Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[CH:14]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:21]([NH:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:22])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C=NC1CCCCC1
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 1A (123 mg, 0.4 mmol) and cyclohexyl isocyanate (63 mg, 0.5 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a solution of DBU (0.076 mL, 0.5 mmol) in CH2Cl2 (5 mL). The mixture was allowed to warm to room temperature and stirred for 14 hours. The mixture was washed sequentially with water, brine and dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (CH2Cl2-MeOH 9:1) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.10 (m, 3H), 1.29 (m, 4H), 1.51 (m, 3H), 1.70 (m, 4H), 1.95 (s, 3H), 2.02 (s, 3H), 3.33 (m, 3H), 5.02 (s, 1H), 6.74 (br d, J=7 Hz, 1H); MS (ESI) m/z 309 (M+H)+. Anal calcd for C17H28N2OS.0.25H2O: C, 65.24; H, 9.18; N, 8.95. Found: C, 65.49; H, 9.30; N, 8.93.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([O:10][CH2:11][CH2:12][OH:13])([CH3:9])[CH3:8].[Cl:14][C:15]1[CH:23]=[CH:22][C:21](F)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].Cl>CN1C(=O)CCC1.O>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:13][CH2:12][CH2:11][O:10][CH:7]([CH3:9])[CH3:8])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: CC(C)OCCO
Reactant: O=C(O)c1cc(F)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)OCCOc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon atmosphere, potassium tert-butoxide (168 mg) was added to a solution of 2-isopropoxyethanol (172 μL) in NMP (1.5 mL). The mixture was stirred at room temperature for 10 minutes, 2-chloro-5-fluorobenzoic acid (87 mg) was added, and it was then stirred at 130° C. for 4 hours. The reaction mixture was cooled on ice bath, water was added, and it was then acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with brine, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude 2-chloro-5-[2-(propan-2-yloxy)ethoxy]benzoic acid. This was dissolved in DMF (2 mL), HATU (61 mg), N,N-diisopropylethylamine (29 μL) and 6-amino-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (50 mg) were added in this order, and it was stirred at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-2-methylphenyl)-6-[({2-chloro-5-[2-(propan-2-yl oxy)ethoxy]phenyl}carbonyl)amino]-2-(methoxymethyl)-1H-benz imidazole-4-carboxamide (41 mg) as white powder. This was dissolved in ethyl acetate (2 mL), and treated with 4N hydrogen chloride/ethyl acetate (1.2 Eq). The precipitate was collected by filtration, and dried to obtain the titled compound (28 mg) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Br:11][CH2:12][C:13](=O)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>C1COCC1.C(O)C>[BrH:11].[C:14]([C:13]1[N:1]=[C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]2[CH:12]=1)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: O=C(CBr)C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: Br
Product: O=C(O)c1ccc2nc(C(=O)c3ccccc3)cn2c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a suspension of 0.33 g of 6-aminonicotinic acid in 5 mL of THF and 3 mL of ethanol is added a solution of 0.654 g of 3-bromo-1-phenylpropane-1,2-dione in 2 mL of THF. The reaction mixture is stirred at 45° C. for 16 hours and for 24 hours at 20° C., and then evaporated to dryness. The residue is taken up in dichloromethane and the solid is filtered off and washed with dichloromethane to give 0.78 g of 2-benzoylimidazo[1,2-a]pyridine-6-carboxylic acid hydrobromide in the form of a yellow solid.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH2:29][C:30]([O:32]C)=[O:31])=[N:21]2)=[CH:17][CH:16]=1)[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].O.[OH-].[Li+].O.Cl>O1CCCC1>[CH3:1][N:2]([C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH2:29][C:30]([OH:32])=[O:31])=[N:21]2)=[CH:17][CH:16]=1)[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)Cc1nn(Cc2ccc(N(C)C(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1ccc2ccccc2c1)c1ccc(Cn2nc(CC(=O)O)c3ccccc32)cc1
Yield: 32.7 %

