Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:7][C:8]([C:10]1[CH:11]=[N:12][N:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])=[N:15][C:14]=12)=[O:9])([CH3:6])[CH3:5].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.CCOC(C)=O>[F:31][C:25]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=1[C@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:16]1[CH:17]=[CH:18][N:13]2[N:12]=[CH:11][C:10]([C:8]([NH:7][C:4]([CH3:6])([CH3:5])[CH2:3][NH:2][S:40]([CH3:39])(=[O:42])=[O:41])=[O:9])=[C:14]2[N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CN)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(CNS(C)(=O)=O)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
(R)—N-(1-amino-2-methylpropan-2-yl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride (24.0 mg, 0.0532 mmol) was dissolved in DCM (0.53 mL) and triethylamine (15.2 μL, 0.109 mmol) followed by MeSO2Cl (4.34 μL, 0.0559 mmol) were added sequentially. The mixture was stirred at ambient temperature for 2 hours and was diluted with EtOAc. The mixture was washed with water and brine and was dried with MgSO4. The solution was filtered and concentrated to afford the title compound (8.0 mg, 30% yield) as a white solid. MS (apci) m/z=493.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=O)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:14]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH4+].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH2:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C1CCOC1
Reactant: O=Cc1cc(Br)c2ncccc2c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Product: C=Cc1cc(Br)c2ncccc2c1

Procedure:
To a solution of methyl-triphenyl phosphonium bromide (1.15 eq) in THF (0.3M) at 0° C. was added K-tOBu (1.15 eq). The resulting mixture was stirred for 30 min after which a solution of the 8-bromo-quinoline-6-carbaldehyde from Step 1 (1.0 eq) was added. The final mixture was stirred at room temperature for 12 h, poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1) afforded the desired compound as a yellow solid.
Reaction SMILES: C([N:3](CC)CC)C.ClC(OC)=O.[CH2:13]([N:20]1[C:28](=[O:29])[CH:27]2[CH:22]([C:23]3([C:31](O)=[O:32])[CH2:30][CH:26]2[CH:25]=[CH:24]3)[C:21]1=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N>[CH2:13]([N:20]1[C:28](=[O:29])[CH:27]2[CH:22]([C:23]3([C:31]([NH2:3])=[O:32])[CH2:30][CH:26]2[CH:25]=[CH:24]3)[C:21]1=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: O=C1C2C3C=CC(C(=O)O)(C3)C2C(=O)N1Cc1ccccc1
Agent: COC(=O)Cl
Agent: N
Product: NC(=O)C12C=CC(C1)C1C(=O)N(Cc3ccccc3)C(=O)C12
Temperature: 0 °C

Procedure:
1.1 g (11 mmol) of triethylamine and then 1.15 g (12 mmol) of methyl chloroformate are added dropwise to 3 g (10 mmol) of 4-benzyl-3,5-dioxo-4-azatricyclo[5.2.1.02,6 ]dec-8-ene-1-carboxylic acid in 20 ml of absolute tetrahydrofiran at 0° C. The mixture is stirred at 0° C. for a further hour and the solution is poured onto 20 ml of ammonia solution. The mixture is stirred at room temperature for 1 hour and extracted several times with chloroform, and the extracts are dried over MgSO4 and concentrated, whereupon the product crystallizes.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH:6]=1)=[O:4].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].C(O)(C(F)(F)F)=O>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5]([C:3]([OH:2])=[O:4])=[CH:6]3)=[CH:16][CH:17]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cn3cc(C(=O)O)c4ccccc43)cc2)cc1

