Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[F:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].Cl>ClCCCl>[F:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([C:12]1[CH:11]=[CH:10][C:9]([O:13][CH3:14])=[CH:8][C:7]=1[OH:6])=[O:19]
Reactant: COc1cccc(OC)c1
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2F)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
Aluminum chloride (2.03 g, 15.2 mmol) was added in portions to a solution of 1,3-dimethoxybenzene (1.86 mL, 15.2 mmol) and 2,4-difluorobenzoyl chloride (1.86 mL, 15.2 mmol) in 1,2-dichloroethane at 0° C. The mixture was allowed to warm to rt over 3 h then heated at reflux for 6 h. The resultant mixture was allowed to cool to rt, then poured into a mixture of ice (˜100 g) and concentrated hydrochloric acid (˜20 mL). The organic layer was separated. The aqueous solution was stirred at ambient temperature overnight, and extracted with dichloromethane. The organic layers were washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvents were evaporated in vacuo to give crude product. A portion of the product was purified by flash chromatography on silica gel, using a gradient of 1%-10% EtOAc/heptane as the eluent to give the title compound 3i (1.8 g). MS: m/z 264.9 (MH+). 1H NMR (CDCl3): δ 3.90 (s, 3H), 6.42 (d of d, 1 H, J=9.0 and 2.5 Hz), 6.50 (d, 1 H, J=2.5 Hz), 6.91-7.04 (m, 2 H), 7.27-7.29 (m, 1 H), 7.44-7.50 (m, 1 H) and 12.44 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[NH:5]C(=O)N(NC2C=CC=CC=2C)C=1CC)#[N:2].[C:21]([O:30][CH2:31][CH3:32])(OCC)(OCC)[CH2:22][CH3:23].[C:33]([O:41]CC)([O:38][CH2:39][CH3:40])(OCC)C>>[C:1]([C:3](=[C:21]([O:30][CH2:31][CH3:32])[CH2:22][CH3:23])[C:4]([NH:5][C:33]([O:38][CH2:39][CH3:40])=[O:41])=[O:20])#[N:2]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCOC(CC)(OCC)OCC
Reactant: CCc1c(C#N)c(=O)[nH]c(=O)n1Nc1ccccc1C
Product: CCOC(=O)NC(=O)C(C#N)=C(CC)OCC

Procedure:
In the same manner, 5-cyano-6-ethyl-1-(2-methylanilino)-2,4-pyrimidinedione is made by using triethyl orthopropionate rather than triethyl orthoacetate to give α-cyano-β-ethoxy-β-ethyl-N-ethoxycarbonylacrylamide, which is reacted with 2-methylphenylhydrazine, followed by cyclization.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]1([N:4]([CH3:17])[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a mixture of N-cyclopropyl-2-nitrobenzenesulfonamide (5.63 g), potassium carbonate (4.82 g) and N,N-dimethylformamide (60 mL), methyl iodide (2.17 mL) was added and stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:diethyl ether=1:0-1:1) to give N-cyclopropyl-N-methyl-2-nitrobenzenesulfonamide (5.35 g) as a brown solid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[C:12](OC)(=[O:17])[C:13]([O:15]C)=[O:14].C[O-].[Na+]>CO>[OH:17]/[C:12](=[C:3]1/[CH2:2][O:1][C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]/1=[O:11])/[C:13]([OH:15])=[O:14]
Reactant: O=C1CCOc2ccccc21
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)/C(O)=C1\COc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of 4-chromanone (6.1097 g, 40.0 mmol) and dimethyl oxalate (5.759 g, 48.28 mmol) in methanol (50 ml), a solution of 0.5M sodium methoxide (96.9 ml, 48.28 mmol) was added dropwise at RT under N2 over 20 min. The colorless solution turned to yellow. The solution was stirred at RT under N2 overnight. After 16 h, the reaction solution was removed under reduced pressure. The residue was diluted with EA, washed with H2O and brine, dried over MgSO4. After filtration, the solvent was removed under reduced pressure to yield crude product methyl ester of (2Z)-hydroxy(4-oxo-2H-1-benzopyran-3(4H)-ylidene)ethanoic acid (8.9096 g, 95.2%) after dried under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=2[Cl:27])[CH:6]=1.[S:29]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:37])[CH:35]=O)=[CH:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[C:18]=2[Cl:27])[CH2:35][CH:34]([C:31]2[CH:32]=[CH:33][S:29][CH:30]=2)[CH3:37])[CH:6]=1
