Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[CH:6]1([S:9]([C:12]2[CH:17]=[CH:16][C:15](/[C:18](=[CH:22]\[CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)/[C:19](O)=[O:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:8][CH2:7]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:6]1([S:9]([C:12]2[CH:13]=[CH:14][C:15](/[C:18](=[CH:22]\[CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)/[C:19]([N:4]([O:3][CH3:2])[CH3:5])=[O:20])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH2:8][CH2:7]1
Reactant: O=C(O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.9 %

Procedure:
To a solution of N-methoxymethanamine hydrochloride (350 mg) in N,N-dimethylformamide (10 mL) was added triethylamine (500 μL), and the mixture was stirred at room temperature for 30 min. (2E)-2-[4-(Cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propan-2-enoic acid (1.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (860 mg) and 1-hydroxybenzotriazole (600 mg) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated to give a crude product (1.15 g) of the title compound as colorless crystals. MS: 380 (MH+).
Reaction SMILES: C1OC2C=CC(CN)=CC=2O1.Cl[C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21](Cl)=[C:20](C)[S:19][C:17]=2[N:18]=1>>[N:18]1[C:17]2[S:19][CH:20]=[CH:21][C:16]=2[CH:15]=[N:14][CH:13]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Agent: NCc1ccc2c(c1)OCO2
Product: c1ncc2ccsc2n1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine gives 2,5-dichloro-6-methyl-4-93,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]([C:15]([F:18])([F:17])[F:16])([C:11]([F:14])([F:13])[F:12])[C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]([C:15]([F:18])([F:17])[F:16])([C:11]([F:14])([F:13])[F:12])[C:8]([Cl:23])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Cl)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Yield: 88.7 %

Procedure:
A mixture of 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid (161 mg.), thionyl chloride (200 mg.), dimethylformamide (20 mg.) and light petroleum (2 ml. b.p. 40°-60° C.) is heated under reflux for 15 minutes and the solvent evaporated. Light petroleum (5 ml. is added, and the evaporation repeated. The residue is dissolved in light petroleum, the solution filtered and evaporated to give 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionyl chloride (151 mg.) as an oil.
Reaction SMILES: [OH-].[K+].NC1[S:5][C:6]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1>O.O1CCOCC1>[NH2:8][C:7]1[C:6]([SH:5])=[C:12]([CH:11]=[CH:10][CH:9]=1)[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1cccc2nc(N)sc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(C(=O)O)c1S
Temperature: 25 °C

Procedure:
28.9 g of potassium hydroxide (85%), dissolved in 38 ml of water, are added dropwise to 3.5 g of methyl 2-amino-benzothiazole-7-carboxylate in 38 ml of dioxane under a nitrogen atmosphere in the course of 20 minutes, while stirring and cooling with ice, such that the internal temperature of 25° C. is not exceeded. Thereafter, the mixture is refluxed at a bath temperature of 140° C., and towards the end of the reaction the internal temperature is increased to 170° C. and dioxane is distilled off by means of a descending condenser. The mixture is then cooled to 0° C. and filtered under a nitrogen atmosphere and the residue is rinsed with 30 ml of ice-water. The title compound can be isolated from the filtrate by acidification to pH 5.5, with severe cooling and stirring at a maximum of 0° C., and extraction with ethyl acetate/tetrahydrofuran (8:2) and washing with concentrated sodium chloride solution. Because of the risk of the formation of the disulfide, the potassium salt in the filtrate (potassium 3-amino-2-mercapto-benzoate) is preferably further reacted directly.