Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Product: COc1ccc(-c2c(C)nn(-c3ccc(CCO)cc3)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 4-methoxyphenylboronic acid: MS (ESI) m/z 323 [M+H]+H-NMR (CDCl3) δ 7.39 (2H, d, J=8.1 Hz), 7.29-7.22 (4H, m), 6.98 (2H, d, J=9.6 Hz), 3.86 (3H, s), 3.74 (2H, br), 2.86 (2H, t, J=6.6 Hz), 2.33 (3H, s), 2.28 (3H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:14].[OH:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: BrCCCCCCCCCCCCBr
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1ccc(OCCCCCCCCCCCCBr)cc1
Yield: 82 %

Procedure:
A solution of 150 mmol (49.2 g) of 1,12-dibromododecane, 50 mmol (10.6 g) of benzyl 4-hydroxybenzoate, and 0.3 mol (41.5 g) of potassium carbonate in 500 ml of acetone was refluxed for 6 hours. The reaction solution was then filtered and concentrated, and the resulting crude product was purified by column chromatography to obtain the objective ester compound of the following formula. (yield: 82%) ##STR34##
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[Cl:24])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc([N+](=O)[O-])ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(Cl)c(OC[C@@H]2CCCN2)c1

Procedure:
(S)-2-(2-Chloro-5-nitro-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (6.94 g, 19.45 mmol) was stirred in 30 mL CH2Cl2 and 20 ml TFA for 3 h. The reaction was concentrated and dissolved in 0.1 N HCl (aq), which was basified to pH>12 with solid NaOH and extracted 3× with EtOAc. The organic layers were washed once with 1 N NaOH then once with a mixture of brine and 1 N NaOH. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness, to yield the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:41])[CH2:24][N:25]2[C:33]3[C:32]([F:35])([F:34])[CH2:31][CH2:30][C:29]([F:37])([F:36])[C:28]=3[C:27]([CH:38]([F:40])[F:39])=[N:26]2)[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.Cl.CN.[CH2:45]([N:47](CC)CC)C>ClCCl>[Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:41])[CH2:24][N:25]2[C:33]3[C:32]([F:35])([F:34])[CH2:31][CH2:30][C:29]([F:37])([F:36])[C:28]=3[C:27]([CH:38]([F:40])[F:39])=[N:26]2)[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5]([NH:47][CH3:45])=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of compound 12C (68 mg, 0.1 mmol) and methylamine hydrochloride (34 mg, 0.5 mmol) in dichloromethane (5 ml) was added triethylamine (697 μL, 0.5 mmol). The reaction mixture was stirring at ambient temperature for 2 hours. The solvent was evaporated and the crude product was purified on reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title product. MS (m/z) 627.24 [M+H]+.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14]>CN1C(=O)N(C)CCC1>[CH:1]1([O:7][CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: COC(COC1CCCCC1)OC
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Cyclohexanol (11.00 g) was added slowly over 2 hours to a stirred suspension of sodium hydride (4.80 g, 50% w/w dispersion in oil) in dry DMPU (100 ml) at 50° C. under argon. The mixture was stirred for an additional 30 minutes, then cooled to 5° C. and treated with 2-bromo-1,1-dimethoxyethane (16.9 g). Stirring was continued for 18 hours at ambient temperature. The mixture was then poured into ice-water (250 ml). The aqueous mixture was extracted with ether (4×100 ml). The combined extracts were washed successively with water (3×100 ml) and saturated brine (100 ml), then dried (MgSO4) and evaporated. Flash chromatography of the residue, eluting successively with hexane, 5% v/v ethyl acetate hexane and 10% v/v ethyl acetate/hexane, gave 2-cyclohexyloxy-1,1-dimethoxyethane as an oil (A) (7.32 g). This was used without further purification. [A sample was distilled under vacuum (bulb to bulb transfer); NMR: 1.29 (5H,m), 1.55 (1H,m), 1.76 (2H,m), 1.92 (2H,m), 3.27 (1H,m), 3.40 (6H,s), 3.50 (2H,d J=5 Hz), 4.48 (1H,t J=5 Hz).]
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:18]1([C@@H:23]([N:27]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[N:28]2)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.O1CCOCC1.O.C(=O)([O-])[O-].[K+].[K+]>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>[CH:18]1([C@@H:23]([N:27]2[CH:31]=[C:30]([C:2]3[C:3]4[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=4[N:5]=[CH:6][N:7]=3)[CH:29]=[N:28]2)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(OCC)n1ccc2c(Cl)ncnc21
Reactant: CC1(C)OB(c2cnn([C@@H](CC#N)C3CCCC3)c2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: CCOC(OCC)n1ccc2c(-c3cnn([C@@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 95 °C
Reaction time: 21 h
Yield: 78 %

