Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([CH2:15][Br:37])=[CH:10][C:9]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1c(Cl)cc(CBr)cc1Cl
Yield: 35.2 %

Procedure:
A refluxing solution of 4-(4-chlorobenzoyl)-3,5-dichlorotoluene (7.19 g, 24.0 mmol) and dibenzoylperoxide (370 mg, 1.53 mmol) in benzene (247 ml) was treated in portions with N-bromosuccinimide (7.53 g, 42.3 mmol). The mixture was refluxed 24 hours, cooled, and filtered. The precipitate was washed once with benzene, and the combined filtrate and washings were evaporated under vacuum. The residue was triturated with diethyl ether and filtered, and the filtrate was evaporated under vacuum. The residue was chromatographed on silica gel (500 g) eluted with 7:3 (v/v) n-hexanedichloromethane using a preparative high-performance liquid chromatograph to provide 3.2 g (35%) of 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide, m.p. 69°-73° C.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1.CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)(=O)=O.O>CO.C(OC)(C)(C)C>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[CH2:14][S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1
Reactant: CS(=O)(=O)OCC1CCCCO1
Reactant: Sc1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: O
Product: c1nc(SCC2CCCCO2)n[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.7 g (173 mmol) of potassium hydroxide and 17.5 g (173 mmol) of 3-mercapto-1,2,4-triazole were dissolved in 200 ml of methanol and heated under reflux for one hour. After the solvent had been distilled off under reduced pressure, the residue was dried by azeotropic distillation with toluene and then taken up in 300 ml of methanol. 33.6 g (173 mmol) of tetrahydropyran-2-ylmethyl methanesulfonate (step a) were then added and the mixture was stirred at room temperature for 24 hours. 200 ml of water and 200 ml of methyl tert-butyl ether were then added to the reaction mixture and the organic phase was separated off, washed with water and dried. The mixture was concentrated and the residue was chromatographed over silica gel, yielding 18.2 g (53% of theory) of a yellow oil. (1H-NMR (CDCl3; δ in ppm): 8.05 (s,1H); 4.15 (d,1H); 3.65 (m,1H); 3.50 (m,1H); 3.25-3.10 (m,2H); 1.85 (m,1H); 1.75-1.25 (m,6H))
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])([O-:23])=[O:22].CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4cccc([N+](=O)[O-])c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.10 g, 4 mmol) in THF (30 ml) was added 3-nitrobenzoyl chloride 1.48 g, 8 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (30 ml) and filtered to give 1.60 g (95%) of product as an off-white solid: mp 245-247° C.; 1H NMR (DMSO-d6) d 10.85 (s, 1H), 10.53 (s, 1H), 8.76 (s, 1H), 8.50-8.37 (m, 3H), 7.95-7.87 (m, 2H), 7.70 (d, J=7.4 Hz, 1H), 5.14 (dd, J=5.7 and 12.7 Hz, 1H), 3.02-2.83 (m, 1H), 2.67-2.47 (m, 2H), 2.15-2.07 (m, 1H); 13C NMR (DMSO-d6) d 171.73, 168.79, 167.19, 166.04, 162.85, 147.84, 135.60, 134.79, 132.92, 131.21, 130.19, 126.87, 126.20, 121.69, 118.83, 48.86, 30.51, 21.63; Anal. Calcd. For C20H14N4O7: C, 56.88; H, 3.34; N, 13.27. Found: C, 56.87; H, 3.33; N, 13.05.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[CH2:31]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH2:32][CH3:33]>>[CH2:31]([C:34]1[CH:40]=[CH:39][C:37]([N:38]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:36][CH:35]=1)[CH2:32][CH3:33]
Reactant: CCCc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 497.17 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-propyl-aniline.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:24]=[CH:23][CH:22]=[C:7]2[C:8]([N:10]([C:13]3([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2].[CH3:25][NH2:26]>>[C:1]([NH:4][C:5]1[CH:24]=[CH:23][CH:22]=[C:7]2[C:8]([N:10]([C:13]3([C:19]([NH:26][CH3:25])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C1(C(=O)Cl)CCCCC1)C2=O
Product: CNC(=O)C1(N2C(=O)c3cccc(NC(C)=O)c3C2=O)CCCCC1

