Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:43]=[CH:44][CH:45]=[CH:46][C:2]1=2.[N+](=[CH2:49])=[N-]>C(OCC)C>[S:1]1[C:5]([C@H:6]([O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:49])=[O:23])=[CH:4][C:3]2[CH:43]=[CH:44][CH:45]=[CH:46][C:2]1=2
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)[Si](O[C@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2cc3ccccc3s2)[C@H](O)C[C@@H]1O
Temperature: 0 °C

Procedure:
(Z)-7-((1R,2R,3R,5S)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3,5-dihydroxycyclopentyl)hept-5-enoic acid, 9a, is dissolved in diethyl ether (0.1 M) and cooled to 0° C. under a nitrogen atmosphere. Diazomethane (freshly prepared solution in diethyl ether) is added to the solution with stirring under a light yellow color persisting. The completion of the reaction is confirmed by the absence of starting material as judged by TLC. Upon completion, the solvents are evaporated and the product is purified by flash chromatography using hexanes-ethyl acetate as eluent to afford the title intermediate 10a.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10]([CH:15]1[C:20](=O)[CH2:19][CH2:18][NH:17][CH2:16]1)(OCC)=[O:11]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:20]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[C:10](=[O:11])[O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(O)cc1C
Reactant: CCOC(=O)C1CNCCC1=O
Product: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3

Procedure:
In the same way as described for example 1, 0.3m of 3,4-dimethyl phenol, 0.2m of 3-carbethoxy-4piperidone were reacted to give 8.4g of crude product. Crystallization from ethyl acetate afforded analytical material, m.p. 173°-5° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O:16][CH:17]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29])(=[O:15])[CH3:14]>>[C:13]([O:16][CH:17]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:29])(=[O:15])[CH3:14]
Reactant: O=C(OCCO)c1ccccc1
Reactant: CCCCCCC(C/C=C\CCCCCCCC(=O)Cl)OC(C)=O
Product: CCCCCCC(C/C=C\CCCCCCCC(=O)OCCOC(=O)c1ccccc1)OC(C)=O

Procedure:
2-Benzoyloxyethyl 12 -acetoxyoleate was prepared by the procedure of Example 1 from 16 gms (0.1 mole) of ethylene glycol monobenzoate and 36 gms (0.1 mole) of 12-acetoxyoleoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]4[CH:22]=[C:23]([Br:26])[CH:24]=[CH:25][C:20]=4[N:19]=[N:18]3)=[N:12][N:11]2[CH:27]=1)(C)(C)C.[ClH:29].O1CCOCC1>>[ClH:29].[Br:26][C:23]1[CH:24]=[CH:25][C:20]2[N:19]=[N:18][N:17]([CH2:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([CH:27]=[C:8]([NH2:7])[N:9]=4)[N:12]=3)[C:21]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1

Procedure:
A solution of compound 10H (0.44 g, 1.0 mmol) in 4N HCl/dioxane (10 mL) was stirred at room temperature for 60 minutes, concentrated and dried in vacuum to give 0.3 g of product (10) as a hydrochloride salt. ESI-MS:m/z 344.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=O)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]C#N)=[CH:14][CH:13]=1.[OH-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:8][O:10][C:18]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=3)=[C:6]2[CH:7]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2onc3ccc(Br)cc23)cc1

