Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:13]=2)[CH:3]=1.Cl[CH2:18][C:19](Cl)=[O:20].[OH-].[Na+].Cl>O1CCOCC1.N1C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:19](=[O:20])[CH2:18][N:10]3[C:9](=[N:13][C:12]([CH:14]4[CH2:16][CH2:15]4)=[N:11]3)[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cc1-c1nc(C2CC2)n[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C1Cn2nc(C3CC3)nc2-c2cc(Cl)ccc2N1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A suspension of 4-chloro-2-(5-cyclopropyl-2H-[1,2,4]triazol-3-yl)-phenylamine (3.95 g, 16.8 mmol) in dioxane (120 mL) and pyridine (1.5 mL) was cooled to 10° C. A solution of chloroacetyl chloride (1.54 mL, 19.3 mmol) in diethylether (5 mL) was then added dropwise over 15 min. The reaction mixture was stirred at this temperature for 30 min and was then treated within 10 min with aqueous sodium hydroxide (2 N, 20.2 mL, 40.4 mmol). The mixture was stirred for 22 h at ambient temperature. After the addition of aqueous HCl (1 N, 2.5 mL) the resulting mixture was evaporated. The residue was stirred for 45 min in water (100 mL) and ethyl acetate (5 mL). The resulting crystals were filtered off and washed with water. Drying in vacuo and trituration with ethyl acetate afforded the title compound (3.02 g, 65%) which was obtained as an off-white solid. MS: m/e=275.0 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:12]([C:17]2[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=2)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.Cl.N1C=CC=CC=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:12]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)C(O)(c1cccc(-c2ccco2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2ccco2)c1)c1c[nH]cn1
Yield: 72 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 1-[3-(2-furyl)phenyl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.54 g) and pyridine hydrochloride (610 mg), the title compound (597 mg) was obtained as colorless plate crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:14]3[CH:15]=[C:16]([CH:19]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[C:11]([NH:33][NH2:34])[CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.[N:35]([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:14]3[CH:15]=[C:16]([CH:19]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[N:35]=[N:34][N:33]=[C:11]3[CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(NN)=N2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
A mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-2-hydrazino-3,5-dihydro-4,1-benzothiazepine (described in Example B16b) (0.0045 mol) in HCl (34 ml) was cooled on an ice bath. A solution of sodium nitrite (0.005 mol) in water (7 ml) was added. The mixture was stirred at 5° C. for 30 min and at room temperature for 30 min, then poured out on ice, basified with K2CO3 10% and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (2.7 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1; 20–45 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone/CH3CN/DIPE. The precipitate was filtered off and dried, yielding 0.44 g (18.9%) of 6-(3-chlorophenyl)-8-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4H,6H-tetrazolo[1,5-a][4,1]benzothiazepine, mp. 162° C.
Reaction SMILES: O/[CH:2]=[CH:3]/[C:4]([C:6]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:5].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C1(C)C=CC=CC=1>[CH2:26]([N:28]([CH2:29][CH3:30])/[CH:2]=[CH:3]/[C:4]([C:6]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:5])[CH3:27]
Reactant: COC(=O)c1ccccc1COc1cc(OC)ccc1C(=O)/C=C/O
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(/C=C/C(=O)c1ccc(OC)cc1OCc1ccccc1C(=O)OC)CC
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a 2 L round bottomed flask was added (E)-methyl 2-[[2-(3-hydroxy-1-oxo-2-propenyl)-5-methoxyphenoxy]methyl]benzoate (104 g, 0.304 mol) and 1 L of toluene. After complete dissolution, diethylamine (28.3g, 40 mL, 0.39 mol) was rapidly added under nitrogen via an addition funnel into the stirred solution. The reaction mixture was stirred under nitrogen for 1 h and it was then concentrated under reduced pressure to give approximately 120 g (100% yield) of the title compound as an orange solid: 1H NMR (300 MHz, CDCl3) δ 8.02 (1H, d), 7.84 (1H, d), 7.67 (2H, bd), 7.51 (1H, t) 7.35 (1H, t), 6.54 (2H, m), 5.75 (1H, d), 5.52 (2H, s), 3.80 (3H, s), 3.23 (4h, br), 1.14 (6H, br).
Reaction SMILES: [C:1](/[N:3]=[C:4](\SC)/[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1)#[N:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>CN(C=O)C>[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:4]2[N:3]=[C:1]([NH2:2])[O:18][N:17]=2)[CH:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: CS/C(=N\C#N)Nc1cc(Cl)cc(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(Nc2cc(Cl)cc(Cl)c2)no1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 10.2 %