Reactant: CC(C=O)c1ccsc1
Reactant: COC(=O)Cc1cccc(OCCCNCc2cccc(C(F)(F)F)c2Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccsc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To a solution of {3-[3-(2-chloro-3-trifluoromethyl-benzylamino)-propoxy]-phenyl}-acetic acid methyl ester (70 mg, 0.17 mmol) in dry dichloromethane (20 ml) was added acetic acid (2 drops) followed by 2-thiophen-3-yl-propionaldehyde (26 mg, 0.19 mmol) and sodium triacetoxyborohydride (72 mg, 0.34 mmol). After the resulting mixture was stirred at room temperature overnight, water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over sodium sulfate and concentrated in vacco. The crude mixture was purified by HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 60 to 100% during 10 min, UV detection at 254 nm) to give 50 mg (32% yield) of the title compound as an oil MS m/e 541.4 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:2].[CH2:15](OC(OCC)(OCC)C)[CH3:16]>C(O)C>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][C:7]2[N:8]3[C:15]([CH3:16])=[N:2][N:1]=[C:3]3[N:4]=[N:5][C:6]=2[CH:12]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc2nc(NN)nnc2c1
Solvent: CCO
Product: COc1ccc2c(c1)nnc1nnc(C)n12
Temperature: 145 °C
Yield: 88.7 %

Procedure:
A mixture of 3-hydrazino-7-methoxy-1,2,4-benzotriazine (0.5 g, 2.62 mmol) and 1,1,1-triethoxyethane (4.24 g, 26.15 mmol) was heated at 145° C. for 3 h, and the ethanol formed during the reaction was distilled off continuously. After cooling in a refrigerator for 12 h, the solid filtered off and washed with ether to give 7-methoxy-1-methyl[1,2,4]triazolo[3,4-c][1,2,4]benzotriazine (Compound Number 1, 0.5 g, 88% yield), 1H-NMR (300 MHz; CDCl3): 8.14 ppm (d, 1H, H-9); 8.14 ppm (d, 1H, H-9); 7.62 ppm (dd, 1H, H-8); 4.05 ppm (s, 3H, OMe); 3.19 ppm (s, 1H, CH3) (Compound no. 1 in table 1).
Reaction SMILES: CC(C)([O-])C.[K+].OC(C)(C)[CH:9]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])C)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>C1COCC1.C(Cl)Cl>[CH3:22][C:19]1([CH3:21])[O:18][C:17](=[O:23])[NH:16][CH:9]1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC(c1cccnc1)C(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)OC(=O)NC1c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.9 %

Procedure:
Potassium tert-butoxide (0.093 g, 0.826 mmol) was added to a 0° C. solution of tert-butyl (2-hydroxy-2-methyl-1-(pyridin-3-yl)propyl)carbamate (0.200 g, 0.751 mmol) in THF (5.0 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to afford a yellow oil. The residual yellow oil was dissolved in DCM and passed through a Silycycle SCX column washing with MeOH and then with 7 N ammonia in MeOH. The ammonia solution was concentrated to afford 5,5-dimethyl-4-(pyridin-3-yl)oxazolidin-2-one (0.150 g, 0.780 mmol, 100% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (s, 3H), 1.53 (s, 3H), 4.74 (s, 1H), 7.44 (ddd, J=7.90, 4.77, 0.64 Hz, 1H), 7.64-7.78 (m, 1H), 8.08 (s, 1H), 8.51 (d, J=2.35 Hz, 1H), 8.55 (dd, J=4.79, 1.66 Hz, 1H). m/z (ESI) 193 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][CH3:14])=[N:9][NH:10]2)=[CH:6][CH:5]=1.[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.O>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][CH3:14])=[N:9][N:10]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1
Reactant: CCc1n[nH]c2cc(Br)ccc12
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(C2CCCC2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.8 %

Procedure:
