Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[N+:10]([C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].C(N(CC)CC)C.O>O1CCOCC1>[N+:10]([C:13]1[CH:14]=[C:15]([S:19]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: NCCc1ccncc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.8 %

Procedure:
To a stirred solution of 4-(2-aminoethyl)-pyridine (1.21 g, 9.93 mmol) in dioxane (25 ml) was added at room temperature 3-nitrobenzenesulfonyl chloride (2.0 g, 9.02 mmol) and triethylamine (1.38 ml, 9.93 mmol). The light yellow suspension was stirred at room temperature for 6 h, poured into water (100 ml) and extracted with dichloromethane (6×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by crystallization from methanol/hexane to yield 3-nitro-N-(2-pyridine-4-yl-ethyl)-benzenesulfonamide (1.63 g, 59%) as an orange solid. MS (ISP) 306.1 [(M−H)−]; mp 153° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17]([NH:19]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[S:18])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17]([NH2:19])=[S:18])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(F)(CNC(N)=S)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-[({[(fluoren-9-ylmethoxy)carbonylamino]thioxomethyl}amino)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester (1896 mg, 3.69 mmol) in DMF (15 ml), piperidine (1.8 ml, 18.5 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, water (100 ml) was added and extraction was performed with ethyl acetate (100 ml×3 times). The extracted organic layer was washed with water (300 ml×2 times) and then with saturated brine; dried over anhydrous sodium sulfate, and then filtered and concentrated. It was subsequently purified by silica gel column chromatography (hexane/ethyl acetate=1/1, ethyl acetate) to obtain 4-{[(aminothioxomethyl)amino]methyl}-4-fluoropiperidinecarboxylic acid tert-butyl ester. The compound was identified by LC-MS. Yield: 900 mg (84%), M+1=292.1
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([C:8]1[O:9][C:10]2[C:11](=[CH:15][C:16]3[CH2:17][CH2:18][CH2:19][N:20]4[C:25]=3[C:24]=2[CH2:23][CH2:22][CH2:21]4)[C:12](=O)[CH:13]=1)([CH3:7])[CH3:6].[F:26][B-:27]([F:30])([F:29])[F:28].[H+]>CCOCC.O1CCCC1.O>[F:26][B-:27]([F:30])([F:29])[F:28].[CH3:4][C:5]([CH:8]1[CH:13]=[C:12]([CH3:1])[C:11]2=[CH:15][C:16]3[CH2:17][CH2:18][CH2:19][N:20]4[C:25]=3[C:24]([CH3+:23][CH2:22][CH2:21]4)=[C:10]2[O:9]1)([CH3:7])[CH3:6]
Reactant: C[Mg]Br
Reactant: CC(C)(C)c1cc(=O)c2cc3c4c(c2o1)CCCN4CCC3
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC1=CC(C(C)(C)C)Oc2c1cc1c3c2[CH3+]CCN3CCC1
Temperature: 0 °C
Reaction time: 17 h
Yield: 44 %

Procedure:
Methyl magnesium bromide (5.0 mL of a 3.0M solution in ether, 15 mmol) was added dropwise at 0° C. to a solution of 11-[1,1-dimethylethyl]-9-oxo-2,3,6,7-tetrahydro-1H,5H-[1]benzopyrano[6,7,8-ij]quinolizine (2.68 g, 9.03 mmol, prepared in Example 34 above) in dry tetrahydrofuran (10 mL) and the solution was allowed to stand at room temperature for about 17 hours. The reaction mixture was then cooled again to 0° C. and more methyl magnesium bromide (1 mL of a 3M solution in ether, 3 mmol) was added dropwise. The reaction mixture was allowed to attain room temperature and stirred for a further 8 hours, after which time the reaction mixture was poured into tetrafluoroboric acid (44 mL of a 4.4% solution in water) and the resultant mixture was extracted with dichloromethane. The organic phase was separated and dried over sodium sulfate. Removal of solvent, followed by trituration of the residue with ethyl acetate and filtration, gave 11-[1,1-dimethylethyl]-9-methyl-2,3,6,7-tetrahydro-1H,5H-[1]benzopyrano[6,7,8-ij]quinolizinium tetrafluoroborate (1.49 g, 44% yield) as a red solid which melted at 168°-170° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][C:7](=[N:12][OH:13])[C:8]([CH3:11])([CH3:10])[CH3:9].O>CS(C)=O>[CH3:9][C:8]([CH3:11])([CH3:10])[C:7](=[N:12][OH:13])[CH2:6][N+:1]([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: CC(C)(C)C(CBr)=NO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)C(C[N+](=O)[O-])=NO
Reaction time: 20 h
Yield: 29.2 %

