Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][C:20](Cl)=[C:19](Cl)[CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.N1CCCCC1.C(N1CC[C@H]([C@H]([OH:62])C)[C@@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.[F:70]C1C=CC(O)=CC=1.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([OH:26])=[O:62])[CH2:28][CH2:29]2)=[N:34][CH:35]=1)#[N:40].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:70])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: Oc1ccc(F)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: C[C@H](Oc1ccc(F)cc1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 4-fluoro-phenol via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as off-white foam. MS (m/e): 547.3 [(M+H)+].
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([N:18]1[N:22]=[N:21][C:20]([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([OH:26])=[O:25])=[N:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].IC>C1COCC1>[CH2:6]([N:18]1[N:22]=[N:21][C:20]([C:23]([CH3:2])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:24]([OH:26])=[O:25])=[N:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: CCCCCCCCCCCCn1nnc(C(C(=O)O)c2ccccc2)n1
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCCCCCCCCn1nnc(C(C)(C(=O)O)c2ccccc2)n1
Reaction time: 3 h
Yield: 1073.2 %

Procedure:
To a THF solution (30 mL) of n-BuLi (0.0055 mol, 1.6M in hexanes) at -78° C. under N2 with stirring was added 1.0 g (0.00027 mol) of (±)-2-dodecyl-α-phenyl-2H-tetrazole-5-acetic acid (Compound d, Example 13). The resulting yellow solution was stirred at -78° C. for 30 minutes before iodomethane (0.34 mL, 0.0055 mol) was added. This solution was stirred for 3 hours before quenching with 1N HCl (20 mL). The mixture was then partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 1.12 g of pure product.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([N:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH:15]=O)=[C:9]1[C:17]([O:19]C)=O)=[CH:5][CH2:6][CH3:7]>C(O)(=O)C.ClCCl>[CH2:4]([N:8]1[C:9]2[C:17](=[O:19])[NH:2][N:3]=[CH:15][C:10]=2[C:11]([CH3:14])=[C:12]1[CH3:13])[CH:5]=[CH:6][CH3:7]
Reactant: CCC=Cn1c(C)c(C)c(C=O)c1C(=O)OC
Reactant: NN
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC=CCn1c(C)c(C)c2cn[nH]c(=O)c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
1.10 g (0.0220 mole) of hydrazine hydrate was added to a solution of 4.50 g (0.0191 mole) of methyl 1-butenyl-3-formyl-4,5-dimethylpyrrole-2-carboxylate (cis/trans=24/76) in 47 ml of acetic acid and the resulting mixture was stirred at 100° C. for 2 hours. The reaction mixture cooled to room temperature was poured into ice-water. Precipitated crystals were collected by filtration and washed with water. The crystals thus obtained were dissolved in 300 ml of dichloromethane and the solution was dried over anhydrous sodium sulfate. Distilling off the solvent gave 3.53 g (0.0163 mole) of 1-(2-butenyl)-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]-pyridazine-7-one (cis/trans=21/79) as pale brown crystals.
Reaction SMILES: C(N=C=S)C1C=CC=CC=1.C(NC(=S)NN)C1C=CC=CC=1.ClC(O[CH2:27][CH3:28])=O.[CH2:29]([N:36]1[C:40]([SH:41])=[N:39][N:38]=[C:37]1[OH:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Br[C:44]1[S:45][C:46]([N+:49]([O-:51])=[O:50])=CN=1>>[CH2:29]([N:36]1[C:40]([S:41][C:44]2[S:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:27][CH:28]=2)=[N:39][N:38]=[C:37]1[OH:42])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: Oc1nnc(S)n1Cc1ccccc1
Reactant: CCOC(=O)Cl
Agent: NNC(=S)NCc1ccccc1
Agent: S=C=NCc1ccccc1
Product: O=[N+]([O-])c1ccc(Sc2nnc(O)n2Cc2ccccc2)s1
Yield: 17.9 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 5 starting with benzyl isothiocyanate. The intermediate 4-benzyl-3-thiosemicarbazide (1.81 g) was treated with ethyl chloroformate (1.09 g) as in Example 5. The reaction product 4-benzyl-3-hydroxy-5-mercapto-1,2,4-triazole (1.04 g) was reacted with 1.05 g of 2-bromo-5-nitrothiazole as in Example 5. Crystallization from ethanol and water gave 0.3 g of 4-benzyl-3-hydroxy-5-[(5-nitrothien-2-yl)mercapto]1,2,4-triazole, a yellow solid, MP 221-224° C.
Reaction SMILES: C([O:8][C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=[C:11]2[O:19][C@H:20]3[CH2:46][N:23]([C:24](=[O:45])[C@H:25]([C:38]4([CH3:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[NH:26][C:27](=[O:37])[O:28][C@@H:29]4[CH2:36][C@H:30]4[CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:10]=12)[C@H:22]([C:47]([O:49][CH3:50])=[O:48])[CH2:21]3)C1C=CC=CC=1>CO.C1COCC1.[Pd].ClCCl>[CH3:44][C:38]1([C@H:25]2[C:24](=[O:45])[N:23]3[CH2:46][C@@H:20]([CH2:21][C@H:22]3[C:47]([O:49][CH3:50])=[O:48])[O:19][C:11]3=[N:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]([OH:8])=[C:10]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]3[CH2:36][C@H:29]3[O:28][C:27](=[O:37])[NH:26]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1(C)CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCC#Cc1c(nc3ccccc3c1OCc1ccccc1)O2
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1(C)CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Yield: 93.4 %

