Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH2:22][N:23]([CH3:25])[CH3:24])=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9](S(C1C=CC=CC=1)(=O)=O)[CH:8]=[CH:7]2)[CH3:2].CCO.[OH-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:5]([CH2:22][N:23]([CH3:24])[CH3:25])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)[CH3:2]
Reactant: CCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccc2[nH]ccc2c1CN(C)C

Procedure:
{[5-Ethoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine (655 mg, 1.831 mmol; Example 133) was added EtOH (5 ml) and 2 M NaOH (5 ml) and heated at 70 oC for 5 h. Water was added and white material precipitated. The mixture was extracted with DCM. The organic phase was extracted with 1 M HCl (3×20 ml). The aqueous phase was made alkaline (pH 9) using 2 M NaOH and extracted with DCM (3×50 ml). The combined organic layers were dried (MgSO4) and evaporated. Yield: 293 mg (74%); brown oil. MS (ESI+) for C13H18N2O m/z 219 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[CH:13]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[CH:13]=2)=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)c(-c2ccccc2)c1
Yield: 47.9 %

Procedure:
Compound 102 (0.2 g, 0.69 mmol) in a solution consisting of Tol/EtOH/2M Na2CO3 aq (5/1/5) was treated with phenylboronic acid (0.12 g, 1.0 mmol) and cat Pd(PPh3)4 and heated to reflux until TLC analysis indicated complete reaction. The reaction was worked up by acidifying with 2 N HCl aq and extracting with EtOAc. The organic layer was washed with saturated NaHCO3 aq, brine, and dried over MgSO4. After filtering and concentrating, the crude material was chromatographed on silica gel (1:9 EtOAc/hexanes to 4:6 EtOAc/hexanes) and then triturated with hexanes to yield 0.10 g of the desired material: Mp.=167–709° C.; 1H NMR (DMSO-d6) δ 9.98 (br s, 1 H), 9.07 (br s, 1 H), 7.68 (d, 1 H, J=8.5 Hz), 7.4–7.38 (m, 3 H), 7.26–7.22 (m, 2 H), 7.18 (d, 1 H, J=8.7 Hz), 6.90 (dd, 1 H, J=8.5 Hz, 2.5 Hz), 6.72 (d, 1 H, J=2.5 Hz), 6.67 (d, 1 H, J=2.3 Hz), 6.62 (dd, 1 H, J=8.7 Hz, 2.4 Hz), 5.81 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.Cl.[N+:11]([CH:14]([CH:17]=O)[CH:15]=O)([O-:13])=[O:12]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH2:9])[C:5]2[CH:17]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=[N:8][C:6]=2[N:7]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Nc1cc(N)nc(N)n1
Agent: Cl
Solvent: CCO
Product: Nc1nc(N)c2cc([N+](=O)[O-])cnc2n1
Reaction time: 0.17 h

Procedure:
About 1 equivalent of 2,4,6-triamino pyrimidine was suspended in about 50 ml of refluxing absolute ethanol with stirring under an atmosphere of nitrogen. Concentrated HCl was added dropwise to effect solution and as soon as solution occurred, about 1.2 equivalents of nitromalonaldehyde was added all at once. Within 10 minutes, a thick reddish voluminous precipitate started forming. TLC analysis indicated the presence of a yellow spot corresponding to that of the desired product along with staring materials. The reaction mixture was stirred at reflux for 3.5 hours, immediately diluted with 30 ml of water, cooled and neutralized with concentrated NH4OH. The precipitate was collected on a funnel and was washed repeatedly with water to remove unreacted triamino pyrimidine to yield pure 2,4-diamino-6-nitropyrido[2,3-d]pyrimidine.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Si:9]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.O>[Si:9]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([Cl:1])=[C:32]1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)([C:22]([CH3:24])([CH3:25])[CH3:23])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)[Si](OCCCCn1c(-c2cccnc2)cc2ccccc21)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](OCCCCn1c(-c2cccnc2)c(Cl)c2ccccc21)(c1ccccc1)c1ccccc1
Yield: 60.9 %

