Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([CH3:21])[N:15]=1.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[NH2:13][C:14]1[N:19]=[C:18]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][CH2:8]2)[CH:17]=[C:16]([CH3:21])[N:15]=1
Reactant: COc1ccc2c(c1)CCCN2
Reactant: Cc1cc(Cl)nc(N)n1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CCCN2c1cc(C)nc(N)n1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A flask containing 6-methoxy-1,2,3,4-tetrahydroquinoline (1.33 g), 2-amino-4-chloro-6-methylpyrimidine (1.00 g), sulfuric acid (0.6 g), and 100 mL of water was heated on a steam bath for 2 hours. The solution was then cooled to room temperature and treated with ammonium hydroxide until the solution was basic (pH 8-9). The resultant solid, which precipitated from solution, was collected by filtration and recrystallized from ethyl alcohol to give 2-amino-4-(6-methoxy-3,4,-dihydro-2H-quinolin-1-yl)-6-methylpyrimidine (0.93 g), m.p. 175.2-175.9° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH:15]=O)=[C:12]([CH3:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:23](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]#[N:23])=[C:12]([CH3:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C#N

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10c) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-methylthiophene-2-carboxaldehyde (2.5 g, 9.2 mmol) that was obtained in Example 11 (11b), hydroxylamine hydrochloride (0.71 g, 10 mmol), triethylamine (2.6 mL, 18 mmol), and N,N′-dicyclohexylcarbodiimide (2.1 g, 10 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (2.5 g) in a yield of 100% as a pale yellowish oily product.
Reaction SMILES: [Br:1][C:2]1[S:14][C:5]2[NH:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:17]I>CN(C=O)C>[Br:1][C:2]1[S:14][C:5]2[N:6]([CH3:17])[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2cc(Br)sc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)sc2n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To solution of ethyl 2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (6.35 g, 23.16 mmol) in DMF (80 mL) at 0° C. was added NaH (60%, 1.54 g, 38.50 mmol) in portions. Reaction mixture was stirred at 0° C. for 15 min before MeI (2.90 mL, 46.58 mmol) was added. It was then allowed to warm to room temperature and was stirred 1.5 h. Reaction mixture was cooled to 0° C. and was quenched with solution of NH4Cl (aqueous saturated, 50 mL). It was then diluted with H2O (˜200 mL) and product was extracted with EtOAc (3×100 mL). Combined organics were washed with NaCl (aqueous saturated, 80 mL) and dried over Na2SO4. After concentration of the solvent residue was purified by column chromatography (EtOAc/hexanes, 0-10% gradient) to yield ethyl 2-bromo-6-methyl-6H-thieno[2,3-b]pyrrole-5-carboxylate (5.47 g) in 82% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][C@@H:6]([C:23]([NH:25][C:26](=[O:50])[C@H:27]([CH2:29][S:30]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[NH2:28])=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][C@@H:6]([C:23]([NH:25][C:26](=[O:50])[C@H:27]([CH2:29][SH:30])[NH2:28])=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)NC(=O)[C@@H](N)CSC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)NC(=O)[C@@H](N)CS)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-S-trityl-L-cysteinamide (0.68 g, 0.95 mmol) in CH2Cl2 (20 mL) is added triethylsilane (0.30 mL, 1.9 mmol), in one portion, followed by dropwise addition of trifluoroacetic acid (10 mL). The yellow solution is stirred at room temperature for 1 hour, after which time solvent is evaporated, and the residue is suspended in water (30 mL), filtered, and the collected solid is washed with water and ether (100 mL each), and dried in vacuo, to yield of N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-L-cysteinamide, as a white solid.
Reaction SMILES: I[C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].CN([CH:26]=[O:27])C.CCCCCC>COC1CCCC1.C([Li])CCC>[CH3:11][C:10]1[CH:9]=[C:8]([CH3:12])[C:7]2[N:6]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=2[C:2]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(C)cc(C)c32)cc1
Agent: [Li]CCCC
Solvent: COC1CCCC1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(C)c32)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-iodo-5,7-dimethyl-1-tosyl-1H-indole (950 mg, 2.1 mmol) and DMF (0.33 mL, 4.2 mmol) in cyclopentyl methyl ether (22 mL), n-butyllithium in hexane (2.2 M, 1.3 mL, 2.8 mmol) was added at −78° C. After stirring for 1 h, additional n-butyllithium in hexane (2.2 M, 0.19 mL, 0.42 mmol) was added. After stirring for 15 min, the reaction was quenched with MeOH (2 mL) and 1M aq. NaHSO4 (4.5 mL), and diluted with EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave a residue that was purified by FCC [(10% DCM/heptane)/(20% EtOAc/DCM)=100/0 to 50/50] to give the title compound. MS (ESI+) m/z 328.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][NH:5][CH:6]=1.C1C=CC2N(O)N=NC=2C=1.C[CH2:21][N:22]=[C:23]=NCCCN(C)C.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[CH3:21][N:22]([CH3:23])[C:7]([C:3]1[C:2]([CH3:1])=[CH:6][NH:5][N:4]=1)=[O:9]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1c[nH]nc1C(=O)O
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]nc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a mixture of 4-methyl-1H-pyrazole-3-carboxylic acid (1.00 g, 7.93 mmol), HOBT (1.07 g, 7.93 mmol) and EDCI (2.27 g, 11.89 mmol) in DMF (10 mL) was added DIEA (2.74 mL, 15.86 mmol). After the mixture was stirred at room temperature for 16 hours, dimethylamine (2M in THF, 11.89 mL, 23.79 mmol) was added. The mixture was stirred at room temperature for 3 hours, then partitioned between EtOAc (300 mL) and water (30 mL). The organics was washed with brine (3×30 mL) and the combined aqueous material was back extracted with EtOAc (2×50 mL). All organic extracts were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% MeOH in CH2Cl2) to obtain the title compound as a brown oil (1.1 g, 92%). m/z (ES+) 154 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[C:6](F)[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:10]2[CH2:9]1.[F:27]C1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:13][CH2:12][N:11]4[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:10]4[CH2:9]3)=[CH:2][CH:3]=2)=[O:20])=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(c1ccccc1)c1cc(F)c(N2CCN3CCCC[C@@H]3C2)c(F)c1
Product: O=C(c1ccc(F)cc1)c1ccc(N2CCN3CCCC[C@@H]3C2)cc1

