Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].O.[NH2:18][NH2:19]>O1CCOCC1>[C:15]([C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[C:2]=1[NH:18][NH2:19])#[N:16]
Reactant: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1Br
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1NN
Yield: 39.2 %

Procedure:
6.4 g (0.02 mol) of 5-bromo-4-cyano-1-(2,4-dichlorophenyl)-pyrazole and 15 g (0.2 mol) of hydrazine hydrate in 80 ml of dioxane are stirred at the reflux temperature for 20 hours, the mixture is then concentrated under reduced pressure and the residue is stirred with water, filtered off with suction and recrystallized twice from ethanol. 2.1 g (40% of theory) of 4-cyano-5-hydrazino-1-(2,4-dichlorophenyl)-pyrazole of melting point 199° C.-204° C. are obtained.
Reaction SMILES: [N:1]([CH:4]([CH3:24])[CH2:5][O:6][CH:7]1[CH2:10][N:9]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C1C[O:48][CH2:47][CH2:46]1.O>>[C:12]1([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]2[CH2:10][CH:7]([O:6][CH2:5][CH:4]([NH:1][C:47](=[O:48])[CH3:46])[CH3:24])[CH2:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCOC1
Reactant: CC(COC1CN(C(c2ccccc2)c2ccccc2)C1)N=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(=O)NC(C)COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A solution of 3-(2-azidopropoxy)-1-(diphenylmethyl)azetidine (350 mg) and triphenylphosphine (340 mg) in THF/water (15 mL/5 mL) was heated under reflux for 2 hr. The mixture was allowed to cool, 1M hydrochloric acid was added thereto, and the mixture was washed with diethyl ether. The obtained aqueous solution was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), acetic anhydride (1 mL) was added thereto, and the mixture was stirred at 60° C. for 5 hr. The mixture was allowed to cool, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.31 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:10]2[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.Cl.N>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2C(O)(c2ccccc2)c2ccc(Br)cc2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: OC(c1ccccc1)(c1ccc(Br)cc1)c1ncc[nH]1

Procedure:
A mixture of 24.8 g. (0.052 mol) of α-(p-bromophenyl)-α-phenyl-1-(toluene-p-sulphonyl)imidazole-2-methanol, 160 ml. of 2 N hydrochloric acid solution (0.156 mol) and about 500 ml. of water was boiled under reflux for 5 hours. After cooling the mixture was made alkaline by addition of ammonia. The precipitated solid was collected, treated with activated carbon in boiling toluene and crystallised from toluene. Melting point of the product was 156°-158° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH2:27]Cl)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[I-].[Na+].[Na].[NH:37]1[CH:41]=[N:40][CH:39]=[N:38]1>CC#N>[CH:1]([O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH2:27][N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCCl)cc3n2C2CCC2)cc1
Reactant: c1nc[nH]n1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCn4cncn4)cc3n2C2CCC2)cc1

Procedure:
To a solution of {4-[6-(3-chloro-propoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (37 mg, 0.08 mmol) in CH3CN (1 mL) is added sodium iodide (71 mg, 0.48 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is then evaporated and the residue is diluted with anhydrous DMF (1 mL) and then treated with the sodium salt of 1,2,4-triazole (0.16 mmol) at room temperature overnight. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and then washed with water. The organic layer is concentrated and triturated with hexane and the precipitate is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1255 (31 mg, 78%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:17]([C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([Cl:34])[CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:29]([C:28]3[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:17]4[C:16]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[CH:26][C:27]=3[Cl:34])=[O:30])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3cccnc3Nc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.2 %

Procedure:
A mixture of 0.197 g of 6,11-dihydropyrido[2,3-b][1,5]benzodiazepine, 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride and 0.155 g of N,N-diisopropylethylamine in 8 ml of dichloromethane is stirred at room temperature for 1.5 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with H2O, saturated NaHCO3, H2O, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:2) to give 0.160 g of solid, m.p. 147° C.-165° C. Anal Found: C, 72.1; H, 5.1; N, 9.1; Cl, 6.3.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[Br:23])(=[O:3])[CH3:2].[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>ClCCCl.CC#N>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[Br:23])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(C(=O)c2ccc(COC(C)=O)c(Br)c2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CC#N
Product: CCOc1ccc(Cc2ccc(COC(C)=O)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.6 %

