Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][C:6]1([CH3:26])[C@@H:8]([C:9]([O-:11])=[O:10])[C@@H:7]1[CH:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH3:5][C:6]1([CH3:26])[C@@H:8]([C:9]([OH:11])=[O:10])[C@@H:7]1[CH:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)[C@@H](C=C(c2ccccc2)c2ccccc2)[C@@H]1C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)[C@@H](C=C(c2ccccc2)c2ccccc2)[C@@H]1C(=O)O

Procedure:
42.7 cc of a 2 N methanolic sodium hydroxide solution were introduced into 100 cc of methanol and 10 cc of water, followed by 18.45 gm of ethyl dl-trans 3,3-dimethyl-2-(2',2'-diphenylvinyl)-cyclopropanecarboxylate were added thereto. The mixture was brought to reflux and maintained there for 1 hour and 30 minutes. The methanol was removed by distillation and water was added. Next the aqueous phase was extracted with ethyl ether to eliminate the neutral fraction and the combined ether extracts were washed with water and the wash water was combined with the principal aqueous phase. Then the entire aqueous phase was acidified with a dilute aqueous solution of hydrochloric acid which was then repeatedly extracted with methylene chloride; the methylene chloride solutions were combined, washed with water, dried and concentrated to dryness to obtain 7.95 gm of dl-trans 3,3-dimethyl-2-(2',2'-diphenylvinyl)-cyclopropanecarboxylic acid having a melting point of 115° C. A sample of this product crystallized from a mixture of isopropyl ether and petroleum ether, had a melting point of 115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]=[N:12]2)=[CH:7][C:4]=1[CH:5]=O.[CH3:20][NH2:21]>ClCCl.C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]=[N:12]2)=[CH:7][C:4]=1[CH2:5][NH:21][CH3:20]
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C=O
Reactant: CN
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNCc1cc(-n2nnnc2C(F)(F)F)ccc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 40 ml of dichloromethane was dissolved 2.72 g of 2-methoxy-5-(5-trifluoromethyltetrazole-1-yl)benzaldehyde, and added thereto was 2.5 ml of 8 M methylamine in ethanol solution, 0.572 ml of acetic acid and 3.12 g of triacetoxy sodium borohydride, the mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with saturated aqueous sodium hydrocarbonate solution, and the organic layers were dried and concentrate. The residue was purified by silica gel column chromatography (chloroform:methanol=49:1 to 4:1), to give 2.2 g of N-{2-methoxy-5-(5-trifluromethyltetrazole-1-yl)benzyl}-N-methylamine as shown in Table 136 below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](C(O)=O)=[CH:7][C:6]=2[C:13]=1[O:14][CH3:15].C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[C:13]=1[O:14][CH3:15]
Reactant: COc1c(F)ccc2sc(C(=O)O)cc12
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(F)ccc2sccc12
Temperature: 200 °C
Yield: 23.5 %

Procedure:
(2Z)-3-(3-Fluoro-2-methoxyphenyl)-2-mercapto-2-propenoic acid (4.865 g, 21.315 mmol) was added in one portion to a solution of iodine (8.255 g, 31.973 mmol) in dimethoxyetheane (30 mL). This was heated in the microwave with 300 W at 120° C. for 25 mins. After this time the reaction was allowed to cool to room temperature and poured onto saturated sodium metabisulphite (200 mL) and ether (400 mL). Ether layer was separated and product extracted with aqueous sodium hydroxide (2 N, 2×100 mL). This was then acidified to pH 2 with aqueous hydrochloric acid (2 N, 250 mL), and product extracted with ether (2×150 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a tan coloured solid (3.240 g, 14.322 mmol, 67%). Which was used without further purification in the next step. 5-Fluoro-4-methoxy-1-benzothiophene-2-carboxylic acid (0.883 g, 3.903 mmol) was added in one portion to DBU (2.04 mL, 13.661 mmol) and dimethyl acetamide (10 mL). This was heated in the microwave with 300 W at 200° C. for 1 h. Reaction was allowed to cool and poured onto water (100 mL). Product was extracted with hexane (2×100 mL), washed with aqueous hydrochloric acid (2 N, 50 mL), aqueous sodium hydroxide (2 N, 50 mL), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ethyl acetate [96:4] to give a pale yellow oil (0.167 g, 23%); δH (300 MHz, CDCl3) 7.60–6.80 (4H, m, Ar), 4.10 (3H, s, OCH3).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].O1CC1C[O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[O:16]>>[C:5]([O:4][CH2:3][CH2:2][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[O:16])(=[O:7])[CH3:6]
Reactant: NC(=O)c1cccc(OCC2CO2)c1
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCOc1cccc(C(N)=O)c1

