Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:28][CH3:29])[NH:11]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:28][CH3:29])[NH:11]1
Reactant: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NS(C)(=O)=O)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 39 h
Yield: 98.7 %

Procedure:
To a stirred solution of 45 mg (0.1 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of ether-CH2Cl2 was added 0.5 mL of pyridine followed by 0.020 mL (0.26 mmol) of methanesulfonyl chloride. The solution was stirred 39 h at ambient temperature and poured into 1 N aq. HCl. The mixture was extracted with EtOAc, then hexanes. The combined organic extracts were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure to afford 52 mg of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-methanesulfonylaminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. Mass ESI+): 526(M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.[K].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:6]1(=[O:16])[N:10]([CH2:2][CH2:3][CH2:4][OH:5])[C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12
Reactant: OCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCO
Temperature: 70 °C
Reaction time: 4 h

Procedure:
3-Bromopropanol (4.0 g, 28.78 mmol), potassium phthalimide (8.0 g, 43.17 mmol) and potassium carbonate (4.0 g, 28.78 mmol) were added to 20 mL DMF. The reaction mixture was stirred at 70° C. for 4 hours, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl solution and evaporated in vacuo to a solid which was crystallized in ethyl acetate (3.5 g, 67%).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([Cl:12])[C:8](Cl)=[N:9][CH:10]=1.O>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([Cl:12])[C:8]([NH:2][NH2:3])=[N:9][CH:10]=1
Reactant: Clc1cc(Br)cnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncc(Br)cc1Cl
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (50 ml) was stirred at 100° C., a solution of 5-bromo-2,3-dichloropyridine (15.0 g) in ethanol (25 ml) was added therein dropwise over an hour and the mixture was stirred at the same temperature. After completion of the reaction, the reaction solution was cooled to room temperature, water (150 ml) was added and stirred at the room temperature. The precipitated solid was collected by filtration to give (5-bromo-3-chloropyridin-2-yl)hydrazine (14.78 g) as a white solid.
Reaction SMILES: C(O)(=O)C.[C:5]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[OH:21])(=[NH:7])[NH2:6].C[O-].[Na+].[CH2:25]([O:32][C:33](=[CH:36]N(C)C)[CH:34]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([O:32][C:33]1[CH:34]=[N:7][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[OH:21])=[N:6][CH:36]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)N)C(O)C1
Reactant: CN(C)C=C(C=O)OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(OCc3ccccc3)cn2)C(O)C1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
A solution of 372 mg (1 mmol) of tert-butyl (3RS,4RS)-4-carbamimidoyl-3-hydroxy-piperidine-1-carboxylate acetate in 10 ml of methanol was treated with 1 ml of 1N sodium methylate solution and stirred at room temperature. Subsequently,205 mg (1 mmol) of 2-benzyloxy-3-dimethylamino-acrolein (EPA 0 477 901) were added thereto and the solution was heated to reflux for 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure and the residue was taken up in 20 ml of methylene chloride and washed with 5 ml of water. The organic phase was separated, dried over sodium sulphate and finally evaporated under reduced pressure. For purification, the residue was chromatographed on silica gel using a 1:4 mixture of methylene chloride and ethyl acetate as the eluent. There were obtained 106 mg (27% of theory) of tert-butyl (3RS,4RS)-4-(5-benzyloxy-pyrimidin-2-yl)-3-hydroxy-piperidine-1-carboxylate as a colourless oil; MS: 386 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][CH:20]=[C:21]4[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:22]=34)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][CH:20]=[C:21]4[CH:25]=[CH:24][NH:23][C:22]=34)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nccc4ccn(COCC[Si](C)(C)C)c34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nccc4cc[nH]c34)nc12
Reaction time: 15 h
Yield: 15 %

