Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=2)[C@H:10]1[CH2:24][CH3:25])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[CH:16]=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@H:9]([OH:8])[C@@H:10]2[CH2:24][CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.3 %

Procedure:
To a solution of 4-[(2S,3S)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chlorobenzonitrile (550 mg) in tetrahydrofuran (3 mL)-methanol (3 mL) was added 6 mol/L hydrochloric acid (4 mL), and the mixture was stirred at room temperature for 72 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless solid (yield: 93.3 mg, 24%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([NH:26][C:27]2[N:32]=[C:31]([C:33]3[CH:34]=[N:35][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=34)[CH:30]=[CH:29][N:28]=2)=[CH:20][C:19]=1[NH2:42].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)[C:19]([NH2:42])=[CH:20][C:21]=1[NH:26][C:27]1[N:32]=[C:31]([C:33]2[CH:34]=[N:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=23)[CH:30]=[CH:29][N:28]=1
Reactant: COc1cc(Br)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.7 mg, 0.03 mmol) was added to a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 137, 215 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was then heated at 100° C. for 1 h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc and this solution was washed three times with water, then with brine. The solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (160 mg, 72%) as a tan solid after trituration with diethyl ether; 1H NMR: 1.79-1.87 (2H, m), 1.96-2.03 (2H, m), 2.29 (3H, s), 2.34-2.40 (2H, m), 2.58 (2H, t), 2.98-3.02 (2H, m), 3.15 (2H, t), 3.75 (3H, s), 4.12 (2H, t), 4.32 (2H, br s), 5.67-5.71 (1H, m), 6.60 (1H, s), 7.01 (1H, d), 7.58 (1H, s), 7.69 (1H, s), 8.09 (1H, s), 8.32 (1H, d); m/z: ES+ MH+ 432.72.
Reaction SMILES: C([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O>C(Cl)Cl>[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.17 h

Procedure:
While maintaning the nitrogen atmosphere, the product of Step (J) above is admixed with 3 fold molar excess of carbobenzoxy-L-phenylalanine [Boc-L-phenylalanine, Peninsula, supra.] dissolved in methylene chloride. The resulting mixture is shaken and after about 10 minutes, 3 fold molar excess of N,N-dicyclohexylcarbodiimide in 15 ml of methylene chloride is added with stirring. The resulting mixture is shaken at room temperature for 4.5 to 5 hours. At the end of this period, the reaction mixture is filtered and the residue washed and dried.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:50])[C:10]1[C:15]([O:16]CC2C=CC=CC=2)=[CH:14][CH:13]=[C:12]([C:24]2[C:25]([N:44]([CH3:49])[S:45]([CH3:48])(=[O:47])=[O:46])=[CH:26][C:27]3[O:31][C:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[C:29]([C:39](=[O:42])[NH:40][CH3:41])[C:28]=3[CH:43]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([NH:8][C:9](=[O:50])[C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([C:24]2[C:25]([N:44]([CH3:49])[S:45]([CH3:48])(=[O:47])=[O:46])=[CH:26][C:27]3[O:31][C:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[C:29]([C:39](=[O:42])[NH:40][CH3:41])[C:28]=3[CH:43]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)NCc4ccccc4)n3)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(C(=O)NCc4ccccc4)n3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of N-benzyl-3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinamide (200 mg, 0.29 mmol) and Pd/C (10 mg) in CH3OH (10 mL) was stirred at room temperature overnight under H2 atmosphere (50 psi). The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-TLC (DCM:EtOAc=5:1) to give the product of N-benzyl-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-hydroxypicolinamide (125 mg, yield: 71.8%). 1H-NMR (CDCl3, 400 MHz) δ 8.73 (br s, 1H), 7.84˜7.87 (m, 3H), 7.63 (d, J=8.4 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.30˜7.36 (m, 4H), 7.26 (d, J=6.0 Hz, 1H), 7.19 (t, J=8.0 Hz, 2H), 6.39 (br s, 1H), 4.60 (d, J=4.8 Hz, 2H), 3.04 (s, 3H), 2.93 (d, J=3.2 Hz, 3H), 2.87 (s, 3H). MS (M+H)+: 603.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=3)[CH2:16][N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:6]2[N:5]=1)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[NH:30][C:31](=[O:33])[CH3:32]>>[CH3:21][S:18]([N:17]([CH2:16][C:15]1[CH:14]=[C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:26][C:27]4[CH:28]=[C:29]([NH:30][C:31](=[O:33])[CH3:32])[CH:34]=[CH:35][CH:36]=4)=[N:5]3)=[CH:10][CH:11]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:22])(=[O:20])=[O:19]
Reactant: CN(Cc1cccc(-c2ccc3cnc(S(C)=O)nn23)c1)S(C)(=O)=O
Reactant: CC(=O)Nc1cccc(N)c1
Product: CC(=O)Nc1cccc(Nc2ncc3ccc(-c4cccc(CN(C)S(C)(=O)=O)c4)n3n2)c1