Procedure:
340 mg of the title compound were prepared as described for [3,5-difluoro-4-((R)-octahydropyrido[1,2-a]pyrazin-2-yl)phenyl]-[phenyl]methanone, using 4,4′-difluorobenzophenone instead of 3,4,5-trifluorobenzophenone.
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[F:18][C:19]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:29]=[C:30]3[CH2:41][CH2:40][NH:39][CH2:38][C:31]3=[N:32][C:33]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:24][CH2:23]1.C=O>CO>[F:18][C:19]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[N:29]=[C:30]3[CH2:41][CH2:40][N:39]([CH3:2])[CH2:38][C:31]3=[N:32][C:33]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:26][CH2:27]1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C)C2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (9.9 mg, 0.047 mmol) was added to a solution of DIPEA (8 μL, 0.047 mmol), 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (12.1 mg, 0.023 mmol) and formaldehyde (2 μL, 0.023 mmol) in MeOH (230 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (8.9 mg, 71.6%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.3 Hz, 6H), 1.90-2.00 (m, 2H), 2.08-2.17 (m, 2H), 2.95-3.06 (m, 3H), 3.12 (br s, 4H), 3.35-3.53 (m, 3H), 3.76 (br s, 1H), 4.15 (dt, J=13.1, 6.5, 6.5 Hz, 1H), 4.19-4.38 (m, 2H), 4.48 (tt, J=7.3, 3.7 Hz, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J=11.4, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 418.3.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:37][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(-c3ccc(-c4nc5ccccc5o4)cc3)c3ccccc3cc2c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1c2ccccc2c(-c2ccc(-c3nc4ccccc4o3)cc2)c2ccccc12
Reaction time: 25 h
Yield: 83.3 %