Procedure:
Into a 100 ml round bottom flask equipped with a stir bar, condenser and 3-way valve connected to nitrogen and vacuum was charged 4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-c]pyrimidine (3b, 3.30 g, 0.0129 mol), (3S)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile ((S)-24, 5.12 g, 0.0146 mol, 1.13 equiv), 1,4-dioxane (33.4 mL, 0.428 mol), water (16.7 mL, 0.929 mol) and potassium carbonate (K2CO3, 8.03 g, 0.0581 mol, 4.5 equiv) at room temperature. The resulting reaction mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (1.49 g, 0.00129 mol, 0.10 equiv). The mixture was degassed four times back filling with nitrogen each time and then warmed to 95° C. The reaction mixture was stirred at 95° C. for 21 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (45 mL) and water (20 mL). The resulting mixture was stirred until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic fractions were washed with 20% aqueous brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0% to 50% ethyl acetate/hexane gradient elution) afford (3S)-3-cyclopentyl-3-{4-[7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-1-yl}propanenitrile ((S)-25, 4.11 g, 5.27 g theoretical, 78% yield) as colorless oil, which was solidified upon standing at room temperature. For (S)-25: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 7.71 (d, 1H, J=3.8 Hz), 7.12 (d, 1H, J=3.8 Hz), 6.76 (s, 1H), 4.53 (td, 1H, J=19.4, 4.3 Hz), 3.68 (m, 2H), 3.52 (m, 2H), 3.26 (dd, 1H, J=9.6, 17.3 Hz), 3.19 (dd, 1H, J=4.3, 17.2 Hz), 2.41 (m, 1H), 1.80 (m, 1H), 1.63-1.09 (m, 13H); C22H28N6O2 (MW, 408.50), LCMS (EI) m/e 409 (M++H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1/[CH:29]=[CH:30]/[C:31](Cl)=[O:32]>C(Cl)Cl>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=[CH:30][C:31]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=1)=[O:32]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)/C=C/c1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Anhydrous pyridine (0.331 g, 4.2 mmol, 1.2 eq) and ethyl 4-aminobenzoate (0.577 g, 3.50 mmol) were added to a solution of (E)-3-(2-naphthyl)propenoyl chloride (prepared from its corresponding acid) (0.757 g, 3.50 mmo) in anhydrous DCM (15 ml) under Ar. After stirring overnight at room temperature, the white precipitate was filtered, washed with DCM (10 ml) and dried under vacuum to give the amide 42 (0.960 g, 2.78 mmol, 80%) as a white solid, mp 173-175° C. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (3H, t, J 7.2 Hz), 4.28 (2H, t, J 7.2 Hz), 6.97 (1H, d, J 15.4 Hz), 7.54-7.57 (2H, m), 7.7 (1H, d, J 15.4 Hz), 7.77 (1H, dd, J 1.6, 9.2 Hz), 7.84 (2H, d, J 8.8 Hz), 7.93-7.97 (5H, m), 8.15 (1H, s), 10.58 (1H, bs). 13C NMR (100 MHz, DMSO-d6) δ 14.88, 61.09, 119.30, 122.91, 124.18, 124.99, 127.47, 127.83, 128.38, 129.09, 129.36, 130.05, 130.98, 132.82, 133.68, 134.26, 141.64, 144.33, 164.69, 166.01. νmax (solid)/(cm−1) 3357, 1702, 1660, 1619, 1607, 1591, 1521, 1403, 1282. MS (API-ES): m/z 346 [M+H]+ (100%), HRMS (API-ES) m/z found 346.1443 [M+H]+.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([C:10]2([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:18]([C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[CH:30]([CH3:32])[CH3:31])=[C:19]=[O:20]>>[CH:30]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH:27]([CH3:28])[CH3:29])[C:21]=1[NH:18][C:19]([NH:16][CH2:15][C:10]1([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:20])([CH3:31])[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)C2(CN)CCCC2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: Cc1ccc(S(=O)(=O)C2(CNC(=O)Nc3c(C(C)C)cccc3C(C)C)CCCC2)cc1
Yield: 75.6 %