Procedure:
N-[3-(7-{3-[(Methanesulfonyl-methyl-amino)-methyl]-phenyl}-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)-phenyl]-acetamide was prepared from N-[3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-N-methyl-methanesulfonamide and 3′-aminoacetanilide in an analogous manner to Example 1049. Product isolated as a yellow foam (25 mg, 22%). LCMS (m/e) 465 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 8.11 (d, 1H, J=7.7 Hz), 8.07 (s, 1H), 7.80 (s, 1H), 7.53-7.45 (m, 1H), 7.43-7.34 (m, 2H), 7.30 (s, 1H), 7.28-7.21 (m, 2H), 7.09 (s, 1H), 7.00 (d, 1H, J=4.8 Hz), 6.83 (d, 1H, J=4.8 Hz), 4.38 (s, 2H), 2.86 (s, 3H), 2.79 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:21][Mg]Br.C1COCC1>>[OH:17][C@:14]1([CH3:21])[C:13]([CH3:19])([CH3:18])[C:12](=[O:20])[N:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=2)[C@@H:15]1[CH3:16]
Reactant: C[Mg]Br
Reactant: COc1cc(N2C(=O)C(C)(C)C(=O)C2C)ccc1C#N
Solvent: C1CCOC1
Product: COc1cc(N2C(=O)C(C)(C)[C@@](C)(O)[C@H]2C)ccc1C#N

Procedure:
Using 2-methoxy-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (100 mg) and methylmagnesium bromide-THF solution (3.67 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as a colorless solid (yield: 96 mg, 90%).
Reaction SMILES: C(OC(=O)[C:5]([C:13]#[N:14])=[C:6]([OH:12])[C:7]([O:9]CC)=[O:8])C.[OH-:16].[Na+]>>[NH2:14][C:13](=[O:16])[CH2:5][C:6](=[O:12])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(O)=C(C#N)C(=O)OCC
Reactant: [OH-]
Agent: [Na+]
Product: NC(=O)CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
The 4-amino-2,4-dioxobutanoic acid was synthesized using the diethyl-2-cyano-3-hydroxy-butenedioate prepared as described above. A 5-liter Morton flask was equipped with an air condenser. Diethyl-2-cyano3-hydroxy-butenedioate (214.2 grams, 1.00 mole, 1.0 equivalent) was dissolved in aqueous sodium hydroxide (1.5 M, 2000 milliliters, 3.0 equivalents) at room temperature in the flask while stirring the contents of the flask. After about one minute, a heating mantle was placed underneath the flask. Using the heating mantle, the flask was heated sufficiently for reflux while the reaction mixture was stirred. After about 4½ hours at reflux, the heat was removed and the reaction mixture was allowed to cool to room temperature and was stirred overnight at room temperature. The reaction solution was placed into an ice-water bath and acidified using 6M HCl until the pH of was equal to about 1. Solids formed after about 5 minutes. The solids were filtered. The colorless solids (27 grams) were analyzed by NMR and were found to include carbonate (13C-NMR δ=162 ppm). The bulk of the water was evaporated using a rotary evaporator at about 40° C. The solids were stirred in acetone (1000 milliliters) and then filtered. The acetone was then removed under a vacuum using a rotary evaporator followed by a vacuum pump to yield the 4-amino-2,4-dioxobutanoic acid in good yield as a viscous yellow oil.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][C@H:12]([C:14]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][CH:19]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:28]12[CH2:34][CH:31]([NH:32][CH2:33]1)[CH2:30][O:29]2.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:28]12[CH2:34][CH:31]([N:32]([C:16]3[CH:15]=[C:14]([C@@H:12]([NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:13])[CH:19]=[CH:18][CH:17]=3)[CH2:33]1)[CH2:30][O:29]2
Reactant: C[C@H](NC(=O)C=Cc1ccccc1)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Reactant: C1OC2CNC1C2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)C=Cc1ccccc1)c1cccc(N2CC3CC2CO3)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 16.1 %

