Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:23])C=1Cl>C1COCC1.O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[CH2:8][CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Brc1ccc2c3c([nH]c2c1)CCCC3
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCc2[nH]c3cc(Br)ccc3c21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
A solution 7-bromo-2,3,4,9-tetrahydro-1H-carbazole (2.87 g, 11.5 mmol) in THF (103 mL) and H2O (11.5 mL) was cooled to 0° C. and treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.23 g, 23.1 mmol) in THF (46 mL) at such a rate that the reaction mixture did not exceed 4° C. The resulting solution was allowed to stir for an additional 45 min at 0° C. The solution was concentrated to dryness under reduced pressure. The resulting solids were suspended in EtOAc (100 mL) and saturated NaHCO3 solution (300 mL). The solids were collected by filtration and washed with additional saturated NaHCO3 solution (400 mL) followed by H2O (150 mL). The solid was dried to provide the title compound (2.46 g, 81%) as a light pink solid: 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.27 (dd, J=8.5, 2.0 Hz, 1H), 2.95 (t, J=6.0 Hz, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.14-2.09 (m, 2H); ESI MS m/z 263 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[NH:12][CH2:11][C:10]3=[CH:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Br:29])[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[N:12]([C:23]([C:22]3[CH:26]=[CH:27][C:28]([Br:29])=[C:20]([CH3:19])[CH:21]=3)=[O:24])[CH2:11][C:10]3=[CH:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: COc1cc2c(cc1OC)NCc1cccn1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)N(C(=O)c1ccc(Br)c(C)c1)Cc1cccn1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of 7,8-dimethoxy-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (3.20 g) in dichloromethane (20 mL) was added 3-methyl-4-bromo benzoyl chloride (3.4 g, 1.1 equiv) and triethylamine (2.0 g, 1.5 equiv) and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue chromatographed on silica gel eluting with a solvent gradient from 5 to 50% ethyl acetate in petroleum ether to provide the title compounds as a yellow crystalline solid (3.5 g), m.p. 165-168° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:7]2.[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[S:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=3[S:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: CC(C)Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(CC(C)C)ccc23)c1

Procedure:
The product from Example 12d (100 mg, 45.3 mmol) was reacted with the product from Example 4c (105 mg, 45.3 mmol) for 18 h following the procedure from Example 1g giving the title compound after purification of the crude product by HPLC with TFA as the trifluoroacetic acid salt (90 mg, 47%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.97 (d, J=6.62 Hz, 6H), 2.13-2.30 (m, 1H), 2.33 (s, 3H), 2.89 (d, J=6.99 Hz, 2H), 6.29 (d, J=6.99 Hz, 1H), 6.73 (d, J=8.46 Hz, 2H), 7.00 (d, J=8.09 Hz, 1H), 7.13-7.34 (m, 4H), 7.81 (d, J=8.46 Hz, 1H), 8.43 (d, J=6.99 Hz, 1H), 9.03 (d, J=8.46 Hz, 1H), 10.99 (br. s., 1H), 14.36 (br. s., 1H); MS (ESI+) m/z 416 (M+H)+; (ESI−) m/z 414 (M−H)−.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:31]2[O:32][C:33]([CH3:38])=[C:34]([CH2:36]I)[N:35]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:31]2[O:32][C:33]([CH3:38])=[C:34]([CH2:36][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:35]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(-c2nc(CI)c(C)o2)cc1OC
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: COc1ccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1OC

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3,4-dimethoxyphenyl)4-iodomethyl-5-methyloxazol as starting materials in the procedure of Example XXXI, gave the product 67 of molecular weight 495.58 (C28H33NO7), MS(ESI): 496.20 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17]#[C:18][Si](C)(C)C)[CH2:5][N:6]1[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]1.[F-].[Cs+].CN(C=O)C>CO>[C:17]([C:16]1[CH:15]=[CH:14][C:4]([CH2:5][N:6]2[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]2)=[CH:3][C:2]=1[F:1])#[CH:18]
Reactant: COC(=O)C1CN(Cc2ccc(C#C[Si](C)(C)C)c(F)c2)C1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reaction time: 2 h

