Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:12])[C:9]=1[CH2:10]2.Cl(O)(=O)(=O)=[O:14]>O1CCCC1>[C:8]1([OH:12])[C:9]2[CH2:10][C@@H:11]([OH:1])[C@H:2]([OH:14])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1CC1OC1C2
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Product: Oc1cccc2c1C[C@@H](O)[C@H](O)C2

Procedure:
Alternatively, the 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substituted-amino)propoxy]-2,3-naphthalenediol isomer XXVII can be prepared from a 5,8-dihydro-1-naphthol of the structure ##STR34## prepared as described hereinbefore, by mixing a cooled solution (temperature less than about 30° C.) of 5,8-dihydro-1-naphthol in ethyl acetate with m-chloroperbenzoic acid and mixing the resulting slurry with a mixture of ethyl ether and aqueous sodium bicarbonate, to form 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol ##STR35## and reacting the 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol in tetrahydrofuran with aqueous perchloric acid at a temperature within the range of from about 0° to about 60° C., to form trans-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol XXV which can be converted to the 2,3-trans-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol XXVI which in turn can be converted to the 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-substituted amino)propoxy]-2,3-naphthalenediol XXVII in a manner similar to that described hereinbefore.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[NH2:28][C:29]1[C:30]([N:35]([CH3:37])[CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=1>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:28][C:29]2[C:30]([N:35]([CH3:37])[CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: CN(C)c1ncccc1N
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C)c1ncccc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate), 3-amino-2-(dimethylamino)pyridine (commercially available, CAS RN 5028-25-1) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light yellow solid (73%). MS (ESI): m/z=403.072 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([C:24]([OH:26])=[O:25])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2].[N+]([O-])(O)=O.C[C:32]1C=C(C)[N:34](C(N)=N)[N:33]=1>N1C=CC=CC=1>[CH2:1]([CH:3]([C:24]([OH:26])=[O:25])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][CH:32]=[N:33][NH2:34])=[CH:21][CH:22]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2]
Reactant: CCC(C(=O)O)N(CCCCc1ccc(N)cc1)c1cccc(C#N)c1
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: c1ccncc1
Solvent: O=[N+]([O-])O
Product: CCC(C(=O)O)N(CCCCc1ccc(NC=NN)cc1)c1cccc(C#N)c1
Yield: 58.3 %

Procedure:
Part E. A solution of ethyl N-[4-[4-aminophenyl]butyl]-N-[3-cyanophenyl]glycine (0.12 gm, 0.34 mmol) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.103 gm, 0.51 mmol) in 10 mL pyridine was heated to 100° C. under a nitrogen atmosphere for 3 hrs. The reaction mixture was allowed to cool and was partitioned between ethyl acetate and water. The combined organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product. The product was purified by flash chromatography on silica gel eluting chloroform:methanol (v:v, 80:20) to give ethyl N-[4-[4-[(aminoiminomethyl)amino]phenyl]butyl]-N-[3-cyanophenyl]glycine 0.078 gm (58%) MS 394(M+H)+ 1 H NMR (CDCl3): 7.0(m, 10H), 6.8(m, 2H), 4.2(q, 2H), 4.0(s, 2H), 3.4(m, 2H), 2.7(m, 2H), 1.2(t, 3H).
Reaction SMILES: [CH:1]1([CH:4]2[CH2:8][CH2:7][NH:6][CH2:5]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[C:20](Cl)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]>CC#N>[Br:18][C:19]1[C:20]([N:6]2[CH2:7][CH2:8][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5]2)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: C1CC(C2CC2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1Br
Temperature: 80 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
To a solution of 3-cyclopropylpyrrolidine (250 mg, 2.25 mmol) and DIEA (1.178 mL, 6.74 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (752 mg, 2.25 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 18 h before being cooled, concentrated, and charged (DCM) to a 40 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 745 mg (81%). 1H NMR (500 MHz, DMSO-d6) δ 5.05-5.00 (m, 1H), 3.25-3.19 (m, 2H), 3.15-3.11 (m, 1H), 2.94-2.90 (m, 1H), 2.62 (s, 3H), 2.36 (s, 3H), 2.06 (br. s., 1H), 1.73-1.69 (m, 2H), 1.29-1.27 (m, 6H), 0.72-0.69 (m, 1H), 0.45-0.40 (m, 2H), 0.16-0.10 (m, 2H). UPLC (M+H)=411.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)=[CH:11][C:5]=2[C:4](=[O:32])[O:3]1.[CH:34](=O)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:34]([N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)=[CH:18][CH:19]=1)[C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([CH3:33])([CH3:1])[O:3][C:4](=[O:32])[C:5]=2[CH:11]=1)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(C(F)(F)F)cc4)cc3)ccc2O1
Reactant: CCCCCC=O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(C(F)(F)F)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Yield: 77.6 %

