Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:22][O:23][CH2:24][O:25][CH2:26][C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH2:18]([CH:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:39]([C:36]2[CH:35]=[CH:34][C:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][O:25][CH2:24][O:23][CH3:22])[CH:28]=3)=[CH:38][CH:37]=2)=[O:40])=[CH:6][CH:7]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][CH3:21]
Reactant: COCOCc1cccc(-c2ccc(C(=O)O)cc2)c1
Reactant: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(COCOC)c3)cc2)cc1)C(=O)OCC
Yield: 85.7 %

Procedure:
In a similar manner to that described in Example 5, a reaction was carried out using ethyl 3-[4-(2-aminoethoxy)phenyl]-2-butylpropionate (358 mg), which is the product of Reference example 6, 3′-methoxymethoxymethylbiphenyl-4-carboxylic acid (333 mg), which is the product of reference example 15(c), and carbonyldiimidazole (238 mg) and the reaction mixture was treated to afford the desired compound (573 mg) as a brown syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.Br[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[N:6][N:5]2[C:8](=[O:11])[N:9]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[N:10]=[C:4]2[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(Cl)cnn12
Reactant: FC(F)(F)c1ccc(CBr)cn1
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(Cl)cc3)c(Cl)cnn12

Procedure:
Using the procedure described in Example 274, 7-chloro-8-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one prepared as described in Example 273 was reacted with 5-(bromomethyl)-2-(trifluoromethyl)pyridine to give the title compound, 7-chloro-8-(4-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)methyl-[1,2,4]triazolo[4,3-b]pyridazin-3 (2H)-one.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>CC(O)C>[N:1](=[CH:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:4]([CH3:3])[CH:5]=1)[NH2:2]
Reactant: NN
Reactant: Cc1cc(Nc2ncnc3ccc(C=O)cc23)ccc1Oc1ccccc1
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1cc(Nc2ncnc3ccc(C=NN)cc23)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(6-Hydrazonomethylquinazolin-4-yl)-(3-methyl-4-phenoxyphenyl)amine is prepared by adding hydrazine (50 mg, 1.00 mmol) to a solution of 4-(3-methyl-4-phenoxyphenylamino)-quinazoline-6-carbaldehyde (250 mg, 0.70 mmol) in a 1:1 mixture of DCM:IPA (6 mL). After stirring at room temperature for 4 hours, excess hydrazine and solvent are removed under reduced pressure to give the desired hydrazone as a brown solid which is carried forward without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@@H:25]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@H:25]([CH3:24])[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-chloro-phenyl]-acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: CI.[O:3]=[C:4]1[NH:13][CH:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22][CH3:23])[C:11]2[C:10](=[O:24])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.[C:35](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:35][N:13]1[CH:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22][CH3:23])[C:11]2[C:10](=[O:24])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:4]1=[O:3]
Reactant: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyliodide (70 μL, 1.10 mmol) is added to a mixture of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methylsulfanyl-benzonitrile (INTERMEDIATE 6; 177 mg; 0.354 mmol) and cesium carbonate (300 mg, 0.921 mmol) in DMF (2.4 mL) and the mixture is stirred at room temperature for 2 h. During the reaction, more cesium carbonate is added in small portions (total of 700 mg; 2.15 mmol). The reaction mixture is filtered and the filtrate is purified by reversed phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA). Yield: 26 mg. ESI mass spectrum: [M+H]+=472; Retention time HPLC: 1.10 min (Z018_S04).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.S(Cl)([Cl:14])=O>>[F:1][C:2]1[C:3]([C:9]([Cl:14])=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncc(F)cc1F
Product: O=C(Cl)c1ncc(F)cc1F

