Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1S[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[N:6]=1.C(OCC)(=O)[CH2:20][C:21](C)=[O:22].C([O-])(=O)C.[Na+].FC(F)(F)C(F)(F)C#N>O.CO>[C:21]([C:4](=[C:5]([NH2:6])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:22])[CH3:20]
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)C(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: N#CC(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)C(F)(F)F
Yield: 37 %

Procedure:
Preparation of Ethyl 2-Chloro-4-Pentafluoroethyl-5-Thiazolecarboxylate To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil; dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo -4-pentafluoroethyl-5-thiazole-carboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoro-ethyl-5-thiazolecarboxylate, nD25 =1 4460.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:15][CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].CN(C)C=O.[H-].[Na+].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>C(Cl)(Cl)Cl>[CH:33]1([CH2:36][N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:18])[CH2:16][O:15][C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[C:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:4]=2)[CH2:35][CH2:34]1
Reactant: Cc1nc(-c2ccccc2)nc(OCC(=O)Nc2ccccc2)c1C
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)nc(OCC(=O)N(CC2CC2)c2ccccc2)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a mixture of 2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)-N-phenylacetamide (1.5 g) obtained in Example 189 and dimethylformamide (30 ml) is added sodium hydride (about 60% oily, 0.2 g) at 0-5° C., and the mixture is stirred at 0° C. for one hour. To the mixture is added cyclopropylmethyl bromide (0.67 g) at the same temperature, and the mixture is stirred at room temperature for two hours. To the reaction solution are added chloroform and ice-water, and the chloroform layer is collected, washed with water, and dried over anhydrous sodium sulfate. The chloroform layer is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from isopropanol to give the desired compound (1.56 g), m.p. 119-121° C.
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH2:36][C:37]1([CH3:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.NC1CCN(CC2C=CN3C=2C(NC2C=CC(OCC4C=CC=C(F)C=4)=C(Cl)C=2)=NC=N3)CC1.C(O)(C(F)(F)F)=O>CO>[NH2:36][C:37]1([CH3:43])[CH2:42][CH2:41][N:40]([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)=[C:22]([Cl:35])[CH:21]=2)=[N:16][CH:15]=[N:14]3)[CH2:39][CH2:38]1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12)c1ccccc1
Reactant: CC1(N)CCNCC1
Agent: NC1CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC1(N)CCN(Cc2ccn3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1

Procedure:
The title compound was prepared from 7B and excess 4-amino-4-methylpiperidine (WO 9732880) by a route analogous to that used for the preparation of 7C. Analytical HPLC retention time=1.43 min. (YMC Xterra S7 C 18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=495.
Reaction SMILES: N1C2C(=C(C3N=[C:12]([N:22]4[CH2:27][CH2:26]OCC4)[C:13]4SC(COC)=[CH:16][C:14]=4N=3)C=CC=2)C=N1.[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[C:32]2[S:37][C:36]([CH2:38][OH:39])=[CH:35][C:33]=2[N:34]=1.N1C=CC=CC=1CCl>CN(C=O)C.[H-].[Na+]>[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:32]2[S:37][C:36]([CH2:38][O:39][CH2:26][C:27]3[CH:16]=[CH:14][CH:13]=[CH:12][N:22]=3)=[CH:35][C:33]=2[N:34]=1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(COCc3ccccn3)cc2n1

Procedure:
Following the procedures for compound 314, (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMF and sodium hydride was alkylated with 2-picolyl chloride to give 4-(2-chloro-6-((pyridin-2-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine. Suzuki coupling of 4-(2-chloro-6-((pyridin-2-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine and 7 was carried out via General Procedure A. Purification using column chromatography gave 317. NMR: CDCl3: 3.80-3.90 (4 H, m, CH2), 4.01-4.08 (4 H, m, CH2), 4.72 (2 H, s, CH2), 4.88 (2 H, s, —CH2), 7.10-7.14 (1H, m, Ar), 7.38 (1 H, s, Ar), 7.40-7.48 (2 H, m, Ar), 7.51 (1 H, d, J 8.23, Ar), 7.65 (1 H, t, J 8.22, Ar), 8.18 (1 H, d, J 7.20, Ar), 8.52 (1 H, d, J 4.60, Ar), 8.96 (1 H, s, Ar) and 10.06 (1 H, s, NH). MS: (ESI+): MH+ 459.17
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Br)=[O:8])=[CH:5][CH:4]=1.[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)O
Reactant: O=C(Br)c1ccc(CBr)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.8 %

