Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:41])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:41])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2cccc3[nH]ccc23)cc1Cl
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To the suspension of 4-(3-chloro-4-fluoro-phenyl)-1H-indole (2.03 g, 8.26 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (99 mL) was added pyridinium tribromide (7.93 g, 24.79 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (40 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (1.39 g, 64%) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-].[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:1][O:13][C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: Cc1cc[n+]([O-])c(C)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1cc(C)ccn1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 29.8 %

Procedure:
Acetic anhydride (30 mL) was added to 2,4-dimethyl-pyridine 1-oxide (1.93 g, 15.7 mmol) described in Manufacturing Example 11-1-1, and the mixture was stirred for 10 minutes at 110° C. The reaction solution was allowed to room temperature and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (774 mg, 29.8%).
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:18])/[CH2:16][OH:17])=[CH:10][CH:9]=1.C(Br)C=C>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([O:17][CH2:16]/[C:15](/[CH3:18])=[CH:14]/[C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)[CH:2]=[CH2:1]
Reactant: C/C(=C\c1ccc(C)cc1)CO
Reactant: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCOC/C(C)=C/c1ccc(C)cc1
Temperature: 5 °C
Yield: 95 %

Procedure:
Solid potassium tert-butylate (47 g, 0.411 mol) was added portion-wise to a solution of E-3-(4-methylphenyl)-2-methyl-2-propen-1-ol (68.05 g, 0.420 mol) in dry THF (800 ml) at room temperature under nitrogen (exothermic to 30° C.). After 1 more hour at room temperature, the reaction was cooled to 5° C. and tetra butyl ammonium iodide (7.9 g, 0.021 mol) was added followed by allyl bromide (102.65 g, 0.840 mol) drop-wise. The reaction was warmed up to room temperature overnight and poured onto water (800 ml). The reaction was extracted twice with ethyl acetate. Each organic phase was washed with water and brine. Combined extracts were dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with diethyl ether and the solvents were removed under vacuum. The product was purified by distillation under vacuum through a 20-cm Widmer column. 79 g of the desired product were obtained (yield=93%). B.P.=82° C./0.001 mbar
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[C:13]([O-])([O-])=O.[Cs+].[Cs+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: O=C1NCc2c(Br)ccc(O)c21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(Br)c2c1C(=O)NC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
A solution of Example 106D (103 mg, 0.45 mmol) in DMF (4 mL) was treated with Cs2CO3 (162 mg, 0.5 mmol) and methyl iodide (0.03 mL, 0.48 mmol), stirred at room temperature for 3 hours, then poured into water. The resulting precipitate was filtered to give 76 mg (70%) of the desired product. MS (ESI(+)) m/e 242,244 (M+H)+.
Reaction SMILES: C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.Cl.CO[C:17]1[CH:41]=[CH:40][C:20]([C:21]([NH:34][CH2:35][CH2:36][NH:37][CH:38]=[O:39])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.COC1C=CC(C(NCCNC=O)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(Cl)Cl.CO>[C:21]([NH:34][CH2:35][CH2:36][NH:37][CH:38]=[O:39])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:19]=[CH:18][CH:17]=[CH:41][CH:40]=1
Reactant: COc1ccc(C(NCCNC=O)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(C(NCCNC=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CO
Solvent: ClCCl
Product: O=CNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
C22H22N2O (330.42); RF=0.87 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl vapour); 2-(4-monomethoxytrityl)aminoethylformamide; C23H24N2O2 (360.46); RF=0.86 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl vapour); 1H NMR (CDCl3, 250.133 MHz):=1.70 (br s, 1 H); 2.32 (tr, 2H, J=6.0 Hz); 3.37 (m, 2H); 3.76 (s, 3H); 5.99 (br s, 1H); 6.78-7.49 (m, 14H); 8.17 (s, 1H). 13C NMR (CDCl3, 62.896 MHz):=38.7 (CH2); 43.1 (CH2); 55.2 (CH3); 70.2 (C); 113.2 (CH); 126.4 (CH); 127.9 (CH); 128.3 (CH); 129.7 (CH); 137.8 (C); 145.9 (C); 158.0 (C); 164.7 (CHO). 2-(4,4′-dimethoxytrityl)aminoethylformamide; C24H26N2O3 (390.49); RF=0.92 (DCM/MeOH 5:1, v/v); spot stains with ninhydrin spray or with HCl).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:44]1[N:45]=[C:46]([NH:49][CH:50]=[O:51])[S:47][CH:48]=1)[C:5]([NH:7][CH:8]1[C:42](=[O:43])[N:10]2[C:11]([C:26]([O:28]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:27])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6].FC(F)(F)C([O-])=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:44]1[N:45]=[C:46]([NH:49][CH:50]=[O:51])[S:47][CH:48]=1)[C:5]([NH:7][CH:8]1[C:42](=[O:43])[N:10]2[C:11]([C:26]([OH:28])=[O:27])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(NC=O)n1
Agent: O=C([O-])C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 4 h