Procedure:
N-Chlorosuccinimide (504 mg) was dissolved in an ethanol (9 ml) and water (1 ml) mixture of the 1-[4-(tert-butyldiphenylsilyloxy)butyl]-2-(3-pyridyl)indole (1.99 g) obtained in the same way as in Example 2(1), and the mixture was reacted at room temperature for 4.5 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate, and the organic phase was washed with brine, then dried over magnesium sulfate, then the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain 1-[4-(tert-butyldiphenylsilyloxy)butyl]-3-chloro-2-(3-pyridyl)indole (1.24 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[C:28]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][C:23]=3[NH:22][N:21]=2)=[O:19])[CH2:14][CH2:13]1.[ClH:36]>C(Cl)Cl.CCOCC>[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[C:28]3[CH2:27][CH2:26][NH:25][CH2:24][C:23]=3[NH:22][N:21]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4c(F)cccc4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2c(F)cccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (55, 94 mg, 0.19 mmol) in CH2Cl2 (3 mL) was added HCl (2N in Et2O, 3 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the mixture concentrated under reduced pressure to yield (4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (56) as a white solid (80 mg, 97%): 1H NMR (300 MHz, DMSO-d6) δ 9.39-9.26 (m, 2H), 7.63-7.47 (m, 3H), 4.76-4.40 (m, 1H), 4.35-4.25 (m, 2H), 3.78-3.39 (m, 4H), 3.25-3.08 (m, 2H), 2.91-2.78 (m, 3H), 2.11-1.88 (m, 2H), 1.81-1.66 (m, 2H); ESI MS m/z 397 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH2:41])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])[CH2:30][OH:31]>>[OH:27][CH2:28][CH:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])[CH2:30][OH:31]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(CO)CO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(CO)CO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B. 16) according to general procedure II. Light yellow solid. MS (ISP) 623.1 [(M−H)−]; mp 215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([NH:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[Cl:23])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].S(=O)(=O)(O)O>C(O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([NH:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[Cl:23])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=C(O)c1cc(Nc2c(F)cc(F)cc2Cl)c(Cl)cc1Cl
Temperature: 90 °C
Yield: 89.7 %

Procedure:
120 mg (0.31 mmol) of ethyl 2,4-dichloro-5-(2-chloro-4,6-difluorophenylamino)benzoate were suspended in 6 ml of an ethanol/2 N sodium hydroxide solution mixture (1:1) and heated at 90° C. for 3 hours. After cooling to room temperature, the pH was adjusted to 2 with 2 N sulfuric acid, and the precipitate was filtered off with suction. 98 mg (88%) of the product were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(Cl)(=O)C(Cl)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)Cl>[CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:25])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)N4CCCC4)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 12 h
Yield: 95.4 %

Procedure:
To a solution of (2E)-3-(4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoic acid (10) (0.135 g, 0.33 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (0.043 mL, 0.49 mmol) under N2. The resultant mixture was stirred at room temperature for 2 h. Reaction mixture was concentrated under reduced pressure to afford the crude acid chloride. The acid chloride was dried (Na2SO4) and re-dissolved in CH2Cl2 (5 mL) at room temperature. To the above solution pyrrolidine (0.055 ml, 0.66 mmol) was introduced slowly and the mixture was stirred for 12 h. Reaction mixture was concentrated under reduced pressure to afford the crude amide. The product was purified by SiO2 column chromatography using hexanes:EtOAc (9:1 to 3:2) as an eluent to afford 0.146 g (96%) of the title compound (243) as a white foam. 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J=9.2 Hz, 1H), 7.55 (s, 1H), 7.54 d, J=15.6 Hz, 1H), 7.27-7.20 (m, 5H), 7.13-7.11 (m, 3H), 7.03 and 7.01 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.57 (d, J=8.8 Hz, 2H), 6.51 (d, J=15.2 Hz, 1H), 3.91 (s, 3H), 3.55 (t, J=6.8 Hz, 4H), 2.22 (s, 3H), 1.94 (quintet, J=6.4 Hz, 2H), 1.85 (quintet, J=6.8 Hz, 2H), 2.26 (s, 3H). LCMS (ESI) m/z 464.15 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][N:24]([CH:26](N(C)C)N(C)C)[CH3:25]>C1(C)C=CC=CC=1>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[O:19])[C:16]([O:17][CH3:18])=[CH:23][N:24]([CH3:26])[CH3:25])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)COC)c2C1
Reactant: CN(C)C(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1CCc2cccc(C(=O)C(=CN(C)C)OC)c2C1

Procedure:
A solution of 2-di-n-propylamino-8-methoxyacetyl-1,2,3,4-tetrahydronaphthalene (1.0 g) and tris(dimethylamino)methane (1.5 ml) in toluene (25 ml) was heated to reflux for 1.5 hours. The reaction was concentrated to give crude 2-di-n-propylamino-8-(1-oxo-2-methoxy-3-(dimethylamino)-prop-2-enyl)-1,2,3,4-tetrahydronaphthalene (1.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[OH:1])[O:9][C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2ccc(O)cc2O1
Solvent: CC#N
Product: O=C1CCc2cc(Br)c(O)cc2O1
Reaction time: 0.17 h
Yield: 54.9 %

Procedure:
A solution of Intermediate 1 (20 g) in acetonitrile (50 ml) was added with N-bromosuccinimide (20 g, WAKO) under ice cooling, and stirred for 10 minutes under ice cooling, and then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then recrystallized from acetonitrile to obtain the title compound (15 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][C:11]#[N:12].[NH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1>C(#N)C>[C:11]([CH2:10][CH2:9][CH2:8][NH:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)#[N:12]
Reactant: NC1CCc2ccccc21
Reactant: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCNC1CCc2ccccc21