Procedure:
Similarly to Example 1(c), by reaction of 200 mg (0.8 mmol) of C-[1-(toluene-4-sulfonyl)-cyclopentyl]-methylamine with 177 mg (0.87 mmol) of 2-isocyanato-1,3-diisopropyl-benzene. 276 mg of 1-(2,6-diisopropyl-phenyl)-3-[1-(toluene-4-sulfonyl)cyclopentylmethyl]-urea is obtained in the form of an off-white powder. (Yield=77%).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][CH:22]([SH:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([S:24][CH:22]([CH3:23])[CH3:21])=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc2c(n1)OCCN(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
A mixture of the compound obtained in Example 28, step 1 (0.50 g), isopropylthiol (0.20 potassium carbonate (0.51 g) and DMF (10 mL) was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed twice with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(isopropylthio)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.38 g, 63%) as a white powder.
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1>C(O)(C)C.Cl>[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[CH2:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]2)[CH2:14][CH2:15]1
Reactant: O=C1CCC([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.97 g of sodium borohydride in 300 ml of isopropanol was treated dropwise while gassing with nitrogen at -70° C. with a solution of 11 g of 4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanone in 200 ml of isopropanol. After about 1 hour the reaction mixture was left to warm to room temperature, diluted with 500 ml of 0.1N hydrochloric acid and extracted three times with 300 ml of methylene chloride each time. The organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. Crystallization of the residue (11 g) from 500 ml of ethyl acetate/petroleum ether (vol. 3:5) gave 6.6 g of pure trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanol with m.p. 129.5° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([O:33]CC)=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([S:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(SCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 63.7 %

Procedure:
A solution of ethyl 2-ethylthio-1-[[2′-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.35 g) in a methanol (7 ml) solution containing 1N NaOH (2.2 ml) was heated under reflux for 2 Hours. After evaporation of the solvent, the aqueous residue was adjusted to about pH 3-4 with 1N-HCl to give crystals. The crystals were collected by filtration. Recrystallization from ethyl acetate-methanol gave colorless crystals (0.21 g, 64%), m.p. 209-210° C. (decomp.).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].[CH2:24](Br)[CH2:25][CH2:26][CH3:27]>O>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:24][CH2:25][CH2:26][CH3:27])[C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCBr
Reactant: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Intermediate c (9 g, 0.042 mol) was added to DMF (100 mL). To the mixture was added NaH (1.3 g, 0.054 mol) in batch under an ice bath. After stirring for 30 min, n-butyl bromide (3.4 mL, 0.042 mol) was added dropwise. Ater the dropwise addition, the reaction was conducted at 70° C. for 6 h. After completion of the reaction, the reaction solution was poured into water (600 mL). A great deal of solid separated out and was filtered by suction. The filtered cake was washed with water and dried to produce Intermediate f (8.2 g) in a yield of 81.4%.
Reaction SMILES: [O:1]=[C:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]([CH:21]=O)=[C:18]([CH3:20])[CH:19]=1)=[O:14]>>[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]([CH:21]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])=[C:18]([CH3:20])[CH:19]=1)=[O:14]
Reactant: COC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1C=c2ccccc2=N1
Product: COC(=O)c1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Yield: 81 %

Procedure:
Oxoindole (105 mg, 0.79 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid methyl ester (110 mg, 0.67 mmol) using method E to give 153.2 mg (81%) of the title compound.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=CC=CC=2)=[N:8][NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:6]=CC=C[CH:2]=1.CC(C)C(=O)CC#[N:31]>>[CH:1]([C:7]1[CH:20]=[C:25]([NH2:31])[N:9]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:8]=1)([CH3:2])[CH3:6]
Reactant: CC(C)C(=O)CC#N
Reactant: c1ccc(C(=NNc2ccc3ncccc3c2)c2ccccc2)cc1
Product: CC(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Yield: 36 %

Procedure:
Using a procedure analogous to Example B3, 6-(2-(diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and 4-methyl-3-oxo-pentanenitrile (1.5 g, 13.5 mmol) were combined to provide to 3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine. (1.1 g, 36% yield). 1H NMR (400 MHz, CDCl3) δ 8.93 (dd, J=4.4, 1.6 Hz, 1H), 8.21-8.18 (m, 2H), 8.05-8.02 (m, 2H), 7.44 (dd, J=8.4, 4.4 Hz, 1H), 5.56 (s, 1H), 3.85 (br s, 2H), 2.97 (m, 1H), 1.31 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 253.2 (M+H+).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]2[N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:25]([OH:27])[CH3:26]>>[OH:27][CH2:25][CH2:26][N:21]1[CH2:22][CH2:23][N:18]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]3[C:10]([C:9]=2[CH:16]=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:19][CH2:20]1
Reactant: O=Cc1c(N2CCNCC2)n(-c2ccccc2)c2ccccc12
Reactant: CC(O)Br
Product: O=Cc1c(N2CCN(CCO)CC2)n(-c2ccccc2)c2ccccc12
Yield: 87 %

