Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[N:25][CH:26]=4)[CH:19]=3)[N:14]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:13]=2)[CH:8]=[N:7]1.[ClH:53]>CCOCC>[ClH:53].[F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[N:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=3)(=[O:42])=[O:41])[CH:13]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (250 mg, 0.34 mmol) was deprotected in HCl in ether (5 ml) to afford 270 mg (crude) of the titled compound. MS: m/z=622.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:9]1([S:15][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[CH:7]=[O:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: O=Cc1sccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=Cc1sccc1Sc1ccccc1
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a stirred solution of 3-bromothiophene-2-carboxaldehyde (1.9 g, 10 mMol) in ethanol (15 mL) is added thiophenol (2.2 g, 20 mMol) and powdered potassium carbonate (3.04 g, 22 mMol). The mixture is stirred overnight and concentrated. The residue is partitioned between water and ether. The aqueous layer is washed with ether and the organics combined, dried(MgSO4) and concentrated. Purification by flash column (SiO2, eluted with 3% ethylacetate/hexanes) afforded the desired aldehyde (2.02 g, 92%) as a yellow liquid.
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:7]([S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: Sc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(CSc2nc[nH]n2)cc1

Procedure:
A solution of 3-mercapto-1H-1,2,4-triazole (100 mg) and benzyl bromide (118 μl) in dimethylformamide (2 ml) was stirred at room temperature for 23 hours. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogencarbonate solution at room temperature, and the resultant mixture was extracted once with ethyl acetate. The organic layer was washed three times with water and subsequently once with saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The residue was filtered off, and the solvent was distilled from the resulting filtrate under reduced pressure to yield the titled compound (172 mg) as white solids.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10](Cl)=[O:11].CCN(C(C)C)C(C)C.O>CCOC(C)=O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10]([N:3]([O:4][CH3:5])[CH3:2])=[O:11]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CON(C)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 35 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (1.48 kg, 14.9 mol) was suspended in EtOAc (16 L) and warmed to 35° C. A solution of 3,4-dichlorobenzoyl chloride (3.00 kg, 13.9 mol) in EtOAc (8 L) was added, followed by addition of DIPEA (5.45 ml, 31.2 mol) while maintaining the temperature below 40° C. The reaction suspension was stirred for 1 h. When TLC analysis confirmed reaction completion by the disappearance of starting material, the reaction mixture was cooled to rt and H2O (10 L) was added to achieve a clear, biphasic solution. After removing the aqueous layer, the organic layer was dried (Na2SO4) and concentrated to afford the title compound (3.49 kg, 100%) as an oil. Upon sitting at rt, the product crystallized. IR (KBr pellet): 3445, 3258, 3091.6, 2981.4, 2945.5, 1942.4, 1645.6, 1588.6, 1557.4, 1462.9, 1414.5, 1368, 1386.2,1262, 1209, 1130, 1112.5, 1071.8, 1030.9, 100.9, 893.8. MS (ES+): mass calculated for C9H9Cl2NO2, 233.00; m/z found 234.0 [M+H]+. Mp: 39.5-43.2° C. 1H NMR (400 MHz, CDCl3): 7.80 (d, J=2 Hz, 1H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 3.54 (s, 3H), 3.34 (s, 3H). 13C NMR (100 MHz, CDCl3): 167.2, 135.0, 133.9, 132.4, 130.7, 130.2, 127.9, 61.5, 33.7.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([OH:48])[CH:41]6[CH:42]([O:43]C(=O)C)[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:49]([CH3:51])[CH3:50])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O>CO>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:47]([OH:48])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:49]([CH3:51])[CH3:50])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O)C13C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
650 mg of compound (3) was dissolved in 46 ml of methanol and stirred together with 13.9 ml of 0.1 N aqueous NaOH at room temperature for 2 hours. The reaction solution mixed with 24 ml of water and stirred at 4° C. for 2 hours. The reaction solution was filtered, and the recovered precipitate was washed with water and dried to give 464 mg of compound (4) as a colorless powder.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12](Br)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][S:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CSCc1cc(Br)c2ncccc2c1
Reactant: OB(O)c1ccccc1
Product: CSCc1cc(-c2ccccc2)c2ncccc2c1

