Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:7]([C:17]([OH:19])=O)[CH2:6]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>C(Cl)Cl>[C:13]([O:12][C:10]([N:8]1[CH2:9][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C@@H:7]1[C:17](=[O:19])[NH:40][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=1)=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(=O)O[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)O[C@@H]1C[C@H](C(=O)NCc2ccc(Cl)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
The crude product (2R,4R)-4-acetoxy-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid from Step A (5.9 g, 21.6 mmol) was dissolved in methylene chloride (22 ml) and treated with EDC (4.5 g, 23.8 mmol) and HOBt (3.2 g, 23.8 mmmol). The mixture was stirred at r.t. for an hour before the addition of 4-chlorobenzylamine (2.9 ml, 23.8 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with DCM (25 ml) and washed with NaHCO3 (sat'd) and brine, dried (Na2SO4), filtered, evaporated and the residue purified by silica gel column chromatography (ethyl acetate/hexane gradient, 10-100% EtOAc) to afford the desired product as a white amorphous solid (6.5 g, 76% over two steps).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]3[CH2:19][CH2:18]3)[N:13]=[C:12](Cl)[C:11]=2[NH:10][C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.CO>C(N)C=C.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([NH:8][C:12]1[C:11]2[NH:10][C:9](=[O:21])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[CH:15]=[C:14]([CH:17]2[CH2:19][CH2:18]2)[N:13]=1)[CH:2]=[CH2:3]
Reactant: O=c1[nH]c2c(Cl)nc(C3CC3)cc2n1Cc1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C=CCN
Solvent: CO
Solvent: ClCCl
Product: C=CCNc1nc(C2CC2)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 85 °C
Yield: 151.9 %

Procedure:
1-Benzyl-4-chloro-6-cyclopropyl-1,3-dihydro-imidazo[4,5-c]pyridin-2-one (100 mg, 0.3 mmol) was dissolved in allylamine (2 mL) in a Reactivial™. Copper (II) sulphate (83 mg, 0.3 mmol) was added and the vial was sealed. The mixture was heated at 85° C. overnight. Further portions of copper (II) sulphate (83 mg, 0.3 mmol) and allylamine (1 mL) were added and the vial was sealed once again. The mixture was heated at 85° C. over the weekend. The mixture was allowed to cool to room temperature. The excess allylamine was removed in vacuo and the residue was dissolved in EtOAc (50 mL) and treated with saturated aqueous NaHCO3 (20 mL). The layers were separated and the organics washed with more saturated aqueous NaHCO3 (10 mL), then brine (10 mL), dried over MgSO4 and concentrated in vacuo to give the crude product (120 mg). Column chromatography through silica gel eluting with 98:2 DCM:MeOH gave the title compound (73 mg) as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:29][C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[N:8]=[CH:9][CH:10]=[CH:11][N:12]=1)[S:37]([C:32]1[CH:33]=[CH:34][C:35]([F:36])=[C:30]([F:29])[CH:31]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: COc1ccc(CNc2ncccn2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2ccc(F)c(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a cold (−78° C.) solution of N-(2,4-dimethoxybenzyl)pyrimidin-2-amine (1.85 g, 7.54 mmol) in tetrahydrofuran (20 mL) was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 8.3 mL, 8.3 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The mixture was cooled to −78° C. and a solution of 3,4-difluorobenzene-1-sulfonyl chloride (1.1 mL, 8.3 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Saturated aqueous ammonium chloride (10 mL) was added, followed by with ethyl acetate (100 mL), causing a precipitate to be deposited. The solid was collected by vacuum filtration to afford N-(2,4-dimethoxybenzyl)-3,4-difluoro-N-(pyrimidin-2-yl)benzenesulfonamide as a colorless solid in 73% yield (2.32 g): 1H NMR (300 MHz, CDCl3) δ8.50 (d, J=4.8 Hz, 2H), 7.74-7.60 (m, 2H), 7.16-7.06 (m, 2H), 6.94 (t, J=4.8 Hz, 1H), 6.39 (dd, J=8.3, 2.2 Hz, 1H), 6.28 (d, J=2.1 Hz, 1H), 5.41 (s, 2H), 3.76 (s, 3H), 3.45 (s, 3H); 19F NMR (282 MHz, CDCl3) δ−129.9 (d, J=20.7 Hz, 1F), −135.4 (d, J=20.7 Hz, 1F).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(C(=O)O)c(Cl)c1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a solution of tert-butyl 2-chloro-4-isopropylbenzoate (150 mg, 0.59 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL) at room temperature. The resultant reaction mixture was stirred at 30° C. for 30 minutes. Thin layer chromatography showed that starting material was consumed completely. The solution was concentrated under reduced pressure to give 2-chloro-4-isopropylbenzoic acid (100 mg, 85.5%) as a white solid which was used in the next step directly. LRMS (M+H+) m/z: calcd 199.04. found 199.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].CCCCCC.C([Li])CCC.[Br:23]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:23][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccc(Br)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
To a solution of N,N-dimethyl-1H-pyrazole-1-sulfonamide obtained in Step A (6.74 g) in tetrahydrofuran (75 mL) was added dropwise n-butyllithium hexane solution (1.3 M, 31.1 mL) over 15 min at −78° C. The reaction mixture was stirred at −78° C. for 15 min, and a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (13.8 g) in tetrahydrofuran (25 mL) was added dropwise thereto over 10 min. The reaction mixture was stirred at −78° C. for 15 min, and then at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.03 g).
Reaction SMILES: [CH2:1]([C:3]1([C:36]([O:38]CC)=[O:37])[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:18]4[NH:19][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:21][C:17]=4[CH:16]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([C:3]1([C:36]([OH:38])=[O:37])[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:18]4[NH:19][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:21][C:17]=4[CH:16]=3)=[CH:13][N:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(-c3ccccn3)c2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(-c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.5 %

