Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:22]=[C:23]([O:28][S:29]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:24]=[C:25]([OH:27])[CH:26]=1.[CH2:38](O)[CH2:39][CH2:40][OH:41].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:20][C:21]1[CH:22]=[C:23]([O:28][S:29]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:24]=[C:25]([CH:26]=1)[O:27][CH2:38][CH2:39][CH2:40][OH:41]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccnc2)c1
Reactant: OCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of triphenylphosphine (1.52 g, 0.0058 mol), 5-methyl-3-(3-pyridinylsulfonyloxy)phenol (1.54 g, 0.0058 mol), as prepared in the preceding step, and 1,3-propanediol (0.42 mL, 0.0058 mol) in anhydrous tetrahydrofuran (50 mL) was treated with diethyl azodicarboxylate (0.92 mL, 0.0058 mol) and allowed to stir at ambient temperature for 3 days. The tetrahydrofuran was evaporated, and the solid residue was treated with hexane. Solvent was decanted and the solid was treated with dichloromethane and diluted with hexane to produce a crystalline solid which was collected by filtration. The filtrate was evaporated to dryness and partitioned between water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether (2×50 mL). The diethyl ether extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. The diethyl ether extract was evaporated to a gum which was purified further by silica gel chromatography using 10% ethyl acetate/90% dichloromethane, followed by 15% ethyl acetate/85% dichloromethane, 20% ethyl acetate/80% dichloromethane, and finally 25% ethyl acetate/75% dichloromethane. The appropriate fractions were combined and evaporated to a gum (1.3 g). 1H-NMR (300 MHz, CDCl3) δ 9.03 (d, 1H), 8.89 (dd, 1H), 8.14 (m, 1H), 6.64 (s, 1H), 6.42 (s, 1H), 6.37 (t, 1H), 4.00 (t, 2H), 3.81 (q, 2H), 2.25 (s, 3H), and 1.99 (pentet, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C15H17NO5S: 278.0 (M-C3H7O+Na). Found: 278.9.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:14][CH2:15][C:16](Br)=[O:17]>ClCCl>[Br:14][CH2:15][C:16]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:9])[CH3:8])=[CH:2][CH:3]=1)=[O:17]
Reactant: O=C(Br)CBr
Reactant: CC(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)CBr)cc1
Reaction time: 2 h

Procedure:
To a solution of cumene (27.8 mL, 200 mmol) and aluminum chloride (32.0 g, 240 mmol) in dichloromethane (300 mL) was added bromoacetylbromide (19.1 mL, 220 mmol) at −10° C., and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into ice-cold water, and an organic layer was separated. The organic layer was washed with a saturated sodium hydrogen carbonate solution and a saturated brine, and then was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 2-bromo-1-(4-isopropylphenyl)ethanone of oily matter. The obtained oily matter was added to a solution of 3,5-dimethylphenol (29.3 g, 240 mmol) and potassium carbonate (33.2 g, 240 mmol) in acetone (500 mL), and the mixture then was stirred under heat and reflux for 12 hours. The reaction solution was ice-cooled and poured into cold water, which was extracted with diethyl ether.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:11][CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCNCC1
Reactant: ClCCCN1CCCCC1
Product: O=C1CCN(CCCN2CCCCC2)CC1

Procedure:
1-(3-(1-Piperidinyl)propyl)-4-piperidone is prepared from 4-piperidone and 1-(3-chloropropyl)piperidine essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH2:33][N:34]3C(=O)C4=CC=CC=C4C3=O)[CH:27]=2)[C:10]1=[O:45].O.NN>C(O)C>[NH2:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([N:11]2[C:12]3=[N:13][C:14]([NH:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:15][CH:16]=[C:17]3[CH2:18][N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[C:10]2=[O:45])[CH:31]=[CH:30][CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 47.5 %

Procedure:
A solution of 30 mg (0.05 mmol) of 3-(2,6-dichlorophenyl)-7-anilino-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 5 ml of ethanol was treated with 0.02 ml of hydrazine hydrate. After 5 hours the mixture was evaporated and 10 ml of dichloromethane were added to the residue. The resulting suspension was filtered and the filtrate was evaporated. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 12 mg (50%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2,6-dichlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 208° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:22][CH3:23])[CH3:21]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:22]([CH2:20][CH3:21])[CH3:23])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CCNC
Solvent: CS(C)=O
Product: CCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and N-ethyl-methylamine (2.89 g, 48.8 mmol) in DMSO (35 mL) at RT according to the general procedure C. Obtained as a pale brown solid (3.21 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[N:9]=[C:10]=[O:11])N=C=O.[NH2:14][C:15]([O:17]CC)=O>>[CH2:2]1[CH:3]([CH2:1][CH:2]2[CH2:13][CH2:12][CH:8]([N:9]=[C:10]=[O:11])[CH2:7][CH2:3]2)[CH2:7][CH2:8][CH:12]([N:14]=[C:15]=[O:17])[CH2:13]1
Reactant: CCOC(N)=O
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Product: O=C=NC1CCC(CC2CCC(N=C=O)CC2)CC1

