Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[F:12][C:13]1[C:21]2[N:20]([CH3:22])[C:19]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[N:30]=[CH:31][NH:32][C:33]=4[CH3:34])[C:26](=[O:27])[C:18]=3[C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[F:12][C:13]1[C:21]2[N:20]([CH3:22])[C:19]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[N:30]=[CH:31][N:32]([C:2]([O:4][CH2:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:3])[C:33]=4[CH3:34])[C:26](=[O:27])[C:18]=3[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CN2CCc3c(c4cccc(F)c4n3C)C2=O)ncn1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of benzyl chloroformate (0.47 ml) in dichloromethane (1 ml) was added to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl -1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (496 mg) and triethylamine (0.67 ml) in dry dichloromethane (50 ml) at 20° under nitrogen, and the mixture was stirred overnight. The cooled reaction mixture was then added to 2N sodium hydroxide (100 ml) and extracted with dichloromethane (2×100 ml). The combined, dried organic extracts were adsorbed onto silica and purified by FCC eluting with System A (200:8:1) to give the title compound (442 mg) as a solid. A sample was recrystallised from hot ethyl acetate, and the resultant solid was triturated with ether to give a crystalline solid, m.p. 126°-128°.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][N:15]=[C:14]3[NH:21][CH:22]=[C:23]([C:28]([O:30]C)=O)[C:24]([O:26][CH3:27])=[O:25])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:30]=[C:28]1[N:15]2[CH:16]=[N:17][C:18]3[CH:19]=[CH:20][C:11]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][C:13]=3[C:14]2=[N:21][CH:22]=[C:23]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NC(=O)CCC3CCCC3)cc12)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Temperature: 255 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
A mixture of dimethyl [[6-(3-cyclopentylpropionamido)-4-quinazolinylamino]methylene]propanedioate (6.9 g) in diphenyl ether (53 ml) was stirred at 255° C. for 15 minutes and cooled to ambient temperature. The resulting solid was collected, washed with hexane and dried. There was obtained methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (4.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)O.C(Br)(Br)(Br)[Br:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[Br:22]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl[3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate (300 mg, 0.993 mmol) was dissolved in CH2Cl2 (10 mL). The solution was cooled to 0° C. and CBr4 (659 mg, 1.986 mmol) was added followed by PPh3 (521 mg, 1.986 mmol). After 1 hour, the reaction was warmed to room temperature and stirred at room temperature for 1 hour. The reaction was filtered through a short plug of silica gel with CH2Cl2. The filtrate was concentrated and the residue was purified by flash chromatography with 5% EtOAc/hexanes to afford methyl[3,5-bis(trifluoromethyl)phenyl](bromo)acetate. Rf=0.24 (5% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 8.02 (s, 2H), 7.87 (s, 1H), 5.41 (s, 1H), 3.83 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([CH3:35])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31](O)=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:17][CH:18]([CH3:35])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2CC(C)C)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2CC(C)C)c1

Procedure:
0.58 g of compound 9 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.10 g of ethyl 4-(2-aminophenoxy)butyrate and 0.64 g of 3-[1-(2-methylpropyl)indol-5-yl]isocrotonic acid obtained according to a similar manner to procedures described in the Reference Examples 1-4.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[O:20][CH2:21][CH:22]([F:24])[F:23])[CH2:5][CH2:4]1.[CH3:28][C:29]1[C:42]([N:43]=[C:44]=S)=[C:41]([CH3:46])[CH:40]=[CH:39][C:30]=1[CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].CC(C)N=C=NC(C)C>>[F:1][C:2]([F:26])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([O:20][CH2:21][CH:22]([F:23])[F:24])=[CH:13][C:14]3[N:18]([CH3:19])[C:44]([NH:43][C:42]4[C:41]([CH3:46])=[CH:40][CH:39]=[C:30]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]=4[CH3:28])=[N:17][C:15]=3[CH:16]=2)=[O:25])[CH2:5][CH2:4]1
Reactant: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N=C=S
Reactant: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1Nc1nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc2n1C

