Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCl.[OH-].[K+].[C:5]1(C)C=CC=CC=1.[CH3:12][C:13]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH2:26])=[O:25]>CCOCC.O>[CH3:12][C:13]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH:26][CH3:5])=[O:25]
Reactant: CO/N=C(/C(N)=O)c1ccccc1COc1cc(C)ccc1C
Reactant: Cc1ccccc1
Agent: CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Methyl chloride (0.45 g, 9.0 mmol), 85% potassium hydroxide (0.30D g, 4.5 mmol) and toluene (9 ml ) were added to (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (0.94 g, 3.0 mmol). The mixture was stirred at 100° C. for 1 hour. After completion of the reaction, water (100 ml) was added. The mixture was extrcted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.88 g, Yield: 90.2%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:19][NH2:20]>>[NH:19]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:11][C:4]=2[CH:3]=1)[NH2:20]
Reactant: NN
Reactant: CC(C)(C)C(=O)N1CCc2nnc(Cl)cc2C1
Solvent: O
Product: CC(C)(C)C(=O)N1CCc2nnc(NN)cc2C1

Procedure:
11.4 g of 3-chloro-5,6,7,8-tetrahydro-6-pivaloylpyrido[4,3-c]pyridazine and 100 cc of hydrazine hydrate are boiled at reflux at a bath temperature of 110° for 11/2 hours while stirring. The crude title compound is taken up in 100 cc of chloroform, is dried with sodium sulphate, the chloroform solution is again concentrated, and recrystallized from 20 cc of absolute ethanol. The title compound has a M.P. of 158°-160° (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1.CCN(CC)CC>O.CS(C)=O>[Cl:18][C:19]1[N:20]=[N:21][C:22]([N:14]2[CH2:15][CH2:16][CH:11]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=4)[CH2:6][CH2:7]3)[CH2:12][CH2:13]2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a 100 mL flask was placed 6-fluoro-1-(piperidin-4-yl)indoline as its corresponding HCl salt, prepared as in STEP 2 above (7.7 g, 30 mmol, 1 equiv) and 3,6-dichloropyridazine (4.69 g, 31.5 mmol, 1.05 equiv). DMSO (40 mL) and Et3N (12.54 mL, 90 mmol, 3 equiv) were added sequentially. The resulting mixture was heated at 80° C. for 7 h. The resulting mixture was then poured into vigorously stirred H2O (800 mL) and stirred for 1 h. The resulting solid was filtered and washed with H2O (30 mL×2), 50% Et2O/hexane (30 mL×2), and the dried to yield 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[F:13])=[CH:8][S:7][CH:6]=1)=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[F:13][CH:12]([O:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:28][CH:27]=1)[C:11]([NH:10][C:9]1[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=1)=[O:15]
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Reactant: COC(=O)c1cscc1NC(=O)C(F)Cl
Product: O=C(O)c1cscc1NC(=O)C(F)Oc1ccc(-c2ccc(F)cc2)cc1

Procedure:
In analogy to Example 2, the title compound was prepared using 4-(2-chloro-2-fluoro-acetylamino)-thiophene-3-carboxylic acid methyl ester and 4-fluoro-4′-hydroxybiphenyl. MS (m/e): 388.2 (M−H).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>C(O)C>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(F)c(F)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (3.5 g) is dissolved in ethanol (25 ml) and thereto cyclopropylamine (0.84 ml) is added dropwise under ice-cooling. After stirring at room temperature for 30 minutes, the mixture is concentrated and the residue is purified with column chromatography (silica-gel, dichloromethane: n-hexane=1:1) to give ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-cyclopropylaminoacrylate (2.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:14][C@H:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][C@H:11]1[C:28]([OH:30])=O)([O-:3])=[O:2].Cl.Cl.[NH2:33][C@@H:34]([CH2:46][CH3:47])[CH:35]([C:37]1[O:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1)[OH:36]>>[O:38]1[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=[C:37]1[C:35]([C@@H:34]([NH:33][C:28]([C@@H:11]1[CH2:12][C@@H:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:26])([F:25])[F:27])(=[O:16])=[O:17])[CH2:14][N:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:30])[CH2:46][CH3:47])=[O:36]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccccc1[N+](=O)[O-]
Reactant: CC[C@H](N)C(O)c1nc2ccccc2o1
Agent: Cl
Product: CC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccccc1[N+](=O)[O-])C(=O)c1nc2ccccc2o1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-1-(2-nitrophenyl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxylic acid (prepared as described in U.S. Pat. Appl. US20100267722) and (2S)-2-amino-1-(benzo[d]oxazol-2-yl)butan-1-ol dihydrochloride in step 1. MS (m/e)=631.15 [M+H+].
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4]>C1COCC1.CO.[Ni]>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(N)cc1

