Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C@:24]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])=[O:30])[CH2:25]2)[CH2:17][CH2:16]1)[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>ClCCl>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C@:24]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[C:35]([O:37][S:56]([CH3:55])(=[O:58])=[O:57])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])=[O:30])[CH2:25]2)[CH2:17][CH2:16]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(O)ccc4OC)C3)CC2)nc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(OS(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.2 %

Procedure:
Treat a stirred solution of 1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(5-hydroxy-2-methoxy-phenyl)-methanone (0.25 g, 0.22 mmol) and dichloromethane (5 mL) at 0° C. with diisopropylethylamine (0.14 mL, 0.84 mmol) and methane sulfonyl chloride (0.04 mL, 0.5 mmol). Stir the reaction mixture at 0° C. for two hours, dilute with dichloromethane and wash with water. Dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the product by column chromatography (silica gel, elute sequentially with 3% methanol in dichloromethane then with 5% methanol in dichloromethane) and concentrate the appropriate fractions to afford 0.19 g of the title compound, Rf=0.28 (silica gel, 5% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods swell known in the art.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH2:13][C:14]3[CH2:19][N:18](NC(OC(C)(C)C)=O)[CH2:17][CH2:16][CH:15]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH2:13][C:14]3[CH2:19][NH:18][CH2:17][CH2:16][CH:15]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NN1CCC=C(CNCc2ccc3c(c2)OCCO3)C1
Solvent: O=C(O)C(F)(F)F
Product: C1=C(CNCc2ccc3c(c2)OCCO3)CNCC1

Procedure:
A solution of tert-butyl 5-{[(2,3-dihydro-benzo[1,4]-dioxin-6-ylmethyl)-amino]-methyl}-3,6-dihydro-2H-pyridine-1-carbamate (0.16 g, 0.44 mmol) in TFA (3 ml) was stirred at room temperature for 30 minutes, concentrated and taken up in saturated bicarbonate solution (30 ml) and dichloromethane (30 ml). The aqueous phase was extracted with dichloromethane (2×30 ml) and the combined organic phases were washed with saturated sodium chloride solution, dried over MgSO4 and concentrated.
Reaction SMILES: N.[C:2]([C:4](=[C:7](SC)[S:8][CH3:9])[C:5]#[N:6])#[N:3].CS.C(#[N:17])C=C>C(O)C>[NH2:17][C:7]([S:8][CH3:9])=[C:4]([C:5]#[N:6])[C:2]#[N:3]
Reactant: C=CC#N
Reactant: CSC(SC)=C(C#N)C#N
Agent: CS
Agent: N
Solvent: CCO
Product: CSC(N)=C(C#N)C#N

Procedure:
Two liters of ethanol were saturated with ammonia gas at 15°. At ambient temperature, 278.3 g of 2-cyano-3,3-bis(methylthio)propenenitrile were added portionwise. A sodium hydroxide trap was used to trap the methyl mercaptan by-product. After complete addition of the propenenitrile the reaction mixture was cooled to approximately 10°. The solid which separated was collected by filtration and washed with cold ethanol to give, after drying, 206.3 g of white 3-amino-2-cyano-3-(methylthio)propenenitrile, m.p. 228°-230°. The nmr was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][C:3]=1[Cl:14].[NH2:15][CH2:16][CH2:17][C:18]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2>O1CCCC1>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:11]([NH:15][CH2:16][CH2:17][C:18]23[CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH2:25]3)=[O:13])=[CH:4][C:3]=1[Cl:14]
Reactant: NCCC12CCCN1CCC2
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCO2
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(=O)NCCC23CCCN2CCC3)c2c1CCO2
Yield: 78.3 %

