Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.Br[C:45]1[C:46]([Cl:54])=[N:47][N:48]([CH2:50][CH2:51][CH2:52][OH:53])[CH:49]=1>>[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28]([C:45]2[C:46]([Cl:54])=[N:47][N:48]([CH2:50][CH2:51][CH2:52][OH:53])[CH:49]=2)=[CH:29][CH:30]=1
Reactant: CNC(=O)c1nc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: OCCCn1cc(Br)c(Cl)n1
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cn(CCCO)nc2Cl)ccc1N
Yield: 51.7 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Compound 48D, 631.2 mg, 2.28 mmol) and 3-(4-bromo-3-chloro-pyrazol-1-yl)-propan-1-ol (Compound 49E, 600 mg, 2.51 mmol) to afford 365 mg of the title compound 52%. 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 4.23 (t, J=6.9 Hz, 2H), 3.56 (t, J=6.1 Hz, 2H), 2.94 (s, 3H), 2.07 (t, J=6.4 Hz, 2H). MS (ESI): m/z=310.20/312.23 [M+H]+. UPLC: tR=min (UPLC-TOF: polar—2 min).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>CN(C)C=O.O>[CH3:15][N:16]([CH3:20])[C:17]([NH:1]/[C:2](/[C:9]([F:10])([F:11])[F:12])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:18]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C(\NC(=O)N(C)C)C(F)(F)F
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
Ethyl 3-amino-4,4,4-trifluorocrotonate (18.4 g, 100 mmol) is added to a stirred solution of sodium hydride (60% in mineral oil, 9.6 g, 250 mmol) in N,N-dimethyl-formamide (60 mL) at 5° C. under nitrogen over a 60 minute period. The reaction mixture is allowed to warm to and held at room temperature for 15 minutes, cooled to 5° C., and treated with dimethylcarbamoylchloride (21.6 g, 200 mmol) over a 60 minute period. The resultant solution is then warmed to and held at room temperature for 2 hours, diluted with water (150 mL), and extracted with ethyl acetate (2×150 mL). The combined organic layers are dried, filtered and concentrated, and the mineral oil layer is removed to obtain a residue. Flash column chromatography of the residue on silica gel using a 85:15 hexanes/ethyl acetate solution gives the title product as a yellow liquid (18.1 g, 71% yield): 1H NMR (DMSO-d6) δ9.18 (s,1H), 5.85 (s, 1H), 4.20 (q, 2H), 2.89 (s, 6H), 1.18 (t, 3H); 19F NMR δ−65.7 (s).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: ClCCCCCCOC(c1ccccc1)c1ccccc1
Product: c1ccc(C(OCCCCCCN2CCNCC2)c2ccccc2)cc1
Yield: 94 %

Procedure:
Using 6-(dipenylmethoxy)hexyl chloride and piperazine, the procedure of Reference Example 16 was otherwise repeated to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CC1(C)OB(c2cc(F)ccc2OCC2CC2)OC1(C)C
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-5-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c4) the title compound is obtained as off-white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][CH:14]([NH:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][OH:16])[C:8]=2[CH:37]=1.[CH3:38]I>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][CH:14]([NH:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:15][O:16][CH3:38])[C:8]=2[CH:37]=1
Reactant: OCC(COc1noc2ccc(Cl)cc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(COc1noc2ccc(Cl)cc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a suspension of 0.44 g of 60% (w/w) sodium hydride in 49 ml of tetrahydrofuran is added 4.85 g of 5-chloro-3-(2-tritylamino-3-hydroxypropoxy)-1,2-benzoisoxazole at 20°-25° C. and they are refluxed for one hour. The reaction mixture is cooled to 5°-10° C., and thereafter, 1.56 g of methyl iodide is added, after which they are subjected to reaction at 20°-25° C. for five hours. The solvent is removed from the reaction mixture by distillation under reduced pressure, ethyl acetate and water are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is crystallized from n-hexane and the crystals are collected by filtration, to obtain 5-chloro-3-(3-methoxy-2-tritylaminopropoxy)-1,2-benzoisoxazole.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1.BrC[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[CH2:25](OCC)C>CN(C)C=O.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:14]([CH3:25])[C:13](=[O:15])[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)=NN1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1C(=O)N(C(=O)OC(C)(C)C)N=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of 0.44 g (11 mmol) of 60% oily sodium hydride in 10 ml of anhydrous dimethylformamide was added dropwise a solution of 2.2 g (10 mmol) of 3-(4-chlorophenyl)-4, 5-dihydropyrazol-5-one in dimethyl-formamide (5 ml) at 0° C. After 30 minutes of stirring at room temperature, 2.1 g (11 mmol) of t-butyl bromoacetate was added dropwise, and stirring was continued for another 2 hours. To the reaction solution was added 50 ml of diethyl ether and 50 ml of water, and vigorously agitated. The resultant solution was separated, and the aqueous layer was extracted twice with 50 ml of diethyl ether. The organic layer was combined and washed successively with water and saturated brine solution, and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1 (v/v)) to give 3.2 g of the object compound as a colorless oil (yield 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:25](CC)CC)C.ClC(OCC)=O.N[C@H:37]1[C@H:40]([O:41][C:42](=[O:44])[CH3:43])[NH:39][C:38]1=[O:45]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]1[C:20]([C@@H:37]1[C@H:40]([O:41][C:42](=[O:44])[CH3:43])[N:39]([NH2:25])[C:38]1=[O:45])=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1Cc2ccccc2N1C(=O)OCc1ccccc1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1N
