Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:13])[C@H:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[NH:12])[NH2:11])[NH2:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[N:23][C:24]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:25])=[CH:18][CH:17]=1.[OH-].[Na+]>O.CO>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[N:23][C:24]([NH:26][C@H:27]([C:35]([NH:5][C@H:4]([C:3]([OH:2])=[O:13])[CH2:6][CH2:7][CH2:8][NH:9][C:10](=[NH:12])[NH2:11])=[O:36])[CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:25])=[CH:18][CH:17]=1
Reactant: COc1ccc(N=NC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(N=NC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc1
Reaction time: 1 h

Procedure:
Operating mode: 1 equivalent of N-(4-methoxyphenylazoformyl)L-phenylalanine arginine methyl ester was taken up in a water/methanol mixture (ratio: 1/2; 3 ml/mmol). 3 equivalent of 1 N sodium hydroxide was added. After 1 h, the reactional medium was acidified, concentrated then extracted with water/dichloromethane. The dichioromethane phase was evaporated then dried. N-(4-methoxyphenylazoformyl)-L-phenylalanyl arginine was obtained as an orange powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:42])[C:12](=[O:41])[C:13]([CH3:40])=[C:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:16](=[O:30])[N:15]2[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([OH:36])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:57]1([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1.CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:42])[C:12](=[O:41])[C:13]([CH3:40])=[C:14]2[C:19]=1[C:18](=[O:20])[N:17]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:16](=[O:30])[N:15]2[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([N:60]1[CH2:59][CH2:58][N:57]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:62][CH2:61]1)=[O:36]
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(C(=O)O)c3)c2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3)c2=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoic acid (1 g, 1.465 mmol), EDC (0.421 g, 2.198 mmol), HOBT (0.337 g, 2.198 mmol) and tert-butyl piperazine-1-carboxylate (0.409 g, 2.198 mmol) in THF (5 ml); cooled to 0° C., was added Hunig's base (0.512 ml, 2.93 mmol). The resulting mixture was stirred under N2 atm for 2 h at room temperature. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was separated and aq. phase was re-extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated in vacuo to obtain crude product, which was carried forward for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17].N1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>C1COCC1.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:34]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=2)(=[O:36])=[O:35])=[C:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: COc1ccccc1Cc1cc(Cl)ccc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1Cc1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To 0.57 g of (2-amino-5-chlorophenyl)(2-methoxyphenyl)methane dissolved in 5 ml of THF are successively added 0.2 ml of pyridine and 0.547 g of 3,4-dimethoxybenzenesulfonyl chloride, and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane, to give 0.832 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[C:7]=1[OH:8].CN(C)C=O.Cl[C:16]([F:21])([F:20])C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH:16]([F:21])[F:20]
Reactant: O=C(O)C(F)(F)Cl
Reactant: Oc1c(Br)cncc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccncc1Br
Temperature: 120 °C

Procedure:
To a stirred solution of 3-bromopyridin-4-ol (L); 0.5 g, 0.00287 mol) in mixture of N,N-dimethylformamide (10.0 mL), water (1 mL), was added 2-chloro-2,2-difluoroacetic acid (0.74 g, 0.00574 mol) and potassium carbonate (0.47 g, 0.00344 mol). The resulting mixture was heated under microwave irradiation at 120° C. for 45 min. The reaction mixture was cooled to room temperature and poured into water (10.0 mL) and extracted with ethyl acetate (2×50.0 mL). Combined organic phase was washed with saturated sodium bicarbonate solution, water, saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under vacuum to afford crude product. The crude was purified by silica gel (60-120) column chromatography using 0-8% methanol in dichloromethane to afford the title compound (IN-13). 1H NMR (400 MHz, DMSO-d6) δ: 8.606-8.60 (d, J=2.4 Hz, 1H), 8.08-8.05 (dd, J=5.2 Hz, 1H), 7.67-7.37 (t, J=58.8 Hz, 1H), 6.38-6.36 (dd, J=7.2 Hz, 1H). MS (M+1): 223.8.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([Cl:10])=[CH2:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[C:4]([CH3:15])[N:3]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.O>C(#N)C>[Cl:10][C:8]([C:7]1[C:2]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[N:3][C:4]([CH3:15])=[N:5][C:6]=1[C:11]([F:14])([F:13])[F:12])=[CH2:9]
Reactant: C=C(Cl)c1c(Cl)nc(C)nc1C(F)(F)F
Reactant: c1c[nH]cn1
Solvent: CC#N
Solvent: O
Product: C=C(Cl)c1c(-n2ccnc2)nc(C)nc1C(F)(F)F
Temperature: 25 °C
Yield: 65.2 %