2.46 g (61.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, was added in 0.5 g portions to a 10° C. solution of 13.17 g (58.5 mmol, 1.0 equiv) 6-bromo-3-ethyl-1H-indazole in 500 mL anhydrous DMF. The mixture was stirred at room temperature for 20 minutes, then a solution of 8.8 mL (81.9 mmol, 1.4 equiv) cyclopentyl bromide in 10 mL anhydrous DMF was added dropwise. After 18 hours, the reaction mixture was poured into 2 L H2O and extracted 2×1 L ethyl acetate. The organic extracts were combined, washed 2×750 mL H2O, 1×500 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 20.7 g of crude product, which was purified on a silica gel column (1.1 kg silica gel, 3% ethyl acetate/hexanes) to give 10.6 g (62%) of an amber liquid: IR (CHCl3)2972, 2875, 1606, 1501, 1048 cm−1 ; 1H NMR (300 MHz, CDCl3) d 7.56 (d, 1H, J=1.3 Hz), 7.52 (d, 1H, J=8.7 Hz), 7.17 (dd, 1H, J=1.5, 8.5 Hz), 4.83 (quintet, 1H, J=7.6 Hz), 2.96 (q, 2H, J=7.6 Hz), 2.15 (m, 4H), 2.0 (m, 2H), 1.65 (m, 2H), 1.36 (t, 3H, J=7.7 Hz); MS (thermospray, NH4OAc) m/z 295/293 (M+H+, base); Anal. calcd for C14H17N2Br: C, 57:35; H, 5.84; N, 9.55. Found: C, 57.48; H, 5.83; N, 9.90.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[C:11]([F:29])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:30]([N:32]([CH2:35]C)[CH2:33]C)C.ClC(OC1C=CC=CC=1)=[O:39].C(OCC)C>O1CCCC1.C(O)C>[CH3:30][N:32]([CH3:35])[C:33](=[O:39])[NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[C:11]([F:29])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C(=O)Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of N-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)malonamide (35 mg) in tetrahydrofuran (2.8 ml) was added triethylamine (0.0245 ml), and then phenyl chloroformate (0.0221 ml) was added dropwise thereto while cooling in an ice water bath, followed by stirring for 30 min. The reaction mixture was concentrated under a reduced pressure. To a suspension of the residue in N,N-dimethylformamide (1.4 ml) was added dimethylamine (0.175 ml, 2.0 M solution in tetrahydrofuran), followed by stirring at room temperature for 5 hrs. Diethylamine hydrochloride (35.8 mg) and triethylamine (0.2 ml) were added further, followed by stirring at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a 1 N aqueous solution of sodium hydroxide (30 ml). The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then subjected to silica gel filtration (FUJI Silysia NH). The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated to give a solid, which was then suspended in ethanol (0.5 ml)-diethyl ether (2.5 ml), filtered off, and dried under aeration to provide the titled compound (12.4 mg, 30%) as pale brown powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([CH:16](O)[C:17]([CH3:19])=[CH2:18])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](OCC)([O:25][CH2:26][CH3:27])[O:22]CC.[C:31](O)(=O)CC>>[CH2:1]([O:8][C:9]([C:11]1[O:12][C:13](/[CH:16]=[C:17](\[CH3:19])/[CH2:18][CH2:31][C:21]([O:25][CH2:26][CH3:27])=[O:22])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)O
Reactant: CCOC(OCC)OCC
Reactant: C=C(C)C(O)c1ccc(C(=O)OCc2ccccc2)o1
Product: CCOC(=O)CC/C(C)=C/c1ccc(C(=O)OCc2ccccc2)o1
Temperature: 138 °C
Reaction time: 8 h
Yield: 161.1 %

Procedure:
To the compound (332 mg, 1.23 mmol) obtained in step 1 were added triethyl orthoformate (5.0 mL, 27 mmol) and propionic acid (0.020 mL, 0.27 mmol), and the mixture was stirred at 138° C. overnight. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate=90/10) to give the title compound (149 mg, 0.435 mmol, 35%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:34]([CH3:35])=[N:33][N:32]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:21]=2)=O)[C@H:10]([CH2:42][C:43]([F:46])([F:45])[F:44])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[N:19]=[C:18]3[N:32]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:33]=[C:34]([CH3:35])[C:17]=23)[C@H:10]([CH2:42][C:43]([F:44])([F:45])[F:46])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1ccc(-c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)C[C@H]3CC(F)(F)F)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COCOc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CC(F)(F)F)c3c(C)nn(C4CCCCO4)c3n2)cc1