Procedure:
The title compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-(2,2-difluoro-ethoxy)-4-methylamino-5-amino-benzoic acid amide and N-(2,4-dimethyl-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to examples 7b/7c.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]([CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][OH:14])[C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]([CH2:15][CH2:16][O:17][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:12][CH2:13][O:14][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCN(CCO)c1cccc2c1OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of II (39.6 g, 0.165 mol) and triethyl amine (69 mL, 0.5 mol) in methylene chloride (250 mL), chilled to 5° C. in an ice-bath, is added a solution of mesyl chloride (38 mL, 0.5 mol) in methylene chloride (50 mL). The addition is carried out over 0.5 h at temperature not exceeding 18° C. The ice-bath is removed and resulting suspension is stirred at ambient temperature for 1 h. At that time, TLC and HPLC showed disappearance of starting material. The reaction mixture is washed with water (1×150 mL) and 5% aqueous NaHCO3 solution (1×150 mL), dried with MgSO4 and concentrated to afford III as red oil, crude yield 67.0 g (102%). 1H NMR (CDCl3) δ 6.85 (m, 1H), 6.63 (m, 2H), 4.28 (m, 8H), 3.55 (t, J=7.5 Hz, 4H), 2.97 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([Br:14])[CH:10]=[C:9]([F:15])[CH:8]=2)=[O:4].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[C:12]([CH:13]=1)=[C:11]([Br:14])[CH:10]=[C:9]([F:15])[CH:8]=2)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc2c(Br)cc(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2c(Br)cc(F)cc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 34 %

Procedure:
To a solution of 4-bromo-6-fluoro-1H-indole-2-carboxylic acid methyl ester (178 mg, 0.65 mmol) in 5 ml anhydrous dimethylformanide was added sodium hydride (52 mg of a 60% suspension in mineral oil, 1.3 mmol) portionwise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes. Benzyl bromide (0.17 ml, 1.43 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for 30 minutes. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by Preparative TLC (10% Ethyl acetate/Hexane) to give 80 mg 1-Benzyl-4-bromo-6-fluoro-1H-indole-2-carboxylic acid methyl ester as a yellow solid (34%). 1H NMR (CDCl3, 300 MHz) δ: 3.89 (s, 3H), 5.78 (s, 2H), 7.17 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:9]2[C:8]3[C:17]4=[C:16]5[C:5](=[CH:6][CH:7]=3)[CH:4]=[CH:3][C:2]([Br:1])=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[CH:20]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc2ccc3c(-c4cccc(-c5ccccc5)c4)ccc4ccc1c2c43
Yield: 69.2 %

Procedure:
To a solution of 1,6-dibromopyrene (5.4 g, 15.0 mmol), [1,1′-biphenyl]-3-ylboronic acid (3.3 g, 16.5 mmol), and K2CO3 (10.4 g, 75.0 mmol) in 1,4-dioxane (320 mL) and water (50 mL) was bubbled with nitrogen for 15 min. Pd(PPh3)4 (0.87 g, 0.75 mmol) was then added to the mixture. The mixture was bubbled with nitrogen for 15 min. The resultant mixture was refluxed for 19 h. The reaction mixture was then extracted by DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography using 15% DCM/hexane (containing 0.25% triethylamine) to yield 1-([1,1′-biphenyl]-3-yl)-6-bromopyrene (4.5 g, 70% yield) as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:25][CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1>>[O:28]1[CH2:29][CH2:30][CH:26]([NH:25][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:27]1
Reactant: NC1CCOC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC2CCOC2)[nH]n1
Yield: 40 %

Procedure:
As described for example 17e, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using rac-3-aminotetrahydrofuran instead of 2,2,2-trifluoroethylamine, to the title compound (46 mg, 40%) which was obtained as a white solid. MS: m/e=388.2 [M+H]+.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15]>C(Cl)Cl>[CH2:9]([O:8][P:1]([C:14](=[O:15])[CH:13]=[C:12]([CH3:17])[CH3:11])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)=CC(=O)Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(=O)C=C(C)C
Yield: 81.7 %

