Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][C:27]=4[F:29])=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(F)cc4F)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 2,4-difluorophenylboronic acid (136 mg, 0.86 mmol) the subtitle compound was obtained, (57 mg, 26%). 1H NMR (DMSO) δ 8.71(d, 1H), 8.53(dd, 1H), 8.01(s, 1H), 7.97(d, 1H), 7.70(m, 3H), 7.48(dt, 1H), 7.30(dt, 1H), 4.12(s, 3H). MS 383 m/z (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:3]1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCl

Procedure:
In analogy to the procedure described for example 1 b], [2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol (example 3 b]) was reacted with thionyl chloride in chloroform to yield 5-chloromethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([O:12][C@H:13]3[C@H:17]4[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]4[O:15][CH2:14]3)[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]2=[N:6][C:7]=1I.[CH3:30][N:31]([CH3:56])[C:32](=[O:55])[O:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:30][N:31]([CH3:56])[C:32](=[O:55])[O:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([C:7]3[N:6]=[C:5]4[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:10]([O:12][C@@H:13]5[CH2:14][O:15][C@@H:16]6[C@H:20]([OH:21])[CH2:19][O:18][C@H:17]56)=[N:11][C:4]4=[CH:3][C:2]=3[Cl:1])=[CH:42][CH:41]=2)[CH2:36][CH2:35]1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Reactant: CN(C)C(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CN(C)C(=O)OC1CCN(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-iodo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl dimethylcarbamate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=1.04 min; Mass spectrum (ESI+): m/z=674 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)[N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[C@H:29]([CH3:39])[CH2:30][O:31]CC2C=CC=CC=2)=[CH:2]1.B(Cl)(Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=3)[N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[C@H:29]([CH3:39])[CH2:30][OH:31])=[CH:2]1
Reactant: C[C@H](COCc1ccccc1)n1cnc2c(NCCc3c[nH]c4ccccc34)nc(-c3cncc(F)c3)nc21
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[C@H](CO)n1cnc2c(NCCc3c[nH]c4ccccc34)nc(-c3cncc(F)c3)nc21

Procedure:
A solution of (R)—N-(2-(1H-indol-3-yl)ethyl)-9-(1-(benzyloxy)propan-2-yl)-2-(5-fluoropyridin-3-yl)-9H-purin-6-amine (b) (0.15 g, 0.29 mmol) in DCM (10 ml) was treated with BCl3 (1M, 2.9 ml, 2.9 mmol) in DCM (10 ml) at −78° C. for 2 hr. 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated and the residue was purified by silica gel column chromatography (5% MeOH in DCM eluant) to provide the title compound. MS m/z 432.2 (M+1).
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C>[S:15]([O:11][CH2:10][C:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])([CH3:13])[CH3:12])(=[O:17])(=[O:16])[CH3:14]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
N-Boc-2-Amino-2-methylpropanol is dissolved in triethylamine under argon at 0° C. Methanesulfonyl chloride is added and the mixture is stirred overnight. The solution is poured into 10% aqueous citric acid and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered and evaporated to give N-Boc-2-amino-2-methyl-1-propyl mesylate.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH:25]=[C:26]([I:28])[CH:27]=2)[C:10]=1[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])C.[OH-].[Na+]>>[C:38]([CH2:37][CH2:36][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH:25]=[C:26]([I:28])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:43])=[O:3])([OH:40])=[O:39]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Yield: 90.5 %

