Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH:34]([C:39]([O:41][CH3:42])=[O:40])[C:35]([O:37][CH3:38])=[O:36]>C(#N)C.CC(=O)OCC>[CH3:38][O:37][C:35](=[O:36])[CH:34]([O:26][C:4]1[C:5]([CH3:25])=[CH:6][C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][N:15]=3)[O:11][N:10]=2)=[CH:8][C:3]=1[CH2:1][CH3:2])[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC(C(=O)OC)C(=O)OC
Temperature: 65 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a solution of the compound of Example 32 (100 mg, 285 μmol) in acetonitrile (2 mL), K2CO3 (56 mg, 427 μmol) followed by dimethyl chloromalonate (57 mg, 341 μmol) is added. The mixture is stirred at 65° C. for 18 h. The mixture is diluted with EA and washed with water. The org. extract is concentrated and the crude product is purified on prep. TLC plates using heptane:EA 4:1 to give 2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-malonic acid dimethyl ester (95 mg) as a colourless oil; LC-MS: tR=1.17 min, [M+H]+=482.01. This material (95 mg, 197 μmol) is dissolved in ethanol (10 mL) and treated with NaBH4 (60 mg, 1.58 mmol). The mixture is stirred at 60° C. for 1 h before the reaction is quenched with water. The mixture is extracted twice with EA and the combined extracts are concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:1 to give the title compound (44 mg) as a colourless oil; LC-MS: tR=1.02 min, [M+H]+=426.01; 1H NMR (CDCl3): δ1.00 (d, J=6.5 Hz, 6H), 1.31 (t, J=7.3 Hz, 3H), 1.95 (hept, J=6.3 Hz, 1H), 2.08 (t br, J=5.5 Hz, 2H), 2.42 (s, 3H), 2.47 (s, 3H), 2.63 (d, J=7.0 Hz, 2H), 2.80 (q, J=7.5 Hz, 2H), 3.91-4.05 (m, 4H), 4.19 (quint, J=4.5 Hz, 1H), 7.95 (s, 1H), 7.98 (s, 1H), 8.10 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[C@H:9]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=2)[CH2:8]1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:17]=1)[C:13]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=2)[CH2:8][C@H:9]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:28]
Reactant: O=C(O)c1cccnc1
Reactant: Cc1ccc(C[C@@H]2CN(CCCN)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CCCNC(=O)c3cccnc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a stirred mixture of (2R)-4-(3-aminopropyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (160 mg), nicotinic acid (33 mg) and triethylamine (0.17 ml) in dichloromethane (2 ml) was added 2-chloro-1-methylpyridinium iodide (78 mg) at room temperature. After stirring for 1.5 hours, the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (30 ml) and water (10 ml). The organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on a silica gel with dichloromethane-methanol (40:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(nicotinoylamino)propyl]piperazine (70 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:31])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH:19]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:17][CH2:16]1)[C:7]2=[O:30].[N].[H][H]>C(O)C.[Pd]>[Cl:31][C:4]1[CH:5]=[C:6]2[C:11](=[CH:2][CH:3]=1)[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH:17]=[C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:19][CH2:20]1)[C:7]2=[O:30]
Reactant: [H][H]
Reactant: O=c1c2cc(Cl)cc(Br)c2ncn1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Agent: [Pd]
Agent: [N]
Solvent: CCO
Product: O=c1c2cc(Cl)ccc2ncn1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Yield: 37 %

Procedure:
Catalytic 10% Pd/C was added to a dried hydrogenation bottle under N2 and slowly under nitrogen 8-bromo-6-chloro-3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone (1.52 g, 3.05 mmol) in 150 mL of ethanol was added. This sample was hydrogenated at 30-40 psi hydrogen pressure overnight. The mixture was filtered over celite and concentrated then chromatographed; 6-chloro-3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone was isolated as a yellow powder (0.47 g). Yield 37%; mp 170° C.; MS: 418.8 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 2.14 (m, 2H), 2.51 (m, 4H), 2.67 (m, 2H), 3.31 (m, 2H), 4.10 (t, J=4.8 Hz), 6.15 (t, 1H), 7.06 (m, 2H), 7.36 (d, 1H), 7.75 (m, 1H), 7.80 (m, 2H), 8.12 (d, 1H), 8.32 (s, 1H), 8.45 (s, 1H), 11.2 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[C:26](Cl)(=[O:30])[O:27][CH2:28][CH3:29]>C(N(CC)CC)C>[O:15]=[C:14]1[CH2:13][CH2:12][N:11]([C:26]([O:27][CH2:28][CH3:29])=[O:30])[CH2:10][CH:9]1[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1OCc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(=O)C(OCc2ccccc2)C1