Procedure:
Methyl 2-[1-[4-(N-methyl-2-naphthamido)benzyl]-1H-indazol-3-yl]acetate (about 1.0 mmol) was dissolved in tetrahydrofuran (30 mL), and in an ice bath, 20 mL aqueous solution dissolving lithium hydroxide monohydrate (210 mg, 5.0 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH=3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered, dried, and purified by preparative liquid phase to obtain a white solid 147 mg, at a total yield over two steps of 32.7%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1.S(=O)(=O)(O)O>C(O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.[CH3:11][CH2:10][C:12]([O-:14])=[O:13]
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2[nH]1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCC(=O)[O-]
Product: FC(F)(F)c1cnc2[nH]ccc2c1
Yield: 172.3 %

Procedure:
Put 0.3 g (1.3 mmol) of 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Angew Chem Int Ed 2004, 43(34), 4526-4528) and 50 mL of ethanol in a 100-mL flask equipped with a magnetic stirrer. Add, to this solution, 0.5 mL of concentrated sulfuric acid. The reaction mixture is then refluxed for 18 hours. The cooled solution is concentrated to dryness at reduced pressure. The residue is taken up in dichloromethane (100 mL), the organic phase is washed successively with a normal aqueous solution of sodium hydroxide (30 mL), with water (20 mL) and then with a saturated aqueous solution of sodium chloride. It is dried over sodium sulfate and then concentrated at reduced pressure. 0.29 g (1.12 mmol) of the expected product is isolated in the form of a yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[CH:17]=2)[C:12]1=[O:24])(=[O:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][Br:30]>>[Br-:30].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([Cl:25])[CH:27]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[CH:17]=2)[C:12]1=[O:24])(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1C(C)=O)C2
Reactant: Clc1cccc(CBr)c1
Product: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+](Cc3cccc(Cl)c3)cc1C(C)=O)C2
Product: [Br-]

Procedure:
The title compound 144 is prepared according to the procedure reported in Example 38.1 with compound 32 (95.1 mg, 0.29 mmol) and 3-chlorobenzyl bromide (65 μL, 0.49 mmol) as reactants. White solid. (Yield 108 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[CH:14]=[N:15][N:16]2[C:21](=O)[CH:20]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[NH:18][C:17]=12.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:42])=O>>[Cl:42][C:21]1[N:16]2[N:15]=[CH:14][C:13]([CH2:12][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=3[CH3:1])=[C:17]2[N:18]=[C:19]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:20]=1
Reactant: Cc1c(Cc2cnn3c(=O)cc(N4CCOCC4)[nH]c23)cccc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1c(Cc2cnn3c(Cl)cc(N4CCOCC4)nc23)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.52 g, 1.32 mmol) and N,N-diethylaniline (0.43 g, 2.92 mmol) under nitrogen was added neat phosphoric trichloride (1.12, 6.63 mmol) dropwise during 15 minutes. The reaction mixture was stirred at 80° C. for 3 hours. Reaction mixture was concentrated under reduce pressure. The residue was dissolved with DCM (50 mL) and water (15 mL). The pH of aqueous layer was adjusted to 8˜9. Two layers were separated. Aqueous layer was then extracted with DCM (30 mL×3). The crude material was then purified with silica gel column chromatography (CH3OH/DCM 0-10%) to provide the titled product. (450 mg, 83%); LC/MS: MS (ES+) m/e 378 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.43 (br. s., 1H) 3.45 (d, J=5.05 Hz, 3H) 3.63-3.71 (m, 4H) 4.00 (s, 2H) 5.55 (s, 1H) 7.16 (s, 2H) 7.22-7.30 (m, 1H) 7.30-7.40 (m, 1H) 7.46 (dd, J=7.83, 1.77 Hz, 1H) 7.72 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([O-:14])=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=1.[Li+].[OH-].Cl>C1COCC1.CO>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: O=C([O-])c1cnc2cc(C(F)(F)F)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc2cc(C(F)(F)F)ccn12
Temperature: 60 °C

Procedure:
To a stirring solution of ethyl 7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (23) (100 mg, 0.387 mmol) in THF:MeOH (4:1, 1.5 mL) was added 2N LiOH (0.25 mL). The reaction was heated at 60° C. for 1 hour. Then, cooled to room temperature and the pH was adjusted between 4-5 with 1N HCl. The solvent was partially concentrated and the resulting aqueous layer was lyophilized to give 7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (24). 1H NMR (400 MHz, d6-DMSO) δ 9.44 (d, J=7.2 Hz, 1 H), 8.40 (s, 1 H), 8.31-8.30 (m, 1 H), 7.48 (dd, J=2.0, 7.6 Hz, 1 H). MS m/z 231.2 (M+1)+.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[C:29]([NH:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(OC(C)(C)C)=O>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:40]3[CH:41]=[CH:42][C:37]([NH:36][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:38][CH:39]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1