Procedure:
To a stirred solution of 2-bromo-4-(4-ethoxybenzoyl)benzyl acetate (0.41 g, 1.09 mmol) and Et3SiH (0.44 μL, 2.76 mmoL) in 1,2-dichloroethane/MeCN (2.5 mL, 1:2), was added dropwise BF3.Et2O (0.21 mL, 1.66 mmol). The reaction was complete after stirring for about 17 h at 25° C. Upon cooling, the reaction was quenched with 0.5 mL of 28.5% NaOH aqueous solution. The aqueous layer was extracted 2× with CH2Cl2, the combined organic layers were washed once with 2M KOH, 2× with H2O containing 10% brine and 2× with brine prior to drying over Na2SO4. After removal of the volatiles, the residue was purified by silica gel column (10:1 petroleum ether/ethyl acetate) to yield 0.24 g of title compound. 1H NMR (CDCl3, 300 MHz): δ 7.39 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 5.15 (s, 2H), 4.01 (q, J=7.0 Hz, 2H), 3.88 (s, 2H), 2.12 (s, 3H), 1.40 (t, J=7.0 Hz, 3H); MS ESI (m/z) 380 (M+NH4)+, calc. 362.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14](OC(=O)C)[C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC1C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCc2ccccc21
Reaction time: 72 h

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (2.2 g) in ethanol (300 ml) containing 10% Pd/C (2.0 g) was placed in a pressure bottle and hydrogenated at 3 atmospheres pressure and 70° for 3 days. The catalyst was filtered off and the filtrate evaporated to give 3-(S)-t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 164°-165° [α]D =-200.6° (c=0.64 in DMF).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C[Mg]Cl.[Cl-].[NH4+].CC1(O)CCC2(CCCC2)CC1>O1CCCC1>[CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH:7]=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CCCC2)CC1
Agent: CC1(O)CCC2(CCCC2)CC1
Agent: C[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C1C=CC2(CCCC2)CC1
Temperature: 25 °C
Yield: 109.1 %

Procedure:
With stirring under nitrogen atmosphere at room temperature, a mixture of 13.4 g of 8-spiro[4.5]decanone and 80 ml of tetrahydrofuran was added dropwise to a tetrahydrofuran solution of 0.205 mol methylmagnesium chloride (which had been prepared from 5.0 g of metallic magnesium, 100 ml of tetrahydrofuran and chloromethane), during which time the temperature was kept below 50° C. The reaction mixture was cooled to room temperature, after which a saturated ammonium chloride aqueous solution was added to stop the reaction. Through ordinary work-up of extraction, washing and drying, and subsequent concentration under reduced pressure, there was obtained 14.43 g (yield 99%) of the target compound, 8-methylspiro[4.5]decan-8-ol. This compound had a purity high enough to use in the subsequent step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:26](Cl)=[O:27]>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=3[C:15]=2[C:26](=[O:27])[C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([CH3:22])[CH:24]=2)=[CH:9][CH:10]=1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COc1ccc2oc(-c3ccc(OCCCl)cc3)cc2c1
Product: COc1ccc2oc(-c3ccc(OCCCl)cc3)c(C(=O)c3cc(C)cc(C)c3)c2c1

Procedure:
Acylation of 2-[4'-(2-chloroethoxy)phenyl]-5-methoxybenzofuran with 3,5-dimethylbenzoyl chloride as described in the procedure of Example 11 gives 2-[4'-(2-chloroethoxy)phenyl]-5-methoxy-3-(3',5'-dimethylbenzoyl)benzofuran.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C=O)C.[CH3:12][O:13][C:14]([CH2:16][CH2:17][C:18]12[CH2:25][CH2:24]C(C(O)=O)([CH2:22][CH2:23]1)[CH2:20][CH2:19]2)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:15])[CH2:16][CH2:17][C:18]12[CH2:23][CH2:22][C:1]([C:2]([Cl:4])=[O:3])([CH2:24][CH2:25]1)[CH2:20][CH2:19]2
Reactant: COC(=O)CCC12CCC(C(=O)O)(CC1)CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CCC12CCC(C(=O)Cl)(CC1)CC2
Reaction time: 2 h

