Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4](Cl)[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[C:15]([C:19]1[CH:20]=[C:21]([CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[OH:31])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[C:15]([C:19]1[CH:20]=[C:21]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[O:31][P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4]([O:31][C:30]2[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:28][C:29]=2[C:32]([CH3:35])([CH3:34])[CH3:33])[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:17])([CH3:18])[CH3:16]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)N1P(Cl)N(C(C)(C)C)P1Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cc(C(C)(C)C)c(OP2N(C(C)(C)C)P(Oc3c(C(C)(C)C)cc(CCC(=O)OC)cc3C(C)(C)C)N2C(C)(C)C)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine, methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and triethylamine to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:27]Br.O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:27][C:26]2[CH:25]=[C:24]([F:23])[CH:31]=[C:30]([F:32])[CH:29]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=C(c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12)C(F)(F)F
Temperature: 80 °C
Yield: 62.6 %

Procedure:
A mixture of 2.0 g (9.4 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, 4.59 g (14.1 mmol) cesium carbonate and 2.14 g (10.4 mmol) 3,5-difluorobenzyl bromide in 90 ml acetonitrile was heated at 80° C. for 3 h. After cooling to room temperature addition of 150 ml water was followed by extraction with three 150-ml portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in 30 ml hot cyclohexane. Filtration gave 2.2 g (64%) of the crude title compound as light brown solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[C:23]3[CH:30]4[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:32][CH:24]3[CH2:25]5)[CH2:29]4)[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.O.O>C1COCC1.CCOCC>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[C:23]3[CH:30]4[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:32][CH:24]3[CH2:25]5)[CH2:29]4)[C:14]3[C:19]([O:20][C:21]=2[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)Oc1ccccc1C2=C1C2CC3CC(C2)CC1C3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Oc1ccc2c(c1)Oc1ccccc1C2=C1C2CC3CC(C2)CC1C3
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
The silylated alkene 5b (1.18 g, 2.6 mmol) was dissolved in 10 ml of THF. n-Bu4NF.3H2O (0.94 g, 3.0 mmol) was added and the yellow solution stirred for 30 min. The solution was then diluted with Et2O (100 mL), washed with H2O (200 mL), and the organic layer was concentrated. Recrystallization from ethyl acetate gave 0.48 g (1.5 mmol, 57.7%) of 5a as a white solid: 235°-240° C. (dec); 1H NMR (CDCl3) delta 1.873 (2, 10H), 1.992 (s, 2H), 3.472 (s, 1H), 3.529 (s, 1H), 6.70-6.76 (m, 2H), 6.96-7.04 (m, 2H), 7.06-7.14 (m, 2H), 7.21-7.29 (m, 2H); HRMS calc. 330.1621, found 330.1617; MS m/e (rel. intensity) 330 (100), 329 (43), 273 (37), 235 (16), 197 (11), 142 (65). Anal. calcd for C23H22O2 : C, 83.64; H, 6.67. Found; C, 83.75; H, 6.69. ##STR38##
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[C:46]([CH:50]=1)[C:47]([OH:49])=[O:48]>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@@H:9]([C:28]([NH:41][C:42]3[CH:43]=[CH:44][C:45]([N:51]4[CH2:55][CH2:54][CH2:53][CH2:52]4)=[C:46]([CH:50]=3)[C:47]([OH:49])=[O:48])=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])=[C:16]([F:22])[CH:17]=1
Reactant: Nc1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(N3CCCC3)c(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 17.4 %

Procedure:
To a stirred solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmol) in dichloromethane (5.00 ml) were added N,N-DIISOPROPYLETHYLAMINE (99.6 mg, 0.770 mmol) and N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (90.3 mg, 0.237 mmol, Chem-Impex) followed by 5-amino-2-(pyrrolidin-1-yl)benzoic acid (38.5 mg, 0.187 mmol, Array). The reaction mixture was stirred for 2 hr. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 8 g, 0.5% to 5% MeOH in CH2Cl2) to give rac-5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-pyrrolidin-1-yl-benzoic acid as white solid (14.6 mg, 15.4%). MS (ES+) m/z Calcd: [(M+H)+]: 655. found: 655.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Br)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1Br)C2
Yield: 74.2 %

