Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C[O-].[Na+].Cl[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CO>[CH3:25][O:24][C:22](=[O:23])[CH2:21][S:16][C:4]1[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: COC(=O)CCl
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CSc1nc(N)nc(-c2ccccc2)c1C#N
Reaction time: 3 h
Yield: 31 %

Procedure:
Following the method of Perez et al. (Synthesis 1983, 402), to a stirred solution of 1.0 g (4.4 mmol) 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile in 50 ml methanol were added 1.0 ml (5.4 mmol) sodium methylate solution (5.4M in methanol) and 0.39 ml (4.4 mmol) methyl chloroacetate and stirring continued for 3 hours at reflux. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (1/1 ethyl acetate/hexane) followed by trituration in 8/1 ethyl acetate/methanol afforded 0.41 g (32%) (2-Amino-5-cyano-6-phenyl-pyrimidin-4-ylsulfanyl)-acetic acid methyl ester as a light yellow crystalline solid. EI-MS m/e (%): 300 (M+, 38), 299 ([M—H]+, 100), 241 (74), 240 (50).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1([CH3:24])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH2:22][CH2:23][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([OH:16])[CH:12]=2)[O:7]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][CH2:4][CH2:5][C:6]1([CH3:24])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH2:22][CH2:23][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([OH:16])[CH:12]=2)[O:7]1
Reactant: COC(=O)CCC1(C)CCc2cc(O)c3c(c2O1)C1CCCC3CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CCCO)CCc2cc(O)c3c(c2O1)C1CCCC3CC1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-propano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester (212 mg, 0.61 mmol) in 50 mL dry THF was added LiAlH4 in 8 portions over a period of 20 min. The reaction was stirred for 2 h and quenched onto ice (80 g). The mixture was extracted with EtOAc (3×50 mL) and combined organic layers were dried over Na2SO4 and concentrated. The crude product was chromatographed (hexane/EtOAc=6:1) to yield 2-(3-hydroxy-propyl)-2-methyl-3,4,7,8,9,10-hexahydro-7,10-propano-2H-benzo[h]chromen-6-ol as a light yellow oil (169 mg). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 6.39 (s, 1 H), 5.78 (s, 1 H), 3.69 (m, 2 H), 3.54 (m, 1 H), 3.40 (m, 1 H), 2.69 (m, 2 H), 2.45 (ws, 1 H), 1.90-1.60 (m, 14 H), 1.26 (m, 5 H); 13C-NMR δ (ppm): 144.3, 142.9, 132.7, 128.9, 118.6, 112.6, 75.0, 63.3, 36.1, 35.7, 32.1, 32.0, 31.9, 29.4, 28.7, 26.8, 26.4, 26.1, 24.2, 23.6, 22.8, 22.4; MS (ESI) m/z: 317 (M+H+, 100%).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][N:15]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][N:15]=1
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (24.4 g, 68.4 mmol) in THF (150 mL) at −78° C. under an atmosphere of nitrogen was added 2.5 M of n-butyllithium in hexane (27 mL, 67.5 mmol) during a period of 12 mins. The reaction was warmed to room temperature to give a deep red ylide solution. To the ylide solution, cooled in ice, was introduced a solution of 6-(trifluoromethyl)nicotinaldehyde (10 g, 57 mmol) in THF (50 mL). The reaction mixture was warmed to room temperature and stirred for 3 hours. The result suspension was heated to 60° C. over 30 minutes and then stirred at 60° C. for 1 hour. After cooling, the mixture was diluted with water (400 mL), and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated. The residue was purified by silica gel column (0-10% EtOAc/hexane) to afford title compound.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16].[N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>ClCCl>[OH:19][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=Nc1ccccc1
Reactant: CCCCC=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCCCC(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of pentanal (86 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17](OC)=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1([C:53]2[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[CH:55][CH:54]=2)[CH2:52][CH2:51]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O.CN(C=O)C>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:49][C:50]3([C:53]4[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[CH:55][CH:54]=4)[CH2:52][CH2:51]3)=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: COC(=O)c1cccc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2(NC(=O)c3cccc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Reaction time: 8 h

