Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[C:20]([Cl:26])=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>C(O)C>[Cl:26][C:20]1[C:21]([OH:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Oc1cccc(CBr)c1Cl
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cccc(O)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (152 mg, 1.1 mmol) was dissolved in absolute ethanol (8 mL), then triethylamine (140 μL, 1.0 mmol) and 3-(bromomethyl)-2-chlorophenol (200 mg, 0.9 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration, and the filtrate was evaporated. The residue was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 2-{[(2-chloro-3-hydroxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (87 mg, 37% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.11 (bs, 1H), 4.44 (s, 2H), 5.99 (bs, 1H), 6.88-6.91 (m, 1H), 7.01-7.10 (m, 2H), 10.24 (bs, 1H); LRMS (ES+) m/z 283 (100%, M+1), 285 (50%, M+3).
Reaction SMILES: N1C=CC=CC=1.F.[CH3:8][O:9][C:10](=[O:47])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][S:16][C@H:17]1[C:21](=[O:22])[CH2:20][C@@H:19]([O:23][Si](C(C)(C)C)(C)C)[C@@H:18]1/[CH:31]=[CH:32]/[C@@H:33]([O:39][Si](C(C)(C)C)(C)C)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CC#N>[CH3:8][O:9][C:10](=[O:47])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][S:16][C@H:17]1[C:21](=[O:22])[CH2:20][C@@H:19]([OH:23])[C@@H:18]1/[CH:31]=[CH:32]/[C@@H:33]([OH:39])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCC[C@@H](/C=C/[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1SCCCSCC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1SCCCSCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Hydrogen fluoride-pyridine (220 μL) was added to a solution of bis-TBDMS ether 7 (70 mg, 0.11 mmol) in CH3CN (2.0 mL) at 0° C. The reaction was warmed to room temperature, stirred 1 h, and recooled to 0° C. The reaction was quenched with saturated aqueous NaHCO3 until gas evolution ceased. The mixture was extracted with CH2Cl2 (4×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 100% CH2Cl2 followed by 30:1 CH2Cl2:MeOH) provided 40 mg (90%) of the above titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24](F)=[C:23](C(F)(F)F)[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[N:40]1([CH2:44]CN2C=C(C3CCCCC3)N=C2C2CCNCC2)[CH2:43][CH2:42][CH2:41]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:44][N:40]4[CH2:43][CH2:42][CH2:41]4)[CH:18]=[C:19]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: c1c(C2CCCCC2)nc(C2CCNCC2)n1CCN1CCC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(C3CCCCC3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 4-[1-(2-azetidin-1-yl-ethyl)-4-cyclohexyl-1h-imidazol-2-yl]-piperidine trifluoroacetate instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=435, obsd.=435).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.OC1C2N=NNC=2C=CC=1.[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH2:42])[CH3:38].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(OCC)(=O)C>[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH:42][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)[CH3:38]
Reactant: O=C(O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCN(CC)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)CCNC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 0 °C
Reaction time: 48 h
Yield: 79.1 %

Procedure:
5-(4,5-diphenyl-1H-imidazol-2-ylthio)-pentanoic acid (3.73 g, 10.58 retool) was dissolved in 40 mL dry dimethylformamide, and treated with solid hydroxybenzotriazole hydrate (1.77 g, 13.10 retool). Then, a 20 mL dimethylformamide solution of N,N-diethylethylenediamine (2.00 mL, 14.24 mmol) was added dropwise. The mixture was cooled to 0° C., and solid dicyclohexylcarbodiimide (2.81 g, 13.62 mmol) was added in small portions over 20 minutes. The mixture was allowed to slowly warm and stirred for 48 hours, then poured into 150 mL ethyl acetate. This mixture was washed with water (3×150 mL), and the water washings were back-extracted in sequence with ethyl acetate (150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to afford a pale yellow oil. The oil was separated by flash chromatography (1:4 methanol-methylene chloride) to afford N-[2-(diethylamino)ethyl]-5-(4,5-diphenyl-1H-imidazol-2-ylthio)-pentanamide (3.77 g, 8.37 mmol, 79%). 1 H NMR (300 MHz, CDCl3): 7.56-7.49 (4H, m); 7.33-7.17 (6H, m); 6.91 (1H, br s); 3.16 (2H, br d, J=6 Hz); 2.97 (2H, t, J=7 Hz); 2.68-2.49 (6H, m); 2.29 (2H, t, J=6 Hz); 2.00-1.57 (4H, m); 1.02 (6H, t, J=7 Hz).
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)[C:12](O)=[O:13])[N:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].[CH3:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][NH2:33])=[N:30][CH:31]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(#N)C>[CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)[C:12]([NH:33][CH2:32][C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[CH:31][N:30]=2)=[O:13])[N:7]=[CH:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3ncnc3C(C)C)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(-n3ncnc3C(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.5 %

