Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:10])[CH2:7][CH2:8][OH:9].Br[CH2:12][CH:13]=[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>O>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH2:12][O:9][CH2:8][CH2:7][CH2:6][OH:10]
Reactant: OCCCO
Reactant: Cc1ccccc1C(=CCBr)c1ccccc1C
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccccc1C(=CCOCCCO)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of n-butyllithium in hexanes (15.2 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to 1,3-propanediol (31 ml) on an ice-bath. When addition was complete the mixture was stirred 0.5 h at room temperature. 3-Bromo-1, 1-bis(2-methylphenyl)-1-propene (11.5 g, 38 mmol), prepared in a similar way to the method described in Example 26) was added and the reaction mixture was stirred at room temperature for 48 h and at 75° C. for 36 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The phases were separated and the organic phase was washed with water (2×50 ml), dried (MgSO4) and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (300 g) using a gradient of n-heptane in ethyl acetate as eluent provided 3.5 g (31%) of 3-(3,3-bis(2-methyl phenyl)-2-propen-1-yloxy)-1-propanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17](Br)[CH:18]=[CH2:19].O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-hydroxyindole (1.23 g, 9.24 mmol) and cesium carbonate (3.01 g, 9.24 mmol) in DMF (40 mL) under nitrogen atmosphere at 0° C. was added allylbromide (879 μl, 10.16 mmol). The reaction mixture was stirred at RT for 2 h and poured into water and extracted with EtOAc (×3). The combined organic layers were washed twice with water, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 9:1) to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.76; tR (conditions a): 3.46 min.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C@:3]12[CH2:8][C@H:7]1[CH2:6][NH:5][CH2:4]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][Cl:20].O>CC(C)=O>[Cl:20][CH2:19][CH2:18][CH2:17][N:5]1[CH2:6][C@H:7]2[C@:3]([N:2]([CH3:9])[CH3:1])([CH2:8]2)[CH2:4]1
Reactant: ClCCCBr
Reactant: CN(C)[C@@]12CNC[C@@H]1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)[C@]12C[C@H]1CN(CCCCl)C2
Temperature: 65 °C
Yield: 40 %

Procedure:
To a solution of (1R,5S)-3-benzyl-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (0.28 g, 1.29 mmol) in MeOH (20 mL) was added 20% Pd(OH)2 (30 mg). The mixture was stirred at rt under H2 overnight and filtered. The filtrate was concentrated in vacuo to give the crude product (1R,5S)—N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (0.16 g), which was used for the next step without further purification. To a solution of (1R,5S)—N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine in acetone (5 mL) was added anhydrous K2CO3 (0.35 g, 2.54 mmol, 2.0 eq) and 1-bromo-3-chloropropane (0.20 mL, 1.91 mmol, 1.5 eq) in turn. The reaction mixture was heated at 65° C. for 4 h, and then cooled to rt. To the reaction mixture was added water (5 mL) and the mixture was extracted with EtOAc (10 mL×3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (30:1 (v/v) CHCl3/CH3OH) to give the title compound as colorless oil (103 mg, 40%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 203.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:16])=[O:10])=[CH:5][CH:4]=1.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C=CC(=O)O)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C=CC(=O)Cl)cc1
Yield: 387.6 %

Procedure:
In a 100-mL three-neck flask, 3.1 g of 4-methoxycinnamic acid and 14.0 g of ethyl acetate were placed to give a suspension. The suspension was combined with 2.2 g of thionyl chloride (1.05 times the mole of 4-methoxycinnamic acid) added dropwise while maintaining the reactor inside temperature at 65° C. to 70° C. After the dropwise addition, a reaction was performed until the conversion from 4-methoxycinnamic acid reached 99% or more. After completion of reaction, 6.1 g of ethyl acetate was distilled off together with unreacted thionyl chloride and an acidic gas at 60° C. under reduced pressure. After the concentration, the resulting mixture was combined with ethyl acetate in an amount equal to the distilled-off amount and yielded 19.2 g of a 4-methoxycinnamoyl chloride/ethyl acetate solution (3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)[C:7]([OH:9])=O)[CH3:2].[NH2:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1>>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:20]1[N:21]=[C:17]([NH:16][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[S:18][CH:19]=1)[CH3:27]
Reactant: CCOc1cc(OCC)cc(C(=O)O)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(OCC)cc(OCC)c2)n1
Yield: 84.6 %