Procedure:
Methyl 1-[4-(trifluoromethyl)benzyl]-1H-indole-7-carboxylate (30.8 g, 97 mmol), HATU (38.6 g, 101 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (24.9 g, 130 mmol) were added to DMF (483 ml). The solution was cooled in an ice bath and DIPEA (50.6 ml, 290 mmol) was added. The mixture was aged overnight at RT and 500 ml of EtOAc was added. The mixture was then poured into 2 L of NaHCO3 (½ sat.). The layers were cut and the aqueous layer was washed 2 more times with DCM. The combined organic layers were washed with brine and dried with Na2SO4. The solvent was removed and the crude mixture purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 9.18 (s, 1H), 7.75 (m, 3H), 7.60 (d, 2H), 7.45 (d, 1H), 7.40 (d, 1H), 7.20 (d, 2H), 7.15 (t, 1H), 6.90 (d, 2H), 6.65 (d, 1H), 5.70 (s, 2H), 3.85 (s, 3H), 1.20 (m, 2H), 0.95 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH:21]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)[C:22]([OH:24])=[O:23])[C:18]([OH:20])=[O:19]>CS(C)=O>[C:12]([C:11]1[C:2]([NH:16][CH:17]([CH:21]([C:25]2[CH:26]=[C:27]([F:32])[CH:28]=[C:29]([F:31])[CH:30]=2)[C:22]([OH:24])=[O:23])[C:18]([OH:20])=[O:19])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:15])=[CH:6][CH:5]=2)([OH:14])=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(C(=O)O)C(C(=O)O)c1cc(F)cc(F)c1
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(C(=O)O)C(C(=O)O)c1cc(F)cc(F)c1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(3,5-difluoro-phenyl)-succinic acid [prepared by analogy to J. Med. Chem. 1973, 16, 1277-1280.; using alkylation of diethyl acetamidomalonate by methyl bromo-(3,5-difluoro-phenyl)-acetate] in DMSO to provide the title compound in good yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2S)[CH:5]=[CH:6][CH:7]=1.OO>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn(-c2cccc(Br)c2)c(S)n1
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cn(-c2cccc(Br)c2)cn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
Step 1) A mixture of commercially available 3-bromophenylisothiocyanate (10.06 g, 47.0 mmol) and 2-aminopropionaldehyde dimethylacetal (5.96 mL, 47.0 mmol) in EtOH (50 mL) was refluxed for 1 h. Evaporated to dryness to give 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methyl-ethyl)-thiourea as an off-white solid (15.69 g, 100%). Step 2) A mixture of the above prepared 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methyl-ethyl)-thiourea (15.69 g, 47 mmol) in H2O (85 mL) and 37% HCl (8.5 mL) was refluxed for 4.5 h. Removed from oil bath, added ice and ice water (total volume: 250 mL), the precipitate was filtered off, washed several times with ice water and dried in vacuum at 60° C. to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole-2-thiol as a light orange solid (8.71 g, 69%). Step 3) To a suspension of the above prepared 1-(3-bromo-phenyl)-4-methyl-1H-imidazole-2-thiol (6.00 g, 22 mmol) in acetic acid (20 mL) and water (5 mL) was added dropwise 35% H2O2 (13.4 mL, 156 mmol) within 15 min keeping the internal temperature below 60° C. Stirred at 23° C. for 30 min, poured onto ice, destroyed excess H2O2 by addition of sat. Na2SO3-sol., adjusted pH with 32% NaOH-sol. until pH 9 is reached, extracted with EtOAc (3×100 mL), the combined organic layers were washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a red oil, which was purified by silica gel column chromatography with EtOAc to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole as a brown oil (3.80 g, 72%). Step 4) A mixture of the above prepared 1-(3-bromo-phenyl)-4-methyl-1H-imidazole (0.313 g, 1.31 mmol), bis(pinacolato)diboron (0.364 g, 1.438 mmol), potassium acetate (0.389 g, 3.96 mmol) and PdCl2(PPh3)2 (0.023 g, 3 mol %) in DMF at 100° C. for 2 h; then addition of Pd(OAc)2 (0.007 g, 3 mol %) and dppf (0.018 g, 3 mol %) and stirred at 100° C. overnight. This solution obtained was used directly.] according to the general procedure VI. Obtained as an off-white solid (0.140 g, 32%). MS (ISP) 394.0 [(M+H)+]; mp 126-132° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[CH3:13][C:14]1[S:18][C:17]([C:19](Cl)=[O:20])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:12][O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:19]([C:17]3[S:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[O:20])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2sc(N)nc12
Reactant: Cc1ccc(C(=O)Cl)s1
Solvent: c1ccncc1
Product: COc1cccc2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole and 5-methyl-thiophene-2-carboxylic acid chloride in pyridine the title compound was obtained as a beige solid (95% yield), MS: m/e=304.1 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[OH-].[Na+]>C(O)C.[Cl-].[Na+].O>[NH2:11][C:10]1[C:2]([CH3:1])=[CH:3][C:4]2[S:8][CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: Cc1cc2scnc2cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2scnc2cc1N
Temperature: 65 °C
Yield: 68.2 %

