Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[CH2:20]([Li])CCC.CI>C1COCC1>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:3]1[C:2]([CH3:20])=[C:6]([C:7]([F:10])([F:9])[F:8])[N:5]([CH3:11])[N:4]=1
Reactant: Cn1nc(-c2cc(F)ccc2F)c(Br)c1C(F)(F)F
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(-c2cc(F)ccc2F)nn(C)c1C(F)(F)F
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 10 g of 4-bromo-3-(2,5-difluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 250 mL anhydrous THF was cooled to -78° C. and stirred with an overhead stirrer. The cold solution was treated with 12 mL of 2.5M n-butyllithium in hexanes never allowing the temperature to exceed -70° C. After stirring for 5 minutes, 1.9 mL of methyl iodide was added quickly. The cooling bath was removed and the solution allowed to warm to room temperature. The solution was diluted with diethyl ether and the combined organic extracts were washed twice with brine, dried over anhydrous magnesium sulfate and concd in vacuo. Chromatographic purification (silica, 5% ethyl acetate in hexanes) gave 5.8 g (72.4%) of 3-(2,5-difluorophenyl)-1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazole as an oil; 1HNMR (CDCl3) δ 2.0 (quintet, 3H, J=2.1 Hz), 3.9 (d, 3H, J=1.2 Hz), 6.9-7.1 (m, 3H). Anal. Calcd for C13H9F5N2: C, 52.18; H, 3.28; N, 10.14. Found: C, 52.20; H, 3.30; N, 10.11.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=1[C:41]([F:44])([F:43])[F:42]>>[C:37]([C:36]1[CH:39]=[CH:40][C:33]([NH:32][C:8](=[O:10])[CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[C:34]([C:41]([F:42])([F:43])[F:44])[CH:35]=1)#[N:38]
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)Nc2ccc(C#N)cc2C(F)(F)F)C2CCCCC2)c(OC)n1

Procedure:
The title compound was prepared in analogy to example 22, int. d) from cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acid and 4-amino-3-trifluoromethylbenzonitrile. The crude product was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile and water (containing 0.5% formic acid). Light brown foam (19%). MS (TS) (M+H+)+: 600.3.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CS(O[CH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: CS(=O)(=O)OCCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC1CC1
Yield: 49.1 %