Procedure:
To a stirred solution of 18.2 g (0.26 m) of sodium nitrite in 130 ml of dimethyl sulfoxide is added, in portions, 29.0 g (0.15 m) of 1-bromo-3,3-dimethyl-2-butanone oxime. A mild exotherm results and external cooling is used to keep the temperature below 27° C. Additional solvent is added to maintain stirrability. After 20 hours stirring, the mixture is poured onto ice and water to give a solid which is collected on a filter. The 10 g of solid, m. 115°-120° C, thus obtained is recrystallized from a hot benzene-petroleum ether mixture to give 7 g of white crystals, m. 124°-125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH2:19])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([N:27]=[C:28]=[O:29])[CH:24]=[CH:23][C:22]=1[F:30].[N-]=C=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH:19][C:28]([NH:27][C:25]4[CH:24]=[CH:23][C:22]([F:30])=[C:21]([Cl:20])[CH:26]=4)=[O:29])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Agent: [N-]=C=O
Product: Nc1ccc(C#Cc2ccc3nc(NC(=O)Nc4ccc(F)c(Cl)c4)cn3n2)cc1

Procedure:
The compound of Example 14 was made by preparing 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine as in Example 20, followed by a procedure similar to Example 3 using 2-chloro-1-fluoro-4-isocyanatobenzene as the isocyanate (see also Schemes 1, 2, and 9).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.Br[C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][C:20]=1Br.[C:30]1([P:36](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.C1(C)C=CC=CC=1.O1CCCC1>[C:30]1([P:36]([C:6]2[CH:5]=[CH:43][CH:38]=[CH:39][CH:40]=2)([C:9]2[CH:18]=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10]=2[C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][C:20]=2[P:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:37])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCCBr
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: Brc1ccc2c(c1-c1c(Br)ccc3c1CCCC3)CCCC2
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc2c(c1-c1c(P(=O)(c3ccccc3)c3ccccc3)ccc3c1CCCC3)CCCC2
Temperature: 94 °C
Reaction time: 7 h
Yield: 64.1 %

Procedure:
A one liter capacity four neck flask was charged with 4.26 g (0.177 mol) of magnesium, the atmosphere in the flask was replaced with nitrogen gas and then a small amount of iodine was added thereto. To this were added 20 ml of dry tetrahydrofuran and, using an injector, 0.6 ml of 1,2-dibromoethane in that order. Through a dropping funnel and spending 7 hours, to this was added dropwise a mixture solution of 330 ml toluene and 90 ml tetrahydrofuran containing 32.5 g (0.0774 mol) of 2,2'-dibromo-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene synthesized in (1). During this step, temperature of the reaction solution was kept at 80° to 90° C. After completion of the dropwise addition, the reaction mixture was stirred at 94° C. for 19 hours. After cooling to 5° C., to the reaction mixture was added dropwise 34.27 g (0.148 mol) of diphenylphosphinic acid chloride spending 30 minutes. Next, the reaction mixture was stirred at 72° C. for 3.5 hours. The resulting reaction mixture was cooled to room temperature and mixed with 100 ml of water, heated to 80° C. and stirred for 20 minutes, and then cooled again to room temperature and allowed to stand overnight. The thus precipitated white solid was collected by filtration, washed twice with 100 ml of water, washed again with 100 ml of hexane-toluene (9:1) mixture solution and then dried at 70° C. for 7 hours under a reduced pressure (0.1 mmHg) to obtain 32.8 g of the title compound with a yield of 64.1%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[ClH:19].Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([C@@H:37]3[CH:42]4[CH2:43][CH2:44][N:39]([CH2:40][CH2:41]4)[CH2:38]3)=[O:36])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.O>CN(C=O)C>[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31]([NH:34][C:35]([C@@H:37]4[CH:42]5[CH2:41][CH2:40][N:39]([CH2:44][CH2:43]5)[CH2:38]4)=[O:36])=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(NC(=O)Nc2ccc(-c3ccc(NC(=O)[C@H]4CN5CCC4CC5)cc3)cc2)c1
Reaction time: 18 h

