt and more 1-aminomethyl-1-cyclohexanol hydrochloride (0.2 g) was added. The solution was stirred overnight and more triethylamine (0.5 mL) was added. After 30 min, the solution was partitioned between saturated aqueous sodium bicarbonate (100 mL) and chloroform (200 mL). The aqueous layer was extracted with chloroform (3×200 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (80 mL), dried over MgSO4, filtered, concentrated under reduced pressure, and dried under vacuum to afford 1-{[(3-nitro[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol as a yellow solid (8.65 g, 100%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:15]=2)[C:10]([CH3:22])=[CH:9][C:8]1=[O:23].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[N:17]1([C:14]2[CH:15]=[C:16]3[C:11]([C:10]([CH3:22])=[CH:9][C:8](=[O:23])[N:7]3[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(-n3ccnc3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n(CC=O)c2cc(-n3ccnc3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 70 mg of 1-(1,3-dioxolan-2-ylmethyl)-7-(1H-imidazol-1-yl)-4-methylquinolin-2(1H)-one, 2 mL of 80% aqueous trifluoroacetic acid solution, was added, and stirred at room temperature for 1 hour, thereafter allowed to stand at room temperature for 14 hours. Ethyl acetate was added, neutralized with aqueous saturated sodium hydrogen carbonate solution, ethyl acetate was added, the organic layer was separated, and the aqueous layer was extracted 3 times with ethyl acetate. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (7-(1H-imidazol-1-yl)-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde as a white solid.
Reaction SMILES: [I-].[Br:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH2:32]([O:35][C:36]1([CH3:65])[CH2:41][CH2:40][N:39]([C:42]2[N:47]3[N:48]=[C:49]([CH:51]=O)[CH:50]=[C:46]3[N:45]=[C:44]([CH3:53])[C:43]=2[C@H:54]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:38][CH2:37]1)[CH:33]=[CH2:34]>C1COCC1>[CH2:32]([O:35][C:36]1([CH3:65])[CH2:37][CH2:38][N:39]([C:42]2[N:47]3[N:48]=[C:49]([CH:51]=[CH:6][CH2:5][C:4]4[CH:26]=[CH:27][CH:28]=[CH:29][C:3]=4[Br:2])[CH:50]=[C:46]3[N:45]=[C:44]([CH3:53])[C:43]=2[C@H:54]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:40][CH2:41]1)[CH:33]=[CH2:34]
Reactant: Brc1ccccc1CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(C=O)nn23)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(C=CCc4ccccc4Br)nn23)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.6 %

Procedure:
To a suspension of (2-bromophenethyl)triphenylphosphonium iodide (0.121 g, 0.212 mmol) in THF (1 ml) at 0° C. was added sodium hydride (8.68 mg, 0.217 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to −78° C. and (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.050 g, 0.106 mmol) dissolved in THF (1 ml) was added dropwise and the mixture was stirred at −78° C. for 1 h then warmed to room temperature and stirred 2 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 20 CV) to give the title compound (0.0386 g, 0.060 mmol, 57.0% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65-7.50 (m, 1H), 7.40-7.30 (m, 1H), 7.28-7.20 (m, 1H), 7.17-7.05 (m, 1H), 6.73-6.55 (m, 1H), 6.54-6.44 (m, 1H), 6.11-5.74 (m, 3H), 5.56-4.97 (m, 2H), 4.33-4.11 (m, 4H), 4.07-3.98 (m, 1H), 3.94 (d, J=4.4 Hz, 1H), 2.62 (s, 3H), 2.01-1.79 (m, 3H), 1.77-1.64 (m, 1H), 1.29-1.19 (m, 15H), (4 piperidine protons not visible in NMR). LCMS (M+H) calcd for C33H43BrN4O4: 640.24. found: 641.4.
Reaction SMILES: [CH2:1]([N:3](C(OC(C)(C)C)=O)[C@H:4]([CH3:9])[CH2:5][C:6]([OH:8])=[O:7])[CH3:2].Cl>C(OCC)(=O)C>[CH2:1]([NH:3][C@H:4]([CH3:9])[CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)[C@H](C)CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN[C@H](C)CC(=O)O

Procedure:
To a mechanically stirred solution of 53 (2.2 g, 9.7 mmol) in ethyl acetate (180 mL) at -15° C. was vigorously bubbled HCl gas for 30 min. The cooling bath (ethanol/ice) was removed and the solution purged with argon for 1.0 h to remove excess HCl. Concentration furnished the amine.HCl 54 as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>ClCCl>[CH2:29]([S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Reaction time: 4 h