Procedure:
Using the same procedure as described in Example 3 but replacing the ammonia with methylamine gives the title mono-methylamide, m.p. 168.5°-170°C. Similarly, reacting 1-(3-acetamidophthalimido)-cyclohexanecarbonyl chloride with methylamine yields 1-(3-acetamidophthalimido)-N-methylcyclohexanecarboxamide, m.p. 205°-207.5°C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(=S)=S.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[O:13])=[CH:20][CH:19]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 28.9 %

Procedure:
Aluminum chloride (26.0 g, 195 mmol) was added in portions to a solution of 4-nitrobenzoyl chloride (27.8 g, 150 mL) and 4-fluorobenzene (15.8 g, 165 mmol) in carbon disulfide (100 mL). After 1 hour, the resulting yellow mixture was carefully treated with concentrated hydrochloric acid (60 mL) and stirred for 30 minutes. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with dilute sodium hydroxide solution, water and brine, dried (MgSO4), and the solvent removed in vacuo. Crystallization from ethyl ether/hexanes gave 4-(4-fluorobenzoyl)-nitrobenzene (10.6 g, 82%) as a white solid, m.p. 87–88° C.; Analysis for C13H8NO3F: Calc.: C, 63.69; H, 3.26; N, 5.7: Found: C, 63.89; H, 3.28; N, 5.78.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:35][CH:36]([F:38])[F:37])=[C:19]([C:21]2[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:23][C:22]=2[NH2:34])[CH:20]=1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:35][CH:36]([F:37])[F:38])=[C:19]([C:21]2[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[N:24]=[CH:23][C:22]=2[NH:34][C:11]([C:10]2[CH:9]=[N:8][N:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][C:4]=23)=[O:12])[CH:20]=1
Reactant: C[Si](C)(C)CCOCn1ncc(N)c1-c1cc(Cl)ccc1OC(F)F
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3ccc(Cl)nc23)c1-c1cc(Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (500 mg, 2.3 mmol) (prepared according to the procedure in Journal of Medicinal Chemistry, 55(22), 10090-10107; 2012) and 5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine (868 mg, 2.3 mmol) were suspended in triethylamine (0.35 mL, 2.5 mmol) and DCM (10 mL) and the mixture was left to stir at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and the resultant organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, and brine, dried (Na2SO4) and evaporated to afford an oil. The resultant oil was purified by flash chromatography on silica eluting with 0-2% MeOH in DCM. Collecting appropriate fractions, followed by evaporation gave 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide as a brown oil (1.19 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.07 (s, 1H), 8.72 (s, 1H), 8.67 (d, 1H, J=7.3 Hz), 8.38 (s, 1H), 7.60 (d, 1H, J=2.3 Hz), 7.51 (dd, 1H, J=2.6, 8.8 Hz), 7.38 (d, 1H, J=8.9 Hz), 6.95 (d, 1H, J=7.2 Hz), 6.43 (t, 1H, J=72.8 Hz), 5.41 (d, 1H, J=10.9 Hz), 5.31 (d, 1H, J=11.0 Hz), 3.76-3.49 (m, 2H), 1.27 (s, 1H), 0.94-0.84 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]([CH2:21][OH:22])[CH2:19][CH3:20])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[Si](O[CH2:31][CH2:32][N:33]([CH3:45])[C:34](=[O:44])[C:35]1[CH:40]=[CH:39][C:38](F)=[C:37]([Cl:42])[C:36]=1F)(C(C)(C)C)(C)C.C(=O)([O-])[O-:47].[K+].[K+].O>CC(N(C)C)=O>[Cl:42][C:37]1[C:36]2[O:47][CH:32]([CH3:31])[N:33]([CH3:45])[C:34](=[O:44])[C:35]=2[CH:40]=[CH:39][C:38]=1[O:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]([CH2:21][OH:22])[CH2:19][CH3:20])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(Cl)c1F
Reactant: CC[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC[C@@H](CO)Oc1cc(Oc2ccc3c(c2Cl)OC(C)N(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 159.5 %

