Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[CH2:7]([OH:10])[C:8]#[CH:9]>[Cu]I>[O:4]1[CH:5]=[CH:6][C:2]([C:9]#[C:8][CH2:7][OH:10])=[CH:3]1
Reactant: C#CCO
Reactant: Brc1ccoc1
Agent: [Cu]I
Product: OCC#Cc1ccoc1
Yield: 17.8 %

Procedure:
To a mixture of 3-bromofuran (10 g, 0.068 mol) and propargyl alcohol (4.3 ml, 0.074 mol) in 200 ml of TEA was added under argon, CuI (0.26 g, 1.4 mmol) and [(C6H5)3P]2PdCl2 (1.05 g, 1.4 mmol) and the mixture was stirred at 0° C. for 2 hours and at room temperature for 72 hours. The reaction mixture was cooled, decanted, and the solid was washed with TEA. The combined TEA solution was concentrated in vacuo and the residue was distilled (Kugelrohr distillation) to afford 1.48 g (17.8%) of 3-(3-furyl)-2-propynyl alcohol.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[CH3:18])[C:5]=1[OH:19])[CH:2]=[CH2:3]>C(Cl)Cl.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[C:5]([OH:19])=[C:4]([CH:1]=[CH:2][CH3:3])[CH:9]=[CH:8][C:7]=2[F:10])=[C:12]([CH3:18])[CH:13]=1
Reactant: C=CCc1ccc(F)c(-c2ccc(Cl)cc2C)c1O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Product: CC=Cc1ccc(F)c(-c2ccc(Cl)cc2C)c1O
Yield: 80.1 %

Procedure:
Treatment of 3-allyl-4′-chloro-6-fluoro-2′-methylbiphenyl-2-ol (2.0 g, 7.22 mmol) in methylene chloride (70 mL) with dichlorobis(acetonitrile)palladium (II) (0.25 g, 1.0 mmol) according to the procedure described for Example 69, Step 5 provided 1.6 g (80%) of 4′-chloro-6-fluoro-2′-methyl-3-(prop-1-enyl)biphenyl-2-ol as a colorless oil, MS (ESI) m/z 275.00 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7](=[O:12])[NH:6][C:5]=2[N:4]=[CH:3]1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22]>CS(C)=O>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:6]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:10]=2[C:9](=[O:11])[NH:8][C:7]1=[O:12])#[N:22]
Reactant: N#CCCCCCBr
Reactant: Cn1cnc2[nH]c(=O)[nH]c(=O)c21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cnc2c1c(=O)[nH]c(=O)n2CCCCCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
To a stirring slurry of 2.69 g 7-methylxanthine (16.2 mmol) (Aldrich, Milwaukee, Wis.) in 50 ml methyl sulfoxide was added 0.39 g sodium hydride (16.2 mmol). After 1 hour, 2.85 g of 6-bromocapronitrile (16.2 mmol) (Lancaster Synthesis, Inc., Windham, N.H.) was added neat and the reaction was stirred for 72 h at room temperature. The mixture was then quenched with 150 mL water and extracted five times with 35 ml methyl acetate. The combined extracts were washed two times with 40 ml saturated aqueous sodium bicarbonate solution and two times with 40 ml saturated aqueous sodium chloride solution and then dried over sodium sulfate. After concentration under vacuum, the residual white powder was recrystallized with ethyl acetate-hexane solution to yield 0.64 g 3-(cyanopentyl)-7-methylxanthine (15% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=3)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)O)[N:10]([CH3:12])[N:11]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH2:13][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[N:10]([CH3:12])[N:11]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cc(NCc3cccc(Cl)c3)nn2C)c2cc(F)cnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(NCc2cccc(Cl)c2)cc1Cc1c[nH]c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [5-(3-chloro-benzylamino)-2-methyl-2H-pyrazol-3-yl]-(5-fluoro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (147, 0.070 g, 0.13 mmol) in 4 mL of dichloromethane, triethylsilane (0.210 mL, 1.31 mmol) and trifluoroacetic acid (0.100 mL, 1.30 mmol) were added and the reaction stirred overnight at room temperature. The reaction was concentrated under vacuum, then ethyl acetate was added, then washed with 1M aqueous potassium carbonate, then brine. The organic layer was dried over sodium sulfate, filtered and the filtrate purified by silica gel flash column chromatography eluting with a gradient of 2-20% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum and the resulting solid washed with ethyl acetate in hexane to provide the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1[C:38]([F:41])([F:40])[F:39]>CN(C=O)C.CCOC(C)=O>[F:39][C:38]([F:40])([F:41])[C:29]1[CH:30]=[C:31]([C:34]([F:37])([F:35])[F:36])[CH:32]=[CH:33][C:28]=1[CH2:27][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc21
