Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]Br.C(OCC)C.[NH4+].[Cl-]>O1CCCC1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([OH:19])[CH3:27])[NH:15][C:12]2=[CH:13][N:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (Example 139) (2.89 g, 8.46 mmol) in tetrahydrofuran (42 mL) was added 3.0 M methylmagnesium bromide in diethyl ether (7.05 mL, 21.2 mmol). The reaction mixture was stirred overnight (16 h) under a nitrogen atmosphere at room temperature. The reaction mixture was poured into a stirring saturated NH4Cl solution. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4. After filtration and concentration, a small amount of the desired product was obtained by trituration with CH2Cl2. Additional material was obtained by purification using Biotage chromatography on silica (eluting with Hex/EtOAc 90:10 to 0:100) to provide 1-[5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]ethanol (1.74 g, 57%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ1.53 (3H, d, J=6.6 Hz), 4.69 (4H, s), 4.90-4.99 (1H, m), 6.08 (1H, s), 6.58 (1H, s), 7.17-7.29 (10H, m), 8.26 (1H, s); ESI MS m/z 358 [C23H23N3O+H]+; HPLC (Method A) 98.5% (AUC), tR=18.2 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[CH2:14]([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[CH2:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][OH:21])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CCOCCCCCCBr
Reactant: OCCCCCCO
Product: CC(C)CCOCCCCCCOCCCCCCO

Procedure:
The above compound may be produced in analogous manner to that described in Example 13, but using 1-bromo-6-isopentyloxy hexane and 1,6-hexandiol.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1C(OCC)=O.Cl.[NH4+].[OH-]>>[C:7]1([N:6]2[C:2]([NH2:1])=[CH:3][CH:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccnn1-c1ccccc1
Yield: 94 %

Procedure:
5-Amino-4-carbethoxy-1-phenylpyrazole (1 eq.) was dissolved in 36% HCl solution (30 eq.) and the reaction mixture was stirred under reflux for overnight. The mixture was cooled, poured onto ice and made basic with NH4OH. The mixture was extracted with DCM (×3). The combined organic fractions were washed with brine, dried (Na2SO4), and the solvent was evaporated under reduced pressure to obtain the product as pale yellow oil in 94% yield. MS (ES+) C9H9N3 requires 159, found: 160 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[S:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:27]1[CH2:28][CH2:29][S:25][CH2:26]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: C1CSCN1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCSC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, thiazolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.51 minutes; C19H16Cl2N4O2S (435.33); mass spectrum: (M+H)+=435.1.
Reaction SMILES: [H-].[K+].Cl[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)CC(NC3C=CC(F)=CC=3)=O)=[CH:13][C:12]=2[F:31])[CH:7]=[CH:6][N:5]=1.ClC1C=CN=CC=1>CN(C=O)C>[F:31][C:12]1[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=1[O:10][C:8]1[CH:9]=[CH:4][N:5]=[CH:6][CH:7]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1)Nc1ccc(F)cc1
Agent: Clc1ccncc1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccncc2)c(F)c1
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
Potassium hydride (30%, 0.520 g, 3.90 mmol, 3.0 eq) was added to a solution of 2-fluoro-4-aminophenol (Compound A of Example 20, 0.254 g, 2.00 mmol, 1.5 eq) in DMF (5.0 mL) at room temperature and the reaction mixture was stirred for 15 minutes. 4-Chloro-pyridine (Aldrich, 0.200 g, 1.30 mmol, 1.0 eq) was added and the reaction mixture was heated to 150° C. for 2 h. The reaction mixture was cooled to room temperature, quenched with 1N NaOH and the solution extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with 1N aqueous NaOH (2×30 mL) followed by 10% aqueous LiCl (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a solid. 1H NMR (DMSO-d6) δ 8.44-8.46 (m, 2H), 6.89-7.03 (m, 1H), 6.87-6.88 (m, 2H), 6.44-6.56 (m, 2H), 5.51 (s, 2H); MS(ESI+) m/z 205 (M+H)+; HRMS(ESI+) calcd.: 205.0777, found: 205.0775.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[S-:14][C:15]#[N:16].[NH4+].O>S1(CCCC1)(=O)=O>[NH2:16][C:15]1[S:14][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: N#C[S-]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [NH4+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1
Temperature: 150 °C
Yield: 134.7 %