Yield: 84.4 %

Procedure:
To a solution of 557 mg of (R)-4-[6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-3-(2,2,2-trifluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester in 8 ml of dry THF 6.9 ml of borane-dimethylsulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 3.5 h. The reaction was quenched by the addition of methanol, and the solvents were evaporated. The residue was purified by flash chromatography (silica, heptanes/ethyl acetate) yielding 460 mg (84%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:10]=O.[CH3:12][N:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>C(O)C.CCOCC>[CH3:12][N:13]1[CH2:19][C:17](=[O:18])[N:16]([CH2:10][NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:14]1=[O:15]
Reactant: C=O
Reactant: CN1CC(=O)NC1=O
Reactant: COc1ccccc1N
Solvent: CCOCC
Solvent: CCO
Product: COc1ccccc1NCN1C(=O)CN(C)C1=O
Yield: 48.2 %

Procedure:
A mixture of 12.3 g of o-anisidine, 3.3 g of paraformaldehyde, and 11.4 g of 1-methylhydantoin in 100 ml of absolute ethanol was refluxed for 8 hrs under nitrogen atmosphere. At the end of this time, the solution was cooled on a dry ice-acetone bath and the solvent was decanted to leave a viscous oil. The oil was dissolved in 800 ml of ether and the etheral solution was allowed to evaporate slowly at room temperature. The resulting precipitate was filtered to give 12 g of 1-methyl-3-(2-methoxyphenylaminomethyl)hydantoin, mp 93°-96.5° C, identified by IR and NMR.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH2:10][C:11]([OH:13])=O.Cl.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:11](=[O:13])[CH2:10][CH2:9][O:8][CH3:7])=[CH:34][CH:33]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COCCC(=O)O
Reactant: Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCC(=O)Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.41 ml) was added to a stirred solution of 3-methoxypropanoic acid (0.45 ml) in methylene chloride (15 ml) containing 1 drop of N,N-dimethylformamide. The mixture was stirred at ambient temperature for 3 hours. A 5 ml aliquot of this reaction mixture was added dropwise to a solution of 4-[3-(2-benzyloxyphenyl)-propyl]-benzeneamine hydrochloride (0.63 g) in dichloromethane (20 ml) containing triethylamine (0.82 ml). Stirring was containued for 16 hours. The reaction mixture was evaporated to dryness and the residue was partitioned between diethyl ether and water. The diethyl ether extract was washed consecutively with aqueous 2N HCl (20 ml), saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml) then dried (MgSO4). The residue obtained on removal of the solvent was subjected to flash chromatography on silica (Merck 9385) eluted with ether, to give, after crystallisation from diethyl ether-hexane mixture, 4-[3-(2-benzyloxyphenyl)propyl]-N-(3-methoxypropionyl)-benzeneamine, m.p. 65°-6° C., yield 0.58 g (80%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][NH:36][CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:36]([CH3:35])[CH:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CNC1CCN(C)CC1
Product: CN1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(1-methyl-piperidin-4-yl)-amino]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Methyl-(1-methyl-piperidin-4-yl)-amine following General Procedure C.