Procedure:
In a 1 L Meyer flask, 3.3 g (8.8 mmol) of 2-[4-(9-anthryl)phenyl]benzoxazole, 50 mL of toluene, and 200 mL of ethyl acetate were placed. Into the solution, 1.6 g (8.8 mmol) of N-bromosuccinimide was added little by little. This solution was stirred under air for 25 hours. After a certain period, the solution was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, and then, the organic layer was dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was condensed to give an oily substance. The oily substance was purified by silica gel column chromatography (toluene:hexane=5:1) to give a solid. The solid was recrystallized with toluene/methanol, giving 3.3 g of the target yellow powder in a yield of 82%.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:21](=O)[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=O)=[CH:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[O:9][C:4]=2[CH:3]=1.[H-].[Na+].C(Br)C#C.[O:30]1C[CH2:33][CH2:32][CH2:31]1>>[F:1][C:2]1[C:12]([N:13]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)=[CH:14]2)=[CH:11][C:5]2[N:6]([O:30][CH2:31][C:32]#[CH:33])[CH2:7][C:8](=[O:10])[O:9][C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: O=C1CNc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2O1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Product: C#CCON1CC(=O)Oc2cc(F)c(-n3cc4c(c3)CCCC4)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A solution of 3 g (0.0095 mol) of 2-[7-fluoro-3H-1,4-benzoxazin-2(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione in 5 ml of tetrahydrofuran is added dropwise at 0° C. to a suspension of 0.42 g (0.014 mol, 80% in oil) of NaH in 5 ml of tetrahydrofuran. After the mixture has been stirred for 30 minutes at room temperature, 1.6 ml (0.014 mol, 80% in toluene) of propargyl bromide are added dropwise and the mixture is refluxed for 2 hours with stirring. Aqueous working-up gives 2.5 (74% of theory) of 2-[7-fluoro-4-propargyloxy-3H-1,4-benzoxazin-2(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-iso-indole- 1-3, dione having a melting point of 189°-190° C.
Reaction SMILES: [CH2:1]1[O:4][C@H:2]1[CH3:3].[Cl:5][C:6]1[CH:15]=[C:14]([SH:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>>[Cl:5][C:6]1[CH:15]=[C:14]([S:16][CH2:1][C@@H:2]([OH:4])[CH3:3])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(S)cc1Cl
Reactant: C[C@H]1CO1
Product: COC(=O)c1ccc(SC[C@H](C)O)cc1Cl

Procedure:
86 mg of (S)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 275 mg of (S)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 220 mg of (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.0 (M)+
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.C([Al]CC(C)C)C(C)C.CC(O)=O>C1(C)C=CC=CC=1>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][OH:2])=[CH:15][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Agent: CC(C)C[Al]CC(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: OCCCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Yield: 64.8 %

Procedure:
To a solution of 4-[(S)-2-(4-benzyl-phenoxymethyl)-pyrrolidin-1-yl]-butyric acid methyl ester (0.37 g, 1 mmol) in toluene (2 mL) was added 1.5M diisobutylaluminum hrdride in toluene (2 mL, 3 mmol) at −60° C. and then stirred the reaction at −30 to −20° C. for 2 h, followed by addition of 15% AcOH dropwise. The reaction was stirred at room temperature for 30 minutes and formed white solid was filtered and washed with acetone. The filtrate was concentrated in vacuo to yield the title compound as a white solid (0.22 g, 79%); MS; m/z 340.8 (M+H). 1H NMR (400 HMz, CDCl3) δ 1.61-2.26 (m, 8H), 2.79 (m, 1H), 2.85 (m, 1H), 3.25 (m, 2H), 3.42 (m, 2H), 3.54 (m, 1H), 3.68 (m, 1H), 3.75 (m, 1H), 3.92 (s, 2H), 6.82 (d, J=8.8 Hz, 2H), 7.09-7.21 (m, 5H), 7.28 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([N:11]3[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]3)=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:3]1[N:2]([CH3:1])[C:6]2[C:7]([N:11]3[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]3)=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: Cc1ccn(-c2cccc3[nH]c(=O)n(C)c23)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccn(-c2cccc3nc(Cl)n(C)c23)n1
Temperature: 80 °C
Reaction time: 120 h