Procedure:
The title compound was prepared following procedure described in Example 32, step c) from 2,2-dimethyl-6-[(4-{[4-(trifluoromethyl)phenyl]ethynyl}benzyl)amino]-4H-1,3-benzodioxin-4-one (427 mg; 0.95 mmol) and hexanal (Aldrich, 170 μl; 1.42 mmol) to give 560 mg of crude. Purification by flash chromatography on silica gel (EtOAc/c-Hexe 5:90 then 10:90) gave 395 mg (78%) of the title compound as a brown powder. HPLC, Rt: 6.21 min (purity: 68.5%). 1H NMR (CDCl3) δ: 7.59 (brs, 4H), 7.47 (m, 2H), 7.30.(m 3H), 6.76-6.83 (m, 2H), 4.50 (s, 2H), 3.38 (m, 2H), 1.68 (s, 6H), 1.61 (m, 2H), 1.28 (m, 6H), 0.86 (m, 3H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[C:10]=[O:11].[Sn]>>[CH2:6]([NH:9][C:10](=[O:11])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][NH:9][C:10](=[O:11])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=C=O
Reactant: OCc1ccccc1
Agent: [Sn]
Product: O=C(NCCCCCCNC(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
Into a 16 oz jar equipped with magnetic stir was charged 120 g benzyl alcohol (MW=108 g/mol, 1.11 mmol) and 10 drops of Fascat 4202 catalyst. The jar was placed in an about 130° C. oil bath. Next, 93.3 g HDI (MW=168 g/mol, 0.56 mmol) was added. An exotherm was observed. IR was checked after 1 hour of reaction and showed no isocyanate peak between 2200 and 2400 cm−1, indicating that the reaction was complete. The reaction contents were poured into a tin pan to cool and solidify. DSC was employed to measure thermal properties of the materials. DHDC is a white powdered material having the following structure:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[F:8].B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c(Br)c1
Agent: B
Solvent: C1CCOC1
Product: CNCc1ccc(F)c(Br)c1
Temperature: 8 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To the solution of 1,1-dimethylethyl [(3-bromo-4-fluorophenyl)methyl]carbamate (0.755 g, 2.48 mmol) in THF (1 mL) was added BH3.THF (12.5 mL, 1.0 M in THF). The mixture was heated in a microwave machine at about 8° C. for about 30 mins twice. The reaction was then quenched with HCl (10 mL, 1 N) slowly, stirred for 2 h at room temperature, basified with NaHCO3 to pH ˜9, and extracted with EtOAc (50+20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated to afford 0.52 g (96%) of the title compound. LC-MS m/z 218 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(COC)OC>[C:18]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)(=[O:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(N2CCOCC2)c(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: COCCOC
Product: CC(=O)Nc1cc(C(C)(C)C)ccc1N1CCOCC1
Temperature: 0 °C
Yield: 85 %

Procedure:
A mixture of 12.5 g. (53 mmoles) of 4-(2-amino-4-tert-butylphenyl)morpholine and 8.7 g. (85 mmoles) of acetic anhydride in 40 ml. of dimethoxyethane was heated at 70° C. for 15 hours. The cooled reaction mixture was then poured into an excess of ice-water and the water mixture extracted twice with 70 ml. of methylene chloride. The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized from a 10:1 mixture of n-hexane and chloroform to give 12.5 g. (85%) of the desired product, m.p. 112°-113° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][CH2:17][C:18]([CH3:20])=[CH2:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][CH2:17][C:18]2([CH3:20])[CH2:19][O:29]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)COCc1ccc(OCc2ccccc2)cc1
Product: CC1(COCc2ccc(OCc3ccccc3)cc2)CO1
Yield: 95 %