Procedure:
Compound 48a was prepared from compound 15a and 2-(BOC-amino)pyridine-5-boronic acid pinacol ester according to procedure described in Example 13, Step A. Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H31N7O4: 453.3 (M+H-BOC). Found 554.2.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([S:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:25]=3)[NH:20][N:19]=2)(=[O:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O>CN(C=O)C>[N:1]([CH2:29][CH2:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[S:15]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)(=[O:16])=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
Sodium azide (0.79 g, 12 mmol) was added to a solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (2.06 g, 3.94 mmol) in DMF (20 mL). The reaction mixture was stirred at 80° C. for 12 hours in a sealed tube. After cooling to ambient temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was washed with 10% ammonium chloride/water solution, water and brine. It was dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 72° C. in vacuo for 40 minutes to yield 5-(2-azido-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a amber gum/foam (1.34 g, 86.5%). Mass spectrum (−EI, [M−H]−) m/z 392. 1HNMR (400 MHz, DMSO-d6): δ8.78 (d, 1H, J=8.70 Hz), 8.56 (dd, 1H, J=7.43 Hz and 1.16 Hz), 8.29 (d, 1H, J=8.35 Hz), 8.06 (d, 1H, J=7.66 Hz), 7.72-7.76 (m, 1H), 7.57-7.67 (m, 3H), 7.31 (d, 1H, J=2.32 Hz), 7.12 (dd, 1H, J=9.16 Hz and 2.32 Hz), 4.22-4.24 (m, 2H), 3.67-3.69 ppm (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17]O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.[ClH:27].O1[CH2:33][CH2:32]OCC1>O1CCOCC1>[ClH:27].[CH2:23]([N:20]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=1)[CH2:22][CH2:21][CH2:26][CH2:25][CH2:32][CH3:33]
Reactant: Nc1ccncc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: C1COCCO1
Agent: Cl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-{[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 4-aminopyridine as starting materials and by operations similar to those of Reference Example 14, Example 286-1, Example 286-2 and Example 265-2 was dissolved in dioxane, an excess amount of 4 mol/L hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound as an amorphous solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:39]3[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=4[F:35])=[C:19]([O:37][CH3:38])[CH:18]=3)[C:9]=12.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C.O>[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([C@H:39]3[CH2:44][CH2:43][C@@H:42]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:41][CH2:40]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][C:26]=4[F:35])=[C:19]([O:37][CH3:38])[CH:18]=3)[C:9]=12.[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([C@H:39]3[CH2:44][CH2:43][C@H:42]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH2:41][CH2:40]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][C:26]=4[F:35])=[C:19]([O:37][CH3:38])[CH:18]=3)[C:9]=12
Reactant: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCOCC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCOCC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Morpholine (0.08 mL, 0.93 mmol) was added into a mixture of N-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.42 g, 0.78 mmol) and acetic acid (0.11 mL, 1.86 mmol) in dichloroethane (25 mL). The mixture was stirred at ambient temperature for 10 minutes. Sodium triacetoxyborohydride (0.23 g, 1.09 mmol) was added and the mixture was stirred at ambient temperature overnight. Water (6 mL) was added followed by sodium bicarbonate (0.38 g, 4.53 mmol). The mixture was stirred for 1 hour and the organic layer was separated. The aqueous layer was extracted with dichloromethane (20 mL). The combine organics were dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on silica using Isco system to provide cis-N1-{4-[4-amino-1-(4-morpholinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.23 g, 0.37 mmol) and trans-N1-{4-[4-amino-1-(4-morpholinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.09 g, 0.14 mmol) as white solids.
Reaction SMILES: [CH3:1][N:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=2)[N:6]=[C:5]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[N:4]=1.B(Br)(Br)[Br:30]>>[BrH:30].[CH3:1][N:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[N:6]=[C:5]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[N:4]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc2nc(Nc3ccccc3C)nc(N(C)c3ccccc3)c2c1
Product: Br
Product: Cc1ccccc1Nc1nc(N(C)c2ccccc2)c2cc(O)ccc2n1
Yield: 43 %

