Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][O:18][CH:19]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1.C(O)C.[OH-].[K+]>O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:19]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[O:18][CH2:17][CH2:16][S:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[CH:7][CH:8]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)CCc1ccc(OCCSCCOC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1ccc(OCCSCCOC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 98 %

Procedure:
A mixture of 3-[4-[2-[2-[Bis(4-chlorophenyl]methoxy]ethylthio]ethoxy]phenyl]propionic acid methyl ester (2.76 g, 5.31 mmol) and 80% aqueous ethanol (50 ml) was treated with a solution of potassium hydroxide (0.7 g, 10.6 mmol) in water (3 ml) and the resulting mixture was heated at 60° C. for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (30 ml) and dichloromethane (50 ml) and acidified to pH4 with 2N hydrochloric acid. The aqueous phase was extracted a second time with dichloromethane and the combined organic extracts were washed with brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure gave 2.63 g (98%) of the title acid as a white solid.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Br[CH2:7][C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9]>C(#N)C>[CH2:1]([NH:5][CH2:7][C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CC(C)COC(=O)CBr
Solvent: CC#N
Product: CCCCNCC(=O)OCC(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
20 g (0.27 mol) of n-butylamine are dissolved in 100 ml of acetonitrile, and 7.8 g (0.04 mol) of 2-methylpropyl bromoacetate are added at 20° C. The mixture is stirred for 2 hours at 20° C. and subjected to rotary evaporation, the residue is taken up in methylene chloride/water, the organic phase is dried and subjected to rotary evaporation, and the residue is filtered over silica gel (eluent hexane:acetone=7:3). 5.3 g (71% of theory) of 2-methyl-propyl N-butylaminoacetate are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]([CH3:49])([CH3:48])[C:46]#[N:47].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:44][C:45]([C:46]#[N:47])([CH3:49])[CH3:48])=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(N)C#N
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C#N)NC(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 2-amino-2-methylpropionitrile (22 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C15H19ClN6O2, 351.13. found 351.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].C([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH:33]1[CH3:38])(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:35]2[CH2:36][CH2:37][NH:32][CH:33]([CH3:38])[CH2:34]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27]
Reactant: O=Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Reactant: CC(C)N1CCNCC1C
Product: CC1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde (INTERMEDIATE AAA 1) and 1-isopropyl-2-methylpiperazine as described in EXAMPLE AAA1, STEP A. 1H NMR (CDCl3, 500 MHz): δ 0.90 (brs, 3H), 0.93 (brs, 3H), 0.98 (brs, 3H), 1.92 (brs, 1H), 2.16 (brs, 1H), 2.31 (brs, 1H), 2.57 (m, 2H), 2.67 (brs, 1H), 3.21 (brs, 1H), 3.40 (s, 2H), 4.22-4.485 (m, 2H), 5.05 (s, 1H), 6.17 (s, 1H), 6.85 (d, 1H, J=3.7 Hz), 7.30-7.60 (m, 7H). MS (API-ES+): 559 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[OH:12][C:13]1[CH:14]=[C:15]([B:19]([OH:21])[OH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:12][C:13]1[CH:14]=[C:15]([B:19]([OH:21])[OH:20])[CH:16]=[CH:17][CH:18]=1)=[O:5]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: OB(O)c1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1cccc(B(O)O)c1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To make compound (6a), a solution of 2,6-dichlorobenzoyl chloride (29 μL, 0.2 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 3-hydroxyphenylboronic acid (21 mg, 0.15 mmol), dried triethyl amine (42 μL, 0.3 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 38 mg (81% yield) of desired compound as a white powder, mp: 238° C.(dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.08–7.19 [m, 1H, Ar—H], 7.22–7.30 [m, 1H, Ar—H], 7.22–7.30 [m, 1H, Ar—H], 7.42–7.50 [m, 1H, Ar—H], 7.54–7.60 [m, 1H, Ar—H], 7.60–7.68 [m, 2H, Ar—H], 7.73–7.78 [m, 3H, Ar—H].
Reaction SMILES: C1(P(=[N:20][C:21]2[CH:25]=[CH:24][S:23][C:22]=2[CH:26]=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=O.N1CCCCC1>CCO>[CH2:33]([O:32][C:30]1[N:20]=[C:21]2[CH:25]=[CH:24][S:23][C:22]2=[CH:26][C:29]=1[C:28]([O:36][CH2:37][CH3:38])=[O:35])[CH3:34]
Reactant: O=Cc1sccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2sccc2nc1OCC