Procedure:
4-Chloro-5-(1-chlorovinyl)-2-methyl-6-trifluoromethylpyrimidine (1.83 g) was dissolved in acetonitrile (20 ml) under stirring in room temperature. The mixture was added imidazole (1.45 g) and refluxed 3 hr and then cooled to room temperature and added water. The mixture was extracted with chloroform. The chloroform layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-THF) to give 5-(1-chlorovinyl)-4-imidazol-1-yl-2-methyl-6-trifluoromethyl-pyrimidine (1.34 g) as pale brown oil. 1H-NMR (δ, ppm); 2.82 (s, 3H), 5.78 (d, 1H), 6.03 (d, 1H), 7.21 (br, 1H), 7.87 (br, 1H), 8.55 (br, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH2:30]([O:37][CH2:38][CH2:39][CH:40]=[O:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:40]([OH:41])[CH2:39][CH2:38][O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=CCCOCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(O)CCOCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 42 g (148 mmol) dibenzylamino-acetic acid ethyl ester in 1 l tetrahydrofuran was stirred at −70° C. with 87 ml (77.6 mmol) lithium diisopropylamide (2M in tetrahydrofurane) for 60 minutes. 28.7 g (175 mmol) 3-(Benzyloxy)propanal were added and stirring was continued overnight. The mixture was allowed to warm to room temperature and 200 ml saturated aqueous ammonium chloride solution was added. Extraction with diethylether and chromatography on silicagel with ethylacetate/heptane 0:100 to 100:0 yielded as first eluting fraction 13.0 g (20%) racemic (2S,3R and 2R,3S)-5-benzyloxy-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester, MS m/e (%): 448.1 (M+H+, 100) and as second diluting fraction 11.0 g (17%) racemic (2R,3R and 2S,3S)-5-benzyloxy-2-dibenzylamino-3-hydroxy-pentanoic acid ethyl ester, MS m/e (%): 448.1 (M+H+, 100).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:13]=[C:12](C(F)(F)F)[S:11][CH:10]=2)[CH:5]=[C:4]([CH3:18])[CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(COC)OC.C(OCC)(=O)C.O>[CH3:18][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=2)[N:7]=[C:6]([O:8][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:20]([F:31])([F:30])[F:19])[CH:5]=1
Reactant: Cc1cc(Br)nc(Oc2csc(C(F)(F)F)c2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Cc1cc(Oc2ccsc2C(F)(F)F)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of 6-bromo-4-methyl-2-{[5-(trifluoromethyl)-3-thienyl]oxy}pyridine (1.16 g, 3.43 mmol) in dimethoxyethane is treated with tetrakis(triphenylphosphine) Pd (79 mg, 0.069 mmol), stirred at room temperature for 30 minutes under N2, treated with α,α,α-trifluoro-p-tolylboronic acid (0.72 g, 3.77 mmol), NaHCO3 (0.95 g, 11.32 mmol) and water, heated at reflux temperature for 1.5 hours, cooled to room temperature, diluted with a mixture of ethyl acetate and water to give a two phase mixture. The phases are separated and the organic phase is set aside. The aqueous phase is extracted with ethyl acetate. The ethyl acetate extracts are combined with the organic phase, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give an amber oil residue. The residue is chromatographed (silica gel, ethyl acetate/hexanes, 5/95) to give the title product as a clear oil, which solidified upon drying in a Kugelrohr, to a waxy white solid, 1.22 g (88% yield), mp 52.5-55.5° C., identified by 1HNMR, 13CNMR, 19FNMR, mass spectral and elemental analyses.
Reaction SMILES: C(O[C:6](=[O:22])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:23]([O:25][C:26](=[O:38])[CH:27](C(OCC)=O)[C:28](OCC)=[O:29])[CH3:24]>>[CH2:23]([O:25][C:26]([C:27]1[C:6](=[O:22])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:28]=1[OH:29])=[O:38])[CH3:24]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2F)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (2,4-difluoro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 349 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:14][C:15]4[CH2:20][CH2:19][NH:18][CH2:17][C:16]=4[N:21]=3)[S:12][C:8]=2[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:37](Cl)(=[O:39])[CH3:38]>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:14][C:15]4[CH2:20][CH2:19][N:18]([C:37](=[O:39])[CH3:38])[CH2:17][C:16]=4[N:21]=3)[S:12][C:8]=2[C:7]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNC4)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(C)=O)C4)nc12
Yield: 89 %

