Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>CO.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:24])=[O:26])=[CH:21][CH:22]=3)=[N:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C2=NN(S(=O)(=O)c3ccc(I)cc3)CCC2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(C2=NN(S(=O)(=O)c3ccc(I)cc3)CCC2)cc1

Procedure:
A solution of 1-(4Iodobenzenesulfonyl)-3-(4-methylthiophenyl)-1,4,5,6-tetrahydropyridazine (1.27 g, 2.69 mmol) in methanol (450 mL) was added to a solution of sodium periodate (0.61 g, 2.82 mmol) in water (6 mL) and stirred at a low heat for 16 hours. The resulting mixture was filtered, concentrated arylphosphonyl dihalide and purified by column chromatography on silica gel using ether/methylene chloride as an eluent to give the title compound as a solid: mp 191°-193° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc2nc[nH]c2c1
Yield: 98 %

Procedure:
To a stirred solution of 5-nitrobenzimidazole (1 g, 6.13 mmol, 1 eq) in THF (100 mL) was added 10% palladium on carbon (385 mg). The flask was purged with H2 and the mixture was stirred under a balloon of H2 for several hours. The flask was purged with N2. The catalyst was filtered and washed with MeOH. The solution was concentrated under reduced pressure giving 800 mg of the desired product.
Reaction SMILES: [CH2:1]([CH:8]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:17].BrBr>O>[Br:17][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14]
Reactant: Br
Reactant: O=C1NC(=O)C(Cc2ccccc2)C(=O)N1
Agent: BrBr
Solvent: O
Product: O=C1NC(=O)C(Br)(Cc2ccccc2)C(=O)N1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-benzylbarbituric acid (1.7 g) in 15 ml of water, cooled to 0-5° C., 1 ml of 48% hydrobromic acid are added followed by the addition dropwise of 0.437 ml of bromine into the reaction mixture. After 1 hour under stirring at a temperature below 10° C. the solid which formed is separated by filtration and washed with water. 2.17 g of the product are obtained. m.p. 164-166° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](F)[CH:25]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>>[NH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:26]1[CH:25]=[C:24]([C:23]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][N:10]3[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:23][CH2:11][NH2:10])[CH:17]=4)=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:29]=[CH:28][N:27]=1
Reactant: Fc1ccc(-c2nn3c(-c4ccnc(F)c4)cccc3c2-c2ccnc(F)c2)cc1
Reactant: NCCCN
Product: NCCCNc1cc(-c2c(-c3ccc(F)cc3)nn3c(-c4ccnc(NCCCN)c4)cccc23)ccn1
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of 2-(4-fluorophenyl)-3,7-bis(2-fluoropyridin-4-yl)pyrazolo[1,5-α]pyridine (34 mg, 0.08 mmol) in 1,3-diaminopropane (1 mL) was heated at 150° C. for 0.25 hours. Upon cooling to room temperature, the mixture was concentrated in vacuo and the residue was triturated with hot ethyl acetate. The resulting solids were collected on filter, washed with ethyl ether and dried to provide N-{4-[3-{2-[(3-aminopropyl)amino]pyridin-4-yl}-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-yl]pyridin-2-yl}propane-1,3-diamine as a light yellow powder (19 mg, 46%). 1H NMR (CD3OD): δ 8.18 (d, 1H), 8.03 (d, 1H), 7.78 (d, 1H), 7.65 (dd, 2H), 7.45 (dd, 1H), 7.30 (s, 1H), 7.1–7.2 (m, 4H), 6.60 (s, 1H), 6.59 (d, 1H), 3.55 (t, 2H), 3.47 (t, 2H), 3.0 (q, 4H), 1.88–2.04 (m, 4H); MS m/z 511 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:11])[C:5]([CH3:10])([CH:7]([CH3:9])[CH3:8])[N:6]=1.CN(C=O)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[Na]>C1COCC1>[C:2]([NH:6][C:5]([CH3:10])([CH:7]([CH3:9])[CH3:8])[C:4]([NH:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:24])=[O:25])=[O:11])(=[O:3])[CH3:1]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC1=NC(C)(C(C)C)C(=O)O1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2,4-Dimethyl-4-isopropyl-2-oxazolin-5-one (2.0 g) is mixed with DMF (50 mL), THF (70 mL) and sodium p-toluene sulfonamide (5.0 g), and the resulting mixture is heated at reflux for 16 hours. At the end of this time the mixture is cooled, and the solvents are removed under vacuum. The residue is mixed with water and the pH adjusted to 8 with NaHCO3. The aqueous mixture is extracted with ethyl acetate and the organic layers are discarded. The aqueous mixture is acidified to pH~4 with HCl and saturated with NaCl and extracted with ethyl acetate. The organic extracts are combined, dried over MgSO4, filtered and evaporated to give 0.66 of the title product.
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])(O)O.Cl[C:16]1[C:17](=[O:35])[N:18]([CH2:33][CH3:34])[C:19]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:23]=[CH:22][C:20]=2[N:21]=1.CCOC(C)=O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[C:19]2[N:18]([CH2:33][CH3:34])[C:17](=[O:35])[C:16]([C:4]3[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=3[CH3:13])[C:7]([OH:9])=[O:8])=[N:21][C:20]=2[CH:22]=[N:23]1
Reactant: CCn1c(=O)c(Cl)nc2cnn(-c3ccc(F)cc3F)c21
Reactant: Cc1c(F)cc(C(=O)O)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(-c2cc(C(=O)O)cc(F)c2C)nc2cnn(-c3ccc(F)cc3F)c21
Temperature: 130 °C

