Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[C:4]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=1)=[O:34].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:11][C:9]1[C:10]2=[C:2]([C:39]3[CH:38]=[CH:37][C:36]([NH:35][C:33]([NH:32][C:23]4[CH:24]=[C:25]([C:28]([F:29])([F:31])[F:30])[CH:26]=[CH:27][C:22]=4[F:21])=[O:34])=[CH:41][CH:40]=3)[C:3]([CH3:20])=[C:4]([CH2:12][N:13]3[CH2:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCCOCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1CN1CCCOCC1
Temperature: 90 °C
Yield: 15 %

Procedure:
To a stirred solution of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.29 mmol) and tetrakis(triphenylphosphine)-palladium(0) (101 mg, 0.088 mmol), in degassed 1,4 dioxane (4.0 mL), was added Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea) (248 mg, 0.59 mmol), K2CO3 (162 mg, 1.18 mmol), and H2O (0.4 mL). The mixture was degassed and heated (90° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous Na2CO3 solution (25 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 24 mg (15%) of the desired product. 1H-NMR (DMSO-d6) δ 9.36 (s, 1H), 8.98-8.97 (m, 1H), 8.63 (dd, J=2.4, 7.2 Hz, 1H), 7.85 (s, 1H), 7.60-7.47 (m, 3H), 7.41-7.33 (m, 1H), 7.33 (d, J=8.7 Hz, 2H), 3.95 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 3.59-3.56 (m, 2H), 3.31 (m, 2H), 2.68-2.62 (m, 4H), 2.10 (s, 3H), 1.83-1.75 (m, 2H); MS [M+H]+=558.1; LCMS RT=2.94.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]([CH2:9][CH2:10][C:11](Cl)=[O:12])([O:7][CH3:8])=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.Cl>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][C:24]([C:11](=[O:12])[CH2:10][CH2:9][C:5]([O:7][CH3:8])=[O:6])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Clc1ccc(-c2ccco2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring mixture of 62 g (0.50 mole) of AlCl3 in 375 ml of 1,2-dichloroethane was added portionwise 75 g (0.5 mole) of 3-carbomethoxypropionyl chloride while keeping the temperature below 25° by means of an ice bath. The reaction mixture was cooled to 15° and a solution of 89 g (0.5 mole) of 5-(4-chlorophenyl)furan in 250 ml of 1,2-dichloroethane was added dropwise with HCl gas being evolved and the temperature rising to 30°. The reaction mixture was stirred at ambient temperature for 1 hour and then added to 1000 ml of ice/water. The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with 1000 ml of 6% sodium carbonate solution with 1000 ml of water and dried over MgSO4. The solvent was removed on a Calab evaporator yielding a residual oil which was extracted several times with refluxing hexane. The hexane extracts were cooled to yield a solid which was filtered, washed twice with 6% sodium carbonate solution, recrystallized from hexane and air dried to yield 7 g (5%). An analytical sample was prepared by drying a sample in a vacuum pistol at room temperature, m.p. 99°-100°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[NH:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=[CH:20]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:21]=[CH:20]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (0.15 g, 0.5 mmol) and commercially available 3-(1H-imidazol-4-yl)-pyridine [CAS-No. 51746-85-1] (0.073 g, 0.5 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.09 g, 45%). MS (EI) 401.1 [(M)+]; mp 228° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[CH2:4][CH2:5][C:6]=1[O:7][CH2:8][CH3:9].C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C1C=CC=CC=1.O.CCO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:8]([O:7][C:6]1[CH2:5][CH2:4][C:3](=[O:10])[C:2]=1[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:9]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC1=C(Br)C(=O)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC1=C(c2ccc(F)cc2)C(=O)CC1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
2-Bromo-3-ethoxy-cyclopent-2-enone (Intermediate NINE2) (10.5 g, 51.2 mmol) and K2CO3 (14.2 g, 102 mmol) in toluene (100 mL), benzene (100 mL) and H2O (50 mL) was treated with a solution of 4-fluorophenylboronic acid (9.31 g, 66.5) in EtOH (100 mL). Tetrakis(triphenylphosphine) palladium(0) Pd(PPh3)4 (3 g, 2.6 mmol), bis(dibenzylideneacetone)palladium(0), Pd2(dba)3 (0.47 g, 0.5 mmol) and triphenylphosphine (0.27 g, 1.0 mmol) were added and the mixture was purged with N2 for 15 m. The mixture was heated to 100° C. for 15 h. The mixture was diluted with water and EtOAc:hexane. After extracting with EtOAc:hexane, the combined organic layers were dried over MgSO4, filtered and evaporated to dryness. The crude oil was purified by column chromatography on silica gel with 2.5% EtOAc:CH2Cl2 to give 3-ethoxy-2-(4-fluoro-phenyl)-cyclopent-2-enone (Intermediate NINE3) 7.85 g (70%).
