Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Br[CH2:34][C:35]([NH2:37])=[O:36].[Br-]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)[CH2:34][C:35]([NH2:37])=[O:36])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2o1
Reactant: NC(=O)CBr
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CN(CCCc1ccc(F)cc1)C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 19.1 %

Procedure:
To a stirred suspension of 6-{trans-4-[3-(4-fluorophenyl)propylamino]-cyclohexyl}-3H-benzoxazol-2-one (110 mg, 0.81 mmol) in DMF (15 mL) was added NaHCO3 (140 mg, 1.6 mmol) and bromoacetamide (300 mg, 0.74 mmol). After 16 hours the reaction mixture was warmed to 50° C. After 4 hours, additional bromide (150 mg, 0.37 mmol) and NaHCO3 (31 mg, 0.37 mmol) were added, and the temperature was increased to 75° C. After 4 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organics were washed with water, saturated NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 95:4.75:0.25 CH2Cl2:MeOH:NH4OH) followed by conversion to the HCl salt gave compound 2-{[3-(4-fluorophenyl)propyl]-[4-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-cyclohexyl]amino}acetamide (60 mg, 17%), as a white solid: mp 266-270° C.; IR (KBr): 3331, 3149, 2943, 1762, 1691 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.47 (s, 1H), 9.08 (br s, 1H), 7.96 (br s, 1H), 7.73 (br s, 1H), 7.29-7.25 (m, 2H), 7.17-7.01 (m, 3H), 6.99 (s, 2H), 4.05-4.02 (m, 1H), 3.81-3.78 (m, 1H), 3.47-3.38 (m, 1H), 3.22-3.12 (m, 3H), 2.63 (t, J=8 Hz, 2H), 2.57-2.52 (m, 1H), 2.14-1.87 (m, 6H), 1.71-1.49 (m, 4H); ESI-MS (m/z): 426 [M+H]+; HPLC: method A, 5.44 minutes (98.0%); HPLC: method E, 6.50 minutes (>99%); Anal. Calcd for C24H28FN3O3.HCl: C, 61.80; H, 6.37; N, 9.01. Found: C, 61.78; H, 6.27; N, 8.80.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2Cl)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:17].O>S1(CCCC1)(=O)=O>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[NH2:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)c1ccc2c(Cl)nccc2n1
Agent: [Cl-]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)c1ccc2c(N)nccc2n1
Temperature: 200 °C
Reaction time: 20 h

Procedure:
A mixture of 22.1 g (100 mmol) of 2-tert-butyl-5-chloro-1,6-naphthyridine (S36), 32.1 g (600 mmol) of ammonium chloride in 100 ml of sulfolane is stirred at 200° C. for 20 h. 300 ml of water are added to the cooled mixture, which is then stirred at room temperature for 2 h. The solid is filtered off with suction, washed twice with 50 ml of water each time and subsequently suspended in a mixture of 50 ml of methanol and 150 ml of conc. ammonia solution. The suspension is stirred at room temperature for 20 h. The solid is filtered off, washed three times with 50 ml of water each time, dried in vacuo and subjected to sublimation (p about 1×10−2 mbar, T=150° C.). Yield: 16.7 g (83 mmol), 83%. Purity: >97% according to 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc(C=O)cc(OC)c1O
Solvent: CO
Product: COc1cc(C=Nc2ccc(F)cc2)cc(OC)c1O