Reaction time: 6.3 h
Yield: 86.5 %

Procedure:
To a stirred mixture of 10 parts of 3-(phenylmethoxy)-1-(phenylmethyl)-4-piperidinone and 65 parts of dichloromethane were added dropwise 5 parts of ethyl carbonochloridate at room temperature. After stirring for 6.30 hours at reflux, there were added 5 parts of N,N-diethylethanamine. Upon completion, stirring at reflux was continued for 24 hours. The reaction mixture was washed successively with water, a diluted hydrochloric acid solution and again with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 8.1 parts (86.5%) of ethyl 4-oxo-3-(phenylmethoxy)-1-piperidinecarboxylate as an oily residue (intermediate 47).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([C:21]([OH:23])=[O:22])[N:11]=[N:10]1.[CH3:24][CH2:25]O>OS(O)(=O)=O>[CH2:24]([O:22][C:21]([C:12]1[N:11]=[N:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[OH:1])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)=[O:23])[CH3:25]
Reactant: O=C(O)c1nnn(-c2ccc(O)cc2O)c1-c1ccc(F)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nnn(-c2ccc(O)cc2O)c1-c1ccc(F)cc1

Procedure:
1-(2,4-Dihydroxy-phenyl)-5-(4-fluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (0.15 g, 0.48 mmol) was refluxed in EtOH (20 mL) in the presence of 5 drops of concentrated H2SO4 for 3 hours. After evaporation of the solvent, EtOAc (20 mL) was added. The organic layer was then washed with sat. NaHCO3 (2×10 mL) and brine (20 mL), dried with NaSO4 and filtered. After evaporation of the solvent, light brown semi-solids (93 mg, 57%) were obtained and purified by prep. TLC (Rf=0.73, EtOAc).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[OH:26][C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([N:30]4[CH2:29][CH2:28][C:27]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)([OH:26])[CH2:32][CH2:31]4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: OC1(c2ccccc2)CCNCC1
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCC(O)(c6ccccc6)CC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 4-hydroxy-4-phenylpiperidine (Aldrich Cat. No. H52201). LCMS (M+H)+: m/z=500.3.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13](C4C=CC(C=O)=CC=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(Cl)Cl.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH:35]1[CH3:40])[CH3:33].[BH4-].[Na+]>CC(O)=O>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:10]2[C:11]3[C:2](=[O:1])[NH:3][N:4]=[C:5]4[CH:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:13][NH:12][C:7]([C:6]=34)=[CH:8][CH:9]=2)[CH2:36][CH:35]1[CH3:40])[CH3:33]
Reactant: CCN1CCNCC1C
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN1CCN(Cc2ccccc2-c2ccc3c4c(n[nH]c(=O)c24)C(c2ccccc2)CN3)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 163.2 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (86 mg, 0.23 mmol) in dryness DCM (15 mL) was added HOAc followed by 1-ethyl-2-methylpiperazine (90 mg, 0.7 mmol), after the addition the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. Sodium borohydride (85 mg, 1.4 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound as white solid (90 mg, yield 71%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 (t, 3H), 1.42 (m, 3H), 3.23 (s, 1H), 3.47-3.56 (m, 6H), 3.80 (t, 2H), 4.46 (m, 3H) 4.91 (m, 10H), 7.20-7.29 (m, 3H), 7.30-7.32 (m, 3H), 7.46-7.48 (m, 3H), 7.59 (m, 1H), 7.69 (t, 1H). LC-MS (ESI) 552 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>C1(C)C=CC=CC=1>[CH:23]1([NH:29][C:30]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NC1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCCCC4)cc3)c2cc1OC
Temperature: 85 °C
