Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:8]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:7]2[CH:8]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[C:7]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)[CH:8]=4)[CH2:23][CH2:22]3)[CH:4]=[N:5][CH:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cncc(CN3CCN(Cc4cncc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
3-Chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine (70 mg) and piperazine (10 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:31]([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:46])[CH:40]([NH:41][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:8])=[O:9])=[O:18])[CH2:42][CH:43]([CH3:44])[CH3:45])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)NC(CC(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.432 g (1.1 mmol) of L-leucine benzyl ester p-toluenesulfonic acid salt, 0.227 g (1.2 mmol) of DCC and 0.122 g (1 mmol) of DMAP were dissolved in 30 mL of CH2Cl2, 0.2 ml (1.4 mmol) of TEA was added. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: CH2Cl2:CH3Cl=1:1) to obtain the product as a oil (0.48 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13]([NH2:15])=[O:14].[OH-].[Na+].[BH4-].[Na+]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:11][CH2:12][C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NCC(N)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: NC(=O)CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.8 %

Procedure:
To a solution of 4-bromobenzaldehyde (100 g, 0.54 mol) and glycinamide hydrochloride (54 g, 0.48 mol) methanol/water (1500 ml, 5.5/1) was added sodium hydroxide (21.6 g, 0.54 mol). After stirring for 17 h at room temperature the reaction mixture was cooled to 0° C. Sodium borohydride (38 g, 1.0 mol) was added and the mixture was stirred until a clear solution was obtained. The reaction was quenched by addition of concentrated hydrochloric acid until pH=3. After stirring for 17 h the mixture was neutralized with a saturated aqueous solution of sodium hydrogen carbonate and the product was extracted into dichloromethane. The combined organic phases were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to afford 2-(4-bromobenzylamino)acetamide (92 g).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10](=[O:12])[N:9]([CH2:13][CH3:14])[C:8]=1[CH3:15])=O.[N+]([O-])(O)=O.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>COCCO>[CH2:13]([N:9]1[C:8]([CH3:15])=[C:7]([C:5]2[CH:4]=[CH:3][N:32]=[C:30]([NH:29][C:26]3[CH:27]=[N:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[N:31]=2)[S:11][C:10]1=[O:12])[CH3:14]
Reactant: CCn1c(C)c(C(=O)C=CN(C)C)sc1=O
Reactant: COc1ccc(NC(=N)N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: CCn1c(C)c(-c2ccnc(Nc3ccc(OC)nc3)n2)sc1=O
Temperature: 120 °C
Yield: 39.4 %

Procedure:
5-(3-Dimethylamino-acryloyl)-3-ethyl-4-methyl-3H-thiazol-2-one (80 mg, 0.333 mmol), N-(6-methoxy-pyridin-3-yl)-guanidine nitrate (76 mg, 0.333 mmol) and K2CO3 (185 mg, 1.332 mmol) were combined in of 2-methoxyethanol (4 mL) and the mixture was heated at 120° C. for 22 h. After cooling, the inorganics were filtered off and the filtrate was concentrated to dryness. The crude product was purified by SiO2 gel chromatography. Pooling of the desired fractions afforded the title compound (45 mg, 39%). 13C-NMR (d6-DMSO) δ: 14.5, 14.7, 37.3, 53.7, 109.0, 110.3, 128.4, 131.82, 132.4, 137.8, 138.4, 152.7, 159.5, 160.3, 164.7, 170.1. Remaining analytical data in Table 2.
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[NH:20][CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[O-]CC.[Na+]>C(O)C>[C:8]1([C:5]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:4][C:3]3[NH:20][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:2]=3[CH:7]=[CH:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C=CNC1CC(c2ccccc2)(c2ccccc2)C=CC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: 0 °C
Reaction time: 18 h
Yield: 4.6 %

