Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH:16]3[CH2:18][CH2:17]3)[O:8][C:6]=2[CH:7]=1.[OH:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:29]([O:28][C:27](=[O:33])[NH:26][C@@H:21]([CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:20][O:19][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH:16]3[CH2:18][CH2:17]3)[O:8][C:6]=2[CH:7]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Clc1ccc2c(c1)OC(C1CC1)c1cnccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1ccc2c(c1)OC(C1CC1)c1cnccc1-2)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 53.4 %

Procedure:
To a stirred solution of 8-chloro-5-cyclopropyl-5H-chromeno[3,4-c]pyridine (275 mg, 1.067 mmol) in toluene (3 mL) was added (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (696 mg, 3.20 mmol), cesium carbonate (427 mg, 1.310 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (272 mg, 0.640 mmol) and palladium (II) acetate (71.9 mg, 0.320 mmol). Nitrogen was bubbled through the reaction mixture for 10 min then the mixture was heated at 80° C. for 12 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (1×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified via silica gel chromatography (ethyl acetate/pet ether) to give tert-butyl-(2S)-1-(5-cyclopropyl-5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-ylcarbamate (250 mg, 0.57 mmol, 50% yield). LCMS (ESI) m/e 439.2 [(M+H)+, calcd for C26H35N2O4 439.3]; LC/MS retention time (Method C): tR=2.16 min.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:38]=[CH:39][CH:40]=1)[O:11][C:12]1[N:13]=[C:14]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[C:15]([C:21]([NH2:23])=[O:22])=[N:16][C:17]=1[CH:18]([CH3:20])[CH3:19])=[O:6].CN(C)C=O.C(N(C(C)C)CC)(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>O>[CH:18]([C:17]1[N:16]=[C:15]([C:21]([NH2:23])=[O:22])[C:14]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[N:13][C:12]=1[O:11][C:10]1[CH:38]=[CH:39][CH:40]=[C:8]([NH:7][C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)[CH:9]=1)([CH3:20])[CH3:19]
Reactant: C1COCCN1
Reactant: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(NC(=O)/C=C/CCl)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(NC(=O)/C=C/CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(3-{[(2E)-4-chlorobuta-2-enoyl]amino}phenoxy)-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (80 mg) and N,N-dimethylformamide (800 μL) were added diisopropylethylamine (25 μL) and morpholine (11 μL), followed by stirring at room temperature overnight. Water was added thereto, and the precipitated solid was collected by filtration and purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1). Diisopropyl ether was added thereto and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-{[(2E)-4-(morpholin-4-yl)but-2-enoyl]amino}phenoxy)pyrazine-2-carboxamide (27 mg) as a solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:38]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[C:14]([C:17]([NH2:18])=[O:38])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccncc2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 4-(pyridin-4-yl)aniline (60 mg, 0.352 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(pyridin-4-yl)phenylamino)pyrazine-2-carbonitrile (41 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(pyridin-4-yl)phenylamino)pyrazine-2-carbonitrile (41 mg, 0.097 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (32 mg). MS 440.3 (M+H); UV 201.7, 242.5, 278.7 nm; t 0.384 min.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[NH:6][C:7]3[N:14]=[CH:13][CH:12]=[CH:11][C:8]=3[C:9](=[O:10])[N:4]2[N:3]=1.[OH-].[K+].[CH3:18]O>>[CH3:1][C:2]1[CH:15]=[C:5]2[N:6]([CH3:18])[C:7]3[N:14]=[CH:13][CH:12]=[CH:11][C:8]=3[C:9](=[O:10])[N:4]2[N:3]=1
Reactant: CO
Reactant: Cc1cc2[nH]c3ncccc3c(=O)n2n1
Agent: [K+]
Agent: [OH-]
Product: Cc1cc2n(C)c3ncccc3c(=O)n2n1
Reaction time: 1 h

Procedure:
3.8 g. of 2-methylpyrazolo[ 1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one are added to a solution of 1 g. of potassium hydroxide in 50 ml. of methanol and the mixture is stirred at room temperature for 2 hours. The potassium salt of 2-methylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is filtered off and suspended in 25 ml. of diethyleneglycol dimethyl ether. 5 g. of methyl iodide are added and the mixture is stirred for 1 hour and then filtered off, and the precipitated 2,4-dimethylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is recrystallized with methanol containing 10% water, yield: 2.1 g. (50%); m.p. 241.9°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][N:12]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:13]2>CO>[NH2:18][C:16]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])[CH2:13]2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=1
Reactant: O=C(N1CCc2c(cc([N+](=O)[O-])cc2-c2ccccc2Cl)C1)C(F)(F)F
Solvent: CO
Product: Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Temperature: 65 °C
Yield: 71.5 %