Procedure:
A mixture of 7-(2-bromophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.49 g), aminoguanidine hydrochloride (0.19 g), concentrated hydrochloric acid (0.39 ml), water (0.39 ml) and ethanol (50 ml) was refluxed for 6.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-water to give 7-(2-bromophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 66) (0.47 g) as colorless crystals.
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][NH:15][CH2:16][CH2:17][NH:18][C:19]([C:21]34[CH2:30][CH:25]5[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]5)[CH2:22]3)[CH2:28]4)=[O:20])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:31]OC1C2OC(CNCCNC(C34CC5CC(CC(C5)C3)C4)=O)=CC=2C=CC=1.Cl.C=O>C(O)C.[Pd]>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][NH:18][C:19]([C:21]34[CH2:22][CH:23]5[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]5)[CH2:30]3)[CH2:28]4)=[O:20])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2cc(CNCCNC(=O)C34CC5CC(CC(C5)C3)C4)oc12
Agent: [Pd]
Agent: C=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cccc2cc(CN(C)CCNC(=O)C34CC5CC(CC(C5)C3)C4)oc12
Reaction time: 24 h
Yield: 58.8 %

Procedure:
N-[2-[[(7-Methoxy-2-benzofuranyl)methyl]amino]ethyl]tricyclo[3.3.1.13,7 ]decane-1-carboxamide hydrochloride hemihydrate (1.0 g, 2.4 mmole), prepared as in Example 2, was dissolved in 100 ml of ethanol and 5 ml of 38% aqueous formaldehyde and 500 mg of 10% palladium on carbon were added. The mixture was hydrogenated at 50 psi on a Parr apparatus for 24 hours. The mixture was then filtered through celite and 300 ml of ether added. It was washed with 100 ml portions of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was purified by column chromatography on 100 g of silica gel with chloroform as eluant and recrystallized from acetone/diethyl ether with the addition of 3 ml of 4N HCl/isopropanol to give 560 mg of the title compound as a white solid, monohydrochloride, quarter hydrate, m.p. 156°-158° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@:8]([CH3:32])([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]3)[CH:17]=2)[CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].N1C=NN=N1.C(N(CC)[P:42]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])C.[OH:55]O>O1CCCC1>[C:1]([O:5][C:6](=[O:33])[NH:7][C@:8]([CH3:32])([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][C@H:22]3[CH2:23][CH2:24][C@H:25]([C:28]([F:30])([F:31])[F:29])[CH2:26][CH2:27]3)[CH:17]=2)[CH:12]=1)[CH2:9][O:10][P:42]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:55])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Reactant: OO
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {(R)-2-Hydroxy-1-methyl-1-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-ethyl}-carbamic acid tert-butyl ester (172 mg, 0.000368 mol) and 1H-tetrazole (0.255 g, 0.00364 mol, ChemPacific) in tetrahydrofuran (3.00 mL, Acros) was added di-tert-butyl N,N-diethylphosphoramidite (512 μL, 0.00184 mol, Aldrich) and the reaction was stirred at rt for 16 hours. Hydrogen peroxide (250 μL, 0.0024 mol, Aldrich) was added and the reaction was stirred for 1.5 hours. The reaction was then quenched with 10% NaS2O3 in saturated sodium bicarbonate, extracted with EtOAc, washed with saturated sodium chloride and then dried with Na2SO4. The drying agent was filtered and the organic layer was concentrated in vacuo. The crude product was taken up in DCM and purified using silica gel chromatography (0-100% ethyl acetate in hexanes). Isolated was the product (Rf=0.52 in 1:1 hexanes/ethyl acetate) in 107.8 mg yield (44%).
Reaction SMILES: O[C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][Cl:20].[CH3:22][O-:23].[Na+]>ClC1C=CC=CC=1>[ClH:20].[ClH:20].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:22][O:23][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:19][CH2:18][N:17]([CH3:21])[CH3:16])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Oc1ccc2sc3ccc(O)cc3c2c1
Reactant: C[O-]
Reactant: CN(C)CCCl
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CN(C)CCOc1ccc2sc3ccc(OCCN(C)C)cc3c2c1
Product: Cl

Procedure:
To 200 ml of chlorobenzene is added 16.1 g (0.0745 mole) of 2,8 -dihydroxydibenzothiophene, 16.8 g (0.156 mole) of 2-dimethylaminoethyl chloride and 8.3 g (0.154 mole) of sodium methoxide. The mixture is stirred and heated to reflux for 16 hours. The cooled reaction mixture is filtered and the filtrate is washed with several portions of water, then dried over anhydrous magnesium sulfate. The chlorobenzene solution is evaporated in vacuo. The oily residue is dissolved in ether and treated with ethereal hydrogen chloride to give 2,8-bis(2-dimethylaminoethoxy)dibenzothiophene dihydrochloride which is crystallized from methanol-butanone, M.P. 248°-250°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:8]([CH:9]([CH3:11])[CH3:10])[N:7]=[C:6]([O:12][CH3:13])[CH2:5][N:4]=1.[Li]CCCC.[CH3:19][O:20][C:21]1[CH:32]=[CH:31][C:24](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1.C(O)(=O)C>C1COCC1.CCOCC>[CH3:30][O:29][C:27](=[O:28])[CH2:26][C@@H:25]([C@H:5]1[C:6]([O:12][CH3:13])=[N:7][C@H:8]([CH:9]([CH3:11])[CH3:10])[C:3]([O:2][CH3:1])=[N:4]1)[C:24]1[CH:31]=[CH:32][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1
Reactant: COC(=O)/C=C/c1ccc(OC)cc1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C[C@H](c1ccc(OC)cc1)[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC
Temperature: -70 °C
Reaction time: 0.67 h
Yield: 81.3 %