Procedure:
3-(5-Isopropyl-[1,2,4]triazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid (1.90 g, 6 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (0.73 g, 6 mmol), EDCI (1.69 g, 9 mmol), HOBt (1.20 g, 9 mmol) and NMM (3.2 mL) were added to 20 mL of acetonitrile. The reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere, then was partitioned between water and EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (IPA/DCM 1:4)) to give 1.63 g of 3-(5-isopropyl-[1,2,4]triazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=428.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10](OC)=[O:11])[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:20]1COC[CH2:21]1>>[CH2:20]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:21].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][OH:11])[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1cc2ccccc2[nH]1
Product: OCc1cccc2cc[nH]c12
Temperature: 25 °C
Yield: 98 %

Procedure:
Indole-7 carboxyldehyde (I-1). Ethyl Indole-7 m carboxylate was prepared according to literature procedure {Batcho B. and Leimgruber, K., Org. Syn. Vol IIV, page 34-40). To a solution of methyl 7-indolecarboxylate (13 g, 74.2 mmol) in 250 ml of anhydrous THF was added LiAlH4 (10.9 g, 0.288 mol) in portions, and reaction mixture was heated to reflux for 2 h. After cooling to room temperature, the excess hydride was quenched by addition of water (12 mL), 15% NaOH (12 mL) and water (26 mL). The solids were removed by filtration through a pad of Celite and filtrate was evaporated in vacuo to yield (1H-indol-7-yl)-methanol (10.7 g, 98%). 1HNMR (CDCl3). To a solution of the alcohol, (1H-indol-7-yl)-methanol (8.0 g, 54.3 mmol) in 400 mL of methylene chloride was added activated manganese (IV) oxide (85%, 41.0 g, 0.40 mol), and stirred at ambient temperature for 72 h. After additional of 200 mL of methylene chloride and 400 mL of methanol to the reaction mixture, the whole mixture was filtered through a pad of silica gel to remove solid materials. The filtrate was concentrated to afford a crude product, which was purified by a column chromatography on silica gel to yield 1H-indole-7-carbaldehyde, I-1 (6.55 g, 83%). 1HNMR (CDCl3).
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])(=O)C.O.[I:24](O)(=O)=O>>[C:10]1([CH3:15])[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH2:7][CH2:6][CH2:5][I:24]
Reactant: [O-][I+2]([O-])O
Reactant: CC(=O)OCCCC(c1ccccc1C)c1ccccc1C
Solvent: O
Product: Cc1ccccc1C(CCCI)c1ccccc1C

Procedure:
The crude 2,2-di-(2-tolyl)-tetrahydrofuran 33a (28 g) was dissolved in acetic acid (250 mL). 5% palladium on Carbon black (3 g) was added and the mixture was hydrogenated in a Parr apparatus at 3 ato at 55° C. for 5 hrs. The catalyst was filtered off and the solvent was evaporated in vacuo. The remaining oil was subjected to CC (n-heptane/ethyl acetate--15:1) to give 4,4-di-(2-tolyl)-1-butanol (17 g). A solution of 4,4-di-(2-tolyl)-1-butanol (19 g) in acetic acid (400 mL) was boiled under reflux for 3 hrs. The cooled solution was evaporated in vacuo to give 4,4-di-(2-tolyl)-1-butyl acetate (17 g) as an oil. A solution of 4,4-di-(2-tolyl)-1-butyl acetate (9.2 g) in 57% aqueous iodic acid (150 mL) was boiled under reflux for 3 hrs. The cooled solution was poured into a mixture of ice and water and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and a saturated aqueous solution of NaCl, dried (Na2SO4) and evaporated in vacuo to give the title compound 34a (11.7 g) as an oil, which was used without further purification. 1H NMR (CDCl3) δ1.80-2.10 (m,4H), 2.28 (s,6H), 3.17 (t,2H), 4.26 (t,1H), 7.12 (s,8H)
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[CH:32][C:31]=3[O:40][CH3:41])[C@H:14]2[CH3:42])[CH:10]=[CH:11][CH:12]=1>C1COCC1.Cl.CCOC(C)=O>[F:39][C:33]1[C:34]([CH:36]([CH3:38])[CH3:37])=[CH:35][C:30]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:20]=2[CH2:19][N:15]2[C@@H:14]([CH3:42])[C@@H:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[CH:2]=[O:1])[O:17][C:16]2=[O:18])=[C:31]([O:40][CH3:41])[CH:32]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cccc(C3OCCCO3)c2)[C@@H]1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cccc(C=O)c2)[C@@H]1C