Procedure:
In a manner analogous to that set forth in A of this example, but substituting 1-bromo-2,3-epoxypropane for 2-bromoethylacetate, 3-(2,3-epoxy-n-propoxy)benzamide was prepared.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH2:24][SH:25]>>[CH3:28][O:27][C:23](=[O:26])[CH2:24][S:25][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCCC2)CC1
Reactant: COC(=O)CS
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCCC2)C2CCC(C)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea (Example 202) and methyl thioglycolate.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[CH:6]=1.[CH2:10](OCC)C.C[Li].O>C(O)C>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])=[O:9])[CH:6]=1
Reactant: CCOCC
Reactant: Cc1cc(C(=O)O)cs1
Agent: [Li]C
Solvent: CCO
Solvent: O
Product: CC(=O)c1csc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Methylthiophene-4-carboxylic acid (14.2 g., 0.1 mole) prepared by the method of Shvedov et al., Khim. Geterotsikl. Soedin. 1010 (1967); Chem. Abstrs., 69, 51922j (1968) in 250 ml. of ethyl ether is cooled to -10° to 0° C. and an ethereal solution of methyl lithium (4.4 g., 0.2 mole) is added dropwise while maintaining the reaction mixture below 0° C. After stirring for 1 hour at 0° C., a solution of 4 g. of water in 100 ml. of ethanol is added cautiously and the mixture allowed to warm to room temperature. The desired product is then isolated by partitioning the reaction mixture between ether and water and evaporation of the organic extracts.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C(N(CC)CC)C>C(O)C>[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:13]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1[N+](=O)[O-]

Procedure:
A solution of 2-chloro-3-nitropyridine (50 g, 0.315 mole), glycine ethyl ester hydrochloride (220 g, 1.58 mole), and triethylamine, (155 g, 1.53 mole) in 1 liter of absolute ethanol was stirred and heated to reflux overnight. The reaction mixture was evaporated to a solid mass, which was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (3×). The combined ethyl acetate layer was evaporated to an oil, which was dried by azeotropic distillation with benzene. The residue was purified by silica gel chromatography (8 cm×27 cm column) by elution with 5% methanol/95% benzene. The appropriate fractions totaled 59.2 g of the title product, m.p. 38°-9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[C:11]([CH2:18]N(CC)CC)[C:10]=3[OH:24])[N:8]=[C:4]2[CH:3]=1.[Cl:27][C:28]1[CH:46]=[CH:45][C:31]2=[N:32][N:33]([C:35]3[CH:40]=[C:39]([CH2:41][CH2:42][OH:43])[CH:38]=[CH:37][C:36]=3[OH:44])[N:34]=[C:30]2[CH:29]=1.CO.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:18]([C:37]1[CH:38]=[C:39]([CH2:41][CH2:42][OH:43])[CH:40]=[C:35]([N:33]2[N:32]=[C:31]3[CH:45]=[CH:46][C:28]([Cl:27])=[CH:29][C:30]3=[N:34]2)[C:36]=1[OH:44])[C:11]1[CH:12]=[C:13]([CH2:15][CH2:16][OH:17])[CH:14]=[C:9]([N:7]2[N:6]=[C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]3=[N:8]2)[C:10]=1[OH:24]
Reactant: CCN(CC)Cc1cc(CCO)cc(-n2nc3ccc(Cl)cc3n2)c1O
Reactant: OCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: OCCc1cc(Cc2cc(CCO)cc(-n3nc4ccc(Cl)cc4n3)c2O)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Yield: 55 %

