Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17][CH3:18])[N:6]([CH2:19][CH2:20][CH2:21]Cl)[C:5]=2[CH:4]=1.[OH:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17][CH3:18])[N:6]([CH2:19][CH2:20][CH2:21][N:29]3[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)N(CCCCl)c1cccc(SC)c1S2
Reactant: OCCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N(CCCN1CCC(CCO)CC1)c1cccc(SC)c1S2
Temperature: 120 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
A mixture of 2-methoxy-6-methylthio-10-(3-chloropropyl)phenothiazine (9.2 g.), 4-hydroxyethylpiperidine (3.2 g.) and sodium bicarbonate (8.4 g.) in dimethylformamide (90 cc.) is heated at 120°C., with stirring, for 6 hours. The solvent is then evaporated under reduced pressure (0.1 mm.Hg) at 60°C. The residue is taken up in chloroform (80 cc.) and distilled water (80 cc.) and purification of the product is effected by making the medium acidic and then reprecipitating the base by the procedure mentioned in Example 1. 2-Methoxy-6-methylthio-10-[3-(4-hydroxyethylpiperidino)propyl]-phenothiazine (7.9 g.) in the crude state, in the form of an amorphous beige powder, is thus obtained. This powder is taken up in boiling acetonitrile (15 cc.). After cooling of the solution for 7 hours at a temperature of about 20°C., the crystals which have formed are filtered off, washed with acetonitrile (10 cc.) and with diethyl ether (60 cc.) and then dried at 45°C. under reduced pressure (0.05 mm.Hg) for 17 hours. 2-Methoxy-6-methylthio-10-[3-(4-hydroxyethylpiperidino)propyl]-phenothiazine (7.37 g.), melting at 101°-103°C., is obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=[C:26]([C:25]([F:24])([F:39])[F:40])[CH:27]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were-added 3,5-bis(trifluoromethyl)benzoyl chloride (117 ml, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give the title compound (73 mg, 31%).
Reaction SMILES: C1C2C(=CC=CC=2)CC1C(O)=O.[CH3:13][C@@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[CH2:15]1.C[O:31][C:32]([CH:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[S:43](Cl)(=[O:45])=[O:44])[CH2:35]1)=[O:33]>>[CH3:13][C@H:14]1[CH2:15][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][N:21]=2)[CH2:17][CH2:18][N:19]1[S:43]([C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[CH2:42][CH:34]([C:32]([OH:33])=[O:31])[CH2:35]2)(=[O:45])=[O:44]
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Agent: O=C(O)C1Cc2ccccc2C1
Product: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2

Procedure:
4-|2-(S)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl|-indan-2-carboxylic acid. The compound 4-[2-(S)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H), 7.82-7.76 (m, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.37 (t, 1H), 6.93-6.88 (m, 1H), 4.35-4.18 (m, 2H), 4.18-4.02 (m, 1H), 3.60-3.46 (m, 1H), 3.45-3.10 (m, 7H), 2.97-2.80 (m, 1H), 1.06-1.01 (m, 3H); MS (ESI): 470.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21]Br)[CH:9]=2)=[O:5])[CH3:2].N1C=CC=CC=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(CBr)cc2C1=O
Reactant: C1COCCN1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(CN3CCOCC3)cc2C1=O
Reaction time: 2 h
Yield: 16.1 %

Procedure:
6-Bromomethyl-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (1.1 g, 2.96 mmol) was dissolved in N,N-dimethylformamide. Pyridine (264 μl, 3.26 mmol) and morpholine (284 μl, 3.26 mmol) were added thereto and the mixture was stirred for 2 hours. After the reaction was completed, the organic layer was extracted with ethyl acetate/ammonium chloride/saturated sodium chloride, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 180 mg of 6-(morpholine-4-yl methyl)-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (180 mg, yield 16.1%) as red oil.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH2:11])=[CH:4][C:3]=1[CH3:12].[C:13]([O:17][C:18](=[O:41])[NH:19][C:20]([C:22]1[S:23][C:24]([S:39][CH3:40])=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=2)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[C:13]([O:17][C:18](=[O:41])[NH:19][C:20]([C:22]1[S:23][C:24]([S:39][CH3:40])=[C:25]([S:27]([C:30]2[CH:31]=[C:32]([C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH2:11])=[CH:4][C:3]=3[CH3:12])[CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(N)cc([N+](=O)[O-])c1Br
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2[N+](=O)[O-])c1

