Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[CH3:13][C:14]([C:17]([NH2:19])=[NH:18])([CH3:16])[CH3:15].Cl.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:14]([C:17]1[NH:18][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])[N:19]=1)([CH3:16])([CH3:15])[CH3:13]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1nc(-c2cccc(C#N)c2)c[nH]1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of 3-(2-bromoacetyl)benzonitrile (500 mg, 2.23 mmol), tert-butylcarbamidine hydrochloride (610 mg, 4.46 mmol), potassium carbonate (770 mg, 5.58 mmol), and acetonitrile (10 mL) was refluxed for 1 hour. After the reaction was completed, the mixture was left to cool to room temperature. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to give 3-(2-tert-butyl-1H-imidazol-4-yl)benzonitrile (500 mg, 2.22 mmol, yield: 99%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11]>>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(CN)OC
Reactant: CC(C)C(=O)Cl
Product: COC(CNC(=O)C(C)C)OC
Yield: 77 %

Procedure:
The product is prepared analogously to Example 1 from isobutyryl chloride and aminoacetaldehyde dimethyl acetal. Distillation at 98° C. and 0.01 mbar gives a yield of 77%. According to GC, the product has a purity of 98%.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(NC2CCCCC2)[CH2:35]CCC[CH2:31]1.COC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:24]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:35][CH2:30][CH2:31][C@H:19]3[C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via dicyclohexylamine and (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([CH2:13][S:14][CH3:15])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]([CH2:13][S:14][CH3:15])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(CSC)cc1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSCc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a −78° C. mixture of methyl 2-methoxy-4-(methylthio-methyl)benzoate (5.29 (g, 23.36 mmol) and CH2Cl2 (80 mL) was added BBr3 (2.4 mL, 24.52 mmol) dropwise. The reaction was stirred for 15 min, warmed to room temperature and stirred for 6 h. The reaction mixture was added to ice/water (100 mL). The suspension was added 2 M NaOH to dissolve the precipitate. After partitioning, the organic layer was extracted with 2 M NaOH. The combined aqueous layer was washed with EtOAc, acidified with 12 N HCl and cooled to room temperature. The solid was filtered with water wash and vacuum dried to give the title compound as a light yellow solid (2.96 g, 64%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:19])=[O:18])[O:14][C:13]3=[O:20])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:21].[CH3:22]N>CO>[CH3:22][NH:19][C:17]([C@@H:15]1[O:14][C:13](=[O:20])[N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][O:5][C:6]=3[CH:11]=2)[CH2:16]1)=[O:18]
Reactant: CN
Reactant: CN1C(=O)COc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)OCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a stirred suspension of (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (EXAMPLE 59, Step 3, 200 mg, 0.65 mmol) in MeOH (5 mL) is added MeNH2 (5 mL, 10 mmol, 2 M solution in MeOH). The resulting solution is stirred for 3 h at room temperature at which time the resulting white precipitate is filtered, washed with additional MeOH (5 mL), and dried under high vacuum to give the title compound (153 mg, 77%); 1H NMR (300 MHz, DMSO) δ 8.56 (br t, 1H), 7.50 (d, 1H), 7.41–7.33 (m, 2H), 5.23 (dd, 1H), 4.85 (s, 2H), 4.45 (dd, 1H), 4.15 (dd, 1H), 3.45 (s, 3H), 2.84 (d, 2H); MS for C14H15N3O5 m/z 306.5 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:28](=[O:29])[NH:27][CH2:25][CH3:26])[CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(-c2ccccc2)cn1S(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)N1CCc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
4-Phenyl-1-(indoline-5-sulfonyl)-2-imidazolone (100 mg, 0.29 mmol) prepared in Preparation 3 was dissolved in 10 ml of toluene, and ethylisocyanate (35 μl, 0.435 mmol) was added thereto. The reaction mixture was stirred for 8 hours at 80° C. The solvent was evaporated therefrom under reduced pressure. The residue was dissolved in 30 ml of dichloromethane, washed twice with brine, dried over anhydrous magnesium sulfate, concentrated to an oily state, and then purified by silica gel column chromatography (eluent:dichloromethane/methanol=15/1, v/v) to obtain 113 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]([Cl:15])=[CH:7][C:6]=2[N:16]=1)#[N:2].[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[NH:17]1[C:1]([C:3]2[O:4][C:5]3[C:14]4[N:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:8]([Cl:15])=[CH:7][C:6]=3[N:16]=2)=[N:2][N:19]=[N:18]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1nc2cc(Cl)c3cccnc3c2o1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc2nc(-c3nnn[nH]3)oc2c2ncccc12
Temperature: 120 °C