Procedure:
16 g (84.1 mmol) of 2-methyl-2-(4-nitro-phenyl)-propionitrile (Example 1d) and 4.16 g of Raney-Ni are shacked in 160 ml of THF-MeOH (1:1) under 1.1 bar of H2 for 12 h at rt. After completion of the reaction, the catalyst is filtered-off and the filtrate is evaporated to dryness. The residue is purified by flash chromatography on silica gel (hexane-EtOAc 3:1 to 1:2) to provide the title compound as an oil. ES-MS: 161 (M+H)+; analytical HPLC: tret=2.13 minutes (Grad 1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[O:30])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:28][C:29]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:39][CH:40]=2)=[O:30])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccc(C(=O)O)cc1)NC(c1ccc(OCc2ccccc2)cc1)c1ccccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: O=C(Cc1ccc(C(=O)O)cc1)NC(c1ccc(O)cc1)c1ccccc1N1CCCCC1

Procedure:
An amount of 1.1 gm (2 m mol) of 4-{N-[α-(4-benzyloxyphenyl)-2-piperidino-benzyl]-aminocarbonylmethyl}-benzoic acid was suspended in 200 ml of ethanol and catalytically debenzylated at 50° C., under a hydrogen pressure of 5 bar, in the presence of 0.4 gm of 10% palladium/charcoal. Then, the catalyst was filtered off, and the filtrate was concentrated by evaporation and recrystallized from acetonitrile.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:14][O:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C@@H:11]3[CH2:12][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][C@H:10]3[OH:13])=[CH:26][CH:27]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 40 g. of 1-benzyl-3,4-epoxypyrrolidine and 42 g. of 4-benzoxyphenol was heated at 130° C. for 8 hr. On cooling, the mixture crystallized. Three crystallizations from petroleum ether-cyclohexane gave fluffy white crystals melting at 98.0°-100.0° C. The yield was 6.0 g (8%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2]>C(Cl)(Cl)Cl.[O-2].[Mn+2]>[CH2:1]([NH:3][C:4]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2]
Reactant: CCNc1nc(Nc2ccccc2)ncc1CO
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCNc1nc(Nc2ccccc2)ncc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of (4-ethylamino-2-phenylamino-pyrimidin-5-yl)methanol (173 mg, 0.71 mmol) in 15 mL of chloroform was added manganese oxide (600 mg, 6.89 mmol). After stirring at room temperature overnight, the mixture was filtered through a pad of Celite, washing with chloroform. The filtrate was concentrated in vacuo to give 170 mg (99%) of 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldehyde; mp 155°-157° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)(C)(C)C.[F-].C([NH3+])CCC.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][OH:6])=[CH:9][CH:10]=1)[CH2:15][CH3:16]
Reactant: CCCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[NH3+]
Agent: O=S(=O)([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
Under argon condition, tert-butyldimethyl((4-propylbenzyl)oxy)-silane (275 mg, 1.04 mmol) was dissolved in 5 mL of dry THF, and then n-butylammonium fluoride (TBAF; 1.56 mL, 1.0 M solution in tetrahydrofuran, 1.56 mmol) were slowly added thereto, and the mixture was stirred for 30 minutes at 0° C. Upon completion of the reaction, the reaction was terminated by adding 5 mL of aqueous saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (5 mL×4) and the organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 198 mg (0.838 mmol, 95%) of the desired compound.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21](OC=C(C#N)C#N)C>C(O)(C)C>[C:1]1([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[C:13]3[N:14]=[CH:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1c(-c2ccccc2)ccnc1Nc1ccccc1
Reactant: CCOC=C(C#N)C#N
Solvent: CC(C)O
Product: c1ccc(-c2ccnc3c2ncn3-c2ccccc2)cc1
Yield: 75 %