Procedure:
A mixture of 0.78 g of 6-methyl-5-nitrobenzothiazole and 3.62 g of stannous chloride dihydrate in 25 mL of ethanol is heated to 65° C. for 4 hours. The cooled reaction mixture is poured into 10 mL of 50% sodium hydroxide and 45 mL of brine and extracted with ether (4×35 mL). The combined organic layers are washed with brine, dried over sodium sulfate and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 15% ethyl acetate/hexanes to provide 0.45 g of 5-amino-6-methylbenzothiazole as a yellow solid.
Reaction SMILES: Br.[CH2:2]([C:4]1[N:5]=[C:6]([C@@H:9]([NH2:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3].[C:21]1([CH2:27][C:28](O)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C.O>[CH2:2]([C:4]1[N:5]=[C:6]([CH:9]([NH:20][C:28](=[O:29])[CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1csc(C(Cc2ccc([N+](=O)[O-])cc2)NC(=O)Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.393 g, 1.1 mmol), phenylacetic acid (0.190 g, 1.4 mmol) and 1-hydroxybenzotriazole (HOBt) (0.094 g, 0.70 mmol) in DMF (10 mL) at 00, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.268 g, 1.4 mmol) followed by triethylamine (0.60 mL, 4.2 mmol). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.260 g (60% yield) of the desired product which is used without further purification. ESI+ MS 396 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1B(O)O>>[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20]
Reactant: OB(O)c1ccncc1F
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccncc3F)ccn2c1=O
Yield: 65.1 %

Procedure:
Methyl 8-(3-fluoropyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (3-fluoropyridin-4-yl)-boronic acid (65.3 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (78 mg, 65%).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:19])=[C:11]([CH:14]=[C:15]([CH2:17][CH3:18])[CH:16]=1)[CH:12]=[O:13])(C(C)(C)C)(C)C.[F-].[K+].I[CH2:23][CH3:24]>CN(C=O)C.CCOC(C)=O>[CH2:23]([O:8][C:9]1[C:10]([F:19])=[C:11]([CH:14]=[C:15]([CH2:17][CH3:18])[CH:16]=1)[CH:12]=[O:13])[CH3:24]
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CCI
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(CC)cc(C=O)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 118C (244 mg, 0.87 mmol) in DMF (2.0 mL) was added potassium fluoride (100 mg) and iodoethane (0.13 mL). The mixture was stirred at rt overnight. It was diluted with EtOAc and the organic extracts were washed with brine and dried. The crude product was purified by column chromatography to give 118D (158 mg, 100% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (t, J=7.69 Hz, 3H) 1.46 (t, J=7.03 Hz, 3H) 2.62 (q, J=7.47 Hz, 2H) 4.13 (q, J=7.03 Hz, 2H) 7.02 (dd, J=7.91, 2.20 Hz, 1H) 7.22 (dd, J=5.27, 2.20 Hz, 1H) 10.35 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.Cl.Cl.[CH3:18][N:19]([CH3:30])[CH:20]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:29][C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[CH:20]([N:19]([CH3:30])[CH3:18])[CH2:21][CH2:22]2
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)C1CCc2cc(N)ccc21
Agent: Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc2c(c1)CCC2N(C)C
Yield: 5.5 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (256 mg, 0.90 mmol) was reacted with N1,N1-dimethyl-2,3-dihydro-1H-indene-1,5-diamine dihydrochloride (0.814 mmol) to afford the desired product (19 mg, 5.5%) as a yellow-brown solid. ESI MS m/z 424 [C22H22BrN3O+H]+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:17]#[N:18])[C:12](=[CH:15][CH:16]=2)[C:13]#[N:14])=[N:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=2)[CH:20]=1>>[C:17]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[CH:29]=3)=[O:31])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14])#[N:18]
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1C#N
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4cccnc4)n[nH]3)n2)cc1C#N

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-phthalonitrile (50 mg) and 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (42 mg) using the method of Example 34(d). Yield 39 mg. 1H-NMR (400 MHz; d6-DMSO): δ 3.73 (q, 2H), 4.40 (t, 2H), 7.02 (d, 1H), 7.21 (s, 1H), 7.49 (m, 1H), 7.88 (s, 1H), 8.11-8.16 (m, 2H), 8.30 (dd, 1H), 8.40-8.58 (m, 1H), 8.48 (d, 1H), 8.56 (d, 1H), 8.99 (s, 1H), 13.78 (br s, 1H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH3:12])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16]>C(#N)C>[CH2:19]([O:18][C:14](=[O:17])[NH:15][NH:16][C:2]1[C:3](=[O:13])[N:4]([CH3:12])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:20]
Reactant: Cn1c(=O)c(Cl)nc2ccccc21
Reactant: CCOC(=O)NN
Solvent: CC#N
Product: CCOC(=O)NNc1nc2ccccc2n(C)c1=O
Temperature: 9 °C

