Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:36])[CH2:34][Cl:33])[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Product: O=C(CCl)NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1

Procedure:
Following a similar procedure to that described in reference example 1 section a, but starting from 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (obtained in example 90) and chloroacetyl chloride, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:7]=1
Reactant: OCc1ccc(F)cc1O
Reactant: Fc1ccc(CBr)cc1
Product: OCc1ccc(F)cc1OCc1ccc(F)cc1

Procedure:
The title compound was prepared from 5-fluoro-2-(hydroxymethyl)phenol and 4-(bromomethyl)-1-fluorobenzene according to the procedure for the preparation of Example 117, part A. 1H NMR (400 MHz, CDCl3): δ 2.07 (1H, t, J=6.8 Hz), 4.67 (2H, d, J=6.0 Hz), 5.05 (2H, s), 6.65-6.68 (2H, m), 7.07-7.11 (2H, m), 7.24-7.28 (1H, m), 7.37-7.41 (2H, m).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][N:30]=[N+:31]=[N-:32])[CH2:17][C:16]=2[CH:18]=[CH:19][CH:20]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Yield: 89.8 %

Procedure:
Treatment of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.75 g, 1.67 mmol) with sodium azide (0.43 g, 6.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.48 g (90%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with triphenylphosphine (0.393 g, 1.49 mmol) generally according to the procedure described for Example 21 afforded 0.348 g (71%) of (±)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 206-208° C.; Anal. calcd. for C15H13Cl2NOHCl: C, 54.49; H, 4.27; N, 4.24. Found: C, 54.38; H, 4.36; N, 4.12.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH3:26])=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1.[CH2:29](N=C=O)[CH2:30]C.CN=C=O>>[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH2:26][CH2:29][CH3:30])=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1
Reactant: CNC(=O)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCCN=C=O
Agent: CN=C=O
Product: CCCNC(=O)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 93 was prepared in the manner of compound 24 substituting propyl isocyanate for methyl isocyanate and refluxing for 16 h [MS 422.3 (M+1)].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=1)=O.[OH-].[NH4+]>OP(O)(O)=O>[I:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:3]([C:2]([F:15])([F:14])[F:1])=[N:5][N:6]=2)[CH:9]=1
Reactant: O=C(NNc1ccc(I)cn1)C(F)(F)F
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: FC(F)(F)c1nnc2ccc(I)cn12
Temperature: 140 °C

Procedure:
The product (145 mg, 0.438 mmol) from Step A was suspended in superphosphoric acid (5 mL), and the mixture was heated at 140° C. for 6 h. The mixture was allowed to cool to room temperature, poured into ice, and neutralized with concentrated aqueous ammonium hydroxide solution. The mixture was extracted several times with ethyl acetate, and the combined extracts were washed with saturated aqueous brine, dried (magnesium sulfate), and concentrated under reduced pressure. The resultant residue was purified by preparative thin layer chromatography (silica, 8% methanol/dichloromethane) to afford the title compound. LC/MS 313.8 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.NC1N=CC2C=CC=CC=2N(CCOC2CCCCO2)C1=O.[C:60]1([C:66]2[C:72]3[CH:73]=[CH:74][CH:75]=[CH:76][C:71]=3[N:70]([CH2:77][CH2:78][O:79][CH:80]3[CH2:85][CH2:84][CH2:83][CH2:82][O:81]3)[C:69](=[O:86])[CH:68]([NH2:87])[N:67]=2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:87][CH:68]1[N:67]=[C:66]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][C:71]=2[N:70]([CH2:77][CH2:78][O:79][CH:80]2[CH2:85][CH2:84][CH2:83][CH2:82][O:81]2)[C:69]1=[O:86])=[O:12]
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CCOC2CCCCO2)C1=O
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC1N=Cc2ccccc2N(CCOC2CCCCO2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOC2CCCCO2)C1=O)c1cc2ccccc2[nH]1