Procedure:
Methyl 1-(3-fluoro-4-(2-(trimethylsilyl)ethynyl)benzyl)azetidine-3-carboxylate (20.9 g, 65 mmol) and cesium fluoride (11 g, 72 mmol) were added to DMF (50 mL). MeOH (100 mL) was added. After 2 h, MeOH was removed and the mixture was extracted with DCM and water. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed and the material was purified by Biotage (75 L, 7-100% EtOAc/hexanes), affording methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate as light yellow oil. MS (ESI) m/z: Calculated: 247.1; Observed: 248.0 (M++1). 1-(4-(2-(5-Benzylpyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylic acid and 1-(4-(2-(5-Benzylpyridin-2-yl)ethyl)-3-fluorobenzyl)azetidine-3-carboxylic acid
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Sn:16](C)([CH3:18])[CH3:17]>O1CCOCC1.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>[CH2:13]([N:11]([CH3:12])[S:8]([C:5]1[CH:6]=[N:7][C:2]([Sn:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:14]
Reactant: C[Sn](C)(C)C
Reactant: CCN(C)S(=O)(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCN(C)S(=O)(=O)c1ccc([Sn](C)(C)C)nc1
Temperature: 90 °C
Yield: 40.2 %

Procedure:
6-chloro-N-ethyl-N-methylpyridine-3-sulfonamide (2.34 g, 10.0 mmol), tetramethyl tin (1.08 g, 10.00 mmol) and Pd(PPh3)4 (572 mg, 0.50 mmol) were mixed in dioxane (5 mL). After degassing, the mixture was heated to 90° C. At completion, the reaction was cooled to room temperature and concentrated. The residue was then flashed over alumina (20-100% chloroform/hexane eluent) to afford N-ethyl-N-methyl-6-(trimethylstannyl)pyridine-3-sulfonamide (1.46 g, 40% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:8]([CH3:18])=[C:7]2[NH:19][C:20]1[C:21]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:22][CH:23]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn]([C:85]#[N:86])(CCCC)CCCC)CCC>CN1CCCC1=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[Pd+2]>[O:35]1[CH2:34][CH2:33][N:32]([C:21]2[C:20]([NH:19][C:7]3[C:6]4[C:11](=[C:2]([C:85]#[N:86])[CH:3]=[CH:4][CH:5]=4)[N:10]=[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[C:8]=3[CH3:18])=[CH:25][C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:23][N:22]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(-c2ccccn2)nc2c(Cl)cccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])C(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2c(C#N)cccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 160 °C

