Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:15])[C:13]=1[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)=O.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:20][CH:19]=1.CN(C=O)C>C(#N)C>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][NH:16][C:4]2[O:5][C:6]3[C:11]([C:12](=[O:15])[C:13]=2[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:23][CH:22]=1
Reactant: Cc1c(S(C)=O)oc2ccccc2c1=O
Reactant: NCc1ccc(CCCCO)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1c(NCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 2-methanesulfinyl-3-methyl-chromen-4-one (0.35 g, 1.78 mmol) in acetonitrile (37 mL), 4-(4-aminomethyl-phenyl)-butan-1-ol (0.47 g, 2.13 mmol) and DMF (18 mL) were added. The reaction stirred in a 50° C. oil bath overnight under N2 atmosphere. The next day, the reaction mixture was cooled to room temperature and concentrated to yield an oil. Purification of the oil by flash column chromatography (100% ethyl acetate) afforded the desired product as a white solid (120 mg, 20% yield). 1H NMR (600 MHz, CDCl3): δ 8.20 (d, 1H, J=7.9 Hz), 7.53 (t, 1H, J=7.8 Hz), 7.35 (t, 1H, J=7.6 Hz), 7.31 (d, 1H, J=8.4 Hz), 7.29 (d, 2H, J=7.9 Hz), 7.21 (d, 2H, J=7.9 Hz), 4.82 (bt, 1H, J=5.9 Hz), 4.66 (d, 2H, J=5.6 Hz), 3.68 (m, 2H), 2.66 (t, 2H, J=7.5 Hz), 1.97 (s, 3H), 1.70 (m, 2H), 1.61 (m, 2H), 1.24 (bt, 1H, J=5.3 Hz); 13C NMR (150 MHz, CDCl3): δ 174.0, 160.3, 152.2, 141.4, 135.5, 130.7, 128.2, 126.9, 125.0, 123.8, 122.3, 115.8, 92.7, 61.5, 44.6, 34.8, 31.8, 27.2, 7.3.
Reaction SMILES: C1C2C(=CC=CC=2)CCC1.[C:11]([C:13](=[CH:22][NH:23][NH:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=1[Cl:33])[C:14]([NH:16][C:17](OCC)=[O:18])=[O:15])#[N:12]>>[Cl:33][C:26]1[CH:27]=[C:28]([Cl:32])[CH:29]=[C:30]([Cl:31])[C:25]=1[NH:24][N:23]1[CH:22]=[C:13]([C:11]#[N:12])[C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: CCOC(=O)NC(=O)C(C#N)=CNNc1c(Cl)cc(Cl)cc1Cl
Solvent: c1ccc2c(c1)CCCC2
Product: N#Cc1cn(Nc2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]c1=O

Procedure:
To 7 ml of tetralin is added 1.5 g of α-cyano-β-(2,4,6-trichlorophenylhydrazino)-N-ethoxycarbonylacrylamide, and this mixture is heated to 180°-200° under nitrogen for 30 minutes. After cooling, the resulting solid is filtered, washed with pentane, slurried with acetone/hexane and again filtered to give 1-(2,4,6-trichloroanilino)-5-cyano-2,4-pyrimidinedione, m.p.>320°.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][CH:31]1[CH2:33][CH2:32]1)=[O:29])[O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([C:18]([O:20]C)=[O:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1.Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][CH:31]1[CH2:33][CH2:32]1)=[O:29])[O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
After adding methanol (48 ml) and 2N aqueous sodium hydroxide (16 ml) to methyl 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate (2.87 g, 6.50 mmol), the mixture was stirred at room temperature for 1.5 hours and at 60° C. for 15 minutes. The reaction solution was allowed to cool to room temperature, and after neutralization by addition of 1N hydrochloric acid, the methanol was distilled off and the precipitated light brown crystals were filtered out, thoroughly washed with water and dried at 70° C. to obtain the title compound (2.628 g, 6.14 mmol, 94.6%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[N:3]=1.Cl.[OH:29][CH:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>N1C=C(C)C=CC=1C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([N:32]2[CH2:33][CH2:34][CH2:35][CH:30]([OH:29])[CH2:31]2)=[N:3][C:4]=3[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1OC
Reactant: OC1CCCNC1
Agent: Cc1ccc(C)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(CNc2nc(N3CCCC(O)C3)nc3c2ncn3C2CCCC2)cc1OC
Temperature: 180 °C
Yield: 82 %

Procedure:
(2-Chloro-9-cyclopentyl-9H-purin-6-yl)-(3,4-dimethoxy-benzyl)-amine (446 mg, 1.15 mmol), 3-hydroxypiperidine hydrochloride (791 mg, 5.75 mmol) and K2CO3 (1.19 mg, 8.63 mmol) were suspended in 2,5-lutidine (10 mL) and the mixture was heated at 180° C. for 4 h. After cooling, CH2Cl2 (50 mL) was added and the solution was extracted with brine (2×15 mL). The organic fraction was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (95:5 CH2Cl2/MeOH) to afford the title compound as an off-white foam (427 mg, %). Anal. RP-HPLC (Phenomenex Jupiter, 5 μ, C18, 300 Å, 4.6×250 mm; 1 mL/min): tR=18.4 min (10-70% MeCN in 0.1% aq CF3COOH over 20 min); tR=16.0 min (35-45% MeCN in 0.1% aq CF3COOH over 20 min); purity>95% (λ=214 nm). DE-MALDI-TOF MS: [M+H]+=453.9 (C24H32N6O3=452.6).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].CC[O-].[Na+].[CH2:10]([CH:14]([C:20]([CH3:22])=O)[C:15](OCC)=[O:16])[CH2:11][CH2:12][CH3:13]>CCO>[CH2:10]([C:14]1[C:15](=[O:16])[NH:2][C:3](=[S:4])[NH:5][C:20]=1[CH3:22])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(C(C)=O)C(=O)OCC
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCc1c(C)[nH]c(=S)[nH]c1=O
Temperature: 25 °C

Procedure:
Sodium metal (1.85 g, 80.5 mmol) is dissolved in EtOH (50 mL). Next, thiourea (5.11 g, 67.1 mmol) is added to the NaOEt solution, followed by ethyl 2-n-butylacetoacetate (2.5 g, 13.4 mmol). The reaction mixture is stirred at reflux for 3 hours and then allowed to cool to room temperature overnight. The EtOH is removed in vacuo. The residue is then suspended in H2O (50 mL) and the resulting mixture carefully treated with concentrated HCl (−7.5 mL) just until pH 4 is reached. After stirring for 15 minutes, the suspension is filtered, and the solid thoroughly washed with H2O. Drying affords pure 5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one as a slightly off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.28 (br s, 1H), 12.05 (br s, 1H), 2.21 (m, 2H), 2.18 (s, 3H), 1.30-1.21 (m, 4H), 0.85 (t, J=6.9 Hz, 3H) ppm. MS; m/z 199 [M+1].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:19]([N:21]2[CH2:26][CH2:25][C:24]3([CH2:35][C:34](=[O:36])[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:37]5[CH:38]=[C:39]([C:43]([OH:45])=[O:44])[CH:40]=[N:41][CH:42]=5)[CH:32]=4)[O:27]3)[CH2:23][CH2:22]2)=[O:20])[CH:7]=[C:8]([O:16][CH2:17][CH3:18])[C:9]=1[C:10]1[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=1)[CH3:2].[OH-].[Na+:47]>O>[Na+:47].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:19]([N:21]2[CH2:26][CH2:25][C:24]3([CH2:35][C:34](=[O:36])[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:37]5[CH:38]=[C:39]([C:43]([O-:45])=[O:44])[CH:40]=[N:41][CH:42]=5)[CH:32]=4)[O:27]3)[CH2:23][CH2:22]2)=[O:20])[CH:7]=[C:8]([O:16][CH2:17][CH3:18])[C:9]=1[C:10]1[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=1)[CH3:2]
Reactant: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)[O-])c4)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Reaction time: 1 h

Procedure:
5-(1′-{[3,5-Diethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl]carbonyl}-4-oxospiro[chroman-2,4′-piperidin]-6-yl)pyridine-3-carboxylic acid (285 mg) was suspended in water (6 mL), and aqueous 1 N sodium hydroxide solution (0.624 mL) was added to it at room temperature, and stirred for 1 hour. The reaction liquid was purified through ODS reversed-phase chromatography (water/methanol) to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.90-8.87 (1.0H, m), 8.74-8.72 (1.0H, m), 8.28-8.26 (1.0H, m), 8.05 (1.0H, s), 7.99-7.95 (2.0H, m), 7.93-7.92 (1.0H, m), 7.22 (1.0H, d, J=9.3 Hz), 6.69 (2.0H, s), 4.35-4.18 (1.0H, br m), 4.08 (4.0H, q, J=6.8 Hz), 3.86 (3.0H, s), 3.69-3.17 (3.0H, m), 2.93 (2.0H, s), 2.15-1.86 (2.0H, m), 1.85-1.74 (2.0H, m), 1.38 (6.0H, t, J=7.0 Hz). MS [M+Na]+=633.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[N:4][CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[S:6][C:5]([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])[S:28]([C:21]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=2[F:19])(=[O:30])=[O:29])=[N:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: COc1ccc(CNc2ncc(Cl)s2)c(OC)c1
Product: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1

Procedure:
Prepared according to Preparation 333 using 5-chloro-N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 208) and 2,4,5-trifluorobenzenesulfonyl chloride. Purification using ISCO™ (12 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 3:7, by volume) afforded the title compound as an orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[N:3]=1.[F:10][C:11]([F:18])([F:17])[C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([N:14]2[CH:15]=[CH:16][C:12]([C:11]([F:18])([F:17])[F:10])=[N:13]2)[N:3]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Cc1cc(Br)nc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)nc(-n2ccc(C(F)(F)F)n2)c1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dibromo-4-methylpyridine (33 mmol, obtained according to the method disclosed by WO 94/22833), 3-trifluoromethyl-1H-pyrazole (21 mmol), potassium carbonate (45 mmol) and N,N-dimethylformamide ((50 mL) is heated at 90° C. for 4 hours. The reaction mixture is partitioned between ethyl acetate ands water. The separated organic phase is washed with brine, dried over sodium sulfate and evaporated in vacuo to provide an oily residue which is purified by flash chromatography. To yield 1.9 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[O:33][CH3:34])[CH:3]=1>CO.C(OCC)(=O)C.[Pd]>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:4]2[CH:3]=[CH:2][N:7]=[N:6][C:5]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:27]([O:33][CH3:34])[CH:28]=1
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(F)ccc1-c1ccnnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a solution of N-[6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridazin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide (50 mg, 96.5 μmol, example 1) in methanol (2 mL) and ethyl acetate (2 mL) was added palladium on activated charcoal (10%, 10 mg, 96.5 μmol) under argon atmosphere. The reaction apparatus was evacuated and purged with hydrogen gas. The reaction was stirred under a hydrogen atmosphere of 1.7 bar for 8 hours. The reaction mixture was filtered over dicalite and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography on a 10 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) to give the title compound as a light brown solid (13 mg, 27.9%). MS (ESI+): m/z=484.095 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[C:5]=2[NH:4][N:3]=1
Reactant: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1n[nH]c2c(-c3ccccc3F)cn(-c3ccccc3Cl)c(=O)c12
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (150 mg), 2-fluorophenylboronic acid (93 mg), tetrakis(triphenylphosphine)palladium(0) (51 mg), potassium carbonate (122 mg), 1,2-dimethoxyethane (5.0 mL) and water (0.5 mL) was stirred overnight at 90° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (38.3 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1NCCc2ccc(O)cc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1NCCc2ccc(OCCCBr)cc21
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A mixture of intermediate 19 (326 mg, 2 mmol), 1,3-dibromopropane (0.62 mL, 6 mmol) and anhydrous K2CO3 (276 mg, 2 mmol) was dissolved in 4 mL of EtOH and the solution was heated to reflux and stirred overnight. The mixture was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=5:1) to give 7-(3-bromopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (intermediate 20) (360 mg, 63%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:24])[C:5]1=[O:35].C(N(C(C)C)CC)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[O:24])[C:5](=[O:35])[N:4]3[CH2:3][CH2:2][NH:1][S:46]([CH3:45])(=[O:48])=[O:47])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[3-(4-morpholinyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.67 (s, 1 H), 1.99 (br. s., 2 H), 2.90 (s, 3 H), 3.07 (d, J=12.07 Hz, 2 H), 3.12-3.28 (m, 4 H), 3.39-3.51 (m, 4 H), 3.59-3.72 (m, 2 H), 3.92-4.04 (m, 1 H), 4.15 (s, 2 H), 4.35 (t, J=7.23 Hz, 2 H), 7.09-7.17 (m, 2 H), 7.29 (t, J=6.60 Hz, 1 H), 7.35-7.44 (m, 2 H), 8.13 (s, 1 H), 8.56 (d, J=1.40 Hz, 1 H), 9.80 (br. s., 1 H), 10.31 (t, J=5.83 Hz, 1 H); ES+ MS: 562 (M+H+).