Procedure:
A suspension of 5.00 g (31.4 mmol) of 3,5-difluoropyridine-2-carboxylic acid in thionyl chloride (21 ml) was heated to reflux for 5 h. The solution was concentrated, and the residue was twice taken up in a little toluene and concentrated again. This gave 3.80 g of a solid, which was converted further directly without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:29]=[C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH:35]=2)=[O:31])[CH:27]=[C:26]([CH3:48])[C:22]=1[C:23](O)=[O:24].ClN1C(=O)CCC1=O.[CH3:57][O:58][C:59](=[O:68])[CH:60]([P:62]([O:66][CH3:67])([O:64][CH3:65])=[O:63])[NH2:61].COC(=O)C(P(OC)(OC)=O)NC(OCC1C=CC=CC=1)=O>ClCCl>[CH3:57][O:58][C:59](=[O:68])[CH:60]([P:62]([O:64][CH3:65])([O:66][CH3:67])=[O:63])[NH:61][C:23](=[O:24])[C:22]1[C:21]([CH3:20])=[CH:29][C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH:35]=2)=[O:31])=[CH:27][C:26]=1[CH3:48]
Reactant: COC(=O)C(N)P(=O)(OC)OC
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(C)c1C(=O)O
Agent: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1c(C)cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1C)P(=O)(OC)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Triphenylphosphine (0.762 g, 2.9 mmol) was added to a suspension of 2,6-dimethyl-4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]benzoic acid (Example 111; 1 g, 2.42 mmol) in dichloromethane (12 mL) at 25° C. The mixture was cooled to 0° C. and N-chlorosuccinimide (0.387 g, 2.9 mmol) was added. After stirring 15 min at 0° C., the mixture was stirred for an additional 15 min at 25° C. and then a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (1.99 g, 6 mmol) in dichloromethane (2 mL) was added in one portion. The reaction was stirred for 5 h (a precipitate formed at 2 h), then was filtered and the solids were washed with dichloromethane and discarded. The filtrate was washed with 1N hydrochloric acid solution (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), then was dried (MgSO4) and concentrated under reduced pressure. The residue was flash chromatographed (silica gel, 10% ethyl acetate in petroleum ether) to yield rac.-N-[2,6-dimethyl-4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (1.33 g, 93% yield) as a colorless foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:18]=O>N1CCCCC1.C(O)C>[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:18]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: Cc1c[nH]c(C=O)c1C
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A reaction mixture of 67.0 mg (0.5 mmoles) of oxindole, 73.0 mg (0.6 mmoles) of the 3,4-dimethylpyrrole-2-carboxaldehyde, and 2 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 87.7 mg (37%) of the title compound as a yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O.[CH:10]1[N:14]2[C:15]3[C:20]([N:21]=[CH:22][C:13]2=[N:12][C:11]=1[CH:23]=O)=[CH:19][CH:18]=[CH:17][CH:16]=3>C(O)C>[CH:10]1[N:14]2[C:15]3[C:20]([N:21]=[CH:22][C:13]2=[N:12][C:11]=1[CH:23]=[N:2][OH:3])=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: O=Cc1cn2c(cnc3ccccc32)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1cn2c(cnc3ccccc32)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
A solution of 1.4 g of hydroxylamine hydrochloride, 1.9 g of sodium acetate and 5 ml of water was added to a suspension of 3.10 g of imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde in 30 ml of ethanol and the mixture was stirred at 90° C. for 4 hours and was evaporated to dryness. The white crystalline residue was triturated with water and was filtered. The product was dried in vacuo over phosphorus pentoxide to obtain 2.83 g of imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde oxime melting at 243°-245° C.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14]CC2C=CC=CC=2)[CH:7]=1)[CH3:5])=[N+]=[N-]>Cl.[Pd]>[NH2:1][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:5]
Reactant: COc1ccc(C(C)N=[N+]=[N-])cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Product: COc1ccc(C(C)N)cc1O

