Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8]C(=O)C(C)(C)C)=[CH:6][N:5]=[C:4]([CH2:15][C:16]([O:18][C:19](C)(C)C)=[O:17])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)C>Cl>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:5][CH:6]=1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ncc1NC(=O)C(C)(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Product: COC(=O)Cc1cc(C)c(N)cn1
Temperature: 0 °C

Procedure:
Tert-butyl 2-(4-methyl-5-pivalamidopyridin-2-yl)acetate (0.200 g, 0.653 mmol) was refluxed in hydrochloric acid 6N (10 ml) overnight. The reaction was concentrated then re-dissolved in MeOH (10 ml) and cooled to 0° C. then added TMS-diazomethane (0.653 ml, 1.305 mmol). When no SM was observed by TLC, the reaction was quenched with glacial acetic acid and concentrated. The residue was taken up with ethyl acetate and washed with NaHCO3. The organic layer was dried over NaSO4, filtered and evaporated to dryness. The residue was purified by chromatography using 40 g ISCO Redisep column and 5% MeOH/DCM solvent system to yield title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
3-Bromophenol (100 g, 580 mmol) and triethylamine (104 mL, 750 mmol) were dissolved in dichloromethane (500 mL), and the solution was cooled in an ice bath. Acetyl chloride (49.7 g, 630 mmol) was added dropwise. After 1 h the cooling bath was removed and the mixture was stirred overnight (approx 16 h) at room temperature. The mixture was washed with hydrochloric acid (1N, 250 mL), water (250 mL), 5% NaHCO3 (250 mL), and brine (250 mL). The organic layer was dried and evaporated to provide 124 g (99%) of 3-bromophenyl acetate as a light brown liquid; 1H NMR (CDCl3) δ7.36 (d, 1H), 7.32-7.20 (m, 2H), 7.05 (d, 1H), 2.28 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:40]=[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]4[CH:47]=3)=[CH:35][CH:34]=2)O1>>[N:40]1[C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:34][CH:35]=2)=[CH:47][N:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=12
Reactant: CC1(C)OB(c2ccc(-c3cn4ccccc4n3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(-c5cn6ccccc6n5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-3-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine was prepared from cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.453 mmol) and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazo[1,2-a]pyridine (0.250 g, 0.679 mmol) in a manner similar to that used for the preparation of cis-N-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a white powder (0.021 g, 9%). 1H NMR (DMSO-d6, 400 MHz) 1.57-1.73 (m, 4H), 2.08-2.50 (m, 12H), 2.16 (s, 3H), 3.37 (m, 1H), 4.82 (m, 1H), 6.92 (t, 1H), 7.27 (t, 1H), 7.61 (d, 1H), 7.74 (d, 2H), 8.15 (d, 2H), 8.24 (s, 1H), 8.56 (d, 1H); RP-HPLC Rt 8.16 min, 97% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 508 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[N:13]1([C:9]2[CH2:8][CH2:7][C:6]3[C:11]([CH:10]=2)=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: O=C1CCc2cccc(Br)c2C1
Product: C1=C(N2CCCC2)CCc2ccccc21

Procedure:
When R2 in the compounds of Formula I is methyl, the methyl-substituted 8-bromo-2-tetralone can be prepared from the corresponding unsubstituted 8-bromo-2-tetralone. The 8-bromo-2-tetralone first is treated with pyrrolidine to produce the corresponding 1,2-dihydro- 3-pyrrolidinyl-naphthalene. The latter, upon treatment with methyl iodide and acid hydrolysis, gives the desired 8-bromo-1-methyl-2-tetralone.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[CH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])C>O1CCOCC1.[OH-].[Na+].O>[NH2:21][C:18]1[S:19][CH:20]=[C:16]([C:5](=[CH:6][C:7]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH3:15])[C:4]([OH:22])=[O:3])[N:17]=1
Reactant: CCOC(=O)C(=Cc1c(C)cc(C)cc1C)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(C=C(C(=O)O)c2csc(N)n2)c(C)c1
Yield: 72 %