Procedure:
1-Phenyl-2-piperazin-1-yl-1H-indole-3-carboxaldehyde is reacted with bromoethanol as described in Example 30 to afford 2-[4-(2-hydroxyethyl)piperazin-1-yl]-1-phenyl-1H-indole-3-carboxaldehyde (87% yield) as a yellow solid. TLC (ethyl acetate-10% methanol) Rf 0.13; ESI/MS 350 (M+H); RT 2.67 min; NMR 10.16 (1H, s); 8.13 (1H, d, J=6 Hz); 7.68 (5H, m); 7.20 (2H, m); 6.91 (1H, d, J=6 Hz); 4.39 (1H, t); 3.47 (2H, q); 3.2 (4H, m); 2.34 (6H, m).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([NH:20][C@@H:21]([C:25]([OH:27])=O)[CH:22]([CH3:24])[CH3:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH3:24][CH:22]([CH3:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[C:25]([NH:45][O:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27]
Reactant: NOCc1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
CDI (2.45 g, 15.1 mmol) is added to a solution of N-(tert-butoxycarbonyl)-D-valine (3.28 g, 15.1 mmol) and CH2Cl2 (60 mL). The solution is stirred for 1 hour at room temperature. Diisopropylethylamine (2.90 mL, 16.6 mmol) and O-benzylhydroxylamine (2.64 g, 16.5 mmol) are added and the solution stirred for 16 hours at room temperature. The solution is concentrated, diluted with EtOAc, and washed with 5% HCl (2×50 mL), NaHCO3 (50 mL) and brine (50 mL). The organic solution is dried (MgSO4), filtered, and concentrated to give 4.42 g (91%) of the title compound as a white solid which is carried on crude.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>>[C:7]1([CH:2]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C(c1ccccc1)n1cncn1
Yield: 43 %

Procedure:
A mixture of (RS) methyl 2-bromo-2-phenylacetate (25 g), 1,2,4-triazole (8.28 g) and potassium carbonate (16.5 g) in aetonitrile (200 ml) was refluxed for 3 hours, cooled evaporated under reduced pressure and the residue partitioned between ethyl acetate and 10% potassium carbonate solution. The organic extracts were washed with water, extracted twice with 2M hydrochloric acid and the combined acid extracts, after washing once with ether, were basified with solid potassium carbonate and extracted with ethyl acetate. The organic extracts were dried over magnesium sulphate and evaporated under reduced pressure to give the title compound as a yellow oil (10.2 g, 43%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.C(N(CC)CC)C.[C:24]1([NH:30][NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC1C=CC=CC=1C>[C:24]1([N:30]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]3=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Reactant: NNc1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1

Procedure:
A suspension of ethyl 4-chloro-quinoline-3-carboxylate (3a) (2.35 g, 0.01 M) in 20 mL of o-xylene was refluxed with triethylamine (2.0 mL, 0.02 M) and phenyl hydrazine (2.89 g, 0.02 M) overnight. The crude product was obtained by filtration followed by washing the solid with cold methanol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[Cl:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][CH:14]2[CH2:19][CH:18]([C:20](OCC)=[O:21])[C:17](=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]2[CH2:15][CH2:16][C:17]3[N:7]=[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]4=[C:20]([OH:21])[C:18]=3[CH2:19]2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1CC(Cc2ccc(Cl)cc2)CCC1=O
Reactant: Cn1cc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1ncc2nc3c(c(O)c21)CC(Cc1ccc(Cl)cc1)CC3
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A solution of 1-methyl-1H-pyrazol-4-amine ((J. Catalan et al., J. Heterocycl. Chem., 1985, 22, 997), 200 mg, 2.06 mmol), ethyl 5-(4-chlorobenzyl)-2-oxocyclohexanecarboxylate (EXAMPLE 69, step 3, 1.43 g, 4.85 mmol), and p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) in toluene (15 ml) was stirred at 120° C. for 2.5 h. After cooling to room temperature, the solvent was removed in vacuo. The residue (ca. 1.5 g) was dissolved in diphenyl ether (10 ml) and heated at 240° C. for 1 h. After cooling to room temperature, the formed solid was collected by filtration, and washed with diisopropyl ether to give 231 mg (34%) of 7-(4-chlorobenzyl)-1-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-b]quinolin-9-ol. 105 mg of this compound was treated with methanolic hydrochloric acid (5 ml) and the mixture was evaporated. The obtained solid was recrystallized from methanol/diisopropyl ether to give 100 mg of the title compound as a gray crystal.