Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[N:8]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:25]=[C:24]([NH:26][CH:27]4[CH2:29][CH2:28]4)[N:23]4[N:30]=[C:31]([CH3:35])[C:32]([CH:33]=O)=[C:22]4[N:21]=3)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[N:9]1.N1CCCCC1>C(O)C.O>[N:8]1([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20]3[CH:25]=[C:24]([NH:26][CH:27]4[CH2:29][CH2:28]4)[N:23]4[N:30]=[C:31]([CH3:35])[C:32]([CH:33]=[C:7]5[NH:1][C:2](=[O:3])[NH:4][C:5]5=[O:6])=[C:22]4[N:21]=3)=[CH:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: O=C1CNC(=O)N1
Reactant: Cc1nn2c(NC3CC3)cc(Nc3ccc(-n4cccn4)cc3)nc2c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: Cc1nn2c(NC3CC3)cc(Nc3ccc(-n4cccn4)cc3)nc2c1C=C1NC(=O)NC1=O
Temperature: 80 °C
Yield: 69.5 %

Procedure:
Hydantoin (3 mg, 0.03 mmol) and 5-(4-(1H-pyrazol-1-yl)phenylamino)-7-(cyclopropylamino)-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (12 mg, 0.03 mmol) were dissolved in ethanol (0.4 mL) along with piperidine (3 uL, 0.03 mmol). The reaction was heated at 80° C. in the microwave for 2 hours. The reaction was then cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was dried in vacuo to give 5-((5-(4-(1H-pyrazol-1-yl)phenylamino)-7-(cyclopropylamino)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (9.5 mg, 65% yield). LCMS (M+1=456)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2Br)[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2].Cl[CH2:35]Cl.[C:37]([O-:40])(=[O:39])C.[Na+].[C]=O>CO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=2[C:37]([O:40][CH3:35])=[O:39])[N:8]([CH3:24])[C:9](=[O:23])[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1Br
Reactant: CC(=O)[O-]
Reactant: ClCCl
Agent: [C]=O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)OC
Reaction time: 19 h

Procedure:
4-(2-Bromo-4-cyano-phenyl)-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (intermediate 8, 7.16 g, 13.7 mmol), 1.1-bis(diphenylphosphino)-ferrocendichloropalladium(H), complex with dichloromethane (1:1) (559.3 mg, 0.69 mmol) and sodium acetate (3.37 g, 41.1 mmol) are suspended in methanol (120 mL) and treated with carbon monoxide at 8 bar and 100° C. for 19 h. A small amount of 1.1-bis(diphenylphosphino)-ferrocendichloropalladium(II), complex with dichloromethane (1:1) is added and the reaction under carbon monoxide is continued at 8 bar and 100° C. for 19 h. The reaction mixture is concentrated and purified by reversed phase HPLC. Yield: 3.70 g. ESI mass spectrum: [M+H]+=502; Retention time HPLC: 1.20 min (HPLC method Z018_S04)
Reaction SMILES: [CH2:1]([CH:7]1[O:9][C:8]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](OCC)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:20]>C(O)C>[NH2:20][C:10]([C:8]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[O:9]1)=[O:11]
Reactant: N
Reactant: CCCCCCC1OC1(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCCCCCC1OC1(C(N)=O)C(=O)OCC
Reaction time: 48 h

Procedure:
A solution of 8.0 g of 2A in 10 ml of ethanol was saturated with ammonia (gas) and the mixture was allowed to stand for 2 days at room temperature. The precipitate that formed was collected and recrystallized from pentane to give 2, as white crystals, mp: 58°-60° C.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=O)C>CO>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Solvent: CO
Product: COC(=O)CN1C(=O)OC[C@@H]1c1ccccc1