Procedure:
Mixture of (S)-trifluoro-methanesulfonic acid 3-[1-(3-phenyl-acryloylamino)ethyl]phenyl ester (Step C in Example 82) (100 mg, 0.25 mmol), 2-oxa-5-aza-bicyclo[2.2.1]heptane (68 mg, 2eq), tetrakis (triphenylphosphine) palladium (0) (10 mol %, 29 mg), potassium carbonate (104 mg, 3eq), and triethylamine (0.2 ml) in toluene (1 ml) was stirred at 80° C. for 15 hours. Reaction mixture was diluted with 20 ml dichloromethane, washed with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane three times. The combined organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography with 40% acetone/hexane to obtain the title compound as a pale yellow solid (14 mg, 16% yield).
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].[C:17](OC)(OC)([O:20][CH3:21])[CH2:18][CH3:19]>>[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:17]([O:20][CH3:21])[CH2:18][CH3:19])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CCC(OC)(OC)OC
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CCC(OC)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthopropionate
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].S(O)(O)(=O)=O.[NH2:37][CH2:38][C:39]#[N:40].C(N(CC)CC)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:40][CH2:39][C:38]#[N:37])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: N#CCN
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(NCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 97.5 %

Procedure:
Following the general procedure outlined in Example 195, the product of Example 48 (500 mg, 1.12 mmol), aminoacetonitrile hydrogen sulfate (1.16 g, 5.6 mmol) and triethylamine (0.78 mL, 5.6 mmol) were reacted at 65° for 2 h to give the crude material 460 mg. LC-MS: 421.8 (MH+, m/z), 2.08 (Rt, min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:29][C:30]([CH3:32])=O.C([O-])(=O)C.[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:30]([CH3:32])[CH3:29])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC(C)=O
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(Cl)cc(N4CCNCC4)c3)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(Cl)cc(N4CCN(C(C)C)CC4)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.7 %

Procedure:
To a solution of 2-(3-chloro-5-(piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 31, 0.054 g, 0.14 mmol), acetone (0.060 g, 1.4 mmol), sodium acetate (0.023 g, 0.27 mmol), and acetic acid (0.16 g, 2.7 mmol) in 1,2-dichloroethane/methanol (5/5 mL) was added sodium triacetoxyborohydride (0.56 g, 2.7 mmol). The mixture was stirred at room temperature for 16 h and then concentrated. The residue was purified by silica gel chromatography eluting with 0-100% 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH4OH and concentrated. The residue was purified by reverse phase HPLC eluting with 10% to 90% CH3CN in H2O without TFA to afford the title compound (0.011 g, 18%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.52 (s, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.18 (t, J=1.5 Hz, 1H), 6.82 (d, J=2.5 Hz, 1H), 6.59 (d, J=2.5 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.35-3.60 (br s, 4H), 2.85-3.15 (br s, 4H), 1.25-1.40 (br s, 1H), 1.23 (d, J=6.5 Hz, 6H); ESI MS m/z 443 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[N:4]([CH2:15][CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:18]1[CH:22]=[C:21]([CH2:23][CH2:24][NH2:25])[N:20]=[CH:19]1>>[CH2:15]([N:4]1[C:3](=[O:17])[C:2]([NH:25][CH2:24][CH2:23][C:21]2[N:20]=[CH:19][NH:18][CH:22]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])[CH3:16]
Reactant: NCCc1c[nH]cn1
Reactant: CCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCN1C(=O)C(NCCc2c[nH]cn2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-ethyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2-(1H-imidazol-4-yl)ethanamine in a similar manner as described for Example 1. 1H NMR (500 MHz, CD3OD): δ 7.54-7.42 (m, 6H), 6.51-6.48 (m, 1H), 3.71 (q, 2H), 3.14 (t, 2H), 2.55 (t, 2H), 1.36 (t, 3H); 13C NMR (125 MHz, CD3OD): δ 159.9, 137.3, 136.1, 132.9, 132.3, 130.6, 129.7, 126.9, 117.2, 107.2, 44.6, 36.0, 27.8, 14.0; Mass Spectrum: M+H+ 347.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:17]([O:19]C)=[O:18])[N:8](C(OCC)=O)[CH2:9]2)=[CH:4][CH:3]=1>Cl>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:17]([OH:19])=[O:18])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1Cc2cc(Cl)ccc2CC1C(=O)OC
Agent: Cl
Product: O=C(O)C1Cc2ccc(Cl)cc2CN1
Temperature: 102.5 °C
Yield: 187.3 %