Procedure:
1.57 moles toluene diisocyanate of 80% 2,4- and 20% 2,6- isomers; urethane content 14.7%; NCO 0.05%; Inh. V. 1.69
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2cc3ccccc3cc2c1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2cc3ccccc3cc2c1Nc1ccc(F)c(Cl)c1
Yield: 77.9 %

Procedure:
Following the procedure of Example 3, the reaction mixture of 141.8 mg (0.60 mmol) of 4-chlorobenzo[g]quinoline-3-carbonitrile, 87.3 mg (0.60 mmol) of 3-chloro-4-fluoroaniline and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 8.0 mL of 2-ethoxyethanol is heated at 110–120° C. for 1 hour to yield 162.5 mg (77.9%) of the product as a bright yellow solid, mp 257–259° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:27])[F:28])[CH:21]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(Cl)nc(OCc2ccccc2)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(OCc2ccccc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
2-Benzyloxy-6-chloro-4-cyanopyridine (0.8 g, 0.0033 mol) and meta-trifluoromethyl phenol (0.58 g, 0.0033×1.1 mol) were dissolved in 20 ml of N-methyl-pyrrolidinone, and anhydrous potassium carbonate (0.5 g, 0.0033×1.1 mol) was added thereto and the resultant solution was stirred for about 2.5 hours at about 100° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25](=[O:27])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=2)[N:3]=1.[BH4-].[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([CH:25]([OH:27])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=2)[N:3]=1
Reactant: COc1ncc(Nc2ncc(C(C)=O)cc2-c2nc(C)nc(N)n2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)O)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
1-(5-(4-Amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (250 mg, 0.677 mmol) was dissolved in THF (1.35 mL), sodium borohydride (128 mg, 3.38 mmol) was added, and the resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was then quenched with water and added to a separatory funnel. The reaction mixture was then partitioned between EtOAc (100 mL) and ammonium chloride (saturated, aqueous). The organic layer was separated, washed 2 times with 75 mL of ammonium chloride (saturated, aqueous), dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 5% (2 M ammonia in MeOH)/DCM) gave the title compound (40% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.90 (s, 1H) 8.87 (s, 1H) 8.34 (d, J=2.15 Hz, 1H) 8.20-8.30 (m, 1H) 8.05 (d, J=1.76 Hz, 1H) 5.41 (br. s., 2H) 4.95 (q, J=6.52 Hz, 1H) 4.03 (s, 3H) 2.57 (s, 3H) 1.83 (br. s., 1H) 1.58 (br. s., 3H). m/z (ESI, +ve ion) 372.0 (M+H)+.
Reaction SMILES: [CH:1]([O:6][CH3:7])(OC)OC.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[CH2:12][C:11](=[O:22])[NH:10]1>C(OC(=O)C)(=O)C.CN(C)C=O>[CH3:7][O:6]/[CH:1]=[C:12]1/[C:11](=[O:22])[NH:10][C:9](=[O:8])[C:18]2[C:13]/1=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2
Reactant: COC(OC)OC
Reactant: O=C1Cc2cc(C(=O)O)ccc2C(=O)N1
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CO/C=C1/C(=O)NC(=O)c2ccc(C(=O)O)cc21
Temperature: 125 °C

Procedure:
Trimethyl orthoformate (0.114 mL, 1.04 mmol) is added to a solution of 1,3-Dioxo-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid (102.5 mg, 0.5 mmol) in acetic anhydride (0.8 mL) and N,N-dimethylformamide (0.2 mL). After it is heated at 125° C. for 30 min, it is cooled and filtered to collected 75 mg (60%) of the title compound as a yellow solid. MS (ESI) m/z 246.1 (M−1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].CS(O[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O>CN(C=O)C>[N:1]1([CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cccn2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of the pyrazole (200 mg, 3.0 mmol) in DMF (20.0 ml) under nitrogen atmosphere was added sodium hydride (120 mg, 3.3 mmol) and the solution stirred for 5 min. After bubbling ceased, the title compound from Step A (400 mg, 3.0 mmol) in 5.0 mL of DMF was added to the solution. The mixture was placed in a microwave reaction vessel and nitrogen was blown into it before closing.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([C:11]2[S:15][C:14]([C:16](Cl)=[O:17])=[CH:13][CH:12]=2)=[N:3]1.ClCCl.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(=O)(O)[O-].[Na+]>O>[CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([C:11]2[S:15][C:14]([C:16]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:17])=[CH:13][CH:12]=2)=[N:3]1
Reactant: Nc1nccs1
Reactant: Cn1nc(-c2ccc(C(=O)Cl)s2)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1nc(-c2ccc(C(=O)Nc3nccs3)s2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.9 %

