Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:27]([NH:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=1)=[O:28]>>[CH3:43][C:42]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][N:31]=2)=[O:28])=[CH:40][C:41]=1[C:2]#[C:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([S:19](=[O:21])(=[O:22])[NH2:20])=[CH:17][CH:18]=3)[C:6]2=[N:5][CH:4]=1
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1I
Reactant: C#Cc1cnc2c(Nc3ccc(S(N)(=O)=O)cc3)cccn12
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1C#Cc1cnc2c(Nc3ccc(S(N)(=O)=O)cc3)cccn12

Procedure:
The title compound was synthesized from 3-ethynyl-N-(4-sulfamoylphenyl)imidazo[1,2-a]pyridin-8-amine and 3-iodo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide in a manner similar to that described for Example 12. The product was obtained as a solid: 591 m/z (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]=[C:22]3[C:25]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:28][CH2:27][CH2:26]3)=[CH:17][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)C>[CH2:36]([NH:43][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]=[C:22]3[C:25]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:26][CH2:27][CH2:28]3)=[CH:17][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)c1ccc(Cl)nc1
Reactant: NCc1ccccc1
Solvent: CCO
Product: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)c1ccc(NCc2ccccc2)nc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
6-Chloro-N-(2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethyl)pyridine-3-sulfonamide (70.0 mg, 0.132 mmol) and benzylamine (14.2 mg, 0.133 mmol) were dissolved in dry ethanol (3 ml) and stirred in a microwave oven at 150° C. for 1 h. The solvent was reduced under vacuo and the residue was purified by column chromatography using silica gel and heptan/ethyl acetate (3:7→7:3) as the eluent. The product was obtained as a white solid (79 mg, 0.132 mmol, 20%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([OH:20])=O)[CH:13]=2)[CH:4]=1.[Cl-].[NH4+].C1C=CC2N([OH:34])N=[N:31]C=2C=1.C(Cl)CCl.C(N(C(C)C)C(C)C)C.CN([CH:51]=[O:52])C>>[C:51]([OH:52])([C:2]([F:22])([F:21])[F:1])=[O:34].[F:21][C:2]([F:1])([F:22])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH2:31])=[O:20])[CH:13]=2)[CH:4]=1
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(-c2cc(C(F)(F)F)cc3[nH]ncc23)ccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(-c2cc(C(F)(F)F)cc3[nH]ncc23)ccn1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4-(6-(trifluoromethyl)-1H-indazol-4-yl)picolinic acid (0.028 g, 0.091 mmol) in DMF (3 mL) were added ammonium chloride (0.024 g, 0.456 mmol), HOBt (0.018 g, 0.137 mmol), and EDC (0.028 g, 0.146 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (0.079 mL, 0.456 mmol). The reaction mixture was stirred for 18 hours at room temperature. The crude reaction mixture was subsequently purified by preparative HPLC, eluting with a gradient of 30-35% acetonitrile (containing 0.035% TFA) in H2O (containing 0.05% TFA) over a period of 6.5 minutes. The product-containing fractions were combined and the solvent removed in vacuo to give a TFA salt of the title compound as an off white solid (0.012 g, 43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (s, 1H), 7.80 (br s, 1H), 7.95-8.15 (m, 2H), 8.27 (br s, 1H), 8.32-8.47 (m, 2H), 8.81 (d, J=5.05 Hz, 1H), 13.89 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C14H9F3N4O, 307.1. found 307.11.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[C:6]=2[N:5]=[C:4]([CH3:14])[N:3]=1.O.[NH2:16][NH2:17]>>[CH2:12]([N:11]1[CH2:10][CH2:9][O:8][C:7]2[C:2]([NH:16][NH2:17])=[N:3][C:4]([CH3:14])=[N:5][C:6]1=2)[CH3:13]
Reactant: NN
Reactant: CCN1CCOc2c(Cl)nc(C)nc21
Solvent: O
Product: CCN1CCOc2c(NN)nc(C)nc21

Procedure:
Using the method of Example 87, 4-chloro-6,7-dihydro-8-ethyl-2-methylpyrimido [5,4-b][1,4]oxazine, from Example 102, was reacted with hydrazine hydrate to provide 6,7-dihydro-8-ethyl-4-hydrazino-2-methylpyrimido[5,4-b][1,4]oxazine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[C:13]([F:21])=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)[CH3:10]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:9][CH3:10])[C:13]=2[F:21])=[N:3][CH:4]=1
Reactant: CCOc1cccc(B(O)O)c1F
Reactant: Brc1ccc(Br)nc1
Product: CCOc1cccc(-c2ccc(Br)cn2)c1F
Yield: 47 %

Procedure:
Obtained (1.18 g, yield 47%) following the procedure described in Intermediate 27, starting with 2,5-dibromopyridine (8.44 mmol, 2.0 g), 3-ethoxy-2-fluorophenylboronic acid (8.43 mmol, 1.55 g).