Procedure:
Into an agitating solution of 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (3.21 g) in absolute tetrahydrofuran (50 ml), was added little by little 1,1-carbonylimidazole (2.43 g) and after lapsed 1 hour, a solution of 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (2.31 g) in absolute tetrahydrofuran (2 ml) was added therein to reflux for 1 hour. After cooled, the solvent was distilled out in vacuo, a residue was dissolved into chloroform, washed with saturated sodium hydrogen carbonate solution and then water, and thereafter, the solvent was distilled out in vacuo. The resulting residue was refined by alumina column chromatography (developing solvent: chloroform) to afford 4.1 g of the titled compound.
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:38][CH2:37][CH2:36][C@H:21]1[C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C>[OH-].[Na+]>[C:4]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:38][CH2:37][CH2:36][C@H:21]1[C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:23])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A solution of 1.0 millimole of N-(1-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolyl-L-phenylalanine in 4 ml of 1N NaOH was kept at room temperature for 18 hours. The solution was put on a column of 300 ml of Dowex 50 (H+) resin. After washing with 500 ml water, the product was eluted with 3% aqueous pyridine solution. After concentration of the eluate in vacuo and lyophilization, the N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-prolyl-L-phenylalanine product was obtained as an amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][N:5]([CH2:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:41][CH2:42][CH3:43])[CH2:38][CH2:39][CH3:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([CH2:22][C:23]2[N:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][N:27]=2)[CH2:15][C:16]2[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=2)=[CH:9][CH:8]=1.Cl>O1CCOCC1>[C:29]([CH2:28][N:24]1[CH:25]=[CH:26][N:27]=[C:23]1[CH2:22][N:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:5]([CH2:4][C:3]([OH:44])=[O:2])[CH2:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:41][CH2:42][CH3:43])[CH2:38][CH2:39][CH3:40])=[CH:8][CH:9]=1)[CH2:15][C:16]1[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=1)([OH:31])=[O:30]
Reactant: CCCN(CCC)CCCCN(CC(=O)OC)Cc1ccc(CN(Cc2nccn2C)Cc2nccn2CC(=O)OC)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2nccn2C)Cc2nccn2CC(=O)O)cc1
Yield: 76.1 %

Procedure:
The compound (23.7 mg) obtained in Example 54-1 was dissolved in 1,4-dioxane (1.0 ml) and added with concentrated hydrochloric acid (1.0 ml) and the whole was refluxed under heating for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, thereby obtaining a hydrochloride (17.2 mg) of the subject compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[N:7]=[C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=3)[S:9][C:5]=2[C:4]=1[N+:22]([O-])=O.[H][H]>CO.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[N:7]=[C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=3)[S:9][C:5]=2[C:4]=1[NH2:22]
Reactant: COc1ccc2nc(-c3ccc4ccccc4c3)sc2c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2nc(-c3ccc4ccccc4c3)sc2c1N
Yield: 52.8 %

Procedure:
1.06 g (3.15 mmol) of 6-methoxy-2-(2-naphthyl)-7-nitro-1,3-benzothiazole are put into suspension in 50 ml of methanol and 5 ml of acetic acid. 105 mg (10%) of palladium on carbon is added to the reaction mixture which is maintained under stirring under 2.5 bars of hydrogen for 24 hours. The catalyst is filtered, then the solvents are evaporated under reduced pressure. 0.51 g (yield=53%) of 6-methoxy-2-(2-naphthyl)-1,3-benzothiazol-7-amine is obtained and used in the following stage without other purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:47]=[C:46]([C:48]([OH:51])([CH3:50])[CH3:49])[O:45][N:44]=2)=[CH:38][C:37]=1[CH3:52].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[N:47]=[C:46]([C:48]([OH:51])([CH3:50])[CH3:49])[O:45][N:44]=6)=[CH:38][C:37]=5[CH3:52])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2noc(C(C)(C)O)n2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6noc(C(C)(C)O)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-bromo-3,5-dimethyl-phenyl)-5-(2-hydroxy-prop-2-yl)-[1,2,4]oxadiazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.25 min; Mass spectrum (ESI+): m/z=573 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[C:21][CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:23].C(=O)(O)[O-].[Na+]>C(O)(C)C.CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:11][N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:21]=1[CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:23]
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Reactant: OC(C#Cc1ccccc1Cl)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Temperature: 55 °C
Yield: 16.7 %

Procedure:
A mixture of 52 mg (0.23 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 50 mg (0.21 mmol) of 3-(2-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-ol, and 30 mg (0.36 mmol) of sodium bicarbonate in 3 mL of isopropyl alcohol was heated at 55° C. overnight with shaking. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 15 mg (0.035 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 5.80 (br s, 1). MS m/z: 431.0 (M+H).
Reaction SMILES: COC[O:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9]([NH:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)=[N:10][O:11][C:7]=2[CH:6]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[N:15]1([CH2:14][CH2:13][NH:12][C:9]2[C:8]3[CH:21]=[CH:22][C:5]([OH:4])=[CH:6][C:7]=3[O:11][N:10]=2)[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1
Reactant: COCOc1ccc2c(NCCN3CCSCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1ccc2c(NCCN3CCSCC3)noc2c1
Reaction time: 24 h
Yield: 72.4 %