Procedure:
A mixture of 5 g of 2-cyano-5-chloro-1,3-oxazolo-[4,5-h]quinoline and 1.0 g of sodium azide and 2 g of ammonium chloride in 100 ml of DMF are heated for 3 hours at 120° C. The reaction mixture is poured into water acidified with dilute HCl, and the product is filtered and recrystallized.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:28][CH2:27]2)[N:10]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.2 %

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt (66.3 mg, Example 11) in methylene chloride (3 mL) were added triethylamine (0.09 mL, 0.617 mmol, Aldrich) and methanesulfonyl chloride (8.9 mg, 0.0774 mmol, Aldrich) at 0° C. After stirring for 0.5 to 1 hour at 0° C., the reaction mixture was concentrated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give [4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone (19.2 mg). HRMS, observed: 406.1546; Calcd for (M+H)+: 406.1544.
Reaction SMILES: C(#N)C.[O:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=2)=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:23](Br)[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[O:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23]/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:19][CH:18]=2)=[CH:13][CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Reactant: BrCC=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C1=C(c2ccc(Oc3ccccc3)cc2)CCN(C/C=C/c2ccccc2)C1
Temperature: 0 °C
Yield: 73 %

Procedure:
To an 8 ml acetonitrile solution of 300 mg of the compound (8) synthesized in Example 1 were added 234 mg cinnamyl bromide and 0.5 ml of triethylamine. This was then heated and refluxed for 3 hours. To the reaction mixture was added 10 ml of ice water. This was then extracted with ethyl acetate. The extract was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=25:1) to obtain the above-referenced compound (18) in an amount of 320 mg (yield 73%).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:4]=1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:35][C:36](Cl)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:35][C:36]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[N:6][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.22) (135 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (20 mg, 7%). MS (ISN) 569.2 [(M−H)−]; mp 168° C.
Reaction SMILES: Cl.[CH3:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH:26]([C:28]([O:30]C)=O)[CH2:25][C:24]=4[CH:32]=3)[N:13]=2)=[CH:7][CH:6]=1>>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH:26]([C:28]([NH:3][CH3:2])=[O:30])[CH2:25][C:24]=4[CH:32]=3)[N:13]=2)=[CH:9][CH:10]=1
Reactant: CN
Reactant: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)cc4)n3)ccc2O1
Agent: Cl
Product: CNC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)cc4)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine, the reaction of methyl amine Hydrogen Chloride with (±)-N4-(4-chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine gave (±)-N4-(4-chlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.40 (s, 1H), 9.02 (s, 1H), 8.05 (m, 2H), 7.84 (dd, 2H, J=2.7 and 9.3 Hz), 7.51 (bs, 1H), 7.32 (bd, 2H, J=8.7 Hz), 7.23 (bd, 1H, J=8.7 Hz), 6.72 (d, 1H, J=8.7 Hz), 5.07 (dd, 1H, J=6.0 and 6.3 Hz), 3.39 (dd, 1H), 3.17 (dd, 1H), 2.60 (d, 3H, J=4.8 Hz); LCMS: purity: 99%; MS (m/e): 414 (MH+).
Reaction SMILES: [N:1]([CH:4]([CH2:9][CH3:10])[CH2:5][C:6](O)=[O:7])=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C>[N:1]([CH:4]([CH2:9][CH3:10])[CH2:5][C:6]([Cl:14])=[O:7])=[N+:2]=[N-:3]
Reactant: CCC(CC(=O)O)N=[N+]=[N-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCC(CC(=O)Cl)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
3-Azidopentanoic acid (1.72 g, 12.2 mmol) was dissolved in oxalyl chloride (1.49 ml, 2.22 g, 17.5 mmol) and to this stirring solution was added one drop of DMF. The mixture was stirred at room temperature for 30 min and heated at 80° C. for 40 min. The residue was distilled under vacuum, bp 33° C. (0.1 mm), to give a colorless oil (936 mg, 48.2%); ir (neat) νmax : 2100 (N3), and 1795 cm-1 (C=O of acid chloride); 1Hmr (CDCl3) δ: 1.03 (3H, t), 1.60 (2H, m), 3.03 (2H, d) and 3.80 ppm (H, m). Anal. calcd for C5H8N3Cl: C 37.16, H 4.99; found: C 37.40, H 4.92.
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][O:11][CH2:12][CH3:13])[N:9]=1.[N+:14]([C:17]1[CH:21]=[N:20][NH:19][N:18]=1)([O-:16])=[O:15].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH2:12]([O:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:19]2[N:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:21]=[N:20]2)[O:6][CH:7]=1)[CH3:13]
Reactant: CCOCc1coc(CCl)n1
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCc1coc(Cn2ncc([N+](=O)[O-])n2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(chloromethyl)-4-(ethoxymethyl)oxazole (260 mg, 1.48 mmol) in DMF (4.2 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (T. E. Eagles et al. Organic preparations and procedures 2 (2), 117-119, 1970; P. N. Neuman J. Heterocycl. Chem. 8, 51-56, 1971) (1.76 g of a 9.6% solution in DMF, 1.48 mmol) in DMF (4.2 mL) pre-treated for 30 min with DIPEA (0.51 mL, 2.96 mmol) and the reaction mixture was stirred overnight at 50° C. Water (20 mL), followed by EA (20 mL) was added. The layers were separated and the org. layer was washed with water (3×10 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.40. LC-MS-conditions 07: tR=0.69 min, [M+H]+=254.06.
Reaction SMILES: C1COCC1.CCCCCC.CC(OC)(C)C.C([O:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24])C(C)C.I[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+:46].[Na+]>O1CCCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([C:29]2[CH:28]=[CH:27][C:26]([S:23]([O-:22])(=[O:24])=[O:25])=[CH:31][CH:30]=2)[CH:37]=1.[Na+:46]
Reactant: CC(C)COS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Ic1cccnc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: O=S(=O)([O-])c1ccc(-c2cccnc2)cc1
Temperature: 50 °C
Yield: 70 %