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (1 g, 4.52 mmol) (prepared according to Evans in U.S. Pat. No. 4,665,171) in 20 mL of anhydrous methanol was treated hourly with 5 equivalents of acetyl chloride, for a total of 20 equivalents. The resulting solution was stirred overnight. The residue obtained after evaporation of the MeOH was redissolved in 30 mL of CH2Cl2 and treated with 50 mL of saturated aqueous Na2CO3. The organic layer was evaporated and dried (MgSO4) to yield the title compound as a colorless oil (1.001 g, 94%); 1H NMR (CDCl3) δ 3.37 (d, J==18.0 Hz, 1H), 3.69 (s, 3H), 4.13 (t, J=8.3 Hz, 1H), 4.28 (d, J=18.0 Hz, 1H), 4.69 (t, J=8.8 Hz, 1H), 5.04 (t, J=8.4 Hz, 1H), 7.26-7.29 (m, 2H), 7.36-7.42 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:10]2[C:15]([N:16]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:18])[N:11]=2.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)[N:13]=[C:12]([CH3:18])[N:11]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Br)n(C3CCOCC3)c2n1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Br)n(C3CCOCC3)c2n1
Yield: 65.5 %

Procedure:
Heat a solution of 8-(2-bromophenyl)-6-chloro-2-methyl-9-(tetrahydro-2H-pyran-4-yl)-9H-purine (0.0023 mol, 1.0 g), 1-methyl piperazine (0.0025 mol, 0.25 g, 1.1 equiv.) and triethylamine (0.0025 mol, 0.25 g, 1.1 equiv.) in ethanol (10.0 mL) at 90° C. for 16 h. Concentrate the reaction mixture under reduce pressure. Dissolve the residue in dry dichloromethane and wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the residue. Purify the residue by silica gel chromatography eluting with dichloromethane:methanol 97:3 to give 8-(2-Bromo-phenyl)-2-methyl-6-(4-methyl-piperazin-1-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine (0.71 g). Used as such for the next step.
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([CH3:44])([CH3:43])[NH:37][S:38]([CH2:41][CH3:42])(=O)=[O:39]>C(Cl)(Cl)Cl>[CH3:35][Si:36]([CH3:44])([CH3:43])[N:37]=[S:38]([Cl:1])([CH2:41][CH3:42])=[O:39]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCS(=O)(=O)N[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCS(=O)(Cl)=N[Si](C)(C)C

Procedure:
Hexachloroethane (0.1110 mol, 26.81 g), triphenylphosphine (0.1121 mol, 29.70 g), triethylamine (0.1110 mol, 15.7 mL), monosilylsulfonamide (3f) (0.1110 mol, 20.1 g). 1H NMR signals (90 MHz, CHCl3): 0.00 (s, 9H), 1.27 (t, 3H), 3.23 (q, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:14])[C:5]([NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2OCC)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:36][C@H:37]1[O:41][C@@H:40]([C@H:42]([NH2:45])[CH2:43][CH3:44])[CH2:39][CH2:38]1.CCN(CC)CC>CC#N>[Cl:1][C:2]1[C:7]([S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[C:6]([OH:14])[C:5]([NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2[NH:45][C@@H:42]([C@H:40]2[CH2:39][CH2:38][C@@H:37]([CH3:36])[O:41]2)[CH2:43][CH3:44])=[CH:4][CH:3]=1
Reactant: CC[C@@H](N)[C@H]1CC[C@@H](C)O1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)C)c2O)c(=O)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)C)c2O)c(=O)c1=O)[C@H]1CC[C@@H](C)O1

Procedure:
To a stirred solution of 253 mg of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N,N-dimethyl-benzenesulfonamide in 5 ml of dry MeCN are added 362 mg of (R)-1-((2R,5R)-5-methyl-tetrahydrofuran-2-yl)-propylamine p-toluenesulfonate salt followed by 94 μl of Et3N at rt under an inert atmosphere of nitrogen. A reaction mixture obtained is heated at reflux for 45 minutes and solvent is evaporatedA residue obtained is purified by flash chromatography on silica eluting with 30-40% EtOAc in iso-hexane. The title compound is obtained. MH+ 472.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH2:4][O:5][C:6]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+].Cl.[CH2:25](O)[CH3:26]>O1CCCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH2:4][O:5][C:6]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[C:8]=1[C:9]([O:11][CH2:25][CH3:26])=[O:10]
