Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:36]I>C1(C)C=CC=CC=1>[I:36][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: II
Reactant: OCCCCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: ICCCCc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 4-phenyl-1-butanol (601 mg, 4.0 mmol), Ph3P (1.57 g, 6.0 mmol, 1.5 equiv.) and imidazole (409 mg, 6.0 mmol, 1.5 equiv.) in toluene (20 mL) was added I2 (1.52 g, 6.0 mmol, 1.5 equiv.) at 0° C. The mixture was allowed to stand overnight, and the reaction was quenched with saturated Na2S2O3 solution. The mixture was extracted with hexane/EtOAc 10:1, and the organic layer was washed with brine and dried over Na2SO4. After concentration, the residue was filtrated through Celite, and the Celite was washed with hexane. After removal of the solvent, (4-iodobutyl)benzene (1.04 g, 100%) was obtained as a pale yellow oil, which was used in the subsequent step without purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:6]2[N:21]=[C:2]([NH:22][C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)=[O:28])=[CH:25][C:24]=3[O:39][CH3:40])[N:3]=[CH:4][C:5]1=2
Reactant: CC1CN(C2CCOCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCOCC1)CC(C)C(=O)N2C
Yield: 56.1 %

Procedure:
A solution of 0.050 g (0.00016 mole) of (rac)-2-chloro-5,7-dimethyl-9-(tetrahydropyran-4-yl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-45), 0.042 g (0.00016 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.047 g (0.00024 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated and the residue diluted with dichloromethane, washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25) to give 0.0483 g of (rac)-4-(5,7-dimethyl-6-oxo-9-(tetrahydro-pyran-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-45) as a white powder. HRMS (ES+) m/z Calcd for C28H39N7O4+H [(M+H)+]: 538.3137. Found: 538.3136.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:26])=[C:7]([CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:10]=1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:26][C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][C:7]=1[NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:10]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccccc2)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
A mixture of 4-(5-amino-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine hydrochloride (25 mg, 0.067 mmol), benzoic acid (10 mg, 0.080 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.4 mg, 0.080 mmol) in dichloromethane (5 ml) was stirred at room temperature for 24 h. The mixture was rotary evaporated to dryness and the residue was purified by column chromatography to give a white solid (14 mg, 47%). 1H NMR (CDCl3): 9.66 (s, 1H), 8.75-8.71 (m, 1H), 8.67 (bs, 1H), 8.40 (s, 1H), 8.08 (dd, J=1.2, 8.4 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.90-7.86 (m, 2H), 7.81 (s, 1H), 7.55-7.38 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 6.71 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[F:1][C:2]1([F:15])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][C:11]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH2:9]2)[CH2:4][CH2:3]1
Reactant: C1CCNC1
Reactant: O=C1CCC(N2CCC(F)(F)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: FC1(F)CCN(C2CC=C(N3CCCC3)CC2)CC1
Yield: 96.2 %

Procedure:
Heat a solution of 4-(4,4-difluoro-piperidin-1-yl)-cyclohexanone (1.93 g 8.88 mmol), pyrrolidine (0.89 mL, 10.7 mmol) and p-toluenesulfonic acid (1 crystal) in cyclohexane (50 mL) to reflux with a Dean-Stark trap for 7 h. Cool the solution and filter through a plug of cotton wool. Evaporate to give 2.31 g, 96% yield of 4,4-difluoro-1-(4-pyrrolidin-1-yl-cyclohex-3-enyl)-piperidine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29]COC)/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1.Cl.[OH-].[Na+].O>O1CCCC1>[OH:29][C:28]1[CH:27]=[CH:26][C:5](/[CH:6]=[CH:7]/[C:8]2[N:16]([CH3:17])[C:15]3[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=3[N:9]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OCOC)c(OC)c3)n2C)n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(OC)c3)n2C)n(CCC)c1=O
Yield: 71.4 %

Procedure:
Compound d (3.00 g, 6.78 mmol) obtained in Reference Example 4 was suspended in 60 ml of tetrahydrofuran, and 2N hydrochloric acid (17 ml) was added thereto, followed by heating under reflux for 1 hour. The reaction mixture was neutralized by adding 2N sodium hydroxide under ice-cooling. Water was added to the reaction mixture, and the resulting precipitate was collected by filtration. The obtained crude product was recrystallized from hexane/ethyl acetate to give 1.93 g (72% yield) of Compound e as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=O)[CH2:21][CH2:20]3)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=[S:38])[CH2:21][CH2:20]3)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)CCC(=O)N4C)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)CCC(=S)N4C)c2)CCOCC1
Yield: 85 %