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (30 ml) and to this solution was added 4-fluoroaniline (600 mg, 5.46 mmol, 0.51 ml). The resultant reaction solution was stirred for forty-eight (48) hours at room temperature under nitrogen. The reaction solution was then cooled in the freezer and the resultant precipitate was isolated by filtration and washed with cold methanol and ether. The isolated light yellow powder was the title product: 1H NMR (300 MHz, CDCl3); δ 8.31 (S, 1H), 7.20-7.04 (m, 4H) 5.85 (S, 1H), 3.98 (S, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH2:32][OH:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@@H:24]([CH:31]([CH3:34])[CH2:32][O:33][C:41](=[O:43])[CH3:42])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)CO)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(C)[C@H]1CC[C@@H](C)[C@@]2(O)[C@@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
To ((1S,2R,4aS,5S,8R,8aR)-2-(acetyloxy)-8a-hydroxy-5-[2-hydroxy-1-methylethyl]-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 140, 63.8 mg, 0.11 mmol) in dichloromethane (1.1 ml) was added acetic anhydride (22 mg, 2.0 □l, 0.22 mmol) and 4-dimethylaminopyridine (14.3 mg, 0.12 mmol) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (20 ml) and washed with aqueous citric acid solution, dried (MgSO4) and concentrated in vacuo to give a gum. The crude product was purified by chromatography on silica eluting with hexane:ethyl acetate (60:40). The pure fractions were combined and concentrated in vacuo, to give the title product as a white solid (42 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][S:14][CH3:15])[C:3]=1[C:4]#[N:5].[S:16](Cl)(=[O:19])(=[O:18])[NH2:17]>>[S:16]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][S:14][CH3:15])[C:3]=1[C:4]#[N:5])(=[O:19])(=[O:18])[NH2:17]
Reactant: NS(=O)(=O)Cl
Reactant: CSCCCOc1cccc(N)c1C#N
Product: CSCCCOc1cccc(NS(N)(=O)=O)c1C#N
Yield: 69 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(3-(methylthio)propoxy)benzonitrile (Example 247b) and sulfamoyl chloride in 69% yield. MS 302 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH2:18][CH2:17]3)=[CH:14][S:13][C:12]=2[CH:30]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:27]([N:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:15]2[C:11]3[CH:10]=[CH:9][C:8]([F:7])=[CH:30][C:12]=3[S:13][CH:14]=2)[CH2:21][CH2:20]1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:29])[CH3:28]
Reactant: CC(=O)NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCCCN1CCN(c2csc3cc(F)ccc23)CC1)C(=O)C(C)C
Yield: 96.6 %

Procedure:
A solution of isobutyryl chloride (2.34 g, 21.9 mmol) in dry dichloromethane (8 mL) was added over 2 minutes to a solution of N-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-acetamide (2.51 g, 7.18 mmol), triethylamine (2.18 g, 21.5 mmol), 4-dimethylaminopyridine (0.877 g, 7.18 mmol), and dry dichloromethane (50 mL) at room temperature under a nitrogen atmosphere. After 2.5 hours the reaction solution was diluted with dichloromethane (100 mL), washed with water (75 mL), dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel with 5% methanol/dichloromethane as eluent to give 2.91 g of an amber solid. Recrystallization from tert-butyl methyl ether/heptane afforded 1.52 g (50%) of the title compound as tan crystals: m.p.=98 °-99° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][CH:8]([O:37][Si:38]([CH2:43]C)([CH2:41][CH3:42])[CH2:39][CH3:40])[C:9]([CH3:36])([CH3:35])[C:10](=[O:34])[CH:11]([CH3:33])[CH:12]([O:24]C(OCC(Cl)(Cl)Cl)=O)[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]>[Zn].C1COCC1.CC(O)=O>[C:1]([O:5][C:6](=[O:45])[CH2:7][CH:8]([O:37][Si:38]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH3:43])[C:9]([CH3:35])([CH3:36])[C:10](=[O:34])[CH:11]([CH3:33])[CH:12]([OH:24])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[Si](CC)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)COCc1ccccc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC[Si](C)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)COCc1ccccc1
Yield: 1022.2 %