Procedure:
A solution of the product of step 4 (870 mg, 1.280 mmol) in MeOH (8532 μl) and THF (4266 μl) was treated with a catalytic amount of 10% palladium on carbon (68 mg). The mixture was hydrogenated at 30 psi. After 6 hours LCMS showed complete reaction. The mixture was diluted with dichloromethane (50 mL) and the solids were removed by filtration. The filtrate was concentrated in rotavap and the residue was purified on a gold cap RediSep® (80 g) silica gel column (gradient: 0 to 40% ethyl acetate in hexanes) to give the title compound (710 mg, 1.196 mmol, 93% yield) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].P([O-])([O-])([O-])=O.I[CH3:26]>C(O)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][CH3:26])=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: CI
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: COn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of 0.3 g (1.1- mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline 2,3(1H,4H)-dione in 30 ml ethanol was added 15 ml 0.5M phosphate buffer pH 7.4. The mixture was added 1 ml (16 mmol) iodomethane, and then stirred overnight. The reaction mixture was evaporated, and the residue was stirred with water to give a precipitate. Recrystallization (dimethylformamide-water) gave 0.2 g (63%) of 7-cyano-1-methoxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 250° C. decomp. 1H-NMR (DMSO-d6): 7.9 (1H, s), 7.6 (1H, s), 4.07 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[CH3:18][C:19]([OH:23])([CH:21]=[CH2:22])[CH3:20].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[OH:23][C:19]([CH3:20])([CH3:18])[CH:21]=[CH:22][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17]
Reactant: C=CC(C)(C)O
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CC(C)(C)O)cc12
Yield: 25.2 %

Procedure:
A stirred solution of 5-bromo-3-(N-methyl-2(R)-pyrrolidinylmethyl)-1H-indole (WO-A-92/06973; 879 mg, 3.0 mmol), 2-methylbut-3-en-2-ol (0.408 ml, 3.9 mmol), tri-o-tolylphosphine (273 mg, 0.90 mmol), palladium(II) acetate (45 mg, 0.20 mmol), triethylamine (0.84 ml, 6.0 mmol) and acetonitrile (50 ml), under nitrogen, was heated under reflux for 24 hours, allowed to cool, then partitioned between ethyl acetate and 2M aqueous sodium carbonate solution. The organic phase was separated, washed sequentially with 2M aqueous sodium carbonate solution (×2) and brine (×1), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of 0.880 aqueous ammonia:methanol: dichloromethane (0:5:95 to 0.5:5:95), to afford the title compound as a solid (226 mg), m.p. 155°-158° C. Rf 0.10 (SS 1). [α]D25 +81° (c=0.1, CH3OH). Found: C,75.27; H,8.96; N,8.99. C19H26N2O; 0.25 H2O requires C,75.33; H,8.82; N,9.25%.
Reaction SMILES: [C:1](Cl)(=[O:5])C(Cl)=O.[NH2:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([O:27][CH3:28])[C:21]([CH3:30])([CH3:29])[CH2:20]2)[N:11]=[C:10]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([O:44][CH3:45])[C:38]([CH3:47])([CH3:46])[CH2:37]2)[N:9]=1>>[CH3:45][O:44][N:39]1[C:40]([CH3:43])([CH3:42])[CH2:41][CH:36]([CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:10]2[N:11]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]3[CH2:24][C:23]([CH3:25])([CH3:26])[N:22]([O:27][CH3:28])[C:21]([CH3:30])([CH3:29])[CH2:20]3)[N:13]=[C:8]([N:7]=[C:1]=[O:5])[N:9]=2)[CH2:37][C:38]1([CH3:47])[CH3:46]
Reactant: CON1C(C)(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Reactant: O=C(Cl)C(=O)Cl
Product: CON1C(C)(C)CC(CCCCNc2nc(N=C=O)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of oxalyl chloride with the compound prepared in Example 20.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1.[H-].[Na+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[CH2:11]([O:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: OCC1=CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=C(COCc2ccccc2)OCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 5.71 g of 6-hydroxymethyl-3,4-dihydro-2H-pyran dissolved in 100 ml of dimethylformamide was added dropwise to a mixture of 2.18 g of sodium hydride (as a 55% w/w dispersion in mineral oil) and dimethylformamide, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour, after which 6.33 g of benzyl chloride were added to it. The mixture was stirred for 16 hours, after which it was poured into 1 liter of water. The resulting mixture was then extracted twice with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The oily residue (13 g) was subjected to column chromatography through 200 g of silica gel. 9.40 g of the title compound were obtained as a colorless oil from those fractions eluted with mixtures of diethyl ether and hexane ranging from 4:100 to 5:100 by volume. It boiled at 125°-130° C. (bath temperature)/1 mmHg (133 Pa).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.O.NN>C1COCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(CN2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnnc1C(=NOCc1cccc(CN)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
To a solution of 2-({6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione (3 g, 6.61 mmol, 1 eq.) in 25 ml of THF was added hydrazine hydrate (1.32 g, 26.46 mmol, 4 eq.). The reaction was stirred overnight at room temperature. The solvent was evaporated and the residue dissolved in EtOAc. Water was added and the layers separated. The aqueous layer was extracted with EtOAc and the organics were combined, dried over MgSO4 and concentrated to give 1-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}methanamine (2.29 g, 93%) as a clear viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[N:6]2[N:22]=[CH:23][CH:24]=[C:5]2[N:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[N:6]2[N:22]=[CH:23][CH:24]=[C:5]2[N:4]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)n2nccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCNCC2)n2nccc2n1
Yield: 75.3 %

