Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:21])([F:20])[CH2:9][C:10]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:13]#[N:14])[C:11]#[N:12]>CCOCC>[F:7][C:8]([F:20])([F:21])[CH2:9][C:10]([CH2:15][C:16]([F:17])([F:18])[F:19])([CH2:11][NH2:12])[CH2:13][NH2:14]
Reactant: N#CC(C#N)(CC(F)(F)F)CC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC(CN)(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
340 mg LiAlH4 (8.95 mmol) was suspended in 15 ml dry Et2O and cooled in an ice bath. A solution of 760 mg 2,2-Bis-(2,2,2-trifluoro-ethyl)-malononitrile in Et2O was added dropwise at such a rate that the temperature was kept below 20° C. The mixture was stirred overnight at room temperature, cooled in an ice bath, and quenched by adding H2O (0.35 ml), 2M aqueous NaOH (0.70 ml), and again H2O (0.35 ml). The suspension was filtered, the filtercake was washed with Et2O, and the combined filtrates were evaporated to dryness under reduced pressure to give 0.72 g of an oil. This material was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[N:10]([C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)[N:11]=[C:12]([CH3:22])[C:13]=2[C:14](=[O:21])[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].[BH4-]>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[N:10]([C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)[N:11]=[C:12]([CH3:22])[C:13]=2[CH:14]([OH:21])[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: CCc1ccc2c(-c3ccnc(Cl)c3)c(C(=O)CCCC(=O)O)c(C)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc2c(-c3ccnc(Cl)c3)c(C(O)CCCC(=O)O)c(C)nn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-oxopentanoic acid (47 mg) in EtOH (1 mL) was added sodium borohydride (5 mg) in an ice-water bath under N2. After 10 min, the mixture was stirred at ambient temperature. After 1 h, another odium borohydride (5 mg) was added. After 2 h, the reaction mixture was partitioned between CHCl3 and H2O. The aqueous layer was extracted with CHCl3 twice. The combined organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by p-TLC (CHCl3-MeOH=10-1) to give 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-hydroxypentanoic acid as yellow amorphous (28 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH3:31][N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]3[CH2:36][CH2:37][CH2:38][N:32]([CH3:31])[CH2:33][CH2:34]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: CN1CCCNCC1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN1CCCN(C)CC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 1-methyl-1,4-diazepane following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 8.82 (br, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.76 (s, 1H), 3.95 (t, 2H), 3.89 (s, 3H), 2.62-2.42 (m, 8H), 2.37 (t, 2H), 2.21 (s, 3H), 1.74 (m, 2H), 1.66 (m, 2H), 1.38 (m, 4H), 1.29 (m, 2H); MS (ESI): 548.3.
Reaction SMILES: [F:1][CH:2]([C:4]1[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[NH:7][C:6](=[O:13])[CH:5]=1)[CH3:3].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:1][CH:2]([C:4]1[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[N:7]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:6](=[O:13])[CH:5]=1)[CH3:3]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)F)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc(C(C)F)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 6-(1-fluoroethyl)-2-propylpyrimidin-4(3H)-one (5.7 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (9.3 g) and potassium carbonate (8.5 g) in acetonitrile (50 mL) was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (5 g, 43%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([N:35]=[C:36]=[O:37])[CH2:33][CH3:34]>CCCCCC>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:36]([NH:35][CH2:32][CH2:33][CH3:34])=[O:37])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCN=C=O
Solvent: CCCCCC