Procedure:
83 g (0.5 mol) of triethyl phosphite were added dropwise to a solution of 60 g (0.5 mol) of β,β-dimethylacrylic acid chloride in 200 ml of methylene chloride in the course of one hour. The reaction mixture was stirred for a further hour at 40° to 45° C.; the solvent was then distilled off under reduced pressure and the crude product which remained was purified by vacuum distillation. 90 g (82% of theory) of 1-oxo-3-methyl-2-butene-phosphonic acid diethyl ester of boiling point 72° C./0.01 mbar were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[NH2:6][C:7]1[CH:11]=[C:10](O)[NH:9][N:8]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:10]1[NH:9][N:8]=[C:7]([NH2:6])[CH:11]=1
Reactant: Nc1cc(O)[nH]n1
Reactant: COCCO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: COCCOc1cc(N)n[nH]1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-methoxyethanol (0.664 mL, 8.41 mmol) and 3-amino-5-hydroxypyrazole (1.00 g, 10.1 mmol) in C6H6 (50 mL) at RT was added cyanomethylenetri-n-butylphosphorane (2.03 g, 8.41 mmol). The mixture was heated to 90° C. in a pressure vessel. After 16 hrs, the solvent was removed in vacuo. The residue was taken up in CH2Cl2 and adsorbed onto silica gel prior to purification by silica gel chromatography using 2-10% MeOH in CH2Cl2 with 1% NH4OH to afford 5-(2-methoxyethoxy)-1H-pyrazol-3-amine as a yellow oil. MH+=158.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Fc1ccccc1C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccccc2F)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
Methyl 2-chloroisonicotinate (5.2 g, 30.31 mmol) and Pd(PPh3)4 (0.700 g, 0.61 mmol) were dissolved under nitrogen in THF (100 mL) and (2-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (90 mL, 45.00 mmol) was added and the brown solution was stirred at 60° C. for 18 h. The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc, washed with NH4Cl (aq) and dried over Na2SO4, then evaporated. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to give methyl 2-(2-fluorobenzyl)isonicotinate (5.42 g, 73%) as a yellow oil. 1H NMR (400 MHz, cdcl3) 3.92 (s, 3H), 4.25 (s, 2H), 7.00-7.13 (m, 2H), 7.18-7.30 (m, 2H), 7.64-7.74 (m, 2H), 8.69 (d, 1H). MS m/z 246 (M+H)+
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[Na+]>CN(C)C=O.O>[CH:1]([N:14]1[CH2:17][CH:16]([C:23]#[N:24])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A mixture of 50 g (0.157 mol) of 1-benzhydryl-3-mesyloxyazetidine (J. Org. Chem. 1972, 37, 3953-3955) and 23.5 g (0.479 mol) of sodium cyanide in 340 ml of dimethylformamide and 43 ml of water is heated to 60° C. for 5 hours. The reaction mixture is left at ambient temperature overnight and is then poured into 2000 ml of water/ice. The solid product is recovered by filtration and is purified by being suspended in 800 ml of water and being filtered. The product thus obtained is dried and crystallized from isopropyl ether to obtain 20 g of 1-benzhydryl-3-azetidinecarbonitrile. M.p. 142°-146° C.
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:5][CH2:6][CH3:7])[C:3]#[CH:4].[Na+].[CH3:10][O:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1/[CH:17]=[C:18]1\[C:19](=[O:34])[NH:20][C:21]2[C:26]\1=[C:25](C#CCCC([O-])=O)[CH:24]=[CH:23][CH:22]=2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:8][C:2]([CH3:1])([CH2:5][CH2:6][CH3:7])[C:3]#[C:4][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1/[C:18](=[CH:17]/[C:13]1[NH:14][CH:15]=[CH:16][C:12]=1[O:11][CH3:10])/[C:19](=[O:34])[NH:20]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)[O-])c21
Reactant: C#CC(C)(O)CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-hexyn-3-ol (98 mg, 0.87 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material I supra) (127 mg, 0.4 mmol) using (Ph3P)2PdCl2 (46 mg) and CuI (22 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 22 h yielding rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 92 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH2:18])=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH:24](Br)[C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1.O>CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([N:18]4[CH2:31][C:26]5[C:25](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:24]4)=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: Cc1ccccc1C(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1Cc2ccccc2C1
Reaction time: 16 h