Procedure:
Potassium carbonate (15.5 g, 112 mmole) and 4-chlorobutyronitrile (11.58 g, 112 mmole) was added to a solution of 1-aminoindan (5.0 g, 37.6 mmole) in acetonitrile (50 ml), and the mixture refluxed for 2 hr. A second portion of 4-chlorobutyronitrile (5.0 g) was then added, the mixture further heated for 24 hr, filtered and the filtrate evaporated to dryness. Unreacted 4-chlorobutyronitrile was removed by treating the residue (20 g) with isopropanolic HCl (16.7 ml, 24%) followed by successive extractions with ether (3×150 ml). The crude product thus obtained was further purified by column chromatography (Silica, CH2Cl2 :MeOH 98:2) to afford 3.7 g (49%) of tan colored crystalline mass.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:3]=1.[S:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1>CO.C(Cl)Cl>[C:18]1([C:4]2[CH:3]=[C:2]([C:27]3([OH:30])[CH2:28][CH2:29][S:24][CH2:25][CH2:26]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1
Reactant: O=C1CCSCC1
Solvent: ClCCl
Solvent: CO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(O)CCSCC3)cc2C2=CCCCC2)n1
Yield: 62 %

Procedure:
The title compound was prepared by the procedure of Example 11 using 4-cyano-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 120 mg, 0.323 mmol) and tetrahydro-thiopyran-4-one (188 mg, 1.62 mmol). Silica gel chromatography (1-3% MeOH/DCM) afforded the title compound (82.3 mg, 62%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.56 (s, 1H), 9.66 (s, 1H), 8.29 (d, 1H, J=8.6 Hz), 7.74 (d, 1H, J=2.5 Hz), 7.42 (dd, 1H, J=8.6, 2.3 Hz), 7.33 (d, 1H, J=2.3 Hz), 5.86 (m, 1H), 3.22 (m, 2H), 2.46-2.54 (m, 2H), 2.22-2.33 (m, 4H), 2.16-2.22 (m, 2H), 2.01-2.09 (m, 2H), 1.73-1.89 (m, 5H). Mass spectrum (ESI, m/z): Calcd. for C22H24N4O2S, 409.2 (M+H). found 409.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[CH2:6][CH2:5]2.C([O:18][C:19](=[O:30])[C:20](=[CH:26]OCC)[C:21](OCC)=[O:22])C>>[F:1][C:2]1[CH:11]=[C:10]2[C:9]3[N:8]([CH:26]=[C:20]([C:19]([OH:30])=[O:18])[C:21]2=[O:22])[CH:7]([C:12]([F:13])([F:15])[F:14])[CH2:6][CH2:5][C:4]=3[CH:3]=1
Reactant: Fc1ccc2c(c1)CCC(C(F)(F)F)N2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: O=C(O)c1cn2c3c(cc(F)cc3c1=O)CCC2C(F)(F)F

Procedure:
6-Fluoro-2-trifluoromethyltetrahydroquinoline is condensed with an equimolar amount of diethylethoxymethylenemalonate according to the method of Example 1. The ester intermediate of Formula III is hydrolyzed according to Example 1, and the solid product is recrystallized from N,N-dimethyl formamide to provide crystals of 6,7-dihydro-9-fluoro-1-oxo-5-trifluoromethyl-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 295°297° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([CH:26]([CH3:28])[CH3:27])[C:19]2=[O:29].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.C(O)(=O)C>ClCCl>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[N:20]([CH:26]([CH3:27])[CH3:28])[C:19]3=[O:29])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)N1C(=O)c2ccc(N)cc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1C(=O)c2ccc(NCc3ccc(Cl)cc3)cc2C1=O
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Sodium triacetoxyborohydride (1.03 g, 4.90 mmol) was added to a stirred solution of 5-amino-2-isopropyl-isoindole-1,3-dione (0.50 g, 2.69 mmol), 4-chlorobenzaldehyde (0.37 g, 2.69 mmol), and acetic acid (160 μl, 2.69 mmol) in anhydrous dichloromethane (10 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (5% methanol in dichloromethane) to afford the title compound as a light brown solid (160 mg, 20%). HPLC retention time 4.86 min. Mass spectrum (ES+) m/z 329 (M+H).
Reaction SMILES: C([O:8][C:9](=[O:54])[C@@H:10]([NH:22][C:23](=[O:53])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][NH:37][CH2:38][C@H:39]([OH:52])[C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:41]=3)[CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])C1C=CC=CC=1>[Pd].C(O)C.C1CCCCC=1>[OH:52][C@H:39]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([NH:47][S:48]([CH3:51])(=[O:49])=[O:50])[CH:41]=1)[CH2:38][NH:37][CH2:36][CH:33]1[CH2:32][CH2:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([NH:22][C@@H:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9]([OH:54])=[O:8])=[O:53])=[CH:25][CH:26]=2)[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc3)CC2)ccc1O
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N[C@@H](CC(=O)O)C(=O)O)cc3)CC2)ccc1O
Temperature: 78 °C
Yield: 39.7 %

