Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:53])[NH:22][C@H:23]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:24][N:25]1[C:30](=[O:31])[C:29](Br)=[C:28]([CH3:33])[N:27]([CH2:34][C:35]2[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:36]=2[F:45])[C:26]1=[O:46])([CH3:19])([CH3:18])[CH3:17]>C(#N)C>[C:16]([O:20][C:21](=[O:53])[NH:22][C@H:23]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH2:24][N:25]1[C:30](=[O:31])[C:29]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]([CH2:14][OH:15])[CH2:10]2)=[C:28]([CH3:33])[N:27]([CH2:34][C:35]2[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:36]=2[F:45])[C:26]1=[O:46])([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: OCC1CNCCN1Cc1ccccc1
Solvent: CC#N
Product: Cc1c(N2CCN(Cc3ccccc3)C(CO)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
(1-Benzyl-piperazin-2-yl)-methanol (200 mg, 0.97 mmol), {(R)-2-[5-bromo-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (50 mg, 0.083 mmol), and acetonitrile (1 mL) were placed in a microwave vessel and stirred at 120° C. for 3 hrs with microwave irradiation. After concentration of the solution, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/1/1) and dried in a vacuum to afford 20 mg of a colorless oil (yield 33%) . 1H NMR (300 MHz, CDCl3) δ 1.37 (9H, s), 2.23 (1H, m), 2.34 (3H, s), 2.41-2.66 (2H, m), 2.85 (1H, m), 3.16 (1H, m), 3.49 (1H, m), 3.72 (1H, m), 3.93-4.15 (3H, m), 4.21 (1H, m), 5.03 (1H, m), 5.42 (2H, dd), 5.74 (1H, m), 7.21 (2H, m), 7.18-7.26 (10H, m), 7.54 (1H, d)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[NH:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[N:9]2[C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Cl)cc2)N1
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Cl)cc2)N1C(=O)Nc1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a solution of (1R,3S)-1-(4-chlorophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline (60 mg, 233 μmol) in CH2Cl2 (1.0 mL) at RT was added 1-fluoro-4-isocyanatobenzene (42 μL, 361 μmol). The reaction was stirred 4 h and directly purified by reverse phase HPLC to give (1R,3S)-1-(4-chlorophenyl)-N-(4-fluorophenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide as a light purple solid. MS (ESI pos. ion) m/z: 395 (M+1).
Reaction SMILES: C(=O)([O-])O.[Na+].[NH2:6][CH2:7][CH2:8][OH:9].[I:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(OCC)(=O)C.O>[OH:9][CH2:8][CH2:7][NH:6][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[I:10]
Reactant: NCCO
Reactant: O=C(Cl)c1ccccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCCO)c1ccccc1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
To a solution of sodium hydrogen carbonate (3.30 g, 39.7 mmol) and 2-aminoethanol (1.80 ml, 29.8 mmol) in ethyl acetate (25 ml) and water (15 ml) was added dropwise the solution of 2-iodobenzoyl chloride in ethyl acetate prepared above under ice-cooling, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give N-(2-hydroxyethyl)-2-iodobenzamide (5.12 g, yield 87.6%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1Cl)[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:29](O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(C)C=C2)CO)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:29])[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)acetic acid (2K) was prepared following the procedure used to prepare compound 1L of Example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethanol (2J) was used instead of compound 1K. 1H-NMR 300 MHz, (CD3OD) δ 8.31 (d, 1H), 7.97 (s, 1H), 7.73 (d, 1H), 7.70-7.60 (m, 3H), 7.42-7.38 (m, 1H), 5.25 (s, 1H), 2.96 (s, 3H), 2.78 (s, 3H), 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C23H25ClNO3: 398.9. Found: 398.2, 400.1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[CH2:15]([N:22]=[C:23]=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([NH:22][C:23]([NH:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:14])[CH:12]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C=NCc1ccccc1
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCc2ccccc2)cn1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine (287 mg, 1.49 mmol) and benzyl isocyanate (199 mg, 1.49 mmol) in acetonitrile (5 mL) were heated at 65° C. for 16 hours. The reaction was cooled down to room temperature and concentrated. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) and triturated with ethyl acetate/hexanes (1/9) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)urea (246 mg, 51%) as a white solid. LC/MS; [M+H] calculated for C17H19N5O2; expected 326.15; found 326.10.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: N#Cc1ccccn1
Reactant: O=C(O)c1cc(F)ccc1S
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2ccc(F)cc12
Temperature: 135 °C
Yield: 4 %

Procedure:
A mixture of 5-fluoro-2-mercaptobenzoic acid (1.50 g, 8.7 mmol), 2-cyanopyridine (0.92 g, 8.8 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 48 hrs as described in Example 9. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The resultant product was recrystallized from ethanol to give the titled compound (0.09 g, 4%).