Procedure:
To a solution of 71 (22.9 mg, 3.2 μmol) in 1:1 THF/AcOH (1.4 mL) was added Zn (5.0 mg, 7.8 μmol, nanosize). The mixture was sonicated for 15 min. More Zn (5.0 mg, 7.8 μmol, nanosize) was added, followed by sonication for a further 15 min. The suspension was filtered through a celite pad, washing with EtOAc several times. The filtrates were washed with sat. NaHCO3, brine, dried over MgSO4 and concentrated under vacuum. The crude residue was passed through a short plug of silica gel eluting with hexane/EtOAc 4:1 to give 17.1 mg (99% yield) of 71a as colorless oil: 1H NMR (400 MHz, CDCl3) δ (m, 6H), 0.96 (t, J=7.9 Hz, 9H), 0.97 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H), 1.11 (s, 3H), 1.26 (s, 3H), 1.44 (s, 9H), 1.84-1.90 (m, 1H), 2.21 (dd, J=6.7 and 17.0 Hz, 1H), 2.36 (dd, J=6.7 and 17.0 Hz, 1H), 3.24-3.29 (m, 1H), 3.44-3.52 (m, 2H), 3.67 (dd, J=3.9 and 8.9 Hz, 1H), 4.36 (dd, J=3.5 and 6.5 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.54 (d, J=12.0 Hz, 1H), 7.32-7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 5.0, 6.9, 9.7, 13.9, 20.2, 21.8, 28.0, 36.3, 40.8, 41.5, 53.7, 72.5, 72.9, 73.2, 73.6, 80.7, 127.4, 127.5, 128.2, 138.6, 171.0, 221.4; IR (film, NaCl, cm−1) 3502, 2959, 2875, 1731, 1683, 1456, 1366, 1154, 1098, 996, 739; LRMS (ESI) calcd for C30H52O6SiCl3Na [M+Na+] 559.3, found 559.3; [α]23D=−41.0 (c=0.4, CHCl3).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:60][C:61]1[S:62][CH:63]=[CH:64][N:65]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:15][CH:16]=2)[C:8]([NH:60][C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Yield: 71.3 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-propionic acid (171 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.86 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 ethyl acetate/methanol) afforded 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (151 mg, 71.2%) as a white foam: EI-HRMS m/e calcd for C24H29N3O2S (M+) 423.1980, found 423.1980.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/OC)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)[C:25](=[O:34])[CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]\[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)[C:25](=[O:34])[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccn(-c2ccoc2)c(=O)c1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(c1)/C(=C/NCc1ccn(-c3ccoc3)c(=O)c1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
A mixture of (4E)-6-tert-butyl-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (50 mg, 0.19 mmol), 4-aminomethyl-1-furan-3-yl-1H-pyridin-2-one hydrochloride (43 mg, 0.19 mmol), and triethylamine (150 μL, 1.1 mmol) in N,N-dimethylformamide (2 mL) is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure, and the residue is triturated with chloroform to provide (4Z)-6-tert-butyl-4-[({[1-(3-furyl)-2-oxo-1,2-dihydropyridin-4-yl]methyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione as a white solid (34 mg, 43%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28](O)[CH:27]=2)=[CH:21][CH:20]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:25][C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)[CH:31]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: Oc1cccc(Nc2ccccc2)c1
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(Nc3ccccc3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 3-hydroxydiphenylamine and cleavage from the resin (Standard Procedure G) gave an oily solid (4%). 1H-NMR (200.15 MHz, CDCl3): δ 7.31–6.81 (m, 8H), 6.83 (d, 2H, J=8.6), 6.65–6.62 (m, 2H), 6.48 (dd, 1H, J=8.2, 2.1), 4.12 (t, 4H, J=6.2), 3.99 (dd, 1H, J=7.0, 4.4), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.4), 2.95 (dd, 1H, J=14.2, 7.0), 2.22 (qn, 2H, J=6.2).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:21]([CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1)([OH:23])=[O:22]
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Reactant: CCOC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCCOc1ccc2sc3ccccc3c(=O)c2c1

