Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:17][CH2:16][C:10]3([CH2:14][NH:13][C:12](=[O:15])[CH2:11]3)[CH2:9][CH2:8]2)[CH:6]=1.[H-].[Na+].[CH3:20]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:17][CH2:16][C:10]3([CH2:14][N:13]([CH3:20])[C:12](=[O:15])[CH2:11]3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: CI
Reactant: O=C1CC2(CCC(n3cc(Br)cn3)CC2)CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC2(CCC(n3cc(Br)cn3)CC2)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro[4.5]decan-3-one (mixture of intermediate 30 and 31 obtained in step 5; 4 g, 13.4 mmol) in DMF (10 mL) was added sodium hydride (60%) (0.8 g, 0.0116 mol) followed by methyl iodide (2.2 mL, 14.8 mmol) at 0° C. The reaction mixture was slowly allowed to warm to RT and stirred for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic phases were washed with water (50 mL) and brine (50 mL), dried over sodium sulphate, filtered and concentrated. Purification by flash chromatography on silica (Pet. ether: ethyl acetate) afforded the title compound (mixture of two isomers) as an off white solid (1.8 g, 43%). 1H NMR (400 MHz, DMSO-d6) δ 8.04-8.03 (m, 1H), 7.51-7.50 (m, 1H), 4.16-4.10 (m, 1H), 3.24 (s, 1H), 3.09 (s, 1H), 2.70-2.69 (m, 3H), 2.21 (s, 1H), 2.09 (s, 1H), 1.90-1.86 (m, 6H), 1.79-1.54 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[O:20])=[CH:14][CH:13]=3)=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([N+:29]([O-])=O)=[CH:4][N:3]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:2]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[O:20])=[CH:14][CH:13]=3)=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([NH2:29])=[CH:4][N:3]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3c(C)sc4c([N+](=O)[O-])cnc(N)c34)cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(NC(=O)Nc2ccc(-c3c(C)sc4c(N)cnc(N)c34)cc2)c1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A suspension of Example 66E (0.44 g, 1.01 mmol), NH4Cl (0.054 g, 1.01 mmol), and iron powder (0.45 g, 8.1 mmol) in ethanol (16 mL) and water (4 mL) was heated at 80° C. for 3 hours, cooled to room temperature, and filtered through diatomaceous earth (Celite®). The pad was washed with ethyl acetate and ethanol and the filtrate was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), flitered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 0.15 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.29 (s, 3H), 4.48 (s, 2H), 4.59 (s, 2H), 6.80 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25–7.29 (m, 3H), 7.30 (s, 1H), 7.31 (s, 1H), 7.60 (d, J=8.81 Hz, 2H), 8.67 (s, 1H), 8.86 (s, 1H); MS (ESI(+)) m/e 404 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=[O:2].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:2]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1[nH]c2ccccc2c1C=O
Temperature: 15 °C
Reaction time: 16 h

Procedure:
3-Formylindole (10.0 g, 69 mmoles) was dissolved in DMF (100 ml). Under N2 was a 60% suspension of NaH in mineral oil (3.0 g) added in portions with cooling (temp<15° C.). At <15° C. was a solution of ethyl bromoacetate (8.4 ml) in DMF (15 ml) added drop wise over 30 minutes. The resulting mixture was stirred at room temperature for 16 hours and evaporated in vacuo. The residue was added water (300 ml) and extracted with ethyl acetate (2×150 ml), the combined organic extracts were washed with satd. NH4Cl, dried (MgSO4) and concentrated to afford 15.9 g ethyl (3-formylindolyl)acetate.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C@H:15]2[CH2:17][C@@H:16]2[CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[CH2:20]([O:19][CH2:18][C@H:16]1[CH2:17][C@@H:15]1[C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[N:11][CH:12]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(COC[C@H]2C[C@@H]2c2cncc(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cncc([C@H]2C[C@@H]2COCc2ccccc2)c1
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of 3-(benzyloxy)-5-[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]pyridine (210 mg, 608 μmol) in EtOAc (10 mL) and methanol (5.0 mL) was added 10% palladium on carbon (42 mg). The atmosphere was exchanged with H2 (3 times), and the mixture was stirred under H2 for 4 h. The resulting mixture was filtered through a cotton plug, and the filtrate was concentrated and azeotroped with toluene (3×5 mL) to give 5-[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]-3-pyridinol as a light-yellow oil (131 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCc2ccc(Cl)c(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3-Fluoro-4-hydroxybenzaldehyde (400 mg, 2.85 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (680 mg, yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[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:27]([CH3:31])([CH3:30])[C:28]#[N:29])=[CH:23][C:22]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[C:36](Cl)([Cl:38])=[O:37]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:35])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:36]([Cl:38])=[O:37])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([C:28]#[N:29])([CH3:30])[CH3:31])=[CH:23][C:22]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, 2-{4-[rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-phenyl}-2-methyl-propionitrile (example 17) was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClC(Cl)C>[C:1]1([C:7]2[CH:8]=[N+:9]([O-:24])[CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1cncc(-c2ccccc2)c1
Solvent: CC(Cl)Cl
Product: O=C(O)c1cc(-c2ccccc2)c[n+]([O-])c1
Reaction time: 15 h
Yield: 37 %

