Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[C:4]1=[O:11].C(N(CC)CC)C.O=C1CCC(=O)N1[C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:44]([O-])=[O:45])=[C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH:33]=2)[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=1>CN(C)C=O.C(OCC)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[C:44]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[C:4]1=[O:11])=[O:45])[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=[CH:26]2
Reactant: CC(C)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Reactant: N[C@H]1CCN(CCO)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCN(CCO)C3=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
(S)-3-Amino-1-(2-hydroxyethyl)pyrrolidin-2-one hydrochloride (101 mg, 0.558 mmol) was dissolved in triethylamine (0.141 mL, 1.01 mmol) and N,N-dimethylformamide (2.5 mL). To this solution was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 225 mg, 0.507 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel, loaded and eluted with 100% acetone to yield pure (S)-5-(2,4-difluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl)-1-isobutyl-1H-indazole-6-carboxamide (Ig) (177 mg, 74%). Mass spec: 473 (M+1). 1H NMR (CDCl3) δ 8.37 (br, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 7.16 (m, 1H), 7.01 (m, 2H), 6.92 (m, 1H), 4.53 (m, 1H), 3.83 (m, 3H), 3.56 (m, 3H), 3.44 (m, 1H), 3.15 (t, 1H), 2.74 (m, 1H), 2.36 (m, 1H), 2.08 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: S=C(NN=Cc1ccccc1)NC1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.4 %

Procedure:
To a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.55 mmol) and benzaldehyde (56 μl, 0.55 mmol) in ethanol (5 mL) was added a solution of sodium acetate (45 mg, 0.55 mmol) in water (1 mL) and the mixture was stirred at room temperature for 24 h. The mixture was diluted with water (1.5 mL) and the resultant precipitate was collected by filtration and isolated as a white solid (14 mg, 9%). 1H NMR (CDCl3): 9.84 (s, 1H), 7.88 (s, 1H), 7.64-7.61 (m, 2H), 7.50 (d, J=7.5 Hz, 1H), 7.42-7.40 (m, 3H), 6.24-6.14 (m, 2H), 4.314.26 (m, 1H), 3.06 (s, 1H), 2.96 (s, 1H), 1.94-1.86 (m, 1H), 1.67 (d, J=9.3 Hz, 1H), 1.52 (d, J=9.0 Hz, 1H), 1.46-1.39 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:7][NH:8]2)=[CH:4][C:3]=1[C:20]([OH:22])=[O:21].[H-].[Na+].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:7][N:8]2[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc2c(/C=C/c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
Under ice cooling, to a solution of 350 mg of 6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic acid obtained by Example 101 in 6 mL of N,N-dimethylformamide was added 103 mg of 60% sodium hydride, stirred for 30 minutes, then added with 390 mg of trityl chloride, and stirred at this temperature for 20 minutes and at room temperature for 1 hour. The reaction solution was added with water and extracted with 80 mL of ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (ethylacetate:toluene=1:9), to afford 370 mg of the title compound as bright yellow crystals.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11]CC)(=[O:10])[C:5]([O:7][CH2:8][CH3:9])=O.[OH:14][C:15]1[C:23](C(=O)C)=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][CH2:18][CH2:19]2>CC1C=CC=CC=1>[O:14]=[C:15]1[C:16]2[CH:17]=[CH:18][C:19]3[CH2:20][CH2:21][CH2:22][C:9]=3[C:8]=2[O:7][C:5]([C:4]([OH:11])=[O:10])=[CH:23]1
Reactant: CC(=O)c1ccc2c(c1O)CCC2
Reactant: CCOC(=O)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(=O)c2ccc3c(c2o1)CCC3
Yield: 57 %

Procedure:
Sodium methylate (24 g) was stirred in methylbenzene (300 ml). A mixture of diethyl oxalate (0.16 mol) and intermediate (2-a) (0.16 mol) in methylbenzene (10 ml) was added dropwise. This mixture was stirred and refluxed for 2 hours. The resulting precipitate was filtered off and dried. The solid was stirred in a mixture of hydrochloric acid (10 ml) and acetic acid (500 ml). The reaction mixture was stirred and refluxed for 1 hour. The mixture was poured out into water. The resulting precipitate was filtered off and dried (vacuum), yielding 21 g of 4,7,8,9-tetrahydro-4-oxocyclopenta[h]-1-benzopyran-2-carboxylic acid (interm. 3-a).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(=O)C)C>[C:24]([CH2:23][CH2:22][CH2:21][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1)#[N:25]
Reactant: N#CCCCCl
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: N#CCCCN1CCOC(c2ccccc2)(c2ccccc2)CC1