Procedure:
To a stirred solution of N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.13 g, 219 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0 to 4% of a solution of methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(1H-pyrrolo[2,3-c]pyridin-7-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (11 mg, 15%). MS: (M+H)+=335; 1H NMR (DMSO-d6) δ: 9.25 (s, 1H), 8.43 (d, J=3.0 Hz, 1H), 8.28 (d, J=5.3 Hz, 1H), 7.96 (s, 1H), 7.65-7.69 (m, 2H), 6.65 (dd, J=2.9, 1.9 Hz, 1H), 1.46 (s, 8H).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[CH:7][CH:8]=2)[C:3]1=[O:14].[NH2:15][C:16]([NH2:18])=[S:17]>CC(C)=O>[NH2:18][C:16]1[S:17][CH:2]2[CH2:10][C:9]3[CH:8]=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=3[C:3]2([OH:14])[N:15]=1
Reactant: NC(N)=S
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CC1Br
Solvent: CC(C)=O
Product: NC1=NC2(O)c3cc([N+](=O)[O-])ccc3CC2S1

Procedure:
1.28 g (5 mmol) of 2-bromo-6-nitroindan-1-one are dissolved in 30 ml of acetone and, while stirring, 530 mg of thiourea in 10 ml of acetone are added. The solution is initially clear but, after a few minutes, the hydrobromide of 2-amino-5-nitro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol crystallizes out. It is stirred at room temperature for 1 h, filtered off with suction and washed with a little acetone. The air-dried hydrobromide is dissolved in about 10 ml of methanol and, after addition of 0.7 ml of triethylamine, stirred for 15 min. Then 50 ml of water are added, and the mixture is stirred at room temperature for 1 h. The crystals which have formed are filtered off with suction and washed with a little cold water. 2-Amino-5-nitro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol is obtained with a melting point above 250° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:14]([OH:16])=O)[S:11][C:12]=1[CH3:13])[CH3:2].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[O:30]=[C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:31])[N:21]1[CH2:20][C@@H:19]([NH:18][C:14]([C:10]1[S:11][C:12]([CH3:13])=[C:8]([C:7]2[N:6]([CH3:17])[N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:9]=1)=[O:16])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:41])([F:40])[F:42]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1cnn(C)c1-c1cc(C(=O)O)sc1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (137 mg, 0.55 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (211 mg, 0.55 mmol)[prepared in Preparation 6] and diisopropylethylamine (0.48 ml, 2.74 mmol) in Dichloromethane (5.47 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (281 mg, 0.60 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxamide (262 mg, 0.45 mmol, 82% yield) as a clear oil: LCMS (ES) m/e 581 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]2[CH2:21][N:20]([S:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:19](=[O:35])[NH:18]2)=[O:16])[CH2:11][CH2:10]1.[CH2:36](I)[CH2:37][CH3:38].[I-].[Na+]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]2[CH2:21][N:20]([S:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:19](=[O:35])[N:18]2[CH2:36][CH2:37][CH3:38])=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4cccc5ccccc45)C(=O)N3)CC2)c1
Reactant: CCCI
Agent: [I-]
Agent: [Na+]
Product: CCCN1C(=O)N(S(=O)(=O)c2cccc3ccccc23)C[C@H]1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
In analogy to example 66, step 4, (S)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-(naphthalene-1-sulfonyl)-imidazolidin-2-one and propyl iodide were reacted in the presence of sodium iodide in a pressure tube to yield (S)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-(naphthalene-1-sulfonyl)-3-propyl-imidazolidin-2-one as a white solid. MS: 535.0 ([M+H])
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]#[N:16])=[C:11](Cl)[C:10]2[CH:18]=[CH:19][S:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1([C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1N2CCN(CC2)C1.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]#[N:16])=[C:11]([N:24]2[CH2:25][CH2:26][N:21]([C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[CH2:22][CH2:23]2)[C:10]2[CH:18]=[CH:19][S:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: N#Cc1c(Cl)c2ccsc2n(Cc2ccccc2)c1=O
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccsc2n(Cc2ccccc2)c1=O
Yield: 28.7 %