Procedure:
[2-(3,5-Diethoxy-benzoylamino)-thiazol-4-yl]-acetic acid ethyl ester (80 mg, 86%) was prepared from 3,5-diethoxybenzoic acid (52 mg, 0.25 mmol) and ethyl 2-aminothiazol-4-ylacetate (93 mg) following synthetic description A.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH3:5][O:6][C:7]1[C:8]([O:25][CH3:26])=[CH:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][NH:14][C:13](=[O:23])[CH2:12][C:11]=2[CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:5][O:6][C:7]1[C:8]([O:25][CH3:26])=[CH:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]([CH2:2][CH2:3][CH3:4])[C:13](=[O:23])[CH2:12][C:11]=2[CH:24]=1
Reactant: CCCI
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NNC(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1N=C(c2ccccc2)c2cc(OC)c(OC)cc2CC1=O
Reaction time: 72 h
Yield: 72 %

Procedure:
Add dropwise under an inert atmosphere 400 μl of iodopropane to a solution of 200 mg (0.675 mmol) of 7,8-dimethoxy-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIaa and 121 mg (0.878 mmol) of K2CO3 in solution in 5 ml of DMF. After 72 hours at room temperature, add 30 ml of H2O and extract three times with 30 ml of Et2O. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt 1/hexane 1). Yield: 72%. M: 48–52° C. 1H-NMR (300 MHz, CDCl3): d 0.83 (t, J=7.34, 3H, CH3), 1.65–1.72 (m, 2H, CH2CH3), 2.85–3.62 (m, 4H, CH2CH2CH3+5-CH2), 3.74 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.67 (s, 1H Ar), 6.89 (s, 1H Ar), 7.43–7.47 (m, 3H Ar), 7.65–7.68 (m, 2H Ar).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([CH:19]=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: Brc1ccc(C=Cc2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)C=Cc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 5.6 %

Procedure:
25.8 g (0.1 mol) of 4,4'-dibromostilbene, 10 g (0.1 mol) of ethyl acrylate, 18.5 g (0.1 mol) of tri-n-butylamine, 0.224 g (0.001 mol) of palladium acetate and 0.6 g (0.002 mol) of tri-o-tolylphosphine are added under argon to 50 ml of p-xylene. The reaction mixture is stirred at 90° C. for 4 hours. Working up gives 2 g (6% of theory) of ethyl 4-bromostilbene-4'-acrylate. Melting point 166.9° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]2[C:7]([O:17][C:18]3[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)=[CH:8][C:9](OC(F)(F)F)=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[CH3:33][C:34]([O:37][C:38]([NH:40][C@H:41]([CH2:45][CH3:46])[C:42](O)=[O:43])=[O:39])([CH3:36])[CH3:35].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH3:25][C:2]1([CH3:1])[C:6]2[C:7]([O:17][C:18]3[N:23]=[CH:22][C:21]([NH:24][C:42]([C@H:41]([NH:40][C:38](=[O:39])[O:37][C:34]([CH3:36])([CH3:35])[CH3:33])[CH2:45][CH3:46])=[O:43])=[CH:20][CH:19]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1
Reactant: Cc1c(OC(F)(F)F)cc(Oc2ccc(N)cn2)c2c1OCC2(C)C
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
6-{[3,3,7-Trimethyl-6-(trifluoromethoxy)-2,3-dihydro-1-benzofuran-4-yl]oxy}pyridin-3-amine (Intermediate 29, 405 mg, 1.27 mmol) was suspended in ethyl acetate (4 mL). Triethylamine (0.44 ml, 3.175 mmol) was added followed by the addition of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (258 mg, 1.27 mmol). The resulting suspension was cooled to 0° C. and T3P 50% w/w solution in ethyl acetate (1.4 mmol) was added drop wise. The reaction mixture was stirred at 0° C. for 1 hour and then warmed to room temperature and stirred for a further hour. An aqueous saturated solution of Na2CO3 was added and the mixture stirred for 10 min. Two phases were separated and the organic layer was washed with water and brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 80:20 to cyclohexane/ethyl acetate 70:30 as eluents affording the title compound (0.50 g) as white foam.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][NH:12][C:13]([O-:15])=[O:14])[CH2:8]2.C(=O)([O-])O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24].O>ClCCl>[Cl:21][CH2:22][C:23]([N:11]([CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)[NH:12][C:13]([O:15][CH2:10][C:1]1[CH:8]=[CH:7][CH:9]=[CH:3][CH:2]=1)=[O:14])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: O=C([O-])NNC1C2CC3CC(C2)CC1C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(NN(C(=O)CCl)C1C2CC3CC(C2)CC1C3)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 144.8 %