Procedure:
Cyclopropanecarboxylic acid [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (0.05, 0.17 mmol) was suspended in dichloromethane (2 mL). Pyridine (0.027 mL, 0.34 mmol) and ethanesulfonyl chloride (0.019 mL, 0.204 mmol) were added and the mixture was stirred for 4 hours. A further equivalent of pyridine and ethanesulfonyl chloride were added and the mixture was stirred overnight. The volatiles were removed in vacuo and the crude product was purified by preparatory HPLC. LCMS method: 2, RT: 3.11 min, MI: 386 [M+1]. NMR (1H, DMSO, 300 MHz): 0.82 (d, 4H), 1.24 (t, 3H), 2.01 (brs, 1H), 3.20 (q, 2H), 7.27 (dd, 1H), 7.36 (d, 2H), 7.68 (m, 2H), 8.02 (d, 2H), 9.98 (brs, 1H), 11.15 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1>>[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])=[CH:10][CH:9]=1
Reactant: COC(=O)CN
Reactant: O=Cc1ccc(O)cc1
Product: COC(=O)CNCc1ccc(O)cc1
Yield: 40 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 4-hydroxybenzaldehyde. Yield 40%. MS M+H calculated 196.1; found 196.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: Clc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 24 h
Yield: 57.2 %

Procedure:
A pressure tube was charged with N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg, 0.29 mmol), 4-chloropyridine hydrochloride (87 mg, 0.58 mmol), triethylamine (59 mg, 0.58 mmol), and ethanol (5 mL), sealed, and placed in a 120° C. bath. After 24 h, the mixture was cooled, concentrated, and the residue purified by column chromatography (SiO2: 5 to 10% 2 N ammonia in methanol:methylene chloride) affording 70 mg (57%) of the title compound.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2>CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2
Reactant: C#CCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCO)c21

Procedure:
Using Method D above, propargyl alcohol (43.9 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material 1 supra) using DPPFPdCl2 (12.8 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH:12]=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Li+].[BH4-].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][OH:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cc(C=O)cnc2c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2cc(CO)cnc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 7-methyl-3-quinoline carboxaldehyde (200 mg, 1.168 mmol) in THF (4.5 ml) was added 2M LiBH4 solution in THF (2.337 ml, 4.67 mmol) at 0° C. Reaction mixture was stirred at 0° C. for 2 h, then slowly poured into NaHCO3 sat. solution and extracted twice with ethyl acetate. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the crude material, which was purified by silica gel chromatography (cyclohexane/ethyl acetate form 100/0 to 0/100) to afford the title compound. HPLC (Method G) Rt=0.68 min, MS (Method V) [M+H]+=174.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]#[N:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([CH3:21])[C:18]#[N:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(CC#N)c2ccccc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Yield: 71 %

Procedure:
To a stirred solution of (1-tert-butoxycarbonyl indol-3-yl)acetonitrile (5.30 g, 20.7 mmol) in THF (20 mL, anhyd) chilled to −78° C. was added dropwise a 1.0M solution of LiHMDS in THF (21 mL, 21 mmol). After 40 min iodomethane (1.3 mL, 21 mmol) was added rapidly, and the reaction mixture was allowed to warm to ambient temperature. After 15 h the reaction was quenched by addition of 0.2N HCl (100 mL) and extracted with Et2O (2×100 mL). The combined extracts were washed with brine, dried (Na2SO4), concentrated and chromatographed (silica gel, 6% EtOAc/Hex) to give the title compound (4.0 g, 71%) as a light yellow oil. 1H-NMR (CDCl3): δ 8.17 (1H, br d), 7.60 (2H, m), 7.37 (1H, br d), 7.30 (1H, app t), 4.10 (1H, q), 1.76 (3H, d), 1.68 (9H, s).
Reaction SMILES: [CH2:1]1[CH:5]2[C:6](=[O:16])[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[CH3:17][O-].[Na+].CI>C(O)C>[CH3:17][N:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10](=[O:11])[N:4]2[CH2:3][CH2:2][CH2:1][CH:5]2[C:6]1=[O:16]
Reactant: O=C1Nc2ccccc2C(=O)N2CCCC12
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Reaction time: 6 h