Procedure:
To a suspension of 0.01 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine hydrochloride in 0.8 ml tetrahydrofurane were added at 0–4° C. 0.02 ml N-ethyldiisopropylamine and 0.002 ml acetyl chloride in 0.25 ml tetrahydrofurane. The mixture was refluxed over night, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with ethylacetate/methanol 95:5 to yield 0.009 g (89%) 1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl]-ethanone as yellow solid; M.p.: 155–157° C.; MS (ISP): m/e=414 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CCC(=O)C.O>[C:14]1([S:20]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=3[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 5 h

Procedure:
A mixture of methyl indole-4-carboxylate (J. Org. Chem. 1980, 45, 3350) (5.0 g, 28.5 mmol), benzenesulphonyl chloride (10.1 g, 57.1 mmol) and anhydrous potassium carbonate (15.78 g, 114 mmol) in butan-3-one (150 ml) was refluxed under nitrogen for 15 hours. Additional benzenesulphonyl chloride (10.1 g) and anhydrous potassium carbonate (10.1 g) were added and refluxing was continued for 5 hours. The mixture was diluted with water (300 ml) and extracted with diethyl ether (3×300 ml). The combined organic solutions were dried (MgSO4) and concentrated to give a white solid which was recrystallised from ethanol (6.35 g, 72%); δH (360 MHz, CDCl3), 8.21 (1H, d, J=8.3 Hz, Ar—H), 7.96 (1H, dd, J=8.1 and 0.7 Hz, Ar—H), 7.87-7.84 (2H, m, Ar—H), 7.69 (1H, d, J=3.7 Hz, Ar—H), 7.56-7.33 (5H, m, Ar—H), 3.94 (3H, s, —OMe); m/z (CI) 316 (M++1).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[C:16](Cl)=[C:15]([F:18])[N:14]=[C:13]([F:19])[C:12]=1Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[C:1]([O:9][CH2:10][C:11]1[CH:16]=[C:15]([F:18])[N:14]=[C:13]([F:19])[CH:12]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1c(Cl)c(F)nc(F)c1Cl)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(OCc1cc(F)nc(F)c1)c1ccccc1
Yield: 59.6 %

Procedure:
(3,5-dichloro-2,6-difluoropyridin-4-yl)methyl benzoate (19.6 g, 61.6 mmol), anhydrous ethanol (150 ml), and 10% palladium on carbon (3 g) were placed into a 500 mL bottle. The mixture was hydrogenated under hydrogen atmosphere (50 psi) for 1.5 hr. The reaction mixture was filtered through celite pad and the pad was washed with ethanol. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:4)) to afford 9.15 g (61%) of (2,6-difluoropyridin-4-yl)methyl benzoate as a white solid. m.p. 83-84° C. 1H NMR (200 MHz, CDCl3) δ 5.42 (2H, s), 6.87 (2H, s), 7.45-7.67 (3H, m), 8.08-8.13 (2H, m).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Clc1cc(Cl)cc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3,5-dichlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (EI): m/e 370.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.58 (s, 1H); 8.45 (d, J=5.5 Hz, 1H); 7.98 (br s, 1H); 7.86 (m, 1H); 7.38 (m, 2H); 7.31 (s, 2H); 6.89 (d, J=5.5 Hz, 1H); 5.88 (br s, 1H); 4.72 (d, J=6.4 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O.CN(C)C=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Br)cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1C(=O)Cl
Reaction time: 6 h

