Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12[CH2:10][CH:7]([CH:8]=C1)[CH:6]1[CH:2]2[C:3](=[O:11])[O:4][CH2:5]1.[Mn]([O-])(=O)(=O)=O.[K+].S([O-])([O-])(=O)=[O:19].[Mg+2].[CH2:24]([OH:26])[CH3:25]>O>[OH:26][CH:24]1[CH:8]([OH:19])[CH:7]2[CH2:10][CH:25]1[CH:2]1[CH:6]2[CH2:5][O:4][C:3]1=[O:11]
Reactant: O=S(=O)([O-])[O-]
Reactant: CCO
Reactant: O=C1OCC2C3C=CC(C3)C12
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Product: O=C1OCC2C3CC(C(O)C3O)C12
Temperature: -40 °C

Procedure:
Initially, 21.7 g (120 mmol) of 4-oxatricyclo[5.2.1.02, 6]dec-8-en-3-one [Compound (A)] was placed in a 1-L reactor equipped with a stirrer, a thermometer, a cooling tube, and a dropping funnel, was dissolved in 318 g of ethanol and was cooled to −40° C. in a Dewar bath. Separately, 19.0 g (120 mmol) of potassium permanganate (KMnO4) and 14.4 g (120 mmol) of magnesium sulfate (MgSO4) were dissolved in water heated at 60° C., and the resulting solution was added dropwise into the reactor. After the completion of the addition, the reactor was taken out from the Dewar bath, the mixture was left stand to room temperature and was aged over night. After the completion of the reaction, the reaction mixture was filtrated, the filtrate was concentrated, the concentrate was filtrated again to remove insoluble matters, and the filtrate was extracted with ethyl acetate (n=5, s/f=2/1). The ethyl acetate layer was concentrated, the deposited solid matter was washed with toluene, was filtrated, was dried and thereby yielded the title compound [Compound (E)] in a yield of 41%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1(C)C=CC=CC=1.Cl>[CH3:23][S:24]([O:15][C:6]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:26])=[O:25]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
21.00 g (0.102 mol) of 2,4-di-tert-butylphenol and 11.84 g (0.117 mol) of triethylamine were dissolved in 200 mL of toluene followed by dropping in 12.24 g (0.107 mol) of methanesulfonyl chloride over the course of 30 minutes at 10° C. Following completion of dropping, the mixture was stirred for 2 hours at 25° C. and the 2,4-di-tert-butylphenol was confirmed to no longer be present. The reaction liquid was placed in 3% aqueous hydrochloric acid solution and following separation of the organic layer, was washed once with saturated aqueous NaHCO3 solution and twice with saturated brine followed by drying with MgSO4 and concentrating. The resulting crude crystals were purified by crystallization with n-heptane to obtain 25.8 g (yield: 90%) of 2,4-di-tert-butylphenyl methanesulfonate (white crystals, melting point: 63° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:31][C@H:28]1[CH2:29][CH2:30][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1N[C@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (266 mg, 1.0 mmol) was treated with (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester following general procedure B to afford 4-((S)-1-tert-butoxycarbonyl-pyrrolidin-3-ylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (345 mg). Thus obtained amino-ester (208 mg, 0.5 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish 3-[(S)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (177 mg). LCMS: m/z 523 [M+1]+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[SnH:9]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13].Cl[C:23]1[N:28]=[C:27]([Cl:29])[CH:26]=[CH:25][N:24]=1>C1COCC1>[Cl:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([Sn:9]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH3:13])[N:28]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: Clc1ccnc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Temperature: -20 °C
Reaction time: 5 h
Yield: 13.7 %

Procedure:
To a solution of LDA (251 ml, 502 mmol) in THF (650 mL) at −20° C. was added SnBu3H (108.5 ml, 402 mmol) dropwise. The mixture was maintained at −20° C. for 15 min, then cooled to −78° C. 2,4-dichloro pyrimidine (50 g, 335 mmol) was added and the reaction was stirred at −78° C. for 5 h. The cooling bath was removed and the reaction was slowly warmed to 0° C. within 30 min. The mixture was poured into 10% NH4Cl at 0° C., and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 1% EtOAc in Hex) to give 4-chloro-2-(tributylstannyl)pyrimidine (18.5 g, 24%) as a pale yellow color syrup. MS (ESI, pos. ion) m/z: 405.1 (M+1); 1H-NMR (400 MHz, CDCl3): δ 8.54 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 1.61-1.54 (m, 6H), 1.37-1.28 (m, 6H), 1.21-1.17 (m, 6H), 0.90 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[O:25]1[CH2:34][CH:26]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:34][CH:26]([OH:25])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: c1ccc(CC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(CC(O)Cc2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 85 °C