Procedure:
13 g 1-bromo-4-nitrobenzene, 7.68 mL 2-(4-fluorophenyl)acetonitrile and 3.9 g sodium hydroxide were stirred in 130 mL ethanol at 40° C. for 24 hours. After the reaction solution was left and cooled, water was added thereto and the reaction solution was extracted with ethylacetate. The organic solvent was washed with brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) and then recrystallized from hexane/ethyl acetate to give 2.9 g of the title compound as pale brown crystals.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:50])(=O)=O)=CC=1.O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=2)[C:10]=3[F:50])[CH2:2][CH2:3]1
Reactant: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)(C(C)C)C(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(-n2nc3cc(OCC4CC4)ccc3c2F)cc1)(C(C)C)C(C)C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (218 mg) in THF (2.5 mL) was added dropwise a THF solution (1.11 M, 0.59 mL) of lithiumdiisopropylamide at −78° C. under an argon atmosphere, and the mixture was stirred for 30 min. To the reaction mixture was added N-fluorobenzenesulfonimide (236 mg) at −78° C., and the mixture was stirred at 0° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with 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 (hexane/ethyl acetate) to give the title compound as colorless crystals (110 mg).
Reaction SMILES: C(O[C:4]1[CH2:10][C:9](=[O:11])[NH:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)C.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(O)=O>[C:17]1([C:16]2[N:5]3[C:4]([CH2:10][C:9](=[O:11])[NH:8][C:7]4[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=43)=[N:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC1=Nc2ccccc2NC(=O)C1
Reactant: NNC(=O)c1ccccc1
Solvent: CC(=O)O
Product: O=C1Cc2nnc(-c3ccccc3)n2-c2ccccc2N1
Temperature: 120 °C

Procedure:
To a solution of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Preparation 3(A) (5 g, 24 mmol) in glacial AcOH (75 mL) was added benzoic acid hydrazide (3.33 g, 24.5 mmol). The reaction mixture was heated to 120° C. for 2 hours and was cooled to room temperature. The solvent was removed in vacuo by azeotropic distillation with heptane (2×). The residue was dissolved in a minimum amount of methylene chloride and 50 mL ethyl acetate and the solution was poured slowly with stirring into a solution of 100 mL saturated NaHCO3/100 mL water. Ether (150 mL) was added and the mixture was stirred for 5 minutes. The precipitate was collected by filtration, was washed with water and the minimum amount of ether to give 5.89 g of 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one. 1H NMR (CDCl3) δ 9.02 (br s, 1H), 7.48-7.36 (m, 6H), 7.10 (t, 1H), 6.95 (d, 1H), 4.23 (d, 1H), 3.60 (d, 1H); MS 277 (M+1).
Reaction SMILES: [CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:4])[OH:3].[N+](=[CH2:31])=[N-]>CCOCC>[CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:3])[O:4][CH3:31]
Reactant: C=[N+]=[N-]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])P(C)(=O)O
Solvent: CCOCC
Product: COP(C)(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
The phosphinic acid of Example 20 is reacted with an excess of diazomethane in ether to give methyl P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate.
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:5]=1[CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)([CH3:3])[CH3:2].O.NN>CO>[CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[CH2:6][NH2:7])([CH3:24])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1CN
Yield: 88.2 %

Procedure:
Then, a mixture of 1.01 g (3.14 mmol) of N-(2, 6-diisopropylbenzyl) phthalimide, 0.3 ml of hydrazine hydrate and 15 ml of methanol was refluxed with heating for 3.5 hours. The reaction mixture was concentrated in vacuo, mixed with 20 ml of water and 40 ml of methylene chloride, and made alkaline with aqueous sodium hydroxide. The organic layer was separated, washed with dilute aqueous sodium hydroxide and water, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo to give 0.53 g of 2, 6-diisopropylbenzylamine as an oil.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30]([C:34]4[CH:35]=[CH:36][C:37]5[NH:38][C:39]6[C:44]([C:45]=5[CH:46]=4)=[CH:43][CH:42]=[CH:41][CH:40]=6)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[Na+]>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[N:38]1[C:37]2[CH:36]=[CH:35][C:34]([C:30]3[CH:31]=[CH:32][C:33]4[N:21]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:22]5[C:27]([C:28]=4[CH:29]=3)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2
Reactant: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1
Reactant: Brc1ccc2sc3ccccc3c2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1C
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5c(c4)c4ccccc4n5-c4ccc5sc6ccccc6c5c4)ccc32)cc1
Yield: 58 %