Procedure:
The solution of (4S,5R)-5-[3-(1,3-dioxan-2-yl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 210) (380 mg, 0.647 mmol) in THF and 1N HCl (3:1) (4 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried and concentrated in vacuo. The crude material was purified by flash chromatography (Si) to provide 3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde. LCMS calc.=530.19; found=530.4 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 10.03 (s, 1 H); 7.88 (s, 0.5 H); 7.87 (s, 0.5 H); 7.77-7.52 (m, 5 H); 7.37 (d, J=3.5 Hz, 0.5 H); 7.36 (d, J=3.4 Hz, 0.5 H); 7.02 (d, J=8.4 Hz, 0.5 H); 6.99 (d, J=8.4 Hz, 0.5 H); 6.71 (d, J=3.5 Hz, 0.5 H); 6.69 (d, J=3.4 Hz, 0.5 H); 4.17 (d, J=15.8 Hz, 0.5 H); 6.98 (d, J=15.8 Hz, 0.5 H); 3.78 (s, 3 H); 3.85-3.71 (m, 1 H); 3.26-3.19 (m, 1 H); 1.30-1.26 (m, 4.5 H); 1.19 (d, J=6.9 Hz, 1.5 H); 0.53 (d, J=6.6 Hz, 1.5 H); 0.40 (d, J=6.6 Hz, 1.5 H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2].[N:21]([Si](C)(C)C)=[N+:22]=[N-:23].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1>[Cl:20][C:6]1[C:7]([CH3:19])=[C:8]([C:17]2[NH:23][N:22]=[N:21][N:18]=2)[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(-c2nnn[nH]2)c1-c1cccc(F)c1
Yield: 85.7 %

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (100 mg, 0.3 mmol), azidotrimethylsilane (0.092 mL, 0.69 mmol), and dibutyloxostannane (13 mg, 0.052 mmol) in toluene (2.9 mL) was heated at reflux overnight. The mixture was evaporated to dryness and purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the desired product (85 mg, 70%). LCMS calculated for C16H13ClFN4O (M+H)+: m/z=331.1. found: 331.0.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.N1[CH:14]=[N:13][CH:12]=[N:11]1.N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O>[CH3:1][Si:2]([CH3:9])([CH3:8])[N:3]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: c1nc[nH]n1
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Product: C[Si](C)(C)n1cncn1
Temperature: 126 °C
Yield: 124.7 %

Procedure:
23.4 ml (0.11 mole) of hexamethyldisilazane were added to a mixture consisting of 10.35 g (0.15 mole) of 1,2,4-triazole and 127 mg (0.75 mmole) of saccharin heated to 126° C. and evolution of ammonia started immediately. After refluxing for 30 minutes, the calculated amount of ammonia was evolved as determined by the method described in Example 1A. Vacuum distillation yielded 19.37 g (91.6%) of 1-trimethylsilyl-1,2,4-triazole boiling at 76.5°-78.0° C. at 12 mm Hg and nD 25=1.4592.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH:30]2[CH2:32][O:31]2)=[CH:26][CH:25]=1>>[OH:31][CH:30]([CH2:29][O:28][C:27]1[CH:33]=[CH:34][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[CH2:32][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: COc1ccc(OCC2CO2)cc1
Product: COc1ccc(OCC(O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 175 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(4-methoxyphenoxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 482 [M+H]; Rt=0.99 min.
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.CCOCC.[Cl-].[Na+]>O1CCCC1.O>[Cl:10][C:2]1([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH:16]([C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[O:17]1
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1(Cl)OC1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 21.9 %

Procedure:
5.55 g of tert.-butyl dichloroacetate in 30 ml of tetrahydrofuran were stirred while 4.64 g of 4-chlorobenzaldehyde were added, and after cooling to -20° C., 30 ml of an N solution of potassium tert.-butylate in tetrahydrofuran were added. The temperature was allowed to rise to 20° C. and after 20 minutes, 50 ml of ether and 40 ml of water saturated with sodium chloride were added, with stirring for 5 minutes. The decanted organic phase was washed with water saturated with sodium chloride, then dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with methylene chloride to obtain 1.90 g of 1,1-dimethylethyl 2-chloro-3-(4-chlorophenyl)-oxirane carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:3]=1.[NH2:14][C:15]1[C:16](=[O:25])[C:17](=[O:24])[C:18]=1OCCCC.O>N1C=CC=CC=1>[NH2:14][C:15]1[C:16](=[O:25])[C:17](=[O:24])[C:18]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: Nc1cccc(-c2ccncc2)n1
Reactant: CCCCOc1c(N)c(=O)c1=O
Solvent: c1ccncc1
Solvent: O
Product: Nc1c(Nc2cccc(-c3ccncc3)n2)c(=O)c1=O
Reaction time: 1 h
Yield: 13.8 %