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][N:12]([CH3:21])[C:11]2=[O:22])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][N:12]1[C:11](=[O:22])[C:10]2([CH2:23][CH2:24][CH2:25][NH:8][CH2:9]2)[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13]1
Reactant: CN1CN(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CN(c2ccccc2)C2(CCCNC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-4-oxo-1-phenyl-1,3,7-triaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester (70 mg, 0.2 mmol) in DCM (5 ml) was added TFA (0.5 ml, 6.5 mmol). The reaction mixture was stirred at RT for 1 hour before applying the reaction mixture to a 1 g SCX-2 cartridge. Impurities were eluted with 1:1 DCM:MeOH, followed by 0.05 M ammonia in 1:1 DCM:MeOH. Product was eluted with 1M ammonia in 1:1 DCM:MeOH. The clean fractions were concentrated in vacuo to afford the title compound. No further purification was performed on the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:30][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Solvent: CO
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCc3ccccc3)c(Br)c2)c(SC)s1
Temperature: 50 °C

Procedure:
To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.020 g, 0.045 mmol), (Example 2: step c), benzylamine (0.005 g, 0.407 mmol), MeOH [2.0 mL]. Reaction vessel was sealed and heated to 50° C. for 72 hours. Removal of the solvents in vacuo followed by chromatography of the residue (10%–20% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. for C19H17BrN2O4S3: 514.45 (M+H); found 513.2, 515.1.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=1)[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>O1CCCC1.[Br-].[Zn+2].[Br-].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:21][C:12]1[CH:11]=[CH:10][C:9]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:20][C:13]=1[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)NCc1cc(Br)ccc1F
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(F)c(CNS(C)(=O)=O)c1
Temperature: 60 °C
Yield: 73.5 %

Procedure:
Dissolve zinc (II) bromide (313 mg, 1.20 mmol) in tetrahydrofuran (2.5 mL) and treat with triethylamine (0.64 mL, 4.80 mmol). After 4 min add N-(5-bromo-2-fluorobenzyl)methanesulfonamide (282 mg, 1.00 mmol), (prepared as described in PREPARATION 35), trimethylsilylacetylene (0.30 mL, 2.12 mmol), and tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.050 mmol) to the reddish solution. Heat to 60° C. in a sealed tube overnight, cool to room temperature and filter through diatomaceous earth with ethyl acetate. Concentrate the filtrate and purify the residue by silica gel chromatography, eluting with 75:25 hexanes:ethyl acetate, to give the title compound as a white crystalline solid (220 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18](=[N:20][OH:21])[NH2:19])=[CH:4][CH:3]=1.Cl[C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:19]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: NC(Cc1c(-c2ccc(Cl)cc2)nc2ccccn12)=NO
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Temperature: -40 °C

Procedure:
To a suspension of 2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N′-hydroxyacetimidamide (83.3 mmol, 25.0 g) in dry CHCl3 (600 mL) was cooled to −40° C. in an ice/EtOH bath under N2 atmosphere, Py. (100.0 mmol, 8.1 mL) was added in one portion, and followed by slowly adding ethyl 2-chloro-2-oxoacetate (166.6 mmol, 18.6 mL). After that, the reaction mixture was allowed to slowly rise up to r.t., and kept stirring for 1.0 H, D, then heated to 80 C for another 2 hs. The reaction mixture was cooled to r.t. and filtered, and the filtrate was evaporated under reduced pressure to give the brown residue, which was applied to C.C.eluted by petroleum/acetone (4:1, 2:1, 1:1, and 0:1). The acetone portion was concentrated in vacuo to give the solid, which was washed with acetone for 3 times, to obtain the product, 18.0 g (58.0%), as a white solid. m/e+=383 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5]2.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH2:5][CH:6]([NH:12][S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH2:7]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(NC1CNc2ccc(Br)cc2C1)c1ccccc1
Reactant: O=Cc1ccccc1
Product: O=S(=O)(NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1)c1ccccc1

Procedure:
The title compound was prepared from 87A and benzaldehyde by procedures analogous to those described in Example 22A.