Yield: 70.4 %

Procedure:
To a stirred solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (500 mg, 1.4 mmol), prepared as described in Example 1, in 7 mL of DMF was added 2,3-epoxypropylbenzene (0.18 mL, 1.4 mmol) and 0.39 g of K2CO3. The resulting red solution was heated to 85° C. for 27 h and, upon cooling to room temp, the mixture was diluted with 200 mL of ethyl acetate and 200 mL of 1N HCL. The layers were extracted, and the organic layer was washed with 200 mL of saturated aqueous NaCl. The organic layer was dried over MgSO4, filtered and evaporated to a yellow oil. The material was purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate/hexanes to give 484 mg of racemic 7,8-bis(4-chlorophenyl)-2-(2-hydroxy-3-phenylpropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as a yellow solid containing 15% starting material 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one. Separation of enantiomers was performed on 200 mg of material using Chiracel OD 5 cm×50 cm 20 micron column, flow rate 50 mL/min isocratic 65% heptane/17.5% ethanol/17.5% methanol, monochrome detection at 220 nm. Fraction A was collected at 49 min post injection to give 47 mg of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one enantiomer A as a yellow solid; Fraction B was collected at 55 min post injection to give 45 mg of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one enantiomer B as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:26][C:25]=1[CH3:32]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Reactant: Cc1cc(C=O)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(F)c(C)c3)CC2)cc1
Temperature: 110 °C
Yield: 59.8 %

Procedure:
A mixture of (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (40 mg, 0.13 mmol) and 4-fluoro-3-methyl benzaldehyde (0.02 ml, 0.16 mmol), NaBH(OAc)3 (84 mg, 0.4 mmol) and CH3COOH (0.076 ml, 1.3 mmol) in DCM (10 ml) was heated at 110° C. (2 cycles of 5 min each) under microwave irradiation. The resulting mixture was purified by SPE-Si (2 g) eluting with a mixture DCM/AcOEt from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D29) (33 mg).
Reaction SMILES: [OH-].[Na+].C1COCC1.Cl.[NH2:9][C@H:10]([C:21]([NH2:23])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1.[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:31][C:32](=[O:33])[NH:9][CH:10]([C:21](=[O:22])[NH2:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
To a solution of 8.35 g (0.21 mol) NaOH in 100 ml of water was added 200 ml of THF followed by 25.0 g (0.104 mol) of L-tryptophanamide hydrochloride. The mixture was cooled on ice and 19.6 g (0.114 mol) of benzylchloroformate was added under vigorous stirring during 5 minutes. The ice bath was removed and the mixture was stirred for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=3)[O:8][C:6]=2[N:7]=1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:25]([O:24][C:22](=[O:23])[CH2:21][O:18][C:14]1[C:13]([CH3:19])=[CH:12][C:11]([C:9]2[O:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[N:10]=2)=[CH:16][C:15]=1[CH3:17])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1 g of 4-(5-chloro-oxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethyl-phenol in 5 ml of dimethylformamide was added slowly to a suspension of 1.2 ml of tert-butyl bromoacetate and 1.3 g of potassium carbonate in 15 ml of dimethylformamide. The mixture was stirred at room temperature for 30 min and then heated to 50° C. for 4 h. After cooling, the solids were removed by filtration and the solvents were distilled off in vacuo to give 1.4 g of the crude title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCCO1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
33 mg (0.10 mmol) of the compound from Example 31A, 29 mg (0.12 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 33 mg (0.39 mmol) of sodium bicarbonate are suspended in 2 ml of dry DMF. The reaction mixture is stirred at RT for 20 h. The mixture is filtered and directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH2:15][CH3:16])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[OH:17].[F:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=O.N1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH2:15]([CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:21]([C:20]4[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:19]=4[F:18])[O:17][C:3]=3[CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1)[CH3:16]