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([C:10]2[N:14]([CH3:15])[C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([C:10]2[N:14]([CH3:15])[C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(CC(=O)O)ccc1C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 3.2 g. (0.01 mole) of ethyl 5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetate and 25 ml. ethanol is brought to reflux. To this is added dropwise 10 ml. of 1N sodium hydroxide solution. After the addition is complete, the ethanol is evaporated and the residue is acidified with dilute hydrochloric acid. The resulting solid, 5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetic acid, is separated by filtration and purified by recrystallization from ethanol, m.p. 192-195° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:24][CH3:25])=[C:9]([CH2:11][C:12]2[S:13][C:14]3[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:15]=3[N:16]=2)[CH:10]=1.[OH-].[Na+].[ClH:29]>COCCOC.[Na+].[Cl-]>[ClH:29].[CH2:24]([C:8]1[N:7]=[CH:6][C:5]([CH2:4][C:3]([OH:26])=[O:2])=[CH:10][C:9]=1[CH2:11][C:12]1[S:13][C:14]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:15]=2[N:16]=1)[CH3:25]
Reactant: CCc1ncc(CC(=O)OC)cc1Cc1nc2c(F)c(F)cc(F)c2s1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ncc(CC(=O)O)cc1Cc1nc2c(F)c(F)cc(F)c2s1
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 6-ethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid-methyl ester (0.27 g, 0.71 mmol) in DME (5 mL, 0.1 M) is cooled to 0° C. under nitrogen and treated with 0.4 M NaOH (3 mL, 1.2 mmol). After stirring for 2 h, the solution is acidified with 2 M HCl, diluted with saturated aq NaCl (10 mL), extracted with ethyl acetate (3×10 mL) and dried over Na2SO4. Purification by HPLC (acetonitrile/water, 0.05% HCl) provided 6-ethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid hydrochloride as a white solid (0.21 g, 80%): mp 220° C. dec; Rf 0.21 (10% methanol in dichloromethane), 1H NMR (DMSO-d6, 300 MHz) δ 8.60 (s, 1 H), 8.18 (br s, 1 H), 7.78 (ddd, J1=11.1 Hz, J2=9.6 Hz, J3=5.9 Hz, 1 H), 4.80 (s, 2 H), 3.79 (s, 2 H), 2.97 (q, J=7.6 Hz, 2 H), 1.20 (t, J=7.6 Hz, 3 H); ESI-LCMS m/z calcd for C17H13F3N2O2S: 366.1; found 367.0 (M+1)+. Anal. Calcd for C17H13F3N2O2S.HCl: C, 50.69; H, 3.50; N, 6.95; S, 7.96. Found: C, 55.41; H, 3.56; N, 6.91; S, 7.98.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([O:24][CH3:25])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:7][CH2:6]1.[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:31]([NH:3][CH2:4][C:5]2([O:24][CH3:25])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:7][CH2:6]2)=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=1
Reactant: COC1(CN)CCN(CCCCS(=O)(=O)c2ccccc2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1(OC)CCN(CCCCS(=O)(=O)c2ccccc2)CC1
Yield: 51.8 %

Procedure:
4-Aminomethyl-4-methoxy-1-(4-phenylsulfonylbutyl)piperidine dihydrochloride (2.2 g) as starting compound, triethylamine (2.2 ml), 4-amino-5-chloro-2-methoxybenzoic acid (1.07 g), 1-hydroxybenzotriazole (0.75 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.07 g) were reacted and treated in the same manner as in Example 270 to give 1.44 g of 4-amino-5-chloro-2-methoxy-N-((4-methoxy-1-(4-phenylsulfonylbutyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:15])[CH3:14])[C:7]#[N:8])([O-:3])=[O:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[NH:18][N:17]=[N:16][N:8]=2)[CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:15])[CH3:14])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2nnn[nH]2)cc1[N+](=O)[O-]

