Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1[C:25](=[O:26])[CH2:24]CC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].N1C(C)=CC=CC=1C.C(OCC)(=[O:65])C>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48][C@@H:25]([OH:26])[CH2:24][OH:65])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CCOC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(C[C@@H](O)CO)n2)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
Triphenylphosphine (172 mg, 0.66 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (133 mg, 0.75 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 146 mg, 0.44 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The reaction was chilled to 0° C. and the combined solution of 3-(3-amino-pyrazol-1-yl)-propane-(R)-1,2-diol (69 mg, 0.44 mmol) and 2,6-lutidine (154 μL, 1.32 mmol) in methylene chloride (4 mL) was added. The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (73 mg, 35%) as a pale pink powder: ESI-LRMS m/e calcd for C21H28ClN3O5S [M+] 469.1, found 470.1 [M+H+], 452.1 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.20 (m, 2H, CH2), 1.41-1.94 (m, 8H, 4×CH2), 2.14-2.26 (m, 1H, CH), 3.02 (br.s., 2H, 2×OH), 3.27 (s, 3H, SO2CH3), 3.44-3.53 (m, 1H, CH of OCH2), 3.56 (dd, J=11.4, 4.2 Hz, 1H, CH of OCH2), 3.63 (t, J=7.6 Hz, 1H, CH), 3.91-4.11 (m, 3H, OCH and NCH2), 6.65 (d, J=2.3, 1H, Ar), 7.29 (d, J=2.3, 1H, Ar), 7.48 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.62 (d, Jm=1.7 Hz, 1H, Ar), 8.07 (d, Jo=8.2, 1H, Ar), 8.44 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:31])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH:23]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)O)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(CC)CC)C.CS(Cl)(=O)=O.O>C(Cl)Cl>[F:31][C:2]([F:1])([O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19](/[CH:22]=[CH:23]/[CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)(=[O:20])=[O:21])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=S(=O)(CC(O)C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(/C=C/C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazin-1-yl}sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)ethanol (3.6 g, 0.008M) was dissolved in DCM (100 ml) and triethylamine (5.58 ml, 0.04 mol) was added. The mixture was cooled to 0° C. and methane sulphonyl chloride (0.94 ml, 0.012M) added with stirring at room temperature overnight. Water was added and the organic phase separated off, dried over MgSO4, filtered and evaporated to dryness to yield 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-{[(E)-2-(tetrahydro-2H-pyran-4-yl)vinyl]sulfonyl}piperazine. Yield (3.15 g, 86.6%).
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S(O[CH2:57][CH2:58][CH2:59][S:60]([CH3:63])(=[O:62])=[O:61])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].ClC1N=CC(O)=CN=1>CN(C)C=O.O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:57][CH2:58][CH2:59][S:60]([CH3:63])(=[O:62])=[O:61])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: Oc1cnc(Cl)nc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCS(C)(=O)=O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a solution of 145 mg (0.224 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.7 ml of N,N-dimethylformamide, 130 mg (0.445 mmol) of 3-(methylsulfonyl)propyl p-toluenesulfonate and 135 mg (0.977 mmol) of potassium carbonate were added, and the mixture was stirred at 80° C. for 4 hours. 44 mg (0.337 mmol) of 2-chloro-5-hydroxypyrimidine was further added thereto, and the mixture was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=55/45-25/75 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 137.0 mg of the title compound as a white solid (yield: 80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[C:6](\[Br:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14]C(C)(C)C)=[O:13].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[C:6](\[Br:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 20 °C
Yield: 105.7 %