Procedure:
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.64 mmol), sodium carbonate (844 mg, 7.9 mmol) and 2-cyclopropylethyl methanesulfonate (1.19 g, 7.3 mmol) were stirred in dimethylformamide (25 ml, dry) for two days at 80° C. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with hydrochloric acid (2N), brine, dried (MgSO4) and then evaporated to dryness. The crude product was triturated with ether and the solid collected by filtration to afford the title compound as a white solid (0.96 g, 49%). m/z 295 [MH+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:18])([F:19])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NCC(F)(F)F
Yield: 79 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.81 ml (0.013 mol) of triethylamine, 1.1 ml (0.013 mol) of 2,2,2-trifluoroethylamine in 30 ml of DMF were reacted at 40° C. for 48 hours affording 4.71 g of oil. This oil was kugelrohr distilled at 53 Pa, pot temperature 110°-120° C. to give 2.82 g (47.3%) of product as a yellow oil, nD25 1 4496.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[S:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].CS(O[CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[Br:40])(=O)=O>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[S:17][C:16](=[O:18])[N:15]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[CH:32][C:31]=3[Br:40])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)S[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)OCc1cc(C(F)(F)F)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)SC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one (50 mg, 0.152 mmol) in THF (1 ml) was added NaH (7.59 mg, 0.190 mmol) at −20° C. 30 Minutes later, a solution of 2-bromo-5-(trifluoromethyl)benzyl methanesulfonate (50.6 mg, 0.152 mmol) in THF (0.5 ml) was added. Stirring of the reaction continued for 1 hour. A crude NMR spectrum showed only 25% product formation. The reaction temperature was increased to −10° C., and stirring was continued for another 1 h. The reaction mixture was left in the freezer under N2 atmosphere overnight. NMR and LCMS indicated around a 65% conversion to the desired isomer, with no undesired epimerized product. The reaction was cooled to −10° C., and additional NaH (2.429 mg, 0.061 mmol) was added. Stirring of the reaction mixture was continued for 20 minutes. 2-Bromo-5-(trifluoromethyl)benzyl methanesulfonate (20.2 mg, 0.061 mmol) was added, and the reaction was continued for another 2 hours at −10° C. The reaction mixture was quenched with ice water, and the mixture was diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by PTLC by using 35% EtOAc in hexane. 1H NMR (500 MHz, CDCl3): δ 7.90 (s, 1H); 7.85 (s, 2H); 7.76 (d, J=8.3 Hz, 1H); 7.59 (s, 1H); 7.48 (d, J=8.5 Hz, 1H); 5.15 (d, J=7.0 Hz, 1H); 5.02 (d, J=16.0 Hz, 1H); 4.45 (d, J=16.0 Hz, 1H); 4.10-4.11 (m, 1H); 0.97 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:28]([O:30]C)=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO>[C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)SCC1(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-phenylalanine, methyl ester (158 mg, 0.36 mmol) in methanol (3 mL). Add a solution of lithium hydroxide hydrate (1 mL in water, 1 mmol) and stir at room temperature under argon overnight. Partition between 1N hydrochloric acid and methylene chloride. Separate the organic phase and extract the acidic phase with methylene chloride (2×10 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo to give the title compound (149 mg, 97%).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1>O1CCCC1.C(Cl)Cl>[CH3:1][NH:2][S:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To 20 ml of a 2 molar solution of methylamine in tetrahydrofuran chilled in an ice bath was added a solution of 5.16 g of 4-(4-chlorophenyloxy)benzene-sulfonyl chloride in 50 ml of tetrahydrofuran and 20 ml of CH2Cl2. The mixture was refluxed for 2 hours and the solvent removed under vacuum and the residue partitioned between CH2Cl2.H2O (1:1). The CH2Cl2 layer was separated and washed with 2 N citric acid, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2Cl2. The filtrate was concentrated to give 4.5 g of N-methyl-4-(4-chlorophenoxy)benzene-sulfonamide as a yellow solid, m.p. 80-83° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:34])[N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:33]=[CH:32][C:19]3[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=3[CH:17]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:11]=[C:2]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:3]3=[O:34])[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: OB(O)c1ccccc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(Br)cc4ccccc43)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(-c4ccccc4)cc4ccccc43)ccc21
Temperature: 25 °C
Yield: 68.4 %

Procedure:
7-[3-(3-Bromo-2-oxo-2H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.5 g), phenylboronic acid(0.12 g), tetrakis(triphenyl phosphine)palladium (0) (0.11 g), and potassium carbonate(0.39 g) were added to dioxane(5 ml). The mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane=1:1→3:1). The purified product was condensed to dryness under reduced pressure, thereby obtaining the title compound(0.34 g) as a white amorphous solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][CH3:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>C(Cl)Cl>[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([N:24]([C:2]2[O:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH3:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: CN[C@@H]1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(c1nc2ccc(Cl)cc2o1)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 0.5 g (2.6 mmol) 2,6-dichloro benzoxazole, 0.68 g (3.58 mmol) ((R)-1-benzyl-pyrrolidin-3-yl)-methyl-amine and 0.4 g (4 mmol) NEt3 in 12 mL DCM was stirred over night at room temperature. DCM was added and the mixture was washed with NaHCO3 aq., dried with MgSO4 and evaporated to dryness to yield the title compound as yellow oil which was used in the consecutive step without further purification. (MH+) 342.1
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.[OH-].[Na+].C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[N:10]([CH3:11])[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[CH:5][C:6]=2[N:12]=1
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21

