Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].Cl>CO.[Cl-].[Na+].O.Cl[Pd]Cl.C(Cl)Cl>[ClH:1].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2ccc(C(C)(C)C)cc2)c1
Temperature: 100 °C
Yield: 76.9 %

Procedure:
Methyl 2-chloroisonicotinate (7 g, 40.80 mmol), 4-tert-butylphenylboronic acid (10 g, 56.17 mmol), potassium carbonate (3.5 g, 25.32 mmol) and PdCl2 (dppf) (0.9 g, 1.24 mmol) were mixed in methanol (30 mL) in two equal portions in 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The solids were removed by filtration and the filtrate evaporated to yield a dark red slurry. DCM and brine were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phases dried over MgSO4 and evaporated. The crude was dissolved in MTBE (180 mL) and the solids filtered off. Hydrogen chloride (4 M in dioxane, 10.20 mL, 40.80 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 1 h. The solid was collected by filtration and washed with MTBE. Methyl 2-(4-tert-butylphenyl)isonicotinate hydrochloride (9.6 g, 77%) was isolated as a dark brown solid. 1H NMR (400 MHz, dmso) δ 1.30 (s, 9H), 3.92 (s, 3H), 7.53 (d, 2H), 7.80 (dd, 1H), 8.04 (d, 2H), 8.29 (s, 1H), 8.85 (d, 1H), 9.86 (br, 1H). MS m/z 270 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10]2[NH:9][C:8](=[O:12])[CH:7]=[CH:6][C:5]=2[C:4](=[O:13])[CH2:3]1.CI.[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]=[C:4]1[CH2:3][C:2]([CH3:14])([CH3:1])[CH2:11][C:10]2[N:9]([CH3:17])[C:8](=[O:12])[CH:7]=[CH:6][C:5]1=2
Reactant: CC1(C)CC(=O)c2ccc(=O)[nH]c2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c2c(ccc1=O)C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 50.3 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-2(1H)-quinolinone (15.0 g), methyl iodide (12.3 g), potassium carbonate (21.6 g), and dimethylformamide (230 ml) was stirred at room temperature for 21 hrs. The reaction mixture was filtered, and the filtrate was concentrated. Ethyl acetate was added to the residue, and the mixture was filtered. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 8.1 g (50%) of 5,6,7,8-tetrahydro-5-oxo-1,7,7-trimethyl-2(1H)-quinolinone.
Reaction SMILES: [CH2:1]([C:11]12C[CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23].[I-].C([Al+][CH2:28][CH3:29])C.C(CN)O>C1(C)C=CC=CC=1>[CH2:4]([CH:5]1[CH2:6][CH:7]2[CH2:28][CH:29]1[CH:9]=[CH:8]2)[CH2:3][CH2:2][CH2:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCC12C=CC(CC1)C2
Reactant: CC[Al+]CC
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: NCCO
Solvent: C=CCCCC
Product: CCCCCCCCCCC1CC2C=CC1C2
Reaction time: 1 h

Procedure:
50 ml dry toluene cosolvent, 7 ml decylnorbornene, 0.8 ml of the 1-hexene solution, and 0.9 ml of the diethylaluminum iodide solution were charged to a dry, nitrogenpurged 7 oz. bottle. 1.1 ml of the MoCl5 solution was charged last, and the bottle was shaken. After 1 hour the reaction was shortstopped using a mixture of 0.1 ml ethanolamine and 0.5 ml Solution A. No antioxidant was added. The polymer cement was coagulated using excess Solution A in a Waring blender. About 4.5 grams of a solid, ring-opened 5-decyl-2-norbornene/1-hexene copolymer was recovered by filtering and vacuum drying.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([NH2:22])[C:15]=1[NH2:23]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[C:15]([NH:23][C:1](=[O:10])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[C:16]=1[NH:22][C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(OC)c(N)c1N
Product: COc1ccc(C(=O)Nc2c(OC)ccc(OC)c2NC(=O)c2ccc(OC)cc2)cc1
Yield: 63.6 %