Procedure:
A solution of 7-benzyl-4-chloro-6,7-dihydro-6-oxo-thieno[2,3-b]pyridine-5-carbonitrile (64) (0.750 g, 0.0025 mol), piperazin-1-yl-thiophen-2-yl-methanone (0.69 g, 0.0035 mol), and DABCO (0.56 g, 0.005 mol) in anhydrous DMF was heated at 110° C. for 12 h. The solution was cooled and poured into a 5% ammonium chloride aqueous solution and the precipitated solid was collected by vacuum filtration. The solid was purified by reverse phase chromatography (MeCN/water) to yield 0.330 g (29%) of 7-benzyl-6-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile. MP 257° C.; 1H-NMR (DMSO-d6) δ 3.83 (m, 8H), 5.28 (s, 2H), 7.16 (m, 1H), 7.33 (m, 7H), 7.51 (d, J=3.2 Hz, 1H), 7.81 (d, J=4.8 Hz, 1H) ppm; EIMS m/z 461 (M+1).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:31])=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: CS(=O)(=O)c1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 1B and 2-(4-(methylsulfonyl)phenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.25-8.35 (m, 1H), 7.97-8.05 (m, 2H), 7.91-7.93 (m, 3H), 7.65-7.67 (m, 2H), 3.83 (s, 3H), 3.82 (d, J=8.4 Hz, 2H), 3.35-3.63 (m, 1H), 3.21 (s, 3H), 3.08-3.11 (m, 4H); MS (ESI+) M/Z 443 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32]C)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=1[CH:16]=[CH:17][NH:18][C:19]3=[O:24])[C:7]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH2:6][C:5]2([CH3:31])[CH3:30].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[C:3]([OH:32])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=1[CH:16]=[CH:17][NH:18][C:19]3=[O:24])[C:7]([OH:29])([C:25]([F:28])([F:26])[F:27])[CH2:6][C:5]2([CH3:30])[CH3:31]
Reactant: COc1c(Cl)c(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc2c(c(O)c1Cl)C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
40 mg (0.083 mmol) of (rac.) 5-{[6-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one is mixed at room temperature with 0.8 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for four hours at room temperature. Since starting material is still present, another 0.8 ml of boron tribromide solution is added, and it is stirred for 16 hours at room temperature. The reaction mixture is mixed drop by drop at −30° C. with saturated sodium bicarbonate solution (pH 8). The batch is mixed with ethyl acetate, and the cold bath is removed. After 10 minutes of vigorous stirring at room temperature, the batch is extracted twice with ethyl acetate. The organic phases are washed with water and with brine, dried, and the residue is chromatographed on silica gel (mobile solvent:methanol/dichloromethane) after the solvent is spun off. 19.9 mg (51.2%) of the desired compound is isolated.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.O.[CH3:39][N:40](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:39]([C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1)#[N:40]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 60 °C
Yield: 60 %

Procedure:
N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (3.54 g, 6.23 mmol), zinc cyanide (0.805 g, 6.86 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.720 g, 0.623 mmol) were stirred in N,N-dimethylformamide (DMF) (27.1 ml) overnight at 80° C. The reaction mixture was added dropwise into water to give a solid. The solids were filtered and dried in a vacuum oven overnight. DCM and MeOH (5:1) were added to solid and heat at 60° C. The mixture was cooled and filtered to obtain N-{3-[5-(2-cyano-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (2.06, 60%). MS (ESI): 559 [M+H]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:44])[CH2:39]1)([CH3:37])[CH3:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:42][CH2:43][N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][C@@H:40]4[CH3:44])[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)N1CCN[C@@H](C)C1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)C[C@@H]4C)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (40.0 mg, 0.077 mmol) was added (S)-1-isopropyl-3-methylpiperazine (33.1 mg, 0.232 mmol) in 1,4-dioxane (1 mL) and triethylamine (15.7 mg, 22 μL, 0.155 mmol). The reaction mixture was stirred at 60° C. for 4 d, after which the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([S:6](=[O:7])(=[O:8])[NH:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:10]=5)[N:23]4[N:22]=3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nn23)c1