Procedure:
A mixture of 2-ethyl 3-methyl 7-chloro-3,4-dihydroisoquinoline-2,3(1 H)-dicarboxylate (2.19 g, 7.36 mmol) in 6 M aqueous HCl (30 mL) was heated to 100-105° C. for 2 days. The resulting mixture was concentrated under reduced pressure and triturated with toluene (2×100 mL). Once the supernatant was removed, the solid residue was dried under high vacuum to give 7-chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1.71 g, 94%) as a faint yellow solid which was used in the next step without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 14.2 (bs, ˜1 H), 10.0 (bs, ˜2 H), 7.41 (s, 1 H), 7.32 (m, 2 H), 4.40 (m, 1 H), 4.32 (m, 2 H), 3.32 (dd, J=17, 4.9 Hz, 1 H), 3.10 (dd, J=17, 11 Hz). LC-MS gives ESI+ MS found for C10H10ClNO2 m/z 212.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[C:34]([NH:38][CH2:39][CH3:40])([CH3:37])([CH3:36])[CH3:35]>ClCCl.CN(C=O)C.C1COCC1>[C:34]([N:38]([CH2:39][CH3:40])[C:16]([C:13]1[N:14]=[CH:15][C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:11][N:12]=1)=[O:18])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCNC(C)(C)C
Reactant: O=C(O)c1ncc(C#Cc2cccc(F)c2)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1ncc(C#Cc2cccc(F)c2)cn1)C(C)(C)C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
(100 mg, 0.41 mmol) 5-(3-Fluoro-phenylethynyl)-pyrimidine-2-carboxylic acid (Example 3, step 1) was suspended in dichloromethane (1 ml) and DMF (10 μl). Oxalyl chloride (40 μl, 0.45 mmol, 1.1 equiv.) was added drop wise at room temperature and the mixture was stirred for 1 hour at reflux. The reaction mixture was then added to a mixture of diisopropylethylamine (235 μl, 1.34 mmol, 3.3 equiv.) and tert-butylethylamine (43 mg, 0.41 mmol, 1 equiv.) in THF (2 ml). The mixture was stirred for 16 hours at room temperature and evaporated in presence of Isolute® sorbent to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column eluting with heptane:ethyl acetate 100:0->0:100. The desired 5-(3-fluoro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide (97 mg, 78% yield) was obtained as a white solid, MS: m/e=326.5 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N+:11]([O-:12])=[N:10][C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:8][C:7]=2[CH:23]=1)[CH3:2].CO.CC[O:28]C(C)=O>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N+:11]([O-:12])=[N:10][C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[N+:8]([O-:28])[C:7]=2[CH:23]=1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCc1ccc2c(c1)nc(NCCCN1CCOCC1)n[n+]2[O-]
Solvent: CO
Product: CCc1ccc2c(c1)[n+]([O-])c(NCCCN1CCOCC1)n[n+]2[O-]

