Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.Cl[Si](C)(C)C.[Cl-].[Mg+2].[Cl-].[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1C(Cl)=O>C1(C)C=CC=CC=1>[CH2:7]([O:6][P:4]([CH2:9][C:10]([C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[F:28])=[O:12])(=[O:5])[O:3][CH2:1][CH3:2])[CH3:8]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: O=C(Cl)c1ccccc1F
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(CC(=O)c1ccccc1F)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 2.34 g (11.9 mmol) of diethylphosphonoacetic acid in toluene at 0° C. was added 4.82 g (47.7 mmol) of triethylamine followed by 1.94 g (17.9 mmol) of chlorotrimethylsilane. The mixture was stirred at ambient temperature for 1 hour, then 1.13 g (11.9 mmol) of magnesium chloride was added and the mixture was stirred for a further 1 hour. To the mixture was added 2.0 g (14.3 mmol) of 2-fluorobenzoyl chloride and the mixture was stirred for 72 hours. The mixture was partitioned between 200 ml of water and 250 ml, 100 ml of dichloromethane. The combined organic portions were dried (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography eluting with 3-5% methanol/dichloromethane to give 2.1 g (64%) of [2-(2-fluorophenyl)-2-oxoethyl]phosphonic acid diethyl ester as a colorless oil; MS: m/e 274.9 [M+H]+.
Reaction SMILES: CC1OC=CC=1.O1C=CC=C1.[Li].[CH3:13][C:14]1[O:15][C:16]([SH:19])=[CH:17][CH:18]=1.Cl[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CCOCC>[CH3:13][C:14]1[O:15][C:16]([S:19][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=1
Reactant: COC(=O)CCl
Reactant: Cc1ccc(S)o1
Agent: Cc1ccco1
Agent: [Li]
Solvent: c1ccoc1
Solvent: CCOCC
Product: COC(=O)CSc1ccc(C)o1
Reaction time: 48 h

Procedure:
The necessary starting material was prepared from 2-methylfuran (16.4 g) by an analogous procedure to that described for furan itself in Example 14, except that in this case the intermediate lithium salt of 2-methylfuran-5-thiol was reacted in dry ether at -20° C. with methyl 2-chloroacetate. The reaction mixture was stirred for 2 days and then partitioned between water (800 ml) and ether (3×400 ml). The organic layers were dried (MgSO4) and evaporated. The residual oil was distilled to give methyl 2-(2-methylfur-5-ylthio)acetate (40.1 g) b.p. 94°-96° C./0.5 mm; NMR (90 MHz): 2.30 (s,3H), 3.45 (s,2H), 3.70 (s,3H), 5.95 (m,1H), 6.45 (d,1H).
Reaction SMILES: S(Cl)(Cl)=O.[ClH:5].S(=O)=O.[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]>CN(C)C=O>[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:5])=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: Cl
Agent: O=S=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
P-acetoxy benzoic acid 180.16 g (1.0 mol) was added to thionylchloride 500 ml, and dimethylformamide (DMF) 1 ml was dropped in as a catalyst and stirred, and when generation of hydrogen chloride and sulfur dioxide stopped and the reaction liquid cleared, p-acetoxy benzoic acid 180.16 g (1.0 mol) was added another 5 times, i.e. a total of 6.0 mol was added. After all 6.0 mol of the p-acetoxy benzoic acid was added and when the generation of hydrogen chloride and sulfur dioxide stopped, and the reaction liquid cleared, it was heated at reflux for 3 hours, then it was distilled and purified (at 173° C., 10 mmHg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:13][C:14]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>C(N(CC)CC)C>[C:1]([NH:13][C:14]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.55 mL of benzoyl chloride was added to 10 mL of a methylene chloride solution containing 1.0 g of methyl 2-amino-4-bromobenzoate and 0.73 mL of triethylamine while ice-cooled and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 0.9 g of methyl 2-(benzamido)-4-bromobenzoate as while solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([O:27][CH2:28][CH3:29])=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C(O)(C)C.[NH3:34]>>[CH2:28]([O:27][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:34])[C:3]2=[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18]3)=[CH:13][CH:12]=2)[N:9]=1)[CH3:29]