Reaction SMILES: [CH2:1]([C:6]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=1[CH:8]=O)[CH2:2][CH2:3][CH:4]=[CH2:5].C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].C(=O)(O)[O-].[Na+]>CO>[CH2:1]([C:6]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=1[CH2:8][NH2:24])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCc1ccc(C(F)(F)F)cc1C=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CO
Product: C=CCCCc1ccc(C(F)(F)F)cc1CN
Temperature: 65 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
Step AJ (3): 2-(Pent-4-enyl)-5-(trifluoromethyl)benzaldehyde (200 mg, 0.83 mmol) and ammonium acetate (9.6 g, 124 mmol) was dissolved in methanol (35 mL). Sodium cyanoborohydride (311 mg, 4.95 mmol) was added. The reaction mixture was stirred at 65° C. in a high-pressure vessel for 2 h. Aqueous sodium bicarbonate solution was added and the reaction mixture was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography to give (2-(pent-4-enyl)-5-(trifluoromethyl)phenyl)methanamine (65 mg, 32%) as a colorless oil. LC-MS (M+H)+=244.21.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(N)cc2)ccn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(-c2ccnc(N(CCCCCCC(=O)NO)c3ccccn3)c2)cc1
Reaction time: 22 h
Yield: 24 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (30 mg, 0.072 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:10) to furnish IV as a yellow oil (7 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1.[C:13](=O)(O)[O-:14].[Na+].BrBr.N1C=CC=NC=1.S(=O)(O)[O-].[Na+].[Cl-].[Na+]>CO.CO.O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:14][CH3:13])=[O:9])[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1
Reactant: COc1c(Cl)nc(Cl)nc1C=O
Reactant: O=C([O-])O
Agent: BrBr
Agent: O=S([O-])O
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: c1cncnc1
Product: COC(=O)c1nc(Cl)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 2,6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde (see Examples 6 and 7 above for methods for preparing this compound) (50 g, 0.24 mol) in methanol (1 L) and water (60 mL) was prepared. To the solution, sodium bicarbonate (400 g) was added. A 2 M solution of bromine (192 g, 1.2 mol) in methanol/water (600 mL, 9:1) was added, dropwise, to the pyrimidine solution for 45 minutes at 0° C. while stirring the mixture. The stirring was continued at the same temperature for 1 h. Later, the mixture was stirred at room temperature for 4 h. While stirring, the reaction mixture was thereafter poured onto a mixture of crushed ice (2 L), sodium bisulfite (50 g), and sodium chloride (200 g). The product was extracted with ethyl acetate (1 L×2), and the combined organic layer was dried over sodium sulfate and filtered. Evaporation of the solvent under reduced pressure produced a thick material, which was then solidified on long standing. This produced the title compound (50.8 g, 87% yield); LC-MS 238 (m+1); HPLC (95% acetonitrile buffered with 0.1% v/v acetic acid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:22]CCC[O:18]2)[C:3]1=[O:23].[F:24][C:25]([F:36])([F:35])[O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O.C([O-])(=O)C.[Na+]>CC(O)=O.CC(=O)OCC.O>[C:17]([O:16][CH2:15][CH2:14][CH2:13][N:4]1[C:5](=[O:12])[C:6]([N+:9]([O-:11])=[O:10])=[C:7](/[CH:8]=[CH:30]/[C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([O:26][C:25]([F:24])([F:35])[F:36])[CH:28]=2)[N:2]([CH3:1])[C:3]1=[O:23])(=[O:18])[CH3:22]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(CCCOC2CCCCO2)c(=O)n1C
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCCn1c(=O)c([N+](=O)[O-])c(/C=C/c2cccc(OC(F)(F)F)c2)n(C)c1=O
Temperature: 140 °C
Yield: 14.3 %

Procedure:
To a solution of 1,6-dimethyl-5-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrimidine-2,4(1H,3H)-dione (1 g, 3.05 mmol) in HOAc (4 mL) was added 3-(trifluoromethoxy)benzaldehyde (0.755 g, 3.97 mmol) and sodium acetate (0.752 g, 9.16 mmol). The reaction was heated at 140° C. for 6 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (5:1 to 2:1) to give (E)-3-(3-methyl-5-nitro-2,6-dioxo-4-(3-(trifluoromethoxy)styryl)-2,3-dihydropyrimidin-1(6H)-yl)propyl acetate (200 mg, 14.3% yield) as a brown oil. LCMS: MH+ 458 and TR=1.689 min.