Procedure:
A solution of 152 g. (0.78 m.) of 3-chloro-1-methyl-1H-quinoxalin-2-one, 116 g. (1.1 m.) of ethyl carbazate and 1 l. of acetonitrile is refluxed for 16 hours. The mixture is cooled to 9° C. and the product collected by filtration and used directly for cyclization.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:18])[N:9]2[CH2:12][CH:13]2OCC[O:14]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:18])[N:9]2[CH2:12][CH:13]=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1cnc2ccc(Br)cc2n1CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)cnc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.38 g of 7-bromo-1-(1,3-dioxolan-2-ylmethyl)quinoxalin-2(1H)-one was dissolved in 15 mL of 80% aqueous trifluoroacetic acid solution, and stirred at room temperature for 16 hours. After the solvent was removed under reduced pressure, and the reaction mixture was alkalized by adding aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (7-bromo-2-oxoquinoxalin-1(2H)-yl)acetaldehyde.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Br:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCO.C([O-])([O-])=O.[Na+].[Na+].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CCOC(C)=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.O>[Br:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:11]=[CH:10]2
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2cccc(Br)c2n1
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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Brc1cccc2ccc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a mixture of 2,8-dibromoquinoline (1.0 g, 3.49 mmol), Pd(PPh3)4 (0.2 g, 0.174 mmol) in toluene:EtOH:H2O (10 mL:1 mL:1 mL) under argon atmosphere was added Na2CO3 (0.44 g, 4.18 mmol) and phenyl boronic acid (0.507 g, 4.18 mmol) and the reaction was heated to reflux for 24 h. The mixture was cooled to RT and diluted with EtOAc (50 mL), washed with water and brine (50 mL). The organic layer was dried, filtered and concentrated. The residue was purified by column chromatography (10:1 hexane:EtOAc) to give 8-bromo-2-phenylquinoline (0.75 g, 76%) as pale brown oil. MS (ESI, pos. ion) m/z: 284.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=O)=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O>[N:23]1([CH2:18][C:17]2[CH:16]=[C:15]([C:8]3[CH:9]=[C:10]4[C:14]5=[C:6]([CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]5[CH:12]=[CH:11]4)[CH:7]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=Cc1cccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)c1
Reactant: C1CCNC1
Solvent: O
Product: O=C1CNCc2cc(-c3cccc(CN4CCCC4)c3)cc3ccn1c23
Yield: 92 %

Procedure:
Using the reductive amination procedure described in Example 82, the title compound was synthesized from 3-(1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-6-yl)-benzaldehyde and pyrrolidine in 92% yield as a pale-yellow solid: mp 158-160° C.; 1H NMR (DMSO-d6) δ 1.71 (br s, 4H), 2.49 (br s, 4H), 3.49 (br s, 2H), 3.68 (br s, 2H), 4.30-4.33 (m, 2H), 6.70 (s, 1H), 7.17 (t, 1H, J=9.0 Hz), 7.38-7.52 (m, 4H), 7.79 (d, 1H, J=9.0 Hz), 7.82 (d, 1H, J=9.0 Hz), 8.38 (t, 1H, J=6.0 Hz). HRMS calcd. for C22H23N3O 345.1841 (M+), found 345.1848. Anal. (C22H23N3O.0.4 H2O) C, H, N.
Reaction SMILES: CN.C1(=O)[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:16][C@H:17]4[N:29]([CH3:30])[CH2:28][CH2:27][C@:23]56[C:24]=3[C:25]=2[O:26][C@H:22]5[C@@H:21]([OH:31])[CH:20]=[CH:19][C@@H:18]46)C(=O)C2=CC=CC=C12>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][C@H:17]3[N:29]([CH3:30])[CH2:28][CH2:27][C@:23]45[C:24]=2[C:25]=1[O:26][C@H:22]4[C@@H:21]([OH:31])[CH:20]=[CH:19][C@@H:18]35
Reactant: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CN
Solvent: CCO
Product: CN1CC[C@]23c4c5ccc(OCCCN)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a 13.4% solution of methylamine in 100 ml of abs. ethanol was added 5.0 g (10.7 mmol) of 3-(3-phthalimidopropoxy)-7,8-didehydro-4,5α-epoxy-17-methylmorphinan-6 α-ol. After stirring at room temperature for 3.5 hrs, the reaction mixture was concentrated to a volume of about 50 ml and diluted with 200 ml of water and 200 ml of chloroform. The organic solution was separated and the aqueous phase was extracted with chloroform (2 × 200 ml). The combined chloroform solution was extracted with 1 N hydrochloric acid (2 × 100 ml). The acidic extracts were combined and made basic with 2 N sodium hydroxide (150 ml). The aqueous suspension was extracted with chloroform (3 × 200 ml). The chloroform solution was washed with water (2 × 200 ml) and dried. Removal of solvent in vacuo afforded 3.8 g of crude product, which, after recrystallization from benzene-ether, yielded pure 3-(3-aminopropoxy)-7,8-didehydro-4,5α-epoxy-17-methylmorphinan-6α-ol, m.p. 132°-134°[α]D25 -110.2°(c 1.06, MeOH).