Procedure:
Preparation H10, Step 1: 5-Phenylnicotinic acid (50 mg) was dissolved in dichloroethane (2 ml) prior to the addition of 77% mCPBA (250 mg). The reaction was stirred for 15 h and then it was concentrated, filtered, and purified by reverse phase HPLC (gradient elution, water/acetonitrile/TFA) to afford 5-phenylnicotinic acid N-oxide (20 mg). MS found: (M+H)+=216.1.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]([O:30][C:31]([O:33][CH:34](I)[CH3:35])=[O:32])([CH3:29])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:34]([O:33][C:31]([O:30][CH:27]([CH3:29])[CH3:28])=[O:32])[CH3:35])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)OC(=O)OC(C)I
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)OC(=O)OC(C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 81.3 %

Procedure:
In the same manner as in Example 81, 137 mg of the title compound was prepared from 133 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 41 and 110 mg of 1-(isopropyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].[O:20]1CCN(CCOC2C=CC(C(=O)CCC)=CC=2)CC1>>[O:20]1[CH2:2][CH2:1][N:3]([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[CH:11][CH:12]=2)[CH2:18][CH2:19]1
Reactant: CCCC(=O)c1ccc(OCCN2CCOCC2)cc1
Reactant: CCCC(N)c1ccc(OCCN(CC)CC)cc1
Product: CCCC(N)c1ccc(OCCN2CCOCC2)cc1
Yield: 70 %

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 25 except that 1-(4-(2-morpholinoethoxy)phenyl)butan-1-one (24) was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-one (21). This produced crude 28 (390 mg, 70%) as a light yellow oil: MS (ES+) m/z 279.2 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[C:9]=1[CH3:25].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[S:15][CH2:14][C:10]1[C:9]([CH3:25])=[C:8]([S:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][N:11]=1)(=[O:35])[CH3:34]
Reactant: Cc1c(SCc2ccco2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1c(SCc2nccc(SCc3ccco3)c2C)nc2ccccc21
Temperature: 20 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
2-{[[4-(2-Furylmethylthio)-3-methyl-2-pyridinyl]methyl]thio}-1H-benzimidazole (5.0 mmol) is suspended in anhydrous methylene chloride (50 ml), triethylamine (11 mmol and acetyl chloride (8 mmol) are added and the mixture is stirred at 20° C. for 20 h. The clear reaction solution is washed with sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated and the residue is crystallized by addition of diisopropyl ether. The title compound is obtained as a colorless powder; m.p. 168-169° C. (decomp.); yield: 97% of theory.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22](OC)=[O:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH3:28]>CO>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]([NH2:28])=[O:23])=[CH:21][C:13]2=3)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Solvent: CO
Product: NC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Reaction time: 72 h
Yield: 100 %

Procedure:
A solution of methyl 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (500 mg, 1.243 mmol) in 7 M NH3 in MeOH (10 mL) was heated to 60° C. and stirred at that temperature for 72 h. The solvent was removed under reduced pressure to provide 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide (481 mg, 1.243 mmol, 100% yield) as a white solid. LCMS (+ESI) m/z=388.1 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22]O)[CH:21]=1)[C:9]2([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH2:22][Cl:3])[CH:21]=1)[C:9]2([CH3:25])[CH3:24]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(CO)c1
Solvent: ClCCl
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(CCl)c1
Temperature: 3.5 °C
Reaction time: 2 h
Yield: 116.3 %

Procedure:
Thionyl chloride (1.4 mL, 19.0 mmol) was added slowly at 0° C. to a solution of 5-chloro-2-(5-hydroxymethyl-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (1.14 g, 3.8 mmol) in DCM (50 mL). After the addition, the reaction mixture was stirred at 2-5° C. for 2 hours before it was poured into satd. aq. NaHCO3 solution (50 mL) and extracted with EtOAc (2×150 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (1.42 g, 92%) as a light yellowish solid. MS: 322.1 (M+H+).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:26][C:19]1[CH:18]=[C:17]2[C:16](=[C:25]3[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]3)[NH:15][S:12](=[O:13])(=[O:14])[C:3]1[C:2]2=[CH:7][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c(N)c1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 11.1 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(5-chloro-quinolin-8-yl)-4-methanesulfonyl-benzenesulfonamide (Intermediate 274) (205 mg, 0.5 mmol), t-butyl nitrite (0.09 ml, 0.75 mmol), AcOH (4 ml) and THF (4 ml) gave the title compound (22 mg, 16%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:9]=1.[C:19](=[O:21])=[O:20].CC(C)=O>CCOCC>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2cccs2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCOCC
Product: COc1ccc(-c2ccc(C(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 6.3 mL of n-butyllithium (2.5 M solution in hexane) in 50 mL of dry ether is added a solution of 3.0 g (15.8 mmol) of 2-(4-methoxyphenyl)thiophene in 20 mL of dry ether under N2 atmosphere. The mixture is stirred at room temperature for 3 hours and then heated at reflux for 30 minutes. After the reaction mixture is cooled to -78° C. with dry ice and acetone bath, dry CO2 gas is bubbled through the reaction mixture for 3 hours and the resulting solution is stirred at room temperature overnight. The reaction mixture is diluted with 200 mL of chloroform, washed with 1% HCl solution (200 mL) and with water (2×200 mL). The separated organic layer is dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1.8 g (50%) of 5-(4-methoxyphenyl)-2-thienoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]#[N:26])[CH:20]=[CH:21][C:22]=1[Cl:23].N>O1CCOCC1.Cl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:24][C:25]1[NH:26][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(Cc3ccc(Cl)c(Cl)c3)nc2c1
Reaction time: 48 h