Temperature: 70 °C

Procedure:
To a mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.130 g, 0.5 mmol) and K2CO3 (0.069 g, 0.500 mmol) in DMF (1 mL) was added 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (0.154 g, 0.500 mmol). The mixture was heated at 70° C. overnight, taken up in EtOAc, washed with water (thrice) and brine. The organics were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound an orange solid (0.195 g). LCMS m/z 486.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A solution of N-(5-bromo-2-nitrophenyl)benzenamine (250 mg, 0.85 mmol) and piperazine (366 mg, 4.26 mmol) in NMP (1 mL) was heated to 110° C. for 16 h. The solution whole cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 10 mL of water, dried (high vacuum, 14 h) to furnish 2-nitro-N-phenyl-5-(piperazin-1-yl)aniline (165 mg, 0.55 mmol), 65% yield. 1H NMR (500 MHz, CDCl3) d (ppm) 9.89 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.45 (m, 2H), 7.34 (d, J=7.0 Hz, 2H), 7.25 (t, J=7.0 Hz, 1H), 6.43 (d, J=2.5 Hz, 1H), 6.35 (dd, 2.5 Hz, 9.75 Hz, 1H), 3.29 (m, 4H), 2.92 (m, 4H).+ESI HRMS (calcd for C16H19N4O2, M+1) 299.1508, found 391.150
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH2:10])=[O:4].[O-:11][C:12]#[N:13].[K+]>C(O)(=O)C.O>[NH:10]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3](=[O:4])[NH:13][C:12]1=[O:11]
Reactant: N#C[O-]
Reactant: COC(=O)c1ccsc1N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2ccsc2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.2 %

Procedure:
To a stirred solution of methyl-2-aminothiophene-3-carboxylate (2.03 g, 12.9 mmol) in acetic acid (65 mL) and water (6.5 mL) was added a solution of potassium cyanate (3.14 g, 38.7 mmol) dissolved in water (10.4 mL) dropwise via syringe. The reaction was stirred at room temperature for 15 h, upon completion of the reaction; the reaction mixture was concentrated to 75% and filtered off white solid. To the solid was added 6% aqueous sodium hydroxide (16 mL) and refluxed for 2 h. After cooling to room temperature, the solution was acidified using 12N HCl to pH=6. The resultant precipitate was filtered, washed with water and dried in a vacuum oven overnight to give 546 mg (25%) of the title compound as an orange-solid which was used without any further purification:
Reaction SMILES: C1(S([C:10](=[CH:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])(=O)=O)C=CC=CC=1.COCCO.[N-:36]=[N+:37]=[N-:38].[Na+]>O>[CH3:30][C:27]([C:18]1[CH:17]=[C:16]([C:15]2[NH:36][N:37]=[N:38][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH:21]=[C:20]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:19]=1[OH:26])([CH3:28])[CH3:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)C(=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)S(=O)(=O)c1ccccc1
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: CNC(=O)c1nn[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A 250 mL 3-neck round-bottom flask immersed in an oil bath, equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen bubbler, was charged with 42.96 g (0.100 mol) of 2-(benzenesulfonyl)-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methylacrylamide (II), 100 mL of 2-methoxyethanol and 6.83 g (0.105 mol) of sodium azide. The yellow mixture was heated at 105° C. for 30 h. The cooled orange solution was poured onto a mixture of 150 g of ice and 150 mL of deionized water. The yellow suspension was agitated for 1 h at 5° C. The resulting solid precipitate was filtered off and washed with 5×50 mL of cold deionized water. The recovered solids were dried in vacuo over potassium hydroxide flakes to afford yellow solids, 30.2 g of crude product (I), 98.7% purity by HPLC.