Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.CN(C)C.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>C1COCC1>[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:9][C:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cc(=O)c(O)co1
Agent: CN(C)C
Solvent: C1CCOC1
Product: Cc1cc(=O)c(OC(=O)c2ccc(F)cc2)co1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
Allomaltol (600 mg; 4.76 mmol) was weighed out into a round bottom flask (100 ml) containing a stir-bar. The contents were diluted with anhydrous THF (˜20 ml) and stirred (˜5 min) to afford a solution. Next, trimethyl amine (840 μl) was added drop-wise and the contents stirred (˜5 min). 4-Fluorobenzoyl chloride (600 μl) was then added drop-wise, capped and stirred at room temperature. The reaction was monitored via silica gel TLC. Once complete, the reaction mixture was concentrated under reduced pressure and the contents purified by silica gel chromatography to afford 1.04 g crystalline product (4.19 mmol; 88% yield). This compound was found to have an EC50 of >1 mM. 1H NMR (DMSO-d6) δ 8.59 (s, 1H; 2-H); 8.18-8.13 (dd, 2H); 7.47-7.41 (t, 2H); 6.44 (s, 1H; 5-H); 2.34 (s, −3H; 6-CH3).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:41])([F:40])[C:20]([C:26]1[CH:39]=[CH:38][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][C:32]2=[O:37])=[CH:28][CH:27]=1)([OH:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:29]4[CH:38]=[CH:39][C:26]([C:20]([OH:25])([C:19]([F:18])([F:40])[F:41])[C:21]([F:24])([F:22])[F:23])=[CH:27][CH:28]=4)[C:32](=[O:37])[CH2:33]3)=[O:14])=[CH:15][CH:16]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: O=C1CNCCN1Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.337 mmol, 79 mg), 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-2-one (0.281 mmol, 100 mg) and triethylamine (0.842 mmol, 85 mg) in dichloromethane (10 ml) was added 1-propanephosphonic acid cyclic anhydride (0.421 mmol, 268 mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (30 mL). The organic phase was concentrated and the resulting residue was purified by column chromatography on silica gel (eluting with 5% methanol/95% dichloromethane) to afford the title compound (36 mg). MS (ESI) m/z 573.0 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[CH2:10][CH:9]1[C:31]([OH:33])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)#[N:45].CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:14]([O:16][CH2:17][C:18]([Cl:20])([Cl:19])[Cl:21])=[O:15])[CH2:10][CH:9]1[C:31]([N:55]1[CH2:54][CH2:53][N:52]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[C:44]#[N:45])[CH2:57][CH2:56]1)=[O:33])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(N(Cc2ccc(F)cc2F)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)O
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(N(Cc2ccc(F)cc2F)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)N1CCN(c2ccccc2C#N)CC1
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 4-[(2,4-difluoro-benzyl)-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (3.5 g, 6.6 mmol), HOBt (1.4 g, 10 mmol), 1-(2-cyanophenyl)piperazine (1.5 g, 7.9 mmol) in DCM (50 ml) were added Et3N (1.8 ml, 13.2 mmol) and EDC.HCl (1.9 g, 10 mmol). The mixture was stirred overnight, then washed with 10% citric acid, Na2CO3, brine, dried and concentrated to give the title product as a colorless oil (4.5 g, 6.4 mmol). MS m/e=700.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:5]([N:7]([CH3:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:6].C(Cl)(=O)C(Cl)=O.[C:31](O)([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[C:31]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]([C:5](=[O:6])[C:4]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:2]([Br:1])[CH:3]=1)[CH3:20])([CH3:34])([CH3:33])[CH3:32]
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1CCCC(=O)O
Reactant: CC(C)(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1CCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
To a cooled solution (0° C.) of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid (1.07 g, 2.60 mmol) in anhydrous DCM (10 mL), oxalyl chloride (0.34 mL, 3.90 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours, concentrated in vacuo and redissolved in anhydrous dichloromethane (5 mL). A solution of t-butanol (960 mg, 13 mmol) in anhydrous DCM (5 mL) was added and the mixture was stirred at room temperature overnight. After dilution with DCM, the mixture was washed with sat NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel column chromatography (EtOAc/Hexanes: 1/4 with gradient up to EtOAc/Hexanes 1/3) afforded 1.1 g of 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenyl}-butyric acid tert-butyl ester as a colorless oil. MS [M+H]+ (fragment): 411.7 (f; tR=3.10 min, (method 1)
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([SH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].I[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(=O)CC>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([S:11][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C@H:23]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])=[CH:21][CH:22]=2)=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: N#Cc1cccc([C@@H](OC2CCCCO2)c2ccc(CI)cc2)c1
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCc1c(SCc2ccc([C@H](OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Yield: 53.4 %

Procedure:
Stir a mixture of 1-(2-Hydroxy-4-mercapto-3-propyl-phenyl)-ethanone (250 mg, 1.18 mmol), (S)-3-[(4-Iodomethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (515 mg, 1.18 mmol) and cesium carbonate (769 mg, 2.36 mmol) in 2-butanone (10 ml) at room temperature under argon for 24 hours. Pour the mixture into water (85 ml) and extract with ethyl acetate (3×25 ml). Combine the organic extracts and wash with water, brine, then dry over sodium sulfate, filter and concentrate. Purify the crude product via silica chromatography eluting with 1:4 ethyl acetate:hexanes to give the title compound (325 mg, 53%). MS (m/z) 514 (M−H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:51]5[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]5)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3CCN(C)CC3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), 1-methylpiperazine (9.80 μL, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({6-methyl-3′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (29 mg, 46.4%). LC-MS m/z 707 (M+H)+, 0.77 min (ret time).