Procedure:
1-[5-(2-Chloro-phenyl)-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (760 mg, 1.97 mmoles) was dissolved in methanol (10 mls) and stannous chloride dihydrate (2.23 g, 9.87 mmoles) was added. The yellow coloured reaction mixture was heated to 65° C. for 2 hours, evaporated and partitioned between ethylacetate (50 mls) and water (50 mls). The solution was then basified by the addition of potassium hydroxide solution (10%) to a pH 11-12. The whole mixture was then filtered through a Celite pad and washed with ethylacetate (20 mls), water (20 mls) and brine (40 mls) and finally dried over anhydrous magnesium sulphate. After filtration and evaporation the yellow oil was triturated with ether (2×25 mls) and hexane (25 mls) to give an oily solid (500 mg, 60% yield). LC-MS (retention 3.60, M+H 356).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>O1CCCC1>[CH:38]1([C:41]([N:19]2[CH2:20][CH2:21][C:15]3[N:14]=[C:13]([C:11]4[S:12][C:8]5[C:7]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=5[N:10]=4)[NH:22][C:16]=3[CH2:17][CH2:18]2)=[O:42])[CH2:40][CH2:39]1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)C3CC3)CC4)nc12
Yield: 93 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.012 g cyclopropanecarbonyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.04 g (90%) cyclopropyl-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-methanone as yellow solid; MS (ISP): m/e=454 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:14])[C:12]#[CH:13].N1C=CC=CC=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([O:14][C:24]([CH:21]1[CH2:23][CH2:22]1)=[O:25])[C:12]#[CH:13]
Reactant: O=C(Cl)C1CC1
Reactant: C#CC(O)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: C#CC(OC(=O)C1CC1)c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
3.6 g of 1-(2-naphthyl)-2-propyn-1-ol and 1.6 g of pyridine are dissolved in 30 ml of methylene chloride, the solution is cooled to 0°-5° C. and a solution of 2.3 g of cyclopropane carboxylic acid chloride in 10 ml of methylene chloride is added with stirring. The mixture is left at room temperature for 2 hours, then poured into water and diluted with 50 ml of methylene chloride. The methylene chloride solution is separated and washed, in sequence, with 2 N hydrochloric acid solution, 10% potassium bicarbonate solution and a semi-saturated sodium chloride solution. The solution is then dried over sodium sulfate and evaporated. The crude product is purified by crystallization or by adsorption chromatography on silica gel to yield pure cyclopropane carboxylic acid 1-(2-naphthyl)-2-propynyl ester, m.p. 94°-96° C. (from cyclohexane).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)[C:16]1=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C(OC(=O)C)(=O)C.O>[CH2:5]([O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][N:17]([C:20]2[C:24]([N+:1]([O-:4])=[O:2])=[CH:23][N:22]([CH3:25])[N:21]=2)[C:16]1=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cn1ccc(N2CCN(CCOCc3ccccc3)C2=O)n1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2CCN(CCOCc3ccccc3)C2=O)n1
Reaction time: 0.08 h

Procedure:
To acetic anhydride (22 mL) was added fuming nitric acid (2.76 mL) under ice-cooling, and the mixture was stirred for 5 min. The obtained solution was added dropwise to a solution of 1-(2-(benzyloxy)ethyl)-3-(1-methyl-1H-pyrazol-3-yl)imidazolidin-2-one (10 g) in acetic anhydride (44 mL) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (8.20 g).
Reaction SMILES: [CH2:1]([C:4]#[C:5][SiH:6]([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[CH:2]=[CH2:3].C([Mg]Br)C=C>>[CH:1]1([C:4]#[C:5][SiH:6]([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:8])[CH3:9])[CH2:3][CH2:2]1
Reactant: C=CCC#C[SiH](C(C)C)C(C)C
Agent: C=CC[Mg]Br
Product: CC(C)[SiH](C#CC1CC1)C(C)C