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1[C@@H](C(=O)C2Cc3ccccc3N2C(=O)OCc2ccccc2)C(=O)N1N
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 1-benzyloxycarbonyl-2-indoline carboxylic acid (320 mg, 1.05 mmol) and triethylamine (106 mg, 1.05 mmol) in chloroform (20 ml), ethyl chloroformate (109 mg, 1 mmol) was added at -15° C. The reaction mixture was stirred at a bath temperature of -10 to 5° C. for 1 hr. Then a precooled solution of (3S,4S)-3-amino-4-acetoxy-azetidin-2-one in ethyl acetate was added at -15° C. and stirring was continued at a bath temperature of -15 to 5° C. for 1 hr. After removal of solvent, the residue was dissolved in ethyl acetate, washed with water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:3) as eluent and the title compound was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:33][C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:32]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 6-phenylpicolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 403.00 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)(O)[C:4]=2[CH:3]=1.S(C1C=CC=CC=1[C:30]([O:32]C(=O)C1C=CC=CC=1S(O)(=O)=O)=[O:31])(O)(=O)=O.[C:49]([OH:53])(=[O:52])[CH2:50][CH3:51].[OH-].[Na+]>O>[C:30]([OH:32])(=[O:31])/[CH:51]=[CH:50]\[C:49]([OH:53])=[O:52].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:4]=2[CH:3]=1
Reactant: CCC(=O)O
Reactant: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Reactant: CN1CCC(C2(O)c3ccccc3Oc3ccc(Cl)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1
Product: O=C(O)/C=C\C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 12.5 g. (0.038 m.) of the xanthene-9-ol, 14.0 g. (0.76 m.) of o-sulfobenzoic anhydride and 380 ml. of propionic acid is refluxed for three hours. The reaction mixture is heated in vacuo at 100° C. and the resulting syrup is dissolved in water, made strongly basic with 40% sodium hydroxide solution, extracted with ether, and the dried extract is evaporated. The residual free base is dissolved in ethyl acetate and maleic acid (4.4 g.) is added to yield 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine maleate, m.p. 206°-207° C.
Reaction SMILES: [Na+].[I-:2].[N:3]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12]Cl)=[O:10])[CH2:5][CH2:4]1>C(#N)C>[N:3]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][I:2])=[O:10])[CH2:5][CH2:4]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCCl)CC1
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCI)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of NaI (1.6 g, 11.09 mmol) in dry acetonitrile (8 mL) was added dropwise 1-tert-butyl 4-chloromethyl piperidine-1,4-dicarboxylate (2.8 g, 10.08 mmol) in 2 mL of acetonitrile. The mixture turned dark orange and was stirred at rt in the dark for 24 h. The reaction mixture was filtered to remove NaCl and the filtrate was concentrated in vacuo. The remaining residue was partitioned between DCM and 5% aq NaHSO3 solution. The organic layer was washed with water and brine, dried (Na2SO4), and concentrated in vacuo to give 1-tert-butyl 4-iodomethyl piperidine-1,4-dicarboxylate as a pale yellow oil (3.5 g, 94%). Attempts to characterize by NMR in DMSO-d6 resulted in rapid decomposition. The material was stored in the dark at −20° C. to minimize decomposition before further use. LCMS: MH=370.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].CSC.B.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-Chloro-2,4-difluorobenzoic acid (5.37 g, 27.9 mmol) was dissolved in THF (20 mL) and the solution was cooled to 0 deg. Borane methylsulfide (2.0 M in THF, 55.8 ml, 112 mmol) was added. The resulting solution was warmed to rt and stirred for 14 h. The solution was cooled in an ice bath, and 10% aqueous Na2CO3 (7 mL) was added slowly. The material was concentrated on the rotovap to a white solid. The residue was acidified with 3M aqueous HCl (30 mL), diluted with dichloromethane (50 mL), and the mixture was filtered through Celite. The layers were separated, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified through silica gel (500 mL) using 30% EtOAc-hexane, to afford the title compound.