Procedure:
Oxalyl chloride (794 mg, 6.25° mmol) in methylene chloride (5 ml) plus a drop of DMF is slowly added to a mixture of 4-(2-Methoxycarbonylethyl)-bicyclo[2.2.2]octane 1-carboxylic acid (XXI, Example 96, 1.2 g, 5 mmol) in methylene chloride (20 ml). The reaction mixture is stirred for 2 hr and concentrated to give the title compound, NMR (400 MHz, CDCl3) δ3.66, 2.29, 1.95, 1.54 and 1.46.
Reaction SMILES: CN1CCCC1=O.[C:8]([OH:13])(=O)[CH2:9][CH2:10][CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27](=[N:57]O)[C:28]1[CH:56]=[CH:55][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][C:46]3[CH:54]=[CH:53][C:49]([C:50]([NH2:52])=[O:51])=[CH:48][CH:47]=3)[CH2:38][CH2:37]2)=[CH:30][CH:29]=1>O.C(OCC)(=O)C>[NH2:57][C:27](=[N:26][O:13][CH2:8][CH2:9][CH2:10][CH3:11])[C:28]1[CH:56]=[CH:55][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][C:46]3[CH:47]=[CH:48][C:49]([C:50]([NH2:52])=[O:51])=[CH:53][CH:54]=3)[CH2:38][CH2:37]2)=[CH:30][CH:29]=1
Reactant: NC(=O)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Reactant: CCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To an N-methyl-2-pyrrolidone (10 mL) solution of 0.42 g of butyric acid was added 0.76 g of 1,1′-carbonyldiimidazole at room temperature, which was then stirred at the same temperature for one hour. An N-methyl-2-pyrrolidone (10 mL) solution of 1.00 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=oxime was added to the mixture at room temperature, which was then stirred at the same temperature for 14 hours. The reaction mixture was added to a mixture of ethyl acetate and water. The precipitate was collected by filtration and washed with ethyl acetate to provide 1.10 g of 4-{3-[4-(3-{4-[amino(n-butyloxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-(butyryl)oxime as white solid form.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:25]=[CH:24][N:23]=[C:22]3[C:13]=2[CH:14]=[CH:15][C:16]2[C:21]3=[N:20][CH:19]=[CH:18][C:17]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.O>C1COCC1.C1(C)C=CC=CC=1>[C:26]1([C:17]2[C:16]3[C:21](=[C:22]4[C:13](=[CH:14][CH:15]=3)[C:12]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=3)=[CH:25][C:24]([C:14]3[CH:2]=[C:1]([CH3:4])[CH:3]=[CH:22][CH:13]=3)=[N:23]4)[N:20]=[C:19]([C:7]3[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][CH:6]=3)[CH:18]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Reactant: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)cc(-c5cccc(C)c5)nc4c3n2)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, 8.8 ml of a 1.7 mol/l t-butyllithium solution (15 mmole) was added dropwise to a solution of 2.55 g of 2-bromo-toluence in 20 ml of THF at 0° C. The resulting mixture was stirred for another 2 hours, and then transferred to a stirred suspension of 1.0 g of bathophenanthroline (3 mmole) in 40 ml of toluene in an ice bath. The resulting deep-red solution was stirred overnight at room temperature, and 10 ml of water was then added. The organic layer was separated, and the aqueous layer was extracted with 30 ml of dicholormethane three times. The combined extracts were stirred with 15 g MnO2 for 2 hours. The mixture then was dried over 15 g of anhydrous MgSO4, filtered, and evaporated to dryness. The clean product was obtained after running chromatography in a silica/CH2Cl2 column with a yield of 75 percent. 1H NMR (500 MHz, CDCl3), ppm: 8.50 (s, 2H), 8.22 (d, J=7.5 Hz, 2H), 8.09 (s, 2H), 7.80 (s, 2H), 7.63-7.48 (m, 10H), 7.45 (dd, J=7.0, 7.0 Hz, 2H), 7.31 (d, J=7.0 Hz, 2H), 2.54 (s, 6H). Analysis for m-TBP. Found: C, 88.29, H, 5.40, N, 5.57. Calculated: C, 89.03, H, 5.51, N, 5.46.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:40]=[CH:39][C:31]3[N:32]=[C:33]([NH:35][C:36](=[O:38])[CH3:37])[S:34][C:30]=3[CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)Cl.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][N:8]([C:6]1[N:7]=[C:2]([C:28]2[CH:40]=[CH:39][C:31]3[N:32]=[C:33]([NH:35][C:36](=[O:38])[CH3:37])[S:34][C:30]=3[CH:29]=2)[CH:3]=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)N(C)c2cccc(Cl)n2)cc1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cccc(N(C)S(=O)(=O)c4ccc(C)cc4)n3)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
N-(6-Chloropyridin-2-yl)-N,4-dimethylbenzenesulfonamide (0.080 g, 0.27 mmol) was dissolved in 1,4-dioxane (6 mL), and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.1 g, 0.3 mmol), tetrakis(triphenylphosphine)palladium (0) (0.04 g, 0.04 mmol) and 2M Na2CO3 (0.3 mL, 0.6 mmol) were added to the mixture. The flask was fit with a reflux condensor and placed into a pre-heated (95° C.) bath and stirred under an inert atmosphere overnight. The mixture was then allowed to cool to ambient temperature and diluted with DCM and saturated NaHCO3. The organic layers were collected by extracting with DCM three times, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography (1-10% IPA/DCM) to give N-(6-(6-(N,4-dimethylphenylsulfonamido)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide as a tan solid. MS (ESI pos. ion) m/z: 453 (MH+). Calculated exact mass for C22H20N4O3S2: 452. 1H NMR (400 MHz, DMSO-d6): 8.35 (s, 1H), 7.93 (t, J=8.0 Hz, 2H), 7.83 (d, J=7.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.5 Hz, 2H), 3.38 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH2:18]([SH:21])[CH2:19][SH:20].B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:21][CH2:18][CH2:19][S:20]2)=[C:4]([CH3:16])[C:3]=1[CH3:17]
Reactant: SCCS
Reactant: Cc1c(Cl)nnc(C(=O)c2ccccc2)c1C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(Cl)nnc(C2(c3ccccc3)SCCS2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
To a DCM solution of (6-chloro-4,5-dimethyl-pyridazin-3-yl)-phenyl-methanone (300 mg, 1.22 mmol) is added 1,2-ethandithiol (0.408 ml, 4.86 mmol) and BF3.OEt2 (0.154 ml, 1.216 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture is stirred at room temperature for 16 h. The reaction was charged with BF3.OEt2 (0.154 ml, 1.216 mmol) and 1,2-ethandithiol (0.408 ml, 4.86 mmol), and heated at 40° C. for 6 h. The reaction is quenched with sat. NaHCO3 at 0° C. and organic phase is washed with brine. The organic layer is dried over Na2SO4, filtered and concentrated to afford a yellow solid. The residue is loaded on silica gel and purified by flash chromatography, eluting with 20-80% EtOAc: heptane. Fractions containing the desired product are combined and concentrated to afford a white solid (280 mg, 73%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH:20]([CH3:22])[CH3:21])[C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[C:16]#[N:17])(=[O:3])[CH3:2].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>>[C:1]([O:4][CH:5]([CH:20]([CH3:22])[CH3:21])[C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:23](=[O:26])(=[O:25])[NH2:24])[C:10]=1[C:16]#[N:17])(=[O:3])[CH3:2]
Reactant: NS(=O)(=O)Cl
Reactant: CC(=O)OC(C(C)C)C(C)(C)COc1cccc(N)c1C#N
Product: CC(=O)OC(C(C)C)C(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 90 %