Procedure:
A suspension of 5.06 g of 2,4-dinitrochlorobenzene and 7.6 g of ammonium thiocyanate in 25 ml of sulpholane is heated, with stirring, to 150° C. and maintained at this temperature for 1.5 hours. The product is discharged into 300 ml of water, and the solid is filtered off with suction and washed with water. After drying, 6.57 g of crude 2-amino-5-nitrobenzothiazole are obtained. The identity was confirmed by TLC comparison (TLC=thin-layer chromatography) with authentic material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10](=[O:20])[NH:9]1.[N+]([O-])(O)=O.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10](=[O:20])[N:9]=1
Reactant: CCOC(=O)C1=C(C)NC(=O)NC1c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1c(-c2ccccc2F)nc(=O)[nH]c1C
Temperature: 25 °C
Yield: 75.4 %

Procedure:
Ethyl 4-(2-fluorophenyl)-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-5-carboxylate (2.00 g, 7.2 mmol) was added in small portions to a stirred solution of a 60% nitric acid solution (12 mL) at 0° C. over 5 min. The resulting solution was warmed to room temperature (30 min) and then poured into ice and basified slowly with 6N NaOH. The product was extracted with CHCl3 (3×50 mL), dried, and concentrated. The residue was purified by Biotage SP1 on packed silica gel column (7%-20% MeOH/CH2Cl2 gradient) to give ethyl 4-(2-fluorophenyl)-1,2-dihydro-6-methyl-2-oxopyrimidine-5-carboxylate as a green foam (1.5 g, 76%). Mass Spec. LCMS 277 (M+1).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C:12]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[C:22]([O:36][CH:37]4[CH2:40][CH2:39][CH2:38]4)=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]([O:33][CH3:34])=[O:32])[C@@H:26]([CH3:35])[CH2:25][CH2:24]4)[N:20]=2)([OH:15])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[CH:37]1([O:36][C:22]2[C:21]([C:19]3[N:20]=[C:16]([C:12]4([OH:15])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]4)[S:17][CH:18]=3)=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][C@H:26]([CH3:35])[N:27]3[C:31]([O:33][CH3:34])=[O:32])[CH2:38][CH2:39][CH2:40]1
Reactant: COC(=O)N1c2ccc(-c3csc(C4(O)CCN(C(=O)OC(C)(C)C)CC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3csc(C4(O)CCNCC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
HCl (4 M in 1,4-dioxane, 0.58 mL, 2.30 mmol) was added to a solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.128 g, 0.230 mmol) in 1,4-dioxane (1.0 mL), and the reaction mixture stirred at rt for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane and then filtered through a plug of silica gel (eluting with 10% ethanol-ethyl acetate). The filtrate was concentrated to afford methyl (S)-5-cyclobutoxy-6-(2-(4-hydroxypiperidin-4-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (62 mg, 59%). 1H NMR (300 MHz, DMSO-d6) 6 ppm 1.11 (d, J=6.45 Hz, 3H), 1.22-1.72 (m, 6H), 1.93-2.24 (m, 7H), 2.39-2.49 (m, 2H), 2.71-2.96 (m, 4H), 3.69 (s, 3H), 4.05-4.20 (m, 1H), 4.47 (dq, J=13.05, 6.50 Hz, 1H), 5.88 (s, 1H), 7.33 (d, J=8.79 Hz, 1H), 7.69 (d, J=8.50 Hz, 1H), 7.77 (s, 1H). MS (ESI, pos. ion) m/z 458 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CS(O[CH2:23][CH2:24][O:25][CH2:26][CH3:27])(=O)=O>CN(C)C=O>[CH2:24]([O:25][CH2:26][CH2:27][O:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCOCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
3.06 g of a 55% sodium hydride dispersion in oil were washed with hexane and covered with 85 ml of dimethylformamide. 17.0 g (71.6 mmol) of t-butyl [4-hydroxyphenethyl]carbamate [see F. Rocchiccioli et al., Tetrahedron, 34, 2917 (1978)] were then added while cooling with ice and the reaction mixture was stirred at room temperature for 15 minutes. After cooling to 0° a solution of 12.04 g (71.6 mmol) of 2-ethoxyethyl methanesulfonate in 85 ml of dimethylformamide was added dropwise within 10 minutes and the reaction mixture was subsequently stirred at room temperature for 24 hours. Thereafter, the reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed on 240 g of silica gel with a mixture of hexane and ethyl acetate as the eluting agent and subsequently recrystallized from ether/hexane, whereby there were obtained 19.1 g of t-butyl [ 4-(2-ethoxyethoxy)phenethyl]carbamate, melting point 56°-57°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:34])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([Br:34])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1