Reactant: N
Reactant: CCOc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Solvent: CC(C)O
Product: CCOc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(N)nccn12
Temperature: -20 °C

Procedure:
7-(8-Chloro-3-ethoxy-imidazo[1,5-a]pyrazin-1-yl)-2-phenyl-quinoline (20.0 mg, 0.050 mmol) was dissolved into a 80 mL sealed tube with isopropyl alcohol (1.0 mL, 3.0 mmol). The solution was cooled to −20° C. and charged with ammonia gas. The reaction was heated to 110 IC for 72 hours. The reaction was then cooled, concentrated in vacuo and dissolved with CH2Cl2. The crude product was purified via silica gel column chromatography, (Jones, 2.0 gram column; 100% EtOAc) to yield the title compound as a yellow solid; MS (ES+): m/z 382.08 (90) [MH+], 383.09 (30) [MH++]. HPLC: tR=2.26 min (OpenLynx, polar—5 min); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (t, J=7.07 Hz, 3H), 4.66 (q, J=7.07 Hz, 2H), 6.96 (d, J=5.05 Hz, 1H), 7.13 (d, J=5.05 Hz, 1H), 7.34-7.63 (m, 3H), 7.75-8.01 (m, 3H), 8.10-8.32 (m, 3H), 8.40 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][NH:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)[CH2:31][CH2:32][C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CNCCc2ccccc2OCc2ccc(Br)cc2)cc1
Reactant: N#Cc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN(CCc2ccc(C#N)cc2)CCc2ccccc2OCc2ccc(Br)cc2)cc1
Yield: 70.5 %

Procedure:
200 mg (0.44 mmol) of methyl 4-({2-[2-(4-bromobenzyloxy)phenyl]ethylamino}methyl)benzoate from Example 5A, 101 mg (0.48 mmol) of 4-(2-bromoethyl)benzonitrile and 51.4 mg (0.48 mmol) of sodium carbonate are heated in 5 ml of acetonitrile to reflux for 5 hours. A further 101 mg (0.48 mmol) of 4-(2-bromoethyl)benzonitrile are then added, and the reaction solution is stirred further under reflux overnight. After the reaction solution has cooled, the mixture is concentrated to dryness, and the residue is taken up in ethyl acetate and washed with water and saturated sodium chloride solution. Drying over sodium sulfate is followed by filtration and concentration. The crude product is purified by preparative HPLC. 183 mg (0.31 mmol, 69% yield) of a pale yellow oil are obtained.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:10]=2)=[O:5])C.[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]2[CH:10]=[C:9]3[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])[N:7]=[CH:8]3)=[CH:13][CH:12]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ncc2cc(-c3ccc(F)cc3)ccc2c1O
Reactant: NCCC(=O)O
Product: O=C(O)CCNC(=O)c1ncc2cc(-c3ccc(F)cc3)ccc2c1O

Procedure:
3-{[7-(4-Fluoro-phenyl)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-propionic acid was prepared from 7-(4-Fluoro-phenyl)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(b) using beta-alanine. MS ESI(−) m/e: 353.1196 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:11]2[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][O:12]2)=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:29][O:30][CH3:31]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH:11]2[O:12][CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][O:16]2)=[C:4]([O:10][CH2:29][O:30][CH3:31])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(C2OCC(C)(C)CO2)c1O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(OC)ccc(Br)c1C1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the solution of 3-bromo-2-(5,5-dimethyl-[1,3]dioxan-2-yl)-6-methoxy-phenol in DCM (20 mL) was added DIEA (697 μL, 4 mmol), followed by addition of chloromethoxymethane (228 μL, 3 mmol). After it was stirred at the room temperature for 72 h, the reaction mixture was evaporated and the residue was partitioned between NaHCO3 (50 mL) solution and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (3×10 mL) and the combined extracts were washed with brine and dried through Na2SO4. Evaporation of solvent afforded the title compound. 1H NMR (CDCl3) δ 0.80 (s, 3H), 1.45 (s, 3H), 3.57 (s, 3H), 3.65 (d, J=12 Hz, 2H), 3.79 (s, 3H), 3.80 (d, J=12 Hz, 2H), 5.11 (s, 2H), 6.00 (s, 1H), 6.76 (d, J=8 Hz, 1H), 7.32 (d, J=8 Hz, 1H).