Reaction SMILES: [Na+].[Br-:2].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])[CH:7]=[CH:8][CH:9]=1>CC(C)=O.CCCCCC>[Br:2][CH:12]([CH3:13])[C:11](=[O:15])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1
Reactant: CC(Cl)C(=O)Cc1cccc(Br)c1
Reactant: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(Br)C(=O)Cc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of NaBr (197 mg, 1.9 mmol) and 1-(3-bromophenyl)-3-chlorobutan-2-one (100 mg, 0.38 mmol) in acetone (2 ml) was stirred at 70° C. for 3 h. The mixture was diluted with hexane and filtered to remove the solid. The solvent was removed under reduced pressure and the residue was used for the next step without further purification. MS (ES+) C10H10Br2O requires: 303, 305 found: 304, 306 [M+H]+(1:1).
Reaction SMILES: IC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[I:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[I:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:38]2[CH:39]=[CH:40][C:35]([I:34])=[CH:36][CH:37]=2)=[S:45])=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(I)cc1
Agent: O=C(N=C=S)c1ccc(I)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(I)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-Iodo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-iodo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-iodo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (92 mg, yield 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>ClC(Cl)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1ccc(O)cc1F
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1cc([N+](=O)[O-])c(O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
3-fluoro-4-methylphenol (3.66 g, 29.0 mmol) was dissolved in dichloroethane (32 mL) and tetrabutylammonium bromide (0.935 g, 2.90 mmol) was added. Nitric acid 70% (3.7 mL, 58 mmol) was diluted with water (33 mL) to make a 7% nitric acid solution. This solution was added to the reaction mixture which was then stirred at room temperature for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into water and extracted with dichloromethane (3×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was absorbed onto silica gel and purified by chromatography on SiO2 to give 5-fluoro-4-methyl-2-nitrophenol as a yellow solid (2.83 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s, 1 H), 7.89 (d, J=8.1 Hz, 1 H), 6.85 (d, J=11.0 Hz, 1 H), 2.13 (s, 3 H).
Reaction SMILES: [C:1]12([C:14]([OH:16])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([C:11]([OH:13])=[O:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:18][CH2:19][CH3:20].N1(C2CCCCCCCCCC2)CCCN=CCC[CH2:24][CH2:23][CH2:22]1>C(#N)C.C(OCC)(=O)C>[C:1]12([C:14]([O:16][CH2:22][CH2:23][CH3:24])=[O:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][C:3]([C:11]([O:13][CH2:18][CH2:19][CH3:20])=[O:12])([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Reactant: CCCBr
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCOC(=O)C12CC3CC(C1)CC(C(=O)OCCC)(C3)C2
Temperature: 25 °C

Procedure:
Di-n-propyl 1,3-adamantanedicarboxylate is prepared by way of the following procedure. A 50 mL round bottom flask equipped with a magnetic stir bar is charged with 1,3-admantanedicarboxylic acid (3.36 g, 15.0 mmol), 1-bromopropane (3.28 mL, 36.0 mmol) and 1,8-diazabicycloundec-7-ene (5.38 mL, 36.0 mmol) in 25 mL acetonitrile. The mixture is heated to reflux overnight and cooled to room temperature. The reaction is diluted with 100 mL of ethyl acetate and washed with saturated NH4Cl/1N HCl, water, saturated sodium bicarbonate, and then brine. The organic layer is dried over sodium sulfate. After filtration, the filtrate is concentrated, and the residue is dried in vacuo. The crude product is further purified by distillation in vacuo to yield the product as a white liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2)(=[O:11])=[O:10]