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate.trifluoroacetate (syn isomer)(1.4 g) in methylene chloride (30 ml) were added anisole (1.4 ml) and trifluoroacetate acid (1.83 ml) with stirring under ice-cooling and the stirring was continued for 4 hours at 5° C. The reaction mixture was evaporated and the residual oil was pulverized in diethyl ether, collected by filtration and then dried to give 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylic acid.trifluoroacetate (syn isomer)(1.1 g).
Reaction SMILES: [SH3+].[I-].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:20](=[O:37])[NH:21][C@H:22]1[CH2:31][CH2:30][C:25]2([O:29][CH2:28][CH2:27][O:26]2)[CH2:24][C@H:23]1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:15][CH2:16][S+](C)C)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>[Cl-].[Na+].O.C(OCC)(=O)C>[CH2:3]([O:10][C:11]([NH:13][C@H:14]1[CH2:15][CH2:16][N:21]([C@H:22]2[CH2:31][CH2:30][C:25]3([O:29][CH2:28][CH2:27][O:26]3)[CH2:24][C@H:23]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:20]1=[O:37])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1NC(=O)[C@H](CC[S+](C)C)NC(=O)OCc1ccccc1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N1CC[C@H](NC(=O)OCc3ccccc3)C1=O)OCCO2

Procedure:
Example 1, Alternative Preparation, Step 2: Sulfonium salt 3 (619.4 g), and cesium carbonate (416.8 g) and anhydrous dimethyl sulfoxide (6.2 L) were combined in a reactor equipped with a scrubber to neutralize volatile sulfides. Vigorous agitation was maintained until complete conversion was obtained (HPLC). Ethyl acetate (12.4 L) was added, followed by 20% brine (3 L). The organic phase was separated, washed twice with brine (2×3 L) and evaporated to obtain a solution of ethyl (7R,8S)-8-((S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4 in ethyl acetate (˜0.8 L). Acetone (2.55 L) was added, followed by aqueous 0.5 M hydrochloric acid solution (2.3 L). With good mixing, the solution was heated to 50 to 60° C. until conversion of 4 to ethyl (1R,2S)-2-((S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-oxo-cyclohexanecarboxylate 5 was complete (HPLC). The mixture was concentrated under reduced pressure while below 40° C., cooled to ˜30° C., and water (4.1 L) was added. The resulting slurry was cooled to 5 to 10° C. and agitated for ˜1 hour. The product was filtered and the cake was washed with water (2×2.5 L). Upon deliquoring, the cake was dried to a constant weight below 40° C. in a vacuum oven. Cyclohexanone 5 (272 g, 70% yield) was obtained (HPLC purity 98.7%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1)=[O:33]
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(SC)nc32)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(S(C)=O)nc32)c1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 84.4 %

Procedure:
At 0° C., to a suspension of N-(3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11a) (450 mg, 1.33 mmol) in 25 mL of DCM was added MCPBA (319 mg of 77% max. from Aldrich, 1.42 mmol). After the reaction mixture was stirred at 0° C. for 35 min, it was diluted with 100 mL of DCM, washed with 20 mL of ice cold sat Na2CO3 solution. The DCM layer was dried over Na2SO4 and concentrated to give N-(3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11b) (398 mg, 84% yield) as an off white crystalline solid. The crude material was used in next step without further purification. m/z (ESI, +ve ion) 355.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) 6 ppm 10.36 (1H, s), 9.30 (1H, s), 8.20 (1H, d, J=9.6 Hz), 7.76 (1H, m), 7.69 (1H, m), 7.51 (1H, t, J=8.0 Hz), 7.06 (1H, d, J=7.6 Hz), 6.94 (1H, m), 6.45 (1H, dd, J=16.9, 10.1 Hz), 6.26 (1H, d, J=16.8 Hz), 5.79 (1H, m), 2.72 (3H, s)
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]2=[O:15])[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[O:15]=[C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][N:8]1[CH:5]1[CH2:6][CH2:7][CH:2]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:3][CH2:4]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(n2cc(Cl)ccc2=O)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(Cl)ccc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-(4-oxo-cyclohexyl)-5-chloro-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]1=O.O=S(Cl)Cl>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=c1ncc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: c1ccc2ncncc2c1
Temperature: 80 °C

