Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13](S(C)(=O)=O)[C:12]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26]OS(C)(=O)=O)[CH2:22][CH2:21]2)=[N:11][C:10]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:26][CH:23]3[CH2:24][CH2:25][N:20]([C:12]2=[N:11][C:10]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:21][CH2:22]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(N2CCC(COS(C)(=O)=O)CC2)n(S(C)(=O)=O)c(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCN2CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
A mixture of ethyl 5-(benzyloxy)-1-(methylsulfonyl)-2-(4-((methylsulfonyloxy)methyl)piperidin-1-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate and K2CO3 (0.051 g, 0.368 mmol) in ethanol (10 mL) was stirred at 60° C. for 4 h and cooled to room temperature. Water was added and the product was extracted with ethyl acetate. The organic phase was washed with brine then dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (Biotage flash chromatography system; 0%-10% methanol/CH2Cl2, 25 CV; 10% methanol/CH2Cl2, 5 CV) to give the title compound as a white glass (0.0248 g, 37% yield). 1H NMR (500 MHz, CDCl3) δ: 7.44 (2H, dd, J=7.3 Hz), 7.30-7.22 (3H, m), 5.27 (2H, s), 4.22 (2H, q, J=7.1 Hz), 4.01-3.94 (2H, m), 3.77-3.70 (2H, m), 3.67 (2H, brs), 3.02 (1H, brs), 2.29-2.24 (2H, m), 1.93-1.88 (2H, m), 1.22 (3H, t, J=7.0 Hz). LCMS (M+H) calcd for C20H24N3O4: 370.17; found: 370.30.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:30][NH:31][O:32][CH3:33].Cl.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:2]([C:20]([N:31]([O:32][CH3:33])[CH3:30])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
To a suspension of Boc-Arg(Tos)-OH (2 g, 4.7 mmol) in DMF (20 mL) at 0° C. was added MeNHOMe.HCl (1 g, 10.3 mmol), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol). The solution was stirred at 0° C. for 10 hours. DMF was evaporated by vacuum. The oily residue was dissolved in EtOAc (200 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3, water (20 mL), 1 M HCl (10 mL) and sat. NaCl (2×20 mL). The organic layer was dried over MgSO4, filtered and evaporated to give a suspension. The suspension was filtered, and the solid was washed with cold EtOAc (10 mL) and dried to give Boc-Arg(Tos)-N(Me)OMe, shown above, (1.5 g, 70% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][O:16]2)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH:28][C:29]1([CH3:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OC1C=CC([C@H](O)CNC2CC3C(=CC(CC)=C(CC)C=3)C2)=C2C=1NC(=O)C=C2)C1C=CC=CC=1>>[CH2:21]([N:28]([C:29]1([CH3:38])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)[CH2:17][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([N+:18]([O-:20])=[O:19])[CH:11]=1)[OH:16])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(NCc2ccccc2)Cc2ccccc2C1
Reactant: O=[N+]([O-])c1cc([C@@H]2CO2)ccc1OCc1ccccc1
Agent: CCc1cc2c(cc1CC)CC(NC[C@@H](O)c1ccc(OCc3ccccc3)c3[nH]c(=O)ccc13)C2
Product: CC1(N(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)Cc2ccccc2C1
Reaction time: 24 h

Procedure:
The title compound is prepared from (R)-2-(4-benzyloxy-3-nitro-phenyl)-oxirane (2.52 g) and benzyl-(2-methyl-indan-2-yl)-amine (2.20 g) by an analogous procedure to that used to prepare (S)-8-Benzyloxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one in Example 19. The reaction is shown to be complete by TLC after 24 hours. The product is purified by flash column chromatography (silica, n-hexane/ethyl acetate 4:1). TLC (silica, n-hexane/ethyl acetate 4:1 Rf=0.30).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=O)[CH2:18][CH2:17]4)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1.Cl.[NH2:26][OH:27]>>[CH3:1][C:2]1([CH3:24])[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)/[C:19](=[N:26]/[OH:27])/[CH2:18][CH2:17]4)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1
Reactant: NO
Reactant: CC1(C)OCC(C)(c2csc(Sc3ccc4c(c3)CCC4=O)c2)O1
Agent: Cl
Product: CC1(C)OCC(C)(c2csc(Sc3ccc4c(c3)CC/C4=N\O)c2)O1
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 68, 5-[4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-ylthio]indan-1-one was reacted with hydroxylamine hydrochloride to give (E)-5-[4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-ylthio]indan-1-one oxime in 60% yield as a foam.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.CCN(C(C)C)C(C)C.[NH2:34][CH2:35][CH:36]([CH3:39])[C:37]#[N:38].C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:38][CH2:37][CH:36]([CH3:39])[C:35]#[N:34])[N:8]=1
Reactant: CC(C#N)CN
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C#N)CNc1nccc(-c2c(Br)nc(C3CC3)n2COCC[Si](C)(C)C)n1
Temperature: 90 °C
Yield: 100 %