Procedure:
The title compound was prepared from 1-(4-nitro-benzyl)-1H-indole-3-carboxylic acid methyl ester and 4-tert-butylbenzenesulfonyl chloride followed the procedure of Example 3 Step 2 as a light brown solid: 1H NMR (DMSO-d6) δ 1.24 (s, 9H), 5.36 (s, 2H), 7.04 (d, J=8.5 Hz, 2H), 7.13-7.18 (m, 4H), 7.45 (dd, J=6.1, 2.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 8.00 (dd, J=6.1, 2.6 Hz, 1H), 8.13 (s, 1H), 10.23 (br s, 1H), 11.98 (br s, 1H); MS (ESI) m/z 463 (MH+), 461 ([M−H]−); HRMS calcd for C26H27N2O4S: 463.1690; found (ESI+): 463.1681; Anal. calcd for C26H26N2O4S.0.06 TFA: C, 67.51; H, 5.67; N, 6.06. Found: C, 67.40; H, 5.65; N, 6.04.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[H-].[Na+].Cl[C:10]1[C:19]2[C:14](=[C:15]([C:20]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([Cl:35])[CH:26]=4)[O:22][N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1>CS(C)=O>[Cl:35][C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH:13]=[CH:12][N:11]=[C:10]4[NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])[N:24]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Reactant: C[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N[C@@H](C)C(=O)O)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A mixture of L-alanine (27.8 mg, 0.312 mmol) and sodium hydride (60%; 9.99 mg, 0.250 mmol) in dimethyl sulfoxide (DMSO) (2 ml) were stirred at room temp for 30 mins. 1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was left to stir at 120° C. under nitrogen for 48 hrs. The reaction mixture was loaded onto a 10 g SCX column and washed with acetonitrile, then eluted with 10% ammonia in acetonitrile. The solvent was evaporated from the appropriate fractions and the residue was dissolved in dichloromethane and washed with water. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as an orange solid (29 mg)
Reaction SMILES: [BH4-].[K+].[C:3]1([C:9]2[NH:10][C:11]([CH3:17])=[C:12]([C:14](=[O:16])[CH3:15])[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([C:9]2[NH:10][C:11]([CH3:17])=[C:12]([CH:14]([OH:16])[CH3:15])[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1nc(-c2ccccc2)[nH]c1C
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: Cc1[nH]c(-c2ccccc2)nc1C(C)O
Reaction time: 8 h
Yield: 89 %

Procedure:
32 Grams (0.59 mol) of potassium borohydride were added portionwise to a solution of 30 g (0.15 mol) of 2-phenyl-4-acetyl-5-methylimidazole in 1500 ml of MeOH. After stirring overnight, a solid material was removed by filtration, then the solvent was evaporated under reduced pressure to give 27 g of 2-phenyl-4-(1-hydroxyethyl)-5-methylimidazole. The crude compound thus isolated was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[CH3:20])[CH2:6]2>CO.[Pd]>[CH3:20][C:12]1[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=1[O:10][CH:5]1[CH2:6][CH:7]2[N:2]([CH3:1])[CH:3]([CH2:9][CH2:8]2)[CH2:4]1
Reactant: Cc1cc([N+](=O)[O-])ccc1OC1CC2CCC(C1)N2C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)ccc1OC1CC2CCC(C1)N2C
Reaction time: 2 h

Procedure:
A suspension of 8-Methyl-3-(2-methyl-4-nitro-phenoxy)-8-aza-bicyclo[3.2.1]octane (495 mg) and palladium (5% on carbon; 63 mg) in methanol (25 mL) was stirred vigorously under a hydrogen atmosphere (atmospheric pressure) for 2 h. Then the catalyst was filtered off and the filtrate concentrated. The product with the molecular weight of 246.35 (C15H22N20); was obtained in this way; MS (ESI) 247 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29]Cl>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCCl
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)CCCN1CCN(C(=O)OCc2ccccc2)CC1
Yield: 103.5 %

Procedure:
A suspension mixture of benzyloxycarbonylpiperazine (14.529, 65.9 mmol), 3-dimethyl-aminopropyl chloride hydrochloride (15.63 g, 98.9 mmol), and triethylamine (20.29, 200 mmol) in ethanol (100 ml) was refluxed for 14 h. Then 3-dimethylaminopropyl chloride hydrochloride (6.32 g, 40 mmol), and triethylamine (11.3 ml, 80 mmol) was added to the reaction mixture and continued to reflux for 24 h. The solvent was evaporated and the residue was extracted with ethyl actate. The extract was washed with water, dried (MgSO4), and concentrated to give 12.65 g of brown viscous oil, which was purified by column chromatography on silica gel (ammonium hydroxide aqueous solution/methanol/dichloromethane: 1/10/100) to give 2.21 g of brown clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN[C@H](C)c1ccc(Br)cc1
Temperature: 120 °C
Yield: 40.2 %