Procedure:
4-(N-Methylphenylamino)-2-[(2-methylphenyl)amino]6-methoxyquinazoline (prepared as described in co-pending EP-A-88311461.3) (3.0 g, 0.0074 mol) and boron tribromide (9.2 g, 0.037 mol) were reacted together under the conditions described in Example 3 to give the title compound (1.39 g), crystallised from methanol/diethyl ether as its hydrobromide salt, m.p. 172°-174°.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11](S(C)=O)=[C:12]3[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:13]=23)=[N:5]1)(=O)C.[CH3:24][C:25]([S-:28])([CH3:27])[CH3:26].[Na+]>C1COCC1>[CH3:19][C:15]1([CH3:20])[CH2:14][C:13]2=[C:9]([C:6]3[CH:7]=[CH:8][NH:4][N:5]=3)[S:10][C:11]([S:28][C:25]([CH3:27])([CH3:26])[CH3:24])=[C:12]2[C:17](=[O:18])[CH2:16]1
Reactant: CC(=O)n1ccc(-c2sc(S(C)=O)c3c2CC(C)(C)CC3=O)n1
Reactant: CC(C)(C)[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)c2c(SC(C)(C)C)sc(-c3cc[nH]n3)c2C1
Yield: 48.4 %

Procedure:
To a stirred solution of 1-(1-acetylpyrazol-3-yl)-6,6-dimethyl-3-methanesulphinyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (73 mg, 0.21 mmol) in THF (7 mL) was added sodium 2-methyl-2-propanethiolate (47 mg, 0.42 mmol). After 90 min more sodium 2-methyl-2-propanethiolate (15 mg, 0.14 mmol) was added, and after a further 30 min the mixture was partitioned between EtOAc (15 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (1:1), to give the title compound (34 mg, 48%) as a yellow solid. mp 220-222° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][C:16](=[CH2:18])[CH2:15][C@H:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[CH2:18]=[C:16]1[CH2:17][C@@H:13]([CH:12]=[O:11])[C@H:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1
Reactant: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1C[C@@H](C=O)[C@H](c2ccccc2)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 89.1 %

Procedure:
To a solution of oxalyl chloride (1.16 mL, 13.3 mmol) in methylene chloride (50 mL) at −70° C. was added dropwise DMSO (1.88 mL, 26.6 mmol). After 15 min, a solution of (+−)-trans-1-hydroxymethyl-4-methylene-2-phenylcyclopentane from Step B (1.0 g, 5.3 mmol) in methylene chloride (10 mL) was added. The reaction was stirred at −70° C. for 1.5 h and then DIPEA (9.25 mL, 53 mmol) in methylene chloride (10 mL) was added dropwise over 5 min. After a further 10 min, the mixture was allowed to warm to rt for 1 h and then diluted with methylene chloride and poured into dilute aq. HCl. The layers were separated. The aq. layer was reextracted with a second portion of methylene chloride and the organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC (20% ethyl acetate in hexanes) to give the title product (0.88 g) after vacuum drying.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CN(C=O)C.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CCOC(C)=O>[Si:22]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 97.3 %

Procedure:
To a mixture of 4-amino-3-nitrophenol (10.07 g, 65.3 mmol) and DMF (20 mL) was added imidazole (11.15 g, 163.8 mmol) followed by t-butyldimethylsilyl chloride (11.82 g, 78.4 mmol) in several portions. After 5 h, the reaction was diluted with EtOAc (150 mL) and washed with water (5×20 mL). The organic layer was MgSO4, dried, filtered, and concentrated. The residue was chromatographed (10% EtoAc/hexanes to 20% EtOAc/hexanes) to give the title compound as a solid (17.06 g, 97%); mp 80-83° C.; IR (CHCl3): 3399, 2932, 1519, 1242, 866 cm−1; NMR (300 MHz, CDCl3): 0.19 (s, 6H), 0.97 (S, 9H), 6.70 (d, 1H, J=9.0), 6.95 (d, 1H, J=3.0), 7.56 (d, 1H, J=2.7); MS(FD): 268.2.