Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][NH:27]2)=[CH:23][CH:22]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([NH:20][C:2]3[C:11]4[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])[CH:29]=2)[CH:25]=[N:26]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1cc2c(Cl)c(C#N)cnc2c(OC)c1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2c(OC)c1OC
Yield: 88.3 %

Procedure:
A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile, 0.147 g of 6-aminoindazole, 0.020 of pyridine hydrochloride, and 15 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 1 hour. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.332 g of 4-(1H-indazol-6-ylamino)-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid, mp 243-245° C.; mass spectrum (EI, m/e): M 375.1331.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([NH:15][C:6]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=1)=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(Cl)nc1

Procedure:
The title compound was prepared by the same method as that described in Example 26, using 6-chloronicotinic acid and t-butylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[C@H:10]([CH3:24])[N:9]=1.[CH2:25]([N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][C:29]1=[O:38])[C:26]#[CH:27].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[C:26][CH2:25][N:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:29]3=[O:38])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[C@H:10]([CH3:24])[N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=N[C@H]2C
Reactant: C#CCN1C(=O)CCc2ccccc21
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CCc4ccccc43)cc1C(c1ccccc1F)=N[C@H]2C

Procedure:
The title compound was prepared by coupling (S)-6-(2-fluorophenyl)-8-iodo-4,1-dimethyl-4H[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with 3,4-dihydro-1-(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 100. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue crystallized very slowly from ethanol/ether to give colorless crystals of (S)-1-{3-[6-(2-fluorophenyl)-4,1-dimethyl4H-[1,2,4]-triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-propynyl}3,4-dihydro-2(1H)-quinolinone with m.p. 155°-160° with foaming. These crystals contained both ethanol and water according analytical and spectral data. [α]D=+87.5° (c=1.0091 in CH2Cl2)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:10][C:11]1[C:12]([Br:19])=[CH:13][C:14]([F:18])=[C:15]([CH:17]=1)[NH2:16])[CH:8]=[CH2:9].N1C=CC=CC=1>C(Cl)Cl>[CH2:7]([O:10][C:11]1[C:12]([Br:19])=[CH:13][C:14]([F:18])=[C:15]([NH:16][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH:17]=1)[CH:8]=[CH2:9]
Reactant: C=CCOc1cc(N)c(F)cc1Br
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOc1cc(NC(=O)OCC)c(F)cc1Br
Temperature: 10 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
Ethyl chloroformate (5.97 g) was added dropwise to a solution of 5-allyloxy-4-bromo-2-fluoroaniline (12.3 g) and pyridine (7.90 g) in methylene chloride (100 ml) at 0° C., and the mixture was stirred at 10° C. for 3 hours. After the reaction, this was extracted with methylene chloride, then washed with diluted hydrochloric acid and an aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. Then, methylene chloride was distilled off to obtain to the objective ethyl N-(5-allyloxy-4-bromo-2-fluorophenyl)carbamate (15.67 g).
Reaction SMILES: [CH:1]1([C:4]2([C:14]3[C:22]4[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[CH:1]1([C:4]2([C:14]3[C:22]4[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CSCc1cccc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
62.0 mg (0.18 mmol) of the compound from Example 93 were introduced into 10 ml of dichloromethane at 0° C., 43.5 mg (0.18 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, and the residue after concentration was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 48 mg (74% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[CH3:24][S:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[CH3:24][S:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:31][CH:30]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CC/C(Nc1ccc(NS(C)(=O)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][CH:46]([CH2:49][NH2:50])[O:45][C:44]=2[CH:51]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][NH:50][CH2:49][CH:46]1[CH2:47][O:48][C:43]2[CH:42]=[CH:41][C:40]([OH:39])=[CH:51][C:44]=2[O:45]1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Reactant: NCC1COc2ccc(O)cc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCCCNCC3COc4ccc(O)cc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
5-Methoxyindole-3-butyric acid (1.5 g, 6.4 mmole), 1-hydroxybenzotriazole hydrate (1.0 g, 7.7 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.4 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.4 g, 6.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using first ethyl acetate and then 5% methanol in ethyl acetate as eluants. Evaporation of product-containing fractions gave 1.6 g (63%) of the desired product, (7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-methoxy-1H-indol-3-yl)-butanamide, as an oily solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[C:14](/[C:16](=[O:21])[NH:17][CH2:18][CH2:19][CH3:20])\[CH3:15])=[CH:10][CH:11]=2)[C:6]([CH2:22][C:23]2[CH:41]=[CH:40][C:26]([C:27]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])(=[O:32])=[O:31])=[O:28])=[CH:25][C:24]=2[O:42][CH3:43])=[CH:5]1)[CH:2]=[CH2:3]>[Pd].C(O)C>[CH3:43][O:42][C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][C:23]=1[CH2:22][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([C:16](=[O:21])[NH:17][CH2:18][CH2:19][CH3:20])[CH3:15])[CH:8]=2)[N:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1)[C:27]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])(=[O:32])=[O:31])=[O:28]
Reactant: C=CCn1cc(Cc2ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc2OC)c2cc(/C=C(\C)C(=O)NCCC)ccc21
Agent: [Pd]
Solvent: CCO
Product: CCCNC(=O)C(C)Cc1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2CCC
Reaction time: 4 h
Yield: 82.8 %