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[CH3:26][S:27]([N:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28].C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:33]3[CH2:34][CH2:35][CH2:36][N:30]([S:27]([CH3:26])(=[O:28])=[O:29])[CH2:31][CH2:32]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CS(=O)(=O)N1CCCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCCN(S(C)(=O)=O)CC3)n2n1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol), 1-(methylsulfonyl)-1,4-diazepane hydrochloride (107 mg, 0.50 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (30-30% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (93.0 mg, 76%). 1H NMR (DMSO-d6) δ: 10.87 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.16 (s, 1H), 6.16 (s, 1H), 4.32 (t, J=5.3 Hz, 2H), 4.00 (t, J=5.9 Hz, 2H), 3.53 (t, J=5.3 Hz, 2H), 3.36-3.45 (m, 2H), 2.90 (s, 3H), 2.37 (s, 3H), 1.95-2.15 (m, 2H), 1.45 (s, 6H); ESI-MS: m/z 487.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([C:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].Cl[CH2:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)=O>>[CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:37][CH2:38][N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 47.3 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (18 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.5 mg) was obtained.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH3:20])[C:15]([OH:17])=O)[N:13]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[CH3:32][C:33]([O:35][CH2:36][C:37]1[CH2:46][S:45][C@@H:40]2[C@H:41]([NH2:44])[C:42](=[O:43])[N:39]2[C:38]=1[C:47]([OH:49])=[O:48])=[O:34]>CC(N(C)C)=O>[C:33]([O:35][CH2:36][C:37]1[CH2:46][S:45][C@@H:40]2[CH:41]([NH:44][C:15](=[O:17])[C:14]([C:12]3[N:13]=[C:9]([NH2:8])[S:10][CH:11]=3)=[N:18][O:19][CH3:20])[C:42](=[O:43])[N:39]2[C:38]=1[C:47]([OH:49])=[O:48])(=[O:34])[CH3:32]
Reactant: CON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
The process of Example 8 was repeated except that after addition of triethylamine to the syn isomer of 2-(2-amino-4-thiazolyl)-2-methoxyimino-acetic acid, the mixture was cooled at 0° C. and the tosyl chloride in dimethylacetamide was added over 15 to 20 minutes. The reaction with 7-amino-cephalosporanic acid took place over 30 minutes.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]4=[CH:26][S:27][CH:28]=[C:24]4[N:23]=[C:22]3[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=O)(C)(C)C.[C:33]1([C:39]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:40]2C(C3C=CC=CC=3C3C=CC(CBr)=CC=3)=[N:43][N:42]=[N:41]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:29]([C:22]1[N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]3[N:40]([C:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)[N:41]=[N:42][N:43]=3)=[CH:15][CH:16]=2)[C:25]2=[CH:26][S:27][CH:28]=[C:24]2[N:23]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1nc2cscc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nc2cscc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
This Step A compound can be prepared in a similar fashion to the preparation of 4'-[(2-butyl-1H-thieno[3,4-d]imidazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid t-butyl ester (Example 1, Step B) except that the alkylating agent used can be 2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl methyl bromide in place of t-butyl-4'-bromomethylbiphenyl-2-carboxylate.
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][CH2:20][CH:8]([C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:7]=2[CH:6]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[OH:1][CH:2]([CH2:21][NH:25][CH:22]([CH3:24])[CH3:23])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][CH2:20][CH:8]([C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:7]=2[CH:6]=1
Reactant: CC(C)N
Reactant: c1ccc2c(c1)C1CCC2c2cc(OCC3CO3)ccc21
Product: CC(C)NCC(O)COc1ccc2c(c1)C1CCC2c2ccccc21
Reaction time: 20 h

Procedure:
40.95 g of 2-[2,3-epoxy-propoxy]-9,10-dihydro-9,10-ethano-anthracene and 48 ml of isopropylamine are dissolved in 700 ml of absolute alcohol and the solution is boiled for 20 hours under reflux. The reaction mixture is then evaporated to dryness and the residue is recrystallised from 180 ml of toluene. 2-[2-Hydroxy-3-isopropylamino-propoxy]-9,10-dihydro-9,10-ethano-anthracene thus obtained, melts at 126°-127° C.