Yield: 73.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (200 mg) was dissolved in toluene (5 ml) with heat, cyclohexyl isocyanate (340 mg) was added, and the admixture was stirred with heat at 80-90° C. for 30 minutes. After the addition of water, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 210 mg of the title compound (yield: 74%).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:21])([F:20])[C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[NH:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].[Br:22]Br.II>O>[Br:22][CH2:15][C:13](=[O:14])[CH2:12][C:11]([NH:10][C:9]1[CH:17]=[CH:18][CH:19]=[C:7]([C:6]([F:20])([F:21])[F:5])[CH:8]=1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A one-liter reaction flask equipped with a mechanical stirrer, air-cooled condenser, thermometer and dropping funnel was charged with 290 ml of acetic acid and 167.3 g (0.68 mole) of 3'-trifluoromethylacetoacetanilide. Only a portion of the latter dissolved. The dropping funnel contained 108.8 g (0.68 mole) of bromine, a crystal of iodine and 65 ml of acetic acid. The pot mixture was stirred as the bromine solution was added dropwise while maintaining the reaction temperature at 20°-25°. The reaction solids appeared to dissolve and reprecipitate as the bromine addition was continued. When about 65% of the bromine solution had been added, a clear reaction solution was obtained. All material remained in solution when the remaining quantity of bromine solution was added. The reaction solution was allowed to stir overnight at ambient temperature. On the following morning, the solidified mass was added to 2.8 liters of cold water and stirred. The white solid was collected on a vacuum filter and the filter cake was washed with an additional one liter of water. After drying, there was obtained 210 g (95%) of 4-bromo-3'-trifluoromethylacetoacetanilide, m.p. 66°-8°. N.M.R. (CDCl3) ##STR3## 5.3 (CH, enol), 7.2-7.8 (aromatic), 9.0 (HNC=O).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].Cl.[N:27]([O-])=O.[Na+]>O1CCOCC1.O>[OH:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:4]=[C:3]([C:24]#[N:25])[C:2]3[N:1]=[N:27][N:8]([CH3:9])[C:7]=3[CH:6]=2)=[CH:11][C:12]=1[C:20]([F:23])([F:21])[F:22]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCCO)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCO)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
3-Amino-6-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)-picolinonitrile (11 g) was dissolved in dioxane (20 ml), and water (20 ml). 1M HCl (16.39 ml) was added. Sodium nitrite (2.111 g) in water (2 mL) was added and reaction mixture was stirred at room temperature for 2 hrs. Product crashed out and was filtered, washed with water, ether and dried in oven to give 6-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (5.7 g) as a pale brown solid. 1H NMR (MeOH) δ: 8.55 (s, 1H), 8.43 (m, 2H), 7.36 (d, 1H), 4.45 (s, 3H), 4.25 (t, 2H), 3.95 (t, 2H). MS m/z 364 (M+H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:47]2[CH2:52][CH2:51][C:50]([C:58]([O:60][CH2:61][CH3:62])=[O:59])([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:49][CH:48]=2)O1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:47]2[CH2:52][CH2:51][C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:49][CH:48]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
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: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 11.3 %

Procedure:
To a sealable vial containing (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.25 g, 0.448 mmol) was added diethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1,1-dicarboxylate (0.374 g, 0.531 mmol), sodium carbonate hydrate (0.167 g, 1.345 mmol), and palladium tetrakis (0.016 g, 0.013 mmol). The mixture was diluted with 1,4-dioxane (4 mL) and water (1 mL) then was flushed with nitrogen and was sealed and heated to 85° C. in an oil bath. After 5 h of heating, the mixture was cooled to rt, was diluted with water (20 mL), and was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10-50% ethyl acetate in hexanes gradient. diethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1,1-dicarboxylate, a white solid, was recovered as the minor isolate (0.032 g, 0.05 mmol, 11.3% yield). LCMS: m/e 634.6 (M+H)+, 2.10 min (method 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>CN(C1C=CN=CC=1)C.ClCCl>[C:21](=[O:22])([O:23][CH3:24])[O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=1[Br:1]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1Br