Procedure:
A mixture of 17 mg (0.0745 mmol) of 1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1,3-dihydro-2H-benzimidazol-2-one in 0.5 mL of phosphorus oxychloride was stirred at 80° C. for 5 days. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was neutralized by 12 N aqueous sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (X2). The combined organic layer was washed with water (X1) and brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC eluting with a 30% ethylacetate/n-hexane mixture to give 2-chloro-1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1H-benzimidazole. A mixture 2-chloro-1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1H-benzimidazole obtained above, 48 mg (0.223 mmol) of 4-bromo-2-methoxy-6-methylaniline and 0.15 mL of 1-methyl-2-pyrrolidinone was stirred at 120° C. for 3 days. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate. The aqueous suspension was extracted with ethyl acetate (X2). The combined organic layer was washed with water (X1) and brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC eluting with a 75% ethylacetate/n-hexane mixture to give 5.7 mg (18%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][N:14]([CH2:18][CH2:19][C:20]4([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH2:15]3)[CH2:11]2)=[O:9])=[C:6]([CH3:33])[N:5]=[CH:4][N:3]=1.[F:34][C:35]([F:43])([F:42])[C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1.CC1(C(O)=O)CC1.CNS(C1C=CC(C(O)=O)=CC=1)(=O)=O.CN(C)S(C1C=CC(C(O)=O)=CC=1)(=O)=O.S(C1C=C(C=CC=1)C(O)=O)(=O)(=O)N.CNS(C1C=C(C=CC=1)C(O)=O)(=O)=O.CN(C)S(C1C=C(C=CC=1)C(O)=O)(=O)=O.CS(NC1C=CC(C(O)=O)=CC=1)(=O)=O.CC(C)(CO)C(O)=O>>[CH3:33][C:6]1[C:7]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][N:14]([CH2:18][CH2:19][C:20]4([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)[CH2:21][CH2:22][N:23]([C:39]([C:36]5([C:35]([F:43])([F:42])[F:34])[CH2:38][CH2:37]5)=[O:40])[CH2:24][CH2:25]4)[CH2:15]3)[CH2:11]2)=[O:9])=[C:2]([CH3:1])[N:3]=[CH:4][N:5]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC3(c4cccc(F)c4)CCNCC3)CC2C1
Agent: CC(C)(CO)C(=O)O
Agent: CC1(C(=O)O)CC1
Agent: CN(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC3(c4cccc(F)c4)CCN(C(=O)C4(C(F)(F)F)CC4)CC3)CC2C1

Procedure:
The following were prepared analogously from (4,6-dimethyl-pyrimidin-5-yl)-(5-{2-[4-(3-fluoro-phenyl)-piperidin-4-yl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone using the carboxylic acid in parenthesis in place of 1-trifluoromethylcyclopropanecarboxylic acid: I-42 (1-methyl-cyclopropanecarboxylic acid), I-15 (4-methylsulfamoyl-benzoic acid), I-16 (4-dimethylsulfamoyl-benzoic acid), I-17 (3-sulfamoyl-benzoic acid), I-18 (3-methylsulfamoyl-benzoic acid), I-19 (3-dimethylsulfamoyl-benzoic acid), I-21 (4-methanesulfonylamino-benzoic acid) and I-44 (2,2-dimethyl-3-hydroxy-propionic acid).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)/[CH:4]=[C:5](\[CH3:13])/[C:6]1[CH:11]=[CH:10][C:9](C)=[CH:8][CH:7]=1.[NH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1CCCCC1.O>C(O)C>[NH2:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)([CH3:13])[CH2:4][C:3]([C:2]([F:1])([F:15])[F:16])=[N:28]2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: C/C(=C\C(=O)C(F)(F)F)c1ccc(C)cc1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: CC1(c2ccccc2)CC(C(F)(F)F)=NN1c1ccc(S(N)(=O)=O)cc1

