Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:21]>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([C:14](=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)Cc1nc(NC(=O)OC(C)(C)C)cs1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(=O)c1nc(NC(=O)OC(C)(C)C)cs1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 78.5 %

Procedure:
Ethyl 2-(4-tert-butoxycarbonylaminothiazol-2-yl)-acetate (5.1 g) was added to a solution of selenium dioxide (2.96 g) in dioxane (60 ml) and water (2 ml) at 110° C. and stirred for 4.5 hours at 110° C. The mixture was evaporated and the residue was dissolved in ethyl acetate and water. The separated ethyl acetate layer was washed with an aqueous sodium chloride and dried over magnesium sulfate. After removing the solvent, the residue was subjected to column chromatography on silica gel and eluted with methylene chloride. The fraction containing an object compound was evaporated to give ethyl (4-tert-butoxycarbonylaminothiazol-2-yl)glyoxylate (4.2 g).
Reaction SMILES: CN(C)C([N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([CH3:21])([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=O.[OH-].[Na+].CO>CS(C)=O>[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:15]([CH3:21])([CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(ccn2C(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of methyl 3-(1-(dimethylcarbamoyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoate (0.7 g, 2.2 mmol), sodium hydroxide (1M aqueous solution, 18 mL), methanol (5 mL), and dimethylsulfoxide (3 mL) was stirred at 100° C. overnight under argon. The reaction mixture was cooled, washed with diethyl ether (20 mL), acidified with 6M hydrochloric acid aqueous solution, and extracted with ethyl acetate (20 mL). The ethyl acetate extract was washed with brine (20 mL), dried (Na2SO4) and concentrated to give 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (0.58 g, 2.0 mmol, 91% yield) as a syrup and used as such for the subsequent step without further purification.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:43]([OH:45])=O)[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:35]=1)=[O:5])C.[CH3:46][N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:33]=[C:32]([C:43]([N:50]3[CH2:51][CH2:52][CH2:53][N:47]([CH3:46])[CH2:48][CH2:49]3)=[O:45])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CN1CCCNCC1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Product: CN1CCCN(C(=O)c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(-c3cccc(F)c3)c2)CC1

Procedure:
The title compound was prepared according to the general procedure described in Steps 7 and 8 of Method C starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and 1-methyl-[1,4]diazepane (15% yield after two steps).
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]2[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([N+:41]([O-:43])=[O:42])[CH:35]=2)=[CH:19][CH:18]=1)([CH2:15][CH3:16])[CH3:14]>CN(C=O)C>[CH:13]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]2[C:34]2[CH:39]=[CH:38][C:37](/[CH:40]=[CH:6]/[N:7]([CH3:9])[CH3:8])=[C:36]([N+:41]([O-:43])=[O:42])[CH:35]=2)=[CH:21][CH:22]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(C)c([N+](=O)[O-])c3)nc3ccccc3c2=O)cc1
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3ccc(/C=C/N(C)C)c([N+](=O)[O-])c3)nc3ccccc3c2=O)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
tert-Butoxybis(dimethylamino)methane (0.75 mL, 3.60 mmol) was added to a solution of 3-(4-sec-butylphenyl)-2-(4-methyl-3-nitrophenyl)quinazolin-4(3H)-one (0.500 g, 1.20 mmol) in DMF (30 mL). Stirring at 40° C. for 3 hours and concentrating in vacuo afforded (E)-3-(4-sec-butylphenyl)-2-(4-(2-(dimethylamino)vinyl)-3-nitrophenyl)quinazolin-4(3H)-one (0.565 g, quantitative).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([C:15]=2[NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[NH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>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>[NH2:32][C:33]1[CH:34]=[C:35]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([C:15]=3[NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[C:13]#[N:14])[CH:5]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: N#Cc1cncc(-c2cccc(Br)c2)c1Nc1ccc2[nH]ccc2c1
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: N#Cc1cncc(-c2cccc(-c3cccc(N)c3)c2)c1Nc1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 5-(3-bromophenyl)-4-(1H-indol-5-ylamino)nicotinonitrile 113 (39 mg, 0.1 mmol), (Ph3P)4Pd (2.3 mg, 0.002 mmol) and 2M aq. Na2CO3 (0.1 mL) in DME (2 mL) was degassed by bubbling nitrogen for 5 min., then 3-aminophenylboronic acid (17 mg, 0.11 mmol) was added and the mixture was heated at reflux for 12 h. After cooling to r.t., the mixture was filtered and the filtrate was purified by preparative HPLC to give 5-(3′-aminobiphenyl-3-yl)-4-(1H-indol-5-ylamino)nicotinonitrile 117. MS: 402 (M+H), HPLC retention time: 1.72 min.(a).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[O:12]1[CH2:16][CH:13]1[CH2:14][OH:15]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH:13]([OH:12])[CH2:14][OH:15])=[CH:7][CH:6]=1
Reactant: OCC1CO1
Reactant: COCCc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COCCc1ccc(OCC(O)CO)cc1
Yield: 86.2 %