Procedure:
To a solution of (R)-2,5-dimethoxy-3-isopropyl-3,6-dihydropyrazine (18.4 g, 100 mmol) in 250 mL of dry THF at −70° C. (internal temperature) was added dropwise a solution of n-BuLi (1.6 M in hexane, 63 mL, 100 mmol) over 3 hours so as to maintain the internal temperature below −70° C. After addition, the solution was stirred at −70° C. for 40 min. To the solution was then added 90 mL of a THF solution of methyl trans-4-methoxycinnamate (21.2 g, 110 mmol) over 1 hour. The resulting solution was stirred at −70° C. for additional 4 hours. The reaction was quenched by the addition of acetic acid (6.1 mL, 100 mmol) at −70° C. and the resulting suspension was warmed to room temperature to give a yellow solution. The solution was diluted with ether to 1000 mL and the organic layer was washed with water (3×80 mL) and brine (3×80 mL) and dried over MgSO4. After removal of the solvent, the residue (44.3 g) was purified by HPLC on silica gel, eluting with ethyl acetate/hexane (1:5.5) to give 3(R)-[(2S,5R)-2,5-dihydro-3,6-dimethoxy-5-(1-methylethyl)-2-pyrazinyl]-3-(4-methoxyphenyl)propanoic acid methyl ester (30.6 g, 81.3 mmol, 81.3%). TLC: Rf=0.3, ethyl acetate/hexane (1/5). HRMS, obs. 377.2071, calc. 377.2076. Anal. cacld for C20H26N2O5: C, 64.16; H, 7.00; N, 7.48. Found: C, 64.05; H, 7.28; N, 7.37.
Reaction SMILES: [Mg].[Br-].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([C:15](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O1CCCC1>[C:3]1([CH:16]([OH:17])[C:15]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccccc1
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCC(=Cc1ccccc1)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 115.2 %

Procedure:
In a 2-liter three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 13.2 g of magnesium and 300 milliliters of tetrahydrofuran were introduced and stirred violently. Then, a solution of 83.2 g of benzene bromide in 100 milliliters of tetrahydrofuran was added dropwise for 40 minutes. At that time, cooling was carried out with an ice bath if required. After the dropwise addition was ended, stirring was carried out at room temperature for 1 hour, and thereafter 108.2 g of α-n-hexyl cinnamaldehyde was added dropwise. After stirring for one day and one night, the solution was poured in ice water containing dilute hydrochloric acid, and extracted with 1 liter of ethyl acetate. After the solution was washed with an aqueous solution of sodium hydrogencarbonate and water, it was dried with anhydrous magnesium sulfate. After removing the solvent off by a rotary evaporator, 169.6 g of 1,3-diphenyl-2-n-hexyl-2-propen-1-ol was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[H][H]>C(O)C.[Rh]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][CH2:14][CH3:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: [H][H]
Reactant: C=CCc1cc(C(=O)OC)cc(Cl)c1O
Agent: [Rh]
Solvent: CCO
Product: CCCc1cc(C(=O)OC)cc(Cl)c1O
Reaction time: 0.5 h

Procedure:
A Parr flask was charged with a solution of 14.784 g (65.2 mmol) of the product of step A dissolved in 80 mL ethanol and 0.485 g of 5% rhodium on alumina catalyst was added. The reaction mixture was mounted in a Parr hydrogenation apparatus, pressurized to 40 psig hydrogen and shaken for 30 minutes. The reaction vessel was then removed from the apparatus, the contents were filtered and the flitrate was evaporated and dried in vacuo to afford 14.878 (99%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[N:10]1([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Oc1ccc(CN2CCCCC2)cc1
Reaction time: 16 h