Procedure:
Following the procedure used for Example 295, step h, reaction of 4-bromo-3-methyl-5-nitro-phenylamine (350 mg, 1.5 mmol, as prepared in Example 135, step a), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (1.0 gm, 2.27 mmol, as prepared in Example 140, step a), tetrakis(triphenylphosine)palladium(0) (433 mg, 0.375 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (6 mL, 2M), and toluene/EtOH mixture (2:1, 18 mL) at 80° C. for 24 h afforded 250 mg (30%) after purification (SiO2, flash elution: 5% to 50% EtOAc in hexanes) of the title compound as a yellow solid. ESI-MS (m/z): Calcd. for C24H26N4O6S3: 563.1 (M+H); found: 562.8, 463.1 (M−Boc).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=2)=[O:15])[CH:11]=[CH:12][CH:13]=1.[I-].C[S+](C)C>CS(C)=O.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[C:10]([C:14]2([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[CH2:1][O:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1cccc(Br)c1)c1cccc(Br)c1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Brc1cccc(C2(c3cccc(Br)c3)CO2)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
KOt-Bu (2.72 g, 24.26 mmol) was added to a stirred suspension of bis(3-bromophenyl)methanone (7.5 g, 22.06 mmol) and trimethylsulfonium iodide (4.50 g, 22.06 mmol) in DMSO (20 mL) and the resulting mixture was stirred at 30° C. for 8 h. The mixture was diluted with ethyl acetate (500 mL), washed with water (500 mL×3) and brine (500 mL). The organic layer was separated and evaporated in vacuo to afford the title compound which was used directly without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:37])[CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH3:36])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:38]([O:45][CH3:46])(=[O:44])/[CH:39]=[CH:40]/[C:41]([O-])=[O:42].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:2]([NH:1][C:41](=[O:42])/[CH:40]=[CH:39]/[C:38]([O:45][CH3:46])=[O:44])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:37])[CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH3:36]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: COC(=O)/C=C/C(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](NC(=O)/C=C/C(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
The crude (S)-tert-butyl 2-amino-6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)hexanoate, prepared above, was taken up in 40 mL acetonitrile along with monomethyl fumarate (610 mg, 4.69 mmol), DIEA (3.0 mL, 18.8 mmol) and HATU (2.4 g, 6.39 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting residue was taken up in 100 mL of EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/pentane) afforded (S)-tert-butyl 6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (500 mg, 30%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.CCN(C(C)C)C(C)C.Br[CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN1CCCC1=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:24]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([OH:13])=[O:12])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc2cc(Br)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 87.2 %

Procedure:
To 5-bromoindole-2-carboxylic acid (1.024 g, 4.26 mmol) in 1-methyl-2-pyrrolidinone (13 mL) at 0° C. were added iPr2NEt (25.6 mmol), tetrabutylammonium iodide (157 mg, 0.426 mmol) and bromodiphenylmethane (1.20 g, 4.86 mmol). The reaction mixture was heated at 50° C. for 21 h before partitioning between diethyl ether and ice water. After adjusting the pH to 3, the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with NaH2PO4, dried over MgSO4 and evaporated to dryness. Purification on silica gel column (15% EtOAc in hexane) yielded 1.51 g (87% yield) of the product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][NH2:19])=O.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:16]([C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[F:13])=[N:18][N:19]=2)[N:3]=1
Reactant: NNC(=O)c1ccccc1F
Reactant: Clc1cc(C2CCC2)c(Cl)nn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C)cc1
Product: Fc1ccccc1-c1nnc2cc(C3CCC3)c(Cl)nn12
Yield: 49 %