Procedure:
This material was synthesized using methods identical to those used to prepare allyldiisopropylsilyl acetylene in Example 1, simply substituting cyclopropyl magnesium bromide for allyl magnesium bromide. 1H-NMR (200 MHz, CDCl3) δ=2.3 (s, 1H), 1.1 (br-m, 14H), 0.61 (m, 2H), 0.45 (m, 2H), −0.44 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](S(CC3C=CC=CC=3)(=O)=O)[CH:16]([CH3:30])[CH2:15]2)[CH:3]=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:31]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:4]2[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=2[O:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:15][CH:16]1[CH3:30])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)Cc1ccccc1
Product: CC1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)c1ccccc1

Procedure:
Prepared by the method of example 30, using the product from example 56 part (a) and benzoyl chloride to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:29][CH2:28][CH2:27][CH2:26]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:30]=[N+:31]=[N-:32].[Na+].N1CCNCC1.[OH-].[Na+]>CN1CCCC1=O.O>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:32]=[N:31][NH:30][N:24]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:26][CH2:27][CH2:28][CH2:29]2)[N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Agent: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and piperazine (10.2 g) in 1-methylpyrrolidin-2-one (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.5 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (2.5 g, 94.4% purity by HPLC).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[NH2:12][NH2:13]>CCO>[Cl:11][C:5]1[N:4]=[N:3][C:2]([NH:12][NH2:13])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1
Reactant: NN
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Solvent: CCO
Product: NNc1nnc(Cl)cc1C(=O)O
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a solution of 3,6-dichloropyridazin-4-carboxylic acid (5 g, 26 mmol) in EtOH (200 mL) was added TEA (4 mL, 30 mmol) and hydrazine (5 mL, 80%). The reaction mixture was stirred at 85° C. for 3 hours. After cooled to room temperature, the mixture was concentrated in vacuum to give crude product 6-chloro-3-hydrazinylpyridazine-4-carboxylic acid (4.8 g), which was used for the next step directly without purification. LRMS (M+H+) m/z: calcd 189; found 189.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9]C)=[C:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1
Reactant: COc1c(F)cc(Br)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Br)cc(F)c1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104.4 %

Procedure:
To a solution of 4-bromo-6-fluoro-2-iso-propylanisole (0.92 g, 3.70 mmol) in CH2Cl2 (10.0 mL) at −78-C was added BBr3 (5.5 mL, 5.5 mmol, 1.0 M in CH2Cl2). After 5 min, the reaction mixture was stirred at room temperature for 16 h, poured into ice (50 g) and extracted with ethyl acetate (20.0 mL). The organic layer was separated, dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford 4-bromo-6-fluoro-2-iso-propylphenol (0.90 g, 100%) as a dark oil, which was used for the next step without flier purification: 1H NMR (300 MHz, CD3OD): δ 7.26 (d, J=10.5 Hz, 1 H), 6.92 (d, J=10.5 Hz, 1 H), 3.30 (m, 1 H), 1.23 (d, J=6.6 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.40.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[O:4].C([O-])(=O)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=O)=[CH:15][CH:14]=1.O>C(O)(=O)C>[OH:4][C:3]1[N:2]=[N:1][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[N:5]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nnc(O)nc2-c2ccc(OC)cc2)cc1
Yield: 95 %

Procedure:
Semicarbazide chlorohydrate (2.22 g, 20 mmol) and sodium acetate (1.80 g, 22 mmol) are added to a solution of 1,2-bis(4-methoxyphenyl)-ethane-1,2-dione (5.4 g, 20 mmol) prepared according to example 1 in acetic acid (25 ml). The mixture is heated at reflux for 12 hours. After returning to ambient temperature, the reaction mixture is poured into water. The raw reaction product is collected by filtration and washed with water. The residue is recrystallized in acetic acid. After filtration and washing in water, 5.9 g (95%) of a yellow solid is obtained after drying. δH (200 MHz, CDCl3), 3.86 (s; 6H), 6.94 (m; 4H), 7.67 (s; 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH3:23])[CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:4]=2[O:3]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:24][C:11]1[C:5]2[C:6]3[CH2:10][CH2:9][CH2:8][C:7]=3[C:2]([CH3:1])([CH3:25])[O:3][C:4]=2[CH:14]=[C:13]([CH:15]([CH3:23])[CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Solvent: c1ccncc1
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)C1=C2CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4,4-dimethyl-9-hydroxy-7-(1,2-dimethylheptyl)-1,2,3,4-tetrahydrocyclopenta[ c][l]benzopyran (6.85 g., 0.02 mole) and acetic anhydride (3.06 g., 0.03 mole) in 20 ml. of pyridine was warmed over a steam bath with stirring for 2 hours. The reaction mixture was allowed to cool to room temperature and the pyridine was removed by evaporation under reduced pressure. Water was added to the residue and this aqueous mixture was extracted with three portions of ether. The ether extracts were washed several times with water, 6N HCl, again with water, and dried over Na2SO4. Solvent evaporation in vacuo left 7.59 g. (99%) of crude acetate. The ir and nmr were in agreement with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][N:14](C=O)C>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-]#N.[C-]#N.[Zn+2]>[C:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])#[N:14]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)c(C)c1