Procedure:
6-Methoxymethoxy-N-[2-(4-thiomorpholinyl)ethyl]-1,2-benzisoxazol-3-amine (1.6 g Example 22) was dissolved in methanolic hydrochloric acid (40 ml) and stirred under nitrogen for 24 hours. The reaction was neutralized with saturated Na2CO3 solution, and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting residue was filtered through a silica gel filter-cake eluting with 5% MeOH/DCM, concentrated in vacuo, and subsequent titration with EtOAc provided the product (1.0 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]#[N:7]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: OB(O)c1ccccc1
Product: Cc1cc(C#N)ccc1-c1ccccc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using 4-bromo-3-methylbenzonitrile instead of tert-butyl N-(4-bromobenzyl)carbamate and phenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: [CH2:1]([N:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][CH:10]([OH:23])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:14]=1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C.[Ni]>[CH2:1]([N:8]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][CH:10]([OH:23])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[C:14]=1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc([N+](=O)[O-])c1O
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)N(Cc1ccccc1)CC(O)COc1cccc(N)c1O

Procedure:
A solution of 16.1 g of crude 1-(N-benzyl-tert.-butylamino)-3-(2-hydroxy-3-nitro-phenoxy)-2-propanol in 150 ml of ethanol is reduced, analogously to Example 4(d), with 15 ml of hydrazine hydrate and Raney nickel to give 1-(N-benzyl-tert.-butylamino)-3-(3-amino-2-hydroxy-phenoxy)-2-propanol. The base forms a dark oil which is used further without further purification. The base crystallises from ether as greenish crystals with a melting point of 105°-110°.
Reaction SMILES: [CH:1]([C@@H:4]([NH2:7])[CH2:5]O)([CH3:3])[CH3:2].O=S(Cl)Cl.[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[NH:7][C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][S:24]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)[C@@H](N)CO
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@H](C(C)C)CS1

Procedure:
(1R)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2-Methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl -4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [C:1]([C:3]1([CH3:27])[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1)#[N:2].[OH-].[Na+].[O:30]1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:27][C:3]1([C:1]([NH2:2])=[O:30])[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1
Reactant: C1CCOC1
Reactant: CN(c1cccc2cc(C3=NCC(C)(C#N)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(c1cccc2cc(C3=NCC(C)(C(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of N-[2-(5-cyano-5-methyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (0.38 g), 2N aqueous sodium hydroxide solution (0.90 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was heated under reflux for 4 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. A mixture of the obtained residue, 1H-1,2,3-benzotriazol-1-ol (0.15 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.21 g) and N,N-dimethylformamide (6 mL) was added at room temperature for 1 hr, and 28% aqueous ammonia (0.22 mL) was added. The mixture was stirred overnight at room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried. The obtained solid was suspended in ethanol, and the mixture was stirred for 15 min. The crystals were collected by filtration, washed with ethanol and ethyl acetate, and dried to give the title compound (0.29 g, yield 74%) as colorless crystals. melting point 248-249° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([O:20][CH2:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1.COC(=O)C(OC)CC1C=CC=C(O)C=1>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([O:20][CH2:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: COC(=O)C(Cc1cccc(O)c1)OC
Product: CCOC(Cc1ccc(O)cc1)C(=O)OC

