Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].Cl.Cl[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([N:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]1[SH:28])[CH:14]([CH3:16])[CH3:15].O>CO>[CH2:13]([N:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]1[S:28][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: ClCc1ccccn1
Reactant: CC(C)Cn1c(S)nc2ccccc2c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(SCc2ccccn2)nc2ccccc2c1=O
Reaction time: 15 h
Yield: 46.1 %

Procedure:
5.4 ml Of 28% methanolic solution of sodium methoxide and 2.3 g of 2-chloromethylpyridine hydrochloride were added, in turn, to a solution of 3.0 g 3-isobutyl-2-mercapto-4(3H)-quinazolinone in 50 ml of methanol, and the stirring was continued at room temperature for 15 hours. The reaction solution was poured into about 300 ml of water and extracted with chloroform. The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica column chromatography eluted with 10% ethyl acetate in chloroform. The fraction obtained from the eluent was further purified by crystallization from a mixture of ethyl acetate and diisopropylether to give 1.92 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.C([O:21]C(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[O:21]1[CH2:3][CH2:4][CH:1]([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:2]1
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Product: O=C(O)c1cc2c(OCC3CCOC3)cccc2[nH]1

Procedure:
4-(Tetrahydro-furan-3-ylmethoxy)-1H-indole-2-carboxylic acid (16b) is synthesized analogous to 16a from 4-(tetrahydro-furan-3-yl)methanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])C=1.C(NC(C)C)(C)C.[CH2:34]([NH:41][CH2:42][CH3:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[CH2:34]([N:41]([CH2:42][CH3:43])[C:8](/[N:10]=[C:11]1\[S:12][C:13]([CH3:26])=[CH:14][N:15]\1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=1)=[O:9])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCNCc1ccccc1
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CCN(Cc1ccccc1)C(=O)/N=c1\sc(C)cn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (45 mg, 0.09 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylamine (21 μL, 0.12 mmol) dissolved in acetonitrile (0.6 mL). Then to the solution was added N-benzylethanamine (14 mg, 0.1 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:13]2[CH:14]=[CH:15][S:11][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1I
Reactant: OB(O)c1ccsc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1c(F)cccc1-c1ccsc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
In a dry round bottom flask were added 2-fluoro-6-iodobenzonitrile (500 mg; 2.02 mmol), 3-thiophene boronic acid (311 mg; 2.43 mmol), sodium carbonate (2.32 g; 21.86 mmol), tetrakis(triphenylphosphine)palladium(0) (77 mg; 0.07 mmol), DME (20 mL) and water (20 mL) and heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×), washed with brine (1×) and water (1×). Organic layers were combined and dried over sodium sulfate and then filtered and solvent removed to yield crude material which was purified by column chromatography (4% ethyl acetate/hexane) to obtain 150 milligrams of 2-fluoro-6-thiophen-3-yl-benzonitrile.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[N:17][CH:16]=1>O1CCOCC1>[CH3:12][O:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]2[N:17]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)[N:21]=2)[CH:16]=1)=[O:22]
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)cn2c1

Procedure:
2-Bromo-1-(4-fluoro-phenyl)-ethanone (1.135 g, 5.23 mmol) and 6-amino-nicotinic acid methyl ester (795.7 mg, 5.23 mmol) were heated under reflux in 50 ml dioxane for 8.5 hours. After cooling the solid was filtered and dried. Yield: 1.36 g, 96%. MS (mass spectrum): M+H+=271.06.
Reaction SMILES: [CH2:1]([Li])[CH3:2].[Cl:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:12][CH:11]=1)=[O:9].[Cl-].[NH4+]>CCOCC>[Cl:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[C:8]([CH2:1][CH3:2])([OH:9])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:14][CH:15]=1
Reactant: CCN(CC)CCOc1ccc(C(=O)c2cccc(Cl)c2)cc1
Reactant: [Li]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCN(CC)CCOc1ccc(C(O)(CC)c2cccc(Cl)c2)cc1

