Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([N:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][C:36]([F:39])([F:38])[F:37])[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=3[O:27][CH3:28])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](C1C=CC=CC=1N(C(C1CCCCC1)=O)CCN1CCN(C2C=CC=CC=2OC)CC1)([O-])=O>>[CH:1]1([C:7]([N:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][C:36]([F:38])([F:39])[F:37])[CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[O:27][CH3:28])[CH2:16][CH2:17]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2OC(F)(F)F)CC1
Agent: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2[N+](=O)[O-])CC1
Product: COc1cc(N)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2OC(F)(F)F)CC1
Yield: 58 %

Procedure:
The title compound was prepared according to the procedure reported in example 27, but substituting the compound of example 55 for the compound of example 2 and heating at reflux for 3 h. The residue was purified by flash chromatography (EtOAc). Yield: 58%.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:21]>>[ClH:21].[CH3:20][S:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[CH:15][CH:14]=1)(=[O:18])=[O:19]
Reactant: CC(=O)N1CCN(c2ccc(NS(C)(=O)=O)cc2)CC1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(N2CCNCC2)cc1

Procedure:
1-Acetyl-4-(4-methanesulphonamidophenyl)piperazine (9.6 g) and 5N aqueous hydrochloric acid (100 ml) were heated at 100° for 1 hour, the solvent was evaporated, and the residue dried by azeotroping with toluene. The residue was crystallised from ethanol, yield of the title compound 8.26 g, m.p. 230° (dec.).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH3:29])[C:10]([CH3:28])([O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:23]C(C)(C)C(C)(C)[O:20]2)=[CH:15][CH:14]=1)[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>Cl.O1CCCC1.O>[Si:5]([O:8][CH:9]([CH3:29])[C:10]([CH3:28])([CH3:11])[O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]([OH:20])[OH:23])=[CH:15][CH:14]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(C)(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)C(C)(C)Oc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl{1,2-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propoxy}dimethylsilane (5.8 g) was dissolved in 1 M hydrochloric acid (20 mL)-tetrahydrofuran (20 mL)-water (20 mL), sodium periodate (5.9 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the title compound as a pale-yellow solid (1.1 g, 23%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19].CN1CCOCC1>ClCCl.C(OCC)C>[Cl:23][CH:21]([O:20][C:18]([NH:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:19])[CH3:22]
Reactant: C=CCOC(=O)CC1(CN)CCCCC1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCOC(=O)CC1(CNC(=O)OC(C)Cl)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of compound (13) (30 g, 0.121 mol) in dichloromethane (100 mL) was slowly added 1-chloroethyl chloroformate (13 mL, 16.9 g, 0.119 mol). The reaction mixture was cooled to 0° C. and N-methylmorpholine (26.39 mL, 24.28 g, 0.24 mol) was slowly added over a period of 1 h while maintaining a temperature of less than 10° C. The resulting turbid solution was stirred for 30 min, and the reaction mixture was then diluted with diethyl ether (250 mL), washed with water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the desired product (14) as light yellow viscous liquid (38 g, 99% yield). 1H NMR (CDCl3, 400 MHz): δ 1.35-1.58 (m, 10H), 1.78 (d, 3H), 2.32 (s, 2H), 3.22 (d, 2H), 4.57 (d, 2H), 5.25 (dd, 1H), 5.32 (dd, 1H), 5.52 (br. s, 1H), 5.90-5.94 (m, 1H), 6.54 (q, 1H).