Procedure:
Using the procedure described in Example 1 except that the reaction mixture was heated to reflux for 15 minutes, 4-[5-fluoro-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-methoxytetrahydropyran was reacted with Lawesson's Reagent to give 4-[5-fluoro-3-(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-methoxytetrahydropyran in 85% yield, m.p. 133.6°-134.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C)[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.Cl.[CH3:21]NOC.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>ClCCl.N1C=CC=CC=1>[Cl:9][C:4]1[C:5]([CH3:21])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[CH:13]=[O:15]
Reactant: Cc1cc(Cl)c(Nc2ccccc2C(=O)O)c(Cl)c1
Reactant: CNOC
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Yield: 120.7 %

Procedure:
A mixture in dry dichloromethane (135 mL) of 2-[(2,6-dichloro-4-methylphenyl)amino]benzoic acid (meclofenamic acid) (7.0 g, 23.6 mmol), N,O-dimethylhydroxylamine hydrochloride (5.0 g, 51.9 mmol), carbon tetrabromide (17.2 g, 51.9 mmol), triphenylphosphine (13.6 g, 51.9 mmol), and pyridine (10 mL) was stirred at ambient temperature for 48 hours. The reaction mixture was poured into 10% HCl (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. Purification by chromatography on silica gel (9:1 hexane/ethyl acetate) provided 7.98 g (99%) of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[C:18]3=[O:34])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:37])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[C:18]3=[O:34])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:37])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(=O)O)cc4Cl)CC3)C2=O)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(=O)Cl)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 203.8 %

Procedure:
To a solution of (S)-5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinic acid (0.40 g, 0.38 mmol) in DCM (20 mL) was added sulfurous dichloride (0.28 g, 2.3 mmol) and DMF (1 drop) and the reaction was stirred at ambient temperature for 3 hours. The reaction was concentrated under vacuum to give (S)-5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinoyl chloride (0.41 g, 100%). The material was used directly in the next step without purification.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:15]=2)=[CH:9][C:8]=1[CH3:35])C.[OH-].[Na+].Cl>C(O)C>[CH2:33]([CH:30]([CH2:31][CH3:32])[CH2:29][O:28][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH3:35])[CH:9]=2)[CH:19]=[C:18]([C:20]#[C:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=1)[CH3:34]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCC(CC)CC)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CC)COc1cc(C#Cc2ccccc2)cc(Sc2ccc(OCC(=O)O)c(C)c2)c1
Reaction time: 16 h

Procedure:
{4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 128 mg (80%). HPLC-MS: m/z: 475.1 (M+H)+; Rt: 3.06 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=O.O.NN.C(O)C>O>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=C1CCSc2c(O)cccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: Oc1cccc2c1SCCC2
Temperature: 200 °C
Yield: 55 %

Procedure:
40 Grams of 8-hydroxy-thiochroman-4-one were added portionwise to a mixture of 53.5 ml of hydrazine hydrate and 220 ml of ethanol. The reaction mixture was refluxed for 1 hour and then evaporated to dryness in vacuo. The residue was taken up in 250 ml of ethyleneglycol, and then 22.1 g of sodium hydroxide, were added in pellet form. The whole was heated to refluxing, while the water of reaction was distilled off as it is formed. The mixture was then heated for 4 hours at 200°C, allowed to cool and the bulk of glycol was expelled under vacuum. The residue was diluted with water and then acidified. The liberated phenol was extracted with chloroform. The chloroform extract was dried and evaporated and the residue distilled under vacuum, to yield 20.1 g of 8-hydroxy-thiochroman, boiling at 105°-110°C under 0.08 mm Hg pressure, in a yield of 55%. After recrystallization from cyclohexane it melted at 86°-88°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1>CO.Cl.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of methyl 3,3-bis(4-chlorophenyl)propenoate (Step A, 3.0 g, 14 mmol) and platinum dioxide (0.30 g) in MeOH (20 mL) and 2 M aqueous hydrochloric acid (1 mL) was degassed and filled with hydrogen with a balloon. After stirring at room temperature for 2 h, the reaction mixture was filtered through CELITE diatomaceous earth, and the filtrate was concentrated to dryness. The residue was dissolved in 50 mL ether and was concentrated with 20 g silica gel. The material was loaded onto a silica gel column, which was eluted with 10% ether in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.29-7.22 (m, 4H), 4.50 (t, 1H), 3.56 (s, 3H), 3.07 (d, 2H). LC-MS: m/e 309 (M+H)+ (4.1 min).
Reaction SMILES: N12CCCN=C1CCCCC2.CO[C:14](=[O:37])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:16]=1[C:33]([O:35]C)=O.Cl.[NH2:39][CH:40]1[CH2:46][CH2:45][C:44](=[O:47])[NH:43][C:41]1=[O:42].O>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[NH:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]2[C:16]=1[C:33](=[O:35])[N:39]([CH:40]1[CH2:46][CH2:45][C:44](=[O:47])[NH:43][C:41]1=[O:42])[C:14]2=[O:37])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: COC(=O)c1cccc(CNC(=O)OCc2ccccc2)c1C(=O)OC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)OCc4ccccc4)c3C2=O)C(=O)N1
Temperature: 120 °C
Yield: 22.9 %