Procedure:
To 125 ml. of a 0.8 molar ethereal ethyl lithium solution a solution of 13.3 g. of 3-chloro-4'-[2-(diethylamino)-ethoxy]-benzophenone in 160 ml. of ether is added dropwise, with stirring under argon atmosphere, at a temperature between -20° C. and -15° C. The reaction mixture is then stirred at room temperature for one hour, and is decomposed with a saturated aqueous ammonium chloride solution, under cooling. The aqueous phase is extracted with ether, the ethereal phases are combined and washed to neutral with water. After drying over anhydrous magnesium sulfate, ether is distilled off under reduced pressure. Crystallization of the solid residue from n-hexane yields 8.9 g. of the title compound, melting at 64° to 65° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][N:14]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:15]2[C:16]([CH3:26])=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1>[CH2:27]([N:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]2[CH:6]=[C:5]([CH:38]=[CH:37][CH:36]=2)[O:4][CH2:3][CH2:2][NH:1][C:40](=[O:41])[O:42][CH3:43])=[CH:35][CH:34]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:16]=1[CH3:26])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCN)c2)cc1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)NCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1

Procedure:
The product from Example 78C (0.050 g, 0.0942 mmoles) in anhydrous THF (1 mL) was treated with methyl chloroformate (0.009 mL, 0.113 mmoles) and mixed overnight at room temperature. Reaction mixture concentrated under reduced pressure, and the residue was purified by preparative HPLC (CH3CN:0.1% trifluoroacetic acid in H2O) on a YMC ODS Guardpak column to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.10-7.30 (mn, 10 H), 6.95 (m, 1 H), 6.89 (d, 2 H), 6.55 (m, 2 H), 6.43 (s, 1 H), 6.26 (d, 1 H), 5.15 (br.s, 1 H), 4.00-4.20 (m, 4 H), 3.96 (t, 2 H), 3.68 (s, 3 H), 3.55 (m, 2 H), 2.90 (s, 3 H), 2.30 (s, 3 H); MS (ESI+) m/z 590 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1[S:49](Cl)(=[O:51])=[O:50]>O1CCCC1.O>[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1[S:49]([N:5]1[C:6]([C:7]2[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]1)(=[O:51])=[O:50]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2c(F)cccc2F)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (664 mg) was added dropwise, and the mixture was stirred for 5 min. 2,6-Difluorobenzenesulfonyl chloride (320 mg) was added, and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:4→2:3) to give the title compound as a colorless oil (yield 430 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([C:18]2[C:25](F)=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[F:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[K].Cl.[O:31]1CCCC1>O>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([C:18]2[C:25]([OH:31])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[F:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: N#Cc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [K]
Solvent: O
Product: N#Cc1cc(O)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3,5-difluorobenzonitrile (522 mg, 1.28 mmol) and potassium trimethylsilonate 90% (655 mg, 4.60 mmol) are combined in 8 ml anhydrous tetrahydrofuran and stirred under nitrogen at room temperature for 2 hours. The precipitated potassium salt of was collected by filtration, washed with a minimum of tetrahydrofuran, and dried in vacuo. A portion of this salt (275 mg, 0.618 mmol) was dissolved in 5 ml water, the pH was adjusted below 6 with concentrated hydrochloric acid, the product collected by filtration, washed with water, sucked dry under a blanket of dry nitrogen, and dried further in vacuo overnight (251 mg, 100%, 98% overall). 1H-NMR (400 MHz, DMSO-d6) δ 11.46 (br s, 1H), 7.74 (d, J=7.81 Hz, 1H), 7.67 (quartet, J=6.76 Hz, 1H), 7.52 (d, J=8.76, 1H), 7.364, (dt, J=10.18, 2.37 Hz, 1H), 7.24 (br s, 1H), 7.17 (br t, J=8.75, 1H), 6.74 (d, J=8.04 Hz, 1H), 5.39 (s, 2H). 19F-NMR (400 MHz, DMSO-d6) δ −109.26 (quintet, J=8.50 Hz, 1F), −113.52 (quartet, J=9.29 Hz, 1F), −118.06 (d, J=9.38 Hz, 1F). LC/MS tr=5.13 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes, then 95% acetonitrile for 2 minutes, at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 407 (M+H). ES-HRMS m/z 407.0381 (M+H calcd for C19H11ClF3N2O3 requires 407.0405).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(O)cc1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: COc1ccc(Oc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 4-methoxyphenol according to the procedure described in Example 74 to afford 2-(4-methoxyphenyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=457 (M++1); Rt=4.50 min; 1H-NMR 500 MHz (CDCl3): δ 3.85 (s, 3H), 6.95 (d, J=9 Hz, 2H), 7.05. (d, J=9 Hz, 2H), 7.21 (d, J=9 Hz, 2H), 7.25-7.30 (m, 4H), 7.39 (d, J=2 Hz, 1H), 8.60 (s, 1H).
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[C:28](Cl)(=[O:33])[CH:29]=[CH:30][CH2:31][CH3:32]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:33])[CH:29]=[CH:30][CH2:31][CH3:32])[CH2:24][CH2:23]2)[N:9]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CCC=CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC=CC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.33 h
Yield: 50.3 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.78 g of 2-pentenoyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from ethanol, to give 1.23 g of the desired Compound No. 5 in the form of pale brown needles melting at 246°-247° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[NH:9][CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:12].Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][N:9]3[C:5]4[C:6](=[O:8])[CH2:7][N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]=4[CH:11]=[CH:10]3)[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: CN1CC(=O)c2[nH]ccc2S1(=O)=O
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CC(=O)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Yield: 79.7 %