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)NCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.7 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (0.36 g, 0.0008 mol) in hexane (15 mL) was added propylisocyanate (0.094 mL, 0.085 g, 0.001 mol), and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was then treated with additional propylisocyanate (0.094 mL, 0.085 g, 0.001 mol) and stirred at ambient temperature overnight and then at reflux for 72 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed using 2:8 hexane-ethyl acetate. The resulting oil was triturated with hexane to give the title compound (0.8 g, 0.00015 mol) as a white solid, mp 78°-80°. 1H NMR (CDCl3) 7.6-7.2(m,10H), 4.4(t,1H,J=7Hz), 3.4-2.9(m,8H), 1.9-1.1(m,19H), 1.0-0.75(m,6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:27])=[C:14]([CH:26]=2)[C:15]([O:17]CC2C=CC=C(Cl)C=2)=[O:16])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:27])=[C:14]([CH:26]=2)[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)OCc1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A solution of (3-chlorophenyl)methyl 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoate from the preparation of Intermediate 84 described above (2.67 g, 6.66 mmol) in 1,4-dioxane (20 ml) and water (10 ml) was treated with lithium hydroxide (419 mg, 9.99 mmol, 1.5 eq). The resulting mixture was stirred at room temperature under argon overnight. A further portion of lithium hydroxide (419 mg, 9.99 mmol, 1.5 eq) was added and stirring continued at room temperature for 2 hours. Stirring continued at room temperature overnight. The solvent was then evaporated to dryness and then partitioned between 2M HCl (100 ml) and diethylether (100 ml). The organic layer was separated and passed through a hydrophobic frit to remove any water and evaporated to dryness to afford the title compound as a white solid (1.98 g) (contains 12% impurity). No further purification carried out. MS (ES−) m/z 275 [M−H]− (C15H1335ClO3).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[C:16]1(/[CH:22]=[CH:23]/B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2](/[CH:23]=[CH:22]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: OB(O)/C=C/c1ccccc1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(/C=C/c2ccccc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (700 mg, 2.82 mmol), trans-2-phenylvinylboronic acid (501 mg, 3.39 mmol), Pd(PPh3)4 (245 mg, 0.212 mmol), sodium carbonate (0.590 mL, 14.11 mmol), toluene (23 mL), and water (6 mL) at 95° C. for 18 h. Purification by column chromatography (silica gel, 0-10% EtOAc in hexanes as eluent) gave (E)-4-chloro-5,7-difluoro-3-methyl-2-styrylquinoline. Mass Spectrum (ESI) m/e=316.0 (M+1).
Reaction SMILES: Br[C:2]1[C:3]2[CH:23]=[CH:22][NH:21][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[N:7]=1.[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[N:7]=[C:2]([C:31]4[CH:32]=[CH:33][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=4)[C:3]4[CH:23]=[CH:22][NH:21][C:4]=4[N:5]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: Brc1nc(Nc2ccc(N3CCOCC3)cc2)nc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2nc(Nc3ccc(N4CCOCC4)cc3)nc3[nH]ccc23)cc1

Procedure:
A mixture of 4-bromo-N-(4-morpholin-4-ylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine B (284 mg, 0.76 mmol), 4-acetoamidophenylboronic acid C (340 mg, 2.5 eq), tetrakis(triphenyl-phosphine)palladium(0) (120 mg, 0.1 mmol), and 1M Na2CO3 (1 ml, 1 mmol) in 1,4-dioxane (15 ml) was heated at reflux overnight. The mixture was cooled, extracted with 3N HCl. The aqueous layer was washed with ethylacetate, and then basified with 6N NaOH. The solid was filtered, and the crude product was purified by preparative HPLC to give the product N-(4-{2-[(4-morpholin-4-ylphenyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)acetamide D (0.8 mg, 0.25%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[C:12](=[O:33])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)[C:14]3[C:19]([C:20]=2O)=[CH:18][CH:17]=[CH:16][N:15]=3)=O)=[CH:4][CH:3]=1.O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:11]3[C:12](=[O:33])[N:13]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:30])[F:31])[CH:23]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:20]=3[NH:36][N:35]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(F)cc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccc(F)cc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(4-fluorophenylacetyl)-4-hydroxy-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (229 mg, 0.5 mmol) produced in Synthesis Example 28 in DMF (4 mL) was added hydrazine monohydrate (purity of 80%, 80 μL), and the mixture was stirred at 110 to 120° C. for 3 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(4-fluorobenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (203 mg, yield 89%).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][F:24])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.ClCCl>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21]/[CH:22]=[CH:23]\[F:24])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(C#CCF)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C/C=C\F)cc1
