Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[NH2:13][CH2:14][CH2:15][CH2:16]N>C(O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[NH:13][CH2:14][CH2:15][CH2:16][N:9]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: NCCCN
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C2=NCCCN2)cc1
Reaction time: 6 h

Procedure:
4-Nitrobenzonitrile (17.76 g) was added to a solution of sodium metal (0.138 g) in dry ethanol (150 ml) at room temperature, and the mixture was stirred for 6 h. To the suspension was added 1,3-diaminopropane (8.88 g) and the mixture was heated under reflux for 4 days. Evaporation of the solvent under reduced pressure gave a solid which was dissolved in hot ethyl acetate (450 ml). The solution was extracted with 2N hydrochloric acid (90 ml, 20 ml). The combined acidic extracts were washed with ethyl acetate (100 ml) and then basified with 5N sodium hydroxide (60 ml). The emulsion was extracted into hot ethyl acetate (250 ml, 2×100 ml), the organic extracts were combined, reduced to about 250 ml by evaporation and hot cyclohexane (125 ml) was added. On cooling the title compound deposited as needles (17.7 g), m.p. 168°-172°.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[CH2:9][C:8]2=[O:24])=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([CH3:25])[CH:2]=[CH:3][C:4]([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=3)[CH2:9][C:8]2=[O:24])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(C)cc3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(N2CC(COc3ccc(C(=O)O)cc3)CC2=O)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 91.7 %

Procedure:
Methyl 4-[1-(4-tolyl)-2-pyrrolidon-4-yl]methoxybenzoate (58.74 g) and sodium hydroxide (10.40 g) are dissolved in about 20 % aqueous methanol (630 ml) and the mixture is heated with stirring at 60° C. for 14 hours. After cooling, the reaction mixture is concentrated under reduced pressure to about the half volume thereof and thereto are added water (130 ml) and conc. hydrochloric acid (22.6 ml). The precipitated crystal is collected by filtration, washed successively with 50 % aqueous methanol and water, and recrystallized from a mixed solvent (about 400 ml) of ethyl acetate/hexane [2:1 (v/v)] to give the desired product (51.65 g), m.p. 212°-213 ° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:10])/[C:6](=[CH:8]/[CH3:9])/[CH3:7].[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.Cl>C(=S)=S>[CH3:7][CH:6]1[CH:8]([CH3:9])[C:15]2[C:14](=[C:13]([CH3:12])[CH:18]=[CH:17][C:16]=2[CH3:19])[C:5]1=[O:10]
Reactant: C/C=C(\C)C(=O)Cl
Reactant: Cc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1ccc(C)c2c1C(=O)C(C)C2C
Temperature: -10 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Under an argon atmosphere AlCl3 (64 g, 0.48 mol) and CS2 (250 ml) were placed in a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus, an addition funnel, an inner thermometer and a reflux condenser. A mixture of tigloyl chloride (33) (42 g, 0.35 mol) and p-xylene (42.8 ml, 0.35 mol) was added over a period of 1 h at −10° C. under vigorous stirring. After 2 h stirring at −10° C. the mixture was allowed to come to ambient temperature and was stirred at that temperature overnight. The brown reaction mixture was then refluxed for 3 h, after cooling to ambient temperature the reaction mixture was poured carefully onto a mixture of concentrated HCl (300 ml) and ice (500 g). Then the mixture was transferred into a separation funnel, the lower CS2 layer was separated and the aqueous layer extracted with diethyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate, filtered, and the solvents removed in a rotary evaporator to give a red brown liquid. This residue was rectified using a 35 cm Vigreux column to afford 2,3,4,7-tetramethyl-1-indanone (35) (34 g, 52%, 95-100° C., 1.5-1.2 mbar) as a pale yellow liquid. (35) was found to be a mixture of the two isomers of 2,3,4,7-tetramethyl-1-indanone (35a to 35b approximately 3:1). The 1H NMR spectrum was identical with the literature (S. Barlow, D. R. Cary, M. J. Drewitt, D. O'Hare, J. Chem. Soc. Dalton Trans. 1997 3867-3878).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH2:37][CH3:38])[CH:32]=2)[CH:27]1[C:39]([OH:41])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[CH2:42]([O:44][CH2:45][C:46]([C:49]1[C:55]([F:56])=[CH:54][C:52]([NH2:53])=[CH:51][C:50]=1[F:57])([CH3:48])[CH3:47])[CH3:43].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH2:37]([O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH:27]([C:39](=[O:41])[NH:53][C:52]1[CH:51]=[C:50]([F:57])[C:49]([C:46]([CH3:48])([CH3:47])[CH2:45][O:44][CH2:42][CH3:43])=[C:55]([F:56])[CH:54]=1)[N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:35][CH2:34]2)[CH3:38]
Reactant: CCOCC(C)(C)c1c(F)cc(N)cc1F
Reactant: CCOc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCC(C)(C)c1c(F)cc(NC(=O)C2c3ccc(OCC)cc3CCN2C(=O)OC(C)(C)C)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
T3P (4.62 mL, 7.85 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (841 mg, 2.62 mmol), 4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoroaniline (600 mg, 2.62 mmol), DIEA (2.285 mL, 13.09 mmol) and DMAP (320 mg, 2.62 mmol) in ethyl acetate (5 mL), and the mixture was stirred at 60° C. overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give tert-butyl 6-ethoxy-1-((4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluorophenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (700 mg, 1.314 mmol, 50.2%) as white crystals.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([Br:13])=[CH:5]2.[OH2:14]>P(=O)(O)(O)O>[Br:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([OH:14])=[CH:11][C:10]=2[CH3:12]
Reactant: Cc1cc(N)cc2cc(Br)cnc12
Reactant: O
Agent: O=P(O)(O)O
Product: Cc1cc(O)cc2cc(Br)cnc12
Temperature: 180 °C