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:17])=[C:13]([I:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1>CN(C)C=O>[ClH:3].[Cl:3][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:17])=[C:13]([I:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ncnc2cc(F)c(I)cc12
Solvent: CN(C)C=O
Product: Cl
Product: Fc1cc2ncnc(Cl)c2cc1I
Reaction time: 1 h
Yield: 67 %

Procedure:
Thionyl chloride (0.6 liters), 4-hydroxy-6-iodo-7-fluoro-quinazoline (36 grams, 124 mmoles), and dimethylformamide (6 ml) were combined in a one liter one-neck flask fitted with a magnetic stir bar. The mixture was placed under anhydrous nitrogen and heated to a gentle reflux for 24 hours. The mixture was allowed to cool, followed by concentrating the reaction mixture to a thick yellowish residue. To this residue was added dichloromethane (0.1 liter) and toluene (0.1 liter). The mixture was concentrated to dryness. This procedure was repeated two additional times. To the resulting solid was added 0.5 liters of dry dichloromethane and the mixture was stirred for one hour. The mixture was filtered and the remaining solids were washed with minimal dichloromethane. The dichoromethane filtrates were combined, concentrated to a solid, and dried under vacuum at room temperature to yield 28.6 grams (67%) of the title compound. 1H NMR (400 MHz, CDCl3-d1) δ: 9.03(s, 1H), 8.76(d, 1H), 7.69(d, 1H). ESI-MS m/z 309(M+1).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([OH:28])=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][N:32]1[C:36]([CH2:37]O)=[CH:35][C:34]([C:39]([F:42])([F:41])[F:40])=[N:33]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([O:28][CH2:37][C:36]3[N:32]([CH3:31])[N:33]=[C:34]([C:39]([F:42])([F:40])[F:41])[CH:35]=3)=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1
Reactant: COC(=O)Cc1csc2c(F)c(O)cc(Cl)c12
Reactant: Cn1nc(C(F)(F)F)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(F)c(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a mixture of tri-n-butylphosphine (0.249 mL), methyl(4-chloro-7-fluoro-6-hydroxy-1-benzothiophen-3-yl)acetate (109.7 mg), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (86 mg) and THF (4.0 mL) was added ADDP (202 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (155 mg).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20]CC)=[O:19].[C:23](=O)([O-])[O-].[K+].[K+].CI.O>CC(C)=O>[CH3:23][O:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cc(-c3ccccc3)nn2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COc1c(C(=O)O)c(C)nc2cc(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
The ethyl 7-hydroxy-5-methyl-2-phenylpyrazolo[1.5-a]pyrimidine-6-carboxylate (297 mg) obtained above was suspended in acetone (5 ml), and potassium carbonate (138 mg) was added thereto and stirred for 30 minutes at room temperature. Methyl iodide (1.0 ml) was added to the mixture which was then refluxed for 2 hours. The reaction mixture was cooled to room temperature, and water was added to the reaction mixture which was extracted with chloroform, and the organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure, and the resulting crystals were dissolved in ethanol (5 ml). 5 N Sodium hydroxide solution (1 ml) was added thereto and stirred for 1 hour at 50° C. The reaction mixture was cooled to room temperature, and water was added to the mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (121 mg, Y.:45%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=2[N+:20]([O-])=O)[C:15]#[N:16])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:23])[NH:6]2.C(O)(=O)C.O.[NH4+].[OH-]>[Fe].C(O)C>[NH2:20][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[NH:11][C:9]1[N:8]=[C:7]2[C:3]([NH:4][C:5](=[O:23])[NH:6]2)=[C:2]([Cl:1])[N:10]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Nc2nc(Cl)c3[nH]c(=O)[nH]c3n2)c1
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(N)c(Nc2nc(Cl)c3[nH]c(=O)[nH]c3n2)c1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 3-(6-chloro-8-oxo-8,9-dihydro-7H-purin-2-ylamino)-4-nitrobenzonitrile (0.41 g, 1.23 mmol) was added glacial acetic acid (30 mL), water (75 mL) and ethanol (150 mL), followed by iron powder (Aldrich, 0.69 g, 12.3 mmol, 10 equiv.) and the reaction mixture was stirred at 90° C. for 15 min (LC-MS monitoring), when it became a clear dark orange solution. It was cooled to r.t., then concentrated NH4OH (50 mL) was added to bring the pH to 11. The reaction mixture was stirred at r.t. for 30 min. Repeated extractions into ethyl acetate, then into 25% isopropanol in CH2Cl2 (total volume 2 L), drying of the combined organic extracts, and in vacuo evaporation of the solvent provided the desired product as a brown solid, which was used in the next step without further purification. MS (EI) m/z 302.1 (MH)+.