Procedure:
In a 5 mL microwave vial, (Z)-methyl N′-cyano-N-(3,5-dichlorophenyl)carbamimidothioate (156 mg, 0.6 mmol, Eq: 1.00), hydroxylamine hydrochloride (347 mg, 5 mmol, Eq: 8.33) and triethylamine (506 mg, 697 μl, 5 mmol, Eq: 8.33) were combined with DMF (6 ml) to give a white suspension. The vial capped and stirred in a 50° C. oil bath for 3.5 hours. The reaction was concentrated in vacuo and the crude material was purified by preparative TLC (silica gel, 1.0 mm, 9:1 DCM/MeOH) to give product, was recrystallized from EtOH then dried in vacuo (80° C., 2 torr, overnight) to give 15 mg (10%) of desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[N:19][C:5]2[N:6]([CH2:17][CH3:18])[C:7]3[N:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[Br:1][C:2]1[CH:20]=[N:19][C:5]2[N:6]([CH2:17][CH3:18])[C:7]3[N:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[N:9]([CH3:23])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CCN1c2nc(F)ccc2NC(=O)c2cc(Br)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(F)nc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To a solution of the 8-bromo-5,11-dihydro-11-ethyl-2-fluoro-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (44 g, 130.5 mmol) in DMF (520 mL) was added NaH (4.28 g, 178 mmol), and the mixture was heated to 50° C. for 30 min. The reaction mixture was cooled to room temperature and treated with MeI (24.4 mL, 522 mmol). After 1.5 h, the reaction mixture was poured over ice water. The solid was filtered, washed with water and then hexane, dried under reduced pressure to give the title compound (43.2 g, 94% yield) as dark grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH2:18][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Clc1ccc(Br)c(CBr)c1
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(OCc2cc(Cl)ccc2Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a solution of 3-methoxyphenol (0.84 mL, 7.3 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (2 g, 7 mmol) in DMF (70 mL) was added potassium carbonate (1.94 g, 14 mmol). The reaction mixture was stirred at room temperature for 16 hours, then poured into water (500 mL) extracted into ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield 1-bromo-4-chloro-2-((3-methoxyphenoxy)methyl)benzene (2 g, 87%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:21](=[O:23])[CH3:22])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc(C2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of 4-(4-bromophenyl)piperidine (400 mg, 1.70 mmol) in dichloromethane (20 mL) was added triethylamine (340 mg, 3.40 mmol) and acetic anhydride (500 mg, 5.10 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue. The material was partitioned between water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was washed two additional times with ethyl acetate (30 mL). The combined organics layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (260 mg, 60% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.27 (d, 2 H), 6.91 (d, 2 H), 4.63 (d, 1 H), 3.77 (d, 1 H), 3.00 (t, 1 H), 2.57-2.42 (t, 2 H), 1.97 (s, 3 H), 1.75-1.68 (m, 2 H), 1.47-1.40 (m, 2 H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][C:8]([CH3:13])([CH3:14])[CH2:7][C:6]2=[O:15]
Reactant: COc1ccc2c(c1)C(=O)CC(C)(C)S2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CC(=O)c2cc(O)ccc2S1
Temperature: -23 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
To a solution of 6-methoxy-2,2-dimethyl-thiochroman-4-one (6.0 g, 27 mmol) in 50 mL CH2Cl2 cooled to −23° C. was added BBr3 (20.0 g, 80.0 mmol; 80.0 mL of a 1M solution in CH2Cl2) over a 20 minute period. After stirring for 5 hours at −23° C. the solution was cooled to −78° C. and quenched by the slow addition of 50 mL of H2O. Upon warming to room temperature the aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with saturated aqueous NaHCO3, H2O, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure gave a green-brown solid which upon recrystallization (Et2O/hexanes) afforded 2.25 g (40%) of 6-hydroxy-2,2-dimethylthiochroman-4-one as a light brown solid. 1H NMR (300 MHz, CDCl3) δ: 7.63 (1H, d, J=2.8 Hz), 7.15 (1H, d, J=8.5 Hz), 7.01 (1H, dd, J=2.8, 8.5 Hz), 2.87 (2H, s), 1.46 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[C:14]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:24].O1CCOCC1>C([O-])([O-])=O.[K+].[K+]>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([N:8]([CH2:9][C:10]([OH:12])=[O:11])[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:15](=[O:24])[NH:16]2)=[CH:21][CH:20]=1
Reactant: O=C(O)CNc1cccc(Cl)c1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)CN(c1cccc(Cl)c1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 3 h
Yield: 37.1 %