Procedure:
0.70 mol of N2,4-diphenylpyridine-2,3-diamine and 2.56 mol of ethoxymethylene malononitrile were added in 10 ml of isopropanol, and refluxed for 6 hours. The solution was removed and was purified by using column chromatography to thereby produce a solid crystalline product at a yield of 75%.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:65][C:66]1[S:67][C:68]2[CH:69]=[N:70][CH:71]=[CH:72][C:73]=2[N:74]=1.SC1SC2C=CN=CC=2N=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:65][C:66]4[S:67][C:68]5[CH:69]=[N:70][CH:71]=[CH:72][C:73]=5[N:74]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Sc1nc2ccncc2s1
Agent: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4ccncc4s3)CS[C@@H]3C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 68.2 %

Procedure:
Using 276 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido}-3-chloromethyl-3-cephem-4-carboxylate and 60 mg of 2-mercaptothiazolo[5,4-c]pyridine in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercaptothiazolo[4,5-c]pyridine, respectively, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 215 mg of the title compound in a yield of 68%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42](=[O:52])[N:43]([CH2:48][CH2:49][CH2:50][CH3:51])[CH2:44][CH2:45][CH2:46][CH3:47])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:41])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[C:25]([O:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[N:53]([CH2:56][C@@H:57]1[CH2:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH2:59][NH:58]1)=[N+:54]=[N-:55]>>[N:53]([CH2:56][C@@H:57]1[CH2:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH2:59][N:58]1[C:10]([C:9]1[CH:13]=[C:14]([C:17](=[O:41])[NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[C:25]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH:15]=[CH:16][C:8]=1[N:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:42]([N:43]([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:48][CH2:49][CH2:50][CH3:51])=[O:52])=[N:4]1)=[O:11])=[N+:54]=[N-:55]
Reactant: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(OCCN5CCOCC5)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])c(C)c1Cl
Yield: 73.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 91, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(8-(2-morpholinoethoxy) naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 183B, 50 mg, 0.066 mmol) and (S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate 92A, 37 mg, 0.20 mmol) were converted to the title compound (45 mg, 73%). 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 9.23-9.11 (m, 1H), 8.21 (d, J=1.9 Hz, 0.5H), 8.13-7.93 (m, 3.5H), 7.76-7.58 (m, 3H), 7.32-7.06 (m, 4.5H), 6.93 (d, J=7.2 Hz, 0.5H), 5.28 (d, J=18.3 Hz, 0.5H), 4.98 (br s, 0.5H), 4.73-4.62 (m, 2H), 4.59-3.21 (m, 15.5H), 3.18-2.69 (m, 3.5H), 2.58 (d, J=16.1 Hz, 0.5H), 2.48-2.40 (m, 0.5H), 2.34-2.21 (m, 3H), 1.55-0.82 (m, 1H), 0.78-0.70 (m, 2H), 0.69-0.55 (m, 1H); MS(ESI+) m/z 924.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][O:16][CH2:17]I.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:15][O:16][CH2:17][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: COCI
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 52.6 %

Procedure:
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.00 g, 51.5 mmol) was dissolved in acetonitrile (40 mL) and stirred at 35° C. for 5 min under nitrogen atmosphere then cooled to room temperature. Iodomethyl methyl ether (21.83 mL, 258 mmol) and potassium carbonate (35.6 g, 258 mmol) were added and the resulting mixture was stirred at 35° C. for 3 h then cooled to room temperature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 100 G silica cartridge (gradient: 0 to 50% AcOEt in hexanes) gave 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.45 g, 50% pure by LCMS, 26%) as a yellow liquid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+]>CS(O)(=O)=O>[CH:11]1[C:16]2[CH:17]3[C:8]([C:19]4[N:20]=[CH:21][NH:22][CH:23]=4)([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=43)[CH2:9][CH2:10][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: OC1c2ccccc2CCC1(Cc1ccccc1)c1c[nH]cn1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)CCC1(c3c[nH]cn3)Cc3ccccc3C21
Temperature: 140 °C