Procedure:
To an ice-cold solution of ethyl 4-ethyl-1-(5-(2-(3-ethylureido)-7-(pyridin-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)piperidine-4-carboxylate (0.20 g, 0.37 mmol) in DMSO (3.0 mL) was added potassium tert-butoxide (0.2.06 g, 1.84 mmol) and the mixture stirred at rt for 16 h. After completion of reaction (by TLC), water (10 mL) was added followed by extraction with EtOAc (3×25 mL) and the organic layer discarded. The pH of the aqueous layer was adjusted up to 4-5, extracted with EtOAc (3×25 mL) and the combined organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with n-pentane to afford Compound 229 as yellow solid (0.10 g, 53%). 1H NMR (DMSO-d6+D2O): δ 8.78 (m, 3H), 8.38 (m, 1H), 7.95-8.0 (m, 2H), 7.69 (s, 1H), 7.39 (br s, 1H), 4.44 (m, 2H), 3.22 (m, 2H), 3.13 (m, 2H), 2.06 (m, 2H), 1.51 (m, 2H), 1.34 (m, 2H), 1.11 (t, J=7.20 Hz, 3H) and 0.80 (t, J=7.20 Hz, 3H). LCMS: 515.19 [M+H]+
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[Br:21]C1C=CC(/C=C/[N+]([O-])=O)=CC=1>>[Br:21][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Yield: 27 %

Procedure:
This compound was synthesized using the same methodology described in Intermediate C, using the commercially available (E)-1-bromo-4-(2-nitrovinyl)benzene as starting material. Yield: 27%.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11]2[N:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][O:22]C3CCCCO3)=[O:20])=[N:15][CH:16]=2)[CH2:6]1.[ClH:33].C(O)C>C(OCC)(=O)C>[ClH:33].[ClH:33].[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11]2[N:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][OH:22])=[O:20])=[N:15][CH:16]=2)[CH2:6]1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3F)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3F)C2)cn1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of (2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (600 mg) and 2N HCl/Ethanol (13.6 ml, 20 eq) was stirred at room temperature for 2 hours. After then, ethyl acetate (10 ml) and IPE (50 ml) was added and stirred. Precipitate was filtered, washed with IPE, and dried under reduced pressure to give 486 mg (83%) of (2E)-3-(5-{[(3R)-1-(2-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide dihydrochloride as a powder.
Reaction SMILES: ON=[C:3]([C:9]1[CH:13]=[N:12][S:11][N:10]=1)[C:4]([O:6]CC)=[O:5].C=[O:15].Cl>O>[S:11]1[N:12]=[CH:13][C:9]([C:3](=[O:15])[C:4]([OH:6])=[O:5])=[N:10]1
Reactant: C=O
Reactant: CCOC(=O)C(=NO)c1cnsn1
Agent: Cl
Solvent: O
Product: O=C(O)C(=O)c1cnsn1