Procedure:
Palladium on carbon (10% w/w, 0.1 g) was added to a solution of E-4-[1-allyl-5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl]-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (0.24 g) in ethanol (10 ml). The mixture was vigorously stirred and hydrogenated at atmospheric pressure for 4 hr. The catalyst was removed by filtration through diatomaceous earth, the filter pad washed with ethanol, and the filtrate evaporated. The white foam obtained was precipitated from a mixture of ethanol and 1M hydrochloric acid to give the title compound (0.2 g, 82%) as a white powder; mp 104°-110° (softens at 84°).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCC1CCN(Cc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 9 h
Yield: 59.3 %

Procedure:
To a solution of ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate (21 g) in ethanol (20 ml) was added sodium borohydride (9.1 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 10.55 g of 1-benzyl-3-hydroxy-4-hydroxymethylpiperidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[O:10]1[CH2:15][CH:14]=[C:13]([C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=O)[CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:18]/[CH2:17][C:16]([C:13]1[CH2:14][CH2:15][O:10][CH2:11][CH:12]=1)([CH3:21])[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(CC=O)C1=CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C1=CCOCC1
Yield: 98.6 %

Procedure:
Step F In a manner similar to the method described in Example 1a, glycine tert-butyl ester (2 g, 15.5 mmol) was reacted with 3-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-butyraldehyde (2.6 g, 15.5 mmol) in CH2Cl2 at room temperature for 5 h to give [3-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (4.3 g, 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[N+]=[N-].[OH-].[Na+]>O1CCCC1>[NH2:7][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16]1
Reactant: [N-]=[N+]=NCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.2 %

Procedure:
To a suspension of 4.70 g of lithium aluminium hydride in 250 ml of dried tetrahydrofuran, a solution of 47.7 g of 4-azidomethyl-N-triphenylmethylpiperidine in 250 ml of dried tetrahydrofuran was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added dropwise with a mixture of tetrahydrofuran and 10% aqueous sodium hydroxide solution under ice-cooling. An insoluble matter in the mixture was filtered off, and washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated to give 48.1 g of a colorless liquid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1([CH3:34])[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([S:30](Cl)(=[O:32])=[O:31])[CH:28]=[CH:29][C:22]=2[O:21]1>O.C(#N)C>[CH3:19][C:20]1([CH3:34])[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([S:30]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][C@H:2]3[C:10]([OH:12])=[O:11])(=[O:32])=[O:31])[CH:28]=[CH:29][C:22]=2[O:21]1
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CCc2cc(S(=O)(=O)N3c4ccccc4C[C@H]3C(=O)O)ccc2O1
Yield: 73 %