Procedure:
6-Amino-3-bromo-8-methylquinoline (12 g) (preparation described in Journal of the American Chemical Society (1955), pages 4175-4176) is suspended in a mixture of water (5 ml) and phosphoric acid (60 ml) and heated in a sealed glass tube to 180° C. for 3 days. The mixture is cooled to ambient temperature, diluted with water then taken to pH 3-4 with aqueous (2M)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:8]=[C:9]([CH3:11])[CH:10]=1)(=[O:3])[CH3:2]>C[Si](OP(=O)=O)(C)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C)cc(CCCC(=O)O)c1
Agent: C[Si](C)(C)OP(=O)=O
Product: CC(=O)Nc1cc(C)c2c(c1)CCCC2=O
Temperature: 0 °C
Yield: 40 %

Procedure:
The product from Example 129 (3 g) was treated with a solution of trimethylsilyl polyphosphate (PPSE) (50 ml in o-dichlorobenzene) at 100° C. for 10 minutes. The reaction was cooled to 0° C., quenched with 2NHCl and extracted with methylene chloride. The organic layer was separated, dried and evaporated to one-half the volume and purified on a small bed of silica gel. The desired tetralone was obtained in 40% yield. m.p.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:24]=[CH:25][CH:26]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(OCc2ccccc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-benzyloxybenzaldehyde in an analogous manner to that described in Example 1 to give 9-(3-benzyloxyphenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from ethanol gave a cream coloured crystalline solid of melting point >300° C. (decomposition).
Reaction SMILES: CC(S([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16])=O)(C)C.Cl>CO.O1CCOCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:21]2[CH:22]=[CH:23][C:18]([S:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][NH2:7])(=[O:17])=[O:16])=[CH:19][CH:20]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)S(=O)NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1

Procedure:
2-Methyl-N-[2-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzyl]propane-2-sulfinamide (Example 177, 285 mg, 0.6 mmol) was dissolved in methanol (5 mL) and 4N HCl in dioxane (5 mL) and stirred overnight at room temperature. The solvent was removed in vacuo and the residue triturated with diethyl ether to give the title compound as the hydrochloride salt (221 mg, 90%). δH (500 MHz, d6 DMSO): 8.46-8.38 (3H, m), 8.13 (1H, d, J=7.8 Hz), 7.89 (2H, d, J=8.3 Hz), 7.84-7.78 (3H, m), 7.71-7.67 (4H, m), 7.45 (1H, d, J=16.5 Hz), 7.30 (1H, d, J=16.5 Hz), 7.23 (2H, t, J=8.7 Hz), 4.28 (2H, s).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[C:9]#[N:10])=[CH:3][CH:2]=1.[CH3:25][O-].[Na+].CI.[Cl-].[NH4+]>CO>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)([CH3:25])[C:9]#[N:10])=[CH:5][CH:6]=1
Reactant: Cc1ccc(SC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cc1ccc(SC(C)(C#N)c2cccc(Oc3ccccc3)c2)cc1
Yield: 86 %

Procedure:
1.245 g of alpha-(p-tolylthio)(m-phenoxyphenyl)-acetonitrile was dissolved in 5 ml of anhydrous methanol, and a 2.2 M methanol solution of sodium methoxide was added at room temperature in an atmosphere of argon. The mixture was stirred, and 0.35 ml of methyl iodide was added dropwise. The mixture was further stirred for 30 minutes at room temperature. Then, an aqueous solution of ammonium chloride (3 g/20 ml) was added, and the mixture was extracted with 20 ml of ether three times. The extract was washed with 30 ml of water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (silica gel; hexane and methylene chloride) to afford 1.125 g (yield 86%) of alpha-(p-tolylthio)-alpha-(m-phenoxyphenyl)propionitrile as a pale yellow oil.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30].Cl>O.O1CCOCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:7][S:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:29]([F:32])([F:30])[F:31])[CH:21]=2)(=[O:27])=[O:26])[CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 64.6 %