Procedure:
Crude 4-(1-azido-ethyl)-2-benzyloxy-1-methoxybenzene is hydrogenated at 50 psi, using 10% Pd/C in ethanolic hydrogen chloride solution to give 5-(1-amino-ethyl)-2-methoxyphenol.
Reaction SMILES: Cl.C(C1C=CC(C(N)=N)=CC=1)CCCCCC.C(OC(=O)C(=COCC)C#N)C.CC[O-].[Na+].[OH-].[Na+].[C:36]([C:38]1[C:39](O)=[N:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:46][CH:45]=2)=[N:42][CH:43]=1)#[N:37].P(Cl)(Cl)([Cl:60])=O>C(O)C>[Cl:60][C:39]1[C:38]([C:36]#[N:37])=[CH:43][N:42]=[C:41]([C:44]2[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:46][CH:45]=2)[N:40]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCc1ccc(-c2ncc(C#N)c(O)n2)cc1
Agent: CCCCCCCc1ccc(C(=N)N)cc1
Agent: CCOC=C(C#N)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Product: CCCCCCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 365 by reaction of p-n-heptylbenzamidine hydrochloride with α-ethoxymethylene-α-cyanoacetic acid ethyl ester and sodium ethylate in ethanol and then with sodium hydroxide solution. The resulting 5-cyano-4-hydroxy-2-(4-n-heptylphenyl)-pyrimidine (melting point 195.6°-198.6° C) is treated with phosphorus oxychloride to give 4-chloro-5-cyano-2-(4-n-heptylphenyl)-pyrimidine having a melting point of 76.3°-76.8° C.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].S(=O)(=O)(O)O.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[OH:22][C:16]1[CH:21]=[CH:20][C:19]2[S:4][C:3]3[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[O:10])[C:18]=2[CH:17]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1c2ccccc2sc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
16 g (103 mmol) thiosalicylic acid was slowly added to 150 mL concentrated sulfuric acid. The mixture is stirred for 5 minutes and 60 g (440 mmol) phenol was added over 30 minutes. The temperature rose to 60° C. The reaction was allowed to continue for 2 hours at 80° C. The reaction was allowed to cool down to room temperature and was added slowly to 3 l boiling water. The mixture was kept at the boiling point for 5 minutes. The mixture was allowed to cool down to room temperature. The precipitated 2-hydroxy-thioxanthen-9-on was isolated by filtration and dried. 14.1 g (63%) of 2-hydroxy-thioxanthen-9-on was isolated (m.p. 232-241° C.).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[Cl:18][C:19]1[N:24]=[C:23]2[CH:25]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[S:27][C:22]2=[CH:21][CH:20]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:28]([C:26]2[S:27][C:22]3[C:23](=[N:24][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH:25]=2)(=[O:29])=[O:30])[C:4]1=[O:17])#[N:13]
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)ccc2s1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride as described in EXAMPLE 1, Part E using 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride in place of benzo[b]thiophene-2-sulfonyl chloride. The product is obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([NH2:11])[CH:3]=1.[CH:12]([NH2:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:14][C:12](=[O:13])[NH:11]2)=[CH:9][CH:10]=1
Reactant: NC=O
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: O=c1ncc2ccc(Cl)cc2[nH]1

Procedure:
4-chloro-2-amino-benzoic acid (10.0 g) was dissolved into 50 mL of formamide, the mixture was reacted under reflux for 5 h. A lot of solid was deposited, which was filtered and dried to obtain 1.5 g of 7-chloro-quinazolone.
Reaction SMILES: [CH3:1][O:2][NH3+:3].[Cl-].[C:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:38])[NH:16][CH2:17][C:18]([N:20]([CH2:27][C:28]([N:30]([CH3:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH:11]=[CH:12][CH:13]=1)(=O)[CH3:6]>O.C(O)C>[CH3:1][O:2]/[N:3]=[C:5](\[C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:38])[NH:16][CH2:17][C:18]([N:20]([CH2:27][C:28]([N:30]([CH3:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH:11]=[CH:12][CH:13]=1)/[CH3:6]
Reactant: CC(=O)c1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2)c1
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CO/N=C(/C)c1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc2)c1
Yield: 33.2 %

Procedure:
0.16 g of 0-methylhydroxylamine hydrochloride in solution in 2 cm3 of water is added to a solution of 0.92 g of 2-{2-[3-(3-acetylphenyl)ureido]-N-phenylacetamido}-N-methyl-N-phenylacetamide in 10 cm3 of ethanol. The mixture is stirred under reflux for 3 hours and then at a temperature close to 25° C for 12 hours and concentrated to a volume of about 3 cm3 under reduced pressure (2.7 kPa) at 40° C. 20 cm3 of distilled water are then added and the insoluble product is separated off by filtration and air-dried. After recrystallization from a methanol/diisopropyl ether mixture (60/40 by volume), 0.31 g of (Z)-2-{2-{3-[3-(1-methoxyiminoethyl)phenyl]ureido}-N-phenylacetamido}-N-methyl-N-phenylacetamide melting at 165° C is obtained.
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([O:11][CH2:12][CH2:13][CH2:14][C:15]1[NH:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I:23]I.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)=O>O1CCOCC1.O>[CH2:4]([O:11][CH2:12][CH2:13][CH2:14][C:15]1[NH:16][C:17]([I:23])=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)c1c[nH]c(CCCOCc2ccccc2)n1
Reactant: II
Agent: O=C=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nc(CCCOCc2ccccc2)[nH]c1I
Reaction time: 1 h
Yield: 82 %