Yield: 98.9 %

Procedure:
cis-hydrogenation using Lindlar catalyst and quinoline: Shake a mixture of recrystallized title compound of Example 1 (1 g, 4.72 mmoles), quinoline (60 mg, 99% pure Aldrich) and Lindlar catalyst of procedure A of Example 2 (200 mg) in ethyl acetate (50 mL) in a Parr apparatus under hydrogen at atmospheric pressure at 30° for 20 min. or until theoretical amount of hydrogen (118 mL) is taken up. Remove catalyst by filtration and wash it with ethyl acetate. Evaporate the solvent under vacuum at 35° to give an oil. Dissolve the oil in dichlormethane (40 mL) and wash the dichloromethane solution successively with ice-cold 1 M HC1 solution, saturated NaHCO3 solution and water, and then dry over anhydrous MgSO4. Evaporate the under vacuum to give the title compound as an oil (1 g). Purify a portion of the oil (220 mg) by column chromatography. Elute the column with ethyl acetate-hexane (1:1, v/v) to give the title compound as an oil (213 mg). The oil was 95% pure and contained 5% of the over-reduced compound 3-(4-methylsulfonylphenyl)-1-fluoropropane and had the following physical and spectral properties:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH3:7].[Li]CCCC.[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25](I)=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14].[NH4+].[Cl-]>[Cl-].[Cl-].[Zn+2].C1COCC1>[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25]([C:2]3[CH:6]=[CH:5][O:4][C:3]=3[CH3:7])=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1occc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3ccoc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A THF solution (10 mL) of 3-bromo-2-methyl furan (prepared as described above) (1.06 gm, 6.58 mmol) is cooled to −78° C. under N2 then treated with nBuLi (1.6 M in hexane, 4.1 mL, 6.6 mmol). After 10 minutes at −78° C., the mixture is treated with ZnCl2 (Aldrich, 0.5 M in THF, 13.2 mL, 6.6 mmol). The resulting mixture is warmed to room temperature then treated with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.13 gm, 3.29 mmol) and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 257 mg, 0.31 mmol). The mixture is heated to 60° C. for 4 hours, then poured into sat. NH4Cl (50 mL) and extracted with diethyl ether (2×50 mL). The combined organic extracts are washed with sat. NaCl, dried over Na2SO4, filtered, and concentrated. The crude product is purified by chromatography using hexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate in hexane) to elute the title product (685 mg, 70% yield) as an oil. ES-MS (m/z): calc'd for C18H23N3O: 297.2. found 298.2 (M+H); 1H NMR (400 mHz, CDCl3): δ 7.45 (d, J=2.0 Hz, 1H), 6.63 (s, 1H), 6.60 (d, J=2.0 Hz, 1H), 3.35-3.31 (m, 1H), 2.51 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H), 1.88-1.75 (m, 4H), 0.86 (t, J=7.5 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2([CH2:22][OH:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I.[H-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2([CH2:22][O:23][CH3:24])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1(c2cn(Cc3ccccc3)cn2)Cc2ccccc2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(c2cn(Cc3ccccc3)cn2)Cc2ccccc2C1

Procedure:
The reaction was performed according to example 9c using 1,66 g of [2-(1-benzyl-1H-imidazol-4-yl)-2,3-dihydro-1H-inden-2-yl]methanol (base) and 1,42 g of methyl iodide as starting materials, sodium hydride (0,84 g of a 50% dispersion of NaH in mineral oil) as reagent and dry tetrahydrofuran as solvent.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=O)[N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[N:6][C:7]=1[Cl:8].O1CCCC1.B.CO>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CCCCCCN1C(=O)CCc2nc(Br)c(Cl)nc21