Procedure:
A mixture of 2,3-dibromo-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (4.05 g), and NBS (1.61 g) in MeCN (30 mL) was refluxed for 10 min, then the reaction mixture was cooled with ice/water bath, the precipitates were collected as the desired product (1.418 g). The title compound, ESI MS (m/z): 583 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]=[CH:12][N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[CH3:18][N:19]([CH3:23])[C:20](=[S:22])[S-:21].C[NH2+]C>C(=S)=S>[CH3:18][N:19]([CH3:23])[C:20](=[S:21])[S:22][CH:11]([CH2:12][N+:13]([O-:15])=[O:14])[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([O:16][CH3:17])[C:5]=1[O:4][C:1](=[O:3])[CH3:2]
Reactant: CN(C)C(=S)[S-]
Reactant: COc1cccc(C=C[N+](=O)[O-])c1OC(C)=O
Agent: C[NH2+]C
Solvent: S=C=S
Product: COc1cccc(C(C[N+](=O)[O-])SC(=S)N(C)C)c1OC(C)=O

Procedure:
As in Example 17, reaction of 2-methoxy-6-(2-nitrovinyl)phenyl acetate from Example 22 with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 2-acetoxy-3-methoxy-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 124° 125.5° C. after recrystallization without heating from dimethylformamide-methanol solution.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[K+]>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][N:12]=[C:11]([C:23]([OH:25])=[O:24])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 11.8 g (28 mmol) of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid, phenylmethyl ester in 115 ml of tetrahydrofuran were added 16 ml water and 35 ml of 1N potassium hydroxide. After stirring overnight at room temperature, 115 ml water was added and the pH was adjusted to 2.5 with 1N hydrochloxic acid. The acid was filtered off, washed with water and dried in vacuo. Yield: 8.6 g; melting point 203.6° C.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9](=[O:25])[CH:10]([O:22][CH2:23][CH3:24])[N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:20])[C:12]2=[O:21])=[C:5]([OH:28])[CH:4]=1)#[N:2].I[CH2:30][C:31]([NH2:33])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:31]([CH2:30][O:28][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:27]=[CH:26][C:6]=1[CH2:7][NH:8][C:9](=[O:25])[CH:10]([O:22][CH2:23][CH3:24])[N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:20])[C:12]1=[O:21])(=[O:32])[NH2:33]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1O)N1Cc2c(C)cccc2C1=O
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(C(=O)NCc1ccc(C#N)cc1OCC(N)=O)N1Cc2c(C)cccc2C1=O
Yield: 21.7 %

Procedure:
(RS)-N-(4-Cyano-2-hydroxy-benzyl)-2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide (300 mg) was dissolved in acetonitrile (10 ml) and treated over night under vigorous stirring at ambient temperature with iodoacetamide (223 mg) and cesium carbonate (411 mg). Pouring onto crushed ice/NH4Cl, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents, followed by flash column chromatography (silica gel, AcOEt/MeOH=10/1), afforded 75 mg of (RS)-N-(2-carbamoylmethoxy-4-cyano-benzyl)-2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide as white solid, MS 437.4 ([M+H]+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:30])[C@H:24]([O:26]C(=O)C)[CH3:25])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1.[OH-].[Na+].Cl>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:30])[C@@H:24]([CH3:25])[OH:26])[S:20][CH:21]=3)[CH2:14][CH2:15]2)=[CH:2]1
Reactant: CC(=O)O[C@H](C)C(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H](O)C(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reaction time: 1 h
Yield: 43.3 %

Procedure:
In ethanol (5 ml) was dissolved 4-[4-(3-indolyl)piperidinomethyl]-2-[(2R)-2-acetoxypropionylamino]thiazole (1 g) and under ice-cooling, 1N aqueous sodium hydroxide solution (2.34 ml) was added. The mixture was stirred for 1 hour at the same temperature and, then, for 1.5 hours at ambient temperature. Thereafter, 1N aqueous sodium hydroxide solution (0.7 ml) was further added and the mixture was stirred at ambient temperature for another 2 hours. The reaction mixture was then neutralized with 1N hydrochloric acid and concentrated under reduced pressure. The residue was extracted with a mixture of chloroform and methanol (10:1 V/V) and the extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (10:1 V/V) to give 4-[4-(3-indolyl)piperidinomethyl]-2-(D-lactoylamino)thiazole (0.39 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.CN(C)C(=N)N(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:11][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1Cl)C(Cn1ccnc1)c1ccccc1
Yield: 12 %