Procedure:
Prepared analogously to example 113a from 3-amino-4-methylamino-benzoic acid methyl ester and 1,3-dichloro-2-isothiocyanato-benzene with DCC in DMF and NaOH in ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.O(N(C)[C:16](=[O:18])[CH3:17])C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:16]([C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: Brc1cncnc1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1cncnc1
Temperature: -78 °C
Yield: 40.9 %

Procedure:
5-Bromopyrimidine (3.18 g, 20 mmol) was dissolved in 50 mL of tetrahydrofuran. While cooled to −78° C., 15 mL of 1.6 M n-butyllithium in hexane solution was added dropwise with stirring. After the solution was stirred for 30 minutes, a solution of N-methoxyl-N-methylacetamide (2.58 g, 25 mmol) in tetrahydrofuran solution (10 mL) was added slowly. The mixture was stirred at −78° C. for 1 hour and then allowed to be warmed slowly. When the temperature of the mixture was at 0° C., aqueous ammonium chloride solution was added. The solution obtained was extracted with ethyl acetate for 3 times. The pooled extracts were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using 5% methanol/methylene chloride as eluent to obtain 1 g of the title compound (45% yield). MS (M+1)=123.05.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[S:29]>C1COCC1>[NH2:3][C:4]1[C:8]([NH:9][C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([F:19])([F:30])[F:31])=[S:29])=[CH:7][S:6][CH:5]=1
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: Nc1cscc1N
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1cscc1NC(=S)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.8 g of 3,4-diaminothiophene dihydrobromide was added to a mixture of 0.74 g of N-ethyl-N,N-diisopropylamine in 40 ml of anhydrous THF, and the mixture was stirred at room temperature for 10 minutes, and then admixed with 0.58 g of 2-trifluoromethylphenyl isothiocyanate. The mixture was stirred at room temperature for 3 hours and at 40° C. for a further 10 minutes, and left to stand at room temperature overnight. After the solvent had been distilled off, the residue was admixed with water and extracted with ethyl acetate, and the insoluble fraction was filtered off. The organic phase was washed with water and dried over sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography on silica gel using a mixture of 1 part by volume of toluene and 1 part by volume of ethyl acetate.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=O)[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[K+].Cl.[NH2:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1.N1C=CC=CC=1>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[N:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Reactant: CC(C)(C)OC(=O)CON
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
Ethyl (2-formamido-5-chlorothiazol-4-yl)glyoxylate (14.5 g) was added to a solution of 1 N aqueous potassium hydroxide (110 ml) at ambient temperature, and the mixture was stirred for 10 minutes to prepare the solution of potassium (υ-formamido-5-chlorothiazol-4-yl)glyoxylate. After this solution was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling, thereto were added pyridine (20 ml) and a solution of tert-butyl 2-aminooxyacetate (10.3 g) in tetrahydrofuran (50 ml), followed by stirring at ambient temperature for 5 hours. After the reaction mixture was washed with ethyl acetate, the remaining aqueous solution was adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave 2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (8.5 g), mp 166° to 167° C. (dec.).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([SH:10])=[CH:3][CH:2]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>S(=O)(=O)(O)O>[F:11][C:12]1[C:17]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[S:10][C:16]=2[C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Product: O=c1c2ccccc2sc2c(O)ccc(F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a solution of 2-thiosalicylic acid (39.32 g, 255 mmol) in concentrated sulfuric acid (700 ml) was added 4-fluorophenol (32.0 g, 280 mmol). The red solution was then stirred at room temperature for 18 hours. Upon completion, the mixture was poured directly onto 4 liters of crushed ice and the resulting red solid was filtered off, and then suspended in water (1 L)and treated with ammonia solution until pH 6 attained whereupon the precipitate was re-filtered to give the title compound as an orange solid (44.48 g, 70.8%) m/z (LC-MS, ESP): 247 [M+H]+, R/T=3.99 mins
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=2[O:23]1>>[O:23]1[C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]4[CH2:14][CH2:13][CH2:12][C@H:11]4[CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:9])=[C:4]([F:21])[CH:3]=3)=[CH:28][C:29]=2[O:30][CH2:22]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2ccc3c(c2)OCO3)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3,4-Methylenedioxybenzene boronic acid. MS (M+H) 397.2
Reaction SMILES: Br[C:2]1[C:3]([Cl:20])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>CCO>[Cl:20][C:3]1[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][N:6]=[C:5]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=12
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(Br)cnc21
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(-c3ccccc3)cnc21
Temperature: 80 °C
Yield: 87.1 %