Procedure:
A similar procedure as described in Example 12, step 9 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3′-fluoro-5-iodo-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (2.23 g, 3.17 mmol) and aqueous 1.0 N sodium hydroxide (31.65 mL) to obtain 4-{2-(2-carboxy-ethyl)-3-[6-(3′-fluoro-5-iodo-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (1.86 g, 91%) as a light yellow oil: ES(+)-HRMS m/e calculated for C31H34FIO6 (M+Na)+ 671.1276, found 671.1271.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([F:12])([F:11])[F:10])=[C:4]([F:13])[CH:3]=1.Cl.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[N:23][CH:24]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.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:13][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[C:19]([CH:20]=2)[C:17]([O:16][CH3:15])=[O:18])[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([F:12])([F:11])[F:10]
Reactant: COC(=O)c1cncc(B(O)O)c1
Reactant: Fc1cc(Br)ccc1CC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cncc(-c2ccc(CC(F)(F)F)c(F)c2)c1
Reaction time: 0.17 h

Procedure:
A solution of 6.78 g (23.7 mmol, purity 90%) of the compound from Example 74A in toluene (339 ml) was admixed under argon at RT with 7.74 g (35.6 mmol) of the compound from Example 29A in ethanol (112 ml) and 3.61 g (26.1 mmol) of potassium carbonate. After stirring for 10 min, 2.74 g (2.37 mmol) of tetrakis(triphenylphosphine)palladium and then 4.14 g (71.2 mmol) of potassium fluoride in water (71 ml) were added. The mixture was stirred under reflux for 8 h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane, dichloromethane/methanol 150:1→100:1). The product fractions were concentrated under reduced pressure and the solid obtained was purified by stirring with diethyl ether. Yield: 6.00 g (50% of theory, purity 62%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]2[O:11][CH2:10][O:9][CH2:8][CH2:7][C:6]=2[CH:12]=1.C([Li])CCC.[CH:20](N1CCOCC1)=[O:21].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:14][O:13][C:4]1[C:5]2[O:11][CH2:10][O:9][CH2:8][CH2:7][C:6]=2[CH:12]=[C:2]([CH:20]=[O:21])[CH:3]=1
Reactant: O=CN1CCOCC1
Reactant: COc1cc(Br)cc2c1OCOCC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)cc2c1OCOCC2
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a solution of 420 mg of 2-bromo-4-methoxy-8,9-dihydro-5,7-dioxa-benzocycloheptene in 10 ml of THF there was added dropwise 0.7 ml of n-butyllithium (2.66 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −70° C. for 10 minutes, 0.5 ml of N-formylmorpholine was added and the temperature was raised from −70° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (235 mg) as an oil.
Reaction SMILES: Cl.C(ON)C.C(N(CC)CC)C.C(=O)=O.C[Si](C)(C)Cl.[CH3:21][Si:22]([O:25][C:26](=[O:35])[N:27]([O:32][CH2:33][CH3:34])[Si](C)(C)C)([CH3:24])[CH3:23]>C(OCC)C>[CH3:24][Si:22]([O:25][C:26](=[O:35])[NH:27][O:32][CH2:33][CH3:34])([CH3:21])[CH3:23]
Reactant: CCON(C(=O)O[Si](C)(C)C)[Si](C)(C)C
Agent: CCON
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCONC(=O)O[Si](C)(C)C

Procedure:
49 g (0.5 mole) of ethoxyamine hydrochloride and 151.5 g (1.5 mole) of triethylamine in 250 ml of dry diethyl ether is treated with carbon dioxide in the same apparatus and same conditions as described in Example 1a. After the carbon dioxide uptake has been finished, 108.5 g (1 mole) of trimethylchlorosilane is added to the reaction mixture over 1.5 hours under vigorous stirring. Following the same procedure as in Example 1a., a mixture of N-ethoxy,N-trimethylsilylcarbamic acid trimethylsilyl ester and N-ethoxycarbamic acid trimethylsilyl ester is obtained. Distillation under reduced pressure give 28.3 g (0.16 mole, 32%; b.p.: 42-45° C./2.5 mbar) of N-ethoxycarbamic acid trimethylsilyl ester and 72.1 g (0.29 mole, 58%; b.p.: 87-91° C./2.5 mbar) of N-ethoxy,N-trimethylsilylcarbamic acid trimethylsilyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:47](#[N:50])[CH:48]=[CH2:49].Cl>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C.CCN(CC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](/[CH:49]=[CH:48]/[C:47]#[N:50])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#C/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 100 °C
Yield: 74 %