Procedure:
Prepared as in Example 215a from 1-(3-amino-2-cyanophenoxy)-2,2,4-trimethylpentan-3-yl acetate (Example 243b) and sulfamoyl chloride in 90% yield. MS 384 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:38]1[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=1>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:38]4[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)nc1
Temperature: 120 °C

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.10 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added 2-chloro-5-ethylpyrimidine (27 mg, 0.20 mmol). The mixture was heated in a microwave at 120° C. for 10 min. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 5-chloro-N2-(4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid. ESMS m/z 522.2 (M+H+).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH:10]2[CH:11]=[CH:12][CH:5]1[CH:6]1[CH:9]2[N:8]=[N:7]1.[CH3:13]I>C(#N)C>[CH3:13][O:3][CH:4]1[CH:10]2[CH:11]=[CH:12][CH:5]1[CH:6]1[CH:9]2[N:8]=[N:7]1
Reactant: CI
Reactant: OC1C2C=CC1C1N=NC21
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COC1C2C=CC1C1N=NC21
Reaction time: 12 h

Procedure:
1 part of NaH was added, a little at a time, to 5 parts of 9-hydroxy-3,4-diazatricyclo[4,2,1,02,5 ]nona-3,7-diene and 100 parts of acetonitrile at 20° C., while stirring. Thereafter, 20 parts of methyl iodide were added and stirring was continued for 12 hours at 20° C. The reaction mixture was evaporated down in a rotary evaporator at from 20° to 50° C. and under 20 mbar, and the residue was extracted with 200 parts of petroleum ether. The petroleum ether phase was evaporated down to give 5 parts (90 mole %) of 9-methoxy-3,4-diazatricyclo[4,2,1,02,5 ]-nona-3,7-diene as an oil. 1H-NMR (δ in ppm): 6.2 (bs, 2H), 4.1 (bs, 2H), 3.1-3.3 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:21][CH3:22])[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:21][CH3:22])[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 5-chloro-3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methylbenzoate (1.06 g, 3.26 mmol) in methanol (10 mL) was added aq. NaOH (5 M, 780 ul, 3.92 mmol). The reaction mixture was stirred at 50° C. for 18 hours. After cooling to 23° C., HCl (2 M, 2 mL)) was added to the mixture and the mixture was acidified to pH=5 and was concentrated in vacuo to give the titled compound as crude products (1.80 g).