Procedure:
39 g of 4-(2-methoxy-ethyl)-phenol are heated to about 120° C., after addition of 0.5 g of benzyl-tributylammonium chloride, and 20.4 g of 2,3-epoxypropanol are added dropwise in the course of 15 minutes. The mixture is allowed to cool, the syrup is dissolved in CHCl3, the solution is washed with water and the CHCl3 residue is purified by preparative HPLC. 50 g of 3-[4-(2-methoxyethyl)-phenoxy]-propane-1,2-diol are obtained.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, off-white solid (87 mg, 81%), MS (ISP) m/z=433.5 [(M+H)+], mp 220° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([CH3:11])[CH:9]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15]>C(OCC)C>[Cl:1][C:2]1[C:3]([C:8]2([CH3:11])[CH2:15][CH2:14][C:16](=[O:17])[CH:18]=[CH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(C)=O
Reactant: CC(C=O)c1ncccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC1(c2ncccc2Cl)C=CC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a 0° C. solution of the product of Example 38D (0.71 g, 4.19 mmol) in diethyl ether (10 mL) was added a solution of potassium hydroxide (3M in methanol, 0.56 mL, 1.68 mmol), followed by methyl vinyl ketone (0.47 g, 0.55 mL, 6.70 mmol). The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with diethyl ether, and washed with water and brine. The organic layer was concentrated, and the residue was chromatographed on silica gel eluting with 25% ethyl acetate-hexane to give the title compound (0.20 g, 22%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.53 (dd, J=1.5, 4.6, 1H), 7.92 (dd, J=1.5, 8.0, 1H), 7.45-7.26 (m, 2H), 5.92 (d, J=10.2, 1H), 2.82-2.67 (m, 1H), 2.64-2.52 (m, 1H), 2.31 (ddd, J=4.8, 7.2, 17.3, 1H), 2.12-2.00 (m, 1H). MS (DCI) m/z 222 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[CH3:1][C:2]1[C:6]2[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)c2c(C)noc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(Oc2ccc(N)cc2)c2c(C)noc2c1
Yield: 139.7 %