Procedure:
A mixture of 3,6-dichloro-4-cyclobutylpyridazine from above (3.0 g, 14.7 mmol), 2-fluorobenzhydrazide (3.0 g, 19.5 mmol) and triethylamine hydrochloride (3.0 g, 21.8 mmol) in p-xylene (50 ml) was stirred and heated at reflux under a stream of nitrogen for 20 hours. Upon cooling the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and water. The aqueous was basified by the addition of solid potassium carbonate. Some dark insoluble material was removed by filtration at, this stage. The aqueous was further extracted with dichloromethane (×2). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 20%→30% ethyl acetate/dichloromethane to give the title compound (2.2 g, 49%) as a light-brown solid. Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.85-2.08 (1H, m), 2.08-2.30 (3H, m), 2.38-2.64 (2H, m), 3.62-3.84 (1H, m), 7.19-7.46 (2H, m), 7.46-7.67 (1H, m), 7.80-7.96 (1H, m), 7.99 (1H, s), MS (ES+) m/e 303 [MH]+, 305 [MH]+.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=O)[N:6]=[N:5]1)[CH:2]=[CH2:3].[CH3:27][O:28][CH:29]([O:38][CH3:39])[CH2:30][NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CCCC(C)C>[CH2:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:31]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:30][CH:29]([O:38][CH3:39])[O:28][CH3:27])=[O:19])[N:6]=[N:5]1)[CH:2]=[CH2:3]
Reactant: COC(CNC1CCCCC1)OC
Reactant: C=CCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)nn1
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Product: C=CCn1cc(-c2cccc(CCOCCC(=O)N(CC(OC)OC)C3CCCCC3)c2)nn1

Procedure:
The subtitled compound (584 mg) was prepared from tert-butyl 3-(3-(1-allyl-1H-1,2,3-triazol-4-yl)phenethoxy)propanoate [Ex 4, Step iii)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii) the elution gradient 20 to 100% ethyl acetate in isohexane. 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.69 and 7.67 (2 s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.322 and 7.318 (2×t, J=7.7 Hz, 1H), 7.20 (d, J=6.9 Hz, 1H), 6.17-6.06 (m, 1H), 5.36-5.27 (m, 2H), 5.06 (d, J=5.9 Hz, 2H), 4.52 and 4.36 (2×t, J=5.5 Hz, 1H), 3.99 and 3.65 (tt, J=5.3 and 11.7 Hz, 1H), 3.76-3.66 (m, 4H), 3.34 (s, 3H), 3.32 (s, 3H), 3.34 and 3.25 (2×d, J=4.9 Hz, 2H), 2.92-2.85 (m, 2H), 2.68-2.61 (m, 2H), 1.79-1.02 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].Cl.[F:20][C:21]1([F:25])[CH2:24][NH:23][CH2:22]1.C1COCC1.N1CCC1>C(N(CC)CC)C>[F:20][C:21]1([F:25])[CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: FC1(F)CNC1
Agent: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CC(F)(F)C3)s2)noc1C(F)(F)F
Yield: 49 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 3,3-difluoroazetidine hydrochloride by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine (containing and additional 1.1 eq to neutralize the azetadinyl hydrochloride salt) and azetidine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried and then chromatographed on silica gel with EtOAc/hexanes (25 then 50%) as eluant to afford product as a colorless solid (43 mg, 49%). 1H NMR (CDCl3) 2.37 (s, 3 H), 4.68 (br, 4 H), 4.19 (br, 2 H), 7.53 (s, 2 H). 19F NMR −100.6, −63.1. LC/MS 6.42 min, [M+1]+ 353.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2.Br[CH2:36][C:37]#[N:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:37]([CH2:36][O:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][NH:13][C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2)#[N:38]
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccccc3)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccccc3)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (6-hydroxy-5-phenyl-naphthalen-2-ylmethyl)-amide (366 mg, 0.813 mmol), prepared in the previous step, bromoacetonitrile (68 μL, 0.976 mmol) and potassium carbonate (562 mg, 4.07 mmol) in 20 mL of DMF was stirred under nitrogen at room temperature for 23 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a brown solid. Purification of the solid on 20 g of silica gel (230-400 mesh) using hexane-ethyl acetate as the eluent gave 2-butyl-benzofuran-3-carboxylic acid (6-cyanomethoxy-5-phenyl-naphthalen-2-ylmethyl)-amide (342 mg, 86%) as a light brown solid, mp 135-138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([NH:15][C:16]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[SH:8])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccccc1S
Product: O=C(Nc1ccccc1)Nc1ccccc1S
Yield: 85 %