Procedure:
A solution of 1-(2,4-dichlorophenyl)-2-phenylpropen-1-one (4 g), imidazole (1.36 g) and tetramethylguanidine (0.5 ml) in tetrahydrofuran (100 ml) was heated at reflux for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure to yield a gum. The gum was dissolved in ethyl acetate, washed with distilled water, and acidified with 4N hydrochloric acid. The resulting aqueous phase was basified with sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was separated, washed with distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield an oil which was chromatographed on silica gel in methanol/dichloromethane (1:9) to yield 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-phenylpropan-1-one (600 mg), which was treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-phenylpropan-1-one, m.p. 110° C., (Found: C, 55.38; H, 4.37; N, 7.40; C18H15Cl3N2O.1/2H2O requires C, 55.34; H, 4.13; N, 7.17) having the formula: ##STR12##
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([NH2:22])=[CH:20][N:19]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C[Al](C)C.CCCCCCC.[Br:53][C:54]1[CH:55]=[C:56]2[C:60](=[CH:61][CH:62]=1)[C:59](=O)[O:58][CH2:57]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.O>[Br:53][C:54]1[CH:55]=[C:56]2[C:60](=[CH:61][CH:62]=1)[C:59](=[O:58])[N:22]([C:21]1[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:12][CH:11]=4)[N:14]=3)[N:19]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=1)[CH2:57]2
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1OCc2cc(Br)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: C[Al](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cc(Br)ccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (332 mg, 0.5942 mmol) dissolved in PhMe (5 mL) and AlMe3 in heptane (1.783 mL of 1.0 M, 1.783 mmol) added at RT under N2. After 30 minutes, a solution of 5-bromo-3H-isobenzofuran-1-one (253 mg, 1.188 mmol) in DCM (5 mL) added with cooling in an ice bath. RM stirred overnight, temperature rising to ambient. RM re-cooled in an ice bath and water (3 mL) added slowly. After 5 minutes, RM diluted with DCM. Resulting mixture filtered to remove bulk of Al salts. Brine added and the layers separated. Aqueous extracted with DCM (×2). Combined organics dried and concentrated to a brown foam (514 mg). This material dissolved in THF (6 mL) under N2 and PPh3 (233.8 mg, 0.8913 mmol) then DEAD (112 μL, 0.7130 mmol) added. Mixture stirred overnight at RT. RM concentrated and residue partitioned between DCM and brine. Aqueous phase extracted with DCM and combined extracts dried and concentrated. Residue treated with 1:1 DCM:MeOH and resulting pale yellow solid collected by filtration and dried under vacuum to give title compound (293 mg, 65%); 1H NMR (400 MHz, DMSO) δ 0.98 (6H, d), 3.28 (1H, sep), 5.40 (2H, s), 5.55 (2H, s), 7.05-7.18 (15H, m), 7.48 (1H, d), 7.55 (1H, dd), 7.74 (2H, d), 7.87 (1H, s), 8.28 (2H, d), 8.39 (1H, s), 8.67 (1H, s); MS (ES+) 754.0.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([Br:18])=[CH:20][C:21]=1[F:26])(=[O:3])[CH3:2]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Reactant: Nc1ccc(Br)cc1F
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) were added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), then 4-bromo-2-fluoroaniline (0.891 g, 4.69 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.42 g, 82%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)=[C:5]2[CH:4]=[N:3]1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([NH:19][C:27]([NH:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:28])[CH:16]=[CH:17][CH:18]=3)=[C:5]2[CH:4]=[N:3]1
Reactant: O=C=Nc1ccccc1
Reactant: Cn1ncc2c(C#Cc3cccc(N)c3)cncc21
Solvent: ClCCl
Product: Cn1ncc2c(C#Cc3cccc(NC(=O)Nc4ccccc4)c3)cncc21

Procedure:
In analogy to GP 5, 100 mg of 3-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-ylethynyl)-phenylamine (Intermediate 3.1, 0.26 mmol, 1 eq.) were treated with 31 μL phenyl isocyanate (0.29 mmol, 1.1 eq.) in 2.6 mL DCM at rt. Aqueous work-up followed by HPLC purification provided the target compound.