Procedure:
6.1 g of the product from Example 25 were dissolved in a mixture of 150 ml of dioxane and 45 ml of 1.5 N sodium hydroxide solution. The solution was boiled under reflux overnight and the dioxane was then stripped off, the residue was diluted with 50 ml of water and the mixture was filtered. The filtrate was adjusted to pH 5 with dilute hydrochloric acid and was filtered off again after 10 minutes. Recrystallization of the residue from methanol gave the desired product in a yield of 72%.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 235.6 %

Procedure:
3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (17.3 g, 66.33 mmol) was suspended in tetrahydrofuran (800 mL) and a solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (20 g, 99.5 mmol) in tetrahydrofuran (300 mL) and triphenylphosphine (34.8 g, 132.66 mmol) were added The reaction mixture was cooled to 0° C. and diethyl azodicarboxylate (23.1 g, 132.66 mmol) was added dropwise. After 2 hours at room temperature, the reaction was concentrated under reduced pressure to yield crude tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate as an orange oil (69.44 g). HPLC-RT: 14.29 min., 19%, (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 Å, 5μm, 150×3.9 mm column).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[C:12]([O:16][C:17](=[O:42])[CH2:18][O:19][C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:30][S:31]([C:34]3[CH:35]=[N:36][C:37](Cl)=[C:38]([Br:40])[CH:39]=3)(=[O:33])=[O:32])[C:24]=2[CH:23]=[CH:22][CH:21]=1)([CH3:15])([CH3:14])[CH3:13]>CN(C)C=O>[C:12]([O:16][C:17](=[O:42])[CH2:18][O:19][C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:30][S:31]([C:34]3[CH:35]=[N:36][C:37]([O:9][C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[Cl:1])=[C:38]([Br:40])[CH:39]=3)(=[O:32])=[O:33])[C:24]=2[CH:23]=[CH:22][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Oc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(F)cc2Cl)c(Br)c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-chloro-4-fluoro-phenol (292 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (28.8 mg, 1.2 mmol) portionwise at 0° C. under nitrogen and stirred at the same temperature for 15 minutes. To the above mixture was added [5-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (212 mg, 0.4 mmol) portionwise at 0° C. Then the reaction mixture was heated at 100° C. overnight. After being cooled to room temperature, the reaction was quenched with water (2 mL), and diluted with ethyl acetate (50 mL). The resulting solution was washed subsequently with water (10 mL), 1N sodium hydroxide solution (10 mL), and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give {5-[5-bromo-6-(2-chloro-4-fluoro-phenoxy)-pyridine-3-sulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester, which was used in the next step without further purification. MS cald. for C27H27BrClFN2O6S 640, obsd. 641 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]3[C:20]([C:21]=2I)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH2:30]([OH:34])[CH2:31][C:32]#[CH:33].O>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]3[C:20]([C:21]=2[C:33]#[C:32][CH2:31][CH2:30][OH:34])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)c(I)c2ccccc21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)c(C#CCCO)c2ccccc21
Temperature: 50 °C
Reaction time: 3.7 h
Yield: 86.6 %