Procedure:
5-Bromo-2-methylbenzoic acid (725 mg, 3.37 mmol, 1 eq) was suspended in dry dichloromethane (9.7 mL). Oxalyl chloride (0.32 mL, 3.74 mmol, 1.1 eq) and N,N-dimethylformamide (0.013 mL, 0.17 mmol, 0.05 eq) were then added at room temperature and the mixture was stirred for 6 hours. The solvent was then evaporated to give 5-bromo-2-methylbenzoyl chloride as yellow oil. This crude product was dissolved in dry dichloromethane (19.3 mL), AlCl3 (49.5 mg, 3.71 mmol, 1.1 eq) and 42 (600 mg, 3.37 mmol, 1 eq) were then added at 0° C. (internal temperature). The resultant mixture was stirred at this temperature for 30 minutes and then at room temperature overnight. The reaction mixture was poured into ice and water, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were gathered, dried over MgSO4, filtered and concentrated. The residue was taken up with n-hexane to form a precipitate which was collected by filtration, washed with n-hexane and dried to afford compound 43 (69% yield) as yellowish crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6].[H-].[Na+]>C1COCC1>[CH:8]1([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(NCCCl)NC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1C1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A −20° C. solution of 1-(2-chloroethyl)-3-cyclopentylurea (8.5 g, 44.6 mmol) in THF (446 mL), under Ar, was treated with NaH (60% in mineral oil, 4.46 g, 111 mmol), stirred at −10° C. for 1 h, 0° C. for 1 h, then RT for 3 h. The mixture was cooled to 0° C., treated with 50% satd. NH4Cl, the layers separated and the aqueous layer extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated to dryness. The material was suspended in Et2O, the solids removed via filtration and the filtrate concentrated to dryness. The resulting material was dissolved in DCM, treated drop-wise with hexane until solids formed and the solids were collected via filtration and dried to afford 1-cyclopentylimidazolidin-2-one (4.3 g, 63%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.16 (s, 1 H), 4.07-3.98 (m, 1 H), 3.28-3.22 (m, 2 H), 3.19-3.14 (m, 2 H), 1.66-1.55 (m, 4 H), 1.52-1.41 (m, 4 H); MS (ESI) m/z: 155.1 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>C(Cl)Cl>[CH3:1][C@@H:2]1[N:7]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:36])[F:37])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 105.6 %

Procedure:
To a solution of 1,1-dimethylethyl(3S)-3-methyl-1-piperazinecarboxylate (2.05 g, 10.2 mmol) in DCM (50 ml) was added DIPEA (2.68 ml, 15.4 mmol) and the mixture stirred at rt for 10 minutes before addition of 4-(trifluoromethyl)benzenesulfonyl chloride (3.00 g, 12.3 mmol) at 0° C. The resultant mixture stirred under an atmosphere of argon for 16 hours before addition of water (50 ml) and DCM (30 ml). The layers were separated using a hydrophobic frit and the organic layers concentrated to dryness giving the title compound (4.40 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].[C:8](Cl)(=[O:10])[CH3:9].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[S:3][C:4]([C:8](=[O:10])[CH3:9])=[CH:5][C:6]=1[Cl:7]
Reactant: CC(=O)Cl
Reactant: Clc1ccsc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-3-chlorothiophene (10.7 g, 51.5 mmol) was dissolved in dichloromethane (73.5 ml). The flask was equipped with a desiccant filled drying tube and the solution was chilled in an ice bath. Acetyl chloride (6.06 g, 77 mmol) was added followed by addition of aluminum trichloride (8.24 g, 61.8 mmol) over about 2 minutes (reaction bubbled vigorously as aluminum trichloride was added). The reaction mixture was stirred overnight, allowing to warm to room temperature, and then added cautiously and with stirring to a 1-L beaker containing ˜200 mL sat sodium bicarbonate. The mixture was stirred for 30 minutes and diluted with dichloromethane (˜100 mL). The layers were separated and the organic layer was washed with aqueous saturated sodium bicarbonate, water, and brine. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give a crude solid. This material was recrystallized from hot hexanes to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>O1CCCC1>[CH2:48]([O:47][C:45](=[O:46])[CH2:44][CH2:43][CH2:42][NH:41][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:49]
Reactant: CCOC(=O)CCCN
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCCNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Yield: 16.9 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.0 g, 0.028 mole), 1,1'-carbonyldiimidazole (4.5 g, 0.028 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and triethylamine (6.3 g, 0.062 mole) and ethyl 4-aminobutyrate hydrochloride (5.2 g, 0.031 mole) were added all at once. The reaction mixture was stirred under nitrogen over the weekend. The tetrahydrofuran was evaporated and the solid residue triturated in water (100 ml) and filtered off to give 4.7 g (42%) of cake. A 2.3-g portion of the filter cake was recrystallized from isopropyl ether-ethanol to give 1.9 g of white solid, mp 127°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([N+:14]([O-])=O)[CH:6]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:14])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1N

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (2.1 g, 5.8 mmol) and ammonium chloride (6.2 g, 116.0 mmol) is heated in ethanol/water (40 ml/20 ml) to 70°. Iron powder (3.2 g, 58.0 mmol) is added in small portions over 15 minutes, and the mixture is then heated under reflux for 2 hours. The reaction is filtered through celite and stripped. The residue is taken up in ether, washed with water, dried and stripped to give 4-(2-chloro-4-trifluoromethylphenoxy)-2-aminoaniline.