Procedure:
5-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carbonyl chloride (100 mg) and dichloromethane (2 ml) were added to a mixture of 2-aminothiazole (68 mg), saturated sodium bicarbonate aqueous solution (1 ml) and dichloromethane (1 ml), followed by stirring at room temperature for 5 hours. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1-2:1) and then washed with diethyl ether to give 5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-N-(2-thiazolyl)thiophene-2-carboxamide (68 mg) as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:14])[C:5](=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[OH-:15].[Na+:16]>O>[C:2]([NH:6][C:5](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O-:3])=[O:14])(=[O:15])[CH3:1].[Na+:16]
Reactant: CC1=NC(=Cc2ccccc2)C(=O)O1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NC(=Cc1ccccc1)C(=O)[O-]
Reaction time: 2 h

Procedure:
In a 100-ml tightly-sealed glass vessel were charged 9.36 g of 2-methyl-4-benzylidene-5-oxazolone and 30 ml of water. Thereafter, 5.3 g of 45% sodium hydroxide solution was added thereto and the resulting mixture was stirred at 40°-45° C. for 2 hours. The 2-methyl-4-benzylidene-5-oxazolone was hydrolyzed to form an aqueous homogeneous solution of sodium α-acetylaminocinnamate. Then, concentrated hydrochloric acid was added to the solution to adjust its pH at 7.2, and subsequently 0.2 g of 5%-palladium-carbon was added thereto. The gas phase in the vessel was purged with nitrogen and then with hydrogen and thereafter the content in the vessel was subjected to catalytic reduction at 40°-45° C. under atmospheric pressure. The reaction time was approximately 90 minutes until hydrogen absorption was completed. During this time period, it was observed that one mole of hydrogen was absorbed to one mole of 2-methyl-4-benzylidene-5-oxazolone.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[N:22]1([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH:26]=[N:25][CH:24]=[N:23]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([N:22]3[CH:26]=[N:25][CH:24]=[N:23]3)=[CH:35][CH:34]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Product: O=C(c1ccc(-n2cncn2)cc1)N(C1CC1)C1CCN(c2ncc(C(F)(F)F)cc2F)CC1

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=4.61 min; Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][CH2:6][C@@:7]1([OH:31])[C:12](=[O:13])[O:11][CH2:10][C:9]2[C:14]([N:16]3[C:28](=[CH:29][C:8]1=2)[C:27]1[N:26]=[C:25]2[C:20]([C:21](N)=[CH:22][CH:23]=[CH:24]2)=[CH:19][C:18]=1[CH2:17]3)=[O:15].[BrH:32]>O>[CH3:5][CH2:6][C@@:7]1([OH:31])[C:12](=[O:13])[O:11][CH2:10][C:9]2[C:14]([N:16]3[C:28](=[CH:29][C:8]1=2)[C:27]1[N:26]=[C:25]2[C:20](=[CH:19][C:18]=1[CH2:17]3)[C:21]([Br:32])=[CH:22][CH:23]=[CH:24]2)=[O:15]
Reactant: Br
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(N)cccc3nc2-1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(Br)cccc3nc2-1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
215 g of NaNO2 in 40 mL of H2O were dropped at 5° C. into a solution of 9 g of 9-amino-camptothecin in 850 mL of 16% HBr. After 1 hr at room temperature the solution was dropped in a flask containing 19 g of CuBr in 200 mL of 16% HBr at 70° C. The reaction mixture was kept at 70° C. for 2 hrs, then it was poured into cold water. The precipitate was filtered and the mother liquors were extracted with CH2Cl2; the organic extract, dried and evaporated, was combined with the precipitate and purified by flash chromatography (eluent: CH2Cl2/CH3OH=95/5) to give 8.19 g of the title product (HPLC assay: 97.3%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:54][CH2:55][CH2:56][CH2:57]O>O1CCCC1>[Br:54][CH2:55][CH2:56][CH2:57][O:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(O)cc2)C1
Reactant: OCCCBr
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(OCCCBr)cc2)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.9 %