Procedure:
To a mixture of indole-2-carboxylic acid (0.19 g), N-hydroxybenzotriazole (0.16 g) and N,N'-dicyclohexylcarbodiimide (0.24 g) in chloroform (10 ml) was added amino-1-{2-((RS)-2-tetrahydropyranyloxy)ethyl}-2H-1,4- benzodiazepine-2-one and (3RS)-1,3-dihydro-5-phenyl-3-amino-1-{2-((SR) -2-tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine-2-one at ambient temperature under stirring. The mixture was stirred for 2 hours under the same conditions. The resultant precipitate was filtered off. The combined filtrate and washings were evaporated under reduced pressure and the residual oil (1.20 g) was subjected to column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate (10:1) to give a mixture (white powder, 0.45 g) of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-1-{2-((RS)-2-tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine-2-one and (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-1-{2-((SR) -2-tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine- 2-one.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Cl-].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][Zn+]>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.C1COCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:20]=2)[C:11]=1[CH3:12]
Reactant: FC(F)(F)c1cccc(C[Zn+])c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cccc(C(F)(F)F)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to procedure Z using 2,4-dichloro-5,7-difluoro-3-methylquinoline (350 mg, 1.411 mmol), Pd(PPh3)4 (163 mg, 0.14 mmol), 3-(trifluoromethyl)benzylzinc chloride (0.5M in THF, 2.96 mL, 1.48 mmol), and THF (3.5 mL). Purification by column chromatography (silica gel, 0-8% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(3-(trifluoromethyl)benzyl)-quinoline as a white solid. Mass Spectrum (ESI) m/e=372.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2scnc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2scnc2c1

Procedure:
A mixture of 5-methylbenzothiazole (5.0 g), N-bromosuccinimide (6.0 g) and carbon tetrachloride (500 ml) was refluxed for 4 hours. Upon cooling, the mixture was evaporated to dryness and the residue chromatographed over silica gel. On elution with a mixture of methylene chloride and hexane (9:1), the title product was obtained as a white solid [0.56 g; NMR(CDCl3,60 MHz): 4.6 (s, 2H), 7.4 (dd, J=7 Hz, 2 Hz, 1H). 7.9 (d, J=7 Hz, 1H), 8.15 (d, J=2 Hz, 1H), 9.0 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Product: CC(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.05 mmol, Step-1 of Example 210, single enantiomer) and acetyl chloride (21 mg, 0.27 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[O:31]=[C:26]1[NH:27][C:28](=[O:30])[C:29](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:10]=3)=[CH:7][CH:8]=2)[S:25]1
Reactant: O=C1CSC(=O)N1
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)OC(C)(C)C
Product: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Yield: 81 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 8 g (25 mmol) of tert-butyl (4′-formyl-biphenyl-3-ylmethyl)methylcarbamate with 2.9 g (25 mmol) of 2,4-thiazolidine dione, 8.6 g (81%) of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([O:20]C)=[C:13]([Cl:19])[C:14]=3[Cl:18])[C:9]2=[O:22])=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([OH:20])=[C:13]([Cl:19])[C:14]=3[Cl:18])[C:9]2=[O:22])=[CH:4][CH:3]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(Cl)cc1)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(c2ccc(Cl)cc2)C(=O)c2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 180 °C

Procedure:
A stirred mixture of 2-(p-chlorophenyl)-2-methyl-4,5-dichloro-6-methoxyindan-1,3-dione (4.42 g., 0.012 mole) and pyridine hydrochloride (40 g.) is heated at 180°C. for 1 hour, then poured into water (500 ml.). The 2-(p-chlorophenyl)-2-methyl-4,5-dichloro-6-hydroxyindan-1,3-dione which separates is filtered and dried.
Reaction SMILES: [C:1]([C:5]1[N:9]2[N:10]=[C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:24]S(O)(=O)=O>>[C:1]([C:5]1[N:9]2[N:10]=[C:11]([CH2:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])=[O:24])[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)c1nnc2ccc(C#Cc3ccc(F)cc3F)nn12
Product: CC(C)(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Temperature: 90 °C
Yield: 98.7 %

