Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][CH:3]=1)=[O:21]
Reactant: Cn1nc(C(F)(F)F)cc1-c1ncc(N)s1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(F)(F)F)cc1-c1ncc(NC(=O)c2ccccc2Cl)s1
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a mixture of 5-amino-2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1,3-thiazole (66, 8.1 mg, 0.03 mmol) in 1 ml DCM were added 2-chlorobenzoyl chloride (3.8 μl, 2 eq), DIEA (52 μl, 3 eq) and DMAP (2 mg). After stirred at r.t for 2 h, the reaction mixture was worked up with DCM/aq. NaCO3, the DCM phase was concentrated to dryness. The solid residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1). 0.06 ml of 1N NaOH were added and mixture was stirred at r.t for 1 h before worked up DCM//aq. NaCO3. DCM phase was concentrated and subjected to prep HPLC purification to give 3.7 mg of (2-chlorophenyl)-N-{2-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl](1,3-thiazol-5-yl)}carboxamide (67) as yellow solid (yield: 31.9%; purity>90%). LC-MS: calcd. for C15H10ClF3N4OS: 387 (M+1).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1.[I:20]I>CCCCCC.O1CCCC1>[I:20][C:13]1[CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:10]=[N:9][C:8]=1[O:7][CH3:6]
Reactant: COc1ccc(-c2ccncc2)nn1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1nnc(-c2ccncc2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
45 ml 1.6M solution of n-butyllithium in hexane are added at −30° C. to a 10.2 g 2,2,6,6-tertamethylpiperidine in 100 ml THF and the mixture stirred at 0° C. for 30 min. After cooling to −75° C. 11.2 g 3-methoxy-6-pyridin-4-yl-pyridazine dissolved 300 ml THF are added and the solution stirred at −75° C. for 35 min. The cold (−75° C.) reaction mixture is subsequently added at a cold (−75° C.) solution of 18.3 g iodine in 400 ml THF (tetrahydrofuran) and stirred at −75° C. for 1.5 h. The reaction is quenched by adding 80 ml methanol/THF (1:1) at −75° C. and 300 ml saturated aqueous NaHCO3 at room temperature and extracted with dichloromethane. The organic layer is ished with 5% aqueous Na2S2O3 and saturated sodium chloride solution, dried (MgSO4) and the solvens removed. The crude product is purified by chromatography on silica gel to yield 14.4 g of 4-iodo-3-methoxy-6-pyridin-4-yl-pyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-:11].[K+].[K+].C(Cl)(Cl)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:10](=[O:11])[O:9][C:3]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(F)cc1O
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=c1[nH]c2ccc(F)cc2o1
Temperature: 25 °C
Yield: 96 %

Procedure:
To 5.0 g (39.3 mmol) 2-amino-5-fluorophenol in 150 ml of CH2Cl2 at 0° C. was added 13.4 (98 mmol) of potassium carbonate and 23 g (47 mmol) of 20 wt. % phosgene in toluene. After warming to room temperature, the reaction was stirred an additional hour before quenching onto 200 ml ice/water. The layers were separated and the aqueous phase was extracted with EtOAc (1×100 ml) before the organics were combined and dried over Na2SO4. The solvent was removed in vacuo to give 5.76 g (96% yield) of the desired product as determined by 1H NMR.
Reaction SMILES: [N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C@H:29]([CH3:36])[CH2:30][C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=3)=[O:21])=[CH:15][C:14]=2[O:37][CH3:38])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([CH:29]([CH3:36])[CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=3)=[O:21])=[CH:15][C:14]=2[O:37][CH3:38])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2ccc(NC(=O)N3CCc4ccccc43)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(CC(=O)Nc2ccc(C(C)CC(=O)O)cc2)ccc1NC(=O)N1CCc2ccccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A suspension of ethyl (R) 3-[4-(2-{4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl}-acetylamino)-phenyl]-butyrate (1.3 g, Reference Example 4) in ethanol (40 mL) and water (15 mL) was treated with sodium hydroxide (5 mL, 1M). After stirring at 50° C. for 3 hours the mixture was evaporated to low bulk and then acidified with hydrochloric acid (1M). The resulting white precipitate was filtered, then washed with water, then with ether, and then dried to give the title compound (1.06 g) as a white powder. HPLC: RT=15.3 minutes (>95% by ELS). MS(ES+): 488(MH+); MS(ES−): 486(M−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.[I-].[Na+]>CC(C)=O.CCOCC>[CH:12]1([CH2:11][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=2)[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: C#Cc1cccc(O)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C#Cc1cccc(OCC2CC2)c1
Yield: 84.2 %

