Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([CH2:23][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Fc1cccc(CCl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CCCC1=O
Reaction time: 0.08 h
Yield: 37.4 %

Procedure:
40% Methanolic Triton B (2.06 mL, 4.53 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (930.0 mg, 3.82 mM) in 5 mL of DMF at 0° C. After 5 minutes, 3-fluorobenzyl chloride (664.0 mg, 4.59 mM) was added and the resultant mixture stirred at 0° C. for 3 h, then at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed three times with 1 N HCl, three times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 502.3 mg (37%) of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow foam. 1H NMR (CDCl3) δ 7.4-7.2 (m, 4H), 6.9 (m, 1H), 6.7 (m, 2H), 5.35 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.65 (t, 2H, J=6 Hz), and 2.3 (m, 2H). IR (CHCl3, cm−1) 3050, 2950, 1725, 1654, 1464, 1451, 1440, 1288 and 1119. MS (ES) m/e 350, 352.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][C@@H:36]([CH3:45])[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][C@@H:36]([CH3:45])[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: C[C@@H](CC(=O)OC(C)(C)C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1,1-dimethylethyl (3S)-3-aminobutanoate using methods similar to Example 563 to provide an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25 (d, J=6.74 Hz, 3 H), 1.39 (s, 9 H), 1.52-1.67 (m, 4 H), 1.99-2.11 (m, 2 H), 2.52-2.58 (m, 2 H), 3.19-3.30 (m, 2 H), 3.49 (t, J=6.84 Hz, 2 H), 4.16 (s, 2 H), 4.35-4.42 (m, 3 H), 7.11-7.17 (m, 2 H), 7.41 (m, 2 H), 8.20 (d, J=1.47 Hz, 1 H), 8.57 (d, J=1.68 Hz, 1 H), 10.41 (d, J=8.21 Hz, 1 H), 17.06 (d, J=5.26 Hz, 1 H); ES+ MS: 581 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[N:12]=[C:11](Cl)[N:10]=[C:9]([CH3:14])[N:8]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:6][C:7]1[N:8]=[C:9]([CH3:14])[N:10]=[C:11]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]=1
Reactant: COCCN
Reactant: Cc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCCNc1nc(C)nc(Cl)n1
Reaction time: 0.08 h
Yield: 31.8 %

Procedure:
2-methoxyethanamine (Aldrich, 0.350 g, 4.66 mmol) was added to a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (0.80 g, 4.88 mmol) in dioxane (10 mL). Heat was generated. Hünig's base (1.0 mL, 5.73 mmol) was added and the mixture was stirred for 5 min. The mixture was partitioned between DCM (15 mL) and water. The organic phase was dried over Na2SO4 and concentrated. The resulting yellow oil was purified by chromatography on silica using EtOAc in hexane (20-80%) to give the desired product as a yellow solid (300 mg). LCMS (ES, pos.): calcd for C7H11ClN4O: 202.1. found: 203.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 5.93 (br. s., 1H); 3.60-3.70 (m, 2H); 3.49-3.58 (m, 2H); 3.38 (s, 3H); 2.42 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:16]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][C:14]([OH:21])=[O:15])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:18])[CH3:17]
Reactant: CC(C)=O
Reactant: CCCc1c(OCCCO)ccc(C(C)=O)c1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCc1c(OCCC(=O)O)ccc(C(C)=O)c1O
Reaction time: 0.25 h
Yield: 57 %

Procedure:
A solution of 2.00 g of 1-[2-hydroxy-4-(3-hydroxypropoxy)-3-propylphenyl]ethanone in 30 ml of acetone was added dropwise over 45 minutes to a stirred, ice cooled solution of 4.0 ml of Jones reagent in 10 ml of acetone. After 15 additional minutes, the cooling bath was removed and the reaction mixture was stirred at 23° for 15 minutes. Jones reagent (0.5 ml) was added and stirring was continued for 15 minutes. The reaction mixture was concentrated in vacuo and the residue was treated with water and extracted with ether. The ether extract was washed with three portions of 1N sodium hydroxide and the aqueous layers were combined and acidified. The product was extracted with ether and the dried (over magnesium sulfate) extract was concentrated in vacuo to a solid (1.48 g). Recrystallization from ether-hexane gave 1.21 g, mp 142°-146°, (57% yield) of 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propanoic acid, the titled compound.
Reaction SMILES: S(Cl)(Cl)(=O)=O.Cl[CH2:7][Cl:8].[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:23][N:22]4[CH2:31][CH2:32]C[C:21]=34)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1>N1C=CC=CC=1>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:23][N:22]4[CH2:31][CH2:32][CH:7]([Cl:8])[C:21]=34)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: Brc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: ClCCl
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: ClC1CCn2nc(-c3ccccn3)c(-c3ccnc4cc(Br)ccc34)c21
Reaction time: 18 h