Procedure:
2-Benzyl-2-(1H-imidazol-4-yl)-1,2,3,4-tetrahydronaphthalen-1-ol (0.68 g) was dissolved in CH3SO3H (17 ml) and heated at 140° C. for 3 hours. After cooling in an ice bath, water (80 ml) was added and pH was adjusted to 11.5-13.5 with 48% NaOH solution. The precipitated crude product (0.41 g) was filtered and washed with water. An analytical sample was purified by flash chromatography using methylene chloride/methanol (95/5) as eluent.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:38]=[CH:37][C:18]3[N:19]=[CH:20][N:21]([C:22]4[S:23][C:24]([C:34](=[O:36])[NH2:35])=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=5)[N:26]=4)[C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>ClCCl>[Cl:33][C:29]1[CH:28]=[C:27]([C:25]2[N:26]=[C:22]([N:21]3[C:17]4[CH:16]=[C:15]([O:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:38]=[CH:37][C:18]=4[N:19]=[CH:20]3)[S:23][C:24]=2[C:34]([NH2:35])=[O:36])[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1sc(-n2cnc3ccc(OC4CCNCC4)cc32)nc1-c1cccc(Cl)c1
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To 0.10 g (0.18 mmole) of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-yl]-3H-benzoimidazol-5-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (I.21a) in 5 mL of dichloromethane at 0 degrees, was added 5 mL of dichloromethane-trifluoroacetic acid (1:1). The mixture was stirred at 0 degrees for 1 hour and then concentrated under reduced pressure. The residue was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from methanol to give 0.050 g 4-(3-chloro-phenyl)-2-[6-(piperidin-4-yloxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.21). MH+/Z=454
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([N:18]([C:21]2[N:26]=[C:25](Cl)[N:24]=[C:23]([Cl:28])[C:22]=2[CH:29]=[O:30])[CH2:19][CH3:20])=[CH:16][CH:15]=1>O1CCCC1>[Cl:28][C:23]1[C:22]([CH:29]=[O:30])=[C:21]([N:18]([CH2:19][CH3:20])[C:17]2[CH:31]=[CH:32][C:14]([Cl:13])=[CH:15][CH:16]=2)[N:26]=[C:25]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:24]=1
Reactant: CCNCC
Reactant: CCN(c1ccc(Cl)cc1)c1nc(Cl)nc(Cl)c1C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)c1nc(Cl)c(C=O)c(N(CC)c2ccc(Cl)cc2)n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 61.4 %

Procedure:
Over five hours, at a temperature of -30° C., a solution of 9.28 g (0.127 mole) of diethylamine and 12.84 g (0.127 mole) of triethylamine in 80 ml of tetrahydrofuran was added dropwise to a solution of 40.0 g (0.121 mole) of 6-(4-chloro-N-ethylanilino)-2,4-dichloro-pyrimidine-5-carbaldehyde in 400 ml of tetrahydrofuran. The solution was then stirred for four hours at -30° C. and for two hours at 20° C., the triethylammoniumchloride was filtered off, and the filtrate evaporated in vacuo. After the filtrate was mixed by stirring with 120 ml of diethylether, 27.3 g of colorless crystals were obtained.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][N:8]=[C:9]([C:13]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[CH2:14][Br:15])[C:10](O)=[O:11].P([O-])(O)(O)=O.[K+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>O1CCCC1.O.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[CH2:14][Br:15])[C:10]([Cl:3])=[O:11]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)Cl
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (1.24 ml) was added to a solution of dry N,N-dimethylformamide (1.01 ml) in dry tetrahydrofuran (2 ml) at -20° C. and stirred at the same temperature for 30 minutes. To the solution was added 2-methoxyimino-3,3-diethoxy-4-bromobutyric acid (syn isomer, 3.3 g) at -20° C. and stirred at -20° to -10° C. for an hour. The resultant solution was added to a solution of potassium dihydrogenphosphate (3.63 g) and sodium phosphate (14.33 g) in water (1000 ml) and stirred under ice-cooling at pH 6.1 for 2 hours. The precipitates were collected by filtration, washed with water and dried to give 2-methoxyimino-3,3-diethoxy-4-bromobutyryl chloride (syn isomer, 3.0 g), mp 33°-35° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH:11]=[CH:10][C:8]3=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:15]1[O:18][CH:16]1[CH3:17]>CN(C)C=O>[N:1]1([CH2:15][CH:16]([OH:18])[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH:11]=[CH:10][C:8]3=2)[CH:3]=[N:2]1
Reactant: CC1CO1
Reactant: c1cc2c(ccc3cn[nH]c32)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)Cn1ncc2ccc3occc3c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, a dimethylformamide (5 ml) solution containing 1.00 g of 1H-furo(2,3-g]indazole was added dropwise to a dimethylformamide (10 ml) solution containing 0.27 g of sodium hydride under cooling with ice-bath, and the mixture was stirred for 30 minutes. A 0.52 ml of propylene oxide was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 41 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by a silica gel column chromatography to give 0.59 g of 1-(1H-furo[2,3-g]indazol-1-yl)propan-2-ol.