Procedure:
6-(methylthiomethyl)-8-bromoquinoline and benzene boronic acid can be combined to form 6-(methylthiomethyl)-8-phenylquinoline, and
Reaction SMILES: CN1C(=O)CC(=O)N(C)C1=O.[CH2:12]([O:14][C:15]([C@:17]1([F:47])[C@@H:22]2[C@H:18]1[CH2:19][C@@H:20]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=1)[C@@:21]2([NH:30]C(OCC=C)=O)[C:23]([O:25][CH:26]([CH2:28][CH3:29])[CH3:27])=[O:24])=[O:16])[CH3:13]>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([O:14][C:15]([C@:17]1([F:47])[C@@H:22]2[C@H:18]1[CH2:19][C@@H:20]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=1)[C@@:21]2([NH2:30])[C:23]([O:25][CH:26]([CH2:28][CH3:29])[CH3:27])=[O:24])=[O:16])[CH3:13]
Reactant: C=CCOC(=O)N[C@@]1(C(=O)OC(C)CC)[C@H](OCc2ccc(Cl)c(Cl)c2)C[C@@H]2[C@H]1[C@@]2(F)C(=O)OCC
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)OC(C)CC)[C@@H]21
Temperature: 50 °C
Reaction time: 1 h
Yield: 112 %

Procedure:
81 mg of 1,3-dimethylbarbituric acid and 12 mg of tetrakis (triphenylphosphine) palladium were added to 190 mg of (1R,2R,3R,5R,6R)-2-allyloxycarbonylamino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester dissolved in chloroform under a nitrogen atmosphere, and the mixture was stirred for 1 hour at 50° C. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (silica gel: Kanto Chemical silica gel 60 (spherical), eluent: hexane-ethyl acetate=5:1), thereby yielding 180 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH:26][C:27](=[O:29])[CH3:28])=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][C:22]([NH:26][C:27](=[O:29])[CH3:28])=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(=O)Nc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: CC(=O)Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 34 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and N-(cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-yl)-acetamide following a procedure analogous to that described in Example 1. Yield: 34% of theory; LC (method 1): tR=1.97 min; Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12>Cl.CC(C)=O.O>[C:4]1(=[O:16])[N:5]([CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:1](=[O:21])[C:2]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:3]12
Reactant: COC(=O)CCCC#CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCCC#CCN1C(=O)c2ccccc2C1=O
Yield: 81.2 %

Procedure:
Methyl 7-phthalimidohept-5-ynoate (1.45 g) was dissolved in a mixture of concentrated hydrochloric acid (7.3 ml), acetone (30 ml) and water (14.6 ml) and the resulting solution was heated at reflux for 3.5 hours. The solution was cooled and then poured into water (175 ml). The precipitate was collected by filtration and recrystallised from ethanol-water to give the title compound (1.12 g) m.p. 120°-122° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[CH:18]1([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:18]1([C:24]2[CH:25]=[CH:26][C:27]([NH:28][C:2]3[N:7]=[C:6]4[N:8]=[C:9]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:11][C:5]4=[N:4][CH:3]=3)=[CH:29][CH:30]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1ccc2ncc(Nc3ccc(C4CCCCC4)cc3)nc2n1
Temperature: 100 °C

Procedure:
83 mg of 1-(3-chloropyrido[2,3-b]pyrazin-6-yl)-3-ethylurea (0.33 mmol), 99 mg of 4-cyclohexylaniline (0.55 mmol), 30 mg of sodium tert-butoxide (0.30 mmol), 29 mg of tris(dibenzylideneacetone)dipalladium(0) (0.03 mmol) and 68 mg of 2-(dicyclohexylphosphanyl)biphenyl (0.19 mmol) were initially charged in 1.5 ml of dried toluene. The reaction mixture was heated to 100° C. under nitrogen in a microwave (100 watt) for 30 minutes. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (dichloromethane/methanol eluent). This gave a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[N+:9]([O-])([OH:11])=[O:10]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:9]([C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccs1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1ccc([N+](=O)[O-])s1