Procedure:
A mixture of 3.3 g of the product of Step B, 30 ml of toluene and 0.33 g of p-toluene sulfonic acid monohydrate was refluxed until gas evolution ceased and was cooled to 20° C. and diluted with ether. The ether phase was washed with water, dried and evaporated to dryness at 40° C. under reduced pressure to obtain 2.9 g of (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=[CH:27]1>>[N:26]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C1=CNC=CN=C1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCCNCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,4-diazepine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J=7.2 Hz, 1 H), 7.86 (d, J=7.2 Hz, 1 H), 7.81 (d, J=8.8 Hz, 1 H), 7.72-7.68 (m, 2 H), 7.58-7.51 (m, 2 H), 6.31 (s, 1 H), 5.32 (s, 2 H), 4.54 (s, 2 H), 4.06-4.04 (m, 2 H), 3.90-3.87 (m, 2 H), 3.72 (s, 2 H), 3.63-3.61 (m, 2 H), 3.46-3.42 (m, 2 H), 2.45 (s, 3 H), 2.32 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O>[C:16]1([CH:15]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])[CH3:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cc1ccccc1
Reactant: Cc1ccccc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(C(C)c2ccccc2)c1C
Reaction time: 0.5 h

Procedure:
O-xylene, 5096g, was charged to a 12 liter bottom outlet Pyrex reactor equipped with a mechanical agitator, heating mantle, addition funnel, cooling coil, thermometer, and a reflux condenser. Sulfuric acid, 981g of 96%, was charged in one portion with agitation. Styrene, 3749g, was added dropwise at 80°-85° C. over 90 min. The mixture was agitated for an additional 30 min. at 80°-85° C. after the styrene addition was complete. The mixture was allowed to settle for 45 min. and the lower sulfuric acid layer was drained off (1294.3g). A solution of sodium hydroxide (80g in 552g of water) was charged and the mixture was adjusted to 80° C. while agitating for 30 min. The mixture was allowed to settle for 30 min. and the lower sodium hydroxide layer was drained off (940.8g) at 80° C. Hot water (1440g) was charged and the mixture was agitated for 15 min. then allowed to settle for 30 min. The water wash was separated leaving 7982g of crude phenylxylylethane alkylate. The phenylxylylethane alkylate was vacuum fractionated to remove excess o-xylene then pure phenylxylylethane, BP 224° C. at 100 mmHg.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:15](=O)[CH2:16][C:17](=O)[CH3:18])[C:9]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:8]1=2)=[O:6])([CH3:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.[NH2:56][NH2:57]>CCO>[F:35][C:32]([F:34])([F:33])[C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=1)[CH2:21][N:14]([C:15]1[CH:16]=[C:17]([CH3:18])[NH:57][N:56]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])[C:8]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:9]1=2
Reactant: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Reactant: NN
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCO
Solvent: O
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2CCCN(C(=O)OC(C)C)c3cc(Cl)ccc32)n[nH]1
Temperature: 0 °C
Yield: 21.2 %

Procedure:
Add cold (ice bath) absolute EtOH (1 mL) slowly to a cooled 0° C. stirred mixture of (+/−)-5-[(3,5-bistrifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester (118 mg, 0.20 mmol) and phosphorus pentoxide (511 mg, 3.6 mmol). Then, add hydrazine hydrate (0.062 mL, 2.0 mmol) dropwise while keeping the mixture cooled at 0° C. Heat at 100° C. overnight in a sealed tube. Cool down the mixture and remove the solvents under reduce pressure. Partition the residue between water and dichloromethane. Separate the layers, and dry organic phase over anhydrous magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, and then by a SCX cartridge to afford the title compound (25 mg, 21%). MS (ES+): 589 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([I:11])[CH:5]=1.[OH-].[Na+].O>CO>[I:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([OH:12])=[O:2]
Reactant: COC(=O)c1ccc(C)c(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methyl-3-Iodo-4-methylbenzoate (3 g, 109 mmol, 1 eq) dissolved in MeOH (30 ml) was added sodium hydroxide (1.3 g, 327 mmol, 3 eq) followed by the addition of water (15 ml). The above solution was stirred at room temperature for 14 h. The solution was concentrated under vacuum, and then added water. The pH of the reaction was bought to 3 using Conc. HCl. The solid obtained was filtered and dried under vacuum. Yield: 2.7 g (96%). 1HNMR (400 MHz, DMSO-d6): δ 2.44 (s, 3H), 7.45 (d, J=8.00 Hz, 1H), 7.85 (d, J=3.18 Hz, 1H), 8.31 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:16]2[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:26][CH:25]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(Cl)cc1
Yield: 50 %