Reaction SMILES: CO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[C:6]([O:14]CC2CC2)[C:5]=1[I:19].Cl>O>[Br:3][C:4]1[C:5]([I:19])=[C:6]([OH:14])[C:7]([O:10][CH:11]([F:13])[F:12])=[CH:8][CH:9]=1
Reactant: FC(F)Oc1ccc(Br)c(I)c1OCC1CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1c(OC(F)F)ccc(Br)c1I
Yield: 85.9 %

Procedure:
To 59.5 ml of methanol solution containing 8.1 g (22 mmol) of 1-bromo-3-cyclopropylmethoxy-4-difluoromethoxy-2-iodobenzene obtained in Reference example 12-(e) was added 59.5 ml of conc. hydrochloric acid, and the mixture was refluxed for 4 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 6.9 g of the title compound as a colorless solid. (Yield: 87%)
Reaction SMILES: [CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22](O)=[O:23])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:55]1([N:58]2[CH2:63][CH2:62][N:61]([C:64]3([CH2:70][N:71]4[CH2:79][C:78]5[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=5)[C:72]4=[O:80])[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[CH2:60][CH2:59]2)[CH2:57][CH2:56]1>ClCCl>[CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([N:67]2[CH2:66][CH2:65][C:64]([N:61]3[CH2:62][CH2:63][N:58]([CH:55]4[CH2:56][CH2:57]4)[CH2:59][CH2:60]3)([CH2:70][N:71]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[C:72]3=[O:80])[CH2:69][CH2:68]2)=[O:23])[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)O)C2CC2)c(C)c1
Reactant: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)N2CCC(CN3Cc4ccccc4C3=O)(N3CCN(C4CC4)CC3)CC2)C2CC2)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenyl-sulfonamido)ethoxy)acetic acid AC7 (0.306 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4.0 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resultant solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of 2-((4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)isoindolin-1-one AM13 (1.2 equiv) in dichloromethane (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give the crude product which was purified by column chromatography. Yield: 50%. MS, Rt=3.4 min, m/z=694.5 [MH]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:22]=[CH:21][C:18](C#N)=[CH:17][CH:16]=1>>[F:12][C:13]([F:23])([F:24])[O:14][C:15]1[CH:22]=[CH:21][C:18]([C:1]2[NH:2][C:3](=[O:11])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Reactant: CNC(=O)c1ccccc1C
Product: O=c1[nH]c(-c2ccc(OC(F)(F)F)cc2)cc2ccccc12
Yield: 24.9 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (5.97 g) and 4-trifluoromethoxybenzonitrile (7.49 g) were reacted, to give 3-(4-trifluoromethoxyphenyl)isoquinolin-1-one (3.04 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.[CH2:29]([NH2:31])[CH3:30].O>C1COCC1>[CH2:29]([NH:31][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1)[CH3:30]
Reactant: N#Cc1c(Cl)nc(OCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2
Reactant: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(OCc2ccccc2)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