Procedure:
Under an argon atmosphere, a solution of 2-(adamantan-2-yl)hydrazinecarboxylate (800 mg, 2.66 mmol) in dichloromethane (30 mL) was added with sodium hydrogen carbonate (450 mg, 5.40 mmol) and chloroacetic acid chloride (300 mg, 2.66 mmol) were added at 0° C., and the resultant was stirred at room temperature for 3 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and benzyl 2-(2-chloroacetyl)-2-(adamantan-2-yl)hydrazinecarboxylate (726 mg, 72.4%) was obtained as a white crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([S:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)(=[O:27])=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (0.25 g, 1.0 mmol), 4-fluorobenzenesulfonyl chloride (0.23 g, 1.2 mmol), and triethylamine (349 μL, 2.5 mmol) are stirred at room temp. for 15 h. The reaction mixture is diluted with EtOAc, washed with water, dried (MgSO4), and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding the title product as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[H-].[Na+].I[CH3:36]>CN(C)C=O>[CH3:36][N:21]([CH2:20][CH2:19][C:18]1[CH:29]=[CH:30][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:31])[F:32])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
To tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) (0.021 g, 0.047 mmol) in anhydrous dimethylformamide (0.023 mL) at 0° C. was added sodium hydride (60% oil dispersion, 0.012 g, 0.30 mmol) and stirred in ice bath for 5 minutes. Iodomethane (0.013 g, 0.094 mmol) was added and the yellow solution immediately turned white. After 10 minutes, the reaction was quenched with water and extracted with dichloromethane. The organic layer was concentrated providing the title compound as a yellow oil (0.022 g, 97%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.39 (dt, J=8.0, 1.0 Hz, 2H), 7.37-7.20 (m, 2H), 3.47 (s, 2H), 2.86 (s, 2H), 1.57 (s, 3H), 1.44 (d, J=13.7 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 463 ([M+H]+).
Reaction SMILES: [S-:1][C:2]#[N:3].[C:4]([O:7][C:8](=O)[CH3:9])(=[O:6])[CH3:5]>N1C=CC=CC=1.ClCCl>[C:4]([O:7][CH2:8][CH2:9][S:1][C:2]#[N:3])(=[O:6])[CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: N#C[S-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCSC#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-bromoethanol (7.0 g) and potassium thiocyanate (5.4 g) in methanol (40 ml) was refluxed for 7 hours. After precipitate was filtered off, the filtrate was evaporated under reduced pressure. The residue was suspended in chloroform/methanol (5/1). The precipitate was filtered off. The filtrate was evaporated under reduced pressure to give the thiocyanate (4.4 g). To a mixture of the thiocyanate in pyridine (4.8 ml)/dichloromethane (20 ml) was added acetic anhydride (5.3 ml) in dichloromethane (5 ml) at 5° C. The mixture was stirred at room temperature for 6 hours. The precipitate was filtered off. The filtrate was washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 2-thiocyanatoethyl acetate (5.6 g).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[C:5]([C:10]([NH:13][C:14]2[N:15]=[N:16][C:17]([C:20]3[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=3)=[CH:18][N:19]=2)([CH3:12])[CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1.C([O-])([O-])=[O:29].[K+].[K+].CS(C)=O.OO>C(O)(=O)C>[F:27][CH:2]([F:1])[O:3][C:4]1[C:5]([C:10]([NH:13][C:14]2[N:15]=[N:16][C:17]([C:20]3[S:21][C:22]([C:25]([NH2:26])=[O:29])=[CH:23][N:24]=3)=[CH:18][N:19]=2)([CH3:12])[CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(Nc1ncc(-c2ncc(C#N)s2)nn1)c1ncccc1OC(F)F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)(Nc1ncc(-c2ncc(C(N)=O)s2)nn1)c1ncccc1OC(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 148.6 %

Procedure:
2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (15 mg, 38 μmol), K2CO3 (50 mg, 0.35 mmol), and DMSO (1 mL) were combined in a vial and cooled to 0° C. H2O2 (0.1 mL of 35% solution) was then added and the reaction was warmed to rt and stirred for 1 h. Acetic acid (0.1 mL) was added, and the reaction was filtered and then purified using reverse phase chromatography to afford 23 mg of 2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carboxamide as a white solid, m/z=408.3 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)[CH3:6])[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C:5]([Br:18])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C)c1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(Br)c1cccc(C(F)(F)F)c1