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([N:25]3[CH:34]([CH3:35])[CH2:33][C:32]4[C:27](=[CH:28][C:29]([C:36]5[CH:40]=[CH:39][NH:38][N:37]=5)=[CH:30][CH:31]=4)[CH2:26]3)[N:22]=[C:21]([NH2:41])[N:20]=2)[CH2:15][CH2:14]1.Br[CH2:43][C:44]#[N:45]>CN(C=O)C>[NH2:41][C:21]1[N:22]=[C:23]([N:25]2[CH:34]([CH3:35])[CH2:33][C:32]3[C:27](=[CH:28][C:29]([C:36]4[CH:40]=[CH:39][N:38]([CH2:43][C:44]#[N:45])[N:37]=4)=[CH:30][CH:31]=3)[CH2:26]2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: N#CCBr
Reactant: CC1Cc2ccc(-c3cc[nH]n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1Cc2ccc(-c3ccn(CC#N)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium tert-butoxide in THF (1.0 M, 74.2 uL, 0.0742 mmol) was added to a solution of 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (15.0 mg, 0.0371 mmol) in DMF (0.3 mL) and stirred at r.t. for 10 min, and then bromoacetonitrile (3.71 uL, 0.0556 mmol) was added. The mixture was stirred at r.t. for 1 h. LCMS showed the reaction was complete. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=444.2.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=O)=O)=CC=1.[C-:19]#[N:20].[Na+]>CS(C)=O>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][CH2:11][C:19]#[N:20]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCc1cccs1
Temperature: 90 °C

Procedure:
A mixture was prepared from 20.8 g of 2-[2-(4-toluenesulfonyloxy)ethyl]thiophene, 5.4 g of sodium cyanide and 175 ml of dimethylsulfoxide and this mixture was heated to 90° C. The mixture was quenched by pouring it into saturated aqueous ammonium chloride solution and the resulting solution was extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give crude 2-thiophenepropionitrile. This product was mixed with 175 ml of 1M diborane in tetrahydrofuran and allowed to stir at room temperature. The reaction was quenched in ethanol and methanolic hydrogen chloride was added. The white solid which formed was separated by filtration, washed with ether and dried in a vacuum oven to give 3-(2-thienyl)propylamine hydrochloride melting at about 197-198° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([Cl:12])[C:6]([CH:9]([CH3:11])[NH2:10])=[N:7][CH:8]=1.C(N(CC)CC)C.[Cl:20][C:21]1[N:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](Cl)=[O:24]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([Cl:12])[C:6]([CH:9]([NH:10][C:23]([C:22]2[C:21]([Cl:20])=[N:29][CH:28]=[CH:27][C:26]=2[Cl:30])=[O:24])[CH3:11])=[N:7][CH:8]=1
Reactant: CC(N)c1ncc(Br)cc1Cl
Reactant: O=C(Cl)c1c(Cl)ccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)c1c(Cl)ccnc1Cl)c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Step C (0.80 g), 1.21 mL of triethyl amine and 0.62 g of 2,4-dichloronicotinoyl chloride were combined in that order at <20° C. in 25 mL of methylene chloride, and the mixture was stirred at room temperature overnight. The reaction mixture was reduced in vacuo to produce the title compound, a compound of the invention, as a solid. NMR (CDCl3; 300 MHz): δ1.59 (d, 3H, J is 6.6 Hz), 5.75 (m, 1H), 7.3 (bs, 1H), 7.34 (d, 1H, J is 5.2 Hz), 7.91 (d, 1H, J is 1.9 Hz), 8.33 (d, 1H, J is 5.4 Hz), 8.49 (d, 1H, J is 1.9 Hz).