Procedure:
Using the procedure described in Example 93, Part A, 4-anisoyl chloride (4.9 mmol) and 3,6-dimethoxy-1,2-benzenediamine (2.0 mmol) yielded 555 mg (65%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:7]=1)=[O:4]>C(OCC)(=O)C.[C].[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:22])[F:23])[CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: O=C(Nc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cccc(NC(=O)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[3-(4-nitrophenoxy)phenyl]acetamide (13.0 g, 39.8 mmol) in ethyl acetate (400 mL) was added 10% palladium-carbon (10 g), and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (11.7 g, 99%) as a pale-gray amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]1[C:28]([NH2:29])=[C:27]([CH3:30])[O:26][N:25]=1.C(N(CC)CC)C>ClCCl>[CH3:23][C:24]1[C:28]([NH:29][C:12]([C:11]2[C:5]3[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=3[C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)=[O:14])=[C:27]([CH3:30])[O:26][N:25]=1
Reactant: Cc1noc(C)c1N
Reactant: CCc1nc2c(OC)ccc(C(=O)O)c2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(OC)ccc(C(=O)Nc3c(C)noc3C)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a suspension of 2-ethyl-4-methoxybenzothiazole-7-carboxylic acid (0.1 g) in dichloromethane (10 ml) was added oxalyl chloride (0.08 ml) and dimethylformanide (1 drop). The reaction was stirred at room temperature for 16 hrs, and then the solvent was removed in vacuo to yield a brown solid residue. This was taken up in dichloromethane is (30 ml) and 3,5-dimethylisoxazol-4-amine (0.05 g) was added followed by triethylamine (0.15 ml) and the reaction stirred at room temperature for 16 hrs. The solvent was removed in vacuo and the product purified by flash chromatography (eluent ethyl acetate) to yield the title compound as an off-white solid (0.016 g). TLC Rf 0.38 (ethyl acetate); Mpt 85-87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>C1(C)C=CC=CC=1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:11]
Reactant: Nc1ccccn1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(CNc1ccccn1)OCC
Temperature: 100 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
A solution of 2-aminopyridine (9.4 g.) in dried toluene (25 ml.) was dropwise added at 100° C to a suspension of 55% sodium hydride (5.04 g.) in dried toluene (10 ml.). The mixture was stirred for 2 hours at 100° C. To the solution were added bromoacetaldehyde diethyl acetal (26 g.) and dried toluene (5 ml.). The mixture was stirred for 19 hours at 115° C and cooled to ambient temperature. The reaction mixture was post-treated according to similar manners to those of the above-mentioned Examples to give oil of 2-pyridylaminoacetaldehyde diethyl acetal (8 g.).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][NH:18][N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].Br[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: Fc1ccc(Br)c(OC2CCN(c3noc(-c4cc[nH]n4)n3)CC2)c1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1