Procedure:
The mixture of 4.6 g of 7,7-diphenyl-hexahydro-1,4-oxazepine, 1.88 g of 4-chlorobutyronitrile, 1.88 g of anhydrous sodium carbonate, 0.3 g of sodium iodide and 60 ml of 2-methyl-4-pentanone is stirred at reflux for 23 hours and evaporated. The residue is partitioned between diethyl ether and water, the ethereal solution separated, washed with saturated aqueous sodium chloride, dried and evaporated, to give the 4-(3-cyanopropyl)-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 89°-90°. (Analogously the 4-(4-cyanobutyl and 6-cyanohexyl)-7,7-diphenyl-hexahydro-1,4-oxazepines are prepared, melting at 67°-69° and showing an I.R. band at 2252cm-1 respectively).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[CH:15]1[CH2:17][CH2:16]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH:15]1([C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[C:4]([OH:5])=[O:3])[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1sc2ccccc2c1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1sc2ccccc2c1C1CC1
Yield: 79.9 %

Procedure:
A solution of compound 674-B (2.68 g, 10.9 mmol) in ethanol (30 mL) was treated with 3N aqueous sodium hydroxide (5.4 mL, 16.2 mmol) and refluxed for 2 h. The solution was cooled, and the solvent was evaporated in vacuo. The residue was dissolved in water and washed with dichloromethane. The aqueous phase was acidified with concentrated hydrochloric acid, and the product was extracted into ethyl acetate, washed with brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo, to afford 1.9 g of compound 674-C as a colorless solid. 1H-NMR (DMSO-d6): δ 0.58-1.37 (m, 4H), 2.44-2.47 (m, 1H), 7.13-7.61 (m, 2H), 7.98 (dd, 2H), 13.33 (br s, 1H).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C.C(OCC)(=O)C>[NH2:12][CH:13]1[NH:15][C:3]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:2][S:14]1
Reactant: NC(N)=S
Reactant: COC(=O)CCCC(=O)CBr
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CCCC1=CSC(N)N1
Temperature: 25 °C

Procedure:
Methyl 6-bromo-5-oxohexanoate and thiourea (1.2 eq) in ethanol (0.2M solution) were refluxed for 18 hrs. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and the residue was purified by flash chromatography (100% ethyl acetate). EI-MS m/z 201 (M+H)+.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[NH:5])#[N:2].Cl.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.O>C(OCC)(=O)C>[ClH:14].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[NH:5])=[NH:2])=[CH:20][CH:19]=1
Reactant: N#CNC(=N)NCc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: N=C(NCc1ccc(Cl)c(Cl)c1)NC(=N)Nc1ccc(Cl)cc1
Yield: 130.2 %

Procedure:
To 20 g of N1 -cyano-N3 -(3,4-dichlorobenzyl)-guanidine and 13.5 g of 4-chloroaniline hydrochloride, 200 ml of water was added, which was heated and refluxed for 2 hours. When cooled gradually after reaction, crystals was precipiated. After filtering the crystals, by drying the crystals obtained by heat treatment in 200 ml of ethyl acetate, 21.8 g of the captioned compound was obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH2:10][C:11](=[CH:15][Br:16])[CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CON=C(C(=O)OC)c1cccc(C)c1
Solvent: ClCCl
Product: CON=C(C(=O)OC)C1=CC=CC(=CBr)C1

Procedure:
15 g (72.4 mmol) of m-methylphenylglyoxylic acid methyl ester O-methyl oxime, 13.5 g (75.8 mmol) of N-bromosuccinimide and 0.1 g (0.6 mmol) of azobisisobutyrodinitrile in 150 ml of CH2Cl2 are exposed for 4 hours to a 300 watt UV lamp, the reaction mixture being refluxed. Thereafter, the organic phase is extracted with water, dried over MgSO4 and evaporated down.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[S:11][C:10]([NH:12][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:25]([O:24][CH3:23])[CH:26]=3)=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccc(F)cc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2Cc2ccc(F)cc2)cc1
Yield: 69.1 %