Procedure:
45.4 mg (0.30 mmol) of 3-methoxyphenyl isocyanate and 84.8 μl (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. A preparative HPLC is carried out for further purification. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 22 mg (27.6% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[N:4][N:3]=2)=[C:35]([O:42][CH3:43])[CH:34]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nncc3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Cl)ccc1-c1nncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
A vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)phthalazine-6-sulfonamide (Intermediate AAAA) (56.22 mg, 0.118 mmol), (4-chloro-2-methoxyphenyl)boronic acid (Combi-Blocks, San Diego, Calif., 26.4 mg, 0.141 mmol), Pd(AmPhos)2Cl2 (4.17 mg, 5.89 μmol), potassium phosphate (75 mg, 0.354 mmol), 1,4-dioxane (442 μl), and water (147 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min h at 90° C. LC/MS showed fairly clean protected product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with MeOH and filtered through diatomaceous earth with the aid of MeOH. The filtrate was concentrated, and the crude product was purified by chromatography on silica gel (12-g column, 0 to 6% MeOH/DCM) to give 1-(4-chloro-2-methoxyphenyl)-N-(thiazol-2-yl)phthalazine-6-sulfonamide (26.3 mg, 0.061 mmol, 51.5% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.97 (br. s., 1H), 9.92 (s, 1H), 8.73 (d, J=1.8 Hz, 1H), 8.22 (dd, J=1.9, 8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.32-7.22 (m, 2H), 6.91 (d, J=4.6 Hz, 1H), 3.70 (s, 3H); m/z (ESI) 433.2 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:26])=[NH:8])[CH:16]=[CH:15][CH:14]=2)[CH:22]=1)[CH3:25]
Reactant: CCOc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1ccnc(-c2cccc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N′-bis (tert-butoxycarbonyl)-N″-(3-(4-ethoxypyridin-2-yl)phenyl)guanidine (200 mg) in dichioromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. To the residue was added 10% ethanol in ethyl acetate (50 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(4-ethoxypyridin-2-yl)phenylguanidine dihydrochloride (126 mg).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:29][CH:28]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-(4-fluorobenzoyl)benzyl bromide (2.93 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as white powder (2.79 g, 74%). 1H-NMR (CDCl3) δ: 3.41(3H,s), 3.60(3H,s), 5.59(2H,s), 7.08-7.86(9H,m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[O:19][C:18](=[O:20])[C:9]3[CH2:10][N:11]([CH2:14][C:15](=O)[CH3:16])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.[CH2:22]([NH2:24])[CH3:23]>>[Cl:1][C:2]1[C:3]([CH3:21])=[CH:4][C:5]2[O:19][C:18](=[O:20])[C:9]3[CH2:10][N:11]([CH2:14][CH:15]([NH:24][CH2:22][CH3:23])[CH3:16])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: CCN
Reactant: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(Cl)cc23)C1
Product: CCNC(C)CN1CCc2c(c(=O)oc3cc(C)c(Cl)cc23)C1
Yield: 20.9 %

Procedure:
Prepared by the method described for example 51 from 9-chloro-1,2,3,4-tetrahydro-8-methyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (6.2 g, 0.020 moles) and ethylamine (6 ml, 0.092 moles). Recrystallization from ethyl acetate gave the product (1.4 g), mp 162°-163° C.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:17]1(=O)[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CO>[N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH2:21][CH2:20][C:19](=[O:22])[CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1CCC(=O)C1
Reactant: Nc1cccc(-c2cnc3ccccn23)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=C1C=C(Nc2cccc(-c3cnc4ccccn34)c2)CC1
Temperature: 25 °C

Procedure:
A solution of 3-imidazo[1,2-a]pyridin-3-yl-phenylamine (210 mg, 1.0 mmol), 1,3-cyclopentandione (110 mg, 1.1 mmol) and p-toluenesulfonic acid monohydrate (17 mg, 0.1 mmol) in toluene (2 ml) was stirred and heated at reflux under N2 for 8 hours. After cooling to RT the mixture was diluted with methanol (˜3 ml) then filtered. The solid was washed with Et2O then dried under vacuum to give the title compound. MS: [M+H]+ 290.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26]O)[CH2:20][CH2:19]1)(=[O:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>ClCCl>[CH3:8][CH2:7][CH2:6][CH:11]([CH3:2])[CH3:10].[C:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([Cl:1])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CC(=O)N1CCN(CCCO)CC1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC(C)C
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 147.2 %