Procedure:
A mixture of ethyl 2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (a mixture of syn and anti isomers) (6.0 g.), 36% aqueous solution of formaldehyde (40 ml.), conc. hydrochloric acid (20 ml.) and water (40 ml.) was treated according to a similar manner to that of Example 6(a)(2) to give crystals of 2-(1,2,5-thiadiazol-3-yl)glyoxylic acid (1.6 g.), mp 130° to 133° C.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])=S)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.OO>CO>[O:16]=[C:15]1[C:14]2[C:13](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(NC(=S)Nc1ccccc1C(=O)Nc1ccccc1)c1ccccc1
Agent: N
Agent: OO
Solvent: CO
Product: O=C(Nc1nc2ccccc2c(=O)n1-c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To a stirred mixture of 11.3 g of the above benzamide, 150 ml of methanolic ammonia and 250 ml of methanol was added, in increments, 25 ml of 30% hydrogen peroxide. After standing overnight, the solid was collected, partially dissolved in 500 ml of hot acetonitrile and filtered. The filtrate was concentrated and chilled, giving 2.0 g of the desired product as white crystals, mp 185°-188° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]#[N:15])([CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyano-piperidine-1-carboxylic acid tert-butyl ester (4.52 g, 20 mmol) in THF (50 mL) was added LHMDS in THF (24 mL, 24 mmol) at 0° C. After stirring at 0° C. for 1 hour, MeI (5.7 g) was added. The reaction mixture was kept at 0° C. for 2 hours, then partitioned between EtOAc and H2O. After concentration in vacuo, the residue was purified by silica column chromatography with EtOAc/hexanes to give the desired product.
Reaction SMILES: [Br:1][C:2]([Br:16])([Br:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])(=[O:5])=[O:4].S(Cl)([Cl:19])=O>CN(C)C=O>[Br:1][C:2]([Br:16])([Br:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:19])=[O:10])(=[O:5])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(S(=O)(=O)C(Br)(Br)Br)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(S(=O)(=O)C(Br)(Br)Br)c1

Procedure:
To 3-tribromomethanesulfonylbenzoic acid (B) obtained in the above-described (Step 1) are added dimethylformamide and thionyl chloride and the mixture is refluxed for one hour. The reaction mixture is filtered, and hexane is added to the filtrate to deposit crystals. The crystals are recovered by filtration and dried to obtain 3-tribromomethanesulfonyl benzoylchloride (C) as white crystals.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>CC(C)=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following a procedure similar to that described in Example 1 but using 3.39 g. sodium in 200 ml. dry acetone, 20 g. valeramidine hydrochloride, and 27.6 g. 3,4-dichlorophenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from acetone 10.5 g. of the hydrochloride of 1-(3,4-dichlorophenyl)-3-(pentanimidoyl)urea; m.p. 177°-179°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12](O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12]([Cl:29])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Cl)cc1OCCCCCCC
Temperature: 25 °C
Reaction time: 60 h
Yield: 100.1 %

Procedure:
To a room temperature mixture of 5 g of product from Example 110 in 80 ml of methylene chloride and 5 drops of dimethylformamide is added 2.72 g of oxalyl chloride. The reaction is stirred at room temperature for 2.5 days and concentrated in vacuo. The residue is dissolved in diethyl ether, passed through a pad of diatomaceous earth and concentrated in vacuo to give 5.27 g of the desired product as colorless crystals.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:19]>S(Cl)(Cl)=O>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([Cl:19])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c2ccccc2cc2ccccc12
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Yield: 59 %

Procedure:
Anthracene-9-carboxylic acid (recrystallized from ethanol, 12.05 g, 54.3 mmol) was suspended in a mixture of chloroform (60 mL, Aldrich, amylenes-stabilized) and thionyl chloride (12 mL) and heated under reflux until a clear solution was obtained (about 30 minutes). The solvent was removed by distillation under reduced pressure and the residual hot oil was dissolved in toluene (20 mL) and hexane (100 mL) was added. After cooling to ambient temperature the crystalline product was collected by filtration and dried in a stream of nitrogen then under high vacuum to give the title compound as a yellow solid (7.69 g, 59%). Non-commercially available carboxylic acids referred to in this section were prepared as described below. If desired they were converted to the corresponding carbonyl chloride using thionyl chloride as described above.
Reaction SMILES: O(CC)CC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19](O)=[O:20].[OH-].[Na+]>O>[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][OH:20]
Reactant: Cn1cccc1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cn1cccc1CCO
Reaction time: 8 h
Yield: 69 %