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 μmol), 3-borono-5-fluoro-4-methylbenzoic acid (175 mg, 0.88 mmol) and 5-chloro-1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (250 mg, 0.80 mmol) in 4.0 mL dioxane and 2.0 mL of 1 N sodium carbonate was heated in a microwave at 130° C. for 30 min. The reaction mixture was treated with EtOAc (15 mL) and extracted with 1N NaOH (3×10 mL). The aqueous extracts were treated with 5 N HCl to pH 2 and extracted with DCM (3×15 mL). The combined DCM layers were dried over MgSO4, filtered and concentrated affording 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoic acid as a light orange-brown viscous oil. This material was used without purification. MS (ES+): 429.1 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[C:2]=[S:3].[NH2:14][CH2:15][CH2:16][OH:17]>C1COCC1>[OH:17][CH2:16][CH2:15][NH:14][C:2]([NH:1][CH:4]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[S:3]
Reactant: Cc1cccc2c1CCC2N=C=S
Reactant: NCCO
Solvent: C1CCOC1
Product: Cc1cccc2c1CCC2NC(=S)NCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
680 mg (3.59 mmol) 1-isothiocyanato-4-methyl-indane is dissolved in 13 ml THF at room temperature under argon. Then 0.21 ml (3.59 mmol) 2-amino-ethanol is added slowly. The reaction mixture is stirred at room temperature overnight. After completion of the reaction as indicated by TLC the solvent is removed under reduced pressure to give the crude product. Subsequent purification by column chromatography on silica gel (CH2Cl2/MeOH 15:1) and stirring in Et2O affords the title compound 1-(2-hydroxy-ethyl)-3-(4-methyl-indan-1-yl)-thiourea as a white powder (Mp 90-93° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[O:10][N:9]=2)[CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:16]1[CH2:15][CH2:14][CH:13]([C:11]2[O:10][N:9]=[C:8]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:12]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Cc3cccnc3)no2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(Cc2noc(C3CCNCC3)n2)c1

Procedure:
tert-Butyl 4-[3-(pyridin-3-ylmethyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate was treated with 10 mL TFA/DCM (1:1) for 30 min at ambient temperature. The reaction mixture was concentrated to give the di-TFA salt of 3-[(5-piperidin-4-yl-1,2,4-oxadiazol-3-yl)methyl]pyridine as an amber oil (4.0 g, 8.47 mmol, 85%, 3 steps). 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.70 (d, 1H, J=5.0 Hz), 8.51 (br.s, 1H), 8.18 (d, 1H, J=7.9 Hz), 7.75 (m, 1H), 4.30 (s, 2H), 3.44-3.30 (m, 3H), 3.09-3.00 (m, 2H), 2.20-2.16 (m, 2H), 1.93-1.80 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][C:13]#[N:14]>>[C:1]([NH:14][CH2:13][CH2:12][C:11]#[N:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CCCN
Product: N#CCCNC(=O)c1ccccc1