Procedure:
Epoxidation of alkene 122 with 3-chloroperbenzoic acid as in Example 2G for 2.5 h, followed by chromatography of the product on silica gel, eluting with 50% CH2Cl2/petroleum ether (foreruns) and then with 50-80% CH2Cl2/petroleum ether and CH2Cl2, gave 2-({[4-(benzyloxy)benzyl]oxy}methyl)-2-methyloxirane (124) (95%) as an oil: 1H NMR (CDCl3) δ 7.45-7.29 (m, 5H), 7.26 (dt, J=8.7, 2.4 Hz, 2H), 6.95 (dt, J=8.7, 2.5 Hz, 2H), 5.07 (s, 2H), 4.52 (d, J=11.6 Hz, 1H), 4.47 (d, J=11.6 Hz, 1H), 3.54 (d, J=11.0 Hz, 1H), 3.42 (d, J=11.0 Hz, 1H), 2.73 (d, J=4.9 Hz, 1H), 2.62 (d, J=4.9 Hz, 1H), 1.39 (s, 3H); HREIMS calcd for C18H20O3 m/z (M+) 284.1412. found 284.1416.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1.[NH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15].[OH-].[Na+]>C(OCC)C.C(O)C>[NH2:12][C@@H:13]([CH2:14][S:15][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[C:16]([OH:18])=[O:17]
Reactant: N[C@@H](CS)C(=O)O
Reactant: COc1ccc(CO)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(CSC[C@H](N)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solvent mixture of diethylether (400 ml) and conc. hydrochloric acid (400 ml) was added in drops 4-methoxybenzylalcohol (280 g, 1780 mmol) dissolved in diethylether (400 ml) for 2 h, and the mixture was stirred for 1 h. The organic layer was separated, and added to a solution prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2N aqueous sodium hydroxide solution (980 ml) in ethanol (1890 ml). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was cooled to 0° C., and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered, and dried to give (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid (250 g, 1035 mmol, Yield: 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:28]=[CH:29]/[C:30]([O:32]C)=[O:31])[CH:5]=[C:6]([F:27])[C:7]=1[C@@H:8]1[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][C@@H:10]([CH3:21])[N:9]1[CH2:22][C:23]([F:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=[CH:17][CH:16]=3.C(O)(C)C.[OH-].[Na+].Cl>O>[F:27][C:6]1[CH:5]=[C:4](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])[CH:3]=[C:2]([F:1])[C:7]=1[C@@H:8]1[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][C@@H:10]([CH3:21])[N:9]1[CH2:22][C:23]([F:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(C)F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: C[C@@H]1Cc2c([nH]c3ccccc23)[C@@H](c2c(F)cc(/C=C/C(=O)O)cc2F)N1CC(C)(C)F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
(E)-Methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (350 g, 766.69 mmol) was charged a 5 L fixed vessel. Isopropyl alcohol (2.80 L) was added to the vessel. Sodium hydroxide (5M, 460 ml, 2.30 mol) was added in one portion and the mixture was stirred at 21 C for 16 hrs. The dark solution was screened through a filter to remove particulates. The filtrate was returned to the reactor vessel. The filter and filtrate collection vessel were washed with isopropanol (700 ml) and the washings were added to the reactor vessel. The reaction mixture was agitated and water (1.75 L) was added. Concentrated hydrochloric acid (37% w/w, 165 ml, 1.92 mol) was charged to the vessel. Further hydrochloric acid (21.5 ml) was added to the vessel to adjust the pH between 4.0 and 4.5. The solution was heated to 50° C. Water (1.92 L) added to the vessel over 1 hour maintaining the internal temperature between 50-53° C. The jacket temperature was raised to 70° C. to maintain the reactor temperature in this range during the addition. Within 10 minutes of completion of the water addition, the mixture self seeded and started to crystallise. The mixture was held at 50-52° C. for 1.5 hours (jacket set temperature 58° C.). The resulting yellow suspension was cooled to 5° C. (jacket temperature) over 6 hours. The slurry was held at 5° C. (jacket temperature) for 11 hrs. The resultant yellow solid was isolated by filtration. The cake was pasted with a spatula to prevent cracking of the cake. The vessel was washed with water (1.05 L). The washings were used to wash the cake. The cake was pulled dry in air then dried in vacuo to constant weight over 4 days (oven temperature=30° C.). (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid was thus isolated as a yellow crystalline solid, “Form B” (319.45 g, 94%). 1H NMR (500 MHz, DMSO, 27° C.) 1.05 (3H, d), 1.08-1.28 (6H, m), 2.35 (1H, dd), 2.58 (1H, dd), 2.8-2.97 (2H, n), 3.47-3.57 (1H, m), 5.22 (1H, s), 6.67 (1H, d), 6.91-7.06 (2H, m), 7.19 (1H, d), 7.41 (1H, d), 7.46 (2H, d), 7.54 (1H, d), 10.58 (1H, s), 12.62 (1H, s).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][SH:34]>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:34][CH2:33][CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: SCCc1ccccn1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(SCCc3ccccn3)C(=O)O2)cc1Cl
Yield: 5 %