Reaction SMILES: [S:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:20][C:21]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[C:23]([C:30]2[C:34]([C:35]([F:38])([F:37])[F:36])=[N:33][N:32]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]=2[NH2:45])[CH:22]=1>ClCCl.N>[Cl:20][C:21]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[C:23]([C:30]2[C:34]([C:35]([F:38])([F:36])[F:37])=[N:33][N:32]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]=2[N:45]=[S:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:22]=1
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Reactant: O=S1CCCC1
Agent: N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1nn(-c2ncccn2)c(N=S2CCCC2)c1-c1cc(Cl)c2c(c1)OCO2
Reaction time: 0.33 h

Procedure:
To a solution of 2.2 equivalents of tetrahydro-thiophene 1-oxide (0.23 g, 2.2 mmo) in dichloromethane at −60° C. under argon was added dropwise trifluoroacetic anhydride (0.46 g, 2.2 mmol). The solution was stirred for 20 min at this temperature. Then the 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.383 g, 1.00 mmol) was added and the solution stirred at −60° C. for 1 h. The reaction was diluted with aqueous ammonia; the organic layer separated and further washed with water and then dried and concentrated.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.C(O[CH:20]=[CH:21][C:22]#[N:23])C>C(O)(C)(C)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:20]=[CH:21][C:22]([NH2:23])=[N:16]2)=[CH:11][CH:10]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC=CC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Nc1ccn(-c2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 44 %

Procedure:
To a hot solution of potassium tert-butoxide (2.54 g, 23 mmol) in tert-butanol (30 ml) was added 4-fluorophenylhydrazine hydrochloride (1.67 g, 10 mmol). After cooling to ambient temperature, a solution of 3-ethoxyacrylonitrile (1.0 g, 10 mmol) in tert-butanol (5 ml) was added and the mixture was refluxed for 3 h. After cooling to ambient temperature, the solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with water. The organic phases were combined, dried and evaporated. Silica gel chromatography using a heptane/ethyl acetate gradient yielded the amine as orange solid (0.78 g, 42%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Br)[N:7]=1)=[O:5])[CH3:2].[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:21][C:18]2[CH:19]=[CH:20][C:15]([I:14])=[CH:16][CH:17]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(CBr)n1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc(COc2ccc(I)cc2)n1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
6-Bromomethyl-pyridine-2-carboxylic acid ethyl ester (1:1.72 g, 48 mmol; from Step 1 above) was dissolved in acetone (250 mL) and 4-iodophenol (11.61 g, 52.8 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) was added, followed by potassium carbonate (7.55 g, 54.6 mmol). The mixture was heated overnight at 65 degrees, and it was then cooled and filtered. The solid was washed with small portions of acetone and the filtrate was concentrated to approximately 100 mL by evaporation. The solution was warmed and then diluted with water (approximately 70 mL). The resulting brown solution was cloudy and started to precipitate an oily solid. The mixture was scratched with a spatula and allowed to cool to room temperature. The off-white precipitate was filtered off, washed with several portions of acetone/water (1:1), and then dried in vacuo over phosphorus pentoxide to give 6-(4-iodo-phenoxymethyl)-pyridine-2-carboxylic acid ethyl ester (13.72 g, 75%) as an off-white crystalline solid. MS (MH+) 384. 1HNMR (CDCl3): δ 1.47 (t, 3H, J=7 Hz), 4.52 (q, 2H, J=7 Hz), 5.33 (s, 2H), 6.78 (d, 2H, J=9 Hz), 7.58 (d, 2H, J=9 Hz), 7.74 (d, 1H, J=7.8 Hz), 7.91 (dd, 1H, J=7.8, 7.8 Hz), 8.09 (d, 1H, J=7.8 Hz).
Reaction SMILES: C[O:2][C:3]1([CH3:18])[CH2:8][CH2:7][C:6]2[C:9]([CH3:17])=[C:10]([O:15][CH3:16])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1.CC(C)=O.Cl>O>[CH3:16][O:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([CH3:18])([OH:2])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:17]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(OC)O2
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(O)O2

Procedure:
A mixture of 84.3 g (0.337 mole) of rac.-2,6-dimethoxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran, 370 ml of acetone, 300 ml of water, and 2.5 ml of conc. hydrochloric acid was distilled until the distillate temperature reached 90° C. After being cooled, the mixture was diluted with water and extracted three times with ether. The ether extracts were combined, washed with saturated brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from aqueous acetone giving rac.-6-methoxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ol as an off-white solid, in crops of 34.6 g (43.5%) and 11.1 g (13.9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH2:25])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH:25][S:33]([CH3:32])(=[O:35])=[O:34])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (133 mg, 0.33 mmol) in DCM was added pyridine (52 mg, 0.66 mmol, 2.0 eq.) followed by methanesulfonyl chloride (76 mg, 0.66 mmol, 2 eq.). The reaction was stirred for 1 h, and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was taken next step without further purification. Yield 75.0% (120 mg). 1H NMR (300 MHz, DMSO-d6): δ 10.30 (s, 1H), 9.30 (s, 1H), 8.56 (s, 1H), 7.83 (s, 1H), 7.45 (s, 1H), 7.44 (s, 2H), 3.16 (s, 3H); LC-MS (ESI): Calculated mass: 479.5; Observed mass: 480.2 [M+H]+ (rt: 1.59 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.OO.NC(N)=[O:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:13])[CH:7]=1
Reactant: NC(N)=O
Reactant: Cc1ccc(Br)cn1
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a solution of 5-bromo-2-methylpyridine (1 g, 5.81 mmol) and urea hydrogen peroxide (1.1 g, 12.2 mmol) in DCM (30 mL) at 0° C. was added trifluoroacetic anhydride (1.6 mL, 11.6 mmol). After warming to 25° C. over 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (660 mg, 60%) as a white solid: LCMS (ES) m/z=190 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)[CH:10]=1)[C:3]([O:2][CH3:1])=[O:39]
Reactant: COC(=O)C(C(=O)OC)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of 2-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-malonic acid dimethyl ester (as prepared in the previous step, 145 mg, 0.262 mmol) in 1.0 mL of DCM (CH2Cl2) was added 1.0 mL of TFA. After stirring at RT for 4 h, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (20-30% EtOAc-hexane) to give 93 mg (84%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C22H22N4O5, 423.1 (M+H). found 422.8.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:25]Cl)[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][N:14]2[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]([CH2:25][CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]2=[O:16])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reactant: ClCC1CC1
Product: CC(C)(C)OC(=O)NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Compound 14o is prepared in a manner similar to that used for preparation of Compound 14 h using previously prepared Compound 13 and cyclopropylmethyl chloride.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[OH-].[Na+].Cl[CH2:11][CH:12]([OH:15])[CH2:13]Cl>C(O)C>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][CH2:11][CH:12]([OH:15])[CH2:13][S:6][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2]
Reactant: CN(C)CCS
Reactant: OC(CCl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCSCC(O)CSCCN(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
2-(Dimethylamino)ethanethiol hydrochloride (10.78 g, 78 mmole) was added portion-wise to a solution of sodium hydroxide (6.2 g, 155 mmole) in ethanol (40 mL) at 0° C. under nitrogen. A further portion of ethanol (20 mL) was added and the mixture stirred at this temperature for 10 minutes. 1,3-Dichloro-2-propanol (5.29 g, 41 mmole) was added dropwise. On completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred for a further 2 hours. The precipitated solid was filtered off and the washed with ethanol. The filtrate was evaporated. The resulting oil was taken up into acetone, filtered and evaporated to give the desired product (8.90 g, 68%) as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:7]=[CH:6][N:5]=1.Br[CH2:20][C:21]#[N:22].[Cl-].[NH4+]>O1CCCC1>[Cl:3][C:4]1[CH:9]=[C:8]([N:10]([CH2:20][C:21]#[N:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:7]=[CH:6][N:5]=1
Reactant: N#CCBr
Reactant: Fc1cccc(Nc2cc(Cl)ncn2)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CCN(c1cc(Cl)ncn1)c1cccc(F)c1F
Temperature: 25 °C
Yield: 68.9 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.07 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.3 g of 4-chloro-6-(2,3-difluoroanilino)pyrimidine was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.18 g of bromoacetonitrile was slowly added dropwise, followed by further stirring for 8 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.24 g of 4-chloro-6-(N-cyanomethyl-N-(2,3-difluorophenyl)amino)pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[S:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21]I>CC(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[NH:19])[S:18][CH3:21])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC(N)=S)cc1
Solvent: CC(C)=O
Product: CSC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