Procedure:
A four-necked flask of one-liter capacity was charged with 25 g of 40% sodium hydroxide/H2O and 125 ml of water, followed by addition of a solution of the imidazole (135a) obtained above in dioxane (125 ml). Then, 70.5 g (278 mmol) of solid iodine was added under ice-cooling and the mixture was stirred. After 1 hour, an aqueous solution of sodium thiosulfate and, then, dry-ice were added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in diethyl ether and 39 g of oxalic acid was added to the solution. The precipitated crystals was collected by filtration, neutralized with sodium carbonate, and extracted with chloroform. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 86.7 g (yield 82%) of 2-(3-benzyloxypropyl)-5-iodo-4-isopropyl-1H-imidazole (135b) as oil.
Reaction SMILES: [Cl:1][CH:2]1[CH:11]([Cl:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:9]=2[CH3:13])[S:4](=[O:25])(=[O:24])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34]>C(Cl)Cl.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][CH:2]1[CH:11]([Cl:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])=[O:15])[C:9]=2[CH3:13])[S:4](=[O:25])(=[O:24])[CH2:3]1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(Cl)C(Cl)CS3(=O)=O)c1O
Reactant: CCCS(=O)(=O)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)Oc1c(C(=O)c2ccc3c(c2C)C(Cl)C(Cl)CS3(=O)=O)cnn1CC
Yield: 87.2 %

Procedure:
1.1 Grams (2.7 mmol) of 3,4-dichloro-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide was dissolved in 5 ml of methylene chloride, and then a solution of 0.65 g (4.7 mmol) of potassium carbonate in 3 ml of water was added. Further, 0.5 ml of (4.7 mmol) of n-propanesulfonyl chloride and 20 mg (0.08 mmol) of benzyltriethylammonium chloride were added, and the mixture was allowed to react at room temperature for 1 day. After the completion of the reaction, a methylene chloride layer was separated, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give 1.2 g (yield 50%) of 3,4-dichloro-5-methyl-6-(1-ethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][CH:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example 49 (step 1), 1.06 g of 3-[(1-(2-fluorophenyl)ethoxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 586 mg of methanesulfonyl chloride, and 518 mg of triethylamine in 19 ml dichloromethane give (1-{5-carbamoyl-4-[1-(2-fluorophenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[C:19]([OH:21])=[O:20])=[O:4].C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CC(C)=O>[C:29]([NH:1][CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][C@H:6]1[C:19]([OH:21])=[O:20])=[O:4])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a solution of (2S,4R) 1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid (0.05 g, 0.17 mmol) and triethylamine (Aldrich) (0.19 mL, 1.37 mmol, 8 equivalents) in acetone (3 mL) was slowly added acetic anhydride (0.13 mL, 1.37 mmol, 8 equivalents) with stirring at room temperature under nitrogen atmosphere. The mixture was stirred for 3 hours while monitored by LCMS. Upon completion, the volatiles were removed in vacuo and the residue was purified by preparative HPLC (column: Xterra MSC 18 50×250 mm, 10 u) using 40/60 to 90/10 methanol/water gradient (0.1% formic acid in methanol and 0.1 formic acid in water) to afford 0.020 g (35% yield) of the desired product as white solid with limited solubility in organic solvents.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28]Br.ClCCl.C(O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 73.1 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (120 mg, 0.32 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (240 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) was added and the solution was washed with 1:1 water/brine (20 mL), water (2×20 mL), aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 45-50% ethyl acetate/petroleum ether, to give an oil. The oil was co-evaporated with ethanol, and the residue was held under high vacuum to give (4S,7R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (128 mg, 73%) as a white solid. APCI(+)-MS (M+H) 531.