Procedure:
2-Thiophenecarboxylic acid (6.4 g, 50 mM) was suspended in acetic anhydride (15 ml) and fuming nitric acid (16 ml) in glacial acetic acid (25 ml) added slowly over 1 hour with stirring, while keeping the temperature of the reaction mixture below 30° C. The reaction mixture was stirred at ambient temperature for 2 hours. The product was purified by subjecting to chromatography (470 ml) on HP20SS resin using methanol/(water +1% acetic acid): as eluant. The pure title compound was obtained together with a mixture of 4- and 5-nitrothiophene-2-carboxylic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([NH2:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([NH:28][CH2:16][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:19])([CH3:18])[CH3:1])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1)[CH3:27]
Reactant: CC(N)c1ccccn1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(NCc1nc2ccccc2n1COCC[Si](C)(C)C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-2-carbaldehyde in CH2Cl2 with 1-pyridin-2-yl-ethylamine and NaBH(OAc)3 gave (1-pyridin-2-yl-ethyl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-ylmethyl]-amine as a pale green oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@:4]1([CH2:17][OH:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.[Br:19]N1C(=O)CCC1=O.O>CCOC(C)=O>[Br:19][C@@H:6]1[C@H:5]2[O:1][CH2:2][CH2:3][C@@:4]2([CH2:17][OH:18])[CH2:8][C@@H:7]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](CO)(CCO)C1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@]2(CO)CCO[C@@H]2[C@H]1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chilled solution of the product of Step F (343.60 g) in EtOAc (4 L) was added N-bromosuccinimide (237.60 g) followed by stirring at rt for 18 h. To the mixture was added water (5 mL) and the reaction heated to 60° C. for 30 min. The reaction was filtered, the filtrate was washed with aqueous sodium thiosulfate until the organic layer was negative for peroxides. The organic layer was washed with aqueous Na2CO3 (10%), dried (Na2SO4) and the reaction was concentrated under reduced pressure. Near the end of the concentration, heptane (1.2 L) was added, and the product was collected by filtration to provide the product of Step G. 1H NMR (400 MHz, CHLOROFORM-d) δ=4.78-4.91 (m, 1H), 4.41 (br. s., 1H), 4.31 (s, 2H), 3.88-3.98 (m, 1H), 3.61-3.77 (m, 3H), 2.08-2.24 (m, 1H), 1.82 (m, 2H), 1.60-1.70 (t, 1H), 1.45 (s, 9H)
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][C:7]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.CN(C)C=O>C1C=CC=CC=1>[C:7]12([CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[O:14]1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: OC1(Cc2ccccc2F)CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CC1(CCCCCC1)O2
Temperature: 0 °C
Yield: 44.2 %

Procedure:
To a stirred suspension of 23.32 g of sodium hydride (as a 50% dispersion in mineral oil) in 1.5 liters of benzene (dried over molecular sieves) was rapidly added a solution of 69.9 g of 1-(2-fluorobenzyl)-1-hydroxycycloheptane in 500 ml of benzene. After the addition the mixture was heated to reflux under nitrogen, and 100 ml of dimethylformamide (distilled over BaO) was added to the refluxing mixture. After 118 hours of reflux, the mixture was cooled in ice water and treated with 2.0 liters distilled water. After stirring for a few minutes the phases were separated and the aqueous phase was extracted with hexane (once with 2 liters and twice with one liter). The combined organic extracts were washed with water (1.0 liter) and saturated sodium chloride solution (1.0 liter) and thereafter dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded 65.9 g of a crude oil which was given a preliminary purification by preparative HPLC using dichloromethane as solvent. This treatment afforded 28.09 g of product as well as 9.2 g of unreacted starting material. The product was further purified by preparatory HPLC, using hexane/dichloromethane (4:1) as a solvent. This treatment afforded 21.18 g of product as an oil which was 97.6% pure by GC. Vacuum distillation of this material afforded 6.17 g of pure distillate, b.p. 85°-87° C. @ 0.20 mm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[N:3]=1.CCOCC.[CH2:18]([O:20][P:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([F:34])[CH:28]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19].C(N(C(C)C)CC)(C)C>ClC(Cl)C.C(O)(C)(C)C.[Cl-].[Zn+2].[Cl-]>[Cl:12][C:4]1[C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:7]=[C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([CH2:26][P:21](=[O:25])([O:20][CH2:18][CH3:19])[O:22][CH2:23][CH3:24])=[CH:28][C:29]=2[F:34])[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(N)c(F)c1)OCC
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(F)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.2 %