Procedure:
Diisopropyl azodicarboxylate (40% in toluene, 13.6 g, 26.9 mmol) was added to a solution of tert-butyl (2S)-2-(4-hydroxyphenyl)morpholine-4-carboxylate (5.0 g, 17.9 mmol), triphenylphosphine (7.1 g, 27.1 mmol) and 3-bromopropanol (3.75 g, 27.0 mmol) in tetrahydrofuran (100 ml) and the solution was stirred for 10 hours at room temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish tert-butyl (2S)-2-(4-(3-bromopropyloxy)phenyl)morpholine-4-carboxylate (7.16 g, 100%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29].[C:30]1([N:40]=[C:41]=[O:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH2:25]([C:6]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:14]=2)[C:3]([CH2:2][NH:1][C:41]([NH:40][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[O:42])=[C:4]([Cl:29])[N:5]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: ClC(Cl)Cl
Product: CCCCc1nc(Cl)c(CNC(=O)Nc2cccc3ccccc23)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 55.2 %

Procedure:
5-Aminomethyl-2-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (1.00 g, 2.4 mmol, 1 eq) and 1-naphthyl isocyanate (0.35 mL, 2.4 mmol, 1 eq), were mixed and stirred in chloroform at room temperature for 3 days. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel in 1:1 hexane/ethyl acetate to yield 770 mg of a white glass. NMR (200 MHz, CDCl3) δ 7.83 (d, 3H, J=6Hz); 7.67 (d, 1H, J=6Hz); 7.56-7.18 (m, 9H); 6.97 (d, 2H, J=7Hz); 6.74 (s, 1H); 5.27 (s, 2H); 4.74 (s, 1H); 4.39 (d, 2H, J=7Hz); 3.58 (s, 3H); 2.60 (t, 2H, J=7Hz); 1.43-1.21 (m, 4H); 0.85 (t, 3H, J=7Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:22])[C:19]2[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=2)[C:13](=O)[CH2:12][CH2:11]1>C1COCC1.C(OC(=O)C)C>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=3)[C:10]([CH3:22])([CH3:9])[CH2:11][CH:12]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of Mg metal (650 mg, 27 mmol) in THF (20 mL) was added 4-bromotoluene (5.3 g, 31 mmol) in THF (40 mL). The mixture was stirred for 2 hours at ambient temperature and heated to 70° C. for 30 minutes. After cooling to ambient temperature, 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound A) (2.1 g, 8 mmol), in THF (5 mL) was added and heated to 70° C. for 24 hours. The mixture was cooled to ambient temperature and the reaction was quenched by addition of H2O. The mixture was diluted with ether:ethylacetate (1:1, 100 mL) and washed with saturated NH4Cl (15 mL), water (10 mL) and brine (10 mL). The organic layer was dried with MgSO4. Solvent was removed under reduced pressure to afford the crude product as an off. The product was dissolved in THF (20 mL). To this solution p-toleune sulfonic acid (pTSA) (35 mg) was added and the mixture was refluxed for 16 hours. The mixture was cooled to ambient temperature, diluted with ethylacetate (160 mL), washed with 10% NaHCO3 (20 mL), brine (20 mL), dried with MgSO4 and the solvent wasremoved by evaporation. Purification by chromatography on silica gel gave the title compound as a white solid.
Reaction SMILES: C[C@H:2]1[C@@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH:5]=[CH:4][C:3]1=[O:16].Cl[C:18]1C=CC2N3C(=C(C)C(=O)CC3)CCC=2C=1>>[CH3:18][C:13]1[CH:14]=[CH:15][C:7]2[N:6]3[CH:11]([CH2:2][C:3](=[O:16])[CH:4]=[CH:5]3)[CH2:10][CH2:9][C:8]=2[CH:12]=1
Reactant: CC1=C2CCc3cc(Cl)ccc3N2CCC1=O
Reactant: C[C@@H]1C(=O)C=CN2c3ccccc3CC[C@H]12
Product: Cc1ccc2c(c1)CCC1CC(=O)C=CN21

Procedure:
(cis) and (trans) 4-methyl4,4a,5,6-tetrahydro-( 11H)-benzo[c]quinolizin-3-one; 8-chloro4-methyl-1 ,2,5,6-tetrahydro-(11H)-benzo[c] quinolizin-3-one;
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:6][C:5]([C:12]([NH2:14])=O)=[N:4]1)[CH3:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([N:3]1[C:7]([CH:8]=[C:9]([CH3:10])[CH3:11])=[CH:6][C:5]([C:12]#[N:14])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(N)=O)cc1C=C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1nc(C#N)cc1C=C(C)C
Temperature: 90 °C

Procedure:
A mixture of 1-ethyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carboxamide (5.0 g, 25.9 mmol) and phosphorous oxychloride (18.5 mL) was heated at 90° C. for 20 minutes. The reaction vessel was cooled in an ice bath and reaction mixture was poured over ice (100 mL). The quenched reaction mixture was made basic with 2 M aqueous sodium carbonate and was extracted with chloroform. The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-ethyl-5-(2-methylprop-1-enyl)-1H-pyrazole-3-carbonitrile, all of which was used in the next step.