Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH2:29][CH2:30][OH:31])[C:14]3=[O:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([O:31][CH2:30][CH2:29][CH2:28][C@H:15]1[CH2:16][C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][CH:33]=3)=[CH:12][CH:11]=2)[C:14]1=[O:32])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1[C@@H](CCCO)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of (3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(3-hydroxypropyl)pyrrolidin-2-one (34 mg, 0.070 mmol) in DCM (3 mL) at 0° C. is added MsCl (50 μL) and TEA (100 μL). The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified on silica gel (0-50% ethyl acetate in hexane) to give 3-{(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidin-3-yl}propyl methanesulfonate (39.1 mg, 99%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.I[CH2:17][CH2:18][CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CCCI
Reactant: Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCOc1ccc(Cc2cc(Br)sc2Cl)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 105.2 %

Procedure:
To a solution of phenol 4 (500 mg, 1.65 mmol) in acetone (25 mL) were added 1-iodopropane (0.5 mL, 4.95 mmol) and Cs2CO3 (460 mg, 4.95 mmol) at room temperature. The mixture was stirred at 60° C. for 12 hours. The reaction mixture was cooled to room temperature and filtered off through celite. The filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 5 (600 mg, 99%).
Reaction SMILES: Cl[S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>C1COCC1>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Reactant: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 430 mg (1.35 mmol) of benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate in 10 mL THF was treated with a 5-fold excess of N,N-dimethyl-ethylenediamine and the mixture was stirred at room temperature for 2 hrs. The THF was removed under vacuum. After dilution with water, the product was extracted with CH2Cl2 and dried. Chromatography on alumina, eluting with EtOAc, gave 450 mg (90% yield) of benzyl 4-({[2-(dimethylamino)ethyl]amino}sulfonyl)-1-piperidinecarboxylate as an oil: 1H NMR (CDCl3) δ 7.40-7.30 (m, 5H), 5.13 (s, 2H), 4.33 (m, exchangeable with D2O, 1H), 3.16 (m, 2H), 3.04 (tt, J=11.9, 3.7 Hz, 1H), 2.81 (br t, J=11.9 Hz, 1H), 2.43 (m, 2H), 2.22 (s, 6H), 2.12 (br d, J=12.8 Hz, 2H), 1.74 (ddd, J=25.0, 12.6, 4.5 Hz, 2H).
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[Cl:28][C:26]1[CH:25]=[CH:24][C:15]2[S:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH:12]([N:9]3[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]3)[CH2:13][C:14]=2[CH:27]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(Cl)ccc3Sc3ccc(F)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Fc1ccc2c(c1)C(N1CCNCC1)Cc1cc(Cl)ccc1S2

Procedure:
24 G. of 2,10-dichloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin in 80 ml. of chloroform are heated together with 38.4 g. of 1-carbethoxy-piperazine under reflux conditions for 20 hours. The reaction mixture is poured over ice water and extracted with chloforom. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained oily 1-carbethoxy-4-(2-chloro-8-fluoro-10,11-dihydro-dibenzo [b,f]thiepin-10-yl)-piperazine. 24.5 G. of 1-carbethoxy-4-(2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine, 350 ml. of ethyleneglycol, 19 g. of potassium hydroxide and 1.5 ml. of water are heated together at 160° for 1 hours. The reaction mixture is poured over water and extracted with chloroform. The organic phase is washed with water, dried over magneisum sulfate and evaporated under reduced pressure, whereby there is obtained 1-(2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]-thiepin-10-yl)-piperazine as a thick oil.
Reaction SMILES: Cl.[C:2]([CH:4]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:3]>CCO.[Pt]=O>[NH2:3][CH2:2][CH:4]([P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOP(=O)(OCC)C(C#N)Cc1ccccc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCOP(=O)(OCC)C(CN)CC1CCCCC1

