Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:10]=2[N:11]=[C:12](S)[CH2:13][N:14]=1.[CH2:21]([NH2:24])[C:22]#[CH:23]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:10]=2[N:11]=[C:12]([NH:24][CH2:21][C:22]#[CH:23])[CH2:13][N:14]=1
Reactant: Cc1nn(C)c2c1C(c1ccccc1F)=NCC(S)=N2
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCNC1=Nc2c(c(C)nn2C)C(c2ccccc2F)=NC1

Procedure:
A mixture of 3.0 g. of 4-(2-fluorophenyl)-1,6-dihydro-1,3-dimethylpyrazolo[3,4-e][1,4]diazepine-7-thiol (prepared as disclosed in U.S. Pat. No. 3,770,762), 1.8 g. of 2-propynylamine and 50 ml. of tetrahydrofuran is heated at reflux for 2 hours, then evaporated at reduced pressure to give a residue of 4-(2-fluorophenyl)-1,6-dihydro-1,3-dimethyl7-(2-propynylamino)pyrazolo[3,4-e][1,4]diazepine; m.p. 202°-204° C. (dec.) after trituration with ether, filtration and drying.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7]CC)=[O:6])=[N+:2]=[N-:3].[C:10]1(C)[CH:15]=CC=C[CH:11]=1>>[CH3:15][C:10]1[N:3]=[N:2][N:1]([CH2:4][C:5]([OH:7])=[O:6])[CH:11]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Product: Cc1cn(CC(=O)O)nn1
Temperature: 120 °C
Yield: 18 %

Procedure:
To a solution of 2.0 g (18 mmol) of 1-(trimethylsilyl)-1-proyne in toluene (20 mL) was added 2.3 g (18 mmol) of ethyl azido-acetate. The reaction mixture was heated at 120° C. overnight then cooled to ambient temperature. All volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a 5-25% acetone in hexanes gradient to yield the title compound as a colorless oil (0.77 g, 18%). 1HNMR (500 MHz, CDCl3): δ 5.01 (s, 2H), 4.2 (m, 2H), 2.25 (s, 3H), 1.22 (m, 3H), 0.295 (s, 9H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH2:10][C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 96.6 %

Procedure:
Sodium metal (0.143 g, 6.21 mmol) was dissolved into ethanol (3 mL) and the resulting solution was cooled with an ice bath. A mixture of 1-(4-chlorophenyl)ethanone (0.756 mL, 5.65 mmol) and diethyl ethanedioate (0.766 mL, 5.65 mmol) were added dropwise, and the reaction mixture was stirred for 16 h. The reaction mixture was quenched with ice water (5 mL) and acidified to ˜pH 3 with 1N HCl. The precipitate was collected by filtration and dried under high vacuum to give 1.39 g (97%) of product. LCMS E-S (M+H)=255.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (m, 3 H), 4.27 (d, J=6.57 Hz, 2 H), 7.60 (d, J=7.58 Hz, 2 H), 8.02 (d, J=6.57 Hz, 2 H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[CH:22][CH:21]=2)C1C=CC=CC=1.C([O-])=O.[NH4+].C(N(CC)CC)C>C(O)C.[Pd]>[N:30]1([CH2:29][CH2:28][O:27][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([C:12]2[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=4)[NH:14][N:13]=2)=[CH:26]3)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: c1ccc(COc2ccc3[nH]nc(-c4cc5cc(OCCN6CCOCC6)ccc5[nH]4)c3c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCOCC5)ccc4[nH]3)c2c1
Temperature: 67 °C
Yield: 61.7 %

Procedure:
1.12 g of 5-benzyloxy-3-[5-(2-morpholin-4-ylethoxy)-1H-indol-2-yI]-1H-indazole are dissolved in 55 ml of absolute ethanol and then 424 mg of palladium-on-charcoal, 587 mg of ammonium formate and 227 μl of triethylamine are successively added. The reaction medium is stirred at 67° C. (internal temperature of the suspension). A substantial amount of gas is seen to be given off. After stirring for one hour, the medium is filtered through paper and the catalyst is rinsed with absolute ethanol. The filtrate is concentrated under vacuum to obtain 558 mg of 3-[5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-1H-indazol-5-ol.
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].CCN=C=NCCCN(C)C.[CH2:52](O)[CH2:53][OH:54]>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:52][CH2:53][OH:54])=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3]
Reactant: OCCO
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)OCCO)cc3)c2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoic acid (0.150 g, 0.270 mmol) was dissolved in DMF (2.7 mL) then treated with EDCI (0.062 g, 0.324 mmol) and DMAP (0.003 g, 0.027 mmol) and allowed to stir at 60° C. for 30 min. Ethylene glycol (3 mL) was then added and the reaction was allowed to stir for 4 hours. The reaction mixture was then cooled to room temperature and dissolved in EtOAc (10 mL) and extracted with brine (3×10 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude mixture was then redisolved in EtOAc (1 mL) and triturated with Hexanes (20 mL) causing the product to precipitate out. The resulting white solid to give the title compound (0.125 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][C:12]=1[O:23][CH3:24].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][C:12]=2[O:23][CH3:24])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CCCNC(=O)c1ccc(N)c(OC)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCCNC(=O)c1ccc(Nc2nc(Cl)ncc2Cl)c(OC)c1