Procedure:
(R)-1-(4-Bromophenyl)ethanamine (6G1) (2.10 mmol, 419 mg), methyl 2-bromoacetate (6G2) (2.10 mmol, 320 mg) and triethylamine (4.19 mmol, 424 mg) were dissolved in DCM (3 ml) and heated in the microwave at 120° C. for 20 min. The crude mixture was concentrated before purification on silica eluting with 20% EtOAc/heptane to give (R)-methyl 2-(1-(4-bromophenyl)ethylamino)acetate (6G3) 230 mg (40.1%); 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 2H) 7.20 (d, 2H) 3.77 (q, 1H) 3.69 (s, 3H) 3.4-3.18 (dd, 2H) 1.34 (d, 3H)
Reaction SMILES: [O:1]=[C:2]([NH:13][CH2:14][C:15]1[NH:16][C:17](=[O:25])[C:18]2[CH2:24][O:23][CH2:22][CH2:21][C:19]=2[N:20]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH2:33][CH2:32][CH2:31]2>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]([C:10]([CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][C:2]([NH:13][CH2:14][C:15]3[NH:16][C:17](=[O:25])[C:18]4[CH2:24][O:23][CH2:22][CH2:21][C:19]=4[N:20]=3)=[O:1])[CH2:5][CH2:6]1)=[O:12])[CH2:33][CH2:32][CH2:31]2
Reactant: COc1ccc2c(c1)CCCN2
Reactant: O=C(CN1CCC(C(=O)O)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Product: COc1ccc2c(c1)CCCN2C(=O)C1CCN(CC(=O)NCc2nc3c(c(=O)[nH]2)COCC3)CC1
Yield: 22.6 %