Procedure:
420 Milligrams of dimethyl aminoterephthalate and 446 mg of 3,4-dichlorophenylacetonitrile were added to 10 mL of 4N hydrogen chloride dioxane solution and stirred for about 2 days. Pouring the reaction mixture into ice, its pH was adjusted to 8-9 with 25% aqueous ammonia. The precipitated crystals were recovered by filtration and washed with water. The crude crystals were dissolved in chloroform-ethyl acetate (1:1) mixed solvent, and after removing the insoluble matter by filtration, the remaining solution was concentrated. The residue was purified on silica gel column chromatography (hexane:ethyl acetate=4:1) to provide 253 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:20])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccc(F)cc1
Temperature: 35 °C
Yield: 99 %

Procedure:
Into a suitable reactor is charged 4-fluorophenylacetic acid (122.5 kg, 795 mol), N,N-dimethylformamide (0.37 kg, 5.1 mol), and toluene (490 kg). Oxalyl chloride (105.2 kg, 829 mol) is added at a rate to maintain the temperature at about 35° C. The solution is stirred for at least 7 hours at about 25° C., typically affording a solution of about 22.1 wt % 4-fluorophenylacetyl chloride (99% yield as determined by HPLC assay).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>CN1CCCC1=O>[CH2:10]([NH:16][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: N#Cc1ccnc(Cl)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCCCNc1cc(C#N)ccn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
2-Chloro-4-cyanopyridine (0.40 g, 2.9 mmol) was dissolved in N-methylpyrrolidone (2.0 ml), and hexylamine (1.15 ml, 8.7 mmol) was added thereto. The reaction mixture was stirred at 100° C. for 4 hrs, combined with water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel (50 g) column chromatography, eluted with hexane-ethyl acetate (3:1, v/v) to give the titled compound (0.26 g, 46%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:29])([F:28])[F:30])[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.265 g, 0.99 mmol), tetrakis(triphenyl-phosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (220 mg, 43%). MS (ISP) 576.3 [(M+H)+]; mp 252° C.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:12])=[CH:6][CH:5]=1
Reactant: Cc1ccc(OC(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)Oc1ccc(CBr)cc1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
270 g of 4-difluoromethoxytoluene in 800 ml of CCl4 were initially introduced and 300 g of N-bromo-succinimide were added. After adding a pinch of azobisisobutyronitrile, the mixture was heated to the reflux temperature. After 8hours, it was cooled, the insoluble succinimide was filtered off and the residue on the filter was washed with CCl4. The carbon tetrachloride was distilled off from the reaction solution and the crude product was purified by fractional distillation. 250 g of 4-difluoromethoxy-benzyl bromide were obtained. Boiling point=82°-5° C./0.4 mm Hg; nD20 =1.5200.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O:7][C:8](=[O:14])[C:9](OCC)=[O:10])[CH3:6]>C(Cl)Cl>[OH:2][CH2:1][CH2:3][NH:4][C:9](=[O:10])[C:8]([O:7][CH2:5][CH3:6])=[O:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: NCCO
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCCO
Temperature: -70 °C
Reaction time: 16 h

Procedure:
To a mixture of 500 parts ethanolamine in methylene chloride (900 ml), cooled to -70° C., was added dropwise 2405 parts diethyloxalate. After stirring at room temperature for 16 hours, the mixture was filtered, concentrated and purified by chromatography to yield pure ethyl 2-hydroxyethyloxamate. A mixture of the oxamate (77 parts), sodium carbonate (50.2 parts) and an inhibitor in chloroform were cooled to 0° C. and acryloylchloride (43.3 parts) was added dropwise. After stirring at 0° C. for 2 hours and room temperature for 3 hours the mixture was filtered to yield 1011 parts crude ethyl N-2-ethyloxamatoacrylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:32]([F:35])([F:33])[F:34])[CH:24]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccccc1CSc1ccc(Cl)cc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 37.3 %

Procedure:
Following General Procedure B, the title compound (936 mg, 37%) was prepared from methyl 2-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (1.41 g, 4.56 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.3 g, 4.56 mmol) in pyridine (10 ml).