Procedure:
Platinum oxide and conc.HCl were added to a solution of diethyl (1-cyano-2-phenylethyl)phosphonate in EtOH, for overnight stirring under hydrogen atmosphere, to obtain diethyl [2-amino-1-(cyclohexylmethyl)ethyl]phosphonate.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.[N:29]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34][CH2:33][CH2:32][CH:31]([C:35]([O:37]CC)=O)[CH2:30]1.[CH:47](=[N:54][Si](C)(C)C)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[O:37]=[C:35]1[C:31]2([CH2:32][CH2:33][CH2:34][N:29]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:30]2)[CH:47]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[NH:54]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)N=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NC2c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 2M LDA in THF/n-heptane/ethylbenzene (10.7 ml, 21.37 mmol) was cooled to −78° C. and a solution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (5 g, 19.43 mmol) in THF (5 mL) was added dropwise. The mixture was stirred for 40 minutes and allowed to warm to 0° C. for 10 minutes and cooled again to −78° C. N-benzylidene-1,1,1-trimethylsilanamine (2.63 ml, 21.37 mmol) was added and the mixture was left to stir for 3 h at 0° C. The reaction was quenched with water (5 ml) and the resulting solution was extracted using ethyl acetate. The organic portion was separated, dried (MgSO4) and concentrated in vacuo to yield a yellow oil. Purification by flash chromatography on silica (220 g column) eluting with 20-70% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=[C:31]([O:43]C(CO)CO)N=1.[H-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:43][CH3:31])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reaction time: 5 h

Procedure:
To a stirred solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1, step (5 g) in dry methanol (40 mL) was added 60% sodium hydride (0.68 g) batchwise over 5 min. The reaction mixture was stirred for 5 h, H2O added and the solvents were partially evaporated. The residue was extracted with EtOAc which was washed with H2O, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with Et2O/iso-hexane (5:95) to give the subtitle compound as a white solid. Yield: 4.05 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.[CH:46](N1CCOCC1)=[O:47].O>C1COCC1.CCCCCC>[OH:47][CH2:46][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: O=CN1CCOCC1
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)C(O)(c1ccc2cc(CO)ccc2c1)c1c[nH]cn1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 106.7 %

Procedure:
1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (5.0 g) was dissolved in THF (100 ml), and was cooled to −70° C. To the solution was slowly added a solution of n-butyllithium in hexane (1.6 M; 11.7 ml), and the mixture was stirred at −70° C. for 20 min. To the mixture was added dropwise a solution of 4-formylmorpholine (1.96 g) in THF (10 ml), and the mixture was stirred for 30 min. To the mixture was added water, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent, hexane:THF=4:1→2:1), followed by recrystallization from hexane-THF (6:1) to give the titled compound (2.69 g) as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[CH:6]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[CH:6]=1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2o1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(CBr)cc2c1
Reaction time: 1 h
Yield: 121.1 %