Procedure:
4-Bromomethylbenzoyl bromide (13.9 g, 50 mmol, 1.0 eq) was added to 50 mL of DCM, followed by t-butanol (9.6 mL, 100 mmol, 2.0 eq) and the mixture was slowly warmed to room temperature. After 20 hours, the reaction was concentrated under reduced pressure, dissolved into 350 mL EtOAc, washed with 400 mL sat. bicarbonate and 200 mL saturated aqueous NaCl. The organic was dried over MgSO4, filtered, and concentrated under reduced pressure to yield intermediate (19a) as a semisolid (7.3 g).
Reaction SMILES: C([NH:8][CH2:9][C:10](O)=[O:11])(OC(C)(C)C)=O.CN(C=O)C.Cl.[NH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:46])=[C:25]([N:27]2[C:32]([CH3:33])=[CH:31][C:30]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])=[C:29]([Cl:44])[C:28]2=[O:45])[CH:26]=1.Cl>CO>[ClH:44].[Cl:44][C:29]1[C:28](=[O:45])[N:27]([C:25]2[CH:26]=[C:21]([CH:22]=[CH:23][C:24]=2[F:46])[CH2:20][NH:19][C:10](=[O:11])[CH2:9][NH2:8])[C:32]([CH3:33])=[CH:31][C:30]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CNC(=O)CN)ccc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 130.1 %

Procedure:
A 25 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with boc-glycine (105 mg, 0.6 mmol) and 8 mL of DMF. The mixture was cooled to 0° C. and isboutylchloroformate (77.5 μL, 0.6 mmol) was added and stirred for 20 min. 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.6 mmol) was added and stirred for 3 h. After completion of the reaction by LC-MS, concentrated HCl (2 mL) and 2 mL of methanol was added to remove the boc group. The reaction was stirred for 24 h, neutralized with 2M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain (196 mg, 66%) of the desired product as a the HCl salt. 1H NMR (400 MHz, (CD3OD) δ 7.6 (q, J=8 and 6.5 Hz, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.0 (m, 2H), 6.63 (s, 1H), 5.35 (s, 2H), 4.4 (q, J=15 and 13.6 Hz, 2H), 3.7 (s, 2H), 2.05 (s, 3H) ppm. ES-HRMS m/z 466.1157 (M+H calcd for C22H20ClF3N3O3 requires 466.1140).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:53][CH:54]1[CH2:57][NH:56][CH2:55]1.CCN(C(C)C)C(C)C>C1COCC1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:42])[CH3:43])=[CH:24][N:23]=[C:22]([N:56]4[CH2:57][CH:54]([F:53])[CH2:55]4)[N:21]=3)[C@H:14]2[CH3:49])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:50])[CH:8]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Reactant: FC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(N3CC(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 52, 180 mg, 0.106 mmol) in THF (5 mL) was added 3-fluoroazetidine hydrochloride (35.4 mg, 0.317 mmol) and DIEA (0.092 mL, 0.529 mmol). It was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated, and the residue was purified on reverse phase HPLC, eluting with water and acetonitrile (10% to 100%), to give the title compound as a yellowish solid after lyophilization (74 mg, 93% yield). LCMS (M+H)+: 752.05. 1H NMR (CDCl3, 500 MHz): δ8.36 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.87 (m, 1H), 7.79 (s, 2H), 5.80 (d, 9.0 Hz, 1H), 4.75 (m, 4H), 4.61-4.53 (m, 4H), 4.47 (m, 1H), 4.09 (m, 1H), 3.76 (s, 3H), 1.33 (s, 9H), 0.82 (d, 7.0 Hz, 3H). RTA IC50: 197 nM.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[O:13][CH2:35][CH2:36][NH:37][C:38]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:44]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1OCCNC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 115 %