Procedure:
The title compound was prepared in a similar manner as described in Example 7 (step 4) from 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]piperidine, sodium hydride and ethyl 3-bromopropionate and obtained as the more polar major isomer.
Reaction SMILES: [K].Cl[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O-:14])=[O:13].C(N1CCOCC1)C.Cl>CN(C)C=O>[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:3]1[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][N:11]=1)([O-:14])=[O:13]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C([O-])c1cccnc1Cl
Agent: CCN1CCOCC1
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
Potassium-2-chloro-nicotinate (89 g, 455 mmole) was suspended in 630 ml of dimethylformamide. To this suspension was added 3-nitroaniline (75.3 gm, 546 mmole), cupric acetate (5.1 g, 25.5 mmole) and N-ethyl morpholine (52.3 g, 455 mmoles). The suspension was refluxed with stirring under N2 for 4 hours. The reaction mixture was cooled to room temperature and the pH was adjusted to 4-5 by the addition of 6M HCl. A yellow precipitate was isolated from the reaction mixture, washed with water and air dried yielding 66.3 g (256 mmole, 56% yield) of 2-(3-nitroanilino)-3-carboxypyridine (mp 262°-264° C.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:8]([O:28][CH3:29])=[C:9]([NH:11][C:12](=[O:27])[NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](O)=[O:25])=[CH:16][CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[OH:64][CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]([N:68]3[CH2:69][CH2:70][CH:65]([OH:64])[CH2:66][CH2:67]3)=[O:25])=[CH:16][CH:15]=2)=[O:27])[C:8]([O:28][CH3:29])=[C:7]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(NC(=O)Nc2ccc(C(=O)O)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(NC(=O)Nc2ccc(C(=O)N3CCC(O)CC3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
85 mg (0.22 mmol) of 4-[3-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-ureido]-naphthalene-1-carboxylic acid (Example 17) was dissolved in 1 mL of DMF. To this clear solution was added sequentially, 92 mg (0.294 mmol) of TBTU, and 82 microL (0.59 mmol) of triethylamine. The clear yellow solution was stirred for 5 min, then 33 mg (0.33 mmol) of 4-hydroxypiperidine was added. The reaction was stirred overnight, then concentrated in vacuo. The resulting amber oil was extracted with EtOAc and water, brine, and then dried over magnesium sulfate. Concentration in vacuo provided an amber oil which was purified on silica gel, eluting with with 33% EtOAc-hexane to provide 57 mg (54%) of the title compound as a pale white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][F:26])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([CH3:43])=[CH:37]2>CC(N(C)C)=O>[F:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([O:33][C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[NH:39][C:38]([CH3:43])=[CH:37]5)=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:19][CH2:20]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(CCF)CC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCN(CCF)CC1
Temperature: 85 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
A solution of 4-chloro-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (240 mg, 0.63 mmol) in DMA (5 ml) was treated with potassium carbonate (96 mg, 0.69 mmol) and 5-hydroxy-2-methylindole (102 mg, 0.69 mmol), (WO 00/47212, Example 48), and stirred at 85° C. for 4 hours. The mixture was cooled and the solvent evaporated under vacuum to give a residue which was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8). Evaporation of the relevant fractions gave an oil which crystallised on trituration with ether to give 7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (150 mg, 48%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C(O[C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1)=[O:26])C.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O.C(O)(=O)C>[F:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][N:32]1[C@@H:28]2[C@@H:27]([CH2:31][CH2:30][CH2:29]2)[C:25]([OH:26])=[C:16]([C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[N:12]=2)[C:17]1=[O:18]
Reactant: CCOC(=O)C1CCCC1NCc1cccc(F)c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3cccc(F)c3)C1=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.7 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-(3-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (0.080 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with N-methylmorpholine (63.7 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.4 mg, 0.315 mmol) and stirred at 25° C. for 4 h. The solvent was removed in vacuo. The crude material was redissolved in ethyl acetate (75 mL) and washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude intermediate was redissolved in ethanol (5 mL) and treated with a 21% w/w solution of sodium ethoxide in ethanol (448 μL, 1.2 mmol) and stirred for 2 h at 60° C. The reaction was allowed to cool to 25° C., treated with glacial acetic acid (0.4 mL), the solvents were removed in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-{3-[1-(3-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (50.9 mg, 0.095 mmol, 31.7%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.46-1.62 (3H, m), 1.97-2.19 (3H, m), 3.06 (3H, s), 3.86-3.93 (1H, m), 4.46-4.55 (1H, m), 4.94 (1H, d, J=15.6 Hz), 7.07-7.12 (1H, m), 7.18-7.20 (2H, m), 7.35-7.41 (1H, m), 7.50-7.53 (1H, m), 7.58-7.60 (2H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C23H23FN4O6S2 534.10, found 535.4 [M+H+].
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:33][C:34]([O:36][C:37](C)(C)C)=[O:35].CCN(C(C)C)C(C)C>C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C)[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 50 °C