Reactant: O=C(O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Preparation of 2-trifluoromethyl-3H-naphthopyran-carboxylic acid. A solution of the ester from Step 1 (0.8 g, 2.5 mmol) was dissolved in 40 mL of ethanol and 10 mL of tetrahydrofuran, treated with sodium hydroxide (2.5 N, 10 mL, 25 mmol) and stirred at room temperature for 16 hours. The reaction mixture was acidified with 1.0 N HCl, whereupon a solid formed that was isolated by filtration. The solid was washed with 20 mL of water to afford 0.7 g (95%) of the title compound as a yellow solid: mp 245.9-248.6° C. 1H NMR (acetone-d6 /300 MHz) 8.57 (s, 1H), 8.28 (d, 1H, J=8.7 Hz), 8.03 (d, 1H, J=9.0 Hz), 7.93 (d, 1H, J=8.7), 7.67 (m, 1H), 7.50 (m, 1H), 7.28 (d, 1H, J=9.0), 5.96 (qH-F, 1H, J=7.2 Hz). FABHRMS m/z 295.0561 (M+H, Calc'd 295.0582). Anal. Calc'd for C15H9O3F3 +3.31% H2O: C, 59.21; H, 3.35. Found: C, 59.17; H, 3.07.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].CC(N(C)C)=O.[Br-].[CH:21]1([Zn+])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[CH:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: [Zn+]C1CCCCC1
Agent: [Br-]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A mixture of 4-bromo-3-(trifluoromethyl)benzonitrile (6 g, 24.00 mmol), DMA (30 mL), cuprous iodide (0.914 g, 4.80 mmol) and 1,1′-bis(diphenylphosphino) ferrocenedichloro palladium(II) dichloromethane complex (1.756 g, 2.400 mmol) was bubbled with nitrogen for 5 min. before 0.5 M THF solution of cyclohexylzinc bromide (100 mL, 50.0 mmol) was added over 20 min. via cannula at room temperature. The black reaction mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure. EtOAc (50 mL), water (100 mL) and saturated aqueous ammonium chloride solution (30 mL) were added. The solid was filtered off over a celite pad and washed with ethyl acetate (3×20 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL). The combined organic solutions were washed with 1 N aqueous HCl (2×40 mL) and then brine (40 mL), dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (silica gel column, 20→100% ethyl acetate in hexanes) afforded 4-cyclohexyl-3-(trifluoromethyl)benzonitrile (2.77 g, 10.94 mmol, 45.6% yield) as a solid. The compound had an HPLC retention time=3.44 min. (condition C); LC/MS [M+H2O]+1=272.2.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(#N)C>ClCCl>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:33](=[O:35])[CH3:34])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 0.230 mmol) in 5 mL of dichloromethane. Added 0.5 mL of acetic anhydride. After 10 min, reaction is complete and trituration with acetonitrile gave 2-[5-(4-acetyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 91%). MS (ESI) m/z 477.3 (M+H)+
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]4[CH2:26][CH:25]5[C:27]6([CH2:31][N:30]([CH2:32][C:33]([F:36])([F:35])[F:34])[S:29](=[O:38])(=[O:37])[NH:28]6)[CH:22]([CH2:23][CH2:24]5)[CH2:21][C:20]=4[CH:39]=3)=[N:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[H][H]>[Pd].C(OCC)(=O)C>[F:41][C:2]([F:1])([F:40])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]4[CH2:26][CH:25]5[C:27]6([CH2:31][N:30]([CH2:32][C:33]([F:36])([F:35])[F:34])[S:29](=[O:37])(=[O:38])[NH:28]6)[CH:22]([CH2:23][CH2:24]5)[CH2:21][C:20]=4[CH:39]=3)=[N:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: O=C(N1CC=C(c2cnc(-c3ccc4c(c3)CC3CCC(C4)C34CN(CC(F)(F)F)S(=O)(=O)N4)s2)CC1)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(N1CCC(c2cnc(-c3ccc4c(c3)CC3CCC(C4)C34CN(CC(F)(F)F)S(=O)(=O)N4)s2)CC1)C(F)(F)F
Yield: 99.7 %

Procedure:
A mixture of the tetrahydropyridine from Example 41 (0.018 g, 0.029 mmol), palladium on carbon (0.01 g) and ethyl acetate (2 mL) was stirred under 1 atmosphere of hydrogen for 16 hours. The catalyst was removed by filtration through a glass fibre pad and the solvent removed in vacuo to give the title compound (0.018 g, quant.). δ (1H, 400 MHz, CDCl3) 1.29-1.38 (2H, m), 1.68-1.82 (4H, m), 2.16-2.20 (2H, m), 2.46-2.49 (2H, m), 2.70-2.80 (2H, m), 2.92-2.98 (1H, m), 3.18-3.33 (4H, m), 3.44 (2H, s), 3.64-3.72 (2H, m), 4.11-4.15 (1H, m), 4.64 (1H, d, J=14 Hz), 4.91 (1H, s) 7.15 (1H, d, J=7.8 Hz), 7.55 (1H, d, J=0.7 Hz), 7.61 (1H, dd, J=1.5 & 7.8 Hz), 7.66 (1H, s). MS (ES+) 623 ([MH]+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[C:5]([CH3:15])=[N:4][C:3]=1I.C([SnH](CCCC)CCCC)CCC.[F-].[K+].C1C[O:35][CH2:34]C1>>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[C:5]([CH3:15])=[N:4][C:3]=1[CH:34]=[O:35]