Procedure:
Benzoyl chloride and aminoethylcyanide are reacted to give N-benzoyl-aminoethylcyanide, which is reacted with hydrogen sulfide in ammonia to yield the thioamide, which is reacted with an appropriate a-halo ketone to yield the desired thiazole. Treatment with 5N hydrochloric acid removes the protecting benzoyl group to give the desired amine product.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]2[C@@H:37]([O:38][CH:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:40][OH:41])[NH:36][C:35]2=[O:48])=[O:32])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:12]1([CH2:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]2[C@@H:37]([O:38][CH:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:40][O:41][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[NH:36][C:35]2=[O:48])=[O:32])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@@H]1OC(CO)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O[C@H]2NC(=O)[C@H]2NC(=O)[C@H](Cc2ccccc2)NC(=O)CCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
p-Toluenesulfonyl chloride (119 mg, 0.62 mmol) was added to an ice-cooled solution of (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-(2-hydroxy-1-phenylethoxy)-azetidin-2-one (260 mg, 0.52 mmol) and pyridine (493 mg, 6.2 mmol) in dichloromethane (7 ml). The mixture was stirred at 0° C. for 2 hrs and then at room temperature overnight. After removal of solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (8:3) as eluent and 160 mg of (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-{2-(p-toluenesulfonyl)oxy-1-phenylethoxy}-azetidin-2-one was obtained (47% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[CH:15]=[C:14]([CH3:22])[N:13]=1.C(O)C>C1COCC1.CCOC(C)=O.CCCCCC>[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([NH:8][C:5]2[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=2)[CH:15]=[C:14]([CH3:22])[N:13]=1
Reactant: Nc1ncc(F)cn1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: Cc1cc(Nc2ncc(F)cn2)c([N+](=O)[O-])c(Cl)n1
Reaction time: 10 h
Yield: 62.6 %

Procedure:
To a mixture of 5-fluoropyrimidin-2-amine (8.2 g, 72.1 mmol) and sodium hydride (5.8 g, 144 mmol) in THF (100 mL) was added 2,4-dichloro-6-methyl-3-nitropyridine (15 g, 72.1 mmol). After stirring for 10 h, ethanol was added. Silica gel chromatography (5:1 Hexane:EtOAc) provided the product as a yellow solid (12.8 g, 63%).
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:8][NH:9]C(=O)OC(C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:8][NH2:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCC(CN1CCCCC1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(CN1CCCCC1)(c1ccccc1)c1ccccc1

Procedure:
The title material was obtained by treating a solution of tert-butyl 2,2-diphenyl-3-(piperidin-1-yl)propylcarbamate (0.109 g) in dichloromethane (5 mL) with trifluoroacetic acid (1 mL) at 23° C. for 45 minutes. The reaction was then concentrated to dryness and the residue was used as such in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:33](=[O:35])[CH3:34])[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.0145 ml acetylchloride (0.2 mmol). After 1.5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 68 mg of an off-white solid (84%). MS (ISP) 493.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:11]=[CH:10][CH:9]=2)=[C:4]([N+:18]([O-])=O)[CH:3]=1.O1CCCC1.C(O)C.[Cl-].[NH4+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:11]=[CH:10][CH:9]=2)=[C:4]([CH:3]=1)[NH2:18]
Reactant: O=[N+]([O-])c1cc(Br)ccc1-c1ccnn1C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(Br)ccc1-c1ccnn1C1CCCC1
Temperature: 70 °C
Yield: 91.3 %

Procedure:
To a mixture of 980 mg of 5-(4-bromo-2-nitrophenyl)-1-cyclopentyl-1H-pyrazole, 9.8 mL of tetrahydrofuran, 19.6 mL of ethanol, and 2.9 mL of water was added 102 mg of ammonium chloride, followed by heating at 70° C. 1.03 g of reduced iron was added thereto, followed by heating to reflux for 4 hours, and cooling to room temperature. The insoluble material was filtered through celite, the filtrate was concentrated, and a mixture of chloroform/water was added thereto. The aqueous layer was separated, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 815 mg of 5-bromo-2-(1-cyclopentyl-1H-pyrazol-5-yl)aniline.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:28]=[CH:27][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:23]([CH3:26])[CH2:24][OH:25])[CH:21]=3)[C:15]([O:17]C)=[O:16])=[C:9]([F:29])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>C1COCC1.O>[N:1]1([C:5]([C:7]2[CH:28]=[CH:27][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:23]([CH3:26])[CH2:24][OH:25])[CH:21]=3)[C:15]([OH:17])=[O:16])=[C:9]([F:29])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(O[C@@H](C)CO)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1