30 mg (0.08 mmol) of 2-chloro-4-(1,3-benzodioxol-5-yl)-6-benzyloxy-3,5-pyridinedicarbonitrile (example 4, step 1) and 10.4 mg (0.23 mmol) of ethylamine are shaken together in 0.12 ml of THF for about 16 h. Water is added to the reaction solution and the product that crystallizes out is filtered off with suction and dried under reduced pressure.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:14]1[N:15]=[C:16]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[C:35](=[O:36])[NH:34][CH2:33][CH2:32][N:31]3[CH2:37][CH3:38])=[CH:26][CH:25]=2)[C:17](=[O:22])[N:18]([CH2:20]C)[CH:19]=1.[F:39][C:40]1[C:45]([NH:46][C:47]([C:49]2[S:53][C:52]3[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=3[CH:50]=2)=[O:48])=[C:44]([CH3:58])[C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][CH:41]=1>O>[CH2:37]([N:31]1[CH2:32][CH2:33][NH:34][C:35](=[O:36])[CH:30]1[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:16]2[C:17](=[O:22])[N:18]([CH3:20])[CH:19]=[C:14]([C:43]3[C:44]([CH3:58])=[C:45]([NH:46][C:47]([C:49]4[S:53][C:52]5[CH2:54][CH2:55][CH2:56][CH2:57][C:51]=5[CH:50]=4)=[O:48])[C:40]([F:39])=[CH:41][CH:42]=3)[N:15]=2)=[CH:29][CH:28]=1)[CH3:38]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1NC(=O)c1cc2c(s1)CCCC2
Reactant: CCN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(CC)c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCNC(=O)C1c1ccc(Nc2nc(-c3ccc(F)c(NC(=O)c4cc5c(s4)CCCC5)c3C)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 41 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (13 mL), water (3 mL) and sodium carbonate (417 mg, 3.93 mmol). After bubbling nitrogen through the resulting mixture for 15 min, 34 (150 mg, 0.370 mmol), N-(6-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydro benzo[b]thiophene-2-carboxamide. (192 mg, 0.460 mmol and tetrakis(triphenyl phosphine)palladium(0) (75 mg, 0.065 mmol) were added, and the reaction mixture then heated at reflux for 5 h. After this time, the reaction mixture was cooled to room temperature, filtered and the filter cake washed with diethyl ether (10 mL). The resulting solid was dissolved in methylene chloride/methanol (10:1), absorbed onto silica gel and purified by flash chromatography to afford 35 in 41% yield (93 mg) as a yellow solid: mp 179-180° C.; 1H NMR (500 MHz, CDCl3) δ 8.31 (bs, 1H), 7.79 (d, 2H, J=8.5 Hz), 7.39 (m, 3H), 7.33 (m, 1H), 7.22 (s, 1H), 7.04 (t, 1H, J=8.0 Hz), 6.68 (s, 1H), 5.80 (d, 1H, J=3.5 Hz), 3.99 (s, 1H), 3.65 (s, 3H), 3.64 (m, 1H), 3.36 (m, 1H), 3.11 (m, 1H), 2.82 (t, 2H, J=6.0 Hz), 2.66 (t, 2H, J=6.0 Hz), 2.59 (m, 2H), 2.36 (s, 3H), 2.27 (m, 1H), 1.85 (m, 4H), 0.99 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 615.3 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[NH:15][C:14](=O)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[NH:13][C:10]2=[N:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]2[N:15]=1
Reactant: O=c1[nH]c2ncc(-c3ccccc3)nc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2nc(-c3ccccc3)cnc2[nH]1
Reaction time: 0.5 h

Procedure:
Reflux a solution of 5-phenyl-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one (200 mg) in phosphorus oxychloride (10 mL) for 18 hours. After cooling, remove the excess POCl3 in vacuo, and triturate the residue in ice-water (200 mL). After stirring for 30 minutes, filter the precipitate to obtain 2-chloro-5-phenyl-1H-imidazo[4,5-b]pyrazine as a gray solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[O:22])=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a solution of p-toluidine (0.44 g, 4.1 mmol) in 10 ml of CH2Cl2 (pre-cooled to 0° C.) are added Et3N (1.14 ml, 2 eq.) and 4-chloro-3-trifluoromethyl-benzoyl chloride (1 g, 4.1 mmol) in 5 ml of CH2Cl2. The mixture is slowly warmed to room temperature and continued to stir at room temperature for an hour. The mixture is diluted with 50 ml of CH2Cl2, washed with 1N HCl solution, and brine. The organic layer is separated, dried over MgSO4, filtered, and concentrated. The residue is purified by column chromatography (EtOAc/Hexanes, 2:3) to give 1.25 g (97%) of 4-chloro-N-p-tolyl-3-trifluoromethyl-benzamide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].O[C@H]1CC[C@@H](NC2C(C#N)=CN=C(S(C)=O)N=2)CC1(C)C.