Procedure:
0.3 g of ethyl 3-(2-oxo-5,5-diphenylcyclohex-3-enylamino)acrylate is dissolved in 6 cm3 of ethanol. The solution obtained is cooled to a temperature in the region of 0° C. 2 cm3 of sodium ethoxide solution (obtained from 0.23 g of sodium in 20 cm3 of ethanol) are added to the preceding solution at a temperature of between 0 and 5° C. After warming to a temperature in the region of 20° C., the resulting mixture is stirred for about 18 hours. About ten grams of crushed ice are then added to the reaction mixture and this mixture is then concentrated under reduced pressure (13 kPa) to half its volume. The mixture thus obtained is extracted five times with diethyl ether (three times 100 cm3, twice 50 cm3). The combined organic phases are successively washed with 100 cm3 and then 50 cm3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica (eluent: cyclohexane/ethyl acetate (85/15 by volume)]. 0.013 g of ethyl 6,6-diphenyl-6,7-dihydro-1H-indole-3-carboxylate is thus obtained in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][S:4][CH2:3]1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:1]=[C:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][S:4][CH2:3]1
Reactant: COC(=O)C1CSCC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)C1CSCC1=O

Procedure:
20 parts by weight of methyl 3-keto-1,5-dihydrothiophene-4-carboxylate, 57.8 parts by weight of ethanol and 1 part by weight of p-toluenesulfonic acid are refluxed for 50 hours, and the mixture is then distilled. 17.1 parts by weight of ethyl 3-keto-1,5-dihydrothiophene-4-carboxylate of melting point 106°-109° C./1.3 mbar are obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]4[N:22]=[CH:23][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:25]=4)[CH:18]([CH3:20])[CH3:19])[CH:13]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[Cl-].[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH:1]1([NH:4][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]4[N:22]=[CH:23][NH:24][CH:25]=4)[CH:18]([CH3:20])[CH3:19])[CH:13]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)NC3CC3)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(O)(c1ccc2cc(C(=O)NC3CC3)ccc2c1)c1c[nH]cn1
Temperature: 60 °C
Yield: 94.2 %

Procedure:
A mixture of N-cyclopropyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthamide (16.0 g) and pyridinium chloride (6.46 g) in methanol (84 mL) was heated at 60° C. for 3 h. The mixture was neutralized with sodium bicarbonate solution. The solvent was evaporated and the residue was dissolved in ethanol and insoluble material was filtered off. The filtrate was concentrated and purified by column chromatography (eluent; CHCl3: 8% methanolic ammonia=19:1→9:1) to give the titled compound (8.9 g) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1C
Temperature: 40 °C
Yield: 63.6 %