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCN1CCCc2nc(Br)c(Cl)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 7-(2-bromo-3-chloro-6-oxo-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (1.0 g, 2.388 mmol) in tetrahydrofuran (10 ml) under a nitrogen atmosphere at 0° C. was treated slowly with 1M borane tetrahydrofuran complex (11.94 ml, 11.94 mmol) and the resultant solution was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature. The mixture was cooled to 0° C. and treated with borane tetrahydrofuran complex borane (2.4 ml, 2.4 mmol). Once the addition was complete the mixture was stirred at 0° C. for 30 minutes and then at RT. The mixture was cooled in ice and carefully treated with MeOH. The mixture was stirred at room temperature for 1 hour and then evaporated under vacuum to give an oil which was purified by chromatography on silica eluting with 0-100% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:28]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]>CC(C)=O>[C:28]([N:31]1[CH2:32][CH2:33][CH:34]([C:37]([O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=3)(=[O:9])=[O:10])=[CH:4][CH:3]=2)=[O:38])[CH2:35][CH2:36]1)(=[O:30])[CH3:29]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)N1CCC(C(=O)Oc2ccc(S(=O)(=O)c3ccc(S(N)(=O)=O)s3)cc2)CC1
Reaction time: 0.25 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g; 0.01 mole) in acetone (60 ml) at -15° was treated with triethylamine (1.11 g; 0.011 mole). Then 1-acetylpiperidine-4-carbonyl chloride hydrochloride (2.41 g; 0.011 mole) was added, portionwise, during 15 minutes at -15°. The cooling bath was removed and stirring was continued. After 20 hours at room temperature, the reaction mixture was treated with triethylamine (1.11 g; 0.011 mole). Then after stirring one hour longer, the reaction mixture was treated with 1-acetylpiperidine-4-carbonyl chloride hydrochloride (2.41 g; 0.011 mole) and triethylamine (2.22 g; 0.022 mole) and stirred at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13]4[CH2:30][CH2:29][NH:28][C:27](=[O:31])[C:14]=4[C:15]([O:16][S:17]([C:20]4[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:19])=[O:18])=[C:9]3[C:8]2=[O:32])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.Br[CH2:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13]4[CH2:30][CH2:29][N:28]([CH2:51][C:52]5[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=5)[C:27](=[O:31])[C:14]=4[C:15]([O:16][S:17]([C:20]4[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:19])=[O:18])=[C:9]3[C:8]2=[O:32])=[CH:33][CH:34]=1
Reactant: BrCc1ccncc1
Reactant: Cc1ccccc1S(=O)(=O)Oc1c2c(n3c1C(=O)N(Cc1ccc(F)cc1)CC3)CCNC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)Oc1c2c(n3c1C(=O)N(Cc1ccc(F)cc1)CC3)CCN(Cc1ccncc1)C2=O
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 8-(4-fluorobenzyl)-10-toluenesulfonyloxy-3,4,7,8-tetrahydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (60 mg, 0.12 mmol) in anhydrous DMF (1 mL), a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 1.5 eq) was added. The mixture was stirred at the same temperature for 30 minutes. A solution of 4-bromomethylpyridine in diethyl ether (generated from the corresponding hydrobromide salt through partition between aq sodium carbonate and ether, and drying the solution by passing it through a plug of activated basic alumina). The reaction mixture was stirred at rt for one hour and concentrated under vacuum. The residue was subjected to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fractions provided the titled compounds.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1.C(Cl)Cl>[C:17]([O:16][C:15](=[O:21])[NH:14][CH2:13][CH2:12][NH:11][C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccccc1O
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a stirring solution of salicylic acid (2.0 g, 14.5 mmol) and t-butyl N-(2-aminoethyl)carbamate (2.32 g, 14.5 mmol) in dry THF (15 mL) was added a solution of 1,3-dicyclocarbodiimide (3.29 g, 16.0 mmol) in CH2Cl2 (5 mL) dropwise at 0° C. The reaction was stirred for 18 h and then filtered. The filtrate was conc in vacuo. The residue was dissolved in EtOAc (50 mL), washed with 5% NaHCO3, dried with MgSO4, and conc in vacuo to a white solid. The solid purified by silica gel chromatography (gradient: 0–70% EtOAc in hexanes) to yield 2.88 grams (71%) of the product as white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([O:30]C)=[O:29])[C:19]([CH3:35])=[C:18]4[CH3:36])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([OH:30])=[O:29])[C:19]([CH3:35])=[C:18]4[CH3:36])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C5CC5)c4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: Cc1c(C)n(Cc2cccc(C(=O)O)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C4CC4)c3)cc12

Procedure:
A solution of (S)-Methyl 3-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)benzoate (˜0.07 mmol) and NaOH (2 M, 0.5 mL) in MeOH (2 mL) and DMSO (1 mL) was stirred at rt for 15 h. It was neutralized and purified by preparative HPLC to yield the title compound as a white solid. ESI-MS (m/z): 467 [M+H]+.