Reactant: COc1ccc(C(=O)Cl)c(F)c1
Reactant: CCC1CC(=O)NN=C1c1ccc(N)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Solvent: O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OC)cc3F)oc2c1

Procedure:
200 mg (857 μmol) 6-(4-amino-3-hydroxy-phenyl)-5-ethyl-4,5-dihydro-2H-pyridazin-3-one are refluxed together with 170 mg (901 μmol) 2-fluoro-4-methoxybenzoyl chloride, 70 mg (885 μmol) pyridine, 160 mg (841 μmol) para-toluenesulphonic acid monohydrate and 5 ml xylene for 4 h. The reaction mixture is evaporated down completely i.V. and the residue is crystallised from acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1(C)[CH:11]=[C:10]([CH3:12])[C:9]2[C:5]([CH:6]=[C:7]([C:13]([O:15]CC)=[O:14])[N:8]=2)=[C:4]1[CH3:18].[OH-].[K+].[C:22](O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]2[C:9](=[C:10]([CH3:12])[C:11]=1[CH3:22])[NH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2
Reactant: CC(=O)O
Reactant: CCOC(=O)C1=CC2=C(C)C(C)(OC)C=C(C)C2=N1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)c(C)c2[nH]c(C(=O)O)cc2c1C

Procedure:
A solution of ethyl 5-methoxy-4,5,7 trimethylindole-2-carboxylate (PREPARATION 19, 1.04 g) in ethanol (30 ml) containing potassium hydroxide (45%, 2.5 ml) is heated under reflux for 1.5 hr. The mixture is acidified with acetic acid (2 ml) and concentrated under reduced pressure. The residue is mixed with water (200 ml) and filtered. The filter cake is washed with water and dried to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[CH:20]=[C:19]([Cl:21])[S:18][C:17]=1[Cl:22].O>CN(C=O)C.C1COCC1>[Cl:22][C:17]1[S:18][C:19]([Cl:21])=[CH:20][C:16]=1[CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Clc1cc(CBr)c(Cl)s1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1cc(Cl)sc1Cl)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a stirred solution of sodium hydride (60% oil dispersion, 7.6 g, 190 mmol) in DMF (32 mL) was added a solution of diethyl malonate (35.2 g, 220 mmol) in THF (120 mL) at 0° C. and the mixture was stirred for 30 min at 0° C. To the mixture was added a solution of 3-(bromomethyl)-2,5-dichlorothiophene (26.9 g, 110 mmol) in THF (50 mL) at -35° C. over 1.5 hours. After stirring at -35° C. for 2 hours, the reaction mixture was poured into water and the whole extracted with ethyl acetate (200 mL×3). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. Fractionally distillation of the residue under reduced pressure (bp 150° C., 1.0 mmHg) provided the subtitle compound (28.6 g, 80% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[CH3:15][Si:16](C#C)([CH3:18])[CH3:17].[CH2:21](N(CC)CC)[CH3:22]>[Pd](Cl)Cl>[CH3:21][C:22]#[C:1][CH:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:8]=2)[S:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CCN(CC)CC
Reactant: CC1CC(C)(C)c2cc(Br)ccc2S1
Agent: Cl[Pd]Cl
Product: CC#CC1CC(C)(C)c2cc([Si](C)(C)C)ccc2S1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
A solution of 201 mg (74 mmol) of 2,4,4-trimethyl-6-bromo-thiochroman (Compound 53) in 1 ml of distilled triethylamine was placed in a heavy walled tube and degassed. The mixture was then treated under argon with 0.53 ml (3.72 mmol) of trimethylsilylacetylene and a powdered mixture of 52 mg (0.074 mmol) of bis-triphenylhosphine palladium (II) chloride and 28 mg (0.15 mmol) of cuprous idodide. The reaction mixture was placed under argon and the tube was sealed. The mixture was heated at 55 degrees C. for 72 hours. The mixture was cooled to room temperature and filtered through celite and the residue washed with CH2Cl2. The filtrate was concentrated in-vacuo and the residue was purified by flash chromatography (silica; hexanes) to give the title compound as a yellow oil. PMR (CDCl3): & 0.24 (9 H, s), 1.22 (3 H, s), 1.33 (3 H, d, J=6.6 Hz), 1.37 (3 H, s), 1.71 (1 H, t, J~13.0 Hz) 1.86 (1 H, dd, J=13.0 Hz, 3.0 Hz) 3.38-3.50 (1 H, m), 7.07 (1 H, dd, J=8.1 Hz, 1.8 Hz), 7.18 (1 H, d, J=1.8 Hz), 7.26 (1 H, d, J=8.1 Hz)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C@H:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([CH3:15])([CH3:14])[C:12]#[N:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.O>C1COCC1>[CH3:14][C:11]([CH3:15])([C@H:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH3:22])[N:2]=[CH:3]2)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:12]#[N:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C#N)[C@@H](c1ccccc1)c1ccc2[nH]ncc2c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: Cn1ncc2cc([C@H](c3ccccc3)C(C)(C)C#N)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a stirred solution of (S)-3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanenitrile (80 mg, 0.29 mmol) in anhydrous THF (5 mL) was added 1.0M NaHMDS in THF (0.30 mL, 0.30 mmol) at RT under nitrogen. After stirring at RT for 10 min, methyl iodide (0.03 mL, 0.48 mmol) was added, and the reaction was stirred overnight. The reaction mixture was poured into water, extracted with ethyl acetate (2×100 mL), dried (MgSO4) and concentrated. The resulting N1 and N2 adducts were separated by HPLC to give 54 mg (62% yield) of the desired N1 adduct (S)-2,2-dimethyl-3-(1-methyl-1H-indazol-5-yl)-3-phenylpropanenitrile. MS found: (M+H)+=290.