Procedure:
A solution of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (2.5 g, 5.8 mmol), DIEA (2.0 mL, 11.6 mmol), and 3-amino-2-methylpropanenitrile (1.49 g, 17.7 mmol) in NMP (10 mL) was treated with Na2CO3 (1.23 g, 11.6 mmol) and the resulting reaction mixture heated at 90° C. overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc (75 mL) and water (100 mL). The layers were separated and the organic portion was washed with saturated aqueous NaHCO3 solution (100 mL), brine (150 mL), dried (Na2SO4) and concentrated to a brown residue. Purification by flash chromatography (0-50% EtOAc-heptane) afforded 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)-2-methylpropanenitrile (2.79 g, 5.8 mmol) as a white solid: LCMS (m/z) 477.1 (MH+), tR=0.98 minute.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[Cl:22][C:23]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[CH:28][C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][N:33]=3)=[CH:30][C:23]=2[Cl:22])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1Cl
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2ccccc2Cl)nc1-c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (2.05 g), 2-chloro-4-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.88 g), anhydrous iron (III) chloride (1.07 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (300 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.87 g of desired compound (melting point: 104.0°-108.0° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([C@@H:14]2[CH2:18][N:17]([CH2:40][C:39]3[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=3)[C@H:16]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:25][CH2:26]3)=[O:20])[CH2:15]2)[N:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccc(F)cc2)CC1
Yield: 11 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 4-fluoro-benzaldehyde (17 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (8.2 mg, 11%) as light yellow oil. MS m/e=573.1 [M+H]+.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=C(C)C=1>[C:1]([O:20][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1cccc(C)c1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCC
Yield: 112.5 %

Procedure:
71.1 grams (0.25 mole) of purified stearic acid (melting point 70° C.) and 101.5 grams (0.375 mole) of 1-octadecanol were added to 5.5 grams of toluenesulfonic acid in 100 ml of m-xylene and charged into a Dean-Stark equipped 1-liter round bottom flask. After 4 hours of reflux under nitrogen at a pot temperature of 180° C., 6 ml of water was collected. The solvent and any excess alcohol were stripped under 29 inches of mercury vacuum at 130° C. to give 151 grams of a solid having a melting point of 58° C. The acid number of the product was 3.0. Infrared spectroscopic analysis showed formation of the ester function.
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][OH:17])[CH:3]=1.O.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(CO)cc1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: O
Product: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution (80 mL) of [5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (7.1 g) in acetonitrile were added tetra-n-propylammonium perruthenate (0.63 g), N-methylmorpholine N-oxide hydrate (4.2 g) and molecular sieves 4A powder (3.5 g) and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 4.6 g, 71%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 134.9 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[[3-(dimethylamino)propyl](methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 83) (500 mg, 1.08 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (5 ml) and stirred at room temperature for 4.5 hours. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane. The residue was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (dichloromethane:methanol) gradually changing to 80:20 (dichloromethane:methanol) to afford the title compound as a colourless glass (595 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH2:67][NH2:68])[CH:62]=1>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:68][CH2:67][C:63]3[CH:62]=[N:61][CH:66]=[CH:65][CH:64]=3)=[O:13])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(CN2CCOCC2)cc1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CN2CCOCC2)cc1
Yield: 68.4 %

Procedure:
To a solution of 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid (490 mg, 1.07 mmol, 1.00 equiv), EDCI (250 mg, 1.31 mmol, 1.22 equiv), HOBt (180 mg, 1.33 mmol, 1.24 equiv), triethylamine (330 mg, 3.27 mmol, 3.04 equiv) and pyridin-3-ylmethanamine (330 mg, 3.06 mmol, 2.84 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at room temperature. The product was precipitated by the addition of 60 mL ice/water. The solid was collected by filtration and washed with water (1×20 mL) and dried in an oven under reduced pressure to give 0.40 g (68%) of 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS: (ES, m/z): 547 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm) δ 9.22 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.86 (d, J=7.6 Hz, 2H), 7.74-7.72 (m, 3H), 7.53 (d, J=7.6 Hz, 2H), 7.36 (s, 1H), 4.67 (s, 2H), 4.51 (d, J=4.0 Hz, 2H), 3.55 (s, 6H), 2.32 (s, 4H), 2.15 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([Cl:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:16])[N:12]=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)n1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: Clc1cc(OCc2ccccc2)cc(N2CCOCC2)n1
Temperature: 130 °C