Procedure:
At room temperature, (3-Chloro-phenylamino)-acetic acid (1.25 g, 6.8 mmol) was dissolved in 10 ml 1N K2CO3 aqueous solution, then 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (2.5 g, 6.8 mmol) and 10 ml 1,4-dioxane were added slowly. After stirred for about 3 h, the solution was concentrated and the water layer was extracted with CH2Cl2. The organic layer was dried, concentrated to obtain the crude product and the crude product was purified by chromatography to obtain 1.2 g yellow solid rac-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][S:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([S:22]([CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)(=[O:24])=[O:23])=[CH:26][CH:27]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2ccccn2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)Cc2ccccn2)cc1

Procedure:
1 g of 2-(bromomethyl)pyridine hydrobromide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(pyridin-2-ylmethylthio)benzoate. 500 mg of methyl 4-(pyridin-2-ylmethylthio)benzoate was reacted via Procedure R to give methyl 4-(pyridin-2-ylmethylsulfonyl)benzoate. 470 mg of methyl 4-(pyridin-2-ylmethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(pyridin-2-ylmethylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(pyridin-2-ylmethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-2-ylmethylsulfonyl)benzamide. MS (Q1) 464.1 (M)+.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C=C2C(O)=C3C(=C(O)C2=CC=1)C=CC=C3.[O:33]=[O:34]>>[OH:33][OH:34].[CH:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=O
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Agent: Oc1c2ccccc2c(O)c2ccccc12
Product: OO

Procedure:
In all previously known anthraquinone processes, the oxidation reaction and the extraction take place in separate steps, and thus also in separate vessels. The oxidation reaction, in which anthrahydroquinone derivatives react with oxygen, forming hydrogen peroxide and anthraquinone derivatives, takes place in the oxidation reactor. From this reactor the organic working solution, which contains dissolved hydrogen peroxide, is directed to another vessel, wherein the hydrogen peroxide is removed by extracting it with water. In the oxidation reactor there are two phases, an organic working solution and an oxygen-containing gas phase. In the extraction vessel there are two liquid phases, an organic solution and an aqueous phase. Two phenomena essential for the process occur in the oxidation reactor, namely the dissolving of oxygen in the organic working solution and the oxidation reaction in the working solution. The key phenomenon occurring in the extraction vessel is the passing of the hydrogen peroxide from the working solution to the aqueous phase.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8](=[O:17])[C:7]=2[CH:18]=1.CO.[BH4-].[K+].[OH-].[Na+]>O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8]([OH:17])[C:7]=2[CH:18]=1
Reactant: CSc1ccc2ccc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSc1ccc2c(c1)C(O)c1ccccc1C=C2

Procedure:
3-Methylmercapto-5H-dibenzo[a,d]cyclohepten-5-one, 27.9 g. (0.11 mole), is dissolved in 500 ml. of methanol. The solution is stirred and heated to refluxing while a solution of 14.9 g. (0.276 mole) of potassium borohydride in 150 ml. of water containing 0.2 ml. of 10 N. sodium hydroxide is added dropwise. After stirring at reflux for 2 hours, the solution is chilled and the precipitated product collected and washed with methanol yielding, typically, 27 g. (96%). An analytical sample melts at 117°-118.5°C. after repeated recrystallizations from methanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(C)=O.C(OCC)(=O)C>[Cl:7][C:8]1[C:9]([N:23]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[S:24]([CH3:27])(=[O:26])=[O:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2
Reactant: COc1nc2cc(Cl)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Yield: 79.7 %

Procedure:
Anhydrous potassium carbonate (1.60 g, 11.2 mmol) was added to a suspension of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-methanesulphonamide (see Preparation 3, 3.0 g, 9.4 mmol) in acetone (70 ml) with stirring. The mixture was heated at reflux for 15 minutes, cooled, and methyl bromoacetate (1.8 ml, 18.7 mmol) was added. The mixture was then heated at reflux for 2 h, cooled, diluted with ethyl acetate (300 ml) and washed with water (2×100 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate) to give the title compound as a white solid (3.177 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2].[CH3:21][Sn](C)(C)C>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH3:21])[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(C(C)(C)C)sc2c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C)c2nc(C(C)(C)C)sc2c1O
Yield: 89.2 %