Procedure:
A solution of 3-hydroxy-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.66 mmol), N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-2,4-difluoro-N-methylbenzamide (239 mg, 0.66 mmol) and potassium carbonate (181 mg, 1.31 mmol) in DMA (3 mL) was heated in a microwave reactor at 160° C. for 6 hours. Water (20 mL) was added and the reaction mixture extracted with ethyl acetate. The organic layer was washed with brine (20 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 2% methanol in ethyl acetate, and then chromatographed by preparative HPLC on C18 reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give the required product (542 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C[N:14]1[CH2:18][C:17](B(O)O)=[C:16]([CH3:22])[O:15]1.[CH2:23](N(CC)CC)C>O.CC(O)C>[CH3:23][C:18]1[C:17]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3=[O:12])=[C:16]([CH3:22])[O:15][N:14]=1
Reactant: CCN(CC)CC
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: CC1=C(B(O)O)CN(C)O1
Solvent: CC(C)O
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(=O)C(=O)N2

Procedure:
5-iodo-1H-indole-2,3-dione (24.0 g, 83.5 mmol) and 2,5-dimethylisoxazole-4-boronic acid (16.0 g, 111.3 mmol) are dissolved in a mixture of water (400 mL) and 2-propanol (800 mL). Triethylamine (36.0 mL, 253.3 mmol) is added followed by 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.0 g, 1.4 mmol). The mixture is purged with argon and then heated at reflux for 5 hours. The solvent is removed in vacuo and the residue partitioned between water and dichloromethane. The organic phase is dried over magnesium sulfate. And the volatiles removed in vacuo. The residue is purified by column chromatography on silica gel using a cyclohexane/ethyl acetate gradient. This afforded the desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][C:10]=3[Br:17])[CH3:2].CS(C)=O.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:29][CH2:28][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][C:10]=3[Br:17])[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cccc(Br)c3nc21
Reactant: NCC1CCCCC1
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cccc(Br)c3nc21
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-8-bromo-1H-pyrazolo[3,4-b]quinoline (2.0 g, 6.44 mmol), DMSO (5 mL) and cyclohexylmethylamine (1.46 g, 12.9 mmol) was heated at 80°-90° C. for 3 hours. The reaction mixture was cooled to room temperature and then was poured into water. The resulting solid was collected by filtration, washed with water and evaporated. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 2.0 g (80%) of 1-ethyl-8-bromo-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 160°-162° C.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14]C=O.C(=O)([O-])[O-].[K+].[K+].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cu]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][O:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[NH:14][C:8]=2[CH:9]=1
Reactant: O=CNc1cc(Cl)ccc1OCOc1ccccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Clc1ccc2c(c1)Nc1ccccc1OCO2
Reaction time: 8 h