Procedure:
A mixture of 4-(benzyloxy)-2,6-dichloropyridine (1.0 equiv.) and morpholine (1.2 equiv.) in NMP (2 M) were heated to 130° C. for 1 h in the microwave. The reaction mixture was partitioned between water and EtOAc. The organic phase was washed with brine and dried over sodium sulfate. The solution was concentrated and dried under vacuo to give crude 4-(4-(benzyloxy)-6-chloropyridin-2-yl)morpholine and was used in the next step without further purification. LCMS (m/z) (M+H)=305.0, Rt=1.10 min.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[CH2:9][CH:10]([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[Cl:4][C:10]([CH2:9][C:8]1[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=1[CH3:6])([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(Cc1ccccc1C)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Product: CCOC(=O)C(Cl)(Cc1ccccc1C)C(C)=O

Procedure:
325 g (2.4 moles) of sulfuryl chloride were added dropwise to 511.0 g (2.2 moles) of ethyl 2-(o-methylbenzyl)-acetoacetate in the course of 2 hours, while stirring. Thereafter, the mixture was heated at 50° to 55° C. for 4 hours. The crude product was purified by vacuum distillation without a column. 547 g (92% of the theoretical yield) of ethyl 2-chloro-2-(o-methylbenzyl)-acetoacetate of boiling point 120° C. at 0.01 mm Hg were obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Br[CH2:36][CH2:37][OH:38].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[OH:38][CH2:37][CH2:36][N:32]1[CH2:31][CH2:30][CH:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: OCCBr
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CCO)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (300 mg), 2-bromoethanol (170 mg), sodium carbonate (280 mg) and ethanol (20 mL) was stirred at 80° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=35/65→0/100 (volume ratio)] to give the title compound as a colorless amorphous compound (205 mg, 63%).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(F)cc1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (0.6 ml), and a solution of 4-fluorobenzoyl chloride (0.8 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]1[N:19]3[CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:18]3=[N:17][C:10]=1[CH:11]=[N:12]2.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([N:23]1[CH2:22][CH2:21][CH2:20][N:19]2[C:9]3[C:8]4[C:13](=[CH:14][CH:15]=[CH:16][CH:7]=4)[N:12]=[CH:11][C:10]=3[N:17]=[C:18]2[CH2:24]1)(=[O:4])=[O:3]
Reactant: c1ccc2c(c1)ncc1nc3n(c12)CCCNC3
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCCn2c(nc3cnc4ccccc4c32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
Methanesulfonyl chloride (2.54 mL, 32.6 g) was added to a solution of 9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline hydrochloride (7.47 g, 27.2 mmol) and triethylamine (22.73 mL, 163.1 mmol) in DMF (50 mL). The reaction was stirred overnight at ambient temperature and then concentrated under reduced pressure to provide 3.065 g of 9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([Cl:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Cl:13][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: ClCc1ccccc1
Product: O=S(=O)(Cl)c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 250 mL flask, fitted with addition funnel, reflux condenser and thermometer, is placed 50 g (0.43 mole) of chlorosulfonic acid. Benzyl chloride, (18 g, 0.14 mole) is added to the reaction mixture, slowly, with continuous stirring, over a period of two hours. The temperature of the reaction is kept near room temperature using a water bath. After the addition is complete, the stirring is continued for at least one hour. After analysis by thin layer chromatography shows that the reaction is complete, the reaction mixture is poured into 150 g of crushed ice. The solid is collected and washed with cold water several times. The crude product is further purified by recrystallization. The product is characterized using 1H NMR spectroscopy.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[C:11]1([C:17]2[N:24]3[C:20]([S:21][CH:22]=[CH:23]3)=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:11]1([C:17]2[N:24]3[C:20]([S:21][CH:22]=[CH:23]3)=[C:19]([CH:9]=[O:10])[N:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(-c2ncc3sccn23)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1nc(-c2ccccc2)n2ccsc12
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (0.6 mL, 6.44 mmol) was added to DMF (2.5 mL) over 5 minutes with cooling in an ice-bath. 5-Phenylimidazo-[5,1-b]-thiazole (500 mg, 2.5 mmol) was added, and the mixture was kept overnight at room temperature. The thick solid that had formed was slurried in methylene chloride and stirred for 30 minutes with 10% aqueous sodium carbonate solution. The organic layer was separated, washed with saturated brine solution and evaporated. The title compound was obtained after flash chromatography eluting with 20% acetone in hexane.