Procedure:
To a microwave tube, was added methyl 4-bromo-3-methylbenzoate (100 mg, 0.437 mmol), Pd(Ph3P)4 (25.2 mg, 0.022 mmol), Zn(CN)2 (51.3 mg, 0.437 mmol) and DMF (2 mL). The mixture was flushed with N2 and capped tightly. The reaction mixture was exposed to microwave irradiation at 150° C. for 5 min. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give methyl 4-cyano-3-methylbenzoate. LCMS calc.=176.1; found=176.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 8.02 (s, 1H); 7.95 (d, J=8.1 Hz, 1H); 7.71 (d, J=8.0 Hz, 1H); 7.29 (s, 1H); 3.98 (s, 3H); 2.64 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([CH:21]3[CH2:24][N:23]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH2:22]3)=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:11]1)C(=O)OC(C)(C)C.Cl.C(O)(C)C>>[CH3:1][NH:2][CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([CH:21]3[CH2:24][N:23]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH2:22]3)=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Agent: Cl
Solvent: CC(C)O
Product: CNC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a round bottomed flask was added tert-butyl methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (3.0 g, 6.51 mmol) and hydrogen chloride, 5-6N in isopropanol (0.237 g, 6.51 mmol) to stir overnight. Solvent was evaporated and the reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, saturated Na2CO3, saturated NaCl, and dried over MgSO4, filtered and concentrated in vacuo to give N-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine (1.0339 g, 2.87 mmol, 44.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.83 (m, 1H) 2.02 (dt, J=12.18, 5.94 Hz, 1H) 2.32 (s, 2H) 3.16-3.28 (m, 1H) 3.32 (br. s., 1H) 3.42-3.52 (m, 1H) 3.54-3.67 (m, 1H) 4.29-4.45 (m, 4H) 6.78 (d, J=8.80 Hz, 1H) 7.17-7.25 (m, 1H) 7.48-7.59 (m, 2H) 7.71 (d, J=7.83 Hz, 1H) 7.91 (d, J=2.54 Hz, 1H) 7.97 (d, J=2.35 Hz, 1H) 8.03 (d, J=8.80 Hz, 1H)
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:17]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:25](=[O:34])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:14]=[N:15][CH:16]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([N:26]2[C:25](=[O:34])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]2[C:13]2[CH:14]=[N:15][CH:16]=[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=2)=[CH:28][CH:29]=1
Reactant: O=c1c2ccccc2nc(-c2cncc(Br)c2)n1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
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: COCCOC
Product: O=c1c2ccccc2nc(-c2cncc(-c3ccccc3)c2)n1-c1ccc(Cl)cc1
Yield: 37.1 %

Procedure:
Phenylboronic acid (0.067 g, 0.55 mmol) and Pd(PPh3)4 (0.005 g) were added to a mixture of 2-(5-bromopyridin-3-yl)-3-(4-chlorophenyl)quinazolin-4(3H)-one (0.190 g, 0.46 mmol) in 2 M Na2CO3 (0.5 mL) and DME (15 mL). After refluxing for 5 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in CHCl3 and washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 70% of EtOAc in heptane, afforded the title compound as a white solid (0.070 g, 37%). 1H-NMR (300 MHz, DMSO-d6): δ8.81 (s, 1H), 8.58 (s, 1H), 8.24 (d, J=8.1 Hz, 1H), 8.02 (s, 1H), 7.90-7.98 (m, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.61-7.70 (m, 1H), 7.43-7.58 (m, 9H). MS (APCI) m/z: 410 (M+H)+.