Procedure:
3-Amino-6-[1-(tert-butoxycarbonyl)-3-iodoindol-2-yl]phtalimide (150 mg, 0.298 mmol) was dissolved in diethylamine (7.5 mL), and the solution was added with bis(triphenylphosphine)dichloropalladium (16.7 mg, 0.0234 mmol), copper iodide (11.4 mg, 0.0596 mmol) and 3-butyn-1-ol (0.226 mL, 2.98 mmol), followed by stirring at 50° C. for 3.7 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 3-amino-6-[1-(tert-butoxycarbonyl)-3-(4-hydroxy-1-butynyl)indol-2-yl]phtalimide (115 mg, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12]([CH3:14])=[O:13].ClC1C=C(C=CC=1)C(OO)=[O:20].C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12]([CH3:14])(=[O:20])=[O:13]
Reactant: CS(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
A solution of 1,5-dichloro-2-(methylsulfinyl)-4-nitrobenzene (1.0 g, 3.9 mmol) in dichloromethane (50 ml) was added 3-Chloroperoxybenzoic acid (1.7 g, 9.8 mmol). The mixture was stirred under nitrogen at room temperature for 3 h. The mixture was added saturated aqueous NaHCO3 (20 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50 ml), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (2:1) to give 1 g (100%) of the title compound as white solids.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:24][CH2:25][C@@H:26]2[O:31][C:30]3[C:32]([CH:39]=O)=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:29]=3[O:28][CH2:27]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[N:4]#[C:3][CH:5]=[CH:39][C:32]1[C:30]2[O:31][CH:26]([CH2:25][O:24][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)(=[O:22])=[O:23])[CH2:27][O:28][C:29]=2[CH:35]=[CH:34][C:33]=1[N+:36]([O-:38])=[O:37]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(C=CC#N)c3O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.44 g (11 mmole) of 60% sodium hydride/mineral oil dispersion in 100 mL of DMF was add 1.8 g (10 mmole) of diethyl cyanomethyl-phosphonate. The mixture was stirred for 30 minutes at room temperature under nitrogen and then 3.0 g (7.6 mmole) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate added and stirring at room temperature continued overnight. The solvent was then removed in vacuum and replaced with 400 mL of dichloromethane. The solution was washed with 300 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum to a yellow oil. This was column chromatographed on silica gel with methylene chloride as eluant to give 2.5 g of the (R)-enantiomer of the title compound as a yellow solid (m.p. 117-118° C.).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](=[N:39]O)[NH2:38]>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:39]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:29][N:38]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1ccccc1Cl
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4ccccc4Cl)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 45.8 mg (0.269 mmol) of 2-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 72.4 mg (55% of theory).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[OH:27].O>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[O:27][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2ccsc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnc2ccsc2c1Oc1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol), potassium carbonate (194.9 mg,1.41 mmol) and 2,4-dichlorophenol (218.3 mg, 1.34 mmol) in 3 mL of N,N-dimethylformamide is stirred at 110° C. for 4 hours and allowed to cool to ambient temperature. The reaction mixture is treated with water and stirred at ambient temperature for 10 minutes. The crude solid is collected by filtration washing with water, dried in vacuo, then purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 244 mg of 7-[(2,4-dichlorophenoxy)]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 158–160° C.; 1H NMR (DMSO-d6) δ 7.63 (dd, J=6, 2 Hz, 1H), 7.68 (d, J=4 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 7.80 (d, J=2 Hz, 1H), 8.33 (d, J=4 Hz, 1H), 9.03 (s, 1H); MS 320.9, 322.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:29])=[C:20]([NH:22][S:23]([CH:26]3[CH2:28][CH2:27]3)(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34]>>[F:29][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[N:7]=2)=[CH:21][C:20]=1[NH:22][S:23]([CH:26]1[CH2:28][CH2:27]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclopropanesulfonamide (80 mg, 0.177 mmol) and 2-aminoethyl-methyl-sulfone (174 mg, 1.413 mmol) the title compound was obtained as a white solid (49 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (s, 1H), 8.13 (d, J=4.8 Hz, 1H), 7.50 (dd, J=7.6, 1.6 Hz, 1H), 7.44 (t, J=4.9 Hz, 1H), 7.25-7.41 (m, 2H), 6.33 (d, J=4.5 Hz, 1H), 3.62 (d, J=5.5 Hz, 2H), 3.32 (br. s., 2H), 3.22-3.27 (m, 1H), 2.97 (s, 3H), 2.52-2.68 (m, 1H), 1.33 (d, J=6.9 Hz, 6H), 0.71-0.96 (m, 4H). MS (ESI): 540.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][N:28]3[CH3:31])=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC>[CH3:31][N:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cnn(C)c5c4)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cnn(C)c5c4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Yield: 10.9 %