Procedure:
To a round bottom flask was added 3-tert-butyl-6-((2,4-difluorophenyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.20 g, 13.5 mmol, Example #9, Step D) and concentrated H2SO4 (50 mL, 560 mmol). The reaction mixture was heated to about 90° C. for about 2 h. The reaction mixture was quenched with ice (500 g) and extracted with DCM (500 mL). The aqueous layer was neutralized to pH of about 7.0 with solid NaOH and additional ice (1000 g) was added to maintain a temperature of about 0-10° C. The aqueous layer was extracted with DCM (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography using MeOH/DCM (10:90) to give the title compound (4.4 g, 99%) as a solid. LC/MS (Table 1, Method a) Rt=3.20 min; MS m/z: 331.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:32]=[CH:31][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4([CH3:30])[CH2:27][O:26]C(C)(C)[O:24]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C(O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O>[CH3:30][C:23]([OH:24])([CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:34])([F:1])[F:33])=[CH:32][CH:31]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH2:27][OH:26]
Reactant: CC1(COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)COC(C)(C)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(O)(CO)COc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.9 %

Procedure:
4-[4-(Trifluoromethoxy)phenoxy]-1-{4-[(2,2,4-trimethyl-1,3-dioxolan-4-yl)methoxy]phenyl}piperidine (223 mg, 0.463 mmol), ethanol (10 mL), and concentrated hydrochloric acid (2 mL) were mixed and stirred at room temperature for 14 hours. Water was added to the reaction mixture, followed by neutralization with sodium carbonate. Ethyl acetate was added to the mixture to conduct extraction. The organic layer was washed with water three times. The organic layer was concentrated under reduced pressure, obtaining 196 mg (yield: 96%) of the objective compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:25]=[C:24]([C:26]#[N:27])[C:19]([C:20]([O:22]C)=O)=[C:18]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CC(O)=O.[Pt]=O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:18]2[C:19]3[C:20](=[O:22])[NH:27][CH2:26][C:24]=3[CH:25]=[C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[N:17]=2)=[CH:30][C:31]=1[CH3:36]
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1ccc(F)c(C)c1
Agent: O=[Pt]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)ccc1F
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A mixture of methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyano-2-(4-fluoro-3-methylphenylamino)nicotinate (75 mg, 0.151 mmol) and platinum oxide (34.2 mg, 0.151 mmol) in DCM (2 mL) and HOAc (0.5 mL) was stirred at RT under H2 atmosphere. The mixture was subsequently filtered through Celite. The filtrate was concentrated and the residue was purified by preparative HPLC to give the title compound (50 mg, 70.6%). [M+H] calc'd for C25H32FN5O3, 470; found, 470.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2/[CH:23]=[CH:24]\[CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[CH2:27]([N:26]([CH2:29][CH3:30])[CH2:25]/[CH:24]=[CH:23]\[C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[S:13]([CH2:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:31][CH3:32])[C:2]([C:35]2[CH:36]=[CH:37][O:33][CH:34]=2)=[CH:11][CH:10]=1)(=[O:15])=[O:14])[CH3:28]
Reactant: OB(O)c1ccoc1
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Temperature: 140 °C