Procedure:
A procedure similar to that in Example 4 was used. 5-(4-fluoro-benzyl)-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 21 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 69.1%, mp: 140-142 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.80 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.18 (2H, s, CH2), 6.79 (1H, d, J=8.68 Hz, ArH), 6.82 (2H, d, J=8.68 Hz, ArH), 7.00 (2H, t, 3JFH=3JHH=8.68 Hz, ArH), 7.21 (2H, dd, 3JHH=8.12 Hz, 4JFH=5.32 Hz, ArH), 7.35 (4H, d, J=9.28 Hz, ArH), 11.00 (1H, br, CONH, exchangable); EI-MS m/e (%): 478.2 (M+, 88), 165.0 (100); HREI-MS Calcd. for C26H23FN2O4S: 478.1363. found: 478.1361. Anal. Calcd. for C26H23FN2O4S: C, 65.26; H, 4.84; N, 5.85. found: C, 65.11; H, 4.68; N, 5.96.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[N:14]=[C:15]([S:25][CH3:26])[N:16]=[N:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH3:12][C:13]1[N:14]=[C:15]([S:25]([CH3:26])=[O:9])[N:16]=[N:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1nc(S(C)=O)nnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
m-Chloroperbenzoic acid (20 g) was added to a stirred solution of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (20 g) in chloroform (600 ml) under ice cooling, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and then concentrated. The resulting residue was crystallized with diethyl ether, and the crystals were collected by filtration, washed with diethyl ether and dried to give 5-methyl-3-methylsulfinyl-6-phenyl-1,2,4-triazine (19.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:19][CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[N:12]1[C:20](=[O:31])[C@H:21]([CH3:30])[NH:22]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH2:1]([O:8][C:9]([CH:11]1[CH2:19][CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[N:12]1[C:20](=[O:31])[C@H:21]([CH3:30])[NH2:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C(C(=O)OCc2ccccc2)CC2CCCCC21
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)N1C(C(=O)OCc2ccccc2)CC2CCCCC21

Procedure:
21.5 g of Boc-Ala-Oic-OBzl are dissolved in 50 ml of trifluoroacetic acid. The solution is concentrated in vacuo, and the residue is digested several times with diisopropyl ether and is dried in vacuo. Yield: 21 g. The proton signal for the tertiary-butyl group is completely absent in the NMR spectrum.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([N:20](C)[C:21](=O)OCC3C=CC=CC=3)[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[CH3:1][C:2]1([CH3:32])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([NH:20][CH3:21])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: CN(C(=O)OCc1ccccc1)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CNc1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Temperature: 65 °C
Yield: 89.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of benzyl N-{2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl}-N-methylcarbamate obtained in Example 3 (7.2 g, 17 mmol) in ethanol (72 ml) were added 10% palladium-carbon (723 mg) and ammonium formate (2.5 g, 39 mmol), and the mixture was stirred with heating at 65° C. for 40 min. After cooling, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was slurry-washed in water (300 ml). The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (4.5 g, yield 90%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]/[CH3:22]>>[C:14]1([C@@H:12]([N:8]2[C:6]3=[N:7][C:2](/[CH:20]=[CH:21]\[CH3:22])=[CH:3][N:4]=[C:5]3[N:10]=[C:9]2[OH:11])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Reactant: C/C=C\B(O)O
Product: C/C=C\c1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 90 °C
Yield: 63 %