Procedure:
1 g (6.13 mmol) of 2,3-dihydro-(2S)-1H-indole-2-carboxylic acid, and 0.97 g (7.05 mmol) of potassium carbonate are solubilised in 2 ml of water. 1.6 g (6.13 mmol) of 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-sulfonyl chloride solubilised in 12 ml of acetonitrile and 2 ml of water are added. Agitation is allowed to take place for 5 hours at ambient temperature. Water is added to the reaction medium, washing is performed with ethyl acetate, the acidity of the aqueous phase is raised to pH 3 by a solution of hydrochloric acid 1 N, and then extraction is performed using ethyl acetate. The organic phases are collected, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/methanol (9/1; v/v) mixture. The expected product is obtained in the form of a beige foam with a yield of 73%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH2:13]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:14]1[O:16][CH2:15]1>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][CH2:15][C@H:14]([OH:16])[CH2:13][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Solvent: CO
Product: COc1ccc(CNC[C@H](O)COCc2ccccc2)c(OC)c1
Yield: 75.4 %

Procedure:
To a stirred solution of 2,4-dimethoxybenzylamine (1.00 g, 5.99 mmol) in MeOH (30 mL) at room temperature was added benzyl(S)-(+)-glycidyl ether (0.88 g, 5.40 mmol). After 12 h the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (75 mL) and washed sequentially with 1 N HCl (25 mL) and brine (25 mL). The solution was dried over MgSO4, filtered and the solvent removed under reduced pressure to give 1.35 g of the crude oil that was used in the next step without further purification. MS (ES+) m/z 332.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:7]([Cl:12])=[O:9])=[CH:5][N:6]=1
Reactant: Cc1ncc(C(=O)O)s1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ncc(C(=O)Cl)s1
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1,5.7 g (0.04 mole) of 2-methylthiazole-5-carboxylic acid were suspended in 100 ml of toluene. Under heating and reflux, phosgene was blown at a rate of 390 ml/hr for 10 hours (0.17 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 5.7 g of 2-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 95.0% and 95.0%, respectively. NMR (δCDCl 3/TMS, ppm): 2.79(3H,s).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:11]O>>[CH3:1][N+:2]([O-:11])([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: OO
Reactant: CCCCCCCN(C)C
Product: CCCCCCC[N+](C)(C)[O-]

Procedure:
To 28.6 g of dimethylheptyl amine was added slowly 100 ml 30% H2O2 as in Example 4 to give the dimethylheptyl amine oxide. NMR showed the resulting semisolid material to contain 29% water and 71% of the amine oxide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1>C(NCC)C.C(Cl)Cl>[CH2:2]([N:3]([CH2:4][CH3:5])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:7]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)c1ccc([N+](=O)[O-])cn1
Yield: 195.5 %

Procedure:
A stirred mixture of 27.6 g (0.174 mole) of 2-chloro-5-nitropyridine in 500 ml of diethylamine was heated at reflux for two days. The excess diethylamine was removed by distillation under reduced pressure, leaving a residue. This residue was dissolved in methylene chloride, and the organic solution was washed with an aqueous, 10% sodium hydroxide solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 33.2 g of 2-diethylamino-5-nitropyridine as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH-].[Na+].[O:3]1[C:9]2[CH:8]3[O:10][CH:5]([CH2:6][CH:7]3[S:11]([O:14]C)(=O)=O)[C:4]1=2.Cl>>[OH:3][CH:4]1[CH:9]2[CH:8]3[CH:7]([CH2:6][CH:5]1[O:10]3)[S:11][O:14]2
Reactant: COS(=O)(=O)C1CC2OC1C1=C2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: OC1C2CC3SOC1C3O2
Temperature: 21.5 °C
Reaction time: 4 h
Yield: 16.6 %

