Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[NH:12][CH:13]=[N:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Compound 8 (2.39 g, 10 mmol) was dissolved in dry DMF (100 mL), cooled to 0° C., sodium hydride (0.48 g, 20 mmol) was added, and the mixture stirred at room temperature for 30 min. Ethyl bromoacetate (1.22 mL, 11 mmol) was added dropwise for 1 h. Stirring was continued for 2 h at room temperature and the reaction was quenched with methanol (2 mL). The solvents were evaporated under reduced pressure. The residue was subjected to column chromatography (DCM/MeOH; 9.5/0.5) to obtain 9 as a white solid: yield 1.3 g (40%); MS(+ESI): m/z 326 [M+H]+; 1H NMR (400 MHz, CDCl3): δ9.02 (s, 1H), 8.83 (s, 1H), 8.11 (s, 1H), 8.05 (d, 2H, J=7.2 Hz), 7.62 (t, 1H, J=7.2 Hz), 7.54 (t, 2H, J=7.2 Hz), 5.06 (s, 2H), 4.31 (q, 2H, J=7.2 Hz), 1.38 (t, 3H, J=7.2 Hz); 13C NMR (400 MHz, CDCl3): δ=166.76, 164.53, 152.96, 152.50, 149.83, 143.22, 133.68, 132.80, 128.89, 127.85, 122.56, 62.53, 44.33, 14.09.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][S:12][C:13](=N)N.BrC[CH2:18][CH2:19][Cl:20]>O>[Cl:20][CH2:19][CH2:18][CH2:13][S:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1
Reactant: ClCCCBr
Reactant: N=C(N)SCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1ccccn1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
A solution of sodium hydroxide pellets (151 g) in distilled water (342 cc) is added, in the course of 5 minutes, at a temperature which does not exceed 10° C., to a solution, originally at 5° C., of 2-(pyrid-2-ylmethyl)-isothiourea dihydrochloride (453 g) in distilled water (840 cc). After heating the reaction mixture for 20 minutes at a temperature of about 70° C., and then cooling to 3° C., a solution of sodium hydroxide pellets (92.5 g) in distilled water (210 cc) is added dropwise in the course of 3 minutes. After stirring the reaction mixture for 5 minutes at 10° C., 1-bromo-3-chloropropane (303 g) is added. Stirring is then continued for 20 hours at a temperature of about 20° C. The reaction mixture is then extracted four times with methylene chloride (1100 cc in total). The combined organic extracts are washed three times with distilled water (600 cc in total) and then dried over anhydrous sodium sulphate. After filtering, the resulting solution is poured onto neutral silica gel (380 g) contained in a column of diameter 6 cm, and the column is then washed with methylene chloride (2700 cc). A first fraction of effluent (600 cc) is discarded and a second fraction (3200 cc) is then collected and concentrated to dryness under reduced pressure (20 mm Hg) at 20° C. Pyrid-2-ylmethyl 3-chloropropyl sulphide (330 g) is thus obtained in the form of a yellow liquid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][NH2:21]>>[CH2:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][NH:21][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: NCCC1CC1
Product: O=C(NCCC1CC1)c1cccc(-c2ccccc2)c1

Procedure:
Using Preparation Method 1, 3-phenylbenzoic acid was reacted with (2-cyclopropyl)ethylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2 100%. A white crystalline solid was obtained (69%). NMR 1H (ppm, CDCl3): 7.97 (s, 1H), 7.69 (d, J3=7.7 Hz, 2H), 7.60 (d, J3=7.2 Hz, 2H), 7.51-7.33 (m, 4H), 6.29 (br. s., 1H), 3.60-3.53 (m, 2H), 1.54 (quart., J3=7.0 Hz, 2H), 0.78-0.67 (m, 1H), 0.52-0.46 (m, 2H), 0.14-0.06 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32](C(OC(C)(C)C)=O)[CH2:33][CH2:34][OH:35])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24].[OH-].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([NH:32][CH2:33][CH2:34][OH:35])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCO)C1CCN(c2ccc(N)cc2C#N)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)Nc2ccc(N3CCC(NCCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1

Procedure:
The reaction and treatment in the same manner as in Example 150 were conducted using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (1.19 g) and 5-amino-2-[4-(N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino)piperidin-1-yl]benzonitrile and the resulting mixture was further stirred in trifluoroacetic acid (10 ml) under ice-cooling for 1 h. The reaction mixture was treated with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give the title compound (0.29 g), melting point: 181° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[C:25]2[C:20](=[C:21]([N:26]([CH3:28])[CH3:27])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]2[CH2:29][CH2:30][CH2:31][C:17]=12)=[O:15])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:28][N:26]([CH3:27])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[C:18]1[CH2:29][CH2:30][CH2:31][C:17]1=[C:16]2[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: CN(C)c1cccc2c(C(=O)CCCCCO[Si](C)(C)C(C)(C)C)c3c(cc12)CCC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)c1cccc2c(C(=O)CCCCCO)c3c(cc12)CCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