Procedure:
To a stirring solution of the above benzofuran (5.00 g, 28.25 mmol) and benzoyl peroxide (0.68 g, 2.83 mmol) in carbon tetrachloride (200 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (4.04 g, 14.12 mmol). The mixture was irradiated with a 200 watt lamp while stirring for 1 hour, cooled and partitioned between dichloromethane/water. The organic phase was washed with water (2×100 mL) and brine (2×100 mL), dried (MgSO4), decolorized (charcoal), and concentrated in vacuo to afford 7.12 g of crude product. Recrystallization from ethyl acetate/hexane afforded 4.38 g (61%) of 2-bromomethyl-5-nitro-benzofuran as an off-white solid: 1H NMR (CDCl3): δ 8.49 (d, 1H), 8.25 (dd, 1H), 7.58 (d, 1H), 6.91 (s, 1H), 4.59 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([OH:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1.[H-].[Na+].C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:12][C@@H:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:11])[N:15]=1
Reactant: C[C@@H](O)c1cccc([N+](=O)[O-])c1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1cncc(Cl)n1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
To a solution of (R)-1-(3-nitrophenyl)ethanol (167 mg, 1 mmol) and 2,6-dichloropyrazine (164 mg, 1.1 mmol) in dioxane was added sodium hydride (88 mg, 60% oil dispersion, 2.2 mmol) in one portion and the mixture was heated at reflux for 4 hours. After this time the mixture was allowed to cool to room temperature and was poured into saturated aqueous sodium hydrogen carbonate (25 mL) and ethyl acetate (25 mL). The two phases were separated and the aqueous phase was extracted with ethyl acetate (25 mL). The combined organic phases were washed with brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to give (R)-2-chloro-6-(1-(3-nitrophenyl)ethoxy)pyrazine (250 mg, 89%) as an orange oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:11]1=[O:26])=[O:4].O[Li].O>C1COCC1.CO.O>[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[S:6][C:5]=3[C:3]([OH:4])=[O:2])[C:11](=[O:26])[C@@H:12]([CH2:22][C@H:23]([OH:25])[CH3:24])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](C[C@@H](C)O)OC[C@H]1C1CCCCC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H](O)C[C@H]1OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of 3-[(2R,5R)-5-cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (650 mg, 1.41 mmol, 1.0 equiv) in THF (10 mL), MeOH (5 mL) and water (5 mL) was added LiOH.H2O (177 mg, 4.22 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for 2 hours. The volatile solvent was removed under vacuum and to the residue was added water (15 mL). The mixture was cooled to 0° C. and acidified by addition of 3.0 N HCl aqueous solution until pH=1. The precipitate was isolated by filtration to give product (586 mg, 93%) as white solid. MS: 448.3 [M−H+]. 1H NMR (400 MHz, CD3OD): 1.09-1.31 (m, 8H) 1.32 (s, 9H) 1.45-1.85 (m, 5H) 1.89-2.10 (m, 3H) 3.56-3.61 (m, 1H) 3.93-4.00 (m, 1H) 4.00-4.10 (m, 1H) 4.12-4.22 (m, 2H) 6.99 (s, 1H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12]([Cl:13])=[C:11]([C:14]2[N:19]=[C:18](S)[N:17]([CH3:21])[C:16](=[O:22])[CH:15]=2)[CH:10]=[CH:9][N:8]=1>CN(C)C=O>[Cl:3][C:18]1[N:17]([CH3:21])[C:16](=[O:22])[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([Cl:6])[C:12]=2[Cl:13])[N:19]=1
Reactant: Cn1c(S)nc(-c2ccnc(Cl)c2Cl)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc(-c2ccnc(Cl)c2Cl)cc1=O
Temperature: 60 °C
Yield: 72.2 %

Procedure:
After one hour stirring of a solution of phosphorus oxychloride (2.9 g, 18.9 mmol) in dimethylformamide (30 ml) at room temperature, 6-(2,3-dichloropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one (3.58 g, 12.4 mmol) was added and heated at 60° C. for 2 hours. The resulting suspension was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was washed by hexane to furnish 2-chloro-6-(2,3-dichloropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (2.6 g, 8.95 mmol, 72%) as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:3]=1[N+:18]([O-:20])=[O:19].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: Nc1ccccc1Cl
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCCSc1nc(Nc2ccccc2Cl)c([N+](=O)[O-])c(N2CCOCC2)n1
Temperature: 55 °C

Procedure:
A mixture of the product from step (i) (1 g), 2-chloroaniline (0.4 g) and N,N-diisopropylethylamine (0.404 g) in isopropylalcohol (12ml) was heated at 55° C. for 14 h. The mixture was cooled and the isopropylalcohol decanted off. Yield 0.82 g
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[N:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[N:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cncc(Br)c1
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid amide (example B.1) (215 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (330 mg, 66%). MS (ISP) 494.3 [(M+H)+]; mp 238° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.2 %