Procedure:
A sealed tube was charged with N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example 5 (0.76 g), Pd(OAc)2 (0.0070 g), P(o-tolyl)3 (0.033 g), acrylonitrile (0.14 mL), NEt3 (0.59 mL), and DMF (4 mL). The tube was capped tightly and heated at 100° C. overnight behind a blast shield. The reaction was cooled to room temperature and poured into 20 mL 1N HCl. The resulting solid was filtered, dissolved in hot EtOH, and adsorbed onto silica. Chromatography on a Biotage Flash 40S column (eluent 1.5% MeOH:CH2Cl2 (2 L) followed by 2.5% MeOH:CH2Cl2 (1 L) and 3% MeOH:CH2Cl2 (1 L)) afforded the desired product as a tan solid (0.47 g, 74%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](=[O:18])[C:9]2[S:19][CH:20]=[CH:21][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH2:22]([Mg]Br)[CH3:23].[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH:1]([O:4][C:5]([N:7]1[CH:12]([CH2:22][CH3:23])[CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10](=[O:18])[C:9]2[S:19][CH:20]=[CH:21][C:8]1=2)=[O:6])([CH3:2])[CH3:3]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1cn(C(=O)OC(C)C)c2ccsc2c1=O
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)c2sccc2N(C(=O)OC(C)C)C1CC
Temperature: -78 °C
Yield: 93 %

Procedure:
Mix 7-oxo-7H-thieno[3,2-b]pyridine-4,6-dicarboxylic acid 6-ethyl ester 4-isopropyl ester (0.512 g, 1.66 mmol) and copper(I) iodide (0.695 g, 3.65 mmol) in THF (35 ml). Cool the mixture to −78° C. Inject ethyl magnesium bromide (3.0 M in diethyl ether, 1.66 ml) and stir for 1.5 h. Add another portion of ethyl magnesium bromide (3.0 M in diethyl ether, 3.30 ml) and keep the reaction at −78° C. for one more hour. Warm up to −20° C. overnight in a freezer. Pour the reaction mixture into saturated ammonium chloride solution (200 ml). Extract with ethyl acetate (3×200 ml). Combine all the organic layers, dry over Na2SO4, filter and concentrate to give 5-ethyl-7-oxo-6,7-dihydro-5H-thieno[3,2-b]pyridine-4,6-dicarboxylic acid 6-ethyl ester 4-isopropyl ester (0.520 g, 93%) as a crude oil. MS (ES+): 340 (M+H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH2:12][OH:13])[CH:11]=1)[N:8](COCC[Si](C)(C)C)[N:7]=[CH:6]2.FC(F)(F)C1C=C2C(=C(C=O)C=1)N(COCC[Si](C)(C)C)N=C2.[BH4-].[Na+]>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2
Reactant: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CO)c21
Agent: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(C=O)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1cc(C(F)(F)F)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(5-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methanol To a solution of 5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carbaldehyde (1 g, 2.9 mmol) in ethanol (15 mL) at 0° C. was added sodium borohydride (0.055 g, 1.45 mmol). The ice bath was removed and stirring continued for 15 min. The reaction was cooled to 0° C. and quenched by addition of saturated ammonium chloride. The reaction was concentrated to remove most of the ethanol and poured into diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 0.985 g (98%) as an oil which solidified upon standing. 1H-NMR (CDCl3, 500 MHz) δ 8.08 (s, 1H), 8.00 (s, 1H), 7.57 (d, J=1.2 Hz, 1H), 5.96 (s, 2H), 5.07 (s, 2H), 3.53 (m, 2H), 3.34 (bs, 1H), 0.85 (m, 2H), −0.08 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 139.0, 135.1, 125.9, 125.3, 124.52 (q, J=272 Hz), 124.51, 124.2 (q,J=33 Hz), 119.3, 80.1, 66.7, 62.6, 17.8, −1.5.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24](Cl)[CH3:25].Cl>C1(C)C=CC=CC=1.O.C(OC)(C)(C)C>[CH3:23][N:24]([CH3:25])[C:3](=[O:4])[C:2]([CH3:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: CN(C)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Dissolve 2-methyl-2-phenyl-propionic acid (15.08, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition over 5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, a 40% aqueous solution of dimethylamino hydrochloride (20 mL, 0.18 mol) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer over (Na2SO4), filter, evaporate the filtrate in vacuo and purify by crystallization to give 2-methyl-2-phenyl-propionic acid, dimethylamide (15.35 g, 88%) as a white solid; mp 57-59° C.
Reaction SMILES: [CH2:1]([C:4]#[C:5][SiH:6]([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[CH:2]=[CH2:3].[CH2:13]([Mg]Br)C=C>>[CH2:13]=[C:1]([C:4]#[C:5][SiH:6]([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:8])[CH3:9])[CH2:2][CH3:3]
Reactant: C=CCC#C[SiH](C(C)C)C(C)C
Reactant: C=CC[Mg]Br
Product: C=C(C#C[SiH](C(C)C)C(C)C)CC