Procedure:
2-Hydroxy-thioxanthone (4.56 g) was mixed with dimethylformamide (125 ml), ethyl 4-chlorobutyrate (6.02 g), potassium carbonate (2.80 g) and potassium iodide (0.50 g) and the mixture was stirred under reflux for four hours. The resulting mixture was poured carefully with stirring into cold distilled water. The yellow solid which precipitated, which is the ethyl ester of 2-(3-carboxypropoxy)thioxanthone, was collected by filtration and recrystallised from ethanol. The ethyl ester of 2-(3-carboxy-propoxy)thioxanthone (4.2 g) was dissolved in triethanolamine (50 ml) and a solution of potassium hydroxide (5.0 g) in distilled water (5 ml) and ethanol (20 ml) was slowly added with stirring. The resulting mixture was stirred under reflux for two hours, cooled, poured into a large excess of distilled water, and then acidified with hydrochloric acid. The resulting yellow precipitate was filtered off and recrystallised from ethanol to give 2-(3-carboxy-propoxy)thioxanthone.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])C.Cl.[OH2:29]>C[O-].[Na+].CO>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:27][CH2:26][CH2:8][CH2:9][CH2:10][C:11]([OH:17])=[O:29])=[O:5])[N:7]=[C:8]2[C:26]#[N:27])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Reactant: O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCCCCC(=O)O)c(O)c2ccc(Oc3ccc(F)cc3Cl)cc12
Yield: 45 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(4-fluoro-2-chloro-phenoxy)-isoquinoline-3-carboxylic acid ethyl ester (50 mg, 0.13 mmol) and 5-amino-petanoic acid (45 mg, 0.39 mmol) in 0.5 M NaOMe/MeOH solution was microwaved at 130° C. for 1 h. Reaction mixture was diluted with water (60 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried. Crude product was then purified by silica gel chromatography, eluting with 5-70% EtOAc/hexanes to provide the title compound 27 mg (0.06 mmol) in 45% yield. LC-MS ESI−: 455.89 (M−1)−.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:27]([CH2:30][CH2:31][CH3:32])([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>>[N+:27]([CH:30]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:31][CH3:32])([O-:29])=[O:28]
Reactant: CCC[N+](=O)[O-]
Reactant: O=C(O)CCCCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]

Procedure:
6-Phenylhexanoic acid (0.100 g, 0.52 mmol) and CDI (0.169 g, 1.04 mmol) were added together and then reacted with nitropropane (0.070 g, 0.78 mmol) and DBU (0.198 g, 1.30 mmol) according to the general procedure. Purification by column chromatography gave 0.059 g (43%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 2H), 7.17 (m, 3H), 5.04 (dd, J=4.4, 9.6 Hz, 1H), 2.60 (m, 4H), 1.62 (m, 6H), 1.31 (m, 2H) 1.02 (t, J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 199.3, 142.5, 128.6, 128.5, 126.0, 95.8, 39.5, 35.9, 31.3, 28.7, 23.5, 23.3, 10.6 ppm; IR νmax (cm−1) 2922, 2855, 1730, 1559, 1454, 1363, 1030, 747, 699; HRMS (FAB) calcd for C15H21NO3 (MNa+) 286.1414, found 286.1410.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 26.8 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 3-(trifluoromethyl)aniline (0.062 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.035 g of desired product. 1H NMR (DMSO-d6): δ 3.95 (s, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.76-7.68 (m, 5H), 7.82 (t, J=8.7 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 10.37 (s, 1H), 12.75 (br s, 1H); MS (m/z): 524.96[M+H]+.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:11][C@H:12]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C1C=CC=CC=1.[H][H]>[Pd].CO.C(O)(=O)C>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:11][C@H:12]2[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2N
Yield: 99.3 %

Procedure:
(1R*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 18; 7.07 g, 14.7 mmol) and 10% palladium on activated charcoal (2 g) were taken up in methanol (100 mL) and acetic acid (100 mL), and the mixture was hydrogenated at 50 psi hydrogen for 16 hours at room temperature. The suspension was filtered and the filtrate concentrated in vacuo. The residue was then suspended in saturated aqueous sodium hydrogen carbonate solution (200 mL) and extracted with dichloromethane (2×400 mL). The extracts were dried (MgSO4) and concentrated to give the title compound as a brown oil (4.4 g, 14.6 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1CCO[CH:9]1[CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[CH:16][C:15]1=[O:26].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[CH:16][C:15](=[O:26])[N:14]2[CH2:13][CH:9]=[O:8])=[N:19][CH:20]=1
Reactant: COc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2ccc(=O)n(CC=O)c2c1

Procedure:
To 184 mL of 80% trifluoroacetic acid, 4.60 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one was dissolved, and the resultant solution was stirred at room temperature for 11 hours and at 60° C. for 3.5 hours. The reaction mixture was charged with chloroform and alkalified with a 10% aqueous sodium hydroxide solution under cooling with ice. The organic layer was separated, and washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a yellow solid.