Procedure:
A solution of 3-[(triphenylphosphoranylidene)amino]-2-thiophenecarbaldehyde (11-2, 2.50 g, 6.45 mmol, 1 equiv), diethyl malonate (1.96 mL, 12.9 mmol, 2.00 equiv), and piperidine (0.319 mL, 3.23 mmol, 0.500 equiv) in EtOH (50 mL) was heated at reflux for 16 h. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (heaxane, initally, grading to 30% EtOAc in hexane) to give ethyl 5-ethoxythieno[3,2-b]pyridine-6-carboxylate (11-3) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 7.84 (d, 1H, J=7.4 Hz), 7.37 (d, 1H, J=7.2 Hz), 4.55 (q, 2H, J=7.0 Hz), 4.40 (q, 2H, J=7.1 Hz), 1.48 (t, 3H, J=7.0 Hz), 1.41 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15]4=[C:16]([CH2:18][S:19][CH2:20][CH2:21][N:14]4[C@H:13]4[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][C@@H:12]34)[CH:17]=2)=[C:5]([CH3:33])[CH:4]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15]4=[C:16]([CH2:18][S:19][CH2:20][CH2:21][N:14]4[C@H:13]4[CH2:22][CH2:23][NH:24][CH2:25][C@@H:12]34)[CH:17]=2)=[C:5]([CH3:33])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CCSC3)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(C)c1

Procedure:
To a solution of tert-butyl (7bR,11aS)-6-(4-methoxy-2-methylphenyl)-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate (34 mg, 0.07 mmol) in CH2Cl2 (5 ml) at 25° C. was added trifluoroacetic acid (1 mL). The mixture was stirred at ambient temperature for 1 hour before saturated NaHCO3 (10 mL) was added and then extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate and concentrated to afford the title compound of EXAMPLE 9. 1H NMR(CDCl3, 300 MHz): δ 7.16 (d, 1H, J=8.0 Hz), 6.88 (s, 1H), 6.75 (m, 3H), 3.80 (s, 3H), 3.80 (m, 1H), 3.65 (m, 1H), 3.52 (m, 1H), 3.23-2.85 (m, 6H), 2.61 (m, 1H), 2.24 (s, 3H), 2.90 (m, 4H). LRMS (ES+): 367 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[CH:7]=3)=[CH:4][C:3]=1[F:21].[Cl:22]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[C:7]=3[Cl:22])=[CH:4][C:3]=1[F:21]
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(N)c(Cl)c1C2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCCCC12CCC(=O)C(Cl)=C1c1cc(F)c(N)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 80.1 %

Procedure:
A solution of 7-amino-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.054 g, 0.175 mmol) in anhydrous N,N-dimethylformamide (0.35 mL) was cooled in an ice bath, placed under a nitrogen atmosphere, and treated with N-chlorosuccinimide (0.024 g, 0.18 mmol). The mixture was stirred at room temperature for 18.5 hours and then heated in an oil bath at 35° C. for 3 hours. The reaction mixture was partitioned between EtOAc and water, and the organic phase was dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative HPLC on a YMC-Pak ODS column (2×10 cm), eluting with 0.1% TFA in 10–100% MeCN/H2O (15 min gradient) at a 20 mL/min flow rate. The product-containing fractions (UV detection at 350 nm) were diluted with EtOAc, washed with 5% NaHCO3, water, and brine, dried over MgSO4, filtered, and evaporated under vacuum. The residual film was triturated with hexanes and the solid residue was dried under a N2 stream to afford 7-amino-9a-butyl-4,8-dichloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (48 mg, 80%).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][NH:8][C:9]1[C:18]2[CH:17]=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[N:12]=[C:11]2[C:20](=[O:25])[NH:21][NH:22][C:23](=[O:24])[C:10]=12)=[O:5])C.Cl>>[C:4]([CH2:6][CH2:7][NH:8][C:9]1[C:18]2[CH:17]=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[N:12]=[C:11]2[C:20](=[O:25])[NH:21][NH:22][C:23](=[O:24])[C:10]=12)([OH:5])=[O:3]
Reactant: CCOC(=O)CCNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Agent: Cl
Product: O=C(O)CCNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A mixture of 10-(2-ethoxycarbonylethylamino)-7-chloro-2,3-dihydropyridazino[4,5-b]quinoline-1,4-dione (0.08 g, 0.22 mM) and 1N hydrochloric acid was refluxed for 1 hr and then cooled to room temperature and filtered. The collected orange solid was washed with water and air dried to provide (0.07 g, 97%) the title compound as an orange powder, mp 356°-359° C.; MS(CI): 335 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[C:8]([N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH3:20])[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: CN(c1ccccc1)c1ncccc1NC(=O)c1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN1c2ccccc2C(c2ccccc2Cl)=Nc2cccnc21