Reaction SMILES: [C:1]1([CH:7](O)[CH:8]=[CH:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CC[O:15]CC.C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:1]1([CH:7]=[CH:8][CH:9]([OH:15])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: CC=CC(O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(O)C=Cc1ccccc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
1-Phenyl-2-buten-1-ol (135.88 g) was dissolved in 2300 mL of dioxane and treated with 2750 mL of dilute hydrochloric acid (2.3 mL of concentrated hydrochloric acid in 2750 mL of water) at room temperature. The mixture was stirred overnight and then poured into 4333 mL of ether and neutralized with 2265 mL of saturated sodium bicarbonate. The aqueous phase was extracted with 1970 mL of ether. The combined extract was dried over anhydrous potassium carbonate. Evaporation of the solvent followed by Kugelrohr distillation at 30° C. for 30 minutes afforded 131.73 g (96.8%) of the desired 4-phenyl-3-buten-2-ol as an oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1]CN(CC)CC.[NH2:8][C:9]1[N:18]=[CH:17][C:16]2[C:15](=[S:19])[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=1.CI>CS(C)=O>[NH2:8][C:9]1[N:18]=[CH:17][C:16]2[C:15]([S:19][CH3:1])=[N:14][CH:13]=[N:12][C:11]=2[CH:10]=1
Reactant: Nc1cc2nc[nH]c(=S)c2cn1
Reactant: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CI
Product: CSc1ncnc2cc(N)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
NEt3 (6 mL, 43 mmol) is added to a solution of 7-amino-4-thiono-3H-pyrido[4,3-d]pyrimidine (0.77 g, 4.3 mmol) in DMSO (7 mL) stirred under N2 at 25° C. After the two phases have been stirred for 20 min, MeI (0.26 mL, 4.2 mmol) is added. After 2 h, the reaction mixture is poured onto stirring ice-water. Solid forms instantly. After further cooling at 0° C., the solid is collected by suction filtration and dried in a vacuum oven to give 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (0.564 g, 68%). 1H NMR (DMSO) δ 8.98 (1H, s), 8.71 (1H, s), 6.94 (2H, brs), 6.49 (1H, s) 2.63 (3H, s).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4](I)[C:3]=1[NH:11][C:12]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:13]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]1[C:3]2[NH:11][C:12](=[O:13])[N:14]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:4]=2[CH:5]=[C:6]([CH3:9])[C:7]=1[F:8]
Reactant: Cc1cc(I)c(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1F
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc2c([nH]c(=O)n2C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,1-dimethylethyl 4-({[(2,3-difluoro-6-iodo-4-methylphenyl)amino]carbonyl}amino)-1-piperidine-carboxylate D21 was dissolved in 1 ml dioxan. Under an argon atmosphere, a mixture of 1,4-dioxane (3 ml), Pd2 dba3 (35 mg, 0.4 mmol), NatBuO (120 mg, 1.20 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (21 mg, 0.4 mmol) was stirred for 10 minutes at room temperature and then 1,1-dimethylethyl 4-({[(2,3-difluoro-6-iodo-4-methylphenyl)amino]carbonyl}amino)-1-piperidine-carboxylate D21 (300 mg) was added and the mixture heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, quenched with NH4Cl (saturated solution) and extracted with ethyl acetate, Drying (MgSO4), evaporation, and crystallisation from diethyl ether gave 150 mg of the title compound. M−−H=366.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:20][CH2:21][C:22]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)=[CH:28][C:27]=1[F:42])([CH3:25])[CH2:23][OH:24]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH2:21][OH:20])[CH2:23][OH:24])=[C:27]([F:42])[CH:28]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1F
Agent: Cl
Solvent: CN(C)C=O
Product: CC(CO)(CO)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Temperature: 50 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (195 mg, 0.62 mmol, 1.0 eq) in DMF (10 mL) was added TEA (190 mg, 1.24 mmol, 2.0 eq) followed by phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)-3-fluorophenylcarbamate (200 mg, 0.62 mmol, 1.0 eq) at RT and the mixture was stirred for 16 h at 50° C. The reaction mixture was concentrated under vacuum and the residue purified by neutral alumina column chromatography using MeOH/CHCl3 (0.5:9.5) as eluent to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,3-dihydroxy-2-methylpropan-2-yl)-3-fluorophenyl)urea (170 mg; 54%) as a white solid (TLC system: MeOH/CHCl3 (1:9); Rf: 0.45).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:6]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[NH:7][C:8](=O)[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C@@H:6]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[NH:7][C:8](=[S:40])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)N[C@@H]1c1ccc(C#N)cc1
Temperature: 120 °C
Reaction time: 17 h
Yield: 31.8 %

Procedure:
To a solution of (R)-4-(4-cyano-phenyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester (14.5 g, 35 mmol) (prepared according to WO 2006/082412, which is incorporated herein by reference in its entirety) in toluene (105 mL) under an atmosphere of N2, was added Lawesson's reagent (17 g, 42 mmol), and the resulting mixture stirred at 120° C. for 17 hours. The reaction mixture was allowed to cool to RT and then evaporated in vacuo. The resulting residue was dissolved in diethyl ether, filtered, and the filtrate collected, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 10-40% EtOAc in cyclohexane to yield the title compound as a yellow foam (4.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)[CH3:15].[OH-].[K+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(=O)c1ccccc1
Agent: [Fe]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Clc1ccc2ccc(-c3ccccc3)nc2c1

Procedure:
To a solution of 4-chloro-2-nitrobenzaldehyde (55.7 g, 300 mmol) in ethanol (600 mL) and water (60 mL) was added iron powder (167 g, 3000 mmol) and conc. HCl (5 mL, 60 mmol), the resulting mixture was stirred with a mechanical stirrer under refluxing condition. 1 h later, LC-MS showed ca. 50% conversion, there was not much change after another one hour. Conc. HCl (2 mL) was added, LC-MS showed the reduction was complete after the mixture was refluxed for an additional 30 min. Then acetophenone (35 mL, 300 mmol) and KOH (50.5 g, 900 mmol) were added, the resulting mixture was further refluxed for 1 h, LC-MS showed the reaction was complete and the desired product was formed. The mixture was cooled to 40° C. and diluted with methylene chloride (1 L), then filtered through celite and the filtrate was concentrated. The residue was dissolved in methylene chloride (1 L) and washed with brine (2×300 mL), and dried over anhydrous sodium sulfate. The solvent was concentrated to ca. 200 mL and diluted with hexanes (500 mL), the light-yellow solid was collected by filtration as the first batch of desired product. The mother liquid was concentrated and then recrystallized with acetonitrile to give the second batch of the title compound as a light-yellow solid; LC-MS (ES, Pos.): 240/242 (3/1) [MH+]; 1H NMR (CDCl3, 400 MHz) δ 7.46-7.56 (m, 4H), 7.77 (d, J=8.7 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 8.14-8.18 (m, 3H), 8.20 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]=1[O:17][CH3:18].[Cl:19]OC(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[Br:1][CH2:2][CH2:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([Cl:19])[CH:16]=1
Reactant: CC(C)(C)OCl
Reactant: CCOC(=O)COc1ccc(CCBr)c(OC)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COc1cc(OC)c(CCBr)cc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 2-[4-(2-bromoethyl)-3-methoxyphenoxy]acetate (640 mg) in dichloromethane (4 ml) was added tert-butyl hypochlorite (251 μl) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of sodium sulfite (504 mg) in water (2 ml) and the resulting mixture was stirred for 30 minutes at room temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=7/1) gave ethyl 2-[4-(2-bromoethyl)-2-chloro-5-methoxyphenoxy]acetate (685 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:23]3[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=3)=[CH:22][C:17]2=[N:16][CH:15]=1)=[O:13].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:51][C@H:52]1[CH2:57][CH2:56][CH2:55][C@@H:54]([CH3:58])[N:53]1[CH2:59][CH2:60][NH2:61].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:51][C@H:52]1[CH2:57][CH2:56][CH2:55][C@@H:54]([CH3:58])[N:53]1[CH2:59][CH2:60][NH:61][C:6]([C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]4[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[CH:4]=1)=[O:8]
Reactant: Cn1nccc1-c1ccn2c(C(=O)Nc3cc(C(=O)O)ccc3F)cnc2c1
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccnn4C)ccn23)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
4-Fluoro-3-{[7-(2-methyl-2H-pyrazol-3-yl)-imidazo[1,2-a]pyridine-3-carbonyl]amino}-benzoic acid (step 2) (450 g, 1.19 mol), EDC.HCl (454.8 g, 2.372 mol) and HOBt (181.6 g, 1.186 mol) in DMF (3.2 L) at 25° C. were stirred for 1.5 hr. The reaction was monitored by HPLC. To the reaction mixture was dropwise added cis 2-(2,6-dimethyl-piperidin-1-yl)-ethylamine (222.5 g, 1.423 mol) over 10 min and stirring continued for 30 min. To the reaction mixture was dropwise an aqueous solution of Na2CO3 (5%, 6 L) over 120 min and the resulting solid was collected by filtration and washed with water (5 L). To the solid was added ethanol (5 L) followed by heating to 70° C. to obtain a clear solution. Water (1. 5 L) was dropwise added at 70° C. and stirred for 30 min. The clear solution was slowly cooled to 25° C. over 2 hr. The solid was filtered, washed with ethanol (500 mL) and dried under vacuum at 50° C. overnight to afford the title compound as a white solid;