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2cc(NS(=O)(=O)c3cc(Cl)ccc3Cl)ccc2n1
Reaction time: 0.08 h
Yield: 51.7 %

Procedure:
To a solution of 2,5-dichlorobenzenesulphonyl chloride (163 mg, 0.664 mmol) in dichloromethane (4 mL) was added pyridine (130 μL, 1.58 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylquinoline (100 mg, 0.632 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (120 mg, 52%), single spot at Rf 0.68 (ethyl acetate). mp 124.6-125.0° C., HPLC purity 99+% (tR 2.22 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.98 (1H, d, 2.2 Hz), 7.94 (1H, d, J=8.4 Hz), 7.88 (1H, d, J=8.9 Hz), 7.57 (1H, d, J=2.2 Hz), 7.45-7.35 (3H, m), 7.27-7.24 (2H, m), 2.68 (3H, s). LCMS: 365.10 (M−). FAB-MS (MH+, C16H12Cl2N2O2S): calcd 367.0075, found 367.0074.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=1)#[CH:11]>C(NC(C)C)(C)C.C1(C)C=CC=CC=1.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.[Cu]I>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:11][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[CH:13][C:14]=1[CH3:19]
Reactant: COc1cncc(Br)c1
Reactant: C#Cc1ccc(F)c(C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: COc1cncc(C#Cc2ccc(F)c(C)c2)c1
Temperature: 60 °C
Yield: 51.1 %

Procedure:
Dissolve 3-bromo-5-methoxypyridine (1.0 g, 5.35 mmol) in diisopropylamine (17 mL) and toluene (10 mL) under nitrogen. Add tetrakis(triphenylphosphine)palladium (0.200 g, 0.16 mmol). Heat at 60° C. and add 4-ethynyl-1-fluoro-2-methylbenzene (717 mg, 5.35 mmol) and copper (I) iodide (20 mg, 0.11 mmol). After 20 h add additional 4-ethynyl-1-fluoro-2-methylbenzene (100 mg, 0.75 mmol) and heat at 60° C. for 5 h. Concentrate and purify using silica gel chromatography, eluting with 30:70 to 40:60 ethyl acetate:hexanes, to give the title compound (660 mg, 51%).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])(=[O:5])[CH3:4].Cl[CH:15]1[CH2:19][CH2:18][CH:17]=[CH:16]1>CN(C=O)C>[CH:19]1([O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:3](=[O:5])[CH3:4])[CH2:18][CH2:17][CH:16]=[CH:15]1
Reactant: CC(=O)Nc1ccccc1O
Reactant: ClC1C=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1OC1C=CCC1
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a suspension of sodium hydride (60 proc. in paraffin; 297 mg, 7.43 mmol, 1.1 equiv.) in DMF (3 ml) a solution of 2-acetamido-phenol (1.02 g, 6.75 mmol, 1.0 equiv.) in DMF (12 ml) was added dropwise at 0° C. After 30 minutes chlorocyclopent-2-ene (R. Moffett. Organic Synthesis, Wiley: New York 1963, Collect. Vol. IV, p.238-241) (762 mg, 0.76 ml, 7.43 mmol, 1.1 equiv.) was added by a syringe and stirring was continued overnight. Aqueous work-up followed by flash chromatography on silica gel (heptane/ethyl acetate, 2:1 continued to 1:1) afforded 992 mg (68%) of the subtitle compound as a dark, yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[OH-:10].[Na+].[N:12]1[C:19](Cl)=[N:18][C:16]([Cl:17])=[N:15][C:13]=1Cl>CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:13]1[N:15]=[C:16]([Cl:17])[N:18]=[C:19]([O:10][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[CH:2])[CH:8]=2)[N:12]=1)#[CH:2]
Reactant: [OH-]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C#Cc1cccc(O)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: C#Cc1cccc(Oc2nc(Cl)nc(Oc3cccc(C#C)c3)n2)c1
Yield: 95.8 %

Procedure:
The bis-(m-ethynylphenoxy)-chloro-1,3,5-triazine is prepared by first adding m-ethynylphenol (11.4 g, 0.097 mole) in 20 ml of a 5 N NaOH dropwise to a stirred solution of cyanuric chloride (9.22 g, 0.05 mole) in 50 ml of acetone with stirring at 15°-18° C. After stirring for one hour at this temperature, the resulting mixture is filtered to remove a white solid which is washed with water and dried in vacuum overnight at 35° C. The yield of the product is 16.14 g (yield of 95.8%). The product has a melting point of 121°-125° C. which increases to 127°-128° C. upon one recrystallization from chloroform/heptane. This product is analyzed by NMR and determined to be bis-(m-ethynylphenoxy)-chloro-1,3,5-triazine represented by the formula:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:18]2[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:19]=2[N:20]=[CH:21][N:22]=1.CCN(C(C)C)C(C)C>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH3:15])[C:17]2[C:18]3[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H]1CCCN(Cc2ccccc2)C1