Reaction SMILES: [CH:1]1([N:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]([CH3:18])[CH2:9]2)[C:5](=[O:7])[CH3:6])[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([N:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:10]([CH3:18])[CH2:9]2)[C:5](=[O:7])[CH3:6])[CH2:2][CH2:3]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)N(C1CC1)C1CC(C)Nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)C3CC3)CC2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To the solution of N-cyclopropyl-N-(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-acetamide (82 mg, 0.34 mmol) in DCM (5 mL) was added 4-methoxybenzoyl chloride (68 mg, 0.40 mmol), followed by DIPEA (104 mg, 0.80 mmol). The reaction mixture was stirred at r.t. overnight. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate. The reaction mixture was washed with sat. sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate) to afford only the cis isomer as a slightly yellow solid product (81 mg, 68%). The mixture of two enantiomers was purified by chiral HPLC using the OD column and the two enatiomers were obtained:
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=2)[C:13]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.[NH2:28][C:29]1[C:34]([C:35]#[N:36])=C(Cl)[N:32]=[CH:31][N:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.CC(O)C.CO>[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:6]([NH:7][C@H:8]([C:10]2[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=3)[C:13]3[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=3[N:11]=2)[CH3:9])[N:32]=[CH:31][N:30]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of {(S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (165 mg, 0.44 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford a yellow oil. A mixture of this residue, 4-amino-6-chloropyrimidine-5-carbonitrile (68 mg, 0.44 mmol) and DIPEA (230 mL, 1.32 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) followed by trituration from EtOAc/cyclohexane/Et2O to afford 277 as an off white solid (73 mg, 42% over 2 steps). 1H NMR (DMSO-d6, 400 MHz): δ 8.66 (1H, d, J=2.64 Hz), 8.62 (1H, s), 8.11-8.03 (1H, m), 7.83 (1H, s), 7.78-7.73 (2H, m), 7.26-7.04 (4H, m), 5.64-5.54 (1H, m), 1.58 (3H, d, J=6.77 Hz). LCMS (Method K): RT 3.40 min [M+H]+ 393
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)C.[F:16][C:17]([Si](C)(C)C)([F:19])[F:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:16][C:17]([F:19])([F:18])[CH:4]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[OH:13]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=Cc1ccc(C(O)C(F)(F)F)cc1
Yield: 76.5 %

Procedure:
According to Reference Example 8-12, by use of 4-(diethoxymethyl)benzaldehyde (400 mg, 1.92 mmol), (trifluoromethyl)trimethylsilane (0.34 mL, 2.3 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 0.19 mL, 0.19 mmol) and tetrahydrofuran (8 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Then, purification by silica gel column chromatography (chloroform/methanol=1/0 to 3/1) was performed to give 4-(2,2,2-trifluoro-1-hydroxyethyl)benzaldehyde (300 mg, yield: 77%).
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC(=O)[C:14]([CH2:26]OS(C)(=O)=O)([CH2:20]OS(C)(=O)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([CH2:20][S:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:26][S:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:19]
Reactant: CCOC(=O)C(COS(C)(=O)=O)(COS(C)(=O)=O)C(=O)OCC
Reactant: SCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CSCc1ccccc1)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Sodium (0.268 g, 11.6 mmol) was dissolved in ethanol (25 mL) and the resulting solution was treated with benzyl mercaptan (1.87 mL, 15.9 mmol). The reaction mixture was cooled on ice and the 2,2-bis-methylsulfonyloxymethyl-malonic acid diethyl ester (2.00 g, 5.31 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then heated at 55° C. for 1.5 hours. The resulting solution was cooled to room temperature and poured into ice water. The product was extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 3-benzylsulfanyl-2-benzylsulfanylmethyl-propionic acid ethyl ester (1.589 g, 83% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.[OH:31]O.O>CCO.C(Cl)Cl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([OH:31])=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: OO
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)n1
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CNc1nccc(-c2cccnc2Oc2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridin-3-yl)pyrimidin-2-amine (0.414 g, 1.02 mmol) in 2 mL EtOH at 0° C. was added hydrogen peroxide, 30 wt. % solution in water (0.984 ml, 10.2 mmol). The reaction was allowed to warm to ambient temperature. After 1 h, the reaction was diluted with DCM, and the layers were separated. The aqueous layer was extracted with 5%MeOH/DCM. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, (EtOAc/hexanes) to give 4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenol as a white solid. MS m/z=295[M+H]+. Calc'd for C16H14N4O2: 294.3.