Procedure:
A four-neck flask having an internal capacity of 300 mL and fitted with a stirrer, a dropping funnel and a thermometer was charged with a 5.0 (mol/L) aqueous solution of sodium hydroxide, and 29.5 g of methyl 2,3-epoxy-7-oxabicyclo[2.2.1]hept-2-ene-5-sulfonate was added dropwise to the flask from the dropping funnel so that the internal temperature of the flask was maintained within a range from 20 to 23° C. Following completion of the dropwise addition, the reaction mixture was stirred for 4 hours, and then while the flask was cooled in an ice bath, concentrated hydrochloric acid was added dropwise to adjust the pH to 7.3. Subsequently, the reaction mixture was extracted 4 times with 300 mL samples of ethyl acetate, the thus obtained organic layers were combined and concentrated, and the resulting concentrate was separated and purified by silica gel column chromatography, yielding 4.75 g (purity: 98.8%, 0.024 mol) of 2-hydroxy-4,8-dioxa-5-thiatricyclo[4.2.1.03,7]nonane=5,5-dioxide.
Reaction SMILES: [Li+].C[CH:3]([N-:5]C(C)C)C.[CH2:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10]1.S(C#N)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[O:19]=[C:16]1[CH2:17][CH2:18][C:13]2([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:14][CH:15]1[C:3]#[N:5]
Reactant: O=C1CCC2(CCCC2)CC1
Reactant: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1CC2(CCCC2)CCC1=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
LDA (1.83 mL, 3.66 mmol, 2.0 M in hexanes) was combined with THF (3.2 mL) and cooled to −78° C. To this mixture was added a solution of spiro[4.5]decan-8-one (0.50 g, 3.3 mmol) in THF (3.2 mL). The resulting mixture was stirred at −78° C. for 20 mins then taken up in a syringe and added to a mixture of tosyl cyanide (0.59 g, 3.3 mmol) in THF (3.2 mL) at −78° C. The reaction mixture was allowed to stir at −78° C. for 45 mins then quenched with 0.5M NaOH and extracted with EtOAc (2×). The combined organic extracts were washed with 1N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by MPLC on silica gel (using a gradient elution of 0-50% EtOAc/hexanes). Desired fractions were identified, combined and concentrated in vacuo to afford the title compound. The residue was carried forward without further purification.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[S:10][C:9]([C:11]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]5[N:20]([C:22]([C:25]6[S:26][CH:27]=[CH:28][N:29]=6)=[CH:23][N:24]=5)[CH:21]=4)=[CH:14][N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:12]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[ClH:49].O>O1CCCC1.CO>[ClH:49].[ClH:49].[NH:1]1[C:5]([C:6]2[S:10][C:9]([C:11]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]5[N:20]([C:22]([C:25]6[S:26][CH:27]=[CH:28][N:29]=6)=[CH:23][N:24]=5)[CH:21]=4)=[CH:14][NH:13][N:12]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc4ncc(-c5nccs5)n4c3)c(-c3ccc(-c4nnn[nH]4)s3)n2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: c1csc(-c2cnc3ccc(-c4c[nH]nc4-c4ccc(-c5nnn[nH]5)s4)cn23)n1
Reaction time: 3 h

Procedure:
60 mg 6-{3-[5-(1H-tetrazol-5-yl)-thiophen-2-yl]-1-trityl-1H-pyrazol-4-yl}-3-thiazol-2-yl-imidazo[1,2-a]-pyridine obtained in Example 441 was dissolved in 8.0 mL solvent mixture of tetrahydrofuran and methanol (1:1), then 3.0 mL of 5 N hydrochloric acid was added thereto, and the mixture was left at room temperature for 3 hours. Water was poured into the reaction solution, and the precipitated crystals were collected by filtration and washed with diethyl ether, to give 14.5 mg of the title compound as pale pink crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.1 %

Procedure:
To a solution of 3-fluorophenylacetic acid (5.0 g, 32 mmol) in MeOH (25 mL) and CH2Cl2 (25 mL) at 0° C. was added trimethylsilyldiazomethane (2 M in hexane, 30 mL, 60 mmol). After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude methyl 3-fluorophenylacetate (5.6 g), which was used without further purification. Thus, the crude methyl 3-fluorophenylacetate obtained above (2.5 g, 15 mmol) was converted to the title compound (purified on silica gel) by reacting with 4-chlorobenzyl bromide (4.6 g, 22 mmol) and sodium hexamethyldisilazide (1 M in THF, 15 mL, 15 mmol) following the procedure described in Reference Example 10, Step A. 1H NMR (400 MHz, CD3OD): δ 7.35-6.88 (m, 8H), 3.92 (t, 1H), 3.60 (s, 3H), 3.34 (dd, 1H), 3.00 (dd, 1H). LC-MS: m/e 305 (M+Na)+ (3.9 min).