Reactant: O=C1CCc2c(Cl)ncnc2N1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncnc2c1CCC(=O)N2)[C@H]1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
A solution of (S)-1-benzyl-N-methylpiperidin-3-amine (0.2 g, 1.0 mmol), 4-chloro-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (90 mg, 0.5 mmol) and DIEA (253 mg, 2.0 mmol) was heated in a sealed tube at 100° C. overnight. The reaction mixture was cooled to rt and poured into ice water. The reaction mixture was extracted with EtOAc (3×15 mL) and the combined EtOAc layer was dried over Na2SO4, evaporated in vacuo to give the crude product which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford (100 mg, 29%) of the titled intermediate. 1H NMR (400 MHz, CD3OD): δ 7.97 (s, 1H), 7.33-7.26 (m, 5H), 4.60-4.57 (m, 1H), 4.01-3.99 (m, 2H), 3.53 (s, 2H), 2.92 (s, 3H), 2.58-2.53 (m, 3H), 2.25-2.21 (m, 1H), 2.07-2.01 (m, 2H), 1.76-1.69 (m, 2H), 1.43-1.33 (m, 3H). LC-MS: m/z [M+1]=451 & [M+23]: 473.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]=[CH2:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.BrN1C(=[O:26])CCC1=O.CC([O-])(C)C.[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]4[CH2:19][O:26]4)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1c2cc(C3CO3)ccc2ccc2ncc(Cl)cc12
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.30 g, 1.12 mmol) was dissolved in 17 mL DMSO and 3.0 mL water. N-Bromosuccinimide (0.20 g, 1.12 mmol) was added and the reaction was heated in an oil bath at 60° C. for 1 hour at which time an additional 0.1 g N-Bromosuccinimide (0.56 mmol) was added and the mixture was stirred an additional 45 min at 60° C. The resulting mixture was diluted with water and extracted with ethyl acetate three times. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude residue was dissolved in 30 mL tetrahydrofuran and 6 mL t-BuOH. t-BuOK (2.24 mL of 1.0 M in THF, 2.24 mmol) was added dropwise and the resulting orange slurry was stirred at room temperature for 45 min. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organics were washed with brine, dried over magnesium sulfate, concentrated in vacuo, and purified via flash chromatography (silica, 0-25% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.79 (d, 1H); 8.49 (d, 1H); 8.20 (d, 1H); 7.57 (d, 1H); 7.55 (dd, 1H); 7.27 (d, 1H); 7.23 (d, 1H); 3.99 (dd, 1H); 3.21 (dd, 1H); 2.84 (dd, 1H).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[NH:10][N:9]=1)([CH3:3])[CH3:2].[NH2:19][C:20]([CH:24]([F:26])[F:25])=[CH:21][C:22]#[N:23]>C(O)(=O)C.C1COCC1>[F:25][CH:24]([F:26])[C:20]1[NH:19][C:20]([CH:24]([F:26])[F:25])=[C:21]([C:22]#[N:23])[CH:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[C:21]=1[C:22]#[N:23]
Reactant: CC(C)OCCOc1n[nH]c2ccc(C=O)cc12
Reactant: N#CC=C(N)C(F)F
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)OCCOc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12
Temperature: 25 °C

Procedure:
80 mg (0.32 mmol) 3-(2-isopropoxyethoxy)-1H-indazole-5-carbaldehyde (Example 32A), 84 mg (0.71 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] and a small amount of powdered 4 Å molecular sieve in acetic acid (310 μl) were heated to 115° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with THF and filtered. The filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) to give 85 mg (59% of th.) of the title compound.