Reaction SMILES: [CH:1]1([N:5]2[C:10]([NH2:11])=[C:9]([NH2:12])[C:8](=[O:13])[NH:7][C:6]2=[O:14])[CH2:4][CH2:3][CH2:2]1.[C:15](O)(=O)[CH3:16]>>[CH:1]1([N:5]2[C:10]3[N:11]=[C:15]([CH3:16])[NH:12][C:9]=3[C:8](=[O:13])[NH:7][C:6]2=[O:14])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)O
Reactant: Nc1c(N)n(C2CCC2)c(=O)[nH]c1=O
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C1CCC1

Procedure:
A solution of 2.2 g of 1-cyclobutyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (X) in 10 ml of acetic acid was refluxed for 2 hours. The solution was evaporated. The received oil was refluxed in 30 ml of 5N NaOH for 1 hour and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 100 ml ethanol.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[OH:22].[Li+].[OH-]>CO>[F:12][C:11]1[C:2]([O:22][C:15]2[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].[CH3:21][O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=1[O:22][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(F)c1O
Reactant: COC(=O)c1cccc(F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cccc(F)c1Oc1c(F)cccc1OC
Product: COc1cccc(F)c1Oc1c(F)cccc1C(=O)O
Yield: 60 %
Yield: 90 %

Procedure:
Methyl 3-fluoro-2-(2-fluoro-6-methoxyphenoxy)benzoate (0.88 g, 60%) was prepared from methyl 2,3-difluorobenzoate (0.86 g, 5 mmol) and 2-fluoro-6-methoxyphenol (0.78 g, 5.5 mmol) as described in procedure A. Hydrolysis of this ester with LiOH in aqueous methanol furnished 2-(2-methoxy-6-fluorophenoxy)-3-fluorobenzoic acid (0.86 g, 90%). To a solution of 3-fluoro-2-(2-fluoro-6-methoxyphenoxy)benzoic acid (0.56 g, 2.0 mmol) in 1,2-dichloroethane (10 ml) was added oxalyl chloride (0.18 ml, 2.2 mmol). The solution was stirred at room temperature for 45 min. To this solution was added NaN3 (390 mg, 6 mmol) and the mixture was heated to reflux for 3 h. 2-Aminothiazole (200 mg, 2 mmol) was then added to this mixture and was further refluxed for 3 h. The mixture was concentrated and the residue was purified by column chromatography (silica, CH2Cl2 then 10% ethyl acetate in CH2Cl2) to afford 1-[3-fluoro-2-(2-fluoro-6-methoxyphenoxy)phenyl]-3-(thiazol-2-yl)urea in (414 mg, 55%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)([O-])=O.[H][H]>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccccc1CCNC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1ccccc1CCNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
N-(2-Nitrophenethyl)-1-benzylpiperidin-4-amine (1.98 g, 5.83 mmol) was dissolved in methanol (60 mL). Platinum(IV) oxide (55 mg, 0.242 mmol) was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 75 minutes. Mixture was removed from the apparatus and then filtered over celite. Filtrate was concentrated to dryness. Title compound was obtained as brown oil in quantitative yield. MS (M+H)+=310.4.