Procedure:
A mixture of 2-chloro-N-(1-methyl-1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (90 mg, 0.20 mmol), 4-aminobenzamide (55 mg, 0.40 mmol) and TMSCl (0.200 mL, 1.58 mmol) in nBuOH (2 mL) was stirred at 135° C. for 44 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give 4-(4-(1-methyl-1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (12 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=O)=[CH:5][CH:4]=1)[CH3:2].CN(C)C=O.[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2ccccc2C(=O)O)cc1
Reaction time: 6 h

Procedure:
(b.1) A solution of 2-(4-ethylbenzoyl)benzoic acid in acetic acid (115 ml) and the dimethylformamide (115 ml) containing 10% palladium on carbon (4.9 g) was shaken in a hydrogen atmosphere at 60 p.s.i. for 6 hours. The solution was then filtered and the filtrate was added to water (2000 ml), producing a precipitate of 2-(4-ethylbenzyl)benzoic acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>>[C:1]([NH:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1C
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1c(C)ccc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
3-Acetamido-4-methylbenzoic acid (205 g, 1061 mmol) was added portionwise over 45 min to stirred fuming nitric acid (1 L) at −5° C., maintaining a reaction temperature below 0° C. The mixture was stirred for an additional 1 h and then crushed ice (2.5 kg) was added. The mixture was stirred for a further 30 min. The precipite that formed was filtered off and thouroughly washed with water. The resulting cake was air dried and suspended in 1 L of acetic acid at 65° C. The suspension was sitrred for 1 hour, allowed to cool down to RT and then filtered. The filtrate was washed with acetic acid and ether to give 3-acetamido-4-methyl-2-nitrobenzoic acid (160 g, 63%) as a white solid. MS (M+H)+ 239.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si](C(C)(C)C)(C)C)[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].Cl[CH2:59][CH2:60][CH2:61][CH2:62]C>CN(C)C=O>[CH2:59]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:14])=[O:16])[C:18]([CH:53]([CH3:55])[CH3:54])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:44]([OH:45])[CH:41]1[O:40]3)[O:36]2)[CH2:60][CH2:61][CH3:62]
Reactant: CCCCCCl
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg of compound (6) was dissolved in 0.5 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 5 mg of sodium hydride under cooling with ice. After 30 minutes, 78.7 μl of 1-chloropentane was added, and the reaction solution was stirred at room temperature for 4 hours. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with n-hexane-ethyl acetate (5:1). The fraction containing the desired product was concentrated to dryness to give 22.0 mg of compound (38).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH3:12].[Li]C(C)(C)C.[C:18](=[O:20])=[O:19]>C(OCC)C>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:18]([OH:20])=[O:19])[CH:3]=2)[NH:7][N:6]=1)[CH3:12]
Reactant: CCc1n[nH]c2ccc(Br)cc12
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCc1n[nH]c2ccc(C(=O)O)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a −78° C. solution of 5-bromo-3-ethyl-1H-indazole (5 g, 22 mmol) in diethyl ether (150 mL) was added t-BuLi (4.84 g, 75.6 mmol). The mixture was stirred at −78° C. for 1 hour. Dry CO2 gas was passed through the reaction mixture at −78° C. for 1 hour and the temperature was slowly raised to room temperature for 2 hours. The reaction mixture was stirred at room temperature for 1 hour and quenched with saturated NH4Cl solution. The ether layer was separated and concentrated to recover unreacted starting material. The pH of the aqueous layer was made acidic with 2 N HCl, which was filtered to afford the title compound (2 g, 47%) as a pale brown solid. 1H NMR (DMSO-d6): δ12.6-13.0 (br, 2H), 8.4 (s, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 3.0 (q, 2H), 1.4 (t, 3H).