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(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C[N:34]([CH3:37])C=O>>[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:25]([C:24]3[CH:28]=[CH:29][C:30]([N:34]4[CH:37]=[CH:9][C:8]([CH3:15])=[N:7]4)=[CH:31][C:23]=3[F:22])=[O:26])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(F)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (3.0 g, 15.2 mmol) in dimethylformamide (35 mL) under nitrogen was added potassium carbonate (6.3 g, 45.6 mmol) followed by a solution of the crude 2,4-difluorobenzoylchloride of Step A (22.8 mmol) in dimethylformamide (15 mL). After stirring at room temperature for 20 minutes, the reaction mixture was washed with water and stirred to give a solid which was collected by filtration. The solid was dissolved in chloroform and washed with 1 N sodium hydroxide and brine. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided the title compound (2.6 g, 51%) as a white foam which crystallized by sonication from hexane-ethanol, m.p. 16114 163° C.
Reaction SMILES: C(Cl)Cl.[CH2:4]([C:7]1([CH2:17][C@@H:18]2[O:20][C@@:19]2([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:12]([O:13][CH3:14])=[CH:11][CH2:10][CH:9]=[C:8]1[O:15][CH3:16])[CH:5]=[CH2:6].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CCOC(C)=O.CCCCCC>[CH2:4]([C@:7]12[CH2:17][CH:18]3[O:20][C@@:8]1([O:15][CH3:16])[C@@H:9]([C@:19]3([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:10][CH:11]=[C:12]2[O:13][CH3:14])[CH:5]=[CH2:6]
Reactant: C=CCC1(C[C@@H]2O[C@@]2(C)CCC=C(C)C)C(OC)=CCC=C1OC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC[C@]12CC3O[C@@]1(OC)[C@H](CC=C2OC)[C@]3(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A DCM (6 mL) solution of 8 (100 mg, 0.30 mmol, 1 equiv.) and 2,6-di-tert-butyl-4-methylpyridine (124 mg, 0.60 mmol, 2 equiv.) was cooled to −78° C. in a 20-mL scintillation vial, and trimethylsilyl trifluoromethanesulfonate (65 μL, 0.36 mmol, 1.2 equiv.) was added dropwise. Immediately upon this addition, the solution turned bright yellow. After stirring at −78° C. for 30 min, the reaction was quenched with saturated aqueous NaHCO3 and allowed to warm to room temperature. The mixture was then extracted four times with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a slight yellow oil. Flash column chromatography (50 mL SiO2, 99:1 hexane:EtOAc) afforded 85 mg (0.26 mmol, 85% yield) of 9 as a clear, colorless oil. TLC Rf 0.53 (9:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 6.02 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.04 (t, J=7.1 Hz, 1H), 5.01-4.95 (m, 2H), 4.54 (dd, J=5.7, 2.1 Hz, 1H), 3.75 (d, J=5.3 Hz, 1H), 3.48 (s, 3H), 3.47 (s, 3H), 2.42 (dd, J=14.1, 7.3 Hz, 1H), 2.29 (dd, J=14.1, 7.0 Hz, 1H), 2.19 (ddd, J=18.1, 6.7, 2.2 Hz, 1H), 2.07-2.02 (m, 2H), 2.01-1.93 (m, 1H), 1.86 (dd, J=12.4, 5.3 Hz, 1H), 1.81 (d, J=12.4 Hz, 1H), 1.72-1.65 (m, 4H), 1.58 (s, 2H), 1.47-1.42 (m, 1H), 1.25-1.20 (m, 1H), 1.14 (s, 3H). 13C NMR (125 MHz; CDCl3): δ 158.1, 138.3, 131.7, 124.9, 115.8, 112.5, 90.7, 79.1, 54.6, 51.3, 46.3, 44.4, 42.0, 38.87, 38.72, 33.6, 28.1, 25.9, 22.9, 20.1, 17.8. IR (NaCl, thin film, cm−1) 2966, 2930, 1671, 1578, 1460, 1439, 1376, 1304, 1215, 1168, 1136, 1062, 1001, 906. HRMS-ESI (m/z): [M+Na]+ calculated for C21H32O3, 355.2244. found, 355.2245.