Procedure:
A solution of 2-amino-5-chlorobenzoic acid (5.0 g, 29.1 mmol), N,O-dimethylhydroxylamine hydrochloride (3.1 g, 32.0 mmol), and HOBt (3.9 g, 29.1 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. and treated with EDCI (17.3 g, 87.3 mmol). The reaction was stirred at 25° C. for 12 h, diluted with H2O, and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and concentrated. Chromatography (SiO2, 1:1 Hex/EtOAc) gave 8 (3.7 g, 60%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH2:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:19]=O>CCOCC>[N:1]1([CH2:19][NH:18][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: C=O
Reactant: NCCc1ccccc1
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCOCC
Product: c1ccc(CCNCn2nnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To a mixture of 17.7 g (0.149 mole) benzotriazole and 18 g (0.149 mole) of phenethylamine in 700 mL of ether was added dropwise 12 mL (0.149 mole) of 37% aqueous formaldehyde. The reaction mixture was stirred at room temperature overnight. The solution was dried over calcium chloride, filtered and concentrated under pressure. Hexane was added under ice-cooled bath and the resulting solid was collected by filtration and washed with hexane dried to give 38.0 g of benzotriazol-1-ylmethyl-phenethyl-amine as a light yellow oil).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[C:14]([CH3:30])=[N:15][C:16]([CH3:29])=[C:17]([C:26]([OH:28])=O)[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.CN(C=O)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][O:10][C:11](=[O:12])[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[C:17]([C:26]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:28])[C:16]([CH3:29])=[N:15][C:14]=2[CH3:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C1CCNC1
Reactant: Cc1nc(C)c(C(=O)OCCC(c2ccccc2)c2ccccc2)c(-c2cccc(Cl)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(C)c(C(=O)N2CCCC2)c(-c2cccc(Cl)c2)c1C(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
100 mg (0.200 mmol) of 4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester, 21.3 mg (0.300 mmol) of pyrrolidine, 46.0 mg (0.240 mmol) of WSC hydrochloride and 3.00 mg (0.0250 mmol) of 4-dimethylaminopyridine were stirred in 1.5 ml of dichloromethane at room temperature overnight. 3.7 mg (0.160 mmol) of WSC hydrochloride and 1 ml of DMF were added and further stirred at 60° C. overnight. After adding ethyl acetate and being washed with water, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the thin layer silica gel chromatography (hexane/ethyl acetate=1/3) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])[C:24]([F:43])=[CH:23][N:22]=1>>[F:43][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1F
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Product: CNC(=O)CN1CCc2cc(Nc3ncc(F)c(Nc4ccc(N5CCN(C)CC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.041 g, 42%). MP: 95-136° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.27 (d, 1H, J=8.6 Hz), 8.15 (s, 1H), 7.92-7.89 (m, 1H), 7.39 (s, 1H), 7.38-7.32 (m, 1H), 7.20-7.17 (m, 1H), 6.63 (s, 1H), 6.58-6.55 (m, 1H), 6.54-6.49 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.22-3.16 (m, 4H), 3.11 (s, 2H), 2.90 (d, 3H, J=5.1 Hz), 2.88-2.82 (m, 4H), 2.72-2.66 (m, 4H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS: 579.30 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:15]([C:18]1[C:26]2[O:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH2:32][CH2:33][CH2:34]Br)[CH2:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[N:4]([CH2:34][CH2:33][CH2:32][O:31][C:19]2[CH:20]=[CH:21][C:22]3[C:23]([C:27]([F:29])([F:30])[F:28])=[N:24][O:25][C:26]=3[C:18]=2[CH2:15][CH2:16][CH3:17])[C:3]1=[O:8]
Reactant: CC1(c2ccncc2)NC(=O)NC1=O
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCN2C(=O)NC(C)(c3ccncc3)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
A mixture of crude rac-5-methyl-5-(4-pyridyl)-imidazolidinedione (29 mg), 7-propyl-3-trifluoromethyl-6-(3-bromopropyloxy)-1,2-benzisoxazole (27 mg) from Example 7, and Cs2CO3 (71 mg) in DMF (3.0 mL) was allowed to react overnight. Water (0.4 mL) was added and the resulting mixture separated by HPLC to yield the title compound as a clear oil.