Procedure:
Following the procedure of Example 58, 2-chloro-N-[2-(methylphenylamino)-3-pyridinyl]benzamide was cyclized to the title compound with phosphorus oxychloride and isolated, recrystallizing from isopropyl alcohol as yellow solid, m.p. 131.5°-133° C.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[NH2:20][C@H:21]([CH:24]([CH3:26])[CH3:25])[CH2:22][OH:23].CCN(C(C)C)C(C)C>>[OH:23][CH2:22][C@H:21]([NH:20][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CC(C)[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](CO)NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-2-amino-3-methyl-butan-1-ol and DIEA to give 2-((R)-1-hydroxymethyl-2-methyl-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 342 (MH+).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[S:6][CH3:7])([O-:3])=[O:2].[CH2:10]([NH:14][CH3:15])[CH2:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:10]([N:14]([C:5]([S:6][CH3:7])=[CH:4][N+:1]([O-:3])=[O:2])[CH3:15])[CH2:11][CH2:12][CH3:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CCCCNC
Solvent: Cc1ccccc1
Product: CCCCN(C)C(=C[N+](=O)[O-])SC

Procedure:
A solution of 8.26 g (0.05 mol) of 1-nitro-2,2-di(methylthio)ethylene and 5.25 g (0.06 mol) of N-n-butyl-N-methylamine in toluene is refluxed for 2 hours. After evaporation of the toluene under vacuum, 10.2 g of 2-(N-butyl-N-methylamino)-2-methylthio-1-nitroethylene are isolated as an oil (nD21 =1.584). (Compound 2.1, Table 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19](S(O)(=O)=O)=[CH:18][CH:17]=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:26]([N:11]1[CH2:12][CH:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OC1(c2cccc(Br)c2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(C2=CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
A solution of 28.2 g (81.4 mmol) of 4-(3-bromophenyl)-piperidin-4-ol in 600 ml of toluene was treated with 30 g (157 mmol) of p-toluenesulphonic acid monohydrate and heated to reflux on a water separator for 4 hours. Subsequently, the reaction mixture was cooled to room temperature and adjusted to pH 10 with 3 N sodium hydroxide solution. Thereafter, it was firstly extracted three times with 500 ml of methylene chloride. The combined organic phases were washed three times with 200 ml of water each time, dried over magnesium sulphate and then evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of methylene chloride and hexane as the eluent. There were obtained 9.5 g (36% of theory) of 1-benzyl-4-(3-bromophenyl)-1,2,3,6-tetrahydro-pyridine as a light yellow oil; MS: 327, 329 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][NH:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CCBr)OC
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(I)c(=O)n(C(=O)c2ccccc2)c1=O)OC
Yield: 91.8 %

Procedure:
3-Benzoyl-5-iodo-1H-pyrimidine-2,4-dione (Prep 6, 2.1 g, 6.13 mmol), K2CO3 (846 mg, 6.13 mmol) and 3-bromo-1,1dimethoxy-propane (1 mL, 7.4 mmol) were dissolved in dry DMF under Nitrogen (8 mL). After stirring the reaction at room temperature for 48 h, water was added and the product extracted with diethylether. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (35-65) to give 2.5 g of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(Oc2ccccc2F)cc1[N+](=O)[O-]
Temperature: 160 °C
Reaction time: 48 h
Yield: 383.5 %

Procedure:
To 4-fluoro-2-nitrotoluene (25 g, 0.016 mol), 2-fluorophenol (15.8 mL, 0.017 mol) in NMP (350 mL) was added potassium carbonate (22.27 g, 0.016 mol) and the mixture was stirred at 160° C. for 48 h. After cooling at room temperature, water (350 mL) was added and the solution was extracted into ethyl acetate (2×150 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated and the residue was purified by flash chromatography eluting with Hex:EtOAc 95:5 to yield 15.17 g of 4-(2-fluoro-phenoxy)-2-nitrotoluene: MS: 248 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[C:11]([NH:18][C:19](=[O:21])[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[C:11]([NH:18][C:19](=[O:21])[CH3:20])[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:14]=1
Reactant: COc1ccc(-c2cc(NC(C)=O)cc([N+](=O)[O-])c2)cc1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: COc1ccc(-c2cc(N)cc(NC(C)=O)c2)cc1
Temperature: 100 °C
Yield: 87 %

Procedure:
To a solution of N-(4′-methoxy-5-nitrobiphenyl-3-yl)acetamide (4 g, 13.98 mmol) in ethanol (50 ml) were added calcium chloride (3.1 g, 27.96 mmol, 2 eq.) and iron powder (1.45 g, 27.96 mmol, 2 eq.) and the mixture was heated at 100° C. for 2 h and filtered. The filtrate was diluted with water and extracted as in Example 1(d). The solvent was distilled off to afford the product in 87% yield (3.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[F:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:31][C:23]1[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=[CH:27][C:22]=1[O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:13])[F:14])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCOC(=O)C1=Cc2ccc(O)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 83.9 %