Procedure:
A mixture of (Z)-methyl 3-bromo-6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-2-methoxybenzoate (Intermediate 161, 0.163 g), furan-3-yl boronic acid (0.041 g), palladium (II) chloride dppf complexed with DCM (0.025 g), cesium carbonate (0.282 g) in water (0.5 ml) and dioxane (3 ml) was degassed and then heated in the microwave at 140° C. for 10 minutes. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-5% to give (Z)-methyl 6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-3-(furan-3-yl)-2-methoxybenzoate as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:32]([O:34][CH2:35][CH2:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[N:46]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH3:33]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:49]2[CH2:50][CH2:51][CH2:52][N:46]([C:38]3[N:37]([CH2:36][CH2:35][O:34][CH2:32][CH3:33])[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=3)[CH2:47][CH2:48]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(OC)c(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)c1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 102.1.2 using 1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.55 g, 1.27 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.71 g, 1.3 mmol) to give, after chromatography on silica gel eluting with dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.05, the title compound: Rf=0.85 (silica gel, dichloromethane/methanol/concentrrated aqueous ammonia 90/10/0.1).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])=[CH:14][CH:13]=2)[N:8]=[C:7]([NH:23][C:24]2[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=2)[CH:6]=1)=O.[BH4-].[Li+]>C1COCC1>[OH:2][CH2:3][C:5]1[N:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])=[CH:16][CH:17]=2)[N:8]=[C:7]([NH:23][C:24]2[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=2)[CH:6]=1
Reactant: CCC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(C(=O)OC)n2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc(Sc2nc(CO)cc(Nc3cc(C)n[nH]3)n2)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of [6-methoxycarbonyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (2 g, 4.85 mmol) in THF (100 mL) is added lithium borohydride (0.32 g, 14.5 mmol). The reaction mixture is stirred at 50° C. for 1.5 hours. The reaction is then quenched with dilute HCl and extracted with ethyl acetate. The organic layer is successively washed with aqueous saturated NaHCO3 and brine, dried over MgSO4 and evaporated. The solid residue is triturated in ethyl acetate and the resulting white solid is collected by filtration to give the desired product [6-hydroxymethyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Li].[CH3:27][N:28]([CH3:32])[C:29](Cl)=[S:30]>C1COCC1>[CH3:27][N:28]([CH3:32])[C:29]([N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])=[S:30]
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CN(C)C(=S)Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CN(C)C(=S)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
To a solution of 5.0 g (0.014 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole in 50 ml of THF was added dropwise 15 ml of 1.6 M methyl lithium solution, followed by a solution of 5.5 g (0.045 mole) of dimethylthiocarbamoyl chloride in 25 ml THF. The reaction mixture was heated at reflux several hours, then concentrated by rotary evaporation. The residue was shaken with ether and 1 N hydrochloric acid. The ether layer was washed with 10% sodium bicarbonate solution, then dried and concentrated. The residue (7.8 g) was purified by chromatography on silica gel, eluting with toluene to give 0.8 g of product, mp 133°-133.5° (recrystallized from methyl cyclohexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:7]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](F)=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1.[F-].[K+]>CN(C=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:1][C:2]2[CH:3]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([N:8]3[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:7]=2)=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: CC(=O)Nc1cc(N)cc(-n2cccc2)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Nc2ccc(Br)cc2[N+](=O)[O-])cc(-n2cccc2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of N-(3-amino-5-pyrrol-1-yl-phenyl)acetamide (5 g, 23.23 mmol) in anhydrous DMF (5 ml), 4-bromo-1-fluoro-2-nitrobenzene (5.11 g, 23.23 mmol) and potassium fluoride (1.35 g, 23.23 mmol) were added. The mixture was stirred at 110° C. for overnight. Then the mixture was brought to RT and DMF was removed under vacuum. Residue was subjected to flash column chromatography (50% ethyl acetate in hexanes) to get the compound in 63% yield (6.1 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[CH2:9]([C:11]([C:29]1[S:33][C:32]([S:34]([NH2:37])(=[O:36])=[O:35])=[C:31]([CH3:38])[CH:30]=1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([CH3:28])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CC(OC(C)=O)=O>ClCCl>[C:1]([O:5][C:6](=[O:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:23]([CH3:24])([CH3:25])[C:22](=[O:27])[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]([C:29]2[S:33][C:32]([S:34]([NH2:37])(=[O:36])=[O:35])=[C:31]([CH3:38])[CH:30]=2)([CH2:9][CH3:10])[CH2:12][CH3:13])=[CH:15][C:16]=1[CH3:28]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)OC(C)(C)C
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Yield: 92.3 %

Procedure:
A mixture of (5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid tert-butyl ester (360 mg, 0.63 mmol), pyridinium dichromate (179 mg, 0.48 mmol) and Ac2O (66 μL, 0.7 mmol) in dichloromethane (10 ml) is refluxed for 3 h. The reaction is concentrated and chromatographed (Hex to 15% EtOAc/Hex) to give the title compound (330 mg, 92%); 1H NMR (CDC3): δ 6.96, 7.23 (m, 2H), 6.56 (s, 1H), 6.51 (d, 1H, J=8.3 Hz), 6.57 (s, 1H), 5.08 (t, 1H), 4.85 (s, 2H), 3.71 (d, 2H, J=5.4 Hz), 2.40 (s, 3H), 2.26 (s, 3H), 2.07 (q, 4H), 1.40 (s, 9H), 1.26 (s, 9H), 0.90 (s, 9H), 0.70 (t, 6H);