Procedure:
Quinazolone Z.8 (817 mg, 3.36 mmol) is combined with SOCl2 (20 mL) and DMF (0.05 mL) and heated to 80° C. for 2 h. The solvent is removed and quinazoline D*.3 (879 mg, 100%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24](C(C)(C)C)=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.C[Al](C)C.C(OC(=O)C1C=CC([Br:49])=CC=1OCC)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:49][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:34])[N:9]=2)=[C:22]([O:31][CH2:32][CH3:33])[CH:23]=1
Reactant: CCOC(=O)c1ccc(Br)cc1OCC
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1cc(Br)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
To a solution of meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (3 g, example 1) in toluene cooled to 0° C. was added dropwise 2 M solution of trimethylaluminum in toluene (5.33 mL, 10.66 mmol). After the addition, the mixture was stirred at 0° C. for 15 min then the ice bath was removed. After 30 min, the mixture was warmed up to 80-100° C. for about 30 min before being slowly cooled down to room temperature. At room temperature, a solution of 4-bromo-2-ethoxy-benzoic acid ethyl ester (3.18 g, 11.64 mmol) in toluene (10 mL) was added, and the yellow reaction mixture was heated at reflux for 48 h. Upon cooling to room temperature, 1 M Rochelle solution (˜20 mL) and ethyl acetate (˜50 mL) were added. The biphasic mixture was stirred rigorously at room temperature for 3 h. The layers were separated and the aqueous layer was extracted with ethyl acetate (1×100 mL). The combined organic layers were washed with saturated solution of sodium bicarbonate (1×20 mL), brine (1×20 mL), dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated to dryness. Purification of the crude residue by flash chromatography (120 g of silica gel, eluting with 5-10%, 20%, 40% then 80% ethyl acetate in hexane) gave the title compound as light yellow foam (3.25 g, 65%). HR-MS (ES, m/z) calculated for C25H24N2OCl2Br [(M+H)+] 517.0444, observed 517.0443.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([OH:14])=O)[CH:4]=[CH:3][N:2]=1.[Br:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH2:21])[S:19][CH:20]=1>>[Br:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH:21][C:12](=[O:14])[CH2:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[CH:1]=[N:2][CH:3]=[CH:4]3)[S:19][CH:20]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1cccc2ccncc12
Product: O=C(Cc1cccc2ccncc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-8-yl)acetamide was prepared from 2-(isoquinolin-8-yl)acetic acid (53 mg, 0.286 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (35 mg, 0.143 mmol) according to protocol A. Retention time (min)=1.769, method [7], MS(ESI) 414.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 9.84 (bs, 1H), 8.55 (bs, 1H), 8.41 (d, J=6.0 Hz, 1H), 8.26-8.23 (m, 2H), 8.18 (dd, J=8.1, 7.2 Hz, 1H), 7.99 (d, J=4.0 Hz, 1H), 7.09 (s, 1H), 4.61 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15](O)=[O:16])[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:67][O:68][C:69](=[O:78])[C@H:70]([CH2:72][CH2:73][C:74]([O:76][CH3:77])=[O:75])[NH2:71].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:71][C@@H:70]([CH2:72][CH2:73][C:74]([O:76][CH3:77])=[O:75])[C:69]([O:68][CH3:67])=[O:78])=[O:16])[S:14][C:7]=12
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC[C@H](NC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1)C(=O)OC
Temperature: 60 °C

Procedure:
To a stirred suspension of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous tetrahydrofuran were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was heated at 60° C. for 10 minutes, followed by addition of L-glutamic acid dimethyl ester hydrochloride (55 mg, 0.26 mmol). The mixture was heated at 60° C. for another 20 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give dimethyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate as white solid. Yield: 126 mg, 94%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:14][NH2:15])=[N:4][N:3]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1nnc(Cl)c2ccccc12
Temperature: 25 °C

Procedure:
10 g commercially available dichlorophthalazine are added portionwise at 90° C. to a solution of 50 ml ethanol and 20 ml hydrazine hydrate. After 10 min the reaction mixture is cooled to ambient temperature, the precipitate is filtered with suction and rinsed with ethanol to yield 8.4 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9](C(C3C=CC=CC=3)O)=[CH:10][C:5]=2[N:4]=[CH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2cc(C(O)c3ccccc3)ccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1cnc2ccccc21
Reaction time: 4 h