An oven-dried 25 mL one-necked round-bottomed flask was charged with compound 12 (0.040 g, 0.091 mmol) and THF (15 mL). TBAF (0.18 mL of a 1.0 M THF solution, 0.18 mmol) was added and the mixture was stirred at rt for 3 h. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:1). The solution was then concentrated under reduced pressure and the reaction residue was purified by silica gel flash column chromatography, eluting with AcOEt/n-hexane 6:4, to provide 0.027 g of the title compound as a yellow oil in a 91% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: COc1ccccc1O
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1Oc1ccnc(Cl)c1
Yield: 97 %

Procedure:
Using the method of Example 3, Step A, 2-methoxyphenol (2.35 g, 18.9 mmol), 60% sodium hydride in mineral oil (0.757 g, 18.9 mmol), and 2-chloro-4-nitropyridine (3.00 g, 18.9 mmol) were reacted to provide 2-chloro-4-(2-methoxyphenoxy)pyridine (4.32 g, 96.9% yield) as a white powder. 1H NMR (CDCl3) δ 8.20 (d, 1H), 7.27 (m, 1H), 7.10 (d, 1H), 6.99-7.06 (m, 2H), 6.72-6.75 (m, 2H), 3.79 (s, 3H).
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=[S:11])[NH:4][CH2:3][CH2:2]1.S(NN=[C:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26])(C1C=CC(C)=CC=1)(=O)=[O:13].C(N(CC)CC)C>C(Cl)Cl>[OH-:13].[OH:26][C:25]1[N+:4]2[CH2:3][CH2:2][S:1][C:7]3[CH:8]=[CH:9][S:10][C:6]=3[C:5]=2[S:11][C:24]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)NN=C(C(=O)Cl)c2ccccc2)cc1
Reactant: S=C1NCCSc2ccsc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Oc1c(-c2ccccc2)sc2[n+]1CCSc1ccsc1-2
Product: [OH-]

Procedure:
0.6 g of 3,4-dihydro-thieno[2,3-f][1,4]thiazepine-5(2H)-thione and 1.0 g of α-(tosylhydrazono)phenylacetyl chloride were stirred for a long time in 50 ml of methylene chloride at room temperature and in the presence of 0.84 ml of triethylamine. The solvent was removed in vacuo and the residue was chromatographed on silica gel. There was obtained 5,6-dihydro-8-hydroxy-9-phenyl-thiazolo[3,2-d]thieno[2,3-f][1,4]thiazepinium hydroxide (internal salt) of m.p. 190°-195°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Br-].[CH3:21][C:22]([CH3:25])=[CH:23][CH3:24]>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:24][CH:23]=[C:22]([CH3:25])[CH3:21])[CH:3]=1
Reactant: Cc1cccc(S)c1
Reactant: CC=C(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCSc1cccc(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 g (40 mmol) of 3-methylthiophenol, 5.6 g (40 mmol) of potassium carbonate and 50 ml of DMF are introduced into a three-necked flask. 7.2 g (48 mmol) of 3-methyl-2-butene bromide are added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 7.8 g (100%) of the expected product are collected in the form of a yellow oil.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:19](Cl)[CH:20]=[CH2:21]>CS(C)=O>[CH2:21]([C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:9](=[O:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH:20]=[CH2:19]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCC(O)(C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
90 ml of a 10% by weight aqueous sodium hydroxide solution are added with cooling in a nitrogen atmosphere to a solution of 42.4 g (0.2 mol) benzoin in 400 ml DMSO, and 22 ml (0.27 mol) allyl chloride are added dropwise at 20°C within 15 minutes. The reaction solution is further stirred for 2 hours and then poured into ice/water. The crystalline crude product (50 g) is recrystallised from petroleum ether and gives 37.9 g (75% of theory) α-allyl-benzoin of melting point 89°- 93°C. A further 5.1 g of melting point 85°- 90°C are obtained from the mother liquor.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:22]([NH:23]C(OC(C)(C)C)=O)=[CH:21][O:20][N:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1>Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:22]([NH2:23])=[CH:21][O:20][N:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(COc2ccc(-c3nocc3NC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(COc2ccc(-c3nocc3N)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[4-(4-tert-Butoxycarbonylamino-isoxazol-3-yl)-phenoxymethyl]-benzoic acid methyl ester was suspended in 4N hydrochloric acid in dioxane (20 volumes) and stirred at rt for 16 hours (reaction progress monitored by TLC). The solvent was removed by evaporation to give 4-[4-(4-amino-isoxazol-3-yl)-phenoxymethyl]-benzoic acid methyl ester as the hydrochloride salt, which required no further purification. M+1=325.2