Procedure:
This material was synthesized by methods identical to those used to prepare allyldiisopropylsilyl acetylene (Example 1), simply substituting 2-lithio-1-butene (generated in situ by treating 2-bromo-1-butene with n-BuLi in tetrahydrofuran at −78° C.) for allyl magnesium bromide. 1H-NMR (200 MHz, CDCl3) δ=5.76 (q, J=1.2 Hz, 1H), 5.55 (quint, J=1.2 Hz, 1H), 2.41 (s, 1H), 1.06 (br. s, 14H), 2.19 (q, t, J=9.5, 1.2 Hz, 2H), 1.10 (t, J=9 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][O:9][C:8]=2[C:18]([O:20]C)=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C>O>[C:1]1([C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][O:9][C:8]=2[C:18]([OH:20])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1occ(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1occ(-c2ccccc2)c1-c1ccccc1
Yield: 54.8 %

Procedure:
Methyl 3,4-diphenyl-2-furancarboxylate (10.00 g) and sodium hydroxide (1.73 g) in a mixed solution of ethanol (20 ml) and water (20 ml) were heated at reflux for 3 hours while stirring. After evaporating the solvent under reduced pressure, 1 M hydrochloric acid was added, and the thus-precipitated crystals were filtered, thereby giving 5.20 g of the desired compound.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18]>>[OH:18][C@@H:17]([C:16]([CH3:20])([CH3:19])[CH3:15])[C@@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: CC(C)(C)C=O
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@@H](O)C(C)(C)C