Procedure:
A solution of 1 M sulfuryl chloride in dichloromethane (20 mL, 20 mmol) is added to a solution of 7-bromo-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (2.2 g, 5.62 mmol) in dry pyridine (50 mL). The mixture is stirred for 18 h and concentrated in vacuo. The residue is partitioned between chloroform and saturated sodium chloride. The organic layer is dried (sodium sulfate), filtered, concentrated in vacuo, and the residue chromatographed on SiO2 (dichloromethane to 20% methanol in dichloromethane) to yield the title compound as a red solid, 1.8 g (75%).
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[N:14]O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.B.[Na].S(=O)(=O)(O)O.CO>COCCOC>[NH2:14][CH:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(CCc1ccccc1)=NO
Agent: B
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: COCCOC
Solvent: CO
Product: NC(CO)CCc1ccccc1
Temperature: 62 °C
Reaction time: 5 h

Procedure:
33.2 g (0.15 mole) 2-hydroxyimino-4-phenyl butyric acid ethyl ester were steadily introduced under agitation into a suspension of 24.15 g (0.64 mole) sodium boron hydride in 200 ml 1,2-dimethoxyethane (DME). Within 1 h a solution of 17.2 ml (0.32 mole) conc. sulfuric acid in 60 ml DME was added dropwise thereto, during which the temperature was maintained at 20°-30° C. The mixture was subsequently heated slowly to 62° C., then agitated 5 h at this temperature and cooled overnight under agitation to room temperature. After a careful addition of 50 ml methanol the batch was evaporated to dryness, the residue taken up in 120 ml water and compounded with 25 ml conc. hydrochloric acid, during which a vigorous development of gas began. After the addition of 150 ml toluene the mixture was agitated until the end of the development of gas, then alkalinized with 35 ml 50% sodium hydroxide solution and heated to 60° C. The organic phase was separated and the aqueous phase extracted again with 80 ml toluene at this temperature. The combined organic phases were dried over sodium sulfate and evaporated. 25.0 g raw (RS)-2-amino-4-phenyl-1-butanol remained as residue in the form of a brownish, viscous oil. The structure was corroborated by a 1H-NMR spectrum.
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][Si](C(C)(C)C)(C)C)[CH:47]=2)=[O:43])[CH:39]=[C:38]([Cl:60])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([OH:37])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:60][C:38]1[CH:39]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([OH:52])[CH:47]=2)=[O:43])[CH:41]=[C:20]([Cl:19])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:2])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(C(=O)N[C@@H](CNC(=O)c3cccs3)C(=O)O)c(Cl)c2)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran; 3.94 mL, 3.94 mmol) was added to a solution of N-[2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (2.38 g, 3.6 mmol) in tetrahydrofuran (30 mL). The solution was stirred at room temperature for 3 h, then diluted with ethyl acetate and concentrated. The residue was chromatographed (50-100% ethyl acetate/hexanes then 10% methanol/ethyl acetate) to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (1.68 g, 85%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.C(N(CC)CC)C.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[S:47](Cl)(=[O:49])=[O:48]>ClCCl>[C:12]1([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:9]2[CH:10]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:47]([C:38]3[CH:39]=[CH:40][C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:37]=3)(=[O:49])=[O:48])[N:7]=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2ccccc2c1
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of the product from step c (465 mg, 1.22 mmol) and triethylamine (185 μl, 1.33 mmol) in dry dichloromethane (15 ml) was added 2-naphthalenesulfonyl chloride (227 mg, 1.22 mmol). The solution was stirred for 2 h and the solvent evaporated. Flash column chromatography (silica; 5% methanol/dichloromethane) of the residue afforded the product as a colourless foam (588 mg, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:13])[NH:50][C:49]2[CH:51]=[CH:52][C:46]([Cl:45])=[CH:47][CH:48]=2)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 7a (1 g; 3.48 mmol) is suspended in acetonitrile (7 ml) and N,N-diisopropyl ethyl amin (1.22 ml; 6.96 mmol) is added at 25° C. BOP-Cl (1.772 g; 6.96 mmol) is added as a solid and after stirring for 30 min at 25° C. 4-chloroaniline (0.444 g; 3.48 mmol) is added to the reaction mixture. The mixture is stirred for 18 h at 25° C., evaporated to dryness and dissolved in ethyl acetate (100 ml). The organic phase is washed with saturated aquous Na2CO3 solution (100 ml), 2 N HCl (50 ml), water and brine and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. The crude product is purified by silica gel chromatography. Yield: 0.5 g (36.2%), ESI-MS: m/z=395 [M−H]−, Cl-pattern
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CC(O)C>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:18]([F:21])([F:20])[F:19])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: FC(F)(F)c1ccccc1-c1ccc2c(Cl)ccnc2c1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(Nc2ccnc3cc(-c4ccccc4C(F)(F)F)ccc23)cc1