Procedure:
In 100 ml of xylene were dissolved 37.0 g (93.9 mmols) of crude 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)-6-(N,N-diethylaminomethyl)phenol synthesized in Example 10 and 27.2 g (93.9 mmols) of the purified product of 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol synthesized in Example 7. 5 ml of methanol solution of 28% sodium methylate was added, and the mixture was refluxed in a nitrogen stream for 10 hours. The subsequent treatment was carried out in the same manner as in Example 12, giving 30.8 g of 2,2'-methylenebis[6-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol] as pale yellow crystals (yield 55.0%, purity 99.0%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([C:16]([F:19])([F:18])[F:17])[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[N:9]1.N1C=CC=CC=1.[NH2:33][C:34]1[C:35]([F:43])=[C:36]([C:39]([F:42])=[CH:40][CH:41]=1)[C:37]#[N:38]>CN(C=O)C.ClCCl.C1COCC1>[C:37]([C:36]1[C:35]([F:43])=[C:34]([NH:33][C:13]([C:12]2[N:8]([CH3:7])[N:9]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:11]=2[C:16]([F:18])([F:17])[F:19])=[O:15])[CH:41]=[CH:40][C:39]=1[F:42])#[N:38]
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Reactant: N#Cc1c(F)ccc(N)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(F)c(C#N)c1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 44.3 %

Procedure:
Oxalyl chloride (0.85 ml, 1.2 g, 9.8 mmol) followed by DMF (3 drops) were added to 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (2.03 g, 6.50 mmol) in dichloromethane (15 ml), and the mixture was heated to 50° C. After 5 h at 50° C., the mixture was concentrated under reduced pressure, THF (15 ml) and pyridine (1.1 ml, 1.0 g, 13 mmol, 2 eq.) were added, followed by 3-amino-2,6-difluorobenzonitrile (1.0 g, 6.5 mmol, 1.0 eq.) in THF (3 ml). The mixture was left at room temperature for 24 h, HC10N aq. solution) was added, the mixture was extracted with ethyl acetate and the extract was washed with HC10N aq. solution) and NaOH (2N aq. solution). The extract was dried over MgSO4 and filtered through silica gel. After concentration under reduced pressure, the product was purified by column chromatography on silica gel (hexane/ethyl acetate), giving N-(3-cyano-2,4-difluorophenyl)-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (1.29 g, 44%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]ccc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 51 %