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH3:25])[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccccc1N1CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Methylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.14 (m, 2H), 6.98 (m, 2H), 5.37 (s, 2H), 3.60 (m, 4H), 2.89 (m, 2H), 2.81 (m, 2H), 2.27 (s, 3H), 2.20 (s, 3H) ppm; MS (ES) M+H expect=401.1, found=401.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:19])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCC(C(=O)c2ccc(Br)cc2)C1
Reactant: Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCC(C(=O)c2ccc(-c3ccc(N)cc3)cc2)C1
Temperature: 80 °C

Procedure:
To a solution of 3-(4-bromo-benzoyl)cyclohexanecarboxylic acid methyl ester (500 mg, 1.54 mmol) and 4-aminophenyl boronic acid (252 mg, 1.85 mmol) in toluene (40 mL) and dioxane (10 mL), 2 N aqueous Na2CO3 (10 mL) was added, and the mixture was degassed by bubbling with a flow of argon for 45 minutes. (1,1-Bis(diphenylphosphino)ferrocene)-dichloropalladium (63 mg, 0.08 mmol) was added to the mixture, which was then heated at 80° C. overnight. The reaction mixture was cooled to rt, and then filtered through a pad of Celite®, rinsing with ethyl acetate. The organic layer was separated, washed with water and brine, and dried (Na2SO4). The solvent was removed by rotary evaporation, and the solid residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 3:1 hexane/EtOAc). The product 3-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid methyl ester was obtained as a brown solid (200 mg, yield 38.5%). 1H NMR (300 MHz, DMSO) δ 7.90 (d, 2H), 7.60 (d, 2H), 7.45 (d, 2H), 6.80 (d, 2H), 3.70 (s, 3H), 3.25 (m, 1H), 2.50 (m, 1H), 2.20-1.90 (m, 4H), 1.70-1.50 (m, 4H); LC-MS ret. time 3.80 nm in (method 2), m/z 338.17 (MH+).
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1>>[C:16]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=[CH:18][C:19]([C:22]([N:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:23])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)CNc1cccnc1S2
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Sc2ncccc21

Procedure:
As described for Example 26, 5,6-dihydropyrido[2,3-b][1,4]benzothiazepine is reacted with [1,1'-biphenyl]-4-carbonyl chloride to give the product as a solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:12]([Si:15]([Cl:18])([Cl:17])[Cl:16])[CH2:13]Cl>>[C:1]1([CH:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][Si:15]([Cl:18])([Cl:17])[Cl:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: ClCC(Cl)[Si](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CC(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 54.1 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 25.2 ml (282 mmol) of benzene and 0.80 g (6.0 m) of aluminum chloride were alkylated with 6.60 g (28.2 mmol) of (1,2-dichloroethyl)trichlorosilane for 20 min at 70° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane(50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, the reaction products were vacuum distilled to give 4.82 g of (2,2-diphenylethyl)trichlorosilane (bp; 117° C./0.5 torr, yield; 54%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[N:14][C:13]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[N:21][C:12]2=3)[CH2:4]1.[O:24]=[C:25]1[NH:36][C:29]2[N:30]=[C:31]([CH:34]=O)[N:32]=[CH:33][C:28]=2[CH2:27][CH2:26]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CO.C(Cl)[Cl:61]>>[ClH:61].[ClH:61].[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:13]2[N:14]=[CH:15][C:16](=[O:17])[N:11]([CH2:10][CH2:9][N:5]3[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][CH2:34][C:31]4[NH:30][C:29]5=[N:36][C:25](=[O:24])[CH2:26][CH2:27][C:28]5=[CH:33][N:32]=4)[CH2:4]3)[C:12]=2[N:21]=1
Reactant: O=Cc1ncc2c(n1)NC(=O)CC2
Reactant: ClCCl