Reactant: C1CCOC1
Reactant: Cc1nc(I)c(Cl)n1-c1ccc(C#N)cc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: [F-]
Agent: [K+]
Product: Cc1nc(C=O)c(Cl)n1-c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
A solution of the product from (b) (1.03 g, 3 mmol) and tetrakis (triphenylphosphine)palladium (0.3 g) in THF (70 ml) was installed under an atmosphere of carbon monoxide and heated to 50° C. Tributyltin hydride (0.96 g, 3.3 mmol) in THF (40 ml) was instilled by motor-driven syringe over 4.5 hours. After an additional 0.5 hours the mixture was stirred with 100 ml of 10% potassium fluoride solution for 15 minutes, then extracted twice with dichloromethane. The organic layers were dried over magnesium sulphate and evaporated to an orange solid.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]O.C(N(C(C)C)CC)(C)C.[CH2:34]([C:38]1[N:39](C(OC(C)(C)C)=O)[CH:40]=[C:41]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:42]=1)[CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[CH2:34]([C:38]1[N:42]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[Cl:16])[C:41]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:40][N:39]=1)[CH2:35][CH2:36][CH3:37]
Reactant: OCc1ccccc1Cl
Reactant: CCCCc1nc(CCC(=O)OCC)cn1C(=O)OC(C)(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1ncc(CCC(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of trifluoromethanesulfonic anhydride (163 μL, 0.966 mmol) in methylene chloride (1 mL) held at -75° C. under argon was added 2-chlorobenzyl alcohol (138 mg, 0.966 mmol) and diisopropylethylamine (168 μL, 0.966 mmol) in methylene chloride (2 mL) over one minute. After being stirred for 15 minutes, a solution of ethyl 3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-4-yl]propanoate (285 mg, 0.878 mmol) in methylene chloride (2 mL) was added over a 3-minute interval at -75° C. The reaction mixture was then allowed to warm to room temperature and was stirred for 18 hours. The solvent was evaporated, and this crude product was flash chromatographed over silica gel with a gradient of ethyl acetate in hexane to give 179 mg (58%) of ethyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-propanoate as an oil. TLC on silica gel with 1:1 hexane/ethyl acetate showed a single product with an Rf of 0.41.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:34][CH2:35][CH2:36][OH:37])=[N:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[C:8]([Cl:38])[N:7]=1)(=O)C.C[O-].[Na+]>CO.C(Cl)Cl>[Cl:38][C:8]1[N:7]=[C:6]([CH2:5][OH:4])[C:11]2[C:12]([O:34][CH2:35][CH2:36][OH:37])=[N:13][N:14]([C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]=2[CH:9]=1
Reactant: CC(=O)OCc1nc(Cl)cc2c1c(OCCO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (6-chloro-3-(2-hydroxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (491.9 mg, 0.932 mmol) in MeOH (2 ml) and DCM (2 ml) was charged with sodium methoxide (25 wt % in MeOH, 0.45 ml, 1.968 mmol) and stirred at RT for 2 hr. Quenched with sat aq NH4Cl and extracted 3× with DCM. Washed organics with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 2-((6-chloro-4-(hydroxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)oxy)ethanol. MS: [M+H]+ m/z 486.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[NH:18][CH2:17][CH:16]([O:19][C:20](=[O:30])[C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH2:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[C:31]([O-:34])(O)=O.[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH2:47]([NH:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=1)[CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH3:53]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[N:18]([C:31](=[O:34])[N:54]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH:52]=[CH2:53])[CH2:55][C:56]3[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=3)[CH2:17][CH:16]([O:19][C:20](=[O:30])[C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH2:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC=CCCCCNCc1ccc(OC)cc1