Procedure:
To a solution of Na2CO3 (11.7 g, 110.7 mmol) in water (50 mL) and 1,4-dioxane (50 mL) at 60° C. was added 2-amino-4-chloro-benzoic acid (5.0 g, 29.14 mmol) followed by 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (20.15 g, 72.48 mmol) in 3 portions and heated the resulting reaction mixture at 80° C. for 4 hours. 2N HCl Was added until the reaction mixture became acidic (pH=˜2) and obtained white solid was filtered, washed with water, dried under high vacuum to obtain title compound (7.8 g) in 65% yield. MS (ES) M+Na expected 436.0, found 435.8.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-].[K+].[OH:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[C:6]1([CH2:5][C:4]#[C:3][CH2:2][O:14][N:15]2[C:16](=[O:25])[C:17]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]3[C:19]2=[O:20])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCC#CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1OCC#CCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
51.3 g (0.23 mol) of the 1-bromo-4-phenyl-2-butyne obtained above were added dropwise in the course of 30 minutes to a mixture consisting of 230 ml of N-methylpyrrolid-2-one, 3 g of potassium iodide, 37 g (0.23 mol) of N-hydroxyphthalimide and 20.6 g (0.15 mol) of potassium carbonate. Stirring was carried out for a further 5 hours at 60° C. and then overnight at room temperature, the mixture was poured into 800 ml of ice water and the precipitated crystals were filtered off under suction and washed thoroughly with water and isopropanol.
Reaction SMILES: [S:1]([O:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Na+].[NH2:23]Cl.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:23][N:14]1[CH:15]=[CH:16][C:12]([O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])=[C:13]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: NCl
Reactant: COC(=O)c1[nH]ccc1OS(=O)(=O)c1ccc(C)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(OS(=O)(=O)c2ccc(C)cc2)ccn1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Solid methyl 3-(tosyloxy)-1H-pyrrole-2-carboxylate (1.33 μm, 4.50 mmole) was added in portions to an ice-cooled suspension of NaH (60% in mineral oil, 234 mg, 5.85 mmole) in dry DMF (15 mL) under a dry N2 atmosphere. Upon completion of the addition, the reaction was removed from the bath and left stirring at RT. After 1 hr, a solution of NH2Cl (59 mL; 0.1 M in Et2O prepared according to J. Chem. Soc. C, 1971, 824; 5.85 mmole) was added and the reaction was left stirring for 1.3 hr. It was then cooled to −5° C. and an aqueous solution of Na2S2O4 (20 mL, 1.0 M) was slowly added over 5 min. Water (60 mL) was added and the bath was removed. After 10 min, this was extracted with EtOAc (2×200 mL) and the organic extracts were washed with brine and dried (Na2SO4). Removal of the solvents followed by flash chromatography on silica gel using step gradient elution (hexane:EtOAc from 100:0 to 70:30) afforded the title compound (1.22 gm, 88% yield) as a solid. 1H NMR (CDCl3): 2.39 (s, 2H), 3.62 (s, 3H), 5.44 (s, 2H), 5.76 (m, 1H), 6.73 (m, 1H), 7.26 (m, 2H), 7.66 (m, 2H); MS: 311 (M+H)+; HPLC Ret Time: 1.28 min (YMC Xterra S7 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:19](=[O:36])[NH:20][C:21]3[S:22][C:23]([S:26][CH2:27][CH2:28][O:29]C4CCCCO4)=[CH:24][N:25]=3)[C:5]2=[CH:6][CH:7]=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:19](=[O:36])[NH:20][C:21]3[S:22][C:23]([S:26][CH2:27][CH2:28][OH:29])=[CH:24][N:25]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCOC3CCCCO3)s1)c1ccc(Cl)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCO)s1)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
The methyl 5-chloro-1-((5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)thio)thiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (90.0 mg, 0.163 mmol) obtained in Example 136 was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL). Thereafter, a 12 N aqueous solution of hydrochloric acid (0.2 mL) was added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 10 minutes. Thereafter, the reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (63.0 mg, 82%) in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[CH2:21][C:20]([CH3:23])=[CH:19]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:30](I)([CH3:32])[CH3:31]>CN(C=O)C>[CH:30]([N:11]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH2:17][C:18]2[C:22]=1[CH:21]=[C:20]([CH3:23])[CH:19]=2)[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])([CH3:32])[CH3:31]
Reactant: CC(C)I
Reactant: CC1=Cc2cccc(CCNS(=O)(=O)c3ccc(C)cc3)c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1=CC2=C(CCN(C(C)C)S(=O)(=O)c3ccc(C)cc3)C=CCC2=C1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
At room temperature, to a solution of 11.4 g (34.8 mmol) of 4-methyl-N-[2-(2-methyl-1H-inden-7-yl)ethyl]-benzenesulfonamide in 75 mL of dry DMF, 17.0 g (52.3 mmol) of Cs2CO3 was added, and then 11.9 g (69.8 mmol) of iPrI was added dropwise over a period of 10 minutes. This mixture was then stirred for 3 days at 50° C., and then evaporated via vacuum. To the residue, 200 mL of water and 200 mL of dichloromethane were added. The organic layer was separated, and the aqueous layer was washed with 200 mL of dichloromethane. The combined organic extract was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent—dichloromethane). Yield, 10.9 g (85%) of white solid. This product was further used without additional purification. 1H NMR (CDCl3): δ 7.20 (m, 1H, 5-H in indenyl), 7.15 (m, 1H, 6-H in indenyl), 6.95 (m, 1H, 4-H in indenyl), 6.52 (m, 1H, 3-H in indenyl), 4.06 (set, J=6.8 Hz, 1H, CHMe2), 3.13-3.27 (m, 4H, 1,1′-H in indenyl and CH2CH2N), 2.96-3.07 (m, 2H, CH2CH2N), 2.34 (s, 3H, 2-Me in indenyl), 0.99 (d, J=6.8 Hz, 6H, CHMe2). Anal. Calc. for C22H27NO2S: C, 71.51; H, 7.36; N, 3.79%. Found: C, 72.01; H, 7.49; N, 3.33%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][NH:17][CH3:18].C(O)C>CN(C)C=O.C(OCC)(=O)C>[CH3:16][N:17]([CH3:18])[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CNC
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)c1ccccc1C=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 84.6 %