Procedure:
A suspension of 200 mg (1 mmol) of Compound 12, 385 mg (1.5 mmol) of 1-(3-chloropropyl)-4-(4-fluorophenyl) piperazine and 207 mg (1.5 mmol) of potassium carbonate in 15 ml of 2-butanone was refluxed for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent:chloroform), whereby 335 mg of the title compound were obtained yield: (80%).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[C:7]([O:11][C:12]([N:14]([C:22]1[C:27]([C:28]#[C:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[N:26][C:25]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:24][N:23]=1)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C>CN(C=O)C>[C:7]([O:11][C:12]([N:14]([C:22]1[C:27]([C:28]#[C:29][Si:30]([CH3:31])([CH3:33])[CH3:32])=[N:26][C:25]([N:34]2[CH2:35][CH2:36][N:37]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:38][CH2:39]2)=[CH:24][N:23]=1)[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1C#C[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CCN(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C#C[Si](C)(C)C)n2)CC1
Reaction time: 0.08 h
Yield: 109.3 %

Procedure:
Ethanesulfonyl chloride (147.0 mg, 108.3 μL, 1.143 mmol) was added slowly to a stirred solution of tert-butyl N-tert-butoxycarbonyl-5-(piperazin-1-yl)-3-((trimethylsilyl)ethynyl)pyrazin-2-ylcarbamate (494 mg, 1.039 mmol) and DIPEA (161.2 mg, 217.3 μL, 1.247 mmol) in DMF (5 mL) at ambient temperature. The reaction was allowed to stir for 5 minutes and then partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (3×) and the combined organics washed with brine, dried (MgSO4), filtered and concentrated to give the product as a terracotta oil (645 mg, quantitative yield). MS (ES+) 590.05
Reaction SMILES: F[C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:23]=[C:24]([C:26]1[CH:27]=[CH:28][C:29]([CH3:44])=[C:30]([NH:32][C:33]([C:35]2[N:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]3=[N:37][CH:36]=2)=[O:34])[CH:31]=1)[NH2:25]>CN1C(=O)CCC1>[F:9][CH:2]1[CH2:3][CH:4]([C:6]2[O:8][N:23]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH3:44])=[C:30]([NH:32][C:33]([C:35]4[N:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]5=[N:37][CH:36]=4)=[O:34])[CH:31]=3)[N:25]=2)[CH2:5]1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: O=C(O)C1CC(F)(F)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC(F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 3,3-difluorocyclobutanecarboxylic acid (264 mg, 1.94 mmol) in anhydrous NMP (6 mL) was added 1,1′-carbonyldiimidazole (315 mg, 1.94 mmol). The reaction was stirred for 5 minutes. 5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (500 mg, 1.62 mmol) was added and the reaction was stirred for 25 minutes, then heated in the microwave at 120° C. for 12 minutes. The crude product was purified by silica chromatography to give N-(5-(5-(3-fluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F13). 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 9.53-9.50 (m, 1H), 8.70 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.90-7.87 (m, 1H), 7.83 (d, J=1.6, 8.0 Hz, 1H), 7.70-7.65 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.33-7.29 (m, 1H), 3.93-3.84 (m, 1H), 3.25-3.02 (m, 4H), 2.37 (s, 3H). MS m/z 410.3 (M+1)+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].O.[Br:11][C:12]([CH3:17])([CH3:16])[C:13](Br)=[O:14]>C(Cl)(Cl)Cl>[Br:11][C:12]([CH3:17])([CH3:16])[C:13]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC(C)(N)C(=O)O
Reactant: CC(C)(Br)C(=O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(Br)C(=O)NC(C)(C)C(=O)O
Temperature: -10 °C
Reaction time: 15 h
Yield: 33.3 %