Reactant: COc1ccc2ncc(=O)n(CCN3CCC[C@@H](CN)C3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC[C@@H](CNCC4=NC=C5CCC(=O)N=C5N4)C3)c2n1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-{2-[(3S)-3-(aminomethyl)-1-piperidinyl]ethyl}-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (0.072 g, 0.23 mmol) in 1:1 MeOH/DCM (20 mL), was added 7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2-carbaldehyde (for a preparation see Example 125(c)) (0.04 g, 0.23 mmol), and excess Na2SO4. The solution was stirred at ambient temperature for 16 h followed by the addition of NaBH(OAc)3 (1.68 g, 7.92 mmol). The resulting solution was stirred for an additional 2 hours. Analysis by LCMS showed only 50% product, therefore an additional portion of 7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2-carbaldehyde (0.04 g, 0.23 mmol) was added and the reaction was stirred for an additional 16 h. The solution was then concentrated onto silica gel under vacuum and the crude residue purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the free base of the desired product as a yellow oily film (0.034 g, 32%). LCMS: m/z 479.2 (MH+). 1H NMR (400 MHz, CDCl3) δ 1.57-1.69 (m, 2H) 1.73-1.82 (m, 1H) 1.95 (d, J=8.59 Hz, 21H) 2.18 (td, J=10.99, 3.03 Hz, 1H) 2.51-2.63 (m, 21H) 2.67-2.75 (m, 4H) 2.81-2.92 (m, 1H) 2.92-3.01 (m, 2H) 3.21-3.32 (m, 1H) 3.88-4.00 (m, 2H) 4.00-4.05 (m, 3H) 4.57-4.68 (m, 2H) 6.73 (d, J=8.59 Hz, 1H) 8.00-8.04 (m, 1H) 8.23 (s, 1H) 8.36 (s, 1H).
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[CH2:25](Br)[CH:26]=[CH2:27].C([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:23])=[CH:8][CH:7]=2)[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:3]([CH2:1][CH3:2])[C:4]1=[O:24])[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Product: C=CCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(OC)cc2)c2cc(F)ccc21
Yield: 81 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) was treated with allyl bromide according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-1-allyl-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (81%). MS (ESI) m/z 369 ([M+H]+); HRMS: calcd for C21H21FN2O3, 368.1537; found (ESI+), 369.16115.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[C:47]([F:48])[C:39]1=2)#[N:27].CO>C1COCC1.CO.O>[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[CH:44]=[C:45]([S:49]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:51])=[O:50])[CH:46]=[C:47]([F:48])[C:39]1=2)#[N:27]
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Cl)cc(F)c21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)cc(F)c21
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (0.071 g, 0.322 mmol) was added THF (0.955 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (0.351 ml, 0.351 mmol), faster than dropwise. After 15 mins of stirring a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.123 g, 0.292 mmol) in THF (0.5 ml) was added dropwise, then washed with 0.2 ml THF and added. The mixture was stirred for 1 hr (ice melt) providing a turbid brown mixture with product as the primary species according to LC-MS (m/z=605). To the turbid brown solution was added MeOH and the mixture dried under reduced pressure. To the crude residue was added DCM (2 ml) and TFA (0.2 ml). After 2 hr the mixture was dried under reduced pressure and purified with a 25 g SNAP column ramping EtOAc in heptane (0-75%, 10% DCM throughout) to yield product as a sticky white solid which was lyophilized from MeOH/H2O affording product as a fluffy white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.074 g, 0.153 mmol, 52.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.39 (br. s., 2 H) 3.80-4.20 (m, 2 H) 6.87 (d, J=4.50 Hz, 1 H) 7.12 (dd, J=10.71, 2.01 Hz, 1 H) 7.20 (t, J=1.66 Hz, 1 H) 7.30 (d, J=4.69 Hz, 1 H) 7.41 (d, J=8.80 Hz, 1 H) 7.91-7.96 (m, 1 H) 8.35 (d, J=2.15 Hz, 1 H) 12.83 (br. s., 1 H). m/z (ESI) 485.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30]>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([N:29]([CH3:30])[CH3:28])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CNC
Agent: Cl
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)N(C)C)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.51 g, 1.32 mmol) in CH3CN, was added solid dimethylamine hydrochloride. The reaction was stirred at room temperature until complete by TLC (1 h). The reaction was washed with a minimal amount of saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of EtOAc and hexanes (1:1), providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3,3-dimethylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.51 g, 91% yield). 1H NMR (500 MHz, CDCl3) δ 2.00 (s, 3H), 2.02 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 3.17 (s, 6H), 3.79-3.82 (m, 1H), 4.06-4.13 (m, 1H), 4.22 (dd, 1H, J=4.7, 12.5 Hz), 5.16-5.24 (m, 2H), 5.31 (dd, 1H, J=9.4 Hz), 5.72 (d, 1H, J=9.2 Hz), 5.77 (d, 1H, J=8.4 Hz).