Procedure:
The THF-Hexane-MTBE solution containing 23 g (93.3 mmol) of 4-(isobutoxysulfonyl)phenylboronic acid was concentrated to a concentration of ca. 7 ml/g. A portion of this solution containing ca. 4.7 g (19 mmol, 0.26 eq) was added to a solution of 15.4 g (75 mmol) of 3-iodopyridine dissolved in 100 ml of degassed tetrahydrofuran. To this solution, tris(dibenzylidene acetone) dipalladium (0) (0.5 g, 0.6 mol %) and degassed aqueous sodium carbonate solution (300 ml, 3 eq) were added. The reaction mixture was heated to ca. 50° C. to initiate the coupling reaction. During the reaction, Pd2(dba)3 (0.5 g per addition) and rich organic concentrate containing 4-(isobutoxysulfonyl)phenylboronic acid (4.7 g, 0.26 eq per addition) were added in several portions until all the 3-iodopyridine was consumed. The reaction mixture was further heated at ca. 55° C. for an additional 4 hours. The reaction mixture was filtered and washed with methyl-tert-butyl ether. The pH of the product-rich aqueous solution was adjusted to ca. 4, treated with trithiacyanuric acid (Ig) and filtered to remove Pd containing by-products. The pH of the product-rich aqueous solution was adjusted to ca. 7 and was saturated with solid NaCl (118 g) to initiate the crystallisation of the product. The salted-out product was dried in vacuo at less than 70° C. For recrystallization, the dried product was dissolved in 350 ml of 190 proof ethanol at ca. 75° C. The solution was filtered and concentrated to ca. 100 ml and cooled to ca. 30° C. to initiate crystallization. About 200 ml of MTBE was added to maximize the yield. The crystal slurry was filtered, washed and dried in vacuo less than 70° C., to give 13.4 g (70% yield) of sodium 4-(3-pyridinyl)benzenesulfonate.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][N:15]3[C:19](=[O:21])[CH3:20])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+:23]>C(Cl)Cl.CO.O>[C:19]([N:15]1[CH2:14][C@@H:13]2[CH2:18][C@H:16]1[CH2:17][N:12]2[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O-:4])=[CH:10][CH:9]=1)(=[O:21])[CH3:20].[Na+:23]
Reactant: CC(=O)Oc1ccc(CN2C[C@@H]3C[C@H]2CN3C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc([O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 4-{[(1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenyl acetate (2.33 g, 8.08 mmol, 1 equiv.) in CH2Cl2 (12.1 mL) and MeOH (8.1 mL) was added a solution of NaOH (0.323 g, 8.08 mmol, 1 equiv.) in water (4.1 mL). The solution was stirred at rt for 3 h. The reaction mixture was concentrated to afford product as an off-white solid (100%). 1H NMR (500 MHz, CD3OD): 7.01 (dd, J=8.8, 2.7, 2H), 6.61 (d, J=8.2, 2H), 4.63 (s, 0.5H), 4.41 (s, 0.5H), 3.63-3.53 (m, 4H), 3.35 (s, 3H), 3.28 (m, 0.5H), 3.19 (d, J=11.5, 0.5H), 2.91 (dd, J=10.3, 2.1, 0.5H), 2.82 (dd, J=10.2, 2.2, 0.5H), 2.67 (m, 1H), 1.94 (m, 1H), 1.76 (d, J=9.9, 0.5H), 1.66 (d, J=9.9, 0.5H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[C:12]1([CH3:17])[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH:9]=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1ccn(-c2ccccc2C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-n1ccc(C(=O)O)n1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
1-o-Tolyl-1H-pyrazole-3-carboxylic acid ethyl ester (238 mg, 1.03 mmol) was dissolved in a mixture of THF (2.0 mL) and MeOH (2.0 mL). To this was added NaOH (20% aqueous, 1.0 mL). The reaction mixture was stirred for 2 h, and was then diluted with EtOAc and washed with 1M HCl. The aqueous layer was extracted with EtOAc and the combined organics were dried over Na2SO4, filtered and concentrated to give the product as a white solid (164 mg, 0.81 mmol, 79%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[OH:13])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:19]O>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([O:9][CH3:19])=[O:8])[C:5]=1[OH:13])([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1O