Procedure:
2,4,5-Trichloropyrimidine (1.0 g, 5.4 mmol), 4-amino-3-methoxy-N-propylbenzamide (778 mg, 3.74 mmol), and N,N-diisopropylethylamine (1.19 g, 9.21 mmol) were combined in isopropanol (40 mL) and reacted in a microwave (120° C.) for 5½ hours. The 4-(2,5-dichloropyrimidin-4-ylamino)-3-methoxy-N-propylbenzamide that formed as a yellow solid (1.33 g, 71%) was isolated by filtration. A small amount of this material (50 mg, 0.10 mmol) was combined with 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (35 mg, 0.14 mmol) and 10-camphorsulfonic acid (36 mg, 0.15 mmol) in isopropanol (3 mL) to which had been added 0.05 mL water. The mixture was heated in a microwave (130° C.) for 3 hours and on cooling was concentrated. The organics were extracted into dichloromethane which was washed with saturated sodium bicarbonate solution and subsequently dried (sodium sulfate). Concentration followed by ISCO chromatography (gradient elution: 1 to 10% MeOH:dichloromethane) afforded 4-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-methoxy-N-propyl-benzamide as a white solid (58 mg, 70%). Mp: 193-7° C. (dec). LCMS (m/e) 565 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.58 (d, J=8 Hz, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 7.31 (m, 1H), 7.25 (m, 1H), 7.10 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.11 (m, 1H), 4.03 (s, 3H), 3.72 (m, 4H), 3.48 (m, 2H), 2.86 (m, 2H), 2.70 (m, 2H), 2.57 (s, 4H), 2.10 (m, 2H), 1.68 (m, 3H), 1.47 (m, 2H), 1.03 (t. J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:8]([N:6]1[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CN(Cc2ccccc2)CCN1

Procedure:
(S)-(+)-2-Methylpiperazine (2.63 g), benzylbromide (3.12 ml) and potassium carbonate (5.4 g) were heated together in acetonitrile (120 ml) at 40° C. for 3 days. The mixture was evaporated to dryness in vacuo and the residue partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic phase was separated, dried (magnesium sulphate) and evaporated to dryness in vacuo. The residue was purified by column chromatography over silica gel using gradient elution (95/510 to 92/7/1 dichloromethane/methanol/ammonium hydroxide) to afford the title compound as a solid, 1.12 g.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:4]2[N:5]=[C:6]([N:9]3[C:17]4[CH:16]=[C:15]([C:18]5[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=5)[N:14]=[CH:13][C:12]=4[CH:11]=[N:10]3)[CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:26]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C#N)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C#N)c(N3CCC[C@H](N)C3)n2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-cyano-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.4859 mmol; 248.6 mg) in dichloromethane (8 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 201 was obtained as an off-white solid (361.6 mg, 18%). 1H NMR (400 MHz, DMSO) δ 9.61-9.55 (s, 1H), 9.48-9.44 (s, 1H), 9.37-9.33 (s, 1H), 8.80-8.75 (s, 1H), 8.66-8.62 (s, 1H), 8.26-8.19 (m, 2H), 7.48-7.44 (d, J=8.4 Hz, 1H), 4.29-4.19 (dd, J=10.7, 6.9 Hz, 2H), 3.00-2.94 (m, 1H), 2.66-2.62 (s, 3H), 2.03-1.89 (dd, J=18.5, 10.2 Hz, 2H), 1.80-1.66 (m, 1H), 1.49-1.37 (m, 1H); MS (ESI) m/z: 412.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([Cl:12])=[O:11].[Cl:13]Cl>>[Cl:13][CH:9]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[C:10]([Cl:12])=[O:11]
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: ClCl
Product: O=C(Cl)C(Cl)c1c(Cl)cccc1Cl