Procedure:
To a solution of 4-hydroxy-3-methyl benzaldehyde (3 g, 22 mmol) and ethyl 2-bromo-2-methylpropionate (6.5 mL, 44 mmol) in DMF (100 mL) was added caesium carbonate (15.8 g, 48 mmol). The resulting mixture was heated at 40° C. for 42 h, then allowed to cool to room temperature. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2×150 mL). The organic solution was dried (MgSO4), filtered and evaporated. Purification by Biotage™ chromatography (Silica, 90 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (3.5 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.CN(C)CCN(C)C.C([Li])(CC)C.N#N.Br[C:29]1[CH:51]=[CH:50][C:32]2[C:33]3[N:37]([CH2:38][CH2:39][O:40][C:31]=2[CH:30]=1)[CH:36]=[C:35]([C:41]1[N:42]([CH:47]([CH3:49])[CH3:48])[N:43]=[C:44]([CH3:46])[N:45]=1)[N:34]=3.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>COC(C)(C)C.ClCCl.[Cl-].[Cl-].[Zn+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.N1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH:47]([N:42]1[C:41]([C:35]2[N:34]=[C:33]3[N:37]([CH2:38][CH2:39][O:40][C:31]4[CH:30]=[C:29]([CH:12]5[CH2:11][CH2:10][CH2:9][NH:8]5)[CH:51]=[CH:50][C:32]=43)[CH:36]=2)=[N:45][C:44]([CH3:46])=[N:43]1)([CH3:49])[CH3:48]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: COC(C)(C)C
Solvent: C1CCNC1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCCN4)cc2OCC3)n(C(C)C)n1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of N-(tert-Butoxycarbonyl)pyrrolidine (1.02 mL, 0.00584 mol) and N,N,N′,N′-Tetramethylethylenediamine (0.881 mL, 0.00584 mol) in anhydrous 2-Methoxy-2-methylpropane (12 mL) at −78° C. was added sec-Butyllithium (0.00584 mol, 1.4M in cyclohexane, 4.17 mL). The reaction was stirred for 3 hours at −78° C. A solution of Zinc dichloride (0.00350 mol, 0.5 M in THF, 7.0 mL) was added dropwise with rapid stirring and was stirred at −78° C. for 30 minutes. The reaction was then warmed to room temperature and stirred an additional 30 minutes. To a N2-filled flask containing 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (0.900 g, 0.00232 mol), Palladium Acetate (0.0260 g, 0.116 mmol) and Tri-t-butylphosphonium tetrafluoroborate (0.0420 g, 0.000145 mol) was added the zinc chloride pyrrolidine solution (1.25 equiv., 0.243M, 11.9 mL). The reaction was heated to 90° C. overnight. An incomplete conversion to product was observed by LC/MS. The mixture was diluted with dichloromethane and filtered through celite. Saturated NH4Cl was added and the mixture was extracted 3 times with dichloromethane. The organic layers were combined, dried with Na2SO4 and concentrated. The crude was redissolved in Methylene chloride (4.5 mL). Trifluoroacetic Acid (5.5 mL) was added and the reaction was stirred at room temperature for 30 minutes, then concentrated. The crude was purified by reverse-phase HPLC and the enantiomers were separated by chiral SFC to obtain 10 mg of each enantiomer of 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-2-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a white solid. MS (ESI+) 379.2
Reaction SMILES: [C:1]1([C:7]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](I)[CH3:30]>C(O)C>[CH2:29]([N:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11](=[O:12])[N:10]1[C:13]1[CH:14]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:17][CH:18]=1)[CH3:30]
Reactant: CCI
Reactant: O=c1c(-c2ccccc2)c[nH]n1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1cc(-c2ccccc2)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 2.2 grams of the pyrazolinone prepared above, 2 grams potassium carbonate, 25 ml. ethyl iodide and 25 ml. ethanol was refluxed for about 3 hours. The reaction mixture was worked up in the usual manner to yield an oil which was identified by NMR analysis as the desired product.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]2[C@H:21]([CH3:22])[CH2:20][CH2:19][C:15]=2[N:16]=[CH:17][N:18]=1.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:12][C:13]1[N:18]=[CH:17][N+:16]([O-:9])=[C:15]2[CH2:19][CH2:20][C@@H:21]([CH3:22])[C:14]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Solid 77% maximum m-CPBA (12 g, 53 mmol) was added portionwise to a 0° C. solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5 g, 30 mmol) in CHCl3 (80 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0° C., and then treated by the addition of NaHCO3 (25 g, 196 mmol) slurry in water (100 mL). This was followed by the dropwise addition of Na2CO3 (14 g, 128 mmol) in water (100 mL). The reaction mixture was stirred for 30 minutes. The aqueous phase was extracted with CHCl3. The organic phase was dried with MgSO4 and concentrated under reduced pressure at low temperature (<25° C.) to afford the crude (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (5.5 g, 100%), which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[N:76]1[C:84]2[CH2:83][CH2:82][CH2:81][CH2:80][C:79]=2[CH:78]=[N:77]1>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=2[N:76]2[C:84]4[CH2:83][CH2:82][CH2:81][CH2:80][C:79]=4[CH:78]=[N:77]2)=[CH:12][CH:11]=3)[CH2:5][CH2:6]1
Reactant: Brc1ccccc1-n1ncc2c1CCCC2
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1nc2ccc(-c3ccccc3-n3ncc4c3CCCC4)cc2cc1N1CCOCC1
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.128 g, 0.361 mmol, prepared as in Example 2, Step 1-2), potassium phosphate (0.306 g, 1.443 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.034 g, 0.072 mmol), Pd2db3 (0.017 g, 0.018 mmol), and 1-(2-bromophenyl)-4,5,6,7-tetrahydro-1H-indazole (0.200 g, 0.722 mmol). The vessel was evacuated and flushed with N2 3× before dioxane (2.4 mL) and water (1.2 mL) (each degassed by bubbling N2 gas through the solution for 10 min prior to addition) were added. The reaction mixture was stirred and heated in a microwave reactor at 140° C. for 15 min. The reaction mixture was diluted with 10:1 saturated ammonium chloride/ammonium hydroxide and extracted with EtOAc. The combined organic extracts were washed with 10:1 saturated ammonium chloride/ammonium hydroxide, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting through a plug of silica with 1:1 EtOAc/Hexanes then 1:10 2M NH3 in MeOH/DCM. The sample was further purified by reverse-phase preparative HPLC with 0.1% TFA in CH3CN/H2O, gradient 5-20% over 15 min to provide 3-morpholino-6-(2-(4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)quinolin-2-amine. The purified compound was partitioned between DCM and saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with saturated sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the pure material as a white solid. MS (ESI, pos. ion) m/z: 426 (M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>CC#N>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:28]1[CH:29]=[CH:30][C:25]([C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:24])[CH3:23])=[CH:26][CH:27]=1)(=[O:5])=[O:4]
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(c1ccccc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoromethanesulfonic anhydride (1.99 mL) was added dropwise to a solution of 4-(2-phenylpropan-2-yl)phenol (1.68 g) and pyridine (1.277 mL) in MeCN (10 mL) at 0° C. The mixture was stirred at room temperature for 2 days. The mixture was quenched with 0.1 N HCl aq. at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered through silica-Celite pad (eluted with EtOAc) and concentrated in vacuo to give 4-(2-phenylpropan-2-yl)phenyl trifluoromethanesulfonate (2.65 g) as a yellow oil.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9](CC#C)[CH2:8][CH2:7]1)=[O:5].C([O-])([O-])=O.[K+].[K+].C1(S)CCCCC1>CN(C=O)C>[ClH:1].[CH:25]1([S:24][C:21]2[CH:20]=[CH:19][C:18]([S:15]([C:6]3([C:4]([NH:3][OH:2])=[O:5])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]3)(=[O:17])=[O:16])=[CH:23][CH:22]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Sc3ccccc3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: SC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(NO)C1(S(=O)(=O)c2ccc(SC3CCCCC3)cc2)CCNCC1
Yield: 67 %