Procedure:
tert-Butyl 4-(5-methoxy-pyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate (1.186 g, 3.56 mmol) was stirred for 10 minutes at room temperature in a 1:1 mixture of dichloromethane and trifluoroacetic acid. The mixture was evaporated to dryness under reduced pressure, the residue was dissolved in water, the resulting solution was washed with dichloromethane, basified with 4M NaOH and extracted with dichloromethane (3×). The combined organic phases were washed with water, dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 624 mg of a solid (2.68 mmol, 75%). MS (APCI): m/z=234.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)ethanol (1 eq.) in DCM (0.2 M) was added p-toluenesulfonyl chloride (1.3 eq.) and triethylamine (1.5 eq.). The reaction was stirred at rt for 18 h. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 30% ether in hexane) to afford the title compound as an oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O1CCOCC1>[ClH:1].[ClH:1].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8](=[O:16])[C:7]3=[CH:17][S:18][CH:19]=[C:6]23)=[O:4])[CH2:23][CH2:22]1.[ClH:1].[CH3:8][N:9]1[CH2:7][CH2:6][NH:5][CH2:11][CH2:10]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Agent: CN1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(CC(=O)N2c3ccccc3NC(=O)c3cscc32)CC1
Product: Cl

Procedure:
14.9 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 21 g of N-methylpiperazine and 70 ml of dioxane are stirred at 80° C. for 1 hour, and the obtained solution is concentrated to dryness in vacuo. 150 ml of isopropanol and 40 ml of water are added to the resulting residue, and 25 ml of concentrated hydrochloric acid are then added dropwise; the thus prepared mixture is cooled in an ice-bath, and 9,10-dihydro-4-[(4-methylpiperazin-1-yl)acetyl]-4H-thieno[3,4-b][1,5]benzodiazepin-10-one dihydrochloride is obtained as a mixture with N-methylpiperazine hydrochloride. The hydrochlorides are dissolved in water and chloroform; the pH is adjusted to 8.2 with 2 N sodium hydroxide solution; the aqueous phase is extracted exhaustively by shaking it with chloroform, and the organic solution is dried and concentrated to dryness in vacuo. 16 g of 9,10-dihydro-4-[(4-methylpiperazin-1-yl)acetyl]-4H-thieno[3,4 -b][1,5]benzodiazepin-10-one, m. 177° to 178° C. (from acetone), are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:20].C([OH:23])C.[OH-].[Na+].Cl>O>[CH3:19][C:15]1[CH:16]=[CH:17][C:18]([NH:10][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[Cl:9])=[C:13]([CH2:12][C:11]([OH:20])=[O:23])[CH:14]=1
Reactant: Cc1cc(Cl)c(N2C(=O)Cc3cc(C)ccc32)c(Cl)c1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)c(Nc2ccc(C)cc2CC(=O)O)c(Cl)c1
Temperature: 40 °C
Reaction time: 4.5 h