Procedure:
Methyl 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate (100 mg, 0.25 mmol) was dissolved in THF (2.0 mL and water (0.2 mL) and solid lithium hydroxide (21 mg, 0.5 mmol) added. The resultant mixture was stirred at ambient temperature for 16 hours. Water (10 mL) was added and the mixture partially reduced in vacuo and then extracted with ethyl acetate. The aqueous liquors were acidified with 1M hydrochloric acid and re-extracted with ethyl acetate (2×10 mL). The extracts were combined, washed with brine, dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was used without further purification (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4ccccc4C)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4ccccc4C)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(2-methylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[C:14]([CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:15].[Na]>O.C(Cl)(Cl)Cl.CCO>[CH2:21]([O:20][C:18]([C:17]1[CH:16]=[C:14]([NH2:15])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C(=O)CC#N
Reactant: NNc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Temperature: 135 °C
Yield: 79.9 %

Procedure:
Phenyl hydrazine (2.94 ml, 0.03 moles) was dissolved in water (50 ml) in a 500 ml beaker. Concentrated H2SO4 (1.63 ml, 0.03 mole) was added drop-wise using a pipette while cooling with ice water bath. This phenyl hydrazine solution was then added to a stirred solution of sodium ethyl cyanopyruvate (5.37 g, 0.03 mole) in 70 ml of chloroform in a 500 ml round bottom flask at room temperature. Stirring was maintained for about 24 hrs and the reaction was monitored by LCMS. After the completion of reaction, the organic layer was separated and the aqueous layer was extracted with CHCl3 (2×150 ml). The combined organic layer was then washed with saturated NaHCO3 (1×100 ml), dried over sodium sulfate. Removal of solvent provided a viscous oil which was mainly non-cyclized hydrazone. The crude product was dissolved in minimum amount of dry EtOH (15 ml) and the mixture was heated in sealed tube at 120-150° C. for overnight. After the completion of reaction, ethanol was evaporated in vacuo to give crude product, which was purified by column chromatography eluting with Hexanes/Ethyl Acetate=9/1 to 1/1 to give 5.54 g of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH:25]([CH3:28])[CH:26]=[O:27].O>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH:25]([CH3:28])[CH:26]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[OH:27]
Reactant: Clc1cc(I)ccn1
Reactant: COc1ccc(Cl)c(C(C)C=O)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(C)C(O)c2ccnc(Cl)c2)c1
Reaction time: 1.5 h

Procedure:
2-Chloro-4-iodopyridine (1.03 g, CAS Reg. No. 153034-86-7) was dissolved in THF (50 mL) and a solution of isopropylmagnesiumchloride-lithium chloride complex (14% in THF, 3.13 mL) was added at RT over 3 minutes. The mixture was cooled in an ice bath and 2-(2-chloro-5-methoxy-phenyl)-propionaldehyde (710 mg) dissolved in THF (20 mL) was added drop wise over a period of 10 minutes. Stirring was continued for 1.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the desired compound as a yellow oil (734 mg). MS (m/e)=312.0 (MH+).
Reaction SMILES: OC(O)=O.[C:5]([OH:10])(=[O:9])[CH:6]([CH3:8])[OH:7].[OH-].[Ca+2:12].[OH-]>>[C:5]([O-:10])(=[O:9])[CH:6]([CH3:8])[OH:7].[Ca+2:12].[C:5]([O-:10])(=[O:9])[CH:6]([CH3:8])[OH:7]
Reactant: CC(O)C(=O)O
Agent: O=C(O)O
Agent: [Ca+2]
Agent: [OH-]
Product: CC(O)C(=O)[O-]

Procedure:
When the hydroxycarboxylic acid of the invention is lactic acid, an aqueous solution or suspension of calcium hydroxide is used as an alkaline solution. Isolation of calcium lactate from the aqueous solution obtained by decomposition can be efficiently carried out by using calcium hydroxide. For example, a polymer is added to an aqueous suspension of calcium hydroxide and completely decomposed with stirring at 50~100° C. Unreacted calcium hydroxide is removed from the reaction mixture by such means as filtration. The filtrate is cooled and precipitated calcium lactate is filtered. Calcium lactate thus obtained is dissolved again in water and an equivalent amount of sulfuric acid to calcium is added to the aqueous solution. Precipitated calcium sulfate is filtered off and an aqueous lactic acid solution almost free from calcium can be thus obtained.