Reaction SMILES: NC1C=CC=CC=1[S:8][C@@H:9]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:10]([OH:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[OH:20][C@H:10]1[C:11](=[O:12])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:8][C@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1
Reactant: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(=O)Nc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
(2S,3S)-3-(2-Aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)-N-phenylpropionamide (582 mg) is mixed with chlorobenzene (10 ml), and the mixture is refluxed for 25 hours during which thereto is added p-toluenesulfonic acid monohydrate (112 mg) in 8 portions (14 mg×8) at intervals of three hours. The reaction mixture is cooled to room temperature, and concentrated under reduced pressure to remove the chlorobenzene. To the residue is added methanol (5 ml), and the mixture is refluxed for one hour. The mixture is allowed to cool to room temperature, and stirred to crystallization, and then cooled with ice. The precipitated crystals are collected by filtration, washed with chilled methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (243 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:7][CH:6]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1sc2ncnc(N)c2c1-c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
A 0° C. solution of Example 1E (80 mg, 0.31 mmol) in dichloromethane (4 mL) was treated with pyridine (0.03 mL, 0.38 mmol) and benzoyl chloride (0.038 mL, 0.32 mmol), stirred at 0° C. for 1 hour, then at room temperature overnight. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate to provide 39 mg (35%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H); 8.28 (s, 1H); 7.98 (d, J=8.1 Hz, 4H); 7.63-7.54 (m, 3H); 7.40 (d, J=8.1 Hz, 2H); 2.31 (s, 3H); HRMS(ESI) Calcd. for C20H17N4OS: 361.1118. Found: 36.1122.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[O:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21][CH:22]([N:24]([CH3:31])[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH3:23])=[CH:20][C:14]=2[O:13]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:10][CH2:11][CH:12]1[O:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21][CH:22]([N:24]([CH3:31])[C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])[CH3:23])=[CH:20][C:14]=2[O:13]1
Reactant: CC(Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2)N(C)C(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccc2c(c1)OC(CN)O2)N(C)C(=O)C(F)(F)F
Reaction time: 4 h
Yield: 87.9 %

Procedure:
To a solution of 150 mg (0.33 mmol) of 1I in 10 ml of methanol was added 24 mg of 10% Pd—C, and the mixture was hydrogenated for 4 hours at room temperature under atmospheric pressure using a hydrogen filled balloon. The reaction mixture was filtered through CELITE and the residue was washed with 20 mL of methanol. The filtrates were combined and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash column chromatography using 10% methanol in ethyl acetate to give 95 mg (0.29 mmol, 86%) of 1J as a colorless oil (M+H, 319).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=3)=[CH:10][N:9]([CH:19]([CH3:21])[CH3:20])[N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].C1C[O:36][CH2:35][CH2:34]1>>[C:29]([N:18]([C:14]1[CH:13]=[C:12]([C:11]2[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:8][N:9]([CH:19]([CH3:21])[CH3:20])[CH:10]=2)[CH:17]=[CH:16][N:15]=1)[C:35](=[O:36])[CH3:34])(=[O:31])[CH3:30]
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Reactant: CC(C)n1cc(-c2ccnc(N)c2)c(-c2ccc(Cl)s2)n1
Solvent: CCN(CC)CC
Product: CC(=O)N(C(C)=O)c1cc(-c2cn(C(C)C)nc2-c2ccc(Cl)s2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]pyridin-2-amine (1 eq, 0.31 mmol) and triethylamine (4 eq, 1.3 mmol) in 3 mL THF was added acetyl chloride (2.1 eq, 0.66 mmol). The mixture was then stirred at room temperature for 30 min. Acetyl chloride (1 eq, 0.31 mmol) and triethylamine (2 eq, 0.62 mmol) were then added and the mixture was stirred for 1 h. The solvent was evaporated and the residue was purified by chromatography on silica gel (heptane:ethyl acetate 5:1 to 1:2) to afford 114 mg of N-acetyl-N-{4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]pyridin-2-yl}acetamide (81% yield).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:15]1([C@H:14]2[CH2:13][N:12]([C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])[CH2:11][C@@H:10]2[CH2:9][OH:8])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(C(=O)C(F)(F)F)C[C@@H]1c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(N1C[C@H](CO)[C@@H](c2ccccc2)C1)C(F)(F)F
Temperature: 25 °C

Procedure:
A 11.9 g portion of (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenyl-1-(trifluoroacetyl)pyrrolidine was dissolved in 30 ml of THF, and a THF solution of TBAF (1.0 M, 37 ml) was added thereto at room temperature and stirred for 2Hours. The reaction solution was concentrated under a reduced pressure, and the residue was mixed with water, extracted with diethyl ether and washed with water and saturated brine in that order. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 6.28 g of [(3R,4S)-4-phenyl-1-(trifluoroacetyl)pyrrolidin-3-yl]methanol as a yellow amorphous substance. FP: 274.