Procedure:
To a solution of 3-ethynylphenol (1.18 g, 10.0 mmol) in acetone (30 mL) is added (bromomethyl)cyclopropane (1.02 mL, 10.0 mmol), sodium iodide (0.75 g, 5.0 mmol) and CS2CO3 (6.52 g, 20.0 mmol) at room temperature. After refluxing over night, the reaction mixture is cooled, diluted with Et2O (300 mL) and pass through a thin layer of silica gel. The solution is concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane:1/99) to give the title compound (1.45 g, 84%) as an oil. MS (+) APPI: 173 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(O)cc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccc(O)cc2)c(-c2cccnc2F)c1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-hydroxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (300 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 40° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate, and further recrystallized from a mixed solvent of ethyl acetate-methanol (4:1) to give the title compound as colorless crystals (yield 208 mg, 81%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23](O)=[O:24]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:23]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][N:17]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1cnccn1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1cnccn1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and pyrazine-2-carboxylic acid
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6][C:5]=2[S:4][CH:3]=1.O1CCCC1.C([Li])CCC.[C:23](=[O:25])=[O:24]>CCCCCC>[CH3:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][S:6][C:5]=2[S:4][C:3]=1[C:23]([OH:25])=[O:24]
Reactant: Cc1csc2c1C(C)(C)CCS2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2c1C(C)(C)CCS2
Temperature: -65 °C
Reaction time: 1 h

Procedure:
8.20 g (0.041 mol) of the title compound of Step B was added to 200 mL of tetrahydrofuran under nitrogen. The solution was cooled to about -65° C. and 21 mL (0.053 mol) of 2.5M n-butyllithium was added dropwise while keeping the reaction temperature below -55° C. After stirring for 1 h, an excess of solid CO2 was added in portions and the mixture was allowed to warm to room temperature over 2 hr. The mixture was then diluted with 150 mL of hexane and the precipitate was collected by filtration. The precipitate was added to a mixture of 300 mL of water and 300 mL of methylene chloride, cooled to about 0° C., and then acidified to pH 1 with concentrated hydrochloric acid. The layers were separated and the aqueous layer was extracted with diethyl ether (2×300 mL). The combined organic layers were dried (MgSO4), filtered, and evaporated to dryness to yield 6.36 g of the title compound of Step C as a solid melting at 176°-178° C. 1H NMR (DMSO-d6): δ 1.3 (s,6H), 1.95 (m,2H), 2.6 (s,3H), 3.08 (m,2H), 12.7 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12](C(OC(C)(C)C)=O)[C:11]([CH3:25])=[C:10]2[C:26](=[O:40])[N:27]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH3:28])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[NH:12][C:11]([CH3:25])=[C:10]2[C:26]([N:27]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH3:28])=[O:40])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(S(=O)(=O)N(C)C(=O)C2=C(C)N(C(=O)OC(C)(C)C)c3ccnn3C2c2ccc(Cl)c(Cl)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(C)C(=O)C2=C(C)Nc3ccnn3C2c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 1.5 h

Procedure:
To a mixture of the product obtained from Step C (60 mg, 0.1 mmol) in CH2Cl2 (5.0 mL) at room temperature under N2 was added TFA (5.0 mL). The mixture was stirred for 1.5 h. LC-MS indicated the completion of reaction. Solvent was evaporated, and the mixture was purified by reverse phase HPLC (acetonitrile/water). The desired product was obtained as white solid. LC-MS found: (M+1)+=507.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
5-Bromo-2-chloropyridin-3-amine (1 g, 4.82 mmol) was dissolved in THF (5.5 ml) and a solution of sodium bis(trimethylsilyl)amide (1M in THF, 14.5 ml, 14.5 mmol) was added dropwise. Ten minutes later, 4-methoxybenzene-1-sulfonyl chloride (3 g, 14.5 mmol) was added and the reaction mixture stirred for 2 h. A saturated solution of sodium bicarbonate was then added dropwise and the reaction mixture extracted with dichloromethane (×3). The organic phase was dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The resulting crude was purified by flash chromatography using SP1® Purification System (0% to 10%, dichloromethane-ethyl acetate) to obtain 1.49 g (82% yield) of the title compound. Purity: 100%
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH2:24])[N:23]=3)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH:24][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[CH:27]=4)[N:23]=3)[CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)cn3nc(N)nc23)cc1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cc(C(F)(F)F)cn4n3)c2)CC1