Reaction SMILES: [OH-].[K+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Br>CN(C)C=O>[O:20]1[CH2:19][CH:18]1[CH2:16][N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2
Reactant: BrCC1CO1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1ccccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
Powdered potassium hydroxide (3.36 g, 60 mmol) was added to a solution of carbazole (8.36 g, 50 mmol) in anhydrous N,N-dimethylformamide (50 mL) and stirred at ambient temperature for 1 hour. The reaction mixture was cooled in an ice bath and epibromohydrin (10.3 mL, 125 mmol) was added. The ice bath was removed and the reaction was stirred at room temperature for 20 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), filtered, and concentrated. The crude material was triturated with hexanes, and recrystallized from ethyl acetate/hexanes to yield the desired product as white needles (6.41 g, 58% yield). A second crop of crystals was crystallized from the mother liquor to give additional product (1.2 g, 11%). 1H NMR (CDCl3, 300 MHz) δ 8.11-8.08 (m, 2H), 7.46-7.44 (m, 4H), 7.28-7.25 (m, 2H), 4.68-4.62 (dd, 1H, J=3.1, 15.8 Hz) 4.45-4.38 (dd, 1H, J=4.8, 15.9 Hz), 3.37 (m, 1H), 2.84-2.81 (dd, 1H, J=4.2, 4.3 Hz), 2.60-2.57 (dd, 1H, J=2.5, 5.0 Hz). HPLC analysis: (C18, 5-95% acetonitrile in H2O+0.1% trifluoroacetic acid over 20 min: detention time, % area at 254 nm): 7.83 min, 98.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH:51][C@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:51][C@H:52]1[CH2:56][CH2:55][N:54]([C:25]([C:10]2[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:27])[CH2:53]1
Reactant: O[C@H]1CCNC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CC[C@H](O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (55 mg, 0.15 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol), 1-hydroxybenzotriazole hydrate (23 mg, 0.15 mmol), and CH2Cl2 (3 mL) were added (S)-3-hydroxypyrrolidine (26 mg, 0.30 mmol) and N,N-diisopropylethylamine (53 μL, 0.30 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-60% MeCN/water[10 mM Et2NH]) and then by silica gel column (0-20% MeOH/CH2Cl2) to afford a white foam.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([C:23]([CH3:25])=[CH2:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C=C(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of the aforesaid 1-(6-fluoro-2-pyridyl)-6-(5-isopropenyl-3-pyridyl)pyrazolo[4,3-c]pyridine in Ethanol (50 mL) in a 250 mL round bottom flask was added Pearlman's catalyst (0.3523 mmol; 247.4 mg). The flask was vacuumed and connected with a balloon of Hydrogen. The mixture was stirred at room temperature for 16 hours. The mixture was filtered through Celite. The filtrate was concentrated. The residue was purified on silica eluted with 0 to 5% MeOH in DCM to afford 1-(6-fluoropyridin-2-yl)-6-(5-isopropylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine (479.2 mg, 82%).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][N:8](C(C)(C)C)[CH2:7][C:6]=2[CH:5]=[C:4](C(C)(C)C)[CH:3]=1.FC(F)(F)C1C=CC(B(O)O)=CN=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[O:10]1[C:11]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7][NH:8][CH2:9]1
Reactant: CC(C)(C)c1cc(Br)c2c(c1)CN(C(C)(C)C)CO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccc(C(F)(F)F)nc1
Solvent: O
Solvent: COCCOC
Product: c1ccc2c(c1)CNCO2
Temperature: 80 °C
Yield: 226.3 %

Procedure:
A mixture of 8-bromo-3,6-di-tert-butyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (Intermediate 1) (2.0 g, 6.13 mmol), 2-(trifluoromethyl)pyridine-5-boronic acid [purchased from Frontier Scientific] (1.17 g, 6.13 mmol) and potassium carbonate (1.27 g, 9.20 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (354.2 mg, 0.31 mmol) was then added and the mixture heated at 80° C. in a sealed vial for 24 hours. The cooled reaction mixture was then partitioned between ethyl acetate (80 mL) and 1M aqueous sodium hydroxide (80 mL). The organic phase was separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an orange syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 30% ethyl acetate in hexanes to give the intermediate 3,4-dihydro-2H-benzo[e][1,3]oxazine (1.875 g, 78% yield) as a yellow syrup. The 3,4-dihydro-2H-benzo[e][1,3]oxazine (1.875 g, 4.78 mmol) was dissolved in ethanol (135 mL), 1.0 M aqueous hydrochloric acid (45 mL) added and the reaction mixture stirred at room temperature for 4 days. The reaction mixture was then concentrated under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and 10% w/v aqueous sodium carbonate solution (100 mL). The organic phase was separated, washed with water (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 30% ethyl acetate in hexanes to give the product as a yellow syrup that partially crystallized (1.435 g). The product was dissolved in absolute ethanol (50 mL), 1.0 M aqueous hydrochloric acid (15.1 mL, 15.1 mmol) added, the mixture stood for 20 minutes then concentrated under reduced pressure and the product azeotroped with absolute ethanol (3×60 mL) to give a cream solid. Diethyl ether (50 mL) and absolute ethanol (10 mL) were added and the resulting suspension stirred vigorously overnight then filtered to afford 4-(tert-butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (1.083 g, 54% yield) as a white solid.