Procedure:
A solution of 4-bromo-2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (145 mg, 0.40 mmol), tetramethyl tin (220 μL, 1.6 mmol), dichlorobis(triphenylphosphine)-palladium II (30 mg, 0.04 mmol) in 2.5 mL anhydrous DMF was heated to 130° C. for 1 h. The reaction mixture was cooled, diluted with ethyl acetate, and washed successively with water, saturated sodium bicarbonate, and brine. The organic fraction was dried over anhydrous sodium sulfate, concentrated to a crude residue and purified by column chromatography (eluting from silica gel with a gradient of 10-50% ethyl acetate in hexanes) to give 105 mg of a white solid. MS (ESI−): m/z 293.4 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH3:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.[N:50]1([C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]=[CH:58][N:57]=2)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH3:21])[C:10](=[O:12])[N:53]1[CH2:54][CH2:55][N:50]([C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]=[CH:58][N:57]=2)[CH2:51][CH2:52]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Reactant: Cc1cc(Cl)ccc1CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1CC(NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution containing 2-tert-Butoxycarbonylamino-3-(4-chloro-2-methyl-phenyl)-propionic acid (200 mg, 0.64 mmol) in 30 mL of DMF was added HOBT (0.12 g, 0.76 mmol), EDCI (0.15 g, 0.76 mmol) and NMM (0.19 g, 1.9 mmol) under a nitrogen atmosphere. After stirring for 10 minutes, 4-Piperazin-1-yl-quinazoline (200 mg, 0.93 mmol) was added and stirring continued overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 10% MeOH/DCM gave [1-(4-Chloro-2-methylbenzyl)-2-oxo-2-(4-quinazolin-4-yl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester (0.31 g, 95%.) LCMS (APCI+) m/z 510 [M+H]+; Rt: 2.54 min.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH:5](=[N:4]/[CH2:3][CH2:1][OH:2])\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: NCCO
Solvent: CO
Product: OCC/N=C/c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 88.1 %

Procedure:
To a solution of ethanolamine (1.23 g, 20.1 mmol) in anhydrous MeOH (50 mL) at 0° C. was added benzaldehyde (2.13 g, 20.0 mmol) and molecular sieves (10 pieces). The resulting mixture was gradually warmed to room temperature and stirred for 120 h. The reaction mixture was filtered while rinsing with CH2Cl2. The filtrate was evaporated, and the residue was dried under vacuum overnight to afford off-white oily Compound 1 (2.63 g, 87%). The compound was used for the next step without further purification. 1H NMR (CDCl3) δ 2.40 (s, 1H), 3.70 to 3.80 (m, 2H), 3.85 to 4.0 (m, 2H), 7.35 to 7.50 (m, 3H), 7.68 to 7.79 (m, 2H), 8.32 (s, 1H); 8.11 (d, 2H); 13C NMR (CDCl3) δ 62.28, 63.17, 128.1, 128.52, 130.78, 135.72, 163.10.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:20]=[C:21]([C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][N:28]=2)=[O:26])[CH:22]=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:42][O:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Si:1]([O:18][C:19]1[CH:20]=[C:21]([C:25]([C:27]2[N:28]([C:48]3[CH:47]=[CH:46][CH:45]=[C:44]([O:43][CH3:42])[CH:49]=3)[N:29]=[C:30]3[C:35]=2[CH:34]=[CH:33][CH:32]=[CH:31]3)=[O:26])[CH:22]=[CH:23][CH:24]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1cccc(C(=O)c2n[nH]c3ccccc23)c1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(-n2nc3ccccc3c2C(=O)c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To solution of (3-{[tert-butyl(diphenyl)silyl]oxy}phenyl)(1H-indazol-3-yl)methanone (0.10 g, 0.21 mmol)) in dry CH2Cl2 (4 mL) in a flame-dried flask was added dry pyridine (0.034 mL), anhydrous copper (II) acetate (0.057 g, 0.32 mmol), 3-methoxyphenylboronic acid (0.064 g, 0.42 mmol) and powdered 4 Angstrom molecular sieves (0.25 g). Stir at room temperature for seven days.