Procedure:
1,8-diazabicyclo[5,4,0]undec-7-ene (0.88 g, 6 mmol) was added to a stirred suspension of methyl-3-[(benzyloxycarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (2.07 g, 6 mmol) and aminoglutarimide hydrochloride (0.95 g, 6 mmol) in DMF (15 ml). The mixture was heated to 120° C. for 24 hours. The mixture was cooled to room temperature and poured into water (150 ml). The mixture was extracted with ethyl acetate (3×30 ml) and the combined ethyl acetate extracts were washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the residue was purified by chromatography (dichloromethane/ethyl acetate 8 to 2) to give 0.58 g (24%) of the product as a white solid: mp 166-168° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 7.99-7.71 (m, 4H), 7.37 (m, 5H), 5.19-5.12 (dd, J=5.1 and 17.4 Hz, 1H), 5.07 (s, 2H), 4.70 (d, J=5.7 Hz, 2H), 2.97-2.83 (m, 1H), 2.64-2.51 (m, 2H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.85, 169.89, 167.51, 167.01, 156.55, 139.46, 137.02, 134.87, 132.89, 131.57, 128.44, 127.92, 127.83, 127.06, 121.99, 65.69, 48.89, 30.97, 22.02; Anal. Calcd. For C22H19N3O6: C, 62.70; H, 4.54; N, 9.97. Found: C, 62.53; H, 4.57; N, 9.89.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:23][CH2:22][C:6]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][CH2:4]1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].Cl>C(N(CC)CC)C>[O:20]=[C:19]1[C:9]2[S:8][CH2:7][C:6]3([CH2:22][CH2:23][CH:3]([NH:2][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=4)[CH2:4][CH2:5]3)[O:11][C:10]=2[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]1=[O:21]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NC1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCC(NC(=O)c3cccc(C(F)(F)F)c3)CC1)O2

Procedure:
Compound 70 was synthesized using 4-aminospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione hydrochloride, 3-(trifluoromethyl)benzoyl chloride, triethylamine to neutralize the hydrochloride and conditions outlined in procedure N. M.p.=266-267° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.66 (d, J=7.8 Hz, 1H), 8.21-8.16 (m, 2H), 7.92 (d, J=7.4 Hz, 1H), 7.85 (t, J=7.1 Hz, 1H), 7.80 (t, J=7.1 Hz, 1H), 7.74 (t, J=7.1 Hz, 1H), 7.58 (t, J=7.1 Hz, 1H), 4.08-3.94 (m, 1H), 3.06 (s, 2H), 2.20-2.10 (m, 2H), 1.94-1.72 (m, 7H), LCMS: 488 [M+H].
Reaction SMILES: C(O)(=O)C.[CH3:5][NH:6][NH2:7].[C:8]([CH:11]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[C:12](=S)[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])(=O)[CH3:9]>C(O)C.C(OCC)(=O)C>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:11]1[C:8]([CH3:9])=[N:7][N:6]([CH3:5])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: CNN
Reactant: CC(=O)C(C(=S)Nc1ccc(F)cc1F)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(Nc2ccc(F)cc2F)c1-c1ccc(Cl)cc1Cl