Procedure:
The title compound (56 mg, 22% yield) was prepared following the general procedure of Example 1 from 1-(2-oxo-2-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylamino)ethyl)piperidine-4-carboxylic acid (250 mg, 0.50 mmol) and 6-methoxy-1,2,3,4-tetrahydroquinoline (82 mg, 0.50 mmol). 1H NMR (400 MHz, CDC3) δ 10.68 (br. s., 1H), 8.12 (br. s, 0.5H), 6.97 (br. s., 0.5H), 6.73-6.80 (m, 2H), 4.58 (s, 2H), 4.38 (d, J=5.6 Hz, 2H), 3.97 (t, J=5.6 Hz, 2H), 3.63-3.89 (m, 5H), 3.10 (br. s., 2H), 2.89 (br. s., 3H), 2.71 (t, J=5.3 Hz, 4H), 2.15 (br. s., 2H), 1.82-2.09 (m, 5H), 1.68 (br. s., 1H). HRMS calculated for C26H33N5O5 496.2560. found (ESI, [M+H]+), 496.2561. Retention time=1.29 min.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][CH2:13][C:14]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH3:26])([CH3:16])[CH3:15]>ClCCl>[CH3:11][O:12][CH2:13][C:14]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:3]=[O:4])=[C:18]1[CH3:26])([CH3:16])[CH3:15]
Reactant: CN(C)C=O
Reactant: COCC(C)(C)n1c(C)cc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCC(C)(C)n1c(C)c(C=O)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of 2 ml anhydrous N,N-dimethylformamide dissolved in 80 ml anhydrous dichloromethane was added phosphoryl trichloride (5 g, 32.6 mmol) at 0° C. The resultant reaction mixture was allowed to stirred at 0° C. for 3 hours. 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole (800 mg, 3.7 mmol) was added dropwise at 0° C. Then the resulting reaction mixture was allowed to stir for 1 hour at 0° C., and then warmed to the ambient temperature. The reaction mixture was allowed to stir for 24 hours at room temperature. The reaction mixture was quenched with saturated sodium acetate. The pH was adjusted to around 8 by progressively adding 2N sodium hydroxide below 0° C., extracted with dichloromethane (100 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 10:1→5:1→2:1) to give 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole-3-carbaldehyde (510 mg, 57%) as a light yellow oil. LCMS (M+H+) m/z: calcd. 245.14. found 245.9.
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].Cl[P:9]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12]>BrCCBr.C(OCC)C>[CH2:18]([N:15]([P:9]([N:10]([CH2:11][CH3:12])[CH2:13][CH3:14])[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[CH2:16][CH3:17])[CH3:19]
Reactant: C[Si](C)(C)CCl
Reactant: CCN(CC)P(Cl)N(CC)CC
Agent: [Mg]
Solvent: CCOCC
Solvent: BrCCBr
Product: CCN(CC)P(C[Si](C)(C)C)N(CC)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
In a 50 ml three-necked flask equipped with a dropping funnel and a magnetic stirrer, 0.36 g (14.8 mmol) of magnesium and 10 ml of anhydrous diethyl ether were charged at room temperature in a nitrogen gas atmosphere. After several drops of 1,2-dibromoethane were added so as to activate magnesium, 2.0 ml (14.2 mmol) of chloromethyltrimethylsilane were added dropwise carefully to avoid heat build-up. When the reaction solution was stirred for 1 hour while it was heated mildly with a drier, the solution darkened. Then, after the solution was cooled to −78° C., 3.0 g (14.2 mmol) of chlorobis(diethylamino)phosphine synthesized in (a) were added dropwise to the solution, and the resultant mixture was then returned to room temperature and refluxed for 1 hour. The resulting crystals were filtered off, washed with anhydrous diethyl ether, and purified by vacuum-distillation (0.2 kPa, 74.3-79.5° C.) to obtain 2.29 g of bis(diethylamino)(trimethylsilylmethyl)phosphine in the form of a colorless transparent liquid; the yield was 62%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([F:18])[CH:9]=2)[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.[Br:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Br:23][C:24]1[CH:29]=[C:28]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([F:18])[CH:9]=3)[CH:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Fc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Reactant: OB(O)c1cccc(Br)c1
Product: Fc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.6) (1.79 g, 5.19 mmol) and commercially available 3-bromo-benzene-boronic acid (1.15 g, 5.73 mmol) according to the general procedure IVb. Obtained as a white solid (0.94 g, 39%). MS (EI) 464.0, 466.0 [(M)+]; mp 111° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=O)[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:34])[C:17]=3[CH:35]=2)[C:3]1=[O:36].C(=O)([O-])O.[Na+].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1.C(OCC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[S:51])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:34])[C:17]=3[CH:35]=2)[C:3]1=[O:36]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)C(C)Oc1ccc(C)c(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)Oc1ccc(C)c(-c2nsc3ccc(-n4c(=S)cc(C(F)(F)F)n(C)c4=O)cc23)c1
Yield: 71.2 %

Procedure:
A mixture of methyl 2-{{2-{5-[3,6-dihydro-3-methyl-4-(trifluoromethyl)-2,6-dioxo-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}-p-tolyl}oxy}propionate (2.00 g, 3.80 mmol), sodium hydrogen carbonate (1.24 g, 14.8 mmol) and Lawesson's Reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, 1.70 g, 4.20 mmol) in toluene is refluxed for two hours, filtered to remove solids, and concentrated in vacuo to obtain an orange foam. Column chromatography of the foam using silica gel, and 0% and 1% diethyl ether in methylene chloride solutions gives the title product as an orange foam (1.45 g, mp 110-112° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:17][CH2:18][N:19](CC)CC.ClCC#N>C1COCC1>[C:7]1([N:1]2[CH2:2][CH2:3][N:4]([CH2:17][C:18]#[N:19])[CH2:5][CH2:6]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1
Reactant: c1ccc2c(N3CCNCC3)nccc2c1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: C1CCOC1
Product: N#CCN1CCN(c2nccc3ccccc23)CC1
Reaction time: 3 h
Yield: 34.9 %