Reaction SMILES: [NH2:1][CH:2]([CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.C(N(CC)CC)C>C1COCC1.C(O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][CH:2]([CH:8]2[CH2:9][CH2:10][CH2:11]2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:16]([F:20])=[CH:15][N:14]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)CC(N)C1CCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)CC(Nc1nc(Cl)ncc1F)C1CCC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
To a racemic solution of methyl 3-amino-3-cyclobutylpropanoate, 49a, (0.354 g, 2.252 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (0.414 g, 2.477 mmol) in THF (10 mL) and ethanol (1 mL) was added triethylamine (0.628 mL, 4.504 mmol). The reaction mixture was heated and stirred at 70° C. for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to approximately 5 mL final volume. The crude residue was purified via silica gel chromatography (0-100% EtOAC/hexanes gradient) to afford 289 mg (45%) of the desired product: 1H NMR (300 MHz, CDCl3) δ 7.87 (s, 1H), 5.80 (s, 1H), 4.71-4.38 (m, 1H), 3.68 (s, 3H), 2.84-2.37 (m, 3H), 2.23-1.67 (m, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.08 minutes (M+H) 287.98.
Reaction SMILES: [C:1]([O:5][C:6](=O)[NH:7][C@H:8]([C:14](=[O:34])[NH:15][C@H:16]([CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)[CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])(C)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.CN(C(ON1N=N[C:53]2[CH:54]=CC=N[C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:70](C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl.O>[F:33][C:29]1[CH:28]=[C:27]2[C:32](=[CH:31][CH:30]=1)[N:24]([CH2:23][C@@H:16]([NH:15][C:14](=[O:34])[C@@H:8]([NH:7][C:6]1[O:5][C:1]3[CH:2]=[CH:54][CH:53]=[CH:52][C:3]=3[N:70]=1)[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:25][CH2:26]2
Reactant: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCS(C)(=O)=O)CN1CCc2cc(F)ccc21
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@H](Nc1nc2ccccc2o1)C(=O)N[C@@H](CCS(C)(=O)=O)CN1CCc2cc(F)ccc21
Reaction time: 8 h
Yield: 76 %

Procedure:
{1-(S)-[1-(S)-(5-Fluoro-2,3-dihydro-indol-1-ylmethyl)-3-methanesulfonyl-propylcarbamoyl]-3,3-dimethyl-butyl}-carbamic acid tert-butyl ester. The intermediate from Step A (500 mg, 1.29 mmol) was treated with 2 mL of a solution containing 45% trifluoroacetic acid, 45% dichloromethane and 10% water. The material was allowed to stand overnight and the solvent was removed. The resulting oil was treated with Boc-(L)-tBu-Ala (350 mg, 1.42 mmol), HATU (540 mg, 1.42 mmol) and dichloromethane (5 mL). The resulting suspension was treated with diisopropylethylamine (836 mg, 6.47 mmol) and allowed to stir overnight. The reaction contents were then poured into a separatory funnel and treated with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane a total of 2 times and discarded. The comined organics were dried over MgSO4 and the solvent was removed. The residue was purified by automated silica gel chromatography using a linear gradient of 0 to 100% ethyl acetate in hexane to afford the title compound as a solid (506 mg, 76%): 1H NMR (CDCl1, 400 MHz) δ 0.74 (s, 9H), 1.41 (dd, 1H, J1=8.3, J2=14.5), 1.70 (dd, 1H, J1=4.4, J2=14.5), 2.57-2.72 (m, 2H), 2.85 (dd, 1H, J1=6.8, J2=13.6), 3.02 (dd, 1H, J1=7.7, J2=13.6), 3.07 (dd, 1H, J1=8.7, J2=17.4), 3.17-3.26 (m, 1H), 3.48 (dd, 1H, J1=4.5, J2=11.4), 3.55 (dd, 1H, J1=3.4, J2=11.4), 3.60 (s, 3H), 3.88-3.98 (m, 1H), 4.43 (ddd, 1H, J1=4.3, J2=8.1, J3=12.3), 6.16 (dd, 1H, J1=4.1, J2=8.5), 6.41 (d, 1H, J=7.7), 6.48 (ddd, 1H, J1=2.6, J2=J3=9.0), 6.52-6.56 (m, 1H), 6.75-6.79 (m, 1H), 6.78-6.84 (m, 1H), 6.98-7.10 (m, 3H); HPLC-MS calcd. for C25H40FN3O5S (M+H+) 514.3, found 514.5.