Procedure:
A stirring mixture of 2-aminoisobutyric acid (28.5 g, 0.28 mol), sodium hydroxide (11.1 g, 0.28 mol), 115 mL of water, and 30 mL of chloroform was cooled to −10° C. and stirred vigorously while a solution of 2-bromisobutyryl bromide (57.0 g, 0.25 mol) in 85 mL of chloroform was added dropwise. When addition was complete, the reaction flask was removed from the cold bath and allowed to warm to room temperature. The mixture stirred for 15 hours. Concentrated HCl (10 mL) was then added to the mixture and stirring was continued for another 30 minutes. A white solid (32.0 g) was filtered off, and the aqueous and organic phases of the filtrate were separated. The organic phase was dried over magnesium sulfate, filtered, and evaporated at reduce pressure to leave a white solid (21.0 g). The two solid portions were combined and recrystallized from toluene to afford 27.1 g (43%) of the title compound as a white solid with IR and NMR spectra consistent with the desired product.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=2[N:29]=1>>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:25]([NH:2][C:3]3[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=3)[CH2:6][NH:7][C:8]3[C:17]4[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][N:9]=3)[S:26][C:27]=2[CH:33]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: COc1ccc2nc(Cl)sc2c1
Agent: Cl
Product: COc1ccc2nc(Nc3cccc(CNc4ncnc5c(C(N)=O)cccc45)c3)sc2c1

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-6-methoxy-benzothiazole:
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([C:10](=[O:18])[CH:11]([CH3:17])[CH2:12][S:13]C(=O)C)[CH2:8][CH2:7][S:6]1)=[O:4].[OH-].[Na+]>CO>[SH:13][CH2:12][CH:11]([CH3:17])[C:10]([N:9]1[CH2:8][CH2:7][S:6][CH:5]1[C:3]([OH:4])=[O:2])=[O:18]
Reactant: COC(=O)C1SCCN1C(=O)C(C)CSC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CS)C(=O)N1CCSC1C(=O)O
Temperature: 25 °C

Procedure:
3-(3-Acetylthio-2-methylpropanoyl)-2-thiazolidinecarboxylic acid methyl ester (2.9 g.) is dissolved in methanol (30 ml.) and N sodium hydroxide (30 ml.) is added. The reaction mixture is stirred at room temperature, aliquots are withdrawn every hour and checked by paper electrophoresis for the hydrolysis of the methyl ester. When this hydrolysis is completed (ca. three hours), the reaction mixture is neutralized, concentrated in vacuo to eliminate methanol, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to yield 3-(3-mercapto-2-methylpropanoyl)-2-thiazolidinecarboxylic acid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Br:12][CH2:13][C:14](Cl)=[O:15]>>[Br:12][CH2:13][C:14]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)=[O:15]
Reactant: O=C(Cl)CBr
Reactant: CNc1ccc([N+](=O)[O-])cc1
Product: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-methylamino-nitrobenzene and bromoacetyl chloride
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([OH:23])[CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:22][CH2:21][CH:20]([OH:23])[C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1ccc(C)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: c1ccccc1
Product: Cc1ccc(CCC(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
A mixture of 4-(4-Methylphenyl)butan-2-one (1.62 g) and 2-(3-chlorophenyl)-2-hydroxyethanamine (1.71 g) was refluxed in benzene under Dean & Stark conditions for 4 h. The solvent was removed under reduced pressure, replaced with methanol (100 ml) and sodium borohydride (2 g) added portionwise. The solvent was evaporated under reduced pressure, the residue partitioned between water and ether and the ether layer dried (MgSO4). Removal of the solvent gave an oil which was chromatographed on Kieselgel 60. Elution with 1% methanol-chloroform gave the title compound as an 11:89 mixture of diastereoisomers, mp 75-106 (hexane).