Procedure:
To a solution of 2-hydroxy-4-nitro benzoic acid methyl ester (7.0 g, 0.035 mol), triphenylphosphine (9.31 g, 0.035 mol) and t-butyl N-(2-hydroxyethyl)carbamate (3.82 g, 0.023 mol) in anhydrous THF (400 mL) (stirring for 1 hr.) was added diisopropyl azodicarboxylate (7.03 mL, 0.035 mol) and stirred for 2 days. The reaction was evaporated and the residue purified by ISCO chromatography to give 2-(tert-butoxycarbonylamino-ethoxy)-4-nitro-benzoic acid methyl ester (9.0 g,) as a white solid. 1H-NMR (DMSO-d6) δ 7.90 (s, 1H), 7.86 (s, 2H), 6.86-92 (br, 1H), 4.18-9 d, 2H), 3.85 (s, 2H), 3.31 (d, 2H), 1.37 (s, 9H); LC/MS (ESI+): 363 (M+Na).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][N:34]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:33][CH2:32]1
Reactant: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 72 (397 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 280 mg (55%) of white solids. M.P. 253° C. 1H NMR (DMSO-d6): δ 3.70 (m, 4H), 3.93 (m, 4H), 5.46 (s, 2H), 7.13-7.17 (m, 3H), 7.27 (m, 2H), 7.44 (d, J=9.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.68 (dd, J=2.6, 9.0 Hz, 1H), 7.79 (d, J=4.0 Hz, 1H), 7.89 (s, 1H). EIMS m/z 508 (M+1). Anal. (C26H20FClN4O2S) C, H, N.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[CH3:1][C:2]1([CH3:22])[O:7][C:6](=[S:32])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
The product was prepared, from 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile and Lawesson's reagent using the procedure of Example 9, as a yellow solid: 248-249° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 8.15 (bs, 1H), 8.02 (d, 1H, J=10.48 Hz), 7.85-7.78 (m, 3H), 7.13 (d, 1H, J=8.92 Hz), 1.71 (s, 6H); MS (APCI) m/z 313 ([M+H]+, 100%); Anal. Calcd. For C17H13FN2OS: C, 65.37; H, 4.19; N, 8.97. Found: C, 65.26; H, 4.31; N, 8.61.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH:3]=[C:4](Br)Br.[Li][CH2:17]CCC.CI>C1COCC1>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[C:3]#[C:4][CH3:17]
Reactant: COc1ccc(C(C)(C)C=C(Br)Br)cc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC#CC(C)(C)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a stirred solution of Compound 53 (335 mg, 1.00 mmol) in THF (10 ml) was added n-BuLi (1.69M in hexane, 1.19 ml, 2.01 mmol) at -78° C. under N2, then warmed up to 0° C., and stirred for 1.5 h. MeI (213 mg, 1.50 mmol) was added, and stirred for 1.5 h at 0° C. The mixture was quenched by the addition of NH4Cl aq., and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. This was purified by SiO2 chromatography to give Compound 54 (162 mg, 86%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4]Cl)[CH3:2].[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][CH2:4][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chloromethyl ethyl ether (5.65 g, 0.06 mol) in 20 ml of THF at 0° C. is added to a mixture of 4-hydroxybenzaldehyde (5 g, 0.041 mol) and 12 ml of triethylamine in 30 ml of THF and the mixture is stirred at ambient temperature for 2 hrs. The triethylamine hydrochloride is filtered off and the solvent is evaporated under reduced pressure to give the 4-ethoxymethoxybenzaldehyde in the form of an oil (6.63 g, 90%).
Reaction SMILES: [CH3:1][C:2]1C=CC(C(C)C)=C[CH:7]=1.C([C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16](C(C)C)[CH:15]=1)(C)C>>[CH:2]([C:15]1[CH:14]=[CH:19][C:18]([CH:20]([CH3:21])[CH3:22])=[CH:17][CH:16]=1)([CH3:7])[CH3:1]
Reactant: CC(C)c1cc(C(C)C)cc(C(C)C)c1
Reactant: Cc1ccc(C(C)C)cc1
Product: CC(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
[RuCl2 (1,3,5-triisopropylbenzene)]2 was prepared by stirring a suspension of [RuCl2 (P-cymene)]2 (3 g) in 120 mL 1,3,5-triisopropylbenzene (Aldrich, 97%) for a total of 8 hours at 190° C. under N2. The solution was cooled to room temperature and then placed in a refrigerator for 2-3 days. Solids were collected by cold filtration, washed with heptane, and dried in a vacuum oven at 70° C. A red-brown solid product was obtained (3.25 grams). 1H NMR analysis of this product was consistent with the material being 90+ % pure [RuCl2 (1,3,5-triisopropylbenzene)]2 with a small amount of unreacted [RuCl2 (p-cymene)]2. 1H NMR data for [RuCl2 (1,3,5-triisopropylbenzene)]2 (CDCl3 solvent): δ 1.3 (d, 18H), 3.1 (m, 3H), 5.2 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:46]([O:53][C:54]1[CH:59]=[C:58]([NH:60][C:61]2[N:66]=[C:65]([N:67]3[CH2:72][C@@H:71]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:70][C@@H:69]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:68]3)[N:64]=[C:63]([N:89]3[CH2:94][C@@H:93]([NH:95][C:96]([O:98][C:99]([CH3:102])([CH3:101])[CH3:100])=[O:97])[CH2:92][C@@H:91]([NH:103][C:104]([O:106][C:107]([CH3:110])([CH3:109])[CH3:108])=[O:105])[CH2:90]3)[N:62]=2)[CH:57]=[CH:56][C:55]=1[NH2:111])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[CH2:46]([O:53][C:54]1[CH:59]=[C:58]([NH:60][C:61]2[N:66]=[C:65]([N:67]3[CH2:72][C@@H:71]([NH:73][C:74]([O:76][C:77]([CH3:78])([CH3:79])[CH3:80])=[O:75])[CH2:70][C@@H:69]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:68]3)[N:64]=[C:63]([N:89]3[CH2:90][C@@H:91]([NH:103][C:104]([O:106][C:107]([CH3:110])([CH3:109])[CH3:108])=[O:105])[CH2:92][C@@H:93]([NH:95][C:96]([O:98][C:99]([CH3:102])([CH3:101])[CH3:100])=[O:97])[CH2:94]3)[N:62]=2)[CH:57]=[CH:56][C:55]=1[NH:111][C:4](=[O:6])[C:3]1[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:2]=1[OH:1])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(N)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Reactant: COc1cccc(O)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(O)c1C(=O)Nc1ccc(Nc2nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 34.5 %