Temperature: 25 °C
Yield: 90.4 %

Procedure:
2-Bromo-4-tert-butyl phenol (15.0 g, 65.5 mmol) and DMAP (400 mg, 3.3 mmol) was dissolved in dichloromethane (75 mL) and triethylamine (18.25 mL, 130.9 mmol), cooled to 0° C., then treated with methyl chloroformate (7.6 mL, 98.2 mmol) and allowed to warm to room temperature over 2 h. The reaction was quenched with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined organic extracts dried over Na2SO4. The solution was filtered and concentrated in vacuo to yield an oil that was purified by silica gel chromatography (20% ethyl acetate/hexane) to yield 2-bromo-4-tert-butylphenyl methyl carbonate (17 g, 90% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.67 (d, J=2.3 Hz, 1H), 7.47 (dd, J=2.3, 8.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 3.86 (s, 3H), 1.29-1.26 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[Br:12][C:13]1[C:14]([O:32][CH3:33])=[C:15]([C:21]([CH2:24]SC2C=CC=CC=2)=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[Br:12][C:13]1[C:14]([O:32][CH3:33])=[C:15]([C:21]([CH2:24][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=S([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Sodium 4-fluorobenzenesulphinate (0.517 g) was added to a suspension of ethyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 87, 0.4 g) and sodium bicarbonate (0.24 g) in dimethylacetamide (8 ml) and water (2 ml) and the mixture was stirred at room temperature for 3 hours. The resultant mixture was diluted with water and loaded onto a C-18 SPE column. The column was flushed with water then eluted with DCM and ethyl acetate. The organic eluent was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of t-butyl methyl ether and cyclohexane with a gradient of 0-60% to give ethyl 3-bromo-6-(4-fluorobenzenesulphonyl-methyl)-2-methoxybenzoate (0.37 g) as a colourless gum.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:22]1(C)C=CC(S(OCC)(=O)=O)=C[CH:23]=1>C(O)C>[CH2:22]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1)[CH3:23]
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CCC(n2ccc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-piperidin-4-yl-1H-indole (0.6 g, 3 mmol) in 5 mL of dry ethanol was added anhydrous potassium carbonate (680 mg, 4.9 mmol). After stirring for 15 minutes at ambient temperature, ethyl p-toluenesulfonate (0.48 mL, 4.5 mmol) was added. The reaction was heated under reflux for 24 hours with stirring, quenched with water, extracted with methylene chloride (2×), dried and evaporated to give a residue. The residue was chromatographed on silica gel with toluene/acetone (50:50) to yield 360 mg straw colored material (53% of theory).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)Nc2ccc(Br)cc2)c2cscc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4 g (18.4 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature under nitrogen for 24 hours with 3.6 g (18.4 mmol) of p-bromophenylisocyanate and 1.86 g (18.4 mmol) of triethylamine in 40 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 150 ml of 2-N hydrochloric acid and 100 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is taken up in 500 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 1 g of active carbon and filtered. The filtrate is extracted with four 250 ml portions of semi-saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with three 300 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The residual oil is covered with 5 ml of ethanol, the product separating out after standing for several days. The crystals are filtered off under suction, digested with a small amount of ethanol and dried. There is obtained 3-hydroxy-2-methyl-4-(4-bromophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 138°-140° C.