Procedure:
A mixture of 5.6 parts of 1-methyl-α-phenyl-1H-benzimidazole-5-methanol, 4.05 parts of 1,1'-carbonylbis[1H-imidazole] and 54 parts tetrahydrofuran was stirred for 4 hours at reflux temperature. The tetrahydrofuran layer was evaporated and water was added to the residue. The decanted oil was dissolved in dichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (93:7 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was washed with 2,2'-oxybispropane and dried, yielding 2.9 parts (42.9%) of 5-[1H-imidazol-1-yl)phenylmethyl]-1-methyl-1H-benzimidazole; mp. 138.7° C. (comp. 21).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:10]([NH:13][C:14](=[O:24])[O:15][CH:16]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:3]>[OH-].[Pd+2].[OH-]>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]([C:10]([NH:13][C:14](=[O:24])[O:15][CH:16]2[CH:21]3[CH2:20][CH2:19][N:18]([CH2:23][CH2:22]3)[CH2:17]2)([CH3:11])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: C=C(C)c1cccc(C(C)(C)NC(=O)OC2CN3CCC2CC3)c1
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)c1cccc(C(C)(C)NC(=O)OC2CN3CCC2CC3)c1
Yield: 33.2 %

Procedure:
Using general procedure F, 1-azabicyclo[2.2.2]oct-3-yl {2-[3-(prop-1-en-2-yl)phenyl]propan-2-yl}carbamate (48.8 mg, 0.146 mmol) and palladium hydroxide (30 mg, 20 wt. % on carbon) gave the title compound as an off-white solid (16 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=5.1 Hz, 3H), 7.10 (d, 1H), 5.12 (s, 1H), 4.63 (s, 1H), 3.54-2.96 (m, 1H), 2.89 (s, 1H), 2.68 (s, 5H), 2.17-1.75 (m, 2H), 1.67 (s, 6H), 1.62-1.30 (m, 2H), 1.24 (d, J=6.9 Hz, 6H), 1.15-0.85 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 149.1, 128.5, 124.9, 123.1, 122.5, 55.8, 55.6, 46.6, 34.5, 25.6, 24.6, 24.3, 19.7 ppm. Purity: 94% UPLCMS (210 nm); retention time 0.89 min; (M+1) 331.1.
Reaction SMILES: [O:1]=[C:2]([C:10]([F:13])([F:12])[F:11])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([C:10]([F:11])([F:12])[F:13])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)C(O)C(F)(F)F

Procedure:
To a solution of ethyl 3-keto-2-methyl-4,4,4-trifluorobutanoate (20.1 g, 0.10 moles) in 250 ml of absolute ethanol, cooled in an ice bath, was added sodium borohydride (1.0 g, 0.25 moles) in portions with stirring. The cooling bath was removed and the reaction stirred at room temperature for 30 minutes. Acetone (5 ml) was added to quench any remaining sodium borohydride and the solvents removed by distillation at atmospheric pressure using a Vigreaux column. The residue was diluted with 200 ml of methylene chloride and poured into a separatory funnel containing 75 ml of a 1:1:1 mixture of saturated ammonium chloride:brine:water. The layers were separated and the aqueous phase extracted with methylene chloride (3×25 ml). The combined organic phase and methylene chloride extracts were dried over magnesium sulfate, filtered and distilled at atmospheric pressure to remove the solvents. The residue was then distilled at reduced pressure (20 mmHg) using a Vigreaux column to give ethyl 3-hydroxy-2-methyl-4,4,4-trifluorobutanoate, bp 78°-84° C., 20 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:27])(=[O:26])[NH:20][C:21]4[S:22][CH:23]=[CH:24][N:25]=4)=[CH:15][CH:14]=3)[N:9]([CH2:28][C:29]([OH:31])=O)[N:8]=2)=[CH:4][CH:3]=1.C[N:35](C)C=O.C(Cl)Cl.C(Cl)(=O)C(Cl)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([S:19](=[O:27])(=[O:26])[NH:20][C:21]4[S:22][CH:23]=[CH:24][N:25]=4)=[CH:17][CH:18]=3)[N:9]([CH2:28][C:29]([NH2:35])=[O:31])[N:8]=2)=[CH:32][CH:33]=1
Reactant: CN(C)C=O
Reactant: O=C(O)Cn1nc(Cc2ccc(Cl)cc2)cc1Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)Cn1nc(Cc2ccc(Cl)cc2)cc1Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reaction time: 1 h

Procedure:
2-(3-(4-Chlorobenzyl)-5-(4-(N-thiazol-2-ylsulfamoyl)phenylamino)-1H-pyrazol-1-yl)acetic acid (30 mg, 0.00006 mol) was dissolved in N,N-Dimethylformamide (0.4 uL, 0.000005 mol) and methylene chloride (0.2 mL, 0.003 mol). Oxalyl chloride (7.6 uL, 0.000089 mol) was added and the reaction stirred 1 hour. The reaction was quenched by pouring it into 1.0 mL satd. ammonium hydroxide solution, neutralized with 1.0 N HCl, and extracted 2× with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to give the desired product, which was lyophilized from acetonitrile-water to provide a yellow powder.