Reactant: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1)C(=O)OCC
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of compound 134 (4.5 g, 10.8 mmol) in THF (160 mL) were added NaHCO3 (1 tablespoon) and phosgene in toluene (1.93 M, 11.5 mL, 22 mmol). The mixture was vigorously stirred for 1 h at room temperature, and then filtered and evaporated. The residue was dissolved in CH2Cl2 (160 mL), and NaHCO3 (1 tablespoon) and hept-5-enyl-(p-methoxybenzyl)-amine (4.3 g, 18.5 mmol) were added. After stirring overnight at room temperature the reaction mixture was filtered and evaporated to dryness. Flash column chromatography on silica gel (EtOAc:toluene 25:75→40:60) gave the title compound (6.59 g, 90%) as a light brown syrup.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.C(Cl)Cl.S(=O)(=O)(O)O.[I:19]N1C(=O)CCC1=O>C(OCC)(=O)C.CC(O)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([I:19])=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(Cl)c(Cl)n1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nc(Cl)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
A RBF was charged with 2,3-dichloro-6-methoxypyridine (4.84 g, 27.2 mmol, Accel Pharmtech), DCM (40.0 ml), AcOH (40.0 ml), and sulfuric acid (0.797 ml, 14.95 mmol) to give a clear solution. N-iodosuccinimide (6.12 g, 27.2 mmol) was added in one portion to give a maroon-colored solution. The reaction was stirred for three hours at RT. The mixture was diluted with ethyl acetate, washed with water, washed with 10% aq. sodium thiosulfate, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (80-g Redi-Sep Gold column, 0-15% Et20/Heptane) to afford 2,3-dichloro-5-iodo-6-methoxypyridine (6.29 g, 20.70 mmol, 76% yield) as a white solid. m/z (ESI) 304.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)N>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: COc1cc(N)ccc1OCc1ccccn1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Product: COc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1ccccn1
Yield: 71.3 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (200 mg, 0.9 mmol) and 3-methoxy-4-(pyridin-2-ylmethoxy)aniline (249 mg, 1.08 mmol) to give the title compound as a white solid (262 mg, 72%); NMR Spectrum: 3.80 (s+t, 5H), 4.31 (t, 2H), 5.15 (s, 2H), 7.04 (d, 1H), 7.16 (dd, 1H), 7.35 (s+d, 2H), 7.54 (d, 1H), 7.85 (t, 1H), 8.23 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.58 (d, 1H); Mass Spectrum: 409 (MH+).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH:11]=[C:12]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7][N:6]([CH2:27][C:28]([NH:30][C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])=[O:29])[CH2:5]1)=[O:3].[H][H]>[Pd].CO>[NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH:12]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7][N:6]([CH2:27][C:28]([NH:30][C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])=[O:29])[CH2:5]1)=[O:3]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC=C(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1

Procedure:
A mixture of 4 parts of 3-(aminocarbonyl)-4-[3,3-bis(4-fluorophenyl)-2-propenyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dissolved in acetonitrile. The solution was filtered and the filtrate was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.21 parts of 3-(aminocarbonyl)-4-[3,3-bis(4-fluorophenyl)propyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide; mp. 143.2° C. (compound 170).