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH2:24]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:24]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([O:16][C:15](=[O:17])[CH:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:23])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:35][CH:34]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCC(C(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
300 mg of 2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanoic acid were dissolved in 10 ml of methylene chloride and to this solution, were added successively, 240 mg of benzyl-4-hydroxybenzoate and 116 mg of N,N-dimethylaminopyridine. The reaction mixture was cooled to 0° C. and 217 mg of 1,3-dicyclohexylcarbodiimide was added at once. The mixture was stirred at 0° C. for 2 hours then at room temperature for 2 hours. The reaction mixture was filtered and the resulting filtrate was washed with 2 portions of 25 ml of water. The organic phase was dried over MgSO4 and the solvent evaporated. The oil/solid residue was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes) and gave 403 mg of a colorless oil, 1H NMR (CDCl3): 8.07 (d, J=8.8 Hz, 2H), 7.38-7.50 (m, 4H), 7.27 (m, 3H), 7.15 (m, 1H), 7.08 (d, J=8.8 Hz, 2H), 5.35 (s, 2H), 3.73 (dd, J=9.0, 7.5 Hz, 1H), 2.18 (m, 1H), 1.82 (m, 1H), 1.68 (s, 4H), 1.2-1.5 (m, 6H), 1.29 (s, 3H), 1.28 (s, 9H), 0.88 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (4-bromo-2-tert-butoxyquinolin-6-yl)(4-chlorophenyl)methanone (4 g, 9.55 mmol, 1.00 equip) in tetrahydrofuran (65 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (8.2 mL, 1.30 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (3×150 mL) and the organic layers combined. The resulting mixture was washed with water (2×100 mL) of water and brine (1×100 mL). The resulting mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:4) to yield (4-bromo-2-tert-butoxyquinolin-6-yl)bis(4-chlorophenyl)methanol as white solid. (ES, m/z): [M+H]+ 532
Reaction SMILES: C(OO)(=[O:3])C.OO.C(OC(=O)C)(=O)C.[Cl:15][CH2:16][CH2:17][N:18]([CH2:44][CH2:45][Cl:46])[C:19]1[CH:20]=[CH:21][C:22]([CH3:43])=[C:23]([CH2:25][C@@H:26]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:24]=1>ClCCl>[C:31]([O:30][C:28](=[O:29])[CH2:27][C@H:26]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:25][C:23]1[CH:24]=[C:19]([N+:18]([O-:3])([CH2:44][CH2:45][Cl:46])[CH2:17][CH2:16][Cl:15])[CH:20]=[CH:21][C:22]=1[CH3:43])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(=O)OO
Reactant: Cc1ccc(N(CCCl)CCCl)cc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: OO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: Cc1ccc([N+]([O-])(CCCl)CCCl)cc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Adapting literature known protocols (Tercel, et al., J. Med. Chem. 1995, 38, 1247-1252; and Kirkpatrick, et al., U.S. Pat. No. 7,399,785), peracetic acid (H3CCO3H) is freshly prepared by adding hydrogen peroxide (H2O2) (1.5 mL of a 35 wt-% aqueous solution, 14.0 mmol) dropwise to acetic anhydride (Ac2O) (1.52 mL, 1.65 g, 16.0 mmol). When the reaction mixture is homogeneous, a solution of tert-butyl(3R)-4-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]-3-(tert-butoxycarbonylamino)butanoate (6e) (1.61 g, 3.29 mmol) in dichloromethane (DCM) (20 mL) is added with vigorous stirring at about room temperature for about 2 h. The reaction is followed by TLC and/or LC/MS to completion. The reaction is quenched with 2.0 N hydrochloric acid (HCl), and the aqueous layer separated and repeatedly washed with DCM to the organic extracts are colorless. The aqueous phase is evaporated to dryness under reduced pressure, dried over anhydrous sodium sulfate (Na2SO4), and partially reduced in volume. Diethyl ether (Et2O) is added to separate the title compound 3-[(2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butyl]-N,N-bis(2-chloroethyl)-4-methyl-benzeneamine oxide (22a). The material may be purified by silica gel column chromatography.