Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].C[O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[CH:12][C:11]=1Br.[NH:20]1[CH:24]=[CH:23][N:22]=[N:21]1>CN(C=O)C>[Cl:16][C:14]1[C:13]([CH3:17])=[CH:12][C:11]([N:21]2[N:22]=[CH:23][CH:24]=[N:20]2)=[C:10]([CH:15]=1)[C:9]([OH:8])=[O:19]
Reactant: COC(=O)c1cc(Cl)c(C)cc1Br
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2nccn2)c(C(=O)O)cc1Cl
Temperature: 120 °C

Procedure:
Cs2CO3 (742 mg, 2.28 mmol) was added portionwise to a RT solution of 2-bromo-5-chloro-4-methyl-benzoic acid methyl ester (300 mg, 1.14 mmol) in DMF (3 mL) followed by 1H-1,2,3-triazole (0.1 mL, 1.71 mmol), Cu(I)I (13 mg, 0.068 mmol) and DMCDA (40 μL, 0.23 mmol). The resulting suspension was heated to 120° C. for 4 h. The reaction mixture was cooled to RT, quenched with 2M aq. HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by prep. HPLC (method E) to give the title compound as a pale yellow solid. LC-MS A: tR=0.72 min; [M(35Cl)+H]+=238.01.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].O[CH2:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:26][N:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:23][C:24]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:26][N:25]=2)=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)CCc1ccnc(CO)c1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Reaction time: 1 h
Yield: 31.7 %

Procedure:
Under an argon atmosphere, to a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (164 mg), ethyl 3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (99 mg) and triphenylphosphine (248 mg) in THF (1.5 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (430 μL), and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (72 mg) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1.[CH3:12]I>C1COCC1>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([CH2:8][O:9][CH3:12])=[CH:6][CH:7]=1
Reactant: COc1nc(CO)ccc1Br
Reactant: CI
Solvent: C1CCOC1
Product: COCc1ccc(Br)c(OC)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
step 1—A NaH dispersion (226 mg, 5.64 mmol, 60% mineral oil dispersion) was triturated with hexanes (3×10 mL) and dried under a stream of N2 then suspended in THF (23.5 mL) and cooled to 0° C. A solution of 3-bromo-2-methoxy-6-(hydroxymethyl)pyridine (0.88 g, 3.79 mmol) in THF (10 mL) was added drop-wise and the mixture was stirred for 30 min. To the solution was added MeI (1.00 g, 441 μl, 7.05 mmol) and the mixture was warmed to RT. After 1 h the crude reaction mixture was concentrated in vacuo and the mixture was poured into H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed sequentially with H2O, brine, dried, filtered and concentrated to afford 3-bromo-2-methoxy-6-methoxymethyl-pyridine (136) as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:38]([O:42][C:43]([NH:45][C@@H:46]([C:58](O)=[O:59])[CH2:47][S:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:58](=[O:59])[C@@H:46]([CH2:47][S:48][CH2:49][C:50]1[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=1)[NH:45][C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: COc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: COc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of L-proline tert-butyl ester (0.85 g) and hydroxybenzotriazole (0.67 g) in methylene chloride (10 ml) chilled in an ice bath, dicyclohexylcarbodiimide (1.03 g) and N-tert-butyloxycarbonyl-S-p-methoxybenzyl-D-cysteine (1.7 g) are added in that order. After fifteen minutes, the ice bath is removed and the mixture is stirred at room temperature overnight. The precipitate is filtered off and the filtrate is washed with 10% potassium bisulfate, water, saturated sodium bicarbonate, and water. The organic phase is dried and concentrated to dryness in vacuo to give N-tert-butyloxycarbonyl-S-p-methoxybenzyl-D-cysteinyl-L-proline tert-butyl ester as an oil. Rf =0.2 (silica gel, chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 3-nitrobenzylchloride (5 g, 29.14 mmol), N-methylpiperazine (3.9 mL, 34.97 mmol, 1.2 equiv), potassium carbonate (8 g, 58.28, 2 equiv), and acetone (100 ml) is stirred for 15 h at reflux. The reaction mixture is allowed to cool to RT, filtered and concentrated. The residue is purified by silica gel MPLC (DCM/MeOH+1% NH3aq, 95:5) to afford the title compound as a brow oil: ESI-MS: 236.0 [MH]+; tR=1.40 min (purity: 100%, system 1); TLC: Rf=0.31 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH:6]=1.Cl[CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]=1[CH3:19].CO>COCCOC>[CH3:3][O:4][C:5]1[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[N:15]=[CH:16][N:17]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:18]=2[CH3:19])[C:7](=[O:11])[CH:6]=1