Procedure:
A scintillation vial equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), (Z)-prop-1-enyl boronic acid (2.0 equiv) and (DPPF)PdCl2 (0.10 equiv). The vial was fitted with a septum-lined cap and purged with nitrogen for 5-10 min. To this mixture was added dioxane (16.6 volume equivalents) and degassed 2 N K2CO3 (4.2 volume equivalents) by syringe. The resulting mixture was heated to 90° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, washed with twice with saturated aq. NaHCO3, and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Biotage MPLC 5%-40% EtOAc/Hexanes) provided the title compound (63%) as an off-white foam. LCMS m/z (APCI)=281.1 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][CH2:27][CH3:28])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:24][CH:23]([CH3:25])[CH2:22][N:21]1[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=[C:20]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
7-Benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline (60.3 g, 0.188 mol), prepared as described in Parts A-G of Example 1, and 10% palladium on carbon (10 g) were mixed with ethanol (500 mL). Ammonium formate (101.53 g, 1.61 mol) and ethanol (500 mL) were then added, and the reaction mixture was heated at reflux for two hours. The mixture was allowed to cool to ambient temperature slowly and stirred overnight. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol (1 L), methanol (2 L) and dichloromethane (2 L). The combined filtrates were concentrated under reduced pressure to provide a tan solid, which was triturated with cold ethanol and isolated by filtration to yield 30 g of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol as a tan, granular solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:16][C:15]([Cl:28])=[CH:14][CH:13]=2)=[O:9].I[CH3:30]>CO.O1CCCC1>[CH3:30][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[S:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:21])=[CH:16][C:15]([Cl:28])=[CH:14][CH:13]=2)=[O:9]
Reactant: CI
Reactant: O=C(NCc1ncc[nH]1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ccnc1CNC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a partial suspension of N-[(imidazol-2-yl)methyl] 3-phenylsulfonyl-5-chloroindole-2-carboxamide (Example 35) (42 mg, 0.1 mmol) in 1:1 methanol/tetrahydrofuran (4 mL) was added iodomethane (0.05 mL, 0.8 mmol). The reaction was stirred for three days at room temperature. The solvents were removed under reduced pressure, aq. NaHCO3 added and the product extracted into ethyl acetate/methanol. The organic layer was dried (Na2SO4), filtered, and the solvents evaporated. The residue was purified by chromatography and the product eluted with 3% methanol/chloroform. Appropriate fractions were combined, the solvents evaporated, and the residue triturated with methylene chloride to give pure product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:18][O:19][C:20]=3[CH3:21])=[O:15])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2[C:16]([C:14]([C:9]3[C:8]4[C:12](=[CH:13][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=4)[NH:11][CH:10]=3)=[O:15])=[C:20]([CH3:21])[O:19][N:18]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc2c(C(=O)c3c(-c4ccc(F)cc4)noc3C)c[nH]c2c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c2cc(C(=O)O)ccc12
Yield: 96.4 %

Procedure:
To a solution of 0.7 g (1.85 mmol) 3-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-1H-indole-6-carboxylic acid methyl ester in 12 mL of THF and 6 mL of H2O, was added 0.39 g (9.25 mmol) LiOH.H2O in one portion. The reaction mixture was heated under reflux for 16 h. After the evaporation the mixture was extracted with Et2O (10 mL), and acidified to pH=2-3 with 2 N HCl. The resulting solid was filtered off, washed with water and dried to give 0.65 g of the title compound (intermediate 1) in 97% yield as a white solid. (m/e): 365.1 (MH+; 100%).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Br[CH2:23][C:24]1[CH:35]=[CH:34][C:27]([O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:26]([CH3:36])[CH:25]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH3:36][C:26]1[CH:25]=[C:24]([CH2:23][N:5]([CH2:4][CH2:3][S:2][CH3:1])[C:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:35]=[CH:34][C:27]=1[O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: CSCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COC(=O)COc1ccc(CBr)cc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COc1ccc(CN(CCSC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
To a solution of N-[2-(methylthio)ethyl]-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (0.27 g, 0.864 mmol) in anhydrous MeCN (22 mL) under nitrogen at room temperature was added methyl [4-(bromomethyl)-2-methylphenoxy]acetate (0.248 g, 0.864 mmol) and N,N-diisopropyethylamine (0.15 mL, 0.864 mmol). The resultant mixture was heated to reflux and stirred for 3 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×30 mL) and water (30 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (20 g Silica cartridge), eluted with 1:99–1:33 EtOAc:cyclohexane afforded the title compound as a yellow oil (249 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27][C:28](=[O:34])[C:29](OCC)=[O:30])[CH3:26].CC([O-])(C)C.[K+].C(O)C.Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH2:24][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:34])=[O:30])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 18.5 h

Procedure:
A solution of 4-(3-methyl-4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (example 43, step 1, 41.9 g, 1.0 eq.) and diethyloxalate (18.77 mL, 1.1 eq.) in tetrahydrofuran (241.7 mL) was dropped into a cold (0-5° C.) solution of potassium tert-butylate (28.54 g, 2.0 eq.) and ethanol (43.64 mL, 6.0 eq.) in tetrahydrofuran (1.022 L). The mixture was stirred for 3 h at 0-5° C. and for 18.5 h at room temperature, poured into 1M hydrochloric acid solution. The aqueous phase was extracted 3 times with tert-butylmethylether and the combined organic phases were washed with brine, dried over sodium sulfate, filtered, evaporated to dryness in vacuo and crystallized from ethanol to yield 44.09 g (81%) as white crystals. MS (m/e): 436.2 (M, 5%).