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolone with trimethylacetaldehyde. Rapid addition of the aldehyde to the enolate solution at 0° C. gave a 1:1 ratio of the (2R*,3S*) and (2R*,3R*) isomers. The desired isomer was isolated by silica gel chromatography, then crystallized. 1H-NMR (CDCl3, 400 MHz) δ 8.05 (m, 1H), 7.20-7.27 (m, 4H), 4.24 (dq, J=7,4 Hz, 1H), 3.82 (br t, J=4 Hz, 1H), 2.33 (br d, J=4 Hz, 1H), 1.36(d, J=7 Hz, 3H), 0.99, (s, 9H). 13C-NMR (CDCl3, 100 MHz) δ 175.3, 150.8, 142.2, 127.9, 125.4, 124.9, 116.2, 109.9, 77.6, 40.3, 35.8, 29.7, 26.7, 12.7.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][NH2:25]>>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:14]1[CH:19]=[CH:18][C:17]([NH:25][CH3:24])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CNc1ccc([C@@](C)(NC(=O)OC(C)(C)C)C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 1b from (R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-propionic acid and methylamine.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[S:7]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:7]1[CH:11]=[CH:10][C:9]([C:2]2[N:3]=[CH:4][NH:5][CH:6]=2)=[CH:8]1
Reactant: OB(O)c1ccsc1
Reactant: Ic1c[nH]cn1
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: O
Solvent: COCCOC
Product: c1nc(-c2ccsc2)c[nH]1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 4-iodo-1H-imidazole (0.24 g, 1.25 mmol) and Pd(PPh3)4 (72 mg, 0.06 mmol) in DME (12.5 mL) was degased by purging with argon for 10 min. Thiophene-3-boronic acid (0.32 g, 2.50 mmol) and Na2CO3 (2.5 mL of a 2M solution in water) were added. The mixture was heated to reflux for 18 h. After cooling to RT, the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (4% MeOH/CH2Cl2, silica gel) to give 0.16 g of the desired product as an off-white solid. MS(ES+) m/z 151.3 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].CO[C:11]([CH3:13])=[CH2:12].S(=O)(=O)(O)O>CC(C)=O>[CH3:4][C:3]1([CH2:7][OH:8])[CH2:5][O:6][C:11]([CH3:13])([CH3:12])[O:1][CH2:2]1
Reactant: C=C(C)OC
Reactant: CC(CO)(CO)CO
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1(CO)COC(C)(C)OC1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
1,1,1-Tris(hydroxymethyl)ethane (120.2 g) and 2-methoxypropene (75.0 g) were suspended in acetone (300 ml). After adding one drop of cone, sulfuric acid at 0° C., the mixture was stirred for 1 hour and then at room temperature for additional 2 hours. After distilling off the acetone, a fraction obtained under reduced pressure (1.7 mmHg) at 70° C. was collected to give (1,4,4-trimethyl-3,5-dioxanyl)methan-1-ol (155.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[N:6][C:5]([Cl:10])=[C:4]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:3]=1.[CH2:20]([NH2:23])[CH2:21][CH3:22]>>[Cl:10][C:5]1[N:6]=[C:7]([CH:8]=[N:23][CH2:20][CH2:21][CH3:22])[C:2]([NH2:1])=[N:3][C:4]=1[S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCN
Reactant: CCCCCCCCSc1nc(N)c(C=O)nc1Cl
Product: CCCCCCCCSc1nc(N)c(C=NCCC)nc1Cl

Procedure:
Following the procedures described above in Example 6, Step B, but employing instead 2-amino-5-chloro-3-formyl-6-(n-octylthio)pyrazine (100 mg; 0.342 mMol) prepared in Example 8, Step A, and n-propylamine (25 mg; 0.342 mMol and 20% excess), the title compound was prepared. Elemental Analysis for C16H27N4SCl
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:23]C(=O)O[C:20]2=O)=[CH:15][CH:14]=1.C[O-].[Na+].CO>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:23])[C:20]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][CH:7]=3)[N:1]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Reactant: O=C1OC(=O)C(c2ccc(F)cc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(O)nc(C(O)c3ccc(F)cc3)nc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 2-amino-4-methylbenzamide (3 g, 20.0 mmol) in THF (40 mL) was added 5-(4-fluorophenyl)-1,3-dioxolane-2,4-dione from Example 16 (4.7 g, 24 mmol) and the solution was stirred for 2 h at 50° C. Sodium methoxide in MeOH (25%, 5.2 mL, 24 mmol) was then added and the solution was stirred at 50° C. overnight. The reaction mixture solution was concentrated, 2N HCl was added and the mixture was filtered. The collected solid was dried to give 2-((4-fluorophenyl)(hydroxy)methyl)-7-methylquinazolin-4-ol (5.14 g, 91%) which was used without further purification. LC-MS (ESI) m/z 285 (M+H)+.