Procedure:
Heat a mixture of 4-chloro-7-(2-trifluoromethyl-phenyl)-quinoline (42 mg, 0.14 mmol) and 4-(tert-butyl)aniline (41 mg, 0.29 mmol) in 2-propanol (10 mL) at reflux for 3 hours. Evaporate the mixture, add 1M NaOH (10 mL), extract twice with EtOAc (10 mL each), dry (Na2SO4), and evaporate to provide the crude product. Purify by silica gel chromatography, eluting with 75% hexane-EtOAc to provide (4-tert-Butyl-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine as a white solid. Mass spec. 420.2.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](O)=O>>[CH2:1]([N:8]1[C:9](=[O:18])[C:10]2[C:11](=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=2)[N:17]=[CH:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: Nc1cc(Br)ccc1C(=O)NCc1ccccc1
Product: O=c1c2ccc(Br)cc2ncn1Cc1ccccc1

Procedure:
10 ml of formic acid was added to 18.5 g of N-benzyl-2-amino-4-bromobenzamide, and was heated under reflux for 2 hours. After distilling out excess reagent under reduced pressure, saturated sodium bicarbonate aqueous solution was added, and extracted with ethyl acetate. Ethyl acetated layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel column chromatography (hexane/ethyl acetate=7/3), to obtain 821 mg of the above compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.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.[Cu]I>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([C:30]#[C:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1
Reactant: C#Cc1ccccc1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1c(C#Cc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-furan-2-yl-pyrimidin-4-yl ester, phenylacetylene, bis(triphenylphosphine)palladium(II) chloride, triphenylphosphine, triethylamine and copper (I) iodide in THF. EI-MS m/e (%): 286 (M+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.ClCCCl.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>N1C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)sc2c1
Yield: 98.8 %

Procedure:
Prepared as described in the Amide Coupling section using 1,2-dichloroethane 2-(4-aminophenyl)-6-methylbenzothiazole (2.5 g, 10.4 mmol) and 4-nitrobenzoyl chloride (2.12 g, 11.4 mmol) in dry pyridine (30 ml) to give the title compound (4.0 g, 99%) as small tan-coloured needles after recrystallisation from DMF/water.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8](C(O)=O)=[C:7]2[OH:15].[C:16](C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCOCC>[CH2:1]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][CH:8]=[C:7]2[OH:15])[CH3:16]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Cc1cccc2c(O)c(C(=O)O)nnc12
Solvent: CCOCC
Product: CCc1cccc2c(O)cnnc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 0.7 g of 53D and 2.8 g of benzophenone was heated at 180°-210° C. until no more gas evolved (30 minutes). The mixture was cooled to 0° C., diluted with ether and filtered. The solid was slurried with hot 5 N aqueous sodium hydroxide solution and filtered. The filtrate was acidified with 12 N hydrochloric acid, allowed to cool and stand overnight at room temperature, and filtered. The resulting solid was dried under reduced pressure, and flash chromatographed on silica gel, using a 1:1 v:v mixture of ethyl acetate and methylene chloride as eluent, to give 8-ethyl-4-hydroxycinnoline (53E), as a solid, m.p.: 160°-161° C.
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32](O)=[O:33])[CH:30]=2)[CH:25]=[CH:24][N:23]=1>CN(C)C1C=CN=CC=1>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:32]([C:29]4[CH:30]=[C:31]5[C:26]([CH:25]=[CH:24][N:23]=[C:22]5[Cl:21])=[CH:27][CH:28]=4)=[O:33])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc2ccnc(Cl)c2c1
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccnc(Cl)c4c3)CC1)C2