Procedure:
To a solution of 251 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(methylamino)cyclopentane from Example 15 in 6 mL of acetonitrile was added 0.108 mL of t-butyl bromoacetate and 0.36 mL of DIPEA. The reaction was heated at 50° C. for 5 hours and then concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried with sodium sulfate, combined and evaporated. The residue was purified by FC (0-2.5% methanol in methylene chloride) to afford 294 mg of title compound. Mass spec (ESI): 564 (M+1).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:24]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:8].CI.CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:24]1[CH:29]=[C:28]([O:30][CH3:1])[CH:27]=[CH:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(O)ccn1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OC)ccn1
Temperature: 70 °C
Reaction time: 22 h
Yield: 38.3 %

Procedure:
K2CO3 (15 mg, 0.11 mmol) was added to II (25 mg, 0.073 mmol) in DMF (2 mL) at rt under Ar(g). After 15 min CH3I (5 μL, 0.073 mmol) was added and the reaction was stirred at 70° C. for 22 h. Brine (30 mL) and EtOAc (30 mL) were added, then the phases were separated, and the aqueous phase was extracted with EtOAc (2×20 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (60:40) to furnish III as a colourless oil (10 mg, 40%).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:19]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:20])=[CH:7][CH:6]=1)=[O:2]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CC#N
Product: O=CNNc1ccc(NC(=S)Nc2ccccc2)cc1

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (30 g, 0.20 mole) was dissolved in acetonitrile (550 ml) with heat. Phenyl isothiocyanate (28 g, 0.22 mole) was added in one portion. The mixture was refluxed for 5 minutes and then chilled. The solid was filtered off, washed with acetonitrile and dried at 75° C. Yield 52 g (91%), m.p. 188°-188.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][CH2:13][NH:14][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)=[CH:28][CH:27]=1
Reactant: NCCc1c[nH]c2cc(Cl)c(Cl)cc12
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2cc(Cl)c(Cl)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 14.6 %

Procedure:
N-(2-(5,6-Dichloro-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide was prepared according to Method A starting from 2-(5,6-dichloro-1H-indol-3-yl)ethanamine (0.149 g; 0.651 mmol), 4-(3-fluorobenzyl)benzoic acid intermediate (0.150 g, 0.651 mmol), HATU (0.248 g; 0.651 mmol) and N,N-diisopropylethylamine (0.281 mL; 1.63 mmol) in DMF (5 mL). Flash chromatography (twice) on silica gel (eluent 2 to 60% ethyl acetate in heptane and 1 to 10% ethyl acetate in dichloromethane) furnished 0.042 g (14%) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]=[CH:13][C:7]=2[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.O1CCCC1>[O:18]=[C:9]1[C:8]2[CH:19]=[CH:20][C:5]([CH2:4][CH2:3][OH:2])=[CH:6][C:7]=2[CH:13]=[CH:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]1=2
Reactant: COC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=c1c2ccccc2ccc2cc(CCO)ccc12
Reaction time: 3 h

Procedure:
0.45 G. of methyl(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetate is dissolved in 10 ml. of ether/tetrahydrofuran (1:1) and excess lithium aluminum hydride is added. After 3 hours, excess hydride is destroyed by addition of water and the mixture is extracted with ether. The extract is dried and to it is added 2.0 g. of manganese dioxide. The mixture is left for 4 days and then filtered through celite and evaporated. The residue is recrystallized from hexane to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)ethan1-ol (m.p. 73°-75°C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:10]([CH2:18][C:19](OCC)=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:19](=[O:20])[CH2:18][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)CC(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of m-anisidine (10 g), ethyl benzoylacetate (19 g) and pyridine (2 drops) in xylene (20 mL) was heated to reflux for 5 hr. The mixture was cooled to r.t. and concentrated. The residual material was subjected to chromatography (silica gel; hexane/EtOAc (4:1)), affording the title compound as an oil.