Procedure:
A suspension of 1.4 g. (0.004 moles) of (2-bromophenoxy)-(2-formamido-4-chlorophenoxy)-methane (m.p.: 98° to 100° C.), 0.6 g. (0.0042 moles) of potassium carbonate, 0.2 g. of copper powder and 12 ml. of Dowtherm(®) is heated up to 180° C. and is vigorously stirred at this temperature for 8 hours. The reaction mixture is filtered while hot, then the solvent is evaporated in vacuo. The remaining dark tar is hydrolyzed by boiling in a mixture of 20 ml. of ethanol and 2 ml. of a 20% aqueous sodium hydroxide solution for one hour. The reaction mixture is cooled and neutralized with a 37% aqueous hydrogen chloride solution. The solvent is evaporated and the brown solid residue is extracted with 10 ml. of hot benzene. Thereafter the solvent is eliminated and the residue is crystallized from benzine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Cl[CH2:21][N:22]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=2[CH:34]([CH3:36])[CH3:35])[S:23]1(=[O:25])=[O:24]>O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:21][N:22]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=3[CH:34]([CH3:36])[CH3:35])[S:23]2(=[O:24])=[O:25])=[O:7])=[CH:2]1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: O=C(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1ccsc1)C2=O
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of 3-thiophene carboxylic acid (0.26 g, 2.0 mmol), K2CO3 (0.28 g, 2.0 mmol) and DMF (4 ml) was stirred for 1 hour. 2-Chloromethyl-4-isopropyl-6-methoxy-saccharin (0.61 g, 2.0 mmol) was then added and the mixture was stirred for 24 hours. Water (20 ml) was added to the reaction mixture and the solution was extracted with ether (2×40 ml). The organic layer was separated, washed with water, then brine and was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the solid residue was recrystallized from toluene/hexane to afford 0.5 g (65%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl thiophene-3-carboxylate as a white powder, m.p. 125°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:5]([CH:7]1[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:6].C(O)(C(F)(F)F)=O>Cl.O1CCOCC1>[NH:9]1[CH2:10][CH:7]([C:5]([C:4]2[CH:18]=[C:19]([F:21])[CH:20]=[C:2]([F:1])[CH:3]=2)=[O:6])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)c2cc(F)cc(F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(F)cc(F)c1)C1CNC1

Procedure:
A solution of 400 mg (1.35 mmol) of tert-butyl 3-(3,5-difluorobenzoyl)azetidine-1-carboxylate in 6 mL of HCl in dioxane (4M) and 2.5 mL of TFA was stirred for 4 h at 50° C. The reaction mixture was concentrated, and the residue was washed with hexanes/ether (1/1) to afford the title compound. Mass Spectrum: m/e=199 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.C1COCC1.C([Li])CCC.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1
Reactant: Cn1ccc2cccnc21
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c(B2OC(C)(C)C(C)(C)O2)cc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To a −78° C. solution of 1-methyl-1H-pyrrolo[2,3-b]pyridine (example Rupp-28) (1.17 g, 8.85 mmol) and THF (12 mL) is added 1.6M n-Bu—Li (6.6 mL, 10.62 mmol). The solution is heated to a reflux for 1 hour, cooled to ambient temperature, and 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.60 mL, 17.70 mmol) is added. After 1 hour, the solution is diluted with CH2Cl2 (100 mL), washed with water (2×100 mL), brine (75 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (5%-15% EtOAc gradient) to furnish the title compound (0.25 g, 0.97 mmol, 11%). 1H NMR (CDCl3), δ 1.38 (s, 12H), 4.07 (s, 3H), 7.02 (dd, J=7.9, 4.7 Hz, 1H), 7.07 (s, 1H), 7.92 (d, J=7.9, 1.8 Hz, 1H), 8.39 (d, J=4.7, 1.8 Hz, 1H) ppm. LC/MS (m/z): calcd. for C14H19BN2O2 (M+H)+: 259.2. found: 258.7.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([Cl:17])[C:8]=1[NH2:9].CO[CH:20]1[CH:28]2[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:22](OC)O1.C(OCC)(=O)C>C(O)(=O)C.O>[Cl:6][C:7]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([Cl:17])[C:8]=1[N:9]1[CH:20]=[C:28]2[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:22]1
Reactant: COC1OC(OC)C2CCCCC12
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(-n2cc3c(c2)CCCC3)c(Cl)c1