Procedure:
A mixture of 2-bromodibenzo[b,d]thiophene (3.22 g, 12.24 mmol), 9-phenyl-9H-9′H-3,3′-bicarbazole (2.5 g, 6.12 mmol), and sodium t-butoxide (1.764 g, 18.36 mmol) in 100 mL of xylene was bubbled with N2 for 20 min. Pd2(dba)3 (0.056 g, 0.061 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.100 g, 0.245 mmol) were then added, and mixture was then bubbled with nitrogen for another 20 min. The reaction mixture was refluxed under N2 for 24 h. The mixture was cooled and filtered through Celite. After solvent evaporation, the residue was coated on Celite and purified by column chromatography using up to 50% dichloromethane in hexane as solvent. 9-(dibenzo[b,d]thiophen-2-yl)-9′-phenyl-9H,9′H-3,3′-bicarbazole (2.1 g, 3.55 mmol, 58.1% yield) was obtained.
Reaction SMILES: [CH:1]1([C:6]2[C:15]3[C@@H:14]([OH:16])[CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]=3[N:9]=[C:8]([CH:19]([O:21][CH3:22])[CH3:20])[C:7]=2[C:23]2[C:24]([C:31]([F:34])([F:33])[F:32])=[CH:25][CH:26]=[C:27]([CH:29]=[O:30])[CH:28]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.[C:43]([Si:47](OS(C(F)(F)F)(=O)=O)([CH3:49])[CH3:48])([CH3:46])([CH3:45])[CH3:44]>C1(C)C=CC=CC=1>[C:43]([Si:47]([CH3:49])([CH3:48])[O:16][C@H:14]1[CH2:13][C:12]([CH3:17])([CH3:18])[CH2:11][C:10]2[N:9]=[C:8]([CH:19]([O:21][CH3:22])[CH3:20])[C:7]([C:23]3[C:24]([C:31]([F:34])([F:32])[F:33])=[CH:25][CH:26]=[C:27]([CH:29]=[O:30])[CH:28]=3)=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:15]1=2)([CH3:46])([CH3:45])[CH3:44]
Reactant: COC(C)c1nc2c(c(C3CCCC3)c1-c1cc(C=O)ccc1C(F)(F)F)[C@@H](O)CC(C)(C)C2
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COC(C)c1nc2c(c(C3CCCC3)c1-c1cc(C=O)ccc1C(F)(F)F)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -18 °C
Reaction time: 0.33 h

Procedure:
840 mg 5-(S)-[4-Cyclopentyl-5-hydroxy-2-(1-methoxy-ethyl)-7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-3-yl]-(4-trifluoromethyl-phenyl)-methanone (Diastereomer 1) are dissolved in 20 ml toluene, 823 μl 2,6-lutidine are added and the solution is cooled to −18° C. 811 μl Trifluoromethanesulfonic acid-tert.-butyldimethylsilylester are added dropwise and the mixture is stirred for further 20 minutes at −18° C. Then it is warmed to 0° C. and stirred for 1 hour whereafter the mixture is partitioned between saturated aqueous ammonium chloride solution and ethylacetate. The aqueous phase is twice extracted with ethylacetate and the combined organic phases are washed with brine. After drying with magnesium sulphate the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 95:5 to 80:20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4ccc(Cl)cc4nc3OC)CC2)c1
Yield: 85 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 3.14-3.16 (m, 4H), 3.76-3.80 (m, 7H), 4.14 (s, 3H), 6.46-6.58 (m, 3H), 7.14-7.44 (m, 3H), 7.62-7.74 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[O:5][C:4](=[O:6])[CH2:3]1.S([O-])(O)(=O)=O.[Na+].[CH3:19][OH:20]>>[CH3:19][O:20][C:4](=[O:6])[CH2:3][C:2]([CH3:1])([OH:5])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12]
Reactant: CO
Reactant: CC(C)=CCCC1(C)CC(=O)O1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: COC(=O)CC(C)(O)CCC=C(C)C
Temperature: 10 °C
Reaction time: 1.2 h
Yield: 88.6 %