[NH2:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([S:53]([NH2:56])(=[O:55])=[O:54])=[C:49]([Cl:57])[CH:48]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:57][C:49]1[CH:48]=[C:47]([CH2:46][CH2:45][NH:44][C:11]2[N:10]=[C:9]([NH:8][CH:5]3[CH2:6][CH2:7][CH:2]([OH:1])[C:3]([CH3:21])([CH3:22])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)[CH:52]=[CH:51][C:50]=1[S:53]([NH2:56])(=[O:55])=[O:54]
Reactant: NCCc1ccc(S(N)(=O)=O)c(Cl)c1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Agent: CS(=O)c1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(Nc2nc(NCCc3ccc(S(N)(=O)=O)c(Cl)c3)ncc2C#N)CCC1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, 0.28 mmol) and 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile, 4-(2-amino-ethyl)-2-chloro-benzenesulfonamide (90 mg, 0.38 mmol) and DIEA (72 mg, 0.56 mmol) in THF (4 mL) was stirred at 100° C. in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to afford the title compound (28.6 mg, 0.060 mmol, 26% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 7.93 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 4.26-4.12 (m, 1H), 3.66-3.46 (m, 2H), 3.31-3.25 (m, 1H), 2.87 (t, J=6.8 Hz, 2H), 1.86-1.35 (m, 6H), 0.90 (s, 3H), 0.88 (s, 3H). MS (ESI) m/z 479.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]=[CH2:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].ClC1C=CC=C(C(OO)=[O:22])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]2[CH2:13][O:22]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=Cc1cc(Br)cc(C(=O)OC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc(C2CO2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-bromo-5-vinylbenzoate (1.00 g, 4.15 mmol) in CH2Cl2 (40 mL) at 0° C. was added m-chloroperbenzoic acid (70% purity, 1.43 g, 5.80 mmol) in portions over a 10 minute period. The mixture was warmed to room temperature and stirred for 2 hours upon which it was poured onto saturated sodium bicarbonate (250 mL). The mixture was extracted with ethyl acetate (3×100 mL) and the combined extracts were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (0-50% EtOAc/hexane) to afford the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6): 7.92 (t, 1H, J=1.7 Hz), 7.86 (t, 1H, J=1.5 Hz), 7.78 (t, 1H, J=1.7 Hz), 4.09 (q, 1H, J=2.5 Hz), 3.87 (s, 3H), 3.17-3.14 (m, 1H), 2.92-2.90 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].Br[CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:12][O:11][CH:10]([O:13][CH3:14])[CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ncc[nH]1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(Cn1ccnc1C=O)OC
Temperature: 110 °C
Yield: 31.6 %

Procedure:
To a solution of the imidazole-2-carboxaldeyde (0.41 g, 4.27 mmol) in DMF (1 mL) was added 1.1 eq. of 2-bromo-1,1-dimethoxyethane (0.79 g, 4.69 mmol), potassium carbonate and a catalytic amount of potassium iodide. The reactions were heated at 110° C. for 18 hrs followed by evaporation to dryness and purified utilizing a Biotage SP4 with a gradient method of 5-50% methanol in DCM to yield the desired compound (248 mg, 1.35 mmol, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.9 (s, H), 7.85 (s, H), 7.55 (s, H), 5.82 (m, H), 4.75 (d, 2H), 3.45 (s, 6H).