Procedure:
The title compound was prepared from 3-(4-benzyloxy-phenyl)-2-ethoxy-propionic acid methyl ester (example 375, Step 3) via the same procedure used for the preparation of 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291, Step 4) to produce a yellow oil. MS (ES) for C12H16O4 [M+H]+: 225.2, [M+NH4]+: 242.2, [M+Na]+: 247.2.
Reaction SMILES: CN.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20](O)=[O:21])[CH2:14]3)=[CH:9][CH:10]=2)[CH:5]=[N:4]1.Cl.[CH2:30]([N:32]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:30][NH:32][C:20](=[O:21])[CH:19]([N:15]1[CH2:16][CH2:17][CH2:18][CH:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[NH:3][N:4]=[CH:5]3)[CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
Methylamine (30 mg) and the compound prepared in Example 222 (88 mg) were dissolved in dimethylformamide (1 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (77 mg), and dimethylaminopyridine (5 mg) were added to the solution. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give 52 mg of the title compound as two diastereomers (ratio=ca. 50:50).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][O:13][C:12](=[O:15])[NH:11]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:21]2[N:20]=1.[NH4+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][O:13][C:12](=[O:15])[N:11]2[C:19]2[CH:24]=[CH:23][N:22]3[N:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:21]3[N:20]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: COc1ncc(F)cc1[C@H]1COC(=O)N1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3C(=O)OC[C@@H]3c3cc(F)cnc3OC)nc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
To a solution of (S)-4-(5-fluoro-2-methoxypyridin-3-yl)oxazolidin-2-one (254 mg, 1.20 mmol) in DMF (10 mL) was added sodium hydride (58 mg, 1.44 mmol, 60% in mineral oil). The mixture was stirred at ambient temperature for 20 minutes then treated with ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (270 mg, 1.20 mmol) in one portion. The mixture was stirred for 48 hours then treated with saturated NH4Cl solution (30 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with water (5×10 mL) and brine (10 mL) then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluting with 20% EtOAc/hexanes to 66% EtOAc/hexanes, to afford (S)-ethyl 5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazo lidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (311 mg, 65% yield) as a white foam. MS (apci) m/z=401.9 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[C:24]([F:27])([F:26])[F:25].[Cl-].[NH4+]>O1CCCC1.O>[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[C:24]([F:25])([F:27])[F:26])[CH2:10][CH2:9]1
Reactant: CN1CCC(O)CC1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(Oc2ccc(C#N)cc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
6.68 g of potassium t-butoxide was suspended in 40 ml of anhydrous tetrahydrofuran and a solution of 6.85 g of 1-methyl-4-hydroxypiperidine in 20 ml of anhydrous tetrahydrofuran was added dropwise over 35 minutes while stirring under ice-water cooling and further the mixture was stirred for 30 minutes. On the other hand, 7.50 g of 4-fluoro-3-trifluoromethylbenzonitrile was dissolved in 40 ml of anhydrous tetrahydrofuran, the mixture was stirred under cooling in a dry ice/acetone bath, and the solution prepared earlier was added dropwise at the internal temperature of −70° C. After adding dropwise, the reaction solution was stirred overnight while naturally heating up to room temperature. The reaction solution was ice-cooled, an aqueous saturated ammonium chloride solution and water were added thereto, and then the solvent was distilled off under reduced pressure. The residue was subjected to extraction with ethyl acetate twice. The extracts were washed in turn with water and saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.31 g of the objective compound as colorless crystals.
Reaction SMILES: [CH:1]1([C@@H:4]2[C:11]3[C:7](=[N:8][NH:9][CH:10]=3)[CH:6]([CH2:12][OH:13])[NH:5]2)[CH2:3][CH2:2]1.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1.C(Cl)Cl>[CH:1]1([C@@H:4]2[C:11]3[C:7](=[N:8][NH:9][CH:10]=3)[CH:6]([CH2:12][OH:13])[N:5]2[S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:26])[F:27])=[CH:21][CH:20]=2)(=[O:24])=[O:23])[CH2:3][CH2:2]1
Reactant: OCC1N[C@H](C2CC2)c2c[nH]nc21
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1C(CO)c2n[nH]cc2[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
((4R)-4-cyclopropyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-yl)methanol (36) (627 mg, 3.50 mmol) and 4-trifluoromethylbenzenesulfonyl chloride (2.57 g, 10.5 mmol) were dissolved in pyridine (5 mL) and the resulting mixture was stirred at rt for 12 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed with 1 N aq. HCl (10 mL). The aq. phase was separated and extracted once with CH2Cl2 (10 mL) and the combined organic phases were then dried (Na2SO4), filtered and concentrated under vacuum. The residue was dissolved in THF (5 mL) and 3 N aq. NaOH (3.5 mL) was added. The resulting mixture was stirred at rt for 18 h and was subsequently extracted with EtOAc. The organic phase was then dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give ((4R)-4-cyclopropyl-5-(4-(trifluoromethyl)phenylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-yl)methanol (37) as a white solid. Retention time (min)=5.573, method [7], MS (m/z) 410.0 (M+Na)+.