Procedure:
The ester 51 (0.05 mol) was dissolved in carbon tetrachloride (75 mL) and N-bromosuccinimide (0.05 mol) was added. The mixture was heated at reflux and the progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was cooled and filtered. The solution was concentrated to afford the title compound 52.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[CH2:9]([N:16]1[CH2:27][CH2:26][C:19]2[N:20]=[C:21]([Cl:25])[N:22]=[C:23](Cl)[C:18]=2[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)(C)C.C1COCC1>[CH2:9]([N:16]1[CH2:27][CH2:26][C:19]2[N:20]=[C:21]([Cl:25])[N:22]=[C:23]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:18]=2[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCCCO
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COCCCOc1nc(Cl)nc2c1CN(Cc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 3-methoxypropan-1-ol (0.500 mL, 5.23 mmol) in t-butanol (5 mL) was added a 60% dispersion of NaH in oil (70 mg, 1.75 mmol). The resulting suspension was permitted to stir for 30 minutes at which time the reaction was placed at 0° C. and charged with 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (CAS#778574-06-4, 300 mg, 1.02 mmol) as a solution in THF (1.5 mL). After 20 minutes the mixture was quenched with saturated aqueous NH4Cl, and diluted with ethyl acetate and water. The layers were then separated and the organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The resulting residue was purified via silica gel flash chromatography to provide 6-benzyl-2-chloro-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 348.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C1COCC1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:20]([NH:19][CH2:17][CH3:18])=[O:21])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: CCN=C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A stirred suspension of 4-chlorobenzoic acid, hydrazide (17.1 g, 1.00×10-1 mole), and THF (425 ml) was warmed until homogeneous, at which time ethyl isocyanate (8.7 ml, 1.1×10-1 mole) was added via syringe. A precipitate soon formed. After stirring overnight the reaction was diluted with Et2O and the precipitate was collected by filtration affording a colorless powder: 23.7 g (98%). Crystallization from ethanol gave a colorless solid: 21.4 g (88%), Mp 237°-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[SH:27].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:27][C:19]2[S:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: Sc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Sc2nc3ccccc3s2)cc1)c1cc(Cl)ccc1Cl
Temperature: 110 °C
Yield: 78.2 %

Procedure:
A charge of 269.1 g (1.00 mol) of 2,5-dichloro-4′-fluorobenzophenone, 175.6 g (1.05 mol) of 2-benzothiazolethiol, 152.0 g (1.10 mol) of potassium carbonate and 1.5 L of dehydrated N,N′-dimethylacetamide was weighed into a 3 L three-neck flask equipped with a stirrer, a thermometer, a cooling tube and a nitrogen gas introducing tube. The reaction solution was heated under nitrogen atmosphere to 110° C. for 2 hours using an oil bath. After the disappearance of raw materials was confirmed by thin layer chromatography, the reaction solution was left to cool to room temperature. The reaction solution was then gradually added to 3 L of water to coagulate a product, which was filtered. The product obtained by filtration was dissolved in 4 L of toluene. The organic layer was washed with brine until an aqueous layer became neutral. After the organic layer was dried over magnesium sulfate, the solvent was removed by an evaporator. A crude yield was 350.3 g. A 1.5 L aliquot of toluene heated to 80° C. was used for recrystallization to yield 325.4 g (0.782 mol) of a purified product in 78.2% yield.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]3[C:30](=[O:33])[CH2:31][CH2:32][C:28]=3[N:27]=[C:26]2[CH:34]([CH3:36])[CH3:35])=[CH:20][CH:19]=1>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]2[C:29]3[C:30]([CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3])([OH:33])[CH2:31][CH2:32][C:28]=3[N:27]=[C:26]2[CH:34]([CH3:36])[CH3:35])=[CH:22][CH:23]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CC2
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl acetate (0.234 mL) in dry THF (1 ml) was added dropwise to a stirred solution of LiHMDS, 1M in THF (2.389 mL) cooled to −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 30 minutes. Then, Intermediate 18 (230 mg) in THF (2 ml) was added dropwise. The RM was stirred at −78° C. under nitrogen for 1 hour.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:25]([CH2:36][CH2:37][O:38][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:24]2)(=[O:22])=[O:21])(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][N:23]([S:20]([C:11]2[NH:10][C:18]3[C:13]([CH:12]=2)=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)(=[O:22])=[O:21])[CH2:24][CH:25]1[CH2:36][CH2:37][OH:38])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CCO
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-[(1-benzenesulfonyl-5-chloroindol-2-yl)sulfonyl]-1-(tert-butoxycarbonyl)-2-[2-(tert-butyldiphenylsilyloxy)ethyl]piperazine (4.48 g) in tetrahydrofuran (20 ml) was added a 1.OM tetrahydrofuran solution (5.5 ml) of tetrabutylammonium fluoride, followed by stirring at room temperature for 3.5 hours. After concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate:hexane=1:9 to 1:0) using as a carrier silica gel, whereby the title compound (0.75 g) was obtained as a colorless solid.