Reactant: COC1=CC(=O)NCC1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COC1=CC(=O)N(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)CC1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
Sodium hydride (80% dispersion in oil; 360 mg) was suspended in dry DME (50 ml) under nitrogen and 5,6-dihydro-4-methoxy-2(1H)-pyridinone (1.27 g) in dry DME (20 ml) was added slowly. The resulting suspension was stirred at 20° for 1 h. 4-(Chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (3.72 g) in dry DME (50 ml) was added, and after the initial reaction had subsided the mixture was heated to 50° for 4 h and then cooled. Methanol (5 ml) was added dropwise, and solvent was removed invacuo. 8% Aqueous sodium bicarbonate solution (300 ml) was added to the residue and the resulting solution was extracted with dichloromethane (2×300 ml), dried and evaporated in vacuo to leave an oil which was purified by FCC eluting with System A (200:8:1) to give the title compound (2.84 g), m.p. 181°-184°.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 87.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.49 g, 0.84 mmol) prepared in Example 44a, triethylsilane (0.67 mL), trifluoroacetic acid (0.84 mL) and dichloromethane (8.4 mL), to yield the title compound (318 mg, 88%) as a colorless solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11](=[NH:15])[O:12][CH2:13][CH3:14].[N:16]#[C:17]N>C(O)C.C(OCC)C>[C:17]([N:15]=[C:11]([O:12][CH2:13][CH3:14])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[F:2])#[N:16]
Reactant: N#CN
Reactant: CCOC(=N)Cc1ccc(F)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(Cc1ccc(F)cc1F)=NC#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Example 4A (7.0 g, 29.7 mmol) in ethanol (100 mL) was added a solution of cyanamide (1.25 g, 29.7 mmol) in diethyl ether (25 mL). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then filtered and the filtrate was concentrated to obtain the titled compound. MS (ESI+) m/z 225 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:13]=[C:14]([C:18]2[N:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1>ClCCl>[Cl:3][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:27])([F:26])[F:10])[CH:13]=2)=[N:23][CH:22]=1
Reactant: OCc1ccc(-c2cccc(C(F)(F)F)c2)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2ccc(CCl)cn2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
911 mg (0.56 ml, 7.66 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 970 mg (3.83 mmol) [6-(3-Trifluoromethyl-phenyl)-pyridine-3-yl]-methanol in 30 ml dichloromethane, stirred for 5 min. at 0° C., and at r.t. for 1 h. The mixture is poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), and evaporated. Purification by chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 750 mg (72%) of 5-Chloromethyl-2-(3-trifluoromethyl-phenyl)-pyridine as light yellow crystals
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[BH4-].[Na+]>CO>[F:14][C:2]([F:1])([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH:3]([O:5][CH3:6])[OH:4]
Reactant: COC(=O)C(F)(F)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(O)C(F)(F)c1ccc(F)cc1
Temperature: -57.5 °C
Reaction time: 1.25 h
Yield: 94.6 %

Procedure:
A solution of methyl difluoro(4-fluorophenyl)acetate (2.04 g, 10.0 mmol) from Step E in methanol (10.0 mL) was cooled to −60° C. Sodium borohydride (380 mg, 10.0 mmol) was added in 5 portions at 10 to 15 min. intervals. The mixture was cooled to −60 to −55° C. prior to each addition and allowed to warm to −45° C. following each addition. After the last addition, the mixture was stirred 1.25 h at −50 to −45° C. The mixture was cooled to −60 ° C. and quenched with 1 N aq. HCl (30 mL), with the temperature rising to −20° C. near the end of the addition. After warming to 0° C., the mixture was extracted with ether (3×20 mL). The combined ether layers were washed with water (2×20 mL), dried (sodium sulfate), decanted, and evaporated to give 1.95 g of crude 2,2-difluoro-2-(4-fluorophenyl)-1-methoxyethanol as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f28) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Cu](C#N)[C:13]#[N:14].O>CN1C(=O)CCC1>[C:13]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)#[N:14]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(C#N)cn1
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