Procedure:
Oxidation of 1-oxide 24 (829 mg, 2.6 mmol) with CF3CO3H (ca. 26.1 mmol) gave (i) starting material 24 (270 mg, 32%) and (ii) 1,4-dioxide 25 (206 mg, 24%) as a red solid, mp (MeOH/EtOAc) 142-144° C.; 1H NMR δ 8.55 (br s, 1 H, NH), 8.22 (d, J=9.0 Hz, 1 H, H-8), 8.10 (d, J=1.7 Hz, 1 H, H-5), 7.31 (dd, J=9.0, 1.7 Hz, 1 H, H-7), 3.82-3.87 (m, 4 H, 2×CH2O), 3.66-3.72 (m, 2 H, CH2N), 2.86 (q, J=7.6 Hz, 2 H, CH2), 2.58 (br dd, J=6.2, 6.0 Hz, 2 H, CH2N), 2.49-2.55 (m, 4 H, 2×CH2N), 1.85-1.92 (m, 2 H, CH2), 1.35 (t, J=7.6 Hz, 3 H, CH3); 13C NMR δ 153.9, 150.0, 138.5, 128.8, 128.2, 121.5, 114.9, 66.9 (2), 57.8, 53.9 (2), 41.7, 29.5, 24.4, 14.5. Anal. Calcd for C15H23N5O3: C, 57.6; H, 7.0; N, 21.0. Found: C, 57.6; H, 6.9; N, 20.9%
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[N:17][N:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[N:27][N:28]=4)[N:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C(OC(NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1)=O)(C)(C)C>>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)=[N:17][N:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[N:27][N:28]=4)[N:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2cccc(F)c2)ccn1
Agent: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2cccc(F)c2)ccn1
Yield: 77.4 %

Procedure:
The reaction was carried out in the same manner as in Example 37-2) except for using 4.00 g (8.47 mmol) of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-(3-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained in Example 38-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-phenyl-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole to obtain 2.44 g of the title compound as a white powder. (Yield: 78%)
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].[CH2:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:6].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:5]([N:7]([CH2:2][CH2:3][OH:4])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:6]
Reactant: CCNCCOc1ccc(C)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCN(CCO)CCOc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Add 0.90 g (011 mol) 2-chloroethanol to a solution of 2.0 g (0.11 mol) N-ethyl-N-[2-(4-methylphenoxy)ethyl]amine and 1.7 g (012 mol) potassium carbonate in 50 mL methanol. Stir at room temperature for 24 hr. After this time, remove the solvents in vacuo and dissolve the residue in 25 mL water. Adjust the aqueous to pH=8 with 5% sodium bicarbonate solution and extract 3×50 mL methylene chloride. Dry the combined organics over sodium sulfate and evaporate the solvent to obtain the desired product.
Reaction SMILES: [Li].N.C#CCCCC.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O-:30])([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.[Li+]>CCOCC>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:30])([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: CCCCC#CC(C)([O-])c1ccc(-c2ccc(F)cc2)cc1
Agent: C#CCCCC
Agent: N
Agent: [Li+]
Solvent: CCOCC
Product: CCCCC#CC(C)(O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
8.34 g. of lithium is added at -70°, over three hours, to 900 ml. of liquid ammonia containing 82 g. of 1-hexyne. When the blue color has disappeared, 214 g. of 4'-fluoro-4-acetylbiphenylyl in 200 ml. of ether are added thereto over one hour. The solution contains lithium 2-(4'-fluoro-4-biphenylyl)-3-octyn-2-olate. Subsequently, the ammonia is allowed to evaporate at +25° and simultaneously ether is added at a rate such that the volume of the mixture remains constant. After removal of ammonia, the mixture is allowed to stand for 12 hours at 20°. Thereafter, it is hydrolyzed with 150 ml. water and worked up as usual, to give 2-(4'-fluoro-4-biphenylyl)-3-octyn-2-ol; m.p. 62°.