Procedure:
5-Bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri dine (3.70 g, 9.96 mmol, see Example 6) and phenylboronic acid (1.27 g, 10.5 mmol) were placed in 2:1 toluene:EtOH (30 mL). The contents were then degassed under Ar and heated to 80° C. for 24 hours. The reaction was cooled to room temperature, diluted with DCM, and poured into water. The organic fraction was filtered, dried, and concentrated. Purification was carried out by column chromatography (1:1 to 1:2 hexane:DCM) to give 4-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.20 g, 87.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5](Cl)[CH:6]([OH:9])[CH2:7][CH3:8].[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1.O.Cl>C(O)CCC>[OH2:4].[ClH:1].[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH:6]([OH:9])[CH2:7][CH2:8][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCC(O)C(Cl)Oc1ccccc1Cl
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: OC(CCC1NCCc2ccccc21)COc1ccccc1Cl

Procedure:
A mixture of 11.8 g. (0.05 mole) of 1-(2-chlorophenoxy)-2-hydroxybutyl chloride, 13.3 g. (0.1 mole) of 1,2,3,4-tetrahydroisoquinoline and 100 ml. of n-butanol was heated in a steel bomb at 120° C. for 24 hr. The reaction mixture was filtered at room temperature, the filtrate was mixed with 200 ml. 3N hydrochloric acid and extracted twice with 100 ml. isopropyl ether. The aqueous acidic solution was made basic and extracted with isopropyl ether and treated with ethereal hydrogen chloride. Recrystallization with isopropanol yielded 6 g. of the hydrochloride hydrate of the product which melted at 118°-120° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2=[O:21].Br[CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][O:26][CH3:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:9][O:8][C:7]1[C:2]([O:1][CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][O:26][CH3:27])=[C:3]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:4]=[CH:5][C:6]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: COCC(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Temperature: 100 °C

Procedure:
Compound 303 (0.02 g, 0.07 mmol) and 1-bromo-3-methoxy-2,2-dimethyl-propane (0.12 g, 0.56 mmol) were dissolved in dry DMF (0.8 mL). K2CO3 (0.1 g, 0.68 mmol) were added. The suspension was heated at 100° C. for 18 h. H2O was added and the mixture was extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC afforded the title compound as an oil.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13](OCC)=[O:14].[Na].O>C(OCC)C>[CH:13]([CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:1]([O:10][CH2:11][CH3:12])=[O:9])=[O:14]
Reactant: CCOC=O
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(C=O)C(=O)OCC
Reaction time: 17 h

Procedure:
A mixture of diethyl succinate (26.1 g, 25.0 mL, 0.150 mol) and ethyl formate (I1.1 g, 12.1 mL, 0.150 mol) was added drop wise over 1.5 hours to a stirred suspension of sodium (3.40 g, 0.150 mol) in diethyl ether (120 mL) at 0° C. under nitrogen. On completion of addition, stirring was continued at room temperature for 17 hours. Water (120 mL) was cautiously added to the resulting suspension and stirring continued until all the solids were dissolved. The layers were separated and the aqueous layer was washed with diethyl ether (100 mL). The aqueous layer was then acidified to pH 5 using 11 N HCl and extracted with diethyl ether (3×100 mL), the ethereal extracts of the acidified layer were combined, dried (Na2SO4) then evaporated to dryness under reduced pressure to give the title compound (I105) (16.5 g) as a yellow mobile liquid. The crude product was not purified further and was used directly in the following step.