Procedure:
4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester in an analogous manner to Example 1052a. Product isolated as an orange foam (82 mg, 47%). LCMS (m/e) 627 (M+Na); 1H-NMR (CDCl3, 400 MHz) δ 8.79 (s, 1H), 8.74 (s, 1H), 8.29 (d, 1H, J=8.1 Hz), 7.87 (d, 1H, J=7.9 Hz), 7.62-7.53 (m, 3H), 7.31-7.24 (m, 2H), 7.08 (d, 1H, J=4.8 Hz), 6.88-6.80 (m, 2H), 4.46 (s, 1H), 4.37-4.18 (m, 2H), 2.89-2.75 (m, 2H), 2.75-2.60 (m, 1H), 1.90-1.81 (m, 2H), 1.71-1.60 (m, 2H), 1.49 (s, 9H), 1.17 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[F:16][C:17]([F:38])([F:37])[C:18]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([C:18]([OH:23])([C:19]([F:20])([F:21])[F:22])[C:17]([F:38])([F:16])[F:37])=[CH:25][CH:26]=3)[CH2:32][CH2:33]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1OC(F)(F)F
Reaction time: 1 h
Yield: 113 %

Procedure:
4-Amino-3-(trifluoromethoxy)benzoic acid (2.045 mmol, 0.452 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.700 g) and triethylamine (6.14 mmol, 0.853 mL, 0,621 g) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour. The reaction mixture was diluted with dichloromethane and saturated sodium hydrogen carbonate solution and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (1.26 g). MS (ESI) m/z 546.5 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([CH3:25])=[CH:18][CH:19]=[CH:20][C:21]([O:23]C)=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[CH:16][C:17]([CH3:25])=[CH:18][CH:19]=[CH:20][C:21]([OH:23])=[O:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C=CC=C(C)C=Cc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C=Cc1ccc(OCc2ccccc2)cc1)=CC=CC(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.7 %

Procedure:
A mixture of methyl 7-(4-benzyloxyphenyl)-5-methyl-hepta-2,4,6-trienoate (3.2 g, 9.7 mmol) and potassium hydroxide (1.1 g, 19.4 mmol) in 200 ml of ethanol and 10 ml of water was stirred under nitrogen at room temperature for 48 hrs. The mixture was then concentrated on rotary evaporator and water (250 ml) was added. The solution was extracted with 30 ml of ethyl acetate; the aqueous layer was acidified with 10N HCl to pH 3. The yellow precipitate formed was extracted into ethyl acetate, washed with 30 ml of water, dried (magnesium sulfate) and concentrated on rotary evaporator to give a yellow powder, which was triturated with ethyl acetate to give 1.7 g of the product as yellow powder, mp: 210° C. (sublimed).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:8][C:9]1[C:14]([C:15]2[C:24](=[O:25])[NH:23][C:18]3=[N:19][CH:20]=[CH:21][N:22]=[C:17]3[C:16]=2[OH:26])=[CH:13][CH:12]=[C:11]([Cl:27])[N:10]=1.N1C=CC=CC=1>ClCCl>[Cl:8][C:9]1[C:14]([C:15]2[C:24](=[O:25])[NH:23][C:18]3=[N:19][CH:20]=[CH:21][N:22]=[C:17]3[C:16]=2[O:26][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:13][CH:12]=[C:11]([Cl:27])[N:10]=1
Reactant: O=c1[nH]c2nccnc2c(O)c1-c1ccc(Cl)nc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1c(-c2ccc(Cl)nc2Cl)c(=O)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pivaloyl chloride (0.096 ml) was added dropwise to a solution of 7-(2,6-dichloro-pyrid-3-yl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (Example 1.6) (0.20 g) and pyridine (0.068 ml) in dichloromethane (5 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 hour and was then diluted with more dichloromethane. The organic phase was washed with aqueous sodium hydrogen carbonate (saturated) and brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 2:1) to give Compound No. A14 of Table A as a white solid (0.088 g).