Reaction SMILES: Cl[C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH:12](B(OCCCC)OCCCC)=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O.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>[F:11][C:3]1[C:2]([CH:12]=[CH2:13])=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: C=CB(OCCCC)OCCCC
Reactant: O=C(O)c1ccnc(Cl)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=Cc1nccc(C(=O)O)c1F
Temperature: 135 °C

Procedure:
A solution of 2-chloro-3-fluoroisonicotinic acid (1.50 g, 8.55 mmol, Matrix), dibutyl vinylboronate (2.82 mL, 12.8 mmol, Aldrich), and potassium carbonate (1.42 g, 10.25 mmol) in N,N-dimethylacetamide (9 mL) and water (3 mL) was degassed by bubbling a stream of nitrogen through the solution for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.59 g, 0.51 mmol) was added and the mixture was similarly degassed for a further 10 minutes. The reaction vessel was sealed and heated in the microwave for 25 minutes at 135° C. The reaction mixture was filtered and purified using preparative HPLC (UV-detection) eluting with a gradient of H2O/MeCN containing 0.1% TFA. This reaction was run again on the same scale and the product of both runs were pooled. Solvent was removed from the eluent containing desired product in vacuo (1.3 g, 46%). 1H NMR (300 MHz, CD3OD): δ 8.45 (d, 1H), 7.69 (dd, 1H), 7.07 (ddd, 1H), 6.44 (dd, 1H), 5.65 (dd, 1H); 19F NMR (282 MHz, CD3OD): δ−129.64 (d, 1F); LCMS (M+H)+: 167.9.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:52])[C@@H:8]([N:15](C(OC(C)(C)C)=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]4[CH:32]=[C:31]([C:33](=[O:43])[NH:34][O:35]C(OCC(C)C)C)[S:30][C:29]=4[CH:44]=3)[CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.C(Cl)Cl>[CH:1]1([O:6][C:7](=[O:52])[C@@H:8]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]4[CH:32]=[C:31]([C:33](=[O:43])[NH:34][OH:35])[S:30][C:29]=4[CH:44]=3)[CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(CNc3cccc(CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC4CCCC4)c4ccccc4)c3)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(NO)c1cc2ccc(CNc3cccc(CN[C@H](C(=O)OC4CCCC4)c4ccccc4)c3)cc2s1
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a solution of (S)-[tert-Butoxycarbonyl-(3-{[2-(1-isobutoxy-ethoxycarbamoyl)-benzo[b]thiophen-6-ylmethyl]-amino}-benzyl)-amino]-phenyl-acetic acid cyclopentyl ester (0.100 g, 0.14 mmol) in DCM/MeOH (1 ml:1 ml) was added TFA (8 ml). The solution was stirred for 2 h, then diluted with DCM (200 ml). The solution was washed with saturated sodium bicarbonate (100 ml). The solution was dried (Na2SO4), concentrated and purified by reverse phase HPLC to yield the desired product (8.1 mg, 11% yield). LCMS purity 98%, m/z 531 (M+H)+ 300 MHz, DMSO, δ:1.26-1.85 (8H, m), 3.47 (2H, s), 4.21 (1H, s), 4.38 (2H, d, J 5.8 Hz), 5.02-5.07 (1H, m), 6.32 (1H, t, J 6.0 Hz), 6.45 (2H, d, J 7.9 Hz), 6.57 (1H, s), 6.97 (1H, t, J 7.8 Hz), 7.23-7.35 (5H, m), 7.42 (1H, dd, J 1.2, 8.3 Hz), 7.84 (1H, s), 7.87 (1H, s), 7.93 (1H, s), 9.23 (1H, br s), 11.4 (1H, br s)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH:23]=[CH:24][CH2:25][CH2:26][CH3:27])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: C=CCCCBr
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Product: CCCC=CN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a method analogous to that described in Example 4, with biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide and 5-bromopentene, reacted at 60° C. for 3 hours, the title compound was obtained as a white powder. δC (CDCl3, 62.9 MHz): 25.4, 28.0, 29.6, 30.9, 48.0, 48.3, 62.4, 115.4, 127.3, 127.7, 128.5, 129.1, 137.5, 138.4, 139.4 and 145.3. δH (CDCl3, 250 MHz): 1.56-1.67 (8H, m), 2.03 (2H, m), 3.16 (4H, m), 3.65 (2H, t, J 7.1), 4.94 (2H, m), 5.74 (1H, m), 7.43 (3H, m), 7.59 (2H, d, J 7.0), 7.69 (2H, d, J 8.2) and 7.84 (2H, d, J 8.2).