Procedure:
8-Bromo-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 3-bromo-5-trifluoromethyl-pyridin-2-ylamine, ethoxycarbonylisothiocyanate, and hydroxylamine hydrochloride in a manner analogous to Steps 2a-b. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.24 (s, 1H), 8.08 (s, 1H), 6.62 (bs, 2H). MS=282.9 (MH)+. 102b) 8-(4-Methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and (4-methylsulfonylphenyl)boronic acid in a manner analogous to Step 2c to afford a white solid (67%) MP=236-237° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.28 (s, 1H), 8.42 (d, J=7.8 Hz, 2H), 8.07 (s, 1H), 8.06 (d, J=7.8 Hz, 2H), 6.58 (bs, 2H), 3.29 (s, 3H). MS=356.33 (MH)+. 102c) [8-(4-Methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(3-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a yellow solid (2% yield). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.84 (s, 1H), 8.28 (d, J=8.3 Hz, 2H), 8.14 (d, J=7.2 Hz, 2H), 7.81 (s, 1H), 6.95 (m, 2H), 6.64 (d, 1H), 3.32 (bm, 4H), 3.14 (s, 3H), 2.67 (bm, 4H), 2.44 (s, 3H). MS=531.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.Cl>O1CCCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([B:17]([OH:20])[OH:18])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
33 g (0.15 mol) of 4-bromotrifluoromethylbenzen was put into a 500-mL three-neck flask, and nitrogen substitution in the system was carried out. Then, 200 mL of tetrahydrofuran (THF) was added thereto, and the mixture was stirred. This mixture solution was stirred at −78° C., and 100 mL (0.16 mol) of n-butyllithium (1.6 mol/L) was dropped into the solution through a dropping funnel. After that, the obtained solution was stirred at the same temperature for 1 hour, and 22.3 mL (0.20 mol) of trimethyl borate was added to be stirred for about 12 hours while the reaction temperature was allowed to gradually increase to the room temperature. Then, 100 mL of dilute hydrochloric acid (1 mol/L) was added to the reaction solution, and the solution was stirred for 1 hour. A water layer of the mixture was extracted using ethyl acetate three times, the extracted solution and an organic layer were washed together one time using saturated saline, and the organic layer was dried with magnesium sulfate. The mixture was filtrated naturally to remove magnesium sulfate, and the filtrate was condensed to obtain a solid. The solid was washed with chloroform, whereby 15 g of a white solid, which was a target matter, was obtained with the yield of 54%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[CH:32][C:27]5[O:28][CH2:29][CH2:30][O:31][C:26]=5[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:34][N:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>C1COCC1.C(Cl)Cl>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:40]([C:36]6[N:35]([CH3:34])[CH:39]=[CH:38][CH:37]=6)=[O:41])[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: Cn1cccc1C(=O)Cl
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cccc1C(=O)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Yield: 91.2 %

Procedure:
To a solution of {4-[2-(3-amino-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine (105 mg, 0.24 mmol) in 5 mL THF was added N-methylpyrrole carbonyl chloride (37 mg, 0.26 mmol). When TLC showed the reaction to be complete, the solution was diluted with DCM and washed with a solution of saturated NaHCO3 and with brine. The organic phase was dried over MgSO4 and concentrated. The residue was triturated with diethyl ether to give the title compound as a yellow solid (119 mg, 92%). 1H NMR (400 MHz, d6-DMSO) δ 9.90 (s, 1H), 9.80 (s, 1H), 8.87 (d, J=6.8 Hz, 1H), 8.50 (s, 1H), 8.14 (d, J=6.0 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.51 (m, 1H), 7.43 (m, 1H), 7.27-7.22 (m, 2H), 7.17 (t, J=6.8 Hz, 1H), 7.05-7.04 (m, 2H), 7.00 (s, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.47 (d, J=6.0 Hz, 1H), 6.08-6.07 (m, 1H), 4.22 (m, 4H), 3.85 (s, 3H) ppm. HRMS calculated C31H25N7O3 [M+H]+ 544.2097 found 544.2101.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[C:16]([NH2:19])[C:17](=[CH:10][C:9]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[NH2:18])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: NCCN
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: CCO
Product: COc1cc(C=C(N)C(N)=Cc2cc(OC)c(OC)cc2[N+](=O)[O-])c([N+](=O)[O-])cc1OC
Yield: 84 %