Procedure:
To a stirred solution of 8-chloro-N-(2,5-dimorpholinopyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.180 g, 0.35 mmol) in 1-methylpyrrolidin-2-one (3.46 mL) was added palladium bis(trifluoroacetate) (0.017 g, 0.052 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-biphenyl (0.050 g, 0.11 mmol) followed by tri-n-butyltin cyanide (0.109 g, 0.35 mmol). The reaction was heated to 160° C. for 36 h. A further 0.3 eq of palladium bis(trifluoroacetate) and 0.6 eq of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine was added. The reaction was further heated at 160° C. for 3 h. After which, the reaction was cooled to 23° C. The crude product was filtered through a plug of alumina eluting with EtOAc. The organic layer was washed with water, dried over MgSO4 and filtered and evaporated in vacuo. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc/hexane)) to give the desired product 4-((2,5-dimorpholinopyridin-3-ylamino)-3-methyl-2-(pyridin-2-yl)quinoline-8-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (1H, ddd, J=4.8, 1.8, 1.0 Hz), 8.29 (1H, dd, J=7.1, 1.3 Hz), 8.19 (1H, dd, J=8.5, 1.3 Hz), 8.03-8.08 (2H, m), 7.96 (1H, dt, J=7.9, 1.1 Hz), 7.61-7.65 (2H, m), 7.53 (1H, ddd, J=7.6, 4.8, 1.3 Hz), 6.55 (1H, d, J=2.7 Hz), 3.65 (4H, m), 3.39 (4H, m), 2.95 (4H, m), 2.88 (4H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=508.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])[NH:23][C:22]=1[CH:37]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:37][C:22]4[NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]5[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]5)=[O:29])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(CCC(=O)N2CCN(C)CC2)[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(CCC(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 65 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-5-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (79 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred in an oil bath at 65° C. for 2 hours. The reaction was cooled at room temperature for overnight. The precipitate was collected by vacuum filtration, washed with ethanol (5×) and dried to give 88.9 mg (68%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.15 (s, 1H, NH), 11.55 (br s, 1H, NH), 9.08 (s, 1H), 8.27 (s, 1H), 7.69 (dd, J=2.5 & 6.9 Hz, 1H), 7.30-7.40 (m, 3H), 6.08 (d, J=2.23 Hz, 1H), 3.43 (m, 4H, 2×CH2), 2.89 (t, J=7.4 Hz, 2H, CH2), 2.68 (t, J=7.4 Hz, 2H, CH2), 2.24 (m, 4H, 2×CH2), 2.16 (s, 6H, 2×CH3). MS 524 [M++1].
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1.I[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:22][N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([B:12]3[O:13][C:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[O:16]3)=[C:2]([CH3:1])[C:11]1=2
Reactant: CI
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1NCCO2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1N(C)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
An ice cold mixture of 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (65.0 mg, 0.236 mmol) in N,N-dimethylformamide (DMF) (0.5 mL) was treated with iodomethane (0.044 mL, 0.709 mmol) and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (hexanes/ethyl acetate) to afford a pale yellow residue (40 mg, 59%): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39 (d, J=8.2 Hz, 1 H), 6.69 (d, J=8.2 Hz, 1 H), 4.20-4.14 (m, 2 H), 3.12-3.03 (m, 2 H), 2.66 (s, 3 H), 2.49 (s, 3 H), 1.31 (s, 12 H); LC/MS (m/z) ES+=290 (M+1).
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH:26][CH3:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]>C(O)C.[Pt]=O>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH3:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC=Cc1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Agent: O=[Pt]
Solvent: CCO
Product: CCCc1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
In 7 ml of ethanol was dissolved 757 mg of N-acetyl-N-[2-(propen-1-yl)benzyl]-2-phenoxyaniline (a mixture of the geometrical isomers at a ratio of about 3:2), and 15 mg of platinum oxide was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The catalyst in the reaction solution was removed by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:4) to give 647 mg of N-acetyl-N-(2-propylbenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CC([O-])(C)C.[K+].C1COCC1.[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42](F)[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12>CN(C=O)C>[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42]([O:8][C@@H:7]4[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[O:10])[CH2:3][C@H:2]4[F:1])[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](F)C1
Reactant: Fc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Non-racemic (trans)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (0.192 g, 0.757 mmol) was treated with 1.0 M KOtBu in THF (0.757 mL, 0.757 mmol) and stirred at ambient temperature for 15 minutes. 2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-fluoro quinoline (0.200 g, 0.757 mmol) was added along with DMF (2.25 mL) and the mixture was stirred at 50° C. for 15 hours. The reaction was cooled and chromatographed on SiO2, eluting with a gradient of 2% NH4OH in isopropanol/methylene chloride. After concentration in vacuo, the desired product was isolated as a beige solid (0.306 g). MS APCI (+) m/z 498.1 (M+1) detected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:19]=[O:21])=[C:11]([F:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)CCc1ccc(N)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(N=C=O)c(F)c1

Procedure:
In analogy to the procedure described in example 9.1, 3-(4-amino-3-fluoro-phenyl)-propionic acid tert-butyl ester was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 20 h to give the title compound as yellow oil which was used in the next step without further purification. MS: m/e=265.1 [M+].
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([C:18]#[CH:19])[NH:12]4)[CH2:5][C@H:4]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:3]1.C(N(CC)CC)C.I[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1>CN(C)C=O.[Cu]I>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([C:18]#[C:19][C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[NH:12]4)[CH2:5][C@H:4]([NH:20][C:21](=[O:27])[N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[CH2:3]1
Reactant: Ic1cccs1
Reactant: C#Cc1[nH]c2cccc3c2c1C[C@@H]1[C@@H]3C[C@H](NC(=O)N(CC)CC)CN1C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C#Cc5cccs5)c(c34)C[C@H]2N(C)C1

Procedure:
Under argon, 72 mg of 3-(6-methyl-2-ethynyl-8α-ergolinyl)-1,1-diethylurea is heated in 2 ml of dimethylformamide with 2 ml of triethylamine, 1.5 mg of copper(I) iodide, 0.069 ml of 2-iodothiophene, and 4.8 mg of palladium(O) tetrakis(triphenylphosphine) for 2 hours to 80° C. After evaporation, the mixture is taken up in ethyl acetate and washed in succession with dilute ammonia solution and saturated sodium chloride solution. After chromatography over silica gel with ethyl acetate:ethanol=1:1 and recrystallization from ethanol/hexane, 26 mg of 3-[6-methyl-2-(thien-2-ylethynyl)-8α-ergolinyl]-1,1diethylurea is obtained, mp 252°-256° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[C:3]#N.[C:22]1([Mg]Br)[CH:27]=[CH:26]C=[CH:24][CH:23]=1>>[CH3:1][C:2]([N:5]1[CH2:6][CH2:7][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:9][CH2:10]1)([C:3]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1)[CH3:21]
Reactant: CC(C)(C#N)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: Br[Mg]c1ccccc1
Product: CC(C)(c1ccccc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 59 %