Reaction SMILES: P(CCCC)(CCCC)CCCC.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:28][C:29]([F:49])([F:48])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[C:40]([CH:42]([OH:47])[CH2:43][CH2:44][CH2:45][CH3:46])[CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.O[C:51]1[CH:65]=[CH:64][C:54]([O:55][C:56]([CH3:63])([CH3:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58])=[C:53]([CH3:66])[CH:52]=1>C1COCC1>[CH3:63][C:56]([O:55][C:54]1[CH:64]=[CH:65][C:51]([O:47][CH:42]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:48])([F:28])[F:49])=[CH:35][CH:34]=3)[N:41]=2)[CH2:43][CH2:44][CH2:45][CH3:46])=[CH:52][C:53]=1[CH3:66])([CH3:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58]
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OC(C)(C)C(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
To a solution of nBu3P (47 μL, 0.19 mmol) in dry THF (2 mL), at 0° C. (ice/water bath) under nitrogen was added DIAD (37 mL, 0.19 mmol). After stirring for 10 minutes 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (50 mg, 0.16 mmol) was added, followed after another 20 minutes by ethyl 2-(4-hydroxy-2-methylphenoxy)-2-methylpropanoate (39 mg, 0.16 mmol). The mixture was then allowed to warm to rt over 16 hours and was then reduced under vacuum and the residue partitioned between EtOAc and water. The layers were separated and the organic layer washed with water (2×) then brine, dried (Na2SO4) and reduced to give a brown gum. Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with cyclohexane:EtOAc (19:1) afforded the title compound as a colourless gum (9 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH2:17][CH:18]=[CH2:19])[C:11]2=[O:20])=[N:7][N:6]=1)(=[O:4])=[O:3].[C:21]1(C)[C:22](S(O)(=O)=O)=CC=[CH:25][CH:26]=1>C(O)CCC>[CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][CH2:22][CH2:21][CH2:26][CH3:25])[CH2:14][CH2:13][N:12]([CH2:17][CH:18]=[CH2:19])[C:11]2=[O:20])=[N:7][N:6]=1)(=[O:4])=[O:3]
Reactant: C=CCN1CCC(O)N(c2nnc(S(C)(=O)=O)s2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CCCCO
Product: C=CCN1CCC(OCCCC)N(c2nnc(S(C)(=O)=O)s2)C1=O

Procedure:
Tetrahydro-1-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-3-allyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), butyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-3-allyl-6-butoxy-2(1H)-pyrimidinone.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>O1CCCC1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([B:21]([OH:22])[OH:20])=[CH:3][N:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cncc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cncc2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 4-bromoisoquinoline in tetrahydrofuran is cooled to -78° C. To this solution is added dropwise n-butyllithium (1.6 M in hexane), and the resultant solu-tion is stirred for 30 minutes. To this solution is then added dropwise triisopropylborate and the reaction mixture is then stirred for 18 hours at room temperature. The reaction mixture is then partitioned between ethyl acetate and saturated aqueous sodium chloride. The phases are separated and the aqueous phase extracted well with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is sonicated in a mixture of hexane:ethyl acetate. The resulting suspension is filtered to provide isoquinolin-4-ylboronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([F:22])=[C:11]3[N:20]=[CH:19][N:18]([CH3:21])[C:12]3=[N:13][C:14]=2[C:15]([OH:17])=O)=[C:4]([F:23])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:45]([O:47][CH2:48][CH2:49][O:50][NH2:51])=[CH2:46]>CCOC(C)=O>[CH:45]([O:47][CH2:48][CH2:49][O:50][NH:51][C:15]([C:14]1[N:13]=[C:12]2[N:18]([CH3:21])[CH:19]=[N:20][C:11]2=[C:10]([F:22])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:23])=[O:17])=[CH2:46]
Reactant: C=COCCON
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)O)nc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1nc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