Procedure:
A stirred solution of 2-amino-6-(4-pyridyl)pyridine (0.34 g) and 3-amino-4-n-butoxy-3-cyclobutene-1,2-dione (0.34 g) in pyridine (2 ml) is heated under reflux for 8 hours. The cool mixture is treated with water (15 ml) and the mixture stirred for 1 hour. The solid is filtered, washed with water, ethanol and ether, charcoaled and recrystallised from dimethylformamide to give 73 mg of the title compound, mp >340° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)[CH2:9][C:8](=[O:17])[N:7]([CH2:18][CH3:19])[C:6]=2[CH:20]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][N:14]([CH2:28][CH2:29][CH:30]=[C:31]4[C:37]5[CH:38]=[CH:39][CH:40]=[N:41][C:36]=5[CH2:35][O:34][C:33]5[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]4=5)[CH2:13]3)[CH2:9][C:8](=[O:17])[N:7]([CH2:18][CH3:19])[C:6]=2[CH:20]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCN1C(=O)CN([C@@H]2CCNC2)Cc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN1C(=O)CN([C@@H]2CCN(CCC=C3c4cc(C(C)(C)O)ccc4OCc4ncccc43)C2)Cc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a solution of (R)-8-chloro-1-ethyl-4-pyrrolidin-3-yl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.121 g, 0.32 mmol) in acetonitrile/water (8:2) (3.2 mL) was added K2CO3 (0.368 g, 2.6 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.102 g, 0.27 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride to 10% methanol/90% methylene chloride to 15% methanol/85% methylene chloride) to yield the title compound (0.033 g, 21%). 1H-NMR (CDCl3): 1.17 (t, 3H), 1.55 (s, 6H), 1.73 (septet, 1H), 2.08 (m, 1H), 2.34(pentet, 2H), 2.43–2.61 (m, 4H), 2.85 (t, 1H), 2.92 (d, 1H), 3.10 (q, 1H), 3.22 (m, 1H), 3.52 (q, 2H), 3.91 (septet, 2H), 5.29 (bs, 2H), 6.12 (t, 1H), 6.79 (dd, 1H), 7.15–7.28 (m, 5H), 7.44 (s, 1H), 7.56 (d, 1H), 8.47 (d, 1H). ESI-MS m/z: 587 (M+1), retention time 1.37.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[CH3:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2[CH2:36][NH2:37])[CH:23]=[CH:24][CH:25]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([NH:37][CH2:36][C:27]2[CH:28]=[CH:29][C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:26]=2[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=2)=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: Cc1cccc(-c2cc(C(F)(F)F)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(-c2cc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.8 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (51 mg, 0.185 mmol) and (3′-methyl-5-(trifluoromethyl)biphenyl-2-yl)methanamine (60 mg, 0.222 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (53 mg, 0.2775 mmol), 1-hydroxybenzotriazole (38 mg, 0.270 mmol) and triethylamine (0.06 mL, 0.4625 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-Fluoro-4-(methylsulfonamidomethyl)phenyl)-N-((3′-methyl-5-(trifluoromethyl)biphenyl-2-yl)methyl)propanamide (example 22) (81 mg) was obtained as 84% yield.
Reaction SMILES: [OH-:1].[Na+].[OH2:3].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[C:18]([O:33][CH3:34])=[C:19]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]#N)[CH:26]=4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.Cl>C(O)C>[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[C:18]([O:33][CH3:34])=[C:19]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]([OH:3])=[O:1])[CH:26]=4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12
Reactant: O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)O)c1

Procedure:
Sodium hydroxide (1.0 M) in water (0.70 mL, 0.70 mmol) was added to a mixture of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carbonitrile (0.060 g, 0.14 mmol) in ethanol (1.0 mL) and the resultant mixture was heated at 95° C. for 6 hours. At this time, conc. HCl was added to adjust pH to ˜3. The solvent was removed and the residue was used in the next step without further purification. LCMS calculated for C22H22ClN6O3 (M+H)+: m/z=453.1; Found: 453.2
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].[CH3:14][N:15]([CH3:22])[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]([CH3:13])=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]([CH3:22])[CH3:14])[CH2:17][CH2:18]2)[CH:7]=1
Reactant: CN(C)C1CCNCC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Product: COc1cc(N2CCC(N(C)C)CC2)c(C)cc1[N+](=O)[O-]

Procedure:
Starting Materials: 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (INTERMEDIATE 7) and N,N-dimethylpiperidin-4-amine. m/z 294.