Procedure:
To 194 parts of 1,1'-oxybisethane are added 9.1 parts of lithium aluminum hydride while nitrogen gas is introduced. Then there is added dropwise, during a 2 hours-period, a solution of 14.9 parts of 1-methyl-1H-pyrrole-2-acetic acid in 105 parts of 1,1'-oxybisethane (exothermic reaction). Upon completion, stirring is continued for 8 hours at reflux temperature and for 8 hours at room temperature. The reaction mixture is cooled in an ice-salt bath and decomposed by successive dropwise additions of 9.5 parts of water, 8.5 parts of a sodium hydroxide solution 20% and again 33.3 parts of water. The precipitated product is filtered off and suspended in 1,1'-oxybisethane. The combined 1,1'-oxybisethane phases are dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (93:7) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 9.5 parts (69%) of 1-methyl-1H-pyrrole-2 -ethanol as a residue.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][CH:3]1[C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1.[BH4-].[Na+]>C(O)C>[CH3:20][N:19]([CH3:21])[C:16]1[CH:15]=[CH:14][C:13]([C@H:3]2[CH2:4][C@@H:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:6][C:2]2([CH3:1])[CH3:22])=[CH:18][CH:17]=1
Reactant: CN(C)c1ccc(C2CC(c3ccccc3)=NC2(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc([C@H]2C[C@@H](c3ccccc3)NC2(C)C)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
16 G. of 5,5-dimethyl-2-phenyl-4-(p-dimethylaminophenyl)-1-pyrroline are dissolved in 300 ml. of absolute ethanol and treated with 16 g. of sodium borohydride. The solution is stirred under nitrogen at room temperature for 14 hours. It is subsequently evaporated to dryness under reduced pressure and the residue suspended in water by intensive stirring. The non-dissolved constituent is filtered off, dried and recrystallized, first from n-hexane and then from diisopropyl ether. There is obtained cis-3-(p-dimethylaminophenyl)-2,2-dimethyl-5-phenyl-pyrrolidine, having a melting point of 117°-118° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3-c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 108 h
Yield: 42.7 %

Procedure:
A suspension of 0.20 g (0.43 mmol) [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 1), 0.20 g (1.30 mmol) 3-chlorophenylboronic acid, 0.16 g (0.86 mmol) copper(II) acetate and 0.14 mL (0.14 g, 1.73 mmol) pyridine in 5 mL chloroform was stirred 4.5 days at room temperature. The volatile components were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (100:0 to 75:25 v/v) as eluant to afford 105 mg (42%) of the desired compound as a light-brown foam. MS (ISP): 572.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11])=[O:7].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23]>O1CCCC1>[CH3:20][N:21]([CH3:25])[C:22](=[S:23])[O:3][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6](=[O:7])[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1ccccc1C(=O)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=S)Oc1ccccc1C(=O)c1ccccc1C#N
Temperature: 50 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
1 g (0.041 mol) of sodium hydride is added in small amounts to a solution of 6.7 g (0.030 mol) of the 2-(2-hydroxybenzoyl)benzonitrile obtained in Preparation VIIIc in 200 ml of tetrahydrofuran. The mixture obtained is stirred for 1 hour at 50° C. The reaction medium is cooled to room temperature and a solution of 4.6 g (0.037 mol) of dimethylthiocarbamoyl chloride in 50 ml of tetrahydrofuran is added. The mixture obtained is stirred for 3 hours at room temperature and then hydrolyzed with an ice/water mixture. Extraction is carried out with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. 6 g of the expected product (yield: 64.5%) are obtained after crystallization from ether.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:27])[N:11]([CH3:26])[CH:12]=[C:13]([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16]2)[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:10](=[O:27])[N:11]([CH3:26])[CH:12]=[C:13]([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16]2)[CH:14]=1
Reactant: Cn1cc(-n2ccc(-c3ccccc3)n2)cc(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1cc(-n2ccc(-c3ccccc3)n2)cc(O)c1=O
Reaction time: 8 h
Yield: 40.7 %

Procedure:
3-(Benzyloxy)-1-methyl-5-(3-phenyl-1H-pyrazol-1-yl)pyridin-2(1H)-one (33 mg, 0.092 mmol) was hydrogenated (balloon) with 10% Pd/C (10 mg, 9.40 μmol) in MeOH (1 mL) at R.T. After stirring overnight the mixture was filtered using a 0.45 μm PTFE syringe filter and concentrated. The crude material was purified by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-60% CH3CN/water over 20 min at 20 mL/ruin) to give the title compound (10 mg, 41%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J=7.6 Hz, 2 H); 7.71 (s, 1 H); 7.49-7.39 (m, 3 H); 7.35 (m, 1 H); 7.21 (s, 1 H); 6.95 (bs, 1 H); 6.75 (d, J=2.4 Hz, 1 H); 3.71 (s, 3 H). HRMS (ES) calc (M+H)+=268.1081, found 268.1071.