Procedure:
3,6-dimethyl-4-[(4-nitrophenyl)oxy]-1,2-benzisoxazole (Intermediate 20, 208 mg) was dissolved in ethanol (10.0 ml) and tin chloride dihydrate (991 mg, 4.39 mmol) was added. The reaction mixture was stirred and heated at reflux for 4 hours. After the removal of the volatiles, water was added and the reaction mixture was extracted two times with ethyl acetate. The collected organic were dried over sodium sulphate, filtered and evaporated to afford 260 mg of the title compound.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4][S:3]1.[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4][S:3]1)(=[O:19])[CH3:18]
Reactant: N=C1SCCN1c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N=C1SCCN1c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
0.52 g (2 mmoles) of 2-imino-3-(4'-chloro-2-nitrophenyl)-thiazolidine is dissolved in 20 ml of anhydrous chloroform. 0.24 g (0.21 ml, 3 mmoles) of acetyl chloride and 0.4 ml (0.3 g, 3 mmoles) of triethylamine are added to the solution and it is boiled for 30 minutes. The solution is then evaporated in vacuo, the oily residue is dissolved in 30 ml of dichloromethane and extracted twice with 10 ml of saturated aqueous sodium chloride solution each. The solution is dried and evaporated, the oily residue is crystallized from ethyl acetate.
Reaction SMILES: [C:1]([C:4]1[C:9]2[N:10]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21](=[O:26])[C:11]3=[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:7](=[O:27])[N:6]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[N:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:47]Br.[Br-]>C1COCC1>[Br:47][CH2:2][C:1]([C:4]1[C:9]2[N:10]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21](=[O:26])[C:11]3=[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:7](=[O:27])[N:6]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[N:5]=1)=[O:3]
Reactant: CC(=O)c1nn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Reactant: BrBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)CBr)c32)C1=O
Reaction time: 0.25 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.50 g, 0.98 mmol) in anhydrous THF (20 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide (1.08 mL, 1.08 mmol) in THF was added. After stirring at the same temperature for 15 minutes, bromine (0.24 g, 1.47 mmol) was added and the reaction was stirred at room temperature. The reaction was monitored by LC-MS. Additional solution of lithium bis(trimethylsilyl)amide and bromine were added to drive the reaction to completion. The bromide generated as a solution in THF was used in the following reaction without further workup or purification. ES MS M+1=587
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]([Cl:24])=[CH:21][CH2:22]Cl.Cl>CN(C)C=O>[Cl:19][C:20]([Cl:24])=[CH:21][CH2:22][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: ClCC=C(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCC=C(Cl)Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a mixture of 44 g of N-hydroxyphthalimide, 39 g of potassium carbonate, and 400 ml of N,N-dimethylformamide was added 41 g of 1,1,3-trichloro-1-propene at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into diluted hydrochloric acid to cause the deposition of crystals. These crystals were collected by filtration, washed with water and hexane in this order, and dried under reduced pressure, which afforded 66 g (yield, 90%) of N-(3,3-dichloro-2-propenyloxy)phthalimide.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([CH:13]([C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:12]([O:19][CH3:20])=[O:18])=[O:15]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)[C@@H](C[N+](=O)[O-])c1ccccc1
Temperature: -20 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenylethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), trans-β-nitrostyrene (149 mg, 1.0 mmol), dimethyl malonate (114 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at −20° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), showing that the yield of the product was 93%. The optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 mn), resulting to 94% ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)NCCn2ccnn2)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.5 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide as a yellow solid (51 mg, 43%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][CH2:16][C:9]=2[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O.[CH:26](B1OB(C=C)OB(C=C)O1)=[CH2:27]>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>[CH:26]([C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][CH2:16][C:9]=2[CH:8]=1)=[CH2:27]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: O=S(=O)(Oc1cc2c(nn1)OCCC2)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1cc2c(nn1)OCCC2
Reaction time: 0.33 h
Yield: 77 %

Procedure:
Argon was bubbled for 15 minutes through a solution of 6,7-dihydro-5H-pyrano[2,3-c]pyridazin-3-yl trifluoromethanesulfonate (228 mg, 0.8 mmol) in 1,2-dimethoxyethane (6.5 ml). Tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.0435 mmol) was added and the solution stirred for 20 minutes under argon. The mixture was then treated with potassium carbonate (111 mg, 0.8 mmol), water (1.9 ml) and 2,4,6-trivinylcyclotriboroxane:pyridine complex (180 mg, 0.75 mmol) (for a preparation of this reagent see F. Kerins and D. F. O'Shea, J. Org. Chem. 2002, 67, 4968-4971). After stirring for 2 hours at 80° C., the mixture was cooled and partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous fraction was extracted twice with 20% methanol/dichloromethane. The combined organic solution was dried, evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate to give product as a white solid (100 mg, 77%).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:28]=1)[NH:25][CH:24]=[CH:23]2.C([SiH](CC)CC)C>ClCCl>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:28]=1)[NH:25][CH:24]=[C:23]2[CH:3]1[CH2:4][CH2:5][S:1][CH2:2]1
Reactant: O=C1CCSC1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCSC3)c[nH]c12
Temperature: 0 °C
Yield: 46.9 %