Procedure:
4-Chloro-7-hydroxy-6-methoxyquinazoline (3 g, 14.2 mmol), (prepared as described for the starting material in Example 4), 3-(4-acetylpiperazin-1-yl)propan-1-ol (3.2 g, 17.1 mmol), (prepared as described for the starting material in this example hereinbefore), and triphenylphosphine (4.5 g, 17.1 mmol) were stirred together in dichloromethane (140 ml). Dbsopropyl azodicarboxylate (3.4 ml, 17.1 mmol) was added dropwise and an ice/water bath used to keep the temperature of the reaction mixture below 10° C. After the addition, the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was concentrated under reduced pressure. Column chromatography of the residue (2:1 iso-hexane:ethyl acetate then 3%-5% methanol/dichloromethane) gave 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (3.96 g, 74%) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[C:13](=[O:15])[CH2:12][CH2:11]2.[Br:16]Br.Cl>ClC(Cl)C>[Br:16][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2=[O:15]
Reactant: BrBr
Reactant: O=C1CCc2cccc(F)c21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C1CCc2c(Br)ccc(F)c21
Temperature: 65 °C
Yield: 64.3 %

Procedure:
To a room temperature solution of aluminum chloride (11.77 g, 88 mmol) in dichloroethane (100 mL) was added 7-fluoro-2,3-dihydro-1H-inden-1-one (5.3 g, 35.3 mmol) followed with bromine (1.91 mL, 37.1 mmol). The mixture was heated at 65° C. for 16 hours, then cooled to ambient temperature and poured into a mixture of ice and HCl (1N aqueous). The mixture was extracted twice with ether (200 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel column eluting with 0-10% EtOAc/hexanes) to provide the title compound (5.2 g, 64%). MS (DCI/NH3) m/z 246 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:18]Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:18])=[CH:6][N:7]=1
Reactant: BrBr
Reactant: COC(=O)c1nccnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Commercially available methyl 3-amino-pyrazine-2-carboxylate (available from Aldrich Chemical Company) was brominated using a procedure similar to that of Russ, T., Ried, W., Ullrich, F., and Mutschler, E. Arch. Pharm. (Weinheim) 1992, 325, 761-767. To a solution of methyl 3-amino-2-pyrazine carboxylate (30.0 g, 200 mmol) in acetic acid (200 mL), bromine (11 mL) was added slowly via addition funnel. After complete addition of bromine, sodium carbonate powder was added slowly until precipitation occurred. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was reduced to half-volume in vacuo and then diluted with water (500 mL). The reaction mixture was shaken vigorously and the resulting solid was collected using vacuum filtration. The solid was washed with ether to afford a pure yellow solid (91% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[S:20][CH2:19][CH2:18][CH2:17][CH2:16][S:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:15]1[CH2:16][CH2:17][CH2:18][CH2:19][S:20][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: ClCC1SCCCCS1
Reactant: CCc1cccc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1SCCCCS1

Procedure:
2,6-Diethylaniline (75 grams), 2-chloromethyl-1,3-dithiepane (36.5 grams), potassium carbonate (34 grams) and dimethylformamide (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 18 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dithiepan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: CCCCC.[CH2:6]=[CH:7][C:8](=[CH2:10])[CH3:9].C=CC=CC.[CH:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:8]([C:7]1[CH:6]=[CH:16][CH:20]=[CH:19][C:18]=1[CH3:17])([CH3:10])=[CH2:9]
Reactant: C=CC(=C)C
Reactant: C1=CCC=C1
Solvent: Cc1ccccc1
Solvent: C=CC=CC
Solvent: CCCCC
Product: C=C(C)c1ccccc1C

Procedure:
90 g of isopropenyltoluene, 10 g of C5 fraction (n-pentane/isoprene/1,3-pentadiene/cyclopentadiene=5/6/3/3) obtained by thermal cracking of petroleum naphtha, and 150 g of toluene were charged into an autoclave, and the mixture was reacted by adding in drops, as a catalyst, 1.5 g of BF3 phenol complex over a period of about 10 minutes, keeping the temperature at 0° C. while stirring. Then, the stirring was continued for another 3 hours. Then, 50 ml of a 5 wt % aqueous sodium hydroxide solution was added, and after the mixture was vigorously stirred for 30 minutes to decompose the catalyst, the aqueous phase was separated and polymer oil was obtained. Further, after the polymer oil was washed with water until it became neutral, and the unreacted oil and solvent were distilled off under reduced pressure with heating to obtain a hydrocarbon resin in the form of a white lump. This resin had a softening point Tm of 125° C., a number average molecular weight of 1150, and a weight average molecular weight Mw of 1950.