Procedure:
The sulfonylbenzimidazole compounds wherein R3 is a heterocyclic moiety such as 1,3-dithiane, 1,3-dithiolane, oxadiazole or tetrazole can be prepared by the following methods. The following embodiment illustrates in principle the preparation of the 5(6)-(1-alkyltetrazol-5-yl) sulfonylbenzimidazole compounds of the invention. The process begins by preparing the desired 2-substituted-5(6)-(1-alkyltetrazol-5-yl)benzimidazole reactant as illustrated by the following example. 4-Aminobenzonitrile is acetylated and nitrated to give 3-nitro-4-acetamidobenzonitrile. The benzonitrile is reacted with sodium azide in dimethylformamide in the presence of ammonium chloride to yield 5-(3-nitro-4-acetamidophenyl)tetrazole. The tetrazole moiety is alkylated with methyl iodide in acetone and triethylamine to provide 1(2)-methyl-5-(3-nitro-4-acetamidophenyl)tetrazole as an isomeric mixture. The tetrazole mixture is hydrolyzed with concentrated sulfuric acid at room temperature for several hours to yield 1(2)-methyl-5-(3-nitro-4-aminophenyl)tetrazole. The nitro group of the benzene moiety is hydrogenated in ethanol-ethyl acetate at 30° C. in the presence of palladium-on-carbon to give 1(2)-methyl-5-(3,4-diaminophenyl)tetrazole. The diaminophenyltetrazole is reacted with cyanogen bromide in methanol-water to yield essentially one methyl isomer, 2-amino-5(6)-(1-methyltetrazol-5-yl)benzimidazole. When the benzimidazole is reacted with dimethylsulfamoyl chloride in acetone in the presence of triethylamine, the product is 1-dimethylaminosulfonyl-2-amino-5(6)-(1-methyltetrazol-5-yl)benzimidazole. By employing the appropriate 2-substituted-5(6)-(1-alkyltetrazol-5-yl)benzimidazole reactants and sulfonyl chlorides as described above, other 5(6)-(1-alkyltetrazol-b 5-yl)sulfonylbenzimidole compounds of the invention can be prepared.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.C([N-]C(C)C)(C)C.[Li+].[I:29]I>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([I:29])=[CH:10][C:3]=12
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Example 220A (25 g, 71.2 mmol) in tetrahydrofuran (600 mL) at −78° C. was added slowly 2M lithium diisopropylamide (39.1 mL, 78 mmol) and the mixture was stirred at −78° C. for 1 hour. A solution of iodine (19.87 g, 78 mmol) in tetrahydrofuran (100 mL) was added slowly and the reaction was allowed to warm to room temperature gradually. The reaction mixture was stirred at room temperature for 3 hours and was quenched with saturated aqueous sodium thiosulfate, water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound. MS (CI) m/z 477 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[CH:17]=[C:18]([C:21]([NH2:23])=[O:22])[NH:19][CH:20]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].N1([C:30](N2C=CN=C2)=[O:31])C=CN=C1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[CH:17]=[C:18]3[C:21](=[O:22])[NH:23][C:30](=[O:31])[N:19]3[CH:20]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc2cccc(-c3c[nH]c(C(N)=O)c3)c2nc1NC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2cccc(-c3cc4n(c3)C(=O)NC4=O)c2nc1NC(C)(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A solution of 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-2-carboxamide (Example 420; 21.8 mg, 0.067 mmol), di(1H-imidazol-1-yl)methanone (CDI; Aldrich; 12.02 mg, 0.074 mmol), and NaH (60% w/w in mineral oil; 3.24 mg, 0.081 mmol) in a mixture of THF (1.0 mL) and DMF (0.10 mL) was stirred under argon at 23° C. for 1 h. Additional di(1H-imidazol-1-yl)methanone (12 mg, 0.074 mmol) was added, and the resulting mixture was stirred at 23° C. for 5 min. Additional di(1H-imidazol-1-yl)methanone (72 mg, 0.444 mmol) was added, and the resulting mixture was stirred at 23° C. for 5 min. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes) to provide 6-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (11.9 mg, 0.034 mmol, 51% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.06 (1H, s), 7.82 (1H, d, J=7.6 Hz), 7.66 (1H, dd, J=7.3, 1.3 Hz), 7.40 (1H, d, J=7.6 Hz), 7.32 (1H, d, J=0.7 Hz), 7.30 (0.5; H, br. s), 4.76 (1H, s), 4.05 (0.5; H, s), 2.56 (3H, s), 1.57 (9H, s). m/z (ESI, +ve) 350.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:7][C:6]=2[CH:5]=[C:4]([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:3]=1.[CH3:37][Sn](C)(C)C.[F-].[K+]>CN(C=O)C>[Cl:27][C:23]1[CH:22]=[C:21]([C@H:19]([OH:20])[CH2:18][NH:17][C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:28])[C:11]=2[C:8]2[NH:7][C:6]3[CH:5]=[C:4]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:3]=[C:2]([CH3:37])[C:10]=3[N:9]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C[Sn](C)(C)C
Reactant: CN1CCN(Cc2cc(Br)c3nc(-c4c(NC[C@@H](O)c5cccc(Cl)c5)cc[nH]c4=O)[nH]c3c2)CC1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCN(C)CC2)cc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 100 °C
Yield: 48 %

Procedure:
Through a mixture of (S)-3-[4-Bromo-6-(4-methyl-piperazin-1-ylmethyl)-1H-benzimidazol-2-yl]-4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-1H-pyridin-2-one (80 mg, 0.14 mmol), tetramethyl tin (2.5 mL, excess), PdCl2 (PPh3)4 (10 mg, 0.014 mmol), and KF (40 mg, 0.7 mmol) in DMF (2 mL) in a vial was bubbled nitrogen, sealed, and heated to 100° C. for two days. The reaction mixture was passed through a small pad of celite. After concentration, the residue was purified by prep. HPLC to give the titled compound (34 mg, 48%). 1H NMR (400 MHz, CD3OD) δ 7.53 (1H, s), 7.45 (1H, s), 7.24–7.40 (4H, m), 7.09 (1H, s), 6.22 (1H, d, J=7.6 Hz), 4.99 (1H, t, J=6.4 Hz), 4.04 (2H, br s), 3.61–3.74 (2H, m), 2.98–3.34 (8H, m), 2.80 (3H, s), 2.58 (3H, s). LCMS (M+H)+ m/z 507 (t=1.29 min.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[C:18](OC(Cl)(Cl)Cl)=[O:19]>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1)=[C:18]=[O:19]
Reactant: CC(C)(C)OC(=O)CSc1cccc(N)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CSc1cccc(N=C=O)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
tert-Butyl (3-isocyanatophenylthio)acetate can be obtained in the following manner: a solution of 2.9 g of tert-butyl (3-aminophenylthio)acetate in 25 cm3 of toluene is added dropwise, at a temperature near to -30° C., to a suspension of 0.24 g of carbon in 1.46 cm3 of trichloromethyl chloroformate and 15 cm3 of toluene. The reaction mixture is stirred for 2 hours at a temperature near to 20° C. and then for 2 hours and 30 minutes at a temperature near to 110° C. The reaction mixture is then cooled to a temperature near to 20° C., degassed by bubbling nitrogen in, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 50° C. 2.6 g of tert-butyl (3-isocyanatophenylthio)acetate are thus obtained in the form of an oil which is used as such in the subsequent syntheses.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[OH2:17]>>[C:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: c1ccc(Cc2ccccc2)cc1
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
The same oxidation reaction of diphenyl methane as set forth in Example 19a was carried out using acetonitrile and water in place of acetone and water as the reaction solvents. All other reactants and processing conditions remained the same. Again, 0.7 g of starting material was recovered and 0.92 g of benzophenone was obtained, resulting in an identical yield of 86% based on 59% conversion.