Procedure:
2-Hydroxy-6-methoxy-benzoic acid (87) (0.067 g=0.4 mmol), iPr2EtN (0.6 mmol) and HBTU (0.44 mmol) were dissolved in DMF (2 mL) and shaken in a sealed vial for 25 min. 2-Benzyloxy-N4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-[1,3,5]triazin-2-yl)-benzene-1,4-diamine (83) (0.184 g, 0.2 mmol) was added and the mixture was heated to 80° C. for 3 h. LC-MS indicated complete coupling at this point. Upon concentrating, the crude product was dissolved in CHCl3 (4 mL), washed with aqueous sat. NaHCO3 (2×2 mL), water (2×2 mL) and concentrated to dryness. Purification by ISCO (15–100% EtOAc/hexanes) gave the desired product (88) (0.073 g, 0.069 mmol, 34.5% yield). LC-MS (ESI): (exact mass: 1069.56) m/e═1070.9 [M+1]+ (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:22][CH2:23][CH3:24])[C:14](=O)[CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2.CN(C)CC>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:22][CH2:23][CH3:24])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2
Reactant: CCCN(C(=O)Cc1cccs1)[C@H]1CCc2cccc(OC)c2C1
Agent: CCN(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(CCc1cccs1)[C@H]1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A5-1 when using 340 mg (0.99 mmol) (S)—N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide ((S)-A4-1: R═OMe, Cy=2-thienyl). Flash chromatography was done using a mixture of hexane/ethyl acetate 40/1 in the presence of 0.5% (v/v) dimethylethylamine.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCc2ccccc21
Product: O=C(NC1CCc2ccccc21)c1ccccc1

Procedure:
The title compound was prepared in 77% from (rac)-1-aminoindan (1.0 g, 7.5 mmole) and benzoyl chloride (2.1 g, 15 mmole), under the Schotten-Bauman conditions, according to J. Chem. Soc. 71, 251 (1897) and J. Org. Chem. 27, 4465 (1962), m.p.: 140-2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1)(=[O:12])=[O:11].[CH2:22](O)[CH2:23][CH2:24][OH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:21][CH2:22][CH2:23][CH2:24][OH:25])(=[O:11])=[O:12]
Reactant: COc1ccc(C)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Reactant: OCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To 458 mg (1.49 mmol) 3-(2-methoxy-5-methylphenylsulfonyloxy)-5-methylphenol, as prepared in the preceding step, 1.08 mL (14.9 mmol) of 1,3-propanediol and 782 mg (2.98 mmol) of triphenylphosphine in 10 mL of anhydrous tetrahydrofuran was added 0.470 mL (2.98 mmol) of diethyl azodicarboxylate dropwise over 15 min. After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to a semisolid. The resulting mixture was flash chromatographed on 50 g of silica gel with 8-10% ethyl acetate-dichloromethane. Impure fractions were re-chromatographed on 40 g of silica gel with 50-100% ethyl acetate-hexane. Material from the two purifications was combined to afford 530 mg (97% yield) of the title compound as a colorless oil: 1H-NMR (300 MHz; CDCl3) δ 7.95 (d, 1 H, J=2.2 Hz), 7.40 (dd, 1 H, J=8.5, 2.3 Hz), 6.97 (d, 1 H, J=8.5 Hz), 6.59 (br s, 1 H), 6.53 (br s, 1 H), 6.47 (t, 1 H, J=2.1 Hz), 4.01 (t, 2 H, J=6.0 Hz), 3.98 (s, 3 H), 3.81 (q, 2 H, J=5.7 Hz), 2.29 (s, 3 H), 2.25 (s, 3 H) and 1.98 (m, 2 H).