Procedure:
4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.036 g (50%) of 4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:6](=[O:22])[N:5]([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:4]=2[N:3]=1.N1CCOCC1>O1CCCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])[C:6](=[O:22])[N:5]([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCC(F)(F)F)c(=O)n2CCCC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: O=c1c2[nH]c(Cl)nc2n(CCCC(F)(F)F)c(=O)n1CCCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
8-chloro-7-(2-propen-1-yl)-1,3-bis(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione (478 mg, 1.1 mmol) and morpholine (937 ul, 11 mmol) were degassed with nitrogen in tetrahydrofuran (10 ml) and then tetrakis(triphenylphosphine)palladium(0) (123 mg, 0.11 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and hydrochloric acid 2N. The organic phase was separated and reduced to give the crude product. This was purified by aminopropyl SPE (5 g) followed by re-crystallisation from acetonitrile to afford the title compound (75.5 mg, 16.9%). NMR. δH (400 MHz, CDCl3) 1.96-2.13 (m, 4H), 2.15-2.29 (m, 4H), 4.15-4.23 (m, 4H), 12.94 (br. s, 1H); m/z 407 [MH+].
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:13]=[C:12]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=2)[C:9]=1[C:10]#[N:11].C1COCC1.[O:42]=[C:43]1[O:47][CH:46]([C:48](Cl)=[O:49])[CH2:45][CH2:44]1>C(#N)C>[NH2:7][C:8]1[C:9]([C:10]#[N:11])=[C:12]([C:30]2[CH:31]=[C:32]([NH:36][C:48]([CH:46]3[CH2:45][CH2:44][C:43](=[O:42])[O:47]3)=[O:49])[CH:33]=[CH:34][CH:35]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[N:15]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(N)c2)c(C#N)c(N)n1
Reactant: O=C1CCC(C(=O)Cl)O1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(NC(=O)C3CCC(=O)O3)c2)c(C#N)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a cold (0° C.) mixture of pyridine (0.20 mL, 2.424 mmol), 2-amino-4-(3-aminophenyl)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)nicotinonitrile (starting compound 2, 1.010 g, 2.424 mmol), acetonitrile (10 mL) and THF (2 mL) was added dropwise a solution of 5-oxotetrahydro-2-furancarbonyl chloride (0.360 g, 2.424 mmol) in acetonitrile (4 mL). The mixture was stirred for 2 hrs., allowed to warm to room temperature, stirred for 1 hr., and extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (hexane:Ethyl acetate, 7:3-5:5) to give N-{3-[2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-cyano-4-pyridinyl]phenyl}-5-oxotetrahydro-2-furancarboxamide as a white solid (0.982 g, yield 77%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8][CH2:9][CH3:10])=[CH2:7])CCC.Br[C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[CH3:31]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([O:8][C:6]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[CH3:31])=[CH2:7])[CH3:10]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)N(C)c1ccc(Br)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(N(C)C(C)=O)cc1C
Temperature: 90 °C
Reaction time: 12 h
Yield: 176.3 %

Procedure:
Tributyl(1-ethoxyvinyl)tin (1.07 mmol, 3.18 mmol) and dichlorobis(triphenylphosphine)palladium(II) (101 mg, 0.145 mmol) were added to a solution of N-(4-bromo-3-methylphenyl)-N-methylacetamide (700 mg, 2.89 mmol) in 1,4-dioxane (7 mL), and the mixture was heated with stirring at 90° C. for 12 hours in a nitrogen stream. The reaction mixture was cooled and then filtered through celite. The solution was concentrated under reduced pressure, and the residue was then silica gel column chromatography (hexane-ethyl acetate) to give N-[4-(1-ethoxy-vinyl)-3-methyl-phenyl]-N-methyl-acetamide (440 mg, 65%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[OH-:13].[Na+].[NH2:15]O.Cl>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[N:15][OH:13]
Reactant: [OH-]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Product: ON=Cc1cccc(C(F)(F)F)c1
Yield: 93.5 %