Procedure:
To a suspension of 2-fluorobenzaldehyde (250 μL, 2.37 mmol) and potassium carbonate (328 mg, 2.37 mmol) in 5 mL of dry N,N-dimethylformamide was added dimethylamine/ethanol solution (0.65 mL, 5.6 M, 3.6 mmol) at room temperature. After being stirred at 110° C. for 12 h, the reaction mixture was diluted with ethyl acetate. The solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound as a yellow oil (299 mg, 85%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:38][C:39]([F:42])([F:41])[F:40])=[C:18]([NH:20][C:21]3[N:30]=[CH:29][C:28]4[CH2:27][CH2:26][C:25]5[C:31]([C:35]([NH2:37])=[O:36])=[N:32][N:33]([CH3:34])[C:24]=5[C:23]=4[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1.Cl>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([O:38][C:39]([F:40])([F:41])[F:42])=[C:18]([NH:20][C:21]3[N:30]=[CH:29][C:28]4[CH2:27][CH2:26][C:25]5[C:31]([C:35]([NH2:37])=[O:36])=[N:32][N:33]([CH3:34])[C:24]=5[C:23]=4[N:22]=3)[CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(Nc3cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc3OC(F)(F)F)ncc1CC2
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(C(N)=O)c2c1-c1nc(Nc3cc(N4CCNCC4)ccc3OC(F)(F)F)ncc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8-[5-(4-t-butoxycarbonyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (94 mg, 0.16 mmol) in dioxane (3 ml), 4M HCl in dioxane (0.89 ml, 3.42 mmol) was added. The mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the crude was diluted with Et2O and decanted, to give the final compound as a hydrochloride salt in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH3:26])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]([O:21]C)=[C:14]([CH:23]([CH3:25])[CH3:24])[CH:13]=1)=[O:11].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH3:26])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[C:15]([OH:21])=[C:14]([CH:23]([CH3:24])[CH3:25])[CH:13]=1)=[O:11]
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Yield: 72 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (0.973 g, 2.01 mmol) and 1M boron tribromide/CH2Cl2 (4.23 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 0.679 g (72%) of the title compound. 1H NMR (DMSO-d6) δ 1.13 (d, 12H), 1.82 (s, 3H), 2.18 (s, 3H), 3.31 (septet, 2H), 3.94 (s, 2H), 7.12-7.17 (m, 2H), 7.30 (dt, 1H), 7.42 (s, 2H), 7.52 (d, 1H), 9.10 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]1[CH:44]=[CH:45][C:46]([CH3:53])=[C:47]([S:49](Cl)(=[O:51])=[O:50])[CH:48]=1>C(#N)C>[CH3:53][C:46]1[CH:45]=[CH:44][C:43]([F:42])=[CH:48][C:47]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(F)cc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 39.8 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0287 g, 0.0622 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-fluoro-2-methylbenzenesulfonyl chloride (0.0286 mL, 0.195 mmol) to obtain 4-(2-methyl-5-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0157 g, yield 40%).