Procedure:
A solution of 2,6-Dichloro-5-trifluoromethylpyrimidine (4.76 gm, 22 mmol) in 20 mL of dichloroethane and t-butanol (1:1) was treated with a 1M solution of zinc chloride in ether (22 mL, 22 mmol) and allowed to stir at RT for 30 minutes. The mixture was subsequently cooled to 0° C. and treated with a solution of (4-amino-3-fluorobenzyl)phosphonic acid diethyl ester (Compound 22D, 3.3 g, 7.94 mmol) in dichloroethane and t-butanol (10 mL, 1:1) over 10 min through an addition funnel. After 1 hr, diisopropylethylamine (2.2 mL, 12.6 mmol) was added and the mixture was allowed to stir for 24 hours at RT. The solvents were evaporated and the residue was purified using flash column chromatography (9:1 DCM:EtOAc) to afford 3.9 g of the title compound (71%). 1H NMR (600 MHz, CDCl3): δ=1.23-1.28 (m, 6H), 3.1 (d, J=22 Hz, 2H), 4.02-4.09 (m, 4H), 7.09-7.25 (m, 2H), 7.63 (s, 1H), 8.24-8.27 (m, 1H), 8.58 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[NH:7][N:6]=1)=[O:4].N/[C:17](=[CH:20]\[CH3:21])/[C:18]#[N:19]>CC(O)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]3[C:13]([C:5]#[N:6])=[C:8]([CH3:9])[NH:7][C:20]([CH3:21])=[C:17]3[C:18]#[N:19])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2ccc(C=O)cc12
Reactant: C/C=C(\N)C#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 177.3 %

Procedure:
A mixture of 5-formyl-1H-indazole-3-carboxylic acid methyl ester (92 mg, 0.45 mmol) and aminocrotononitrile (74 mg, 0.9 mmol) in HOAc (1 mL) was kept at 110° C. for 15 mins. After cooling to rt, the reaction mixture was diluted with EtOAc, washed with brine, dried, and concentrated. The crude product was purified by TLC to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-3-carboxylic acid methyl ester (133 mg, 89%) (Cpd. No. 85, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=8.04 (s, 1H), 7.72 (s, 1H), 7.49 (d, 1H), 4.58 (s, 1H), 4.02 (s, 3H), 2.0 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][N:20]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:53]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][N:20]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:53])[C:8]=2[N:17]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1Cc1cc(-c2ccccc2)on1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccccc2)on1

Procedure:
The methods described in Part I of Example 35 were used to treat 2-(ethoxymethyl)-1-[(5-phenylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline (0.650 g, 1.69 mmol) with mCPBA (0.455 g of 77% pure material, 2.0 mmol) followed by p-toluenesulfonyl chloride (0.355 g, 1.86 mmol) and concentrated ammonium hydroxide (15 mL) and purify the final product to provide 0.38 g of 2-(ethoxymethyl)-1-[(5-phenylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine as a tan crystalline solid, mp 221-223° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](NC(c2ccccc2)c2ccccc2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
A solution of 200 mg (0.551 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 110 mg (0.606 mmol) of benzophenone in 5 ml of toluene are kept at reflux for 18 hours. The reaction mixture is then concentrated in a rotary evaporator and dissolved in 3 ml of methanol, and 69 mg (1.10 mmol) of sodium cyanoborohydride are added at RT. The reaction mixture is adjusted to pH=5 with 80 μl of acetic acid and stirred at RT for 68 hours. The title compound ##STR98## is obtained as white foam (120 mg, 41%). TLC: toluene/ethyl acetate (7:3) Rf =0.79, FD-MS: M+ =528,530; IR: 1630 cm-1.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]=[CH:34][N:35]=1)(=[O:3])[CH3:2].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]=[CH:34][N:35]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1nccn1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SC1CCNC/C1=C\c1nccn1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-imidazol-2-yl]methylidene}-1-(triphenylmethyl)piperidine (0.72 g) in dichloromethane (20 ml) was added trifluoroacetic acid (0.29 ml) under ice-cooling, and the resulting mixture was stirred at the same temperature for 15 minutes. The reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of methanol and dichloromethane (1:20 to 1:10) as the eluent to afford the title compound (0.58 g, yield: quantitative) as a colourless amorphous solid.