Procedure:
3-Nitrosalicylic acid (500 g) was dissolved in methanol (2.25 L), concentrated sulfuric acid (0.25 L) was added, and the mixture was refluxed for 22 hours. The reaction solution was cooled on ice, and the precipitated solid was collected by filtration and dried to obtain the title compound (517.3 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)=[O:11])=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH2:31])[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=2)=[CH:18][C:17]=1[O:45][CH3:46]>ClCCl.N1C=CC=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)[CH2:34][CH2:33]3)[N:23]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:10](=[O:11])[C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)=[C:17]([O:45][CH3:46])[CH:18]=3)[C:30]=12
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Trifluoromethoxy)-1-benzenecarbonyl chloride (283 mg, 1.256 mmol) in dichloromethane (1 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.145 mmol) in pyridine (8 mL) at 0° C. After 30 minutes, the ice bath was removed the reaction mixture was stirred at room temperature for 1.5 hour. Solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide (526 mg, 74%). 1H NMR (CDCl3) δ 1.57 (m, 2H), 1.74 (m, 2H), 2.10-2.27 (m, 6H), 2.30 (s, 3H), 2.51 (m, 4H), 2.66 (m, 3H), 4.03 (s, 3H), 4.77 (m, 3H), 5.56 (bs, 2H), 7.26-7.37 (m, 4H), 7.99 (m, 2H), 8.38 (s, 1H), 8.59 (s, 1H), 8.67 (d, J=8.21 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:3]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][O:10][N:11]=[C:7]2[CH:6]=1)=[O:4].Cl.[O:22]([NH2:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:23][O:22][N:24]=[C:17]1[CH2:18][CH2:19][CH:14]([N:2]([CH3:1])[C:3]([C:5]2[CH:13]=[CH:12][C:8]3=[N:9][O:10][N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:15][CH2:16]1
Reactant: CON
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON=C1CCC(N(C)C(=O)c2ccc3nonc3c2)CC1
Reaction time: 8 h
Yield: 70.6 %

Procedure:
N-Methyl-N-(4-oxocyclohexyl)-[2,1,3]-benzoxadiazole-5-carboxamide (0.41 g, 1.5 mmol) was dissolved in chloroform (10 ml), methoxylamine hydrochloride (0.75 g) and triethylamine (1.6 ml) were added, and the mixture stirred overnight. Evaporation of the solvent and chromatography of the residue on silica gel, eluting with chloroform/ethyl acetate (3:2), gave a white solid (0.32 g). Mp=167-168° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=9.3 Hz, 1H); 7.84 (m, 1H); 7.42 (d, J=9.3 Hz, 1H); 4.85-4.70 and 3.80-3.30 (m, 1H); 3.83 (s, 3H); 2.99 and 2.88 (s+s, 3H); 2.60-1.60 ppm (s, 8H).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]2[S:8](=[O:21])(=[O:20])[C:9]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[C:24](C1C=CC2SC3C=C(C(O)=O)C=CC=3CCC=2C=1)(=O)C>>[C:1]([C:4]1[CH:23]=[CH:22][C:7]2[S:8](=[O:21])(=[O:20])[C:9]3[CH:16]=[C:15]([C:17]([O:19][CH3:24])=[O:18])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2(=O)=O
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccc(C(C)=O)cc1CC2

Procedure:
Following the procedure described in Example 10, Step 1, but substituting 2-acetyl-5,5-dioxo-10,11-dihydrodibenzo[b,f]thiepin-7-carboxylic acid (U.S. Pat. No. 4,536,507 (1985)) for 2-acetyl-10,11-dihydrodibenzo[b,f]thiepin-7-carboxylic acid as starting material, the title product was obtained as a solid.