Procedure:
A mixture of (2S)-2-{[4-(4-{[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-amino]-phenyl}-ethyl)amino]methyl}piperidin-1-yl)benzoyl]-amino}butanedioic acid dibenzyl ester (0.074 g, 0.1 mmol) and 0.08 g of 10% palladium on carbon in 4 mL ethanol-cyclohexene (3:1, v/v) was heated at 78° C. until the reduction was complete. The catalyst was filtered (Celite) and the cake was washed with hot methanol. The solvent was removed in vacuo to give 0.023 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21]Br>CN(C=O)C>[CH3:18][O:19][CH2:20][CH2:21][O:1][CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COCCBr
Reactant: COC(=O)c1nc2ccccn2c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1c(C(=O)OC)nc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of methyl 3-(hydroxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (0.30 g) in DMF (5 ml) was added sodium hydride (60 mg) under ice-cooling. The mixture was stirred at room temperature for 30 min, 2-methoxyethyl bromide (220 mg) was added under ice-cooling, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with aqueous potassium carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (0:10-10:0) was concentrated under reduced pressure to give the object product (0.16 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[O:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.Cl>CC(O)C.ClC(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cc(F)cc2c1OC(CO)CC2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(F)cc2c1OC(COC1CCCCO1)CC2
Reaction time: 3 h
Yield: 104.1 %

Procedure:
A mixture of intermediate 14-b (0.25 mol), 3,4-dihydro-2H-pyran (0.50 mol) and hydrochloric acid in 2-propanol (0.5 ml) in trichloromethane (700 ml) was stirred for 3 h on a water bath. The reaction mixture was washed with a 10% NaOH solution. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 81 g of (±)-6-fluoro-3,4-dihydro-8-nitro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran (104% crude residue) (interm. 15-b).
Reaction SMILES: [N:1]([CH:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)[CH3:5])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.Cl>C1COCC1>[NH2:1][CH:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:7]1)[CH3:5]
Reactant: CC(N=[N+]=[N-])C1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(N)C1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 2.5 h

Procedure:
To a solution of 3-(1-azidoethyl)-1-(benzyloxycarbonyl)piperidine (1.95 g, 6.76 mmol) in THF (30.6 mL) was added Ph3P (2.66 g, 10.14 mmol) followed by water (3.4 mL). The mixture was placed in an oil bath at 50° C. for 2.5 h. The reaction mixture was cooled and carefully poured into an Erlenmeyer flask containing 1N HCl. The layers were separated, and the aqueous layer was washed once with EtOAc and the organic layer was discarded. The aqueous layer was then neutralized with saturated aqueous NaHCO3 carefully and was extracted with EtOAc (3×30 mL) and the organic extracts discarded. The aqueous layer was made strongly basic (>pH 12) with SN NaOH, then it was extracted with EtOAc (4×50 mL). The combined organic extracts were washed with brine and dried over Na2SO4. The title compound (950 mg) was used in the next step without purification. Partial 1H NMR (500 MHz, CDCl3): δ 7.3 (m, 5H); 5.12 (s, 2H); 4.1 (brm, 2H); 1.25 (br s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([OH:7])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]([CH2:27][CH2:28]O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[O:20]([CH2:27][CH2:28][O:7][C:4]1[CH:3]=[C:2]([NH2:1])[NH:6][N:5]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCOc1ccccc1
Reactant: Nc1cc(O)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: Nc1cc(OCCOc2ccccc2)n[nH]1
Temperature: 130 °C
Reaction time: 5 h
Yield: 32.8 %

Procedure:
There was suspended, in 2-phenoxy ethanol (25 g, 180 mM), 5-amino-1H-pyrazol-3-ol (4.00 g, 41.4 mM), then p-toluenesulfonic acid monohydrate (15.4 g, 80.8 mM) was added to the suspension and the mixture was stirred at 130° C. for 5 hours under reduced pressure. This reaction liquid was diluted with acetonitrile, the solid precipitated out of the liquid was filtered off and washed with acetonitrile. The resulting solid was suspended in a 6% aqueous sodium bicarbonate solution (250 mL), the suspension was stirred at room temperature and the solid was then filtered off. The resulting solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate and then the solvent was distilled off to thus give the title compound (2.90 g, yield: 33%).