Procedure:
To a mixture of sodium acetate (14.0 g) in 225 ml of acetic acid heated to refluxing is first added 2,6-dichloro-4-nitroaniline (6.40 g, 30.8 mmol), followed by 1,3-dimethoxyoctahydroisobenzofuran (5.73 g, 30.8 mmol). The reaction mixture is heated under reflux for 16 hours, after which the acetic acid is stripped off by rotoevaporation and the residue is poured into ethyl acetate and water. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed with water and with brine and dried. The residue is purified by column chromatography to give 2-(2,6-dichloro-4-nitrophenyl)-4,5,6,7-tetrahydroisoindole, which is then reduced with stannous chloride according to Example 9 procedures to give 3,5-dichloro-4-(4,5,6,7-tetrahydroisoindol-2-yl)aniline.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1Cl)[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:34](OC[C@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(C)C=C2)O)(=O)C(C)(C)C>>[C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:34])[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(Cl)cc2n1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](O)COC(=O)C(C)(C)C)c(C)cc2n1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1

Procedure:
Compound 2I was prepared following the procedure used to prepare compound 1J of Example 1, except that (S)-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl pivalate (2H) was used instead of compound 1I. LCMS-ESI+ (m/z): 468.3, 470.3 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:9]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:12][C:10]=2[N:11]=1)=[O:5])C.O[Li].O.Cl>C1COCC1.O>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:8]2[C:9]3[CH:15]=[CH:14][C:13]([C:16]4[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:12][C:10]=3[N:11]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:29][CH:28]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)c1nc(Nc2ccc(C(C)(C)C)cc2)c2ccc(-c3ncccc3C)nc2n1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccnc1-c1ccc2c(Nc3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 4-(4-t-butyl-phenylamino)-7-(3-methyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine-2-carboxylic acid ethyl ester (25 mg, 0.57 mmol) and LiOH.H2O (8 mg, 0.17 mmol) in a solution of THF (2.5 mL) and H2O (0.2 mL). Stir the mixture overnight at room temperature. Add water 10 mL and acidify with 3 N HCl. Extract the mixture with EtOAc (3×10 mL). Wash the combined organic extracts with brine and dry over Na2SO4. Remove the solvent under reduced pressure to yield the title compound. MS 414.18 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5]1.Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1)=[O:22].Cl>C1COCC1>[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:22])[C:7]=2[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCNCC2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium hydride (46 mg, 1.16 mmol) in THF (5 ml), 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.46 mmol) was added at 0° C. and stirred at RT for 30 min. tert-Butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (147 mg, 0.55 mmol) was added slowly dropwise at RT and stirred for 2 h at RT. After completion of the reaction (monitored by TLC & LCMS), the reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crude product was purified by column chromatography to afford free base, which was converted to HCl salt using ethanolic HCl (38 mg). The NMR confirmed removal of the Boc group when ethanolic HCl was used. 1H NMR (CD3OD, DiHCl salt) δ (ppm): 7.3 (s, 1H), 7.22 (d, 1H), 7.0 (d, 1H), 5.23 (d, 2H), 3.95-4.10 (m, 4H), 3.7-3.9 (m, 4H), 3.36-3.43 (m, 4H), 3.1-3.22 (m, 4H), 3.0 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.[CH3:11]C1C(C)=C(C)N=C(O)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH3:11])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(O)nc(C)c1C
Reactant: Cc1nc(Cl)nc(C)c1C
Product: CCc1c(C)nc(Cl)nc1C

Procedure:
The title compound was prepared in a manner analogous to Intermediate 17, substituting 5-ethyl-4,6-dimethylpyrimidin-2-ol for 4,5,6-trimethylpyrimidin-2-ol. MS (ESI): mass calculated for C8H11ClN2, 170.06, m/z found 171.1 [M+1]+. 1H NMR (500 MHz, CDCl3): 2.65 (q, J=7.6 Hz, 2H), 2.50 (s, 6H), 1.15 (t, J=7.6 Hz, 3H).