Procedure:
In a similar manner as described in Preparation Example 1, by using 3-(trifluoromethyl)benzaldehyde (34.82 g, 200.0 mmol), sodium hydroxide (12.00 g, 300.0 mmol) and hydrochloric acid hydroxylamine (16.68 g, 240 mmol), a white solid required compound (35.33 g, 187 mmol, 93%) was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](B(O)O)=[CH:3][N:2]=1.Cl[C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[IH:22]>>[I:22][C:15]1[CH:20]=[C:19]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=[N:2][CH:3]=2)[N:18]=[CH:17][N:16]=1
Reactant: OB(O)c1cncc2ccccc12
Reactant: I
Reactant: Clc1cc(Cl)ncn1
Product: Ic1cc(-c2cncc3ccccc23)ncn1

Procedure:
The compound was prepared according to Example 1 using isoquinoline-4-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=O)(C)(C)C.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[C:22]([CH:32]=1)[CH2:23][NH:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@H:9]([C:14]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:25]([NH:24][CH2:23][C:22]1[CH:32]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)=[O:31])=[O:16])[NH2:8]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cncn1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](N)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-(tert-butoxycarbonyl)-3-methyl-D-valine (53 mg, 0.23 mmol), N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide (87 mg, 0.23 mmol, 1.0 equiv), EDC (66 mg, 0.34 mmol, 1.5 equiv), HOAt (16 mg, 0.11 mmol, 0.5 equiv) in DMF (1 mL) was brought to pH 6 by addition of Hünig's base and stirred at room temperature for 18 h. The solvent was removed in vacuo, and the resulting residue was dissolved in 2:1 CH2Cl2/TFA (3 mL) and stirred for 1 h. Solvent was again removed in vacuo, and purification by reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 50:50 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 8.93 (s, 1 H), 8.29 (s, 1 H), 8.00 (br s, 1 H), 7.55 (d, J=2.0 Hz, 1 H), 7.39 (dd, J=2.0, 8.4 Hz, 1 H), 7.25 (d, J=8.4 Hz, 1 H), 7.01 (br s, 2 H), 4.47–4.45 (m, 1 H), 4.35–4.30 (m, 2 H), 4.15 (dd, J=5.2, 15.2 Hz, 1 H), 3.80–3.71 (m, 1 H), 3.58–3.52 (m, 1 H), 2.15–2.12 (m, 2 H), 2.01–1.98 (m, 2 H), 1.10 (s, 9 H). HRMS (APCI) M+H: calculated for (C20H27N6O2Cl)+ 419.1957, found 419.1935.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=O)O[C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[CH:4][CH:3]=1.Br/C(=[CH:22]\[C:23]([F:26])([F:25])[F:24])/C#N.[CH2:27]([N:29](CC)CC)C.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[C:22]([C:23]([F:26])([F:25])[F:24])[C:12]=2[C:27]#[N:29])=[CH:4][CH:3]=1
Reactant: O=C1OC(C(F)(F)F)=NC1c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Reactant: N#C/C(Br)=C/C(F)(F)F
Solvent: O
Solvent: CC#N
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
4-(p-Chlorophenyl)-2-(trifluoromethyl)-2-oxazolin-5-one (2.0 g, 7.59 mmol) and 2-bromo-4,4,4-trifluorocrotononitrile (0.81 g, 4.05 mmol) are dissolved in acetonitrile (10 mL). To the resulting yellow solution triethylamine (0.45 g, 4.46 mmol) is added dropwise while the reaction flask is cooled with a water bath. After stirring at 25° C. overnight, the reaction mixture is poured into water. The aqueous layer is extracted with ethyl acetate and the combined organic extracts are washed sequentially with water, 5% sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow solid. The solid is chromatographed using silica gel and eluted with hexane/ethyl acetate 3:1 to yield the title compound as yellow crystals (1.26 g, mp 208° C.)