Procedure:
69 g (0.31 mols) 2,6-dichlorophenyl acetylchloride are heated to 160 degrees C. and chlorinated by introducing chlorine gas under UV radiation for eight hours.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.CS[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][N:19]=1>>[CH3:15][N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][N:19]=1)[CH3:14]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Product: CN(C)Cc1cccc(OCCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)c1
Yield: 56.9 %

Procedure:
3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine (0.98 g) and 2-(methylthio)-5-[(3-pyridinyl)methyl]-4(3H)-pyrimidinone (1 g) were heated at 140° for 16 h. The residue, after column chromatography (silica/methanol -0.88 ammonia, 79:1) gave the title compound as a yellow gum (0.96 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH2:11]([N:13]1[CH:17]=[C:16](B(O)O)[CH:15]=[N:14]1)[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([N:13]1[CH:17]=[C:16]([C:2]2[S:6][C:5]3=[N:7][CH:8]=[C:9]([I:10])[N:4]3[N:3]=2)[CH:15]=[N:14]1)[CH3:12]
Reactant: CCn1cc(B(O)O)cn1
Reactant: Brc1nn2c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1cc(-c2nn3c(I)cnc3s2)cn1

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.18 g, 0.546 mmol, 1 eq), 1-ethyl-1H-pyrazole-4-boronic acid, pinacol ester (0.145 g, 0.655 mmol, 1.2 eq), Pd(PPh3)2Cl2 (0.077 g, 0.109 mmol, 0.2 eq) and 2M aq Na2CO3 (1 mL) in dioxane (3 mL) was refluxed for 2 h. The solvent was evaporated and the residue was treated with water. The suspension was filtered off (avoid taking the heavier reddish solid) and washed with water. The solid (110 mg) was used in the next step of the synthesis with no further treatment. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=3.98 min, [M+H]+ m/z 345.9.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][CH2:17][NH:16][CH:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 35 (415 mg, 2.07 mmol), 1 (343 mg, 2.14 mmol), and acetic acid (629 mg, 10.48 mmol) in methanol (10 mL) was treated with sodium cyanoborohydride (140 mg, 2.23 mmol) at room temperature. The resulting mixture was stirred at room temperature (3 h). The solvent was removed in vacuo. PCTLC (SiO2, 4 mm, 10% EtOH-90% CHCl3) afforded the title compound (36).
Reaction SMILES: [CH:1]1([CH2:7][O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH:1]1([CH2:7][O:8][NH:9][S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
2-(cyclohexylmethoxy)-1H-isoindole-1,3(2H)-dione (11.8 mmol, 3.05 g) was combined with hydrazine (12.9 mmol, 0.41 mL) in anhydrous THF (25 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 48 hours. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (9.5 mmol, 1.97 g) and diisopropylethylamine (11.6 mmol, 2.03 mL) was added. After stirring at room temperature for 18 hours, the reaction was concentrated to a solid residue and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate, and brine, and dried over magnesium sulfate. The product was concentrated to a solid and purified by silica gel chromatography (2:1 hexanes/ethyl acetate) providing 2.55 g (80%) of a yellow solid. H1-NMR (CDCl3): δ 7.81 (2H,d), 6.97 (2H,d), 6.78 (1H,s), 3.85 (3H,s), 3.75 (2H,d), 1.65-1.55 (6H,m), 1.25-1.07 (3H,m), 0.93-0.85 (2H,m).
Reaction SMILES: [O:1]=[C:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:3]=[CH:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([Si:12]([CH3:15])([CH3:14])[CH3:13])[O:10][CH:11]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[O:1]=[C:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([Si:12]([CH3:13])([CH3:15])[CH3:14])[O:10][CH:11]=1
Reactant: CCCCCCCCCCCC(=O)C=CCCc1coc([Si](C)(C)C)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC(=O)CCCCc1coc([Si](C)(C)C)c1
Reaction time: 2 h

Procedure:
To 4-(5-oxo-3-hexadecenyl)-2-trimethylsilylfuran (98 mg, 0.261 mmol), prepared as in Example 3, in ethyl acetate (2 ml) was added platinum oxide (10 mg, 0.044 mmol). This mixture was subjected to one atmosphere of hydrogen at room temperature with stirring for 21/2 hours. The reaction mixture was filtered and concentrated to give a yellow oil. Purification by flash chromatography (silica, 3% ethyl ether/hexane) gave the desired ketone.
Reaction SMILES: CC1NC(C)=CC=1C1C=C[CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH2:32]CC5C=CC=CC=5)[CH2:28][CH2:27]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[N:8]=1.Cl.NO.O.Cl>C(O)C>[CH2:32]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:9]4[N:8]=[C:9]([NH2:8])[CH:13]=[CH:14][CH:10]=4)=[CH:18][CH:17]=3)=[CH:20][CH:21]=2)[CH2:31][CH2:30]1)[CH2:16][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(-c2cccc(-c3ccc(-c4ccc(CN5CCN(CCc6ccccc6)CC5)cc4)cc3)n2)c(C)[nH]1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2ccc(-c3ccc(CN4CCN(CCc5ccccc5)CC4)cc3)cc2)n1
Yield: 135.8 %