Procedure:
In a flask with an inert atmosphere (E)-1,1,1-trifluoro-4-methyl-4-(4-methylphenyl)-3-butene-2-one (1.75 g, 8.2 mmoles), 4-(aminosulphonyl)phenylhydrazine chlorohydrate (2 g, 9 mmoles) and piperidine (0.85 g, 10 mmoles) are added, dissolved in 100 ml of ethanol, and heated under reflux for 5.5 hours. The mixture is cooled, the solvent eliminated with a rotavapor, water added to the residue and the solution extracted with AcOEt. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The crude product is purified using column chromatography through silica gel under pressure, eluting with AcOEt-petrol ether (4:6) obtaining 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-phenyl-5-methyl-3-trifluoromethyl-1H-pyrazole in the form of a white solid (1.46 g, yield: 47%) with a
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:25]=[CH:24][C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:23])=[C:20]([F:22])[F:21])=[O:13])=[CH:10][N:9]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>Cl>[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([NH:7][C:8]2[CH:25]=[CH:24][C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:23])=[C:20]([F:22])[F:21])=[O:13])=[CH:10][N:9]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CCCCOC(=O)c1ccc(N)nc1)=C(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CC(CCCCOC(=O)c1ccc(NS(=O)(=O)c2ccc(C)cc2)nc1)=C(F)F
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
To 5 ml of pyridine was dissolved 0.62 g (2.3 mmol) of 6,6-difluoro-5-methyl-5-hexenyl 6-aminonicotinate, followed by the addition of 0.48 g (2.5 mmol) of toluene-4-sulfonylchloride under ice-cooling, stirring for 10 minutes and then stirring at room temperature for 15 hours. The reaction liquid was then poured in 5% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 0.88 g (yield: 90%) of 6,6-difluoro-5-methyl-5-hexenyl 6-(toluene-4-sulfonylamino)nicotinate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20]Br>CN(C=O)C>[Br:18][CH2:19][CH2:20][O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[F:11]
Reactant: N#Cc1cc(F)c(O)c(F)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(OCCBr)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A suspension of 3,5-difluoro-4-hydroxybenzonitrile (10 g, 0.0649 mol; see Preparation B(iv) above), anhydrous K2CO3 (17.94 g, 0.1298 mol) and 1,2-dibromoethane (73.2 g, 0.389 mol) in dry DMF (100 mL) was stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography over silica gel, using 1.5% ethyl acetate in petroleum ether as eluent, to yield 12 g of the sub-title compound as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18].C(N(CC)CC)C.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>ClCCl>[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:29](=[O:30])[NH:28][CH2:26][CH3:27])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18]
Reactant: CCN=C=O
Reactant: NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.1 %

Procedure:
4-Chloro-5-(3-aminopropoxy)-7-iodoisoindolinone hydrochloride (100 mg, 0.248 mmol) was suspended in dichloromethane (3.0 mL), and the suspension was added with triethylamine (0.104 mL, 0.744 mmol) and ethyl isocyanate (0.029 mL, 0.372 mmol), followed by stirring at room temperature for 13 hours. The solvent was evaported under reduced pressure and the residue was purified by slurry using water and acetonitrile to obtain 4-chloro-5-[3-(ethylcarbamoylamino)propoxy]-7-iodoisoindolinone (100 mg, yield 93%).