Procedure:
A mixture of 1.5 g of N-(2′,6′-dichloro-4′-methylphenyl)-5-methyloxindole, 18 ml of ethanol and 1 ml of water is heated to reflux. 1.9 g of a 30% sodium hydroxide solution is slowly added and reflux is continued for 4-5 h. The solution is cooled to about 40° C. and treated slowly with a solution of 1.5 g of concentrated hydrochloric acid in 12 ml of water up to a pH of 3-4. The obtained suspension is cooled to 20° C. The crystals are collected by filtration, washed with water and dried giving 5-Methyl-2-(2′,6′-dichloro-4′-methylanilino)phenylacetic acid.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:30])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=O)=O)=[CH:21][C:20]=3[F:29])[CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:32]([O:34][NH2:35])[CH3:33].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C>[CH2:32]([O:34][N:35]=[C:1]([C:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:28])=[CH:21][C:20]=3[F:29])[CH:13]=2)[CH2:7][C:6]=1[OH:30])[CH2:2][CH3:3])[CH3:33]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(S(C)(=O)=O)cc3F)c2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCON=C(CC)C1=C(O)CC(c2cccc(Oc3ccc(SC)cc3F)c2)CC1=O
Reaction time: 16 h

Procedure:
A solution of 0.70 g (1.8 mmol) of 2-propionyl-3-hydroxy-5-(3-(2-fluoro-4-(methylsulfonyl)phenoxy)-phenyl)cyclohex-2-en-1-one in 5 mL of methylene chloride and 10 mL of absolute ethanol, at room temperature was treated with 0.22 g (2.3 mmol) of ethoxyamine hydrochloride and 0.19 g (2.3 mmol) of anhydrous sodium acetate. After stirring under a nitrogen atmosphere for 16 hours, the mixture was poured into 100 mL of water and extracted twice with 30 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and the solvent evaporated off leaving the product as a dark yellow oil. Purification via flash chromatography (silica gel, methylene chloride/hexane) the above named product as a light amber oil in a yield of 0.6 g (77 percent of theoretical). 1H NMR (CDCl3): δ1.2-1.5 (m, 6H, both --CH2CH3 's), 2.58 (s, 3H, --SCH3), 2.50-3.65 (m, 7H), 4.25 (q, J=7 Hz, 2H, --OCH2), 6.8-7.5 (m, 7H, aromatics), 14.9 (broad s, 1H, enol H) (Compound 5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CO.[C]=O.C(N(CC)CC)C.[C:35]([O:38][CH2:39]C)(=[O:37])C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11](=[O:23])[NH:12][C:13](=[O:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([C:35]([O:38][CH3:39])=[O:37])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC2=C(c3ccc(I)cc3)C(=O)NC2=O)cc1F
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C2=C(Nc3ccc(C)c(F)c3)C(=O)NC2=O)cc1

Procedure:
A mixture of 3-(3-Fluoro-4-methylphenyl-amino)-4-(4-iodophenyl)-1H-pyrrole-2,5-dione (Example A705, 126 mg, 0.3 mmol), tetrakis(triphenyl phosphine)-palladium(0) (35 mg, 0.03 mmol) and methanol (10 mL) was placed in a 50 mL two necked round bottomed flask. One arm of the flask was sealed with a septum and to the other arm was fitted a reflux condenser, topped with a multiway tap connected respectively to vacuum, a carbon monoxide cylinder and to a balloon. Using the multiway tap, the flask was alternately evacuated and flushed with carbon monoxide, and the process repeated several times to unsure an atmosphere of carbon monoxide within the flask. The balloon was charged with carbon monoxide and this was then opened to the reaction flask for the duration of the reaction in order to maintain a slight positive pressure of carbon monoxide within the flask. Triethylamine (100 uL, 0.7 mmol) was added and the mixture heated at reflux for 16 hours. The mixture was cooled and diluted with ethyl acetate and the resulting solution washed with aqueous hydrochloric acid (1M, 50 mL), water (50 mL) and brine (50 mL). The organic solution was dried over magnesium sulphate and evaporated to afford a solid. This was chromatographed on silica gel using dichloromethane-ether (98:2 v/v) as eluent to afford the tide compound, a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=2)=[CH:4][CH:5]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=O)Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-Bromomethyl-4-trifluoromethyl-benzene (1.55 g, 6.49 mmol) and 1-(4-hydroxy-phenyl)-propan-2-one (1.46 g, 9.74 mmol) were stirred in acetonitrile (65 mL) along with cesium carbonate (5.3 g, 16.23 mmol). After stirring at room temperature for two days the reaction was heated to 60° C. for 3 hours. After cooling the reaction was submitted to standard aqueous workup then purified on silica gel (0-100% (2% MeOH in EtOAC) to hexanes) to yield the title compound.