To a solution of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (1.00 equivalent) and HOBt (1.50 equivalents) is added EDCI (1.50 equivalents) at room temperature. After stirring for 1 hour, O-(2-vinyloxy-ethyl)-hydroxylamine (1.10 equivalents) and TEA (1.20 equivalents) are added. The reaction mixture is stirred for 1 hour and diluted with EtOAc. The resulting mixture is washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si](C)(C)[N-:19][Si](C)(C)C.[Li+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([C:15]([NH2:19])=[NH:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: N=C(N)c1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Referring to Reaction Scheme 4, Stage 1, to a stirred solution of 6-(3,4-dichloro-phenyl)-pyrimidine-4-carbonitrile (1 eq) in anhydrous toluene (20 vol) at 0° C. was added lithium hexamethyldisilazide (2 eq) and the reaction mixture was stirred at ambient temperature for 2 hours under an atmosphere of nitrogen. The reaction mixture was cooled to 0° C. and quenched with HCl (3M). After 30 minutes stirring, water (40 vol) was added, followed by toluene (20 vol). The mixture was partitioned and the precipitate present in the aqueous phase was filtered off. The solid was suspended in a 3M solution of sodium hydroxide, stirred at room temperature for 30 minutes to give 6-(3,4-dichloro-phenyl)-pyrimidine-4-carboxamidine, which was used in the next stage without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([N:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[N:9]2)=[C:4]([C:25]([N:27]2[C@H:36]([CH2:37][OH:38])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)=[O:26])[CH:3]=1.[Si:39](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].N1C=CN=C1>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([N:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[N:9]2)=[C:4]([C:25]([N:27]2[C@H:36]([CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)=[O:26])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(Br)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
To a solution of (S)-1-(4-bromo-2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-5-methyl-1H-pyrazole-3-carboxamide (3.0 g, 5.2 mmol) in DCM (30 mL) were added TBDMS-chloride (0.93 g, 6.2 mmol), imidazole (0.70 g, 10.3 mmol) followed by stirring at RT for 5 h. The reaction mixture was diluted with water, extracted with EtOAc (100 mL×2), twice. The combined organic layers were washed with water (100 mL), brine (50 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a liquid 3.0 g (83%). Rf=0.66 (50% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.40 (m, 3H), 7.30-6.60 (m, 4H), 6.55-6.20 (m, 1H), 5.00-4.10 (m, 2H), 4.10-2.40 (m, 6H), 2.40-2.00 (m, 6H), 1.60-0.50 (m, 23H), 0.20-−0.40 (m, 6H); LC-MS: m/z 695.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].[CH:25]1([N:28]2[CH:32]=[C:31](I)[CH:30]=[N:29]2)[CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:31]3[CH:30]=[N:29][N:28]([CH:25]4[CH2:27][CH2:26]4)[CH:32]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: Ic1cnn(C2CC2)c1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C4CC4)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 1-cyclopropyl-4-iodo-1H-pyrazole.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[OH:18].C([O-])(O)=O.[Na+].[CH2:24](I)[CH:25]=[CH2:26]>C(Cl)Cl>[C:10]([C:9]1[C:4]([CH2:3][NH:2][CH2:26][CH:25]=[CH2:24])=[C:5]([OH:18])[CH:6]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Reactant: C=CCI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.705 g (2.99 mmol) of the product of Example 19 in 15 mL of CH2Cl2 was added 1 g of solid NaHCO3 followed by 0.525 g (3.12 mmol) of allyl iodide. The reaction mixture was stirred overnight at room temperature, then filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 0-1% MeOH in CH2Cl2. Evaporation of the purified fractions and drying in vacuo afforded the title compound.