Procedure:
The title compound was prepared analogously to Example F(7), Step 6, substituting 3-chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (0.201 g, 0.52 mmol, described below) in place of 3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione, and 2-Pyridin-2-yl-ethanethiol in place of 2-mercaptothiazole.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][O:32][C@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:34]1[NH2:42].C(N(CC)CC)C.C(O)CCC>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:25]=[CH:26][N:27]=[C:28]([NH:42][C@@H:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:41][C@@H:33]3[O:32][CH3:31])[CH:29]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1N
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Yield: 78.9 %

Procedure:
A mixture of 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (260.0 mg, 0.0005494 mol), (1R,2S)-2-methoxyindan-1-amine (0.359 g, 0.00220 mol) and triethylamine (115 μL, 0.000824 mol) in 1-butanol (0.97 mL, 0.011 mol) was subjected to microwave irradiation (300 watts, 200° C.) for 30 minutes. The resulting dark brown mixture was filtered and concentrated. The residue was purified by flash chromatography (0 to 15% EtOAc/hexanes) to give 0.26 g (79%) of the title compound. LC/MS: Rt=3.42 min, ES+ 600 (AA standard).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:23][CH3:24])[CH:20]=3)[C:15]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:24][O:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:25])[N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:22]2
Reactant: COc1ccc2c(c1)CN(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CN(C1CCNCC1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-methoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.84 g, 2.44 mmol) in dichloromethane (8.5 mL) was added trifluoro-acetic acid (1.7 mL) and the reaction mixture stirred at rt overnight. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the trifluoroacetate salt. MS (ISP): 247.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([CH3:10])[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([CH2:10][Br:18])[CH:3]=1
Reactant: COc1cnc(C)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cnc(CBr)cc1Br

Procedure:
A solution of 4-bromo-5-methoxy-2-methyl-pyridine (Step AL3) (1.9 g, 9.4 mmol), NBS (1.8 g, 9.9 mmol), AIBN (15 mg, 0.094 mmol) and benzoyl peroxide (23 mg, 0.094 mmol) in CCl4 (2 mL) was stirred at rt for 18 h. The reaction mixture was dissolved in EtOAc and extracted with a saturated aqueous solution of NaHCO3, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (hexane/EtOAc, 100:0→70:30). ESI-MS: tR=0.90 min, [M+H]+ 281.9 (LC-MS 1).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([C:42]([F:45])([F:44])[F:43])[O:24][N:23]=[C:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]([NH:37][CH2:38][CH2:39][S:40][CH3:41])=[O:36])=[CH:27][CH:26]=3)[CH2:21]2)[CH:16]=[C:17]([Cl:19])[CH:18]=1>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([C:42]([F:43])([F:45])[F:44])[O:24][N:23]=[C:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]([NH:37][CH2:38][CH2:39][S:40]([CH3:41])=[O:6])=[O:36])=[CH:27][CH:26]=3)[CH2:21]2)[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: -74 °C
Reaction time: 2.5 h

Procedure:
m-Chloroperoxybenzoic acid (47 mg, 70% purity) was added at −78° C. to a stirred solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-(methylthio)ethyl]-1-naphthalenecarboxamide (i.e. the product of Example 1, Step D, 100 mg) in dichloromethane (10 mL). The reaction mixture was stirred at −78 to −70° C. for 2.5 h, then quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound (102 mg), a compound of this invention, as a white solid. 1H NMR (CDCl3): δ 8.78 (d, 1H), 8.29 (d, 1H), 7.42-7.64 (m, 7H), 7.37 (br t, 1H), 4.23 (d, 1H), 4.00 (q, 2H), 3.88 (d, 1H), 3.18 (dt, 1H), 2.89 (dt, 1H), 2.62 (s, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:43])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15](C2C=C(C)C=CC=2S([O-])(=O)=O)=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.C[O-:45].[Na+]>CO.O>[O:1]=[S:2]1(=[O:43])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15]([OH:45])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: Cc1ccc(S(=O)(=O)[O-])c(-c2c(C(=O)NCc3ccccc3S(C)(=O)=O)nc(N3CCCCS3(=O)=O)c3cccnc23)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(1,1-dioxido-1,2-thiazinan-2-yl)-7-({[2-(methylsulfonyl)benzyl]amino}carbonyl)-1,6-naphthyridin-8-yl-4-methylbenzenesulfonate (220 mg, 0.34 mmol) was dissolved in methanol (10 mL) and NaOMe (55 mg, 1.02 mmol) was added. The reaction was stirred overnight at room temperature. The crude reaction was diluted with water (10 mL) and extracted with CH2Cl2 (2×10 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oily solid. The material was suspended in methanol and a yellow precipitate fell out of solution. Washing with fresh methanol (2×10 mL) gave the desired product as an off-white solid.