Procedure:
To a 100 mL round-bottomed flask equipped with N2 inlet were added 190 mg (0.361 mmol) 2-(2,5-dimethylpyrrolyl)-6-[4′-(4-phenethyl-piperazin-1-ylmethyl)-biphenyl-4-yl]-pyridine, 126 mg (1.81 mmol) hydroxylamine hydrochloride, 1 mL water, and 5 mL ethanol. The reaction was heated at reflux for 36 hours followed by treatment with an additional 50 mg hydroxylamine hydrochloride and refluxing for 24 hours. The reaction was cooled, poured into dilute aqueous hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 1 N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was converted to the hydrochloride salt using 1 N HCl in ether to afford 110 mg (55%) of a solid, mp 267-269° C.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:2]1[C:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: COc1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)c(OC)c1
Yield: 18.7 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 2,4-dimethoxyphenylboronic acid (103.7 mg, 0.57 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) afforded 21 mg (18%) of 3-(2,4-dimethoxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3](=[O:15])[CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5]1.[CH3:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[NH:31][CH2:32][C:33](O)=[O:34])[CH:26]=[CH:27][CH:28]=1>ClCCCl>[CH3:1][N:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3](=[O:15])[CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]1[C:33](=[O:34])[CH2:32][NH:31][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=1)=[O:36]
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CN(C(=O)C1CCC(c2ccccc2)N1)c1ccccc1
Solvent: ClCCCl
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N(C)c3ccccc3)CCC2c2ccccc2)c1
Yield: 49.7 %

Procedure:
By proceeding in a fashion similar to that described in Example 1, but starting from 1.2 g of (2RS,5SR)-N-methyl-N-phenyl-5-phenylprolinamide, 0.94 g of 2-[3-(3-methylphenyl)ureido]acetic acid in suspension in 25 cm3 of 1,2-dichloroethane and 0.33 cm3 of sulphinyl chloride, after recrystallization in acetonitrile, 1 g of (2RS,5SR)-N-methyl-1-[3-(3-methylphenyl)ureidoacetyl]-N-phenyl-5-phenylprolinamide, melting at 210° C., is obtained.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]2[CH:12]3[CH2:13][CH2:14][CH:9]2[C:10](=O)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]2[CH:12]3[CH2:13][CH2:14][CH:9]2[C:10](=[N:23][OH:24])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CC2CCC1C2=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: ON=C1CC2CCC1C2=C(c1ccccc1)c1ccccc1
Yield: 84.9 %

Procedure:
33.7 g (129 mmol) of 7-diphenylmethylenebicyclo[2.2.1]-heptane-2-one were stirred with 9.9 g (142 mmol) of hydroxylamine hydrochloride and 17.8 g (129 mmol) of potassium carbonate in 50 ml of ethanol at room temperature for four hours. Then 200 ml of water were added, and the mixture was extracted three times wit 100 ml of methylene chloride. The combined methylene chloride phases were washed three times with 300 ml of water, dried over sodium sulfate and concentrated in vacuo. 31.7 g of 7-diphenylmethylenebicyclo[2.2.1]heptane-2-one oxime were obtained as an amorphous solid. ##STR17##
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Product: Nc1cccc(CN2CCC(NC(=O)NC(=O)c3ccccc3)CC2)c1
Yield: 46.1 %

Procedure:
1-Benzoyl-3-[1-(3-nitrobenzyl)piperid-4-yl]urea 4.47 g (from Example 13) was hydrogenated with 5% Pd/C (0.5 g) at atmospheric pressure and room temperature until no more hydrogen was taken up. The catalyst was filtered and the filtrate evaporated. The residue was dissolved in water and basified with .880 ammonia. The precipitated solid was filtered, washed well with water, dried, treated with charcoal, and evaporated to give the title compound, (1.9 gms). This was recrystallised from ethanolic HCl to give the dihydrochloride salt, monohydrate, m.p. 194°-195° C.