Procedure:
0.69 g of Na metal were dissolved in 200 g of methanol and cooled to 10° C. 50.47 g (0.279 mol) of 4-methyl-4-(4-methylpent-3-en-1-yl)-2-oxetanone were then added over a period of 17 mins, during which time the temperature rose to 16° C. Next, the mixture was stirred at 20° C. for 1.2 h and then acidified with 4.14 g (30 mmol) of sodium hydrogen sulfate. After being stirred for a further 1.7 h at 20° C., the suspension was filtered. The filtrate was concentrated (80 mbar, 40° C.). The residue (56.56 g) was then fractionated at 1 mbar, and the main fraction distilled at 95° C. to 97° C. 49.52 g (87.1%) of the title product were obtained in the form of an oil.
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33](O)=[O:34].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[Br:27][C:28]1[CH:36]=[C:32]([C:33](=[O:34])[CH2:20][C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:31]=[N:30][CH:29]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CC(=O)c1cncc(Br)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
To a solution of diisopropylamine (5.41 g) in THF (30 mL) was added 1.5 M n-butyllithium hexane solution (35 mL) under dryice acetone cooling and the mixture was stirred at −78° C. for 10 minutes. To this was added tert-butyl acetate (5.87 g) under dryice acetone cooling and the mixture was stirred at −78° C. for 10 minutes and added dropwise to a solution of 5-bromonicotinic acid (3.00 g) and N,N-carbonyldiimidazole (2.65 g) in THF (30 mL) under dryice acetone cooling. The mixture was stirred at −78° C. for 0.5 hour. The mixture was partitioned between ethyl acetate and aq NH4Cl solution. The organic layer was separated, washed with aq NaHCO3 solution and brine, dried over MgSO4, and evaporated in vacuo. The residue was triturated with isopropyl ether to give tert-butyl 3-(5-bromo-3-pyridinyl)-3-oxopropanoate as a colorless powder (3.71 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[H-].[Na+]>N1C=CC=CC=1>[O:7]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccsc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: c1ccc(Oc2ccsc2)cc1
Yield: 73 %

Procedure:
Cuprous chloride (3.08 g, 31.1 mmol) and phenol (8.78 g, 93.3 mmol) were sequentially added to a solution of 3-bromothiophene (5.06 g, 31.1 mmol) in pyridine (150 ml). Sodium hydride (3.73 g, 93.3 mmol, 60% dispersion in mineral oil) was then slowly added. The reaction was heated at reflux for 20 hours under Argon. The pyridine was removed under reduced pressure. The residue was diluted with Et2O (200 ml) and washed with 1 N NaOH (3×100 ml), 1 N HCl (2×150 ml) and 1 N NaOH (150 ml). The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was chromatographed using hexanes to give 3-phenoxy-thiophene as a clear oil (4.0 g, 74% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:41])[CH2:14][CH2:15][N:16]([CH3:40])[C:17](=[O:39])/[CH:18]=[CH:19]/[C:20]1[C:28]2[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=2)[N:22](COCC[Si](C)(C)C)[N:21]=1>>[CH3:41][N:13]([CH3:12])[CH2:14][CH2:15][N:16]([CH3:40])[C:17](=[O:39])[CH:18]=[CH:19][C:20]1[C:28]2[C:23](=[CH:24][C:25](/[CH:29]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=4)=[CH:26][CH:27]=2)[NH:22][N:21]=1
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: CN(C)CCN(C)C(=O)/C=C/c1nn(COCC[Si](C)(C)C)c2cc(C=O)ccc12
Product: Cc1ccc2c(c1)/C(=C\c1ccc3c(C=CC(=O)N(C)CCN(C)C)n[nH]c3c1)C(=O)N2

Procedure:
The title compound was synthesized according to the method described in Example A57 from 5-methylindolin-2-one (8.0 mg, 0.0535 mmol) and (E)-N-(2-(dimethylamino)ethyl)-3-(6-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-methylacrylamide (23 mg, 0.0535 mmol) with a modified purification procedure. The product was extracted into EtOAc after the final deprotection step and washed with NaHCO3(sat) (2×), brine (2×) and the organic layer dried over MgSO4. After removal of solvent the resulting film was titurated with Et2O/hexanes to give after drying 9.4 mg, 41% yield of a yellow solid which was a 77:23 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, CD3OD) δ 8.94, 7.91 (s, 1H), 8.20, 8.16 (d, J=8.7 Hz, 1H), 7.98-7.93 (m, 1H), 7.84 (s, 1H), 7.59, 7.43 (d, J=8.2 Hz, 1H), 7.52-7.42 (m, 2H), 7.08 (d, J=7.2 Hz, 1H), 6.82, 6.78 (d, J=7.6 Hz, 1H), 3.77-3.68 (m, 2H), 3.60, 3.13 (s, 3H), 2.68-2.61 (m, 2H), 2.37 (s, 6H), 2.19 (s, 3H); MS ESI 430.3 [M+H]+, calcd for [C25H27N5O2+H]+ 430.22.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)#[N:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:7]2[C:6](=[O:8])[CH:5]=[N:4][N:3]([C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=3)[C:2]2=[O:1])=[CH:23][CH:22]=1)#[N:20]
Reactant: CC(=O)Nc1cccc(-n2ncc(=O)[nH]c2=O)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1cccc(-n2ncc(=O)n(Cc3ccc(C#N)cc3)c2=O)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 35.4 %