Procedure:
Acetic acid (50 μL) and methylhydrazine (41 μL) were added to a stirred suspension of α-acetyl-2,4-dichloro-N-(2,4-difluorophenyl)benzeneethanethioamide (238 mg, 0.64 mmol) in ethanol (4 mL). The reaction mixture was heated at reflux for 2 h and allowed to cool. Then the reaction mixture was diluted with ethyl acetate (10 mL) and washed with 1 N aqueous NaOH (10 mL), water (10 mL) and brine (10 mL), dried over MgSO4, and concentrated to leave a solid residue. The residue was purified by column chromatography on 5 g of silica gel with a gradient of hexanes/ethyl acetate (2:1 to 1:1) to give the title compound as a solid (170 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:26])([CH3:25])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([O:20][CH2:21][C:22](O)=[O:23])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH2:28]>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:25])([CH3:26])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([O:20][CH2:21][C:22](=[O:23])[NH:28][CH3:27])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN
Reactant: CC(C)(Cc1c[nH]c2c(OCC(=O)O)cccc12)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CNC(=O)COc1cccc2c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a solution of [3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]acetic acid (480 mg, 1.32 mmol) in dimethylformamide (5.0 mL) is added methyl amine (1.52 mL, 1.0 M in tetrahydrofuran, 1.52 mmol) and Bop reagents (670 mg, 1.52 mmol). The reaction mixture is stirred at room temperature for 3 hours before evaporation to dryness. The resulting residue is chromatographed (30% ethyl acetate/hexane) to give 500 mg of [1,1-dimethyl-2-(7-methylcarbamoylmethoxy-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (75%). FDMS m/e=375.1 (M++1).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>O>[N+:18]([C:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1)([O-:20])=[O:19]
Reactant: O=C1CCCCc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCCCc2c1cccc2[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6,7,8,9-Tetrahydro-5H-benzo[a]cyclohepten-5-one (18.5 g, 11.5 mmol) was mechanically stirred at −15° C. and treated with concentrated sulfuric acid (41 mL) over 5 minutes, stirred 10 minutes, treated dropwise over 10 minutes with a mixture of fuming nitric acid (9 mL) and concentrated sulfuric acid (14 mL), stirred at −15° C. for 15 minutes and poured carefully onto a mixture of ice (200 g) and water (200 mL). The resulting solid was collected by filtration, washed with water (100 mL, 2×), dried and recrystallized from ethanol (200 mL). The resulting solid was removed by filtration and the filtrate was suspended on silica gel and purified on silica gel eluting with ethyl acetate:hexanes 12:88 to provide the desired product.
Reaction SMILES: [OH:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5].CN1C=CN=C1.[CH3:28][O:29][C:30](Cl)=[O:31].O>C(Cl)Cl>[CH3:28][O:29][C:30]([O:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5])=[O:31]
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Reactant: COC(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)ON(C)C(=O)C(C)Nc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Yield: 35.4 %

Procedure:
3 g of N-hydroxy-N-methyl-2-(4-methyl-2,6-dinitrophenylamino)propanamide and the product prepared from 0.8 g N-methylimidazole and 0.9 g of methoxycarbonylchloride were reacted as a stirred suspension in 30 ml of methylene chloride for 3 hours. The resulting mixture was poured into water. The methylene chloride layer was dried and evaporated to give 1.2 g (33% yield) of yellow solid product, m.p. 112°-113° C., (d,l) isomer form.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14]C)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Mg].[Cl-].[NH4+].C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1Cc2ccc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
To a stirred suspension-solution of ethyl 6-chloroindole-2-carboxylate (20.0 g, 89.4 mmol) in methanol (350 mL) under Ar was added magnesium turnings (21.7 g, 0.89 mol). After 10 min, the internal temperature had risen to 24° C. and effervescence was apparent. The mixture was cooled to 10-1S ° C. and was maintained for 1.5 h. After this time, the reaction mixture was allowed to warm to ambient temperature, and was stirred for 1 h. The mixture was poured onto saturated aqueous ammonium chloride solution (1 L), and ethyl acetate (300 mL) was added. After 1.5 h stirring, the layers were separated, and the aqueous layer was exacted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine (200 mL), dried (magnesium sulfate) and concentrated in vacuo to give a brown oil. Purification by flash column chromatography [SiO2; ethyl acetate-heptane (1:3)] afforded the title compound (12.0 g, 63%) as an orange oil which crystallised on standing: IR νmax (film)t/cm−1 3375, 2953, 2851,1737, 1610, 1486, 1438, 1321, 1287, 1204, 1161, 1069, 1011, 948, 906, 846, 796, 794, 594 and 548; NMR δH (400 MHz; CDCl3) 3.27 (1H, dd, J 16.0, 5.0 Hz), 3.34 (1H, ddd, J 16.0, 10.5, 1.0 Hz), 3.76 (3H, s), 4.40 (1H, dd, J 10.5, 5.0 Hz), 4.47 (H, br s), 6.68 (1H, br d, J 2 Hz), 6.69 (1H, dd, J 7.5, 2.0 Hz) and 6.96 (1H, d, J 7.5 Hz); hplc [Chiralcel OD; hexane-isopropanol (90:10); 1 mL/min; 260 nm] 50% (10.04 min) and 50% (11.61 min).