Procedure:
A mixture of 4.32 g. of 1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c] [1,4]benzodiazepin-5,11(10H)-dione, 1.2 g. of sodium methylate and 40 ml. of ethanol is stirred at room temperature for 3 houRS and 3 ml. of methyl iodide is added. The reaction mixture is stirred for 6 hours longer and concentrated. The residue is mixed with benzene and water and the layers are separated. The benzene layer is washed with water and concentrated. The product is further purified by recrystallization from ethyl acetate and melts at 124°-126°C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.ClOC(C)(C)C.[CH2:15]([S:17][CH:18]([CH3:24])[C:19](OCC)=[O:20])[CH3:16]>>[CH2:15]([S:17][C:18]1([CH3:24])[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:8]=2)[NH:6][C:19]1=[O:20])[CH3:16]
Reactant: CCOC(=O)C(C)SCC
Reactant: Nc1ccc(F)cc1
Agent: CC(C)(C)OCl
Product: CCSC1(C)C(=O)Nc2ccc(F)cc21

Procedure:
The compound is prepared as described under 1.1, starting with 24.4 g (0.22 mole) of 4-fluoroaniline, 26.2 ml of t-butyl hypochlorite and 35.7 g (0.22 mole) of ethyl 2(ethylthio)propanoate.
Reaction SMILES: C([O:20][CH2:21][C@H:22]1[N:26]2[N:27]=[CH:28][N:29]=[C:25]2[CH2:24][CH2:23]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>Cl.O1CCOCC1>[N:29]1[CH:28]=[N:27][N:26]2[C@H:22]([CH2:21][OH:20])[CH2:23][CH2:24][C:25]=12
Reactant: c1ccc(C(OC[C@@H]2CCc3ncnn32)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: OC[C@@H]1CCc2ncnn21
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
The product form step B above, 0.27 g (0.71 mmol) of (5S)-5-[(trityloxy)methyl]-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole, was dissolved in 35 mL of a 4.0 M solution of hydrogen chloride in anhydrous 1,4-dioxane. The reaction mixture was stirred for 10 min, quenched with 20 mL of methanol, then evaporated to dryness in vacuo. The residue was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-90% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to yield the title compound (0.050 g, 50%). LC-MS: m/z (ES) 140 (MH)+.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:12][CH2:13][CH:14]=[CH2:15]>O1CCCC1>[CH2:15]([P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])[CH2:14][CH:13]=[CH2:12]
Reactant: C=CCCBr
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
Diethyl phosphite (4.14 g, 0.03 mol) was added to a suspension of 60% sodium hydride (1.2 g, 0.03 mol) in dry tetrahydrofuran (60 ml) at ambient temperature. The mixture was stirred for 5 minutes until a pale yellow solution was obtained. 4-Bromobut-1-ene (4.5 g, 0.033 mol) was added dropwise and the reaction mixture heated at reflux for 3 hours. After cooling to ambient temperature and filtering, the filtrate was concentrated under reduced pressure to give an oil. The oil was chromatographed on silica gel (eluting with ethyl acetate-hexane, 50:50) to yield the title compound as a colorless oil (3.85 g, 67%). IR: υmax (film) 3080, 3000, 2940, 2920, 2880, 1645, 1450, 1390, 1260, 1165, 1060, 1030, 970, 820, 790 cm-1. 1H NMR: δH (CDCl3) 1.35 (6H, t, J=7Hz, (OCH2CH3)2), 1.50-2.70 (4H, m, CH2CH2P), 4.10 (4H, m, (OCH2CH3)2) 4.85-5.28 (2H, m, CH2 =CH), 5.5-6.28 (1H, m, CH2 =CH--CH2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:12]([O-])=O.[Na+].F[B-](F)(F)F.[H+]>Cl.O>[N+:1](=[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N:4][CH2:3]1)=[N-:12]
Reactant: O=N[O-]
Reactant: Nc1cnc2ccccc2c1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Product: [N-]=[N+]=C1C=c2ccccc2=NC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 140.2 %

Procedure:
3-Aminoquinoline (10 g, 69 mmol) was dissolved in 70 mL of conc. HCl in a 250 mL round bottomed flask and cooled to 0° C. Sodium nitrite (9.6 g, 139 mmol) in 20 mL water was added drop wise over 0.5 h while maintaining the reaction temperature between 0-5° C. After stirring for another 0.5 h, fluoroboric acid (20 mL) was added and the stirring continued for another 0.5 h. The solid was filtered and dried under vacuum to yield the title compound (15.2 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:27])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[N+:24]([O-:26])=[O:25])=[C:11]([C:28]([O:30]CC)=[O:29])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:27])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[N+:24]([O-:26])=[O:25])=[C:11]([C:28]([OH:30])=[O:29])[N:10]=[N:9]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1ccc(OCOC)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCOc1ccc(C(=O)c2c(C(=O)O)nnn2Cc2ccc(OC)cc2)c([N+](=O)[O-])c1