Procedure:
A heated suspension of 6-nitroveratraldehyde (168.8 g, 0.8 moles) and 1200 ml of ethanol was treated with ethylenediamine (24 g, 0.4 moles) and 200 ml of ethanol. The mixture was nearly in solution when a solid precipitated. Ethanol (500 ml) was added. The suspension was refluxed for 1.5 hrs. The resulting solid was filtered and washed with ethanol to yield 150 g (84%) of the product.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[CH2:32][CH3:33]>>[CH2:32]([C:31]1[N:27]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:28][CH:30]=1)[CH3:33]
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CCC(=O)CBr
Product: CCc1csc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (about 0.211 mmol) of the compound from Example 115A and 38 mg (0.253 mmol) of 1-bromobutan-2-one were reacted according to the General Method 3. Yield: 49 mg (47% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]2[CH:23]=[CH:24][CH:25]=[C:14]2[CH2:13]1)=[O:11])[C:5]#[N:6].[OH-:26].[NH4+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]2[CH:23]=[CH:24][CH:25]=[C:14]2[CH2:13]1)=[O:11])[C:5]([NH2:6])=[O:26]
Reactant: N#Cc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Concentrated sulfuric acid (70 ml) was added to 3-chloro-4-(5H,11H-pyrrolo-[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzonitrile (12.85 g). The mixture was stirred at 60° C. for 3 hours, followed by stirring at room temperature for 18 hours. The reaction mixture was poured over ice and neutralized at 0° C., with 30% ammonium hydroxide (184 ml). The resulting suspension was extracted with ethyl acetate. The aqueous mixture was filtered, and reextracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and the solvent removed in vacuo. The residue was triturated with a mixture of diethyl ether (50-60 ml) and a small quantity of ethyl acetate. Filtration of the precipitate afforded the title compound as a crystalline solid (10.44 g), m.p. 211-212° C.; MS (EI), m/z: 365 (M)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:4]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1ccccn1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Chloroacetylchloride (60 g, 0.53M) was added with stirring to a mixture of 2-aminopyridine (50 g, 0.53M) and diisopropylethylamine (75 ml, 0.53M) in dichloromethane (500 ml) keeping the temperature below 5° C. After the reaction mixture was warmed to room temperature it was filtered and washed with water. The organic layer was dried (MgSO4) and evaporated under reduced pressure to give 72.6 g of a brown solid.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].C(O[CH2:26][CH:27]([N+:30]([O-:32])=[O:31])[CH2:28][CH3:29])(=O)C>N1C=CC=CC=1>[N+:30]([CH:27]([CH2:28][CH3:29])[CH2:26][N:5]1[C:4](=[O:21])[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6]1)([O-:32])=[O:31]
Reactant: CCC(COC(C)=O)[N+](=O)[O-]
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Solvent: c1ccncc1
Product: CCC(Cn1nc(-c2ccccc2)c(-c2ccccc2)c(C#N)c1=O)[N+](=O)[O-]
Yield: 38.2 %

Procedure:
4.0 grams (0.014 mole) of the product of Example 1 was reacted with 2.37 grams (0.014 mole) of 2-nitrobutyl acetate in 100 mls of dry pyridine. This solution was heated to reflux for 1 hour, cooled and the solvent distilled at reduced pressure. The residual solid was recrystallized from methyl alcohol to give 2.0 grams (37% yield) of a white-yellow solid melting at 154°-155° C. The infrared spectrum showed the C-C band at 3.5μ, the nitrile band at 4.5μ, and the amide carbonyl band at 6.0μ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:36]4[CH2:35][CH2:34][N:33]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[F:26])[CH2:38][CH2:37]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(CN2CCN(c3ccccc3F)CC2)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 45.8 %

Procedure:
Compound 8 was prepared using the method described in Example 3, starting with compound 2 (1.0 g, 2.60 mmol), 1-(2-fluorophenyl)piperazine (0.51 g, 2.86 mmol), and cesium carbonate (1.27 g, 3.90 mmol) to give 8 (0.56 g, 46%); C27H33ClFN3O, LRMS (m/z)=471 (MH+).