Procedure:
Part A: To a solution of the sulfone of Example 9, part D (10.1 g, 24.0 mmol) in DMF (20 mL) were added K2CO3 (5.0 g, 36.0 mmol) and cyclohexylmercaptan (4.4 mL, 36.0 mmol), and the solution was heated at 85 degrees Celsius for 6.5 hours. The solution was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as a oil (8.2 g, 67%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([CH3:50])([S:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)[CH:22]=2)[N:17]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:16]=1[CH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][C:12]([CH3:50])([S:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)[CH:22]=2)[N:17]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:16]=1[CH2:44][C:45]([CH3:49])([CH3:48])[CH:46]=[O:47])[CH3:11]
Reactant: CC(C)(CO)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C=O)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution of oxalyl chloride (461 mg, 3.6 mmol) in CH2Cl2 (10 mls) at -78° C. was added dimethylsulfoxide (600 mg, 7.68 mmol) dropwise and the resulting mixture was stirred for 5 mins. A solution of 3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2yl]-2,2-dimethylpropanol (1.81 g, 3.2 mmol) in CH2Cl2 (5 mls) was then added dropwise and the reaction was stirred for 20 mins at -78° C. Triethylamine (1,62 g, 16.0 mmol) was then added dropwise, the cooling bath was withdrawn and the reaction allowed to warm to r.t. It was then diluted with aqueous sat'd NaHCO3 (20 mls) and the layers were separated. The aqueous was extracted with CH2Cl2 (2×20 mls). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 1:1) to afford 1.58 g (86%) of 3-[3-(1,1-dimethylethylthio)-5-(quinolin-2-ylmethoxy)-1-(4-chlorophenylmethyl)indol-2-yl]-2,2-dimethylpropionaldehyde as a lemon yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1
Reactant: COc1ccc(CC(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)c(Br)c1

Procedure:
A solution of 3-bromo-4-methoxyphenylacetic acid (7.5 g, 30.6 mmol), MeOH (24 mL) and H2SO4 (0.8 mL) was stirred at 75° C. for 17 h. The reaction mixture was concentrated. The residue was poured into H2O and extracted with CH2Cl2. The organic layer was washed with brine, dried (NaSO4), filtered and concentrated to afford the title compound. tR: 0.99 min (LC-MS 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:16][CH:18]3[O:20][CH2:19]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cccc(N2CCN(CC3CO3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1.50 g of 4-(3-chlorophenyl)piperazine and 0.31 g of sodium hydride was added 2.4 ml of epichlorohydrin and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was extracted with 100 ml of ethyl acetate, and the extract was washed 5 times with 100 ml of water, then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain the residue which was purified by means of a silica gel column chromatography (eluent:ethyl acetate:n-hexane=1:1) to obtain 1.66 g of 4-(3-chlorophenyl)-1-(2,3-epoxypropyl)piperazine as in the form of an oily substance.