Procedure:
To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under N2. The mixture was heated to 65 C for 3 hours. α,α-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 70 C for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1% CH3OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184°-185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=[C:4]2[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH:37]([C:39]1[CH:40]=[C:41]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:42]=[CH:43][C:44]=1[N+:45]([O-:47])=[O:46])=[O:38]>C(N(CC)CC)C.CN(C)C=O>[CH:37]([C:39]1[CH:40]=[C:41]([N:48]2[CH2:53][CH2:52][N:51]([C:11]([C:9]3[N:10]=[C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]4[CH:8]=3)=[O:13])[CH2:50][CH2:49]2)[CH:42]=[CH:43][C:44]=1[N+:45]([O-:47])=[O:46])=[O:38]
Reactant: O=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: Cc1ccn2cc(C(=O)O)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccn2cc(C(=O)N3CCN(c4ccc([N+](=O)[O-])c(C=O)c4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of 7-methylimidazo[1,2-a]pyridine-2-carboxylic acid (10.56 g), 1-hydroxybenzotriazole (8.1 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.46 g) and N,N-dimethylformamide (360 ml) was stirred for 1 hour at ambient temperature. 1-(3-Formyl-4-nitrophenyl)piperazine hydrochloride (16.2 g) and triethylamine (9.1 g) were added thereto and the mixture was stirred for 1 hour. The resulting precipitates were collected, washed with ethyl acetate (100 ml×2) and water (100 ml×2), and dried to give 1-(3-formyl-4-nitrophenyl)-4-(7-methylimidazo[1,2-a]pyridine-2-carbonyl)piperazine (23.0 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O>[CH3:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CNS(=O)(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: O
Product: CNS(=O)(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
4-fluoro-N-methylbenzenesulfonamide (189 mg, 0.999 mmol) and piperazine (430 mg, 4.99 mmol) were combined and the reaction mixture was stirred at 120° C. for 2 h. It was diluted with water (5 mL) and stirred until a fine suspension resulted. The precipitate was filtered, washed with water (5×3 mL) and dried in vacuum to afford N-methyl-4-(piperazin-1-yl)benzenesulfonamide (222 mg, 0.869 mmol, 87% yield) as a white solid. ESI-MS: m/z 256 (M+H)−.
Reaction SMILES: C(O[C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10](C)[C:9]1=[O:17])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:6][N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[NH:10][C:9]1=[O:17]
Reactant: CN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)NC2CCCC21
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
To a solution of (3aSR, 6aRS)-3-methyl-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 106, step 2) (1.99 g, 8.28 mmol) in 30 ml of dichloromethane was added trifluoroacetic acid (7.55 g, 5.1 ml, 66.3 mmol, 8 equiv.) and the yellow solution was stirred at for 5 h at room temperature. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution and the pH of the aqueous phase was set to 9. After workup with dichloromethane/water, the organic phases were dried, filtered and concentrated in vaccuo to yield 1.07 g of an off-white solid, which was taken up in cold ethyl acetate and filtered to yield the title compound (822 mg, 71%) as a crystalline white solid which was directly used in the next step without further characterisation.
Reaction SMILES: [OH:1][C@H:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][N:7]3[C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Mn]([O-])(=O)(=O)=[O:25].[K+]>C(Cl)(Cl)Cl>[CH:17]([C:13]1[N:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:12])[C@H:2]([OH:1])[C@@H:3]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:4][C:5]=3[C:6]2=[N:15][C:14]=1[CH3:16])=[O:25]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2c3c(ccn2c1C=O)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Temperature: 25 °C
Reaction time: 960 h
Yield: 6.7 %

Procedure:
(8R,9R)-8-hydroxy-2,3-dimethyl-7-oxo-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine (1 g) is dissolved in 20 ml of dried chloroform, and 5 g of potassium permanganate was added. After stirring the reaction mixture at room temperature for 40 days, the solids are filtered off. The filtrate is chromatographed twice on silica gel (eluents: dichloromethane/methanol 13/1) to give 0.07 g of the title compound as a semisolid.