Procedure:
To a solution of 1-(piperazin-1-yl)isoquinoline (459 mg, 2.15 mmol) in THF (15 mL) was added NEt3 (3.6 mL, 27 mmol) and chloroacetonitrile (1.8 mL, 28 mmol) and the reaction was stirred 3 h. The reaction mixture was filtered, concentrated and the residue purified by silica gel chromatography (Biotage 25-short, 25% EtOAc/hexanes to 100% EtOAc/hex) to yield 38 (188 mg, 0.75 mmol, 35%) as a white solid. LC/MS: (ES+) m/z (M+H)+=253; HPLC Rt=1.23 min., column Q, conditions B.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2ccccc2OC)n(C)c(=O)c1O
Reactant: Cc1ccc(CN)cc1Cl
Product: COc1ccccc1-c1nc(C(=O)NCc2ccc(C)c(Cl)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 3-chloro-4-methylbenzylamine (107 mg, 0.75 mmol). The title product was obtained as a brown solid (57.5 mg, 93% yield). 1HNMR (500 MHz, CDCl3) δ: 12.04 (1H, br s), 7.90 (1H, t, J=5.49 Hz), 7.48 (1H, td, J=8.24, 1.83 Hz), 7.30–7.25 (2H, m), 7.17 (1H, d, J=7.94 Hz), 7.10–7.05 (2H, m), 6.98 (1H, d, J=8.55 Hz), 4.50 (2H, d, J 6.41 Hz), 3.82 (3H, s), 3.34 (3H, s), 2.34 (3H, s). HRMS (ESI) calcd for C21H21ClN3O4 (M+H): 414.1221; found: 414.1234.
Reaction SMILES: Cl.Cl[CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.[SH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C)C=O>[N:11]1[C:12]2[CH:3]([S:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:4][CH2:5][CH2:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(S)cc1
Reactant: ClC1CCCc2cccnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(SC2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of 4.08 g (20 mmol) of 8-chloro-5,6,7,8-tetrahydroquinoline hydrochloride, 3.38 g (25 mmol) of 4-mercaptobenzonitrile and 6.91 g (50 mmol) of potassium carbonate in 34 ml of dimethylformamide was stirred under nitrogen at room temperature overnight. The mixture was poured into aqueous saturated sodium chloride and was extracted with ethyl acetate. The extract was washed with ice-cold aqueous 2N sodium hydroxide and water, dried over MgSO4 and evaporated under reduced pressure to obtain 4.72 g (89%) of 4-(5,6,7,8-tetrahydroquinoline-8-ylthio)-benzonitrile as colorless crystals (from methanoldichloromethane).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[CH3:10][O-:11].[Na+]>CO.[Cl-].[Na+].O>[F:8][C:7]1[C:2]([O:11][CH3:10])=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: Fc1ccc(F)c(F)n1
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(F)ccc1F
Temperature: 65 °C
Yield: 78.8 %

Procedure:
2,3,6-Trifluoropyridine (17.91 ml, 188 mmol) was dissolved in anhydrous MeOH (300 ml) and the resulting mixture was placed under argon. This mixture then was treated with a 25 wt % methanolic solution of sodium methoxide (43.0 ml, 188 mmol). The resulting mixture was then heated at about 65° C. for 2 hr. The reaction mixture was cooled to ambient temperature, and concentrated in vacuo to yield a residue which then was mixed with brine (200 mL), and extracted with Et2O (3×200 ml). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give 21.5 g (79% yield) of crude 3,6-difluoro-2-methoxypyridine as a white solid which was carried on to the next step without purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=[O:3].C(O)(=O)C.O.[C:17]([OH:21])(=[O:20])[CH:18]=[O:19]>O>[Cl:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][CH:18]([OH:19])[C:17]([OH:21])=[O:20])[CH:9]=[CH:8][C:7]=1[Cl:10]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(CC(O)C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 23 h
Yield: 38 %

Procedure:
A mixture of 3,4-dichloroacetophenone (3.84 g, 20.3 mmol), glacial acetic acid (20.0 ml), and glyoxylic acid hydrate (1.85 g, 20.1 mmol) was stirred at 90° C. for 23 hours. More glyoxylic acid hydrate (0.93 g) was added, and heating was continued for 41 hours. Water (200 ml) was added, and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate/heptane yielded 2.01 g (38%) of 4-(3,4-dichlorophenyl)-4-oxo-2-hydroxybutyric acid. This acid was used to prepare the title amide using General Procedure (D).