Reaction SMILES: [F:1][C:2]1[C:3]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9]([OH:14])=[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:7]2=[O:26]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:3]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C(C)(C)c2c(ccc(OCc3ccccc3)c2F)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(OCc3ccccc3)c(F)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-2-hydroxy-1,1-dimethyl-4-oxo-7-((phenylmethyl)oxyl)-naphthalene-3-yl)carbonyl)glycinate (0.21 g, 447 μmol) in 2 mL TFA was stirred at room temperature for 30 minutes, M+1=414. The mixture was concentrated and then triturated in DCM/hexane (5:10). The solid was filtered, washed with 10 mL DCM/hexane (5:10), and dried under high vacuum to give 0.16 g of a pale yellow solid. LCMS showed about 10% of debenzylated product. The product was further purified by column chromatography eluting with 1:10:100 TFA/MeOH/DCM to give 108 mg of the pure compound. MS (m/z)=414 (M+H)+. Calculated for C22H20FNO6 413.13.
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[S:12]1[C:20]2C(=O)C=[CH:17][NH:16][C:15]=2[CH:14]=[CH:13]1>C(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:17][N:16]=[C:15]2[CH:14]=[CH:13][S:12][C:20]=12
Reactant: O=c1cc[nH]c2ccsc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ccnc2ccsc12
Temperature: 0 °C
Yield: 103.9 %

Procedure:
In a 250 mL round-bottomed flask 100 mL of methylene chloride and dimethylformamide (6.1 mL, 78.6 mmol) were combined and cooled to 0° C. Oxalyl chloride (57 mL, 114 mmol) was added dropwise over several minutes. 4H-Thieno[3,2-b]pyridin-7-one (5.4 g, 35.7 mmol) was added and the solution was heated to reflux. After 2 hours the flask was cooled to room temperature and the resulting solid was filtered and dried in vacuo to afford 6.29 g (100%) of 7-chloro-thieno[3,2-b]pyridine as a yellow solid. 1H NMR (400 MHz, DMSO) d 8.67 (d, 1H), 8.29 (d, 1H), 7.66 (d, 1H), 7.61 (d, 1H); LC-MS: 171 (MH+); HPLC RT: 4.19.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCC[C@H]1C(O)=O.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cu]I.CS(C)=O>[C:15]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccccc1
Reactant: C1CCNC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: c1ccc(N2CCCC2)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
Pyrrolidine (21.6 g, 304.23 mmol), L-proline (1.12 g, 9.74 mmol), and CuI (960 mg, 5.05 mmol) were added sequentially to 1-iodobenzene (10.0 g, 49.02 mmol). Dimethyl sulfoxide (40 mL) was then added, and the resulting solution was stirred at 60° C. for 20 hours. The reaction mixture was then quenched by adding 400 mL of iced water. The resulting solution was extracted with ethyl acetate (3×150 mL), and the organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to afford 4.3 g (57%) of 1-phenylpyrrolidine as brown oil.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:43]=[CH:42][CH:41]=[CH:40][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH:26]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:30]1[CH2:29][CH2:28][CH:27]([N:25]2[CH:26]=[C:22]([NH:21][C:13]3[N:12]=[C:11]([CH2:10][CH2:9][C:8]4[CH:40]=[CH:41][CH:42]=[CH:43][C:7]=4[C:4]4([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]4)[C:16]([C:17]([F:18])([F:20])[F:19])=[CH:15][N:14]=3)[CH:23]=[N:24]2)[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(C4CCNCC4)c3)ncc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of tert-butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A77 (0.213 g, 0.355 mmol) in DCM (10 mL) was treated with TFA (1.09 mL, 14.2 mmol) and stirred for 16 hours at room temperature. The volatiles were evaporated in vacuo before aq. HCl (2 M, 25 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3×25 mL) and the combined organics were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by column chromatography (Biotage Isolera, 12 g C18 cartridge, 0-100% MeOH in H2O) to give a yellow oil. This oil was taken up in a minimum amount of DCM and the desired product was precipitated by the addition of petroleum spirits. The solid was isolated by filtration to give the title compound 66 as a yellow solid (0.114 g, 64%). LCMS-D: rt 3.07 min; m/z 500 [M+H]+.