Procedure:
The title compound was prepared by a method analogous to that described for Example 2, using 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4) and 1-chloroisoquinoline-7-carboxylic acid, and omitting 4-dimethylaminopyridine. +ESI (M+H) 452.3; 1H NMR (400 MHz, CDCl3, δ): 8.37 (s, 1H), 8.32 (d, J=5.7 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.75-7.79 (m, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.39 (s, 1H), 6.42 (s, 1H), 3.43-3.73 (m, 4H), 2.87 (s, 2H), 1.64-2.01 (m, 4H), 1.61 (s, 9H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[C:28](Cl)(=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[CH3:31][CH:30]([CH3:32])[CH2:29][C:28]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([CH2:14][O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=2[C:7]#[N:8])[CH2:16]1)=[O:33]
Reactant: N#Cc1c(OC[C@H]2CCCNC2)cccc1[N+](=O)[O-]
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
To a suspension of (S)-2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride (Example 1d, 35.84 g, 120.41 mmol) in DCM (600 mL) cooled to 0° C. in an ice bath was added triethylamine (42 mL, 300.94 mmol) followed by dropwise addition of isovaleryl chloride (2.77 mL, 132.35 mmol). The reaction mixture was stirred under N2 for 30 minutes at 0° C., then at room temperature overnight. The solution was diluted with DCM and successively washed with 10% citric acid, saturated NaHCO3 solution, water, brine, dried over Na2SO4, filtered and concentrated to afford crude (S)-2-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)-6-nitrobenzonitrile as a golden brown oil (43.26 g). MS 346 (MH+). This material was used without purification in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:3]=1.[CH3:16][NH:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21]1)=[O:19].CCN(C(C)C)C(C)C>C(O)CCC>[C:14]([C:11]1[S:10][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH:22]4[CH2:23][CH2:24][N:20]([C:18]([NH:17][CH3:16])=[O:19])[CH2:21]4)[CH2:26][CH2:27]3)[CH:3]=2)=[N:13][CH:12]=1)#[N:15]
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Reactant: CNC(=O)N1CCC(N2CCNCC2)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1CCC(N2CCN(c3cc(Nc4ncc(C#N)s4)ncn3)CC2)C1

Procedure:
35-1 (0.106 g, 0.45 mmol), 45-5 (0.095 g, 0.45 mmol) and DIEA (0.18 g, 1.79 mmol) were heated at 150° C. for 3 hours in n-butanol. Upon cooling the precipitate was filtered off, washed with n-butanol and ethyl ether and then dried to afford 45-6. Hi-Res MS: calc: 414.1819 found: 414.1827. 1H-NMR (DMSO-d6): 12.08(s, 1H); 8.42(s, 1H); 8.26(s, 1H); 6.22(s, 1H); 6.02(d, 1H); 3.55(m, 4H); 3.38 (m, 1H); 3.13(m, 1H); 2.97(m, 1H); 2.78(m, 1H); 2.50(complex, 6H); 2.45(m, 2H); 2.06(m, 1H); 1.69(m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[N:19]([CH3:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)[C:8]=1[CH3:25].ClC1C=CC=C(C(OO)=[O:34])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[N:19]([CH3:20])[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)=[O:34])[C:8]=1[CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3n2C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2C)c1C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
0.25 g of 2-{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthio-1-methylbenzimidazole was dissolved in 20 ml of dichloromethane to obtain a solution. 0.18 g of 80% m-chloroperbenzoic acid was added to the solution at -50° C. The obtained mixture was stirred for one hour, followed by the addition of 0.14 g of triethylamine and 20 ml of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was stirred at a room temperature for one hour. The dichloromethane layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate twice, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was purified by silica gel column chromatography to obtain 0.12 g of the title compound as a pale yellow crystal.