Procedure:
A solution of 4-hydroxybenzaldehyde (10 g), piperidine (8.9 mL), and acetic acid (4.7 mL) in DCE (200 mL) was treated with sodium triacetoxyborohydride (24 g). After 16 h, the resulting mixture was treated with saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (5×100 mL). The combined organic phases were dried (magnesium sulfate) and evaporated. Trituration of the residue with ethyl acetate gave the title compound as a white crystalline solid (5.5 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.[NH2:9][CH2:10][C:11]1[CH:12]=[C:13]([B:17]([OH:19])[OH:18])[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:5]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([B:17]([OH:19])[OH:18])[CH:14]=[CH:15][CH:16]=1)(=[O:7])[CH3:6]
Reactant: NCc1cccc(B(O)O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCc1cccc(B(O)O)c1
Reaction time: 1 h
Yield: 23.3 %

Procedure:
Acetic anhydride (76 μL, 0.80 mmol) was added dropwise to a stirred solution of (3-aminomethylphenyl)boronic acid, hydrochloride (150 mg, 0.80 mmol) and DIEA (560 μL, 3.2 mmol) in CH2Cl2 (5 mL) at 0° C. After 1 h, the solution was concentrated in vacuo and purified by preparatory HPLC to give 36 mg (23%) of the title compound as a white solid. [M+H] calc'd for C9H12BNO3, 194; found, 194.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[F:10][C:11]([F:20])([F:21])[O:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([O:12][C:11]([F:10])([F:20])[F:21])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: Fc1cnc(Nc2cccc(OC(F)(F)F)c2)nc1Nc1cccc(OC(F)(F)F)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-trifluoromethoxyaniline were reacted to yield N2,N4-bis(3-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.03 (bd, 1H), 7.62 (bs, 2H), 7.48 (bd, 1H), 7.39 (t, 1H, J=8.1 Hz), 7.34 (m, 1H), 7.29 (t, 1H, J=7.5 Hz), 7.01 (m, 2H), 6.88 (m, 2H); 19F NMR (CDCl3): −16447 (s, 3F), −16459 (s, 3F), −46738 (s, IF); LCMS: ret. time: 33.77 min.; purity: 93%; MS (m/e): 449 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)([N:22]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH2:22])=[O:6]
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 59.1 %

Procedure:
To a solution of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (145.0 mg, 0.33 mmol) in N,N-dimethylformamide (1.50 ml), 1,1′-carbonylbis(1H-imidazole) (60 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 7 hours to obtain a homogeneous solution. Ammonium acetate (65 mg, 0.83 mmol) was added, and stirred for 2 h. Water (10 ml) was added, and the precipitated solid was filtered, washed with hot methanol to obtain 2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide as an yellow solid (85 mg, 58%) LC/MS: [9.59 min; 436, 438]
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C)C=O>[CH2:12]([N:6]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C)n1Cc1ccccc1

Procedure:
Ethyl 5-methyl-1H-pyrrole-2-carboxylate (1.1 g) and benzyl bromide (1.35 g) in N,N-dimethylformamide (30 mL) was treated with NaH (95%, 0.5 g) overnight. The reaction was quenched with ice water. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.CC1(C)CCCC(C)(C)N1.C[Si](C)(C)[N:24]1[CH2:30][CH2:29][CH2:28][CH2:27]C[C:25]1=[O:31].Cl[C:35]1[CH:40]=[CH:39]C=[CH:37][C:36]=1[O:41][CH3:42].C(I)C>C1COCC1>[CH2:4]([C:3]1([C:2]2[CH:39]=[CH:40][CH:35]=[C:36]([O:41][CH3:42])[CH:37]=2)[CH2:27][CH2:28][CH2:29][CH2:30][NH:24][C:25]1=[O:31])[CH3:5]
Reactant: COc1ccccc1Cl
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)N1CCCCCC1=O
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCI
Product: CCC1(c2cccc(OC)c2)CCCCNC1=O
Reaction time: 0.17 h

Procedure:
To 1.6 M n-BuLi in hexane (31.3 mL, 50 mmol) at 0° C. was added a solution of 2,2,6,6-tetramethyl piperidine (8.43 mL, 50 mmol) in anhydrous THF (100 mL) over 5 min. 1-Trimethylsilanyl-azepan-2-one (as described in Example 5, Step A) (9.26 g, 50 mmol) in anhydrous THF (20 mL) was added. After stirring the reaction mixture for 10 min, a further portion of 1.6M n-BuLi in hexane (31.3 mL, 50 mmol) was added, the mixture stirred for 10 min, and 2-chloroanisole (6.34 mL, 50 mmol) was added. After stirring for 30 min under Ar, ethyl iodide (3.90 mL, 48.7 mmol) was added, the reaction mixture was stirred for 30 min, quenched with H2O, concentrated in vacuo, diluted with EtOAc, and washed with 5N HCl (100 mL) and brine. The organic layer was dried (MgSO4), concentrated and purified using SiO2 chromatography (10-15% EtOAc/CH2Cl2) to give the title compound.