Procedure:
2-{[(Phenylamino)carbonyl]amino}thiophenol was prepared from 2-5 aminothiophenol (200 mg, 1.6 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (330 mg, 85%). mp: 194.5° C.; 1H NMR (CD3OD/CDCl3): d 7.48-7.26 (m, 4H), 7.25-7.10 (m, 3H), 7.04-6.79 (m, 2H); EI-MS m/z 244 (M+H)+; Anal. (C13H12N2OS) C, H, N.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[NH:11]([CH2:13][CH2:14][OH:15])[NH2:12]>C(O)C>[NH2:6][C:5]1[N:11]([CH2:13][CH2:14][OH:15])[N:12]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNCCO
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(CCO)n1
Yield: 97.3 %

Procedure:
A solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.00 g, 40.0 mmol), concentrated HCl (0.1 mL), and 2-hydrazino ethanol (2.98 mL, 44.0 mmol) in ethanol (40 mL) was refluxed for 20 h. The reaction mixture was then concentrated in vacuo. The resulting oily solid was washed with cyclohexane (30 mL), and dissolved in MeOH (5 mL) and H2O (5 mL) and lyophilised to give the title compound as a white powder (7.13 g, 97%). LCMS (Method 3): Rt 0.43 min, m/z 184 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:22]1([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:6]#[N:7])=[C:8]([O:28][CH2:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:9]=1
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: OCC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(F)cc(Br)cc1OCC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a stirred solution of the above benzonitrile intermediate (7.5 g, 34.4 mmol) in dry THF (50 mL) at 0° C. was added a mixture of sodium bis(trimethylsilyl)amide (1.0 M, 34 mL, 34 mmol) and cyclopentanemethanol (3.4 g, 34 mmol) in THF (100 mL). The reaction was allowed to warm up to room temperature and stirred overnight. Water (50 mL) was added to the reaction and the product was extracted by CH2Cl2 (2×50 mL). The solvent was washed with brine and dried over Na2SO4. The solvent was removed to give 4-bromo-2-cyclopentylmethoxy-6-fluorobenzonitrile (4.5 g, 43.9%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:8]3.C(N(CC)CC)C.C1(N[S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])C=CC=CC=1>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[N:8]3
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: Cc1nc2cccc3nc(SCCCCCN)c1n23
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3nc(SCCCCCNS(=O)(=O)C(F)(F)F)c1n23
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg (1.82 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 30 ml of acetonitrile were added 0.51 ml (3.66 mmol) of triethylamine and 1.302 g (3.66 mmol) of N-phenyltrifluoromethanesulfonamide. The mixture was stirred for two hours at room temperature. The solvent was distilled off. To the residue was added methylene chloride, which was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 608 mg (82.1%, a pale yellow solid) of the desired compound.
Reaction SMILES: CO[C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=CN=CN=1.BrC1[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]2[CH:27]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[N:28]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:29](=[O:30])[C:21]=2C=1.COCCOC.BrC1C(OC)=NC=NC=1>CS(C)=O>[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([CH3:38])=[C:31]([N:28]2[C:29](=[O:30])[C:21]3[CH:3]=[C:8]([B:9]4[O:10][C:11]([CH3:16])([CH3:17])[C:12]([CH3:14])([CH3:15])[O:13]4)[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]=3[CH:27]2[C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[CH:36]=1
Reactant: COc1ncncc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Agent: COc1ncncc1Br
Solvent: CS(C)=O
Solvent: COCCOC
Product: Cc1ccc(Cl)cc1N1C(=O)c2cc(B3OC(C)(C)C(C)(C)O3)n(C(C)C)c2C1c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 20 %

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate T, but 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate B) and DME were used instead of 5-bromo-4-methoxy-pyrimidine and DMSO respectively. The reaction was performed at 100° C. for 16 h to afford the title compound (20% purity) as a dark brown solid. tR: 8.52 min (HPLC 2); ESI-MS: tR=1.46 min; [M+H]+ 525/527 (LC-MS 1).