Procedure:
Ethyl 7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 1a, Step 1 (0.50 g, 1.73 mmole), 1,2-difluoro-4-nitrobenzene (0.30 g, 1.91 mmole), and cesium carbonate (0.62 g, 1.91 mmole) were mixed in DMF (2 mL). Copper (I) trifluoromethanesulfonate benzene complex (5 mg) was added to above mixture. The mixture was heated to 90° C. for 6 hour. LCMS indicated product formation and there was no starting material present. The reaction was quenched with sodium bicarbonate (sat.) and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous MgSO4. The filtrate was evaporated and dried in vacuo to afford a brown oil, which was purified by Biotage silica chromatography with 20% ethyl acetate in hexane to provide a light yellow oil (0.62 g, 84%): LCMS m/z 449.65 (M+Na). 1NMR (CDCl3/400 MHz) 8.05 (m, 2H), 7.70 (s, 1H), 7.24 (m, 1H), 7.17 (dd, 1H, J=8.8, 8 Hz), 6.66 (m, 1H), 6 65 (s, 1H), 5.69 (q, 1H, J=6.8 Hz), 4.30 (q, 2H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C(OCC)C>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9][CH2:8]1
Reactant: CN1CCNCC1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N1CCN(C)CC1
Reaction time: 72 h
Yield: 61.6 %

Procedure:
A solution of acryloyl chloride (9 g, 0.10 mole) in ethyl ether (20 ml) was added dropwise to a stirring, cold solution of N-methylpiperazine (10 g, 0.10 mole) and triethylamine (30.6 ml, 0.22 mole) in ethyl ether (150 ml) over a thirty minute period. An additional 75 ml of ethyl ether was added and the reaction stirred for 72 hours. The resulting white solid was filtered and washed well with ethyl ether. The ethyl ether was collected, combined with the filtrate and the solvent evaporated on a rotary evaporator to yield 9.5 g of product as an orange oil. NMR confirmed the structure of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22](=[NH:25])[NH:23][OH:24])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:32](N1CCCCC1)#[N:33]>>[NH2:33][C:32]1[O:24][N:23]=[C:22]([C:19]2[N:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=3)[CH2:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[N:17][CH:18]=2)[N:25]=1
Reactant: N#CN1CCCCC1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(=N)NO)cn2)cc1Cl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3noc(N)n3)cn2)cc1Cl
Temperature: 130 °C
Yield: 37 %

Procedure:
A mixture of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxycarbamimidoyl)-pyrazin-2-yl]-propionamide (prepared as in Example 1, 7.00 g, 15.02 mmol) in N-cyanopiperidine (25 mL) was heated at 130° C. in a sealed tube for 1.5 h. The mixture was allowed to cool to 25° C. and then concentrated under a stream of anhydrous nitrogen overnight. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/2 ethyl acetate/hexanes) afforded the N-[5-(5-amino-[1,2,4]oxadiazol-3-yl)-pyrazin-2-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (2.74 g, 37%) as an off-white solid: mp 262–264° C.; (ES)+-HRMS m/e calcd for C21H23ClN6O4S2 (M+Na)+ 513.1082, found 513.1088.
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].Cl[CH:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O1CCCC1>[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)Cl
Reactant: CCCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCSCCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A solution of heptyl mercaptan (13.23 g, 0.105 mol) in tetrahydrofuran (THF) was added to a vigorously stirred suspension of sodium hydride (2.6 g, 0.105 mol) in THF (170 mL) over 45 minutes. The mixture was stirred under argon at room temperature for one hour. Chlorohexanol (13.44 g, 0.1 mol) in THF was added to the vigorously stirred mixture over a period of 30-45 minutes. The mixture was then stirred under argon at room temperature for 24 hours. Reaction completion was then checked by thin layer chromatography. The THF was then evaporated on a rotary evaporator. Water was then added to the mixture, and extraction was performed three times with ethyl acetate (EtOAc). The EtOAc extraction was washed with water. Then the EtOAc extracts were washed with saturated brine, and dried over Na2SO4. The Na2SO4 was filtered and evaporated to a yellow oil on a rotary evaporator. The product was then chromatographed with a Waters Prep 500 HPLC, using hexane-EtOAc. Appropriate fractions were combined and evaporated to a clear, light yellow oil. The oil was then distilled under vacuum, boiling point 85°-100° C./0.01 mm. to yield 7-thiatetradecan-1-ol (19.09 g, 82% yield).