Procedure:
This was prepared according to the procedure described in Example 1 using 2,2-dimethyl-2-[4-(2-keto-1-benzimidazolinyl)piperidinyl]acetonitrile and phenylmagnesium bromide. Yield was 59%.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH2:9]([C:7]1[N:6]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)[C:5]2[CH:20]=[CH:21][C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][C:4]=2[N:8]=1)[CH3:10]
Reactant: OB(O)c1ccccc1
Reactant: CCc1nc2cc(Br)ccc2n1-c1ccc(CCO)cc1
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: COCCOC
Product: CCc1nc2cc(-c3ccccc3)ccc2n1-c1ccc(CCO)cc1
Temperature: 95 °C
Reaction time: 11 h
Yield: 26.6 %

Procedure:
To a solution of 2-[4-(5-bromo-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4, 116 mg, 0.57 mmol) in 1,2-dimethoxyethane (DME, 6 ml) was added PhB(OH)2 (141 mg, 1.16 mmol), K2CO3 (240 mg, 1.75 mmol) and Pd(PPh3)4 (67 mg, 0.06 mmol). This mixture was stirred at 95° C. for 11 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (4×10 ml). The organic layer was dried (MgSO4) and concentrated to give brown oil. This mixture was purified by SiO2 preparative TLC (hexane/ethyl acetate=1/5) to afford 52 mg (27%) of the title compound.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][C:33]([F:37])([F:36])[CH2:32]1>>[ClH:28].[F:36][C:33]1([F:37])[CH2:34][CH2:35][N:31]([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:32]1
Reactant: FC1(F)CCN(CCCl)C1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Agent: Cl
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCN3CCC(F)(F)C3)cc12

Procedure:
6-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 62% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 1-(2-Chloro-ethyl)-3,3-difluoro-pyrrolidine hydrochloride (WO2008/86404).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.O[NH:12][C:13](=[NH:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[C:14]([C:13]1[N:18]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=2)[O:9][N:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=N)NO
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1noc(-c2ccc(Cl)nc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 3.8 g (21.5 mmol) of 6-chloropyridine-3-carbonyl chloride in 100 mL of toluene, in Dean-stark apparatus, are added portionwise 2.5 g (21.5 mmol) N-hydroxy-2,2-dimethylpropanimidamide, and the reaction medium is stirred for 2 hours at room temperature and then heated for 2 hours. After cooling to room temperature, the medium is concentrated under reduced pressure and purified by chromatography on silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 10% EtOAc. 4.1 g of 5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-chloropyridine are obtained in the form of a white solid.
Reaction SMILES: N[CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:27].Cl>C(N(CC)CC)C>[O:27]=[C:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=CCS[C@@H]2C(=O)C(=O)N12

Procedure:
4-Nitrobenzyl 7-amino-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give 4-nitrobenzyl 7-oxo-3-cephem-4-carboxylate. Mp. 141°-142° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:8][N:7]=1.CS(C)=[O:29]>CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:29])=[N:8][N:7]=1
Reactant: Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1Br
Reactant: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2nnc(C(=O)c3ccncc3)c3ccccc23)cc1Br
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 1.22 g (3 mmol) 1-(3-brom-4-methyl-anilino)-4-(4-pyridyl-methyl)-phthalazine (expl. 14 h) and 336 mg (3 mmol) potassium-tert.butylate in 10 ml DMSO is stirred in an open vessel for 10 days at RT. Then the yellow mixture is diluted with EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and partly concentrated. After adding 10 g of SiO2, the residue is dried in vacuo and the resulting powder put on top of a SiO2 -column. Eluation with dichloromethane/EtOAc (5:1→1:1→EtOAc) yields [4-(3-brom-4 -methyl-anilino)phthalazin-1-yl](pyridin-4-yl)ketone (A) followed by [4-(3-brom-4-methyl-anilino)phthalazin-1-yl](pyridin-4-yl)methanol (B). A: m.p. 249-250° C.; FAB MS (M+H)+=419/421. B: m.p. 240° C.; FAB MS (M+H)+=421/423.