Procedure:
The title compound is prepared from 1H-indole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 51% of theory; LC (method 4): tR=1.99 min; Mass spectrum (ESI+): m/z=331 [M+H]+.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](O)([CH3:12])[CH2:8][C:9](=[O:11])[CH3:10]>CO.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[CH:8][C:9](=[O:11])[CH3:10])[CH3:12]
Reactant: CC(=O)CC(C)(O)c1ccccc1-c1ccccc1
Solvent: O
Solvent: CO
Product: CC(=O)C=C(C)c1ccccc1-c1ccccc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a 70° C. warm solution of 104.2 g 4-(p-biphenylyl)-4-hydroxypentan-2-one in a mixture of 450 ml methanol and 80 ml water 206 g ca. 65% sulphuric acid is added dropwise and the mixture is stirred 21/2 hours at 75° C. After cooling to 25° C. the resulting solid is filtered off, washed with water, then with diluted sodium hydroxide solution, again with water, dried and then recrystallised from toluene to give the title compound, m.p. 134°-136° C.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[N:9]1([C:14](=C)[C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:12][N:11]=[N:10]1>>[CH3:6][N:4]([CH3:5])[CH:3]=[C:14]([N:9]1[CH:13]=[CH:12][N:11]=[N:10]1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(OC)N(C)C
Reactant: C=C(C(=O)OC)n1ccnn1
Product: COC(=O)C(=CN(C)C)n1ccnn1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
522 g of dimethylformamide dimethyl acetal were added to 400 g of methyl 2-(1H-1,2,3-triazol-1-yl)acrylate, and the mixture was heated to the boil. Low-boiling components formed were distilled off. After 4 h, the mixture was cooled to 55° C., and 1050 ml of methyl tert-butyl ether/2-propanol (3:1 v/v) were metered in. The resulting suspension was cooled to 22° C. and filtered. The filter cake was repeatedly washed with methyl tert-butyl ether and dried under reduced pressure at 40° C. This gave 493 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:69])([C:65]([F:68])([F:67])[F:66])[CH2:48][CH2:49][CH2:50][CH:51]([CH2:57][CH2:58][CH2:59][CH2:60]CCC=C)[C:52]([O:54]CC)=[O:53]>>[CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:60][CH2:59][CH2:58][CH2:57][CH:51]([CH2:50][CH2:49][CH2:48][C:47]([F:46])([F:69])[C:65]([F:66])([F:68])[F:67])[C:52]([OH:54])=[O:53])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate prepared in Example 6, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@@H:13]1[C:18]([OH:20])=O.[NH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:23]([OH:27])[C:24]([NH2:26])=[O:25].O[NH-].O=[N-]>>[NH2:26][C:24](=[O:25])[C:23](=[O:27])[CH:22]([NH:21][C:18]([C@H:13]1[CH2:14][CH2:15][C:16](=[O:17])[N:12]1[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:20])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccc2ccccc2c1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccc2ccccc2c1

Procedure:
Coupling of (R)-1-naphthalen-2-ylmethyl-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [K].[CH3:2][C:3]1[C:4]([CH3:14])=[C:5]([CH3:13])[C:6]([Si:9](Cl)([CH3:11])[CH3:10])([CH3:8])[CH:7]=1.[CH2:15]1[CH2:19]O[CH2:17][CH2:16]1>>[CH3:2][C:3]1[C:4]([CH3:14])=[C:5]([CH3:13])[C:6]([Si:9]([CH:15]([C:19]2[CH:8]=[CH:6][CH:7]=[CH:3][CH:2]=2)[C:16]2[CH:13]=[CH:5][CH:4]=[CH:14][CH:17]=2)([CH3:11])[CH3:10])([CH3:8])[CH:7]=1
Reactant: CC1=CC(C)([Si](C)(C)Cl)C(C)=C1C
Reactant: C1CCOC1
Agent: [K]
Product: CC1=CC(C)([Si](C)(C)C(c2ccccc2)c2ccccc2)C(C)=C1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium diphenylmethanite (4.91 g, 23.8 mmol) was slowly added to (tetramethylcyclopentadienyl)dimethylsilylchloride (5.11 g, 23.8 mmol) dissolved in about 65 mL of THF at about 25° C. A precipitate formed and the reaction mixture was stirred about 16 hours more at about 25° C. after which time the reaction mixture was filtered, the solvent was removed under reduced pressure and the residue was extracted with hexane and filtered. The solvent was removed under reduced pressure to give the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[CH2:5][CH2:4][NH:3]1.[H-].[Na+].[C:31]([O:35][C:36]([CH:38]=C1CCCCCC1N1C(=O)C=CC(C2C(C3C=CC=CC=3)=NN3C=CC=CC=23)=N1)=[O:37])(C)(C)[CH3:32].BrCC(OCC)=O>CN(C)C=O.O>[CH2:31]([O:35][C:36]([CH2:38][N:3]1[CH2:4][CH2:5][CH:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[C:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=34)=[N:8]2)[C:2]1=[O:1])=[O:37])[CH3:32]
Reactant: CC(C)(C)OC(=O)C=C1CCCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: O=C1NCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1=O
Reaction time: 0.5 h
Yield: 633.2 %