Procedure:
Dihydro-3(2H)-thiophenone (0.381 g, 3.73 mmol) was dissolved in dichloromethane (50 ml) in an oven dried flask containing 3 Å molecular sieves and stirred under Argon at 0° C. TMS-OTf (0.826 g, 3.73 mmol, 0.67 mL) was added slowly to the mixture over 10 min. Ethyl 5-bromo-1H-indole-7-carboxylate (1 g, 3.73 mmol) was dissolved in DCM (6 mL) and added to the reaction via syringe pump over 2 hours, after which it was stirred for 30 min at 0° C. Triethylsilane (0.651 g, 0.89 ml, 5.59 mmol) was then added all at once and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with a saturated sodium bicarbonate solution (35 mL) and extracted with DCM (2×50 mL). The combined organics were washed with water (2×100 mL), brine, dried with MgSO4, and concentrated. The crude compound was purified on Combiflash silica column with 10% EA/Hexane to give 0.620 g (47%) of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl.[BH4-].[Na+]>C1COCC1.CN1C(=O)N(C)CCC1>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][O:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(O)c1
Reactant: COCCOCCl
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COCCOCOc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled suspension (0° C.) of 60% NaH (660 mg, 16.5 mmol) in THF (35 mL) is added dropwise a solution of 3-hydroxybenzaldehyde (1.89 g, 15 mmol) in THF (15 mL) and the resulting mixture stirred for 20 min. To the mixture is added 2-methoxyethoxymethyl chloride (1.88 mL, 16.5 mmol) and DMPU (5 mL), the cold bath removed and stirred for 1 hr. The reaction mixture is cooled to 0° C. then slowly added 2M NaBH4 (in triglyme) (3.75 mL, 7.5 mmol) and let stir for 1 hr. Slowly quenched with 2N HCl soln (3.9 mL) and diluted reaction mixture with ether. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 60% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. MS (EI) 212 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(=O)O[CH2:16][CH2:15][O:14]1.O(C(C)(C)C)[K]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:16][CH2:15][OH:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1OCCO1
Reactant: Nc1ccc2cccc(O)c2n1
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2cccc(OCCO)c2n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 27.7 %

Procedure:
A mixture of 2-amino-8-quinolinol (3.20 g, 20.0 mmol), ethylene carbonate (1.76 g, 20.0 mmol) and KO-t-Bu (2.24 g, 20.0 mmol) in DMF (20 mL) was stirred at 90° C. for 15 h The mixture was poured into brine, extracted with EtOAc, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using toluene/EtOAc/MeOH (50:50-2) as eluent to give 1.13 g (28%) of the title product as a solid HRMS m/z calcd for C11H12N2O2 (M)+ 204.0899. found 204.0906
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[C:14]([SH:19])=[N:15][CH:16]=[CH:17][CH:18]=1>>[CH3:12][C:13]1[C:14]([S:19][C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[Cl:1])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccnc1S
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: Cc1cccnc1Sc1ccc([N+](=O)[O-])cc1Cl
Yield: 50 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 3-methyl-2-pyridinethiol to give 2-chloro-4-nitrophenyl 3-methylpyrid-2-yl sulphide in 50% yield.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([Br:23])=[CH:25][C:26]=3[F:31])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCc1ccccc1
Yield: 77.7 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (8.35 g, 24.8 mmol), (prepared as described for the starting material in Example 4), and 4-bromo-2 fluoroaniline (5.65 g, 29.7 mmol) in isopropanol (200 ml) was heated at reflux for 4 hours. The resulting precipitated solid was collected by filtration, washed with isopropanol and then ether and dried under vacuum to give 7-benzyloxy4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (9.46 g, 78%).