Procedure:
In the same manner as above, a solution of ethyl 1-(4-methoxybenzyl)-5-(4-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate (b-2) (3.16 g, 6.72 mmole) in tetrahydrofuran (50 ml) was hydrolyzed with a 1N aqueous sodium hydroxide solution (13 ml) at room temperature for 3 hours to give 1-(4-methoxybenzyl)-5-(4-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylic acid (c-2': MP) (2.22 g, 75%)
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][C@@H:9]2[CH2:13][C@@H:12]([OH:14])[CH2:11][N:10]2[C:15](OCC)=O)=[C:4]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][C@@H:9]2[CH2:13][C@@H:12]([OH:14])[CH2:11][N:10]2[CH3:15])=[C:4]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(Cl)cc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C[C@H](O)C[C@H]1CCOc1ccc(Cl)cc1CCc1ccccc1
Yield: 46 %

Procedure:
260 mg of (2R,4R)-2-{2-[4-chloro-2-(2-phenylethyl)phenoxy]ethyl}-1-ethoxycarbonyl-4-hydroxypyrrolidine [prepared as described in step (a) above], 10 ml of tetrahydrofuran and 70 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrated substance thus obtained was purified by silica gel column chromatography, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 103 mg (yield 46%) of the title compound as a colorless solid substance, melting at 65°-68° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9](=[O:18])[C:5]([C:6]([OH:8])=[O:7])=[C:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2].[OH-].[Na+:26]>CO>[CH2:1]([N:3]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][C:9](=[O:18])[C:5]([C:6]([O-:8])=[O:7])=[C:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2].[Na+:26]
Reactant: CCn1c(-c2ccccc2)cc(=O)c(C(=O)O)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1c(-c2ccccc2)cc(=O)c(C(=O)[O-])c1-c1ccccc1
Yield: 94.9 %

Procedure:
1.38 gms of 1-ethyl-2,6-diphenyl-4-oxonicotinic acid was treated with 0.19 gms of NaOH in 50 mls of dry methanol. Evaporation of the solvent provided 1.40 gms of sodium 1-ethyl-2,6-diphenyl-4-oxonicotinate as a glassy solid.
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.[F:29][C:30]([F:71])([F:70])[C:31]1[CH:32]=[C:33]([NH:41][C:42](=[O:69])[N:43]([CH:59]2[CH2:64][CH2:63][CH:62]([C:65]([CH3:68])([CH3:67])[CH3:66])[CH2:61][CH2:60]2)[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([C:51](=[O:58])[CH2:52][C:53]3[N:54]=[N:55][NH:56][N:57]=3)=[CH:47][CH:46]=2)[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1>C1COCC1>[F:71][C:30]([F:29])([F:70])[C:31]1[CH:32]=[C:33]([NH:41][C:42](=[O:69])[N:43]([CH:59]2[CH2:60][CH2:61][CH:62]([C:65]([CH3:66])([CH3:67])[CH3:68])[CH2:63][CH2:64]2)[CH2:44][C:45]2[CH:46]=[CH:47][C:48]([CH:51]([OH:58])[CH2:52][C:53]3[N:54]=[N:55][NH:56][N:57]=3)=[CH:49][CH:50]=2)[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)Cc3nn[nH]n3)cc2)C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(O)Cc3nn[nH]n3)cc2)C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c]-[1,3,2]oxazaborole in toluene (17 μl, 0.17 mmol, 1 M) in THF (1 ml) was added boran-THF complex (328 μl, 0.32 mmol, 1 M in THF). Then a solution of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-tert-butylcyclohexyl)-1-[4-(2-2H-tetrazol-5-yl-acetyl)-benzyl]urea (100 mg, 0.17 mmol) in THF (1.0 ml) was added dropwise over a period of 30 min. The reaction mixture was stirred at room temperature overnight and then quenched with 1 N aqueous HCl (100 μl). Solvent was removed by rotary evaporation. The residue was dissolved in THF (500 μl) and injected into a preparative HPLC on a Gilson 2.11 with auto sampler (Xterra MS C18 5 μm 19 mm×100 mm, gradient: 10% acetonitrile in water→100% acetonitrile).