Procedure:
To a solution of 3-[2-(2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (740 mg) in N,N-dimethylformamide (5 ml) was added 60% sodium hydride in mineral oil (120 mg) at O° C. After the mixture was stirred for 30 minutes, to this was added ethyl 2-bromoacetate (0.22 ml). After the reaction mixture was stirred at 0° C. for 1 hour, it was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (CHCl3 -CHCl3 :MeOH (30:1)) to give 3-[2-(1-ethoxycarbonylmethyl-2-oxopyrrolidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.7 g) (yellow oil).
Reaction SMILES: O=O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1>CO.[Ru]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)=C(C(=O)O)c1ccc(Cl)cc1
Agent: [Ru]
Agent: O=O
Solvent: CO
Product: CC(C)[C@@H](C(=O)O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
Ruthenium-catalyzed hydrogenation. -- A catalyst solution was prepared in a glove box (O2 content <1 ppm) by dissolving 0.0914 g (0.119 mmol) of Ru(OAc)2 [(S)-BIPHEMP] in 50 ml of methanol and stirring at 20° for 15 minutes. Then, 5.0 g (23.74 mmol) of 2-(p- chlorophenyl)-3-methylcrotonic acid and 23 ml of methanol were placed in a 185 ml autoclave and the catalyst solution prepared above was added. The autoclave was sealed and the hydrogenation was carried out at 20° while stirring and under a constant pressure of 60 bar. The conversion was 100% after 4 hours. The hydrogenation solution was evaporated at 50°/20 mbar and the residue was distilled in a bulb tube oven at 150°/0.2 mbar. There were obtained 4.6 g (92%) of (R)-2-(p-chlorophenyl)-3-methylbutyric acid as a colorless oil which crystallized out at RT; chemical purity 98.8 area %; 90.5% ee; [α]589 =-42.3° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[C:6]([Cl:18])[C:7]=1[C:8]1[S:9][C:10]2[C:11](Cl)=[N:12][CH:13]=[CH:14][C:15]=2[N:16]=1.[CH3:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[C:6]([Cl:18])[C:7]=1[C:8]1[S:9][C:10]2[C:11]([NH:30][C:26]3[CH:25]=[C:24]([CH3:23])[N:29]=[CH:28][N:27]=3)=[N:12][CH:13]=[CH:14][C:15]=2[N:16]=1
Reactant: Cc1cc(N)ncn1
Reactant: CC(=O)Nc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Cl)c(-c2nc3ccnc(Nc4cc(C)ncn4)c3s2)c(Cl)c1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
A mixture of N-[3,5-dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-acetamide (0.057 g, 0.15 mmol), 6-methylpyrimidin-4-ylamine (0.020 g, 0.18 mmol), Pd2(dba)3 (0.007 g, 0.0075 mmol), XantPhos (0.017 g, 0.03 mmol) and Cs2CO3 (0.098 g, 0.30 mmol) in dioxane (2 mL) was degassed with a stream of N2 and then subjected to microwave irradiation at 150° C. for 30 minutes. After cooling to room temperature, the crude reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, then dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 50-100% EtOAc in cyclohexane followed by 1% MeOH in EtOAc to afford the title compound as a pale yellow solid (21 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 10.53 (s, 1H), 8.63 (d, J=1.2 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 7.89 (s, 2H), 7.82 (d, J=5.6 Hz, 1H), 7.61 (s, 1H), 2.39 (s, 3H), 2.13 (s, 3H). LCMS (Method C): RT=3.02 min, m/z: 445 [M+H+].
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][NH:6][S:7]([C:10]1[S:14][C:13]([NH:15][C:16]([N:18]([CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[O:17])=[N:12][CH:11]=1)(=[O:9])=[O:8])C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.C(OC(=O)CNS(C1SC(N)=NC=1)(=O)=O)C.COC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:30]1([CH2:29][N:18]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)[C:16](=[O:17])[NH:15][C:13]2[S:14][C:10]([S:7]([NH:6][CH2:5][C:4]([OH:35])=[O:3])(=[O:9])=[O:8])=[CH:11][N:12]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)CNS(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: CCOC(=O)CNS(=O)(=O)c1cnc(N)s1
Agent: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)cc1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester the latter prepared in a similar manner as (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.