A solution of compound 79.2 (1.5 mmol) and methyl iodide (6.0 mmol) in acetone (15.0 mL) was stirred at 40° C. overnight. The solvent was removed and the residue was dried in vacuo to give {2-[4-(2-methyl-isothioureido)-phenyl]-ethyl}-carbamic acid tert-butyl ester (compound 79.3) in quantitative yield. 1H NMR (CD3OD, 400 MHz): δ 7.40 (d, J=7.8 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 3.30 (t, J=7.1 Hz, 2H), 2.82 (t, J=7.1 Hz, 2H), 2.73 (s, 3H) ppm; EIMS (m/z): 310.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:6]([N+:10]([O-])=O)=[CH:7][C:8]=1[F:9])[NH2:5].Cl[Sn]Cl>C(O)C>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([NH2:10])=[C:4]([NH2:5])[C:3]=1[F:13]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(Cl)c1F
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(F)c(Cl)c(F)c1N
Yield: 95.6 %

Procedure:
A solution of 348 mg (1.67 mmol) of 3-chloro-2,4-difluoro-6-nitroaniline and 1.57 g (8.28 mmol) of SnCl2 in 8 mL of ethanol was heated at 70° C. for 2 h. The solution was evaporated to remove the ethanol. The residue was treated with 2N NaOH to pH=13. White precipitate was observed. The mixture was extracted by CHCl3 (3×10 mL). The extract was dried (MgSO4) and evaporated to leave a red solid (285 mg, 95%), mp 77°-78° C. 1H NMR (CDCl3), 3.156 (b, 2), 3.704 (b, 2), 6.352 (dd, 1, J=1.86, 9.95).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH2:9][C:10]1[N:14]2[CH2:15][CH2:16][C:17]3[C:18](=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=3)[C:13]2=[N:12][N:11]=1)(C)(C)C.[ClH:38]>O1CCOCC1>[ClH:38].[F:36][C:29]1[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=1[CH2:27][C@@H:8]([NH2:7])[CH2:9][C:10]1[N:14]2[CH2:15][CH2:16][C:17]3[C:18](=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[N:21][CH:22]=3)[C:13]2=[N:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCc1cnc(C(F)(F)F)nc1-2
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCc1cnc(C(F)(F)F)nc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 47 mg (0.89 mmol) of tert-butyl{(1R)-1-(2,4,5-trifluorobenzyl)-2-[9-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4′,3′:1,2]pyrido[3,4-d]pyrimidin-3-yl]ethyl}carbamate was added 1.8 mL of 4M HCl in anhydrous dioxane. The mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was washed with diethyl ether and dried to give the title compound as a white solid. LC-MS 429 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCCC1.CN(C)C=O>C(O)C>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]2=[CH:18][C:9]1[NH:10][C:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1Nc2ccc(F)cc2C1=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A stirred solution of 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (50 mg, 0.194 mmol), 5-fluoro-1,3-dihydro-indol-2-one (28 mg, 0.184 mmol), piperidine (0.05 ml), N,N-dimethylformamide (0.05 ml) in anhydrous ethanol (0.5 ml) was heated to reflux for 2 hours and stirred at room temperature overnight. The resulting mixture was filtered to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-(4-fluoro-phenyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (50 mg, 65.92%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].O.C(OCC)C>O1CCCC1>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[O:17][C:15]1[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:27])=[O:2])[C:13](=[O:26])[CH:14]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a stirred mixture of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (800 mg, 2.00 mmol) in tetrahydrofuran (10 mL) was added 0.5N lithium hydroxide solution (8.0 mL, 4.0 mmol). After addition was complete the mixture was stirred at 25° C. for 2 h. The reaction mixture was poured into water and diethyl ether and the layers were separated. The aqueous layer was made acidic with 1N aqueous hydrochloric acid and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate fractions were washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (740 mg, 97%) as a light brown solid: LR-ES-MS m/z calculated for C19H21ClFNO4 [M]+ 381, observed [M+H]+ 382.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]([C:32](=[O:34])[CH3:33])[C:21]([CH3:31])([CH3:30])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:6]=1.[OH-].[Li+].Cl>C1COCC1>[C:32]([N:20]([CH2:19][C:13]1[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:12]=1[O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:10]=[CH:9][CH:8]=1)[C:21]([CH3:30])([CH3:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:34])[CH3:33]
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN(C(C)=O)C(C)(C)Cc2ccc(F)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)N(Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1)C(C)(C)Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To {3-[2-({acetyl-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethyl]-amino}-methyl)-4-bromo-phenoxy]-phenyl}-acetic acid methyl ester (0.094 g, 0.17 mmol) in THF (2 mL) was added 1N aqueous lithium hydroxide (2 mL), and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was acidified with 1N aqueous HCl and extracted three times with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by preparative HPLC to give the title compound. M+H=529.