Procedure:
According to Scheme 5 Step 5: A suspension of N-(3-(3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (50 mg, 0.203 mmol), 4-cyanobenzylbromide (40 mg, 0.203 mmol) and potassium carbonate (31 mg, 0.223 mmol) in acetonitrile (2 mL) was stirred at 60° C. for 15 h The reaction mixture was then partitioned between AcOEt and water The organic layer was washed twice with water and once with brine. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by flash chromatography over silica gel (Merck Flashmart prepacked column 10 g SiO2) using DCM/MeOH 98/2 as eluent to afford N-(3-(4-(4-cyanobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 9(E) (26 mg, 35%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH:14]=[C:13]2[C@@H:8]([CH2:9][C:10]3[C:11]4[C:18]([NH:19][CH:20]=3)=[CH:17][CH:16]=[CH:15][C:12]=42)[N:7]([C:21](=[O:29])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:6]1)=[O:4].CO.[OH-].[Li+].Cl>O.CO.ClCCl.C1COCC1>[C:23]1([NH:22][C:21]([N:7]2[C@H:8]3[C:13]([C:12]4[CH:15]=[CH:16][CH:17]=[C:18]5[C:11]=4[C:10](=[CH:20][NH:19]5)[CH2:9]3)=[CH:14][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[O:29])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C(=O)Nc2ccccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C(=O)Nc2ccccc2)C1

Procedure:
To a 100 ml round-bottom flask containing (6aR,9R)-7-phenylcarbamoyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carboxylic acid methyl ester (0.8 g, 2.06 mmol) is added methanol (12 ml), THF (24 ml) and a solution of lithium hydroxide (247 mg) in water (12 ml). The reaction mixture is stirred at room temperature for 20 minutes by which time TLC in 20% methanol/dichloromethane showed complete conversion of starting material. The colour of the crude reaction mixture has changed from light yellow to a violet red. The volatiles are removed in vacuo (leaving only water) and the aqueous solution made acidic with the addition of 1 M HCl. The resulting beige precipitate is filtered at the pump and the filter cake washed with distilled water (50 ml). The filter cake is then dried in a high vacuum oven at 50° C. for 16 hours providing product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.C([O-])(=[O:19])C.[Na+].[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)CCC)CCCCCCC.[OH-].[Na+]>CCOCC.C(O)C.O>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:19]
Reactant: CC(=O)[O-]
Reactant: BrCCCCOc1ccc2ccccc2c1
Agent: CCCCCCCC[N+](CCC)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: OCCCCOc1ccc2ccccc2c1
Reaction time: 2 h
Yield: 31.9 %

Procedure:
A mixture of 2-[(4-bromobutyl)oxy]naphthalene (5.5 g), sodium acetate (13.1 g), trioctylpropylammonium chloride (1.21 g) and water (19 ml) was stirred at ca 100° for 2 h. 2N sodium hydroxide solution (32 ml) and ethanol (32 ml) were added to the cooled mixture which was stirred for a further 10 min at room temperature. The ethanol was evaporated in vacuo and the residue diluted with brine (150 ml) and extracted with ether (2×100 ml), which was dried and evaporated in vacuo to give a white solid. The solid was dissolved in ether and purified by FCC eluting with hexane-ether (2:1→1:2) to give the title compound as a white solid (1.36 g), m.p. 66.5°-67.5°.