A mixture of methyl 5-bromopyridine-2-carboxylate (2.8 g) and copper cyanide (3.6 g) in NMP (30 mL) was heated with stirring at 170° C. for 1.5 hours. Water was added to the reaction solution at room temperature, and the insoluble matter was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate-heptane system) to obtain the title compound (920 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([CH3:14])[C:9](OCC)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH:8]([CH3:14])[CH2:9][OH:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)c1ncccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)c1ncccc1Cl
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a −15° C. solution of the product of Example 38B (1.34 g, 6.27 mmol) in tetrahydrofuran (25 mL) was added lithium aluminum hydride (0.238 g, 6.27 mmol). The reaction mixture was kept between −5° C. and −15° C. for 1 hour and then quenched by the addition of solid sodium sulfate decahydrate. The quenched reaction mixture was filtered through a pad of celite with ethyl acetate and the filtrate concentrated. The residue was chromatographed on silica gel with 35% ethyl acetate-hexane to give the title compound (0.90 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ ppm8.49 (dd, J=1.5, 4.6, 1H), 7.85 (dd, J=1.6, 8.1, 1H), 7.26 (dd, J=4.6, 8.1, 1H), 4.70-4.55 (m, 1H), 3.82-3.62 (m, 1H), 3.59-3.39 (m, 2H), 1.16 (d, J=6.5, 3H). MS (DCI) m/z 172 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O)(=[O:11])=[O:10].[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:34]>>[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[C:26]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])=[C:25]1[CH3:34]
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccc(Cl)cc2Cl)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 27c using 2-(2,4-dichlorobenzenesulfonyl)benzaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:8][C:9]1[CH:17]=[C:16]([C:18]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:20])[CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(Br)c2cc[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2cc(Br)c3cc[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
1-Methyl-piperazine (0.21 g, 2.1 mmol) was added to a solution of 4-bromo-1H-indole-6-carboxylic acid (0.50 g, 2.1 mmol), triethylamine (0.43 mL, 3.1 mmol) and HBTU (0.78 g, 2.1 mmol) in DMF (5 mL) and stirred at room temperature overnight. Reaction mixture was concentrated in vacuo and purified by column chromatography (10% methanol in dichloromethane) to yield 0.30 g (45%) of (4-bromo-1H-indol-6-yl)-(4-methyl-piperazin-1-yl)-methanone. Mass spectrum (LCMS, ESI pos.): Calcd for C14H16BrN3O: 321.05. Found 322.0 ; (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)CC)(=O)[CH2:19][CH3:20].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:17][C:18]([CH2:19][CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(Cc1ccccc1)c1cc(Br)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Intermediate 1 (2.0 g, 6.86 mmoles) was taken in a RB flask and to this triethylamine (16 ml) and propionic anhydride (2.80 g, 21.50 mmoles) were added and the mixture was refluxed for 22 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate : petroleum ether to afford the title compound as off-white solid (0.78 g, 31% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.10(d, J=2.4 Hz, 1H), 7.97(dd, J=8.9,2.4 Hz, 1H), 7.68(d, J=8.9 Hz, 1H), 7.46(m, 3H),7.27(d, J=6.9 Hz, 2H), 2.55(q, J=7.5 Hz, 2H), 1.19(t, J=7.5 Hz, 3H).
Reaction SMILES: CCOCC.Cl.Cl[C:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=2[S:12][C:11]2[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=2[N:9]=1>C(Cl)Cl>[CH:15]1[C:14]2[CH:8]=[N:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[S:12][C:13]=2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2
Temperature: 25 °C

Procedure:
Stir at room temperature a mixture of 4.27 gm. (22.54 mmole) of stannous chloride in 200 ml. of dry ether while passing dry hydrogen chloride through the mixture to saturation. Dissolve 3.42 gm. (11.27 mmole) of the 11-chloro ester of Example 6 in 35 ml. of methylene chloride and add this solution to the stannous chloride solution over a 10 minute period. Pass dry hydrogen chloride through the mixture for 30 minutes and decant the supernatant liquid. Wash the residue by decantation with dry ether. Filter and wash with dry ether. Shake the solids for 2 minutes in a mixture of 25 ml. of 5 N aqueous sodium hydroxide and 25 ml. of methylene chloride. Separate the organic layer and extract the aqueous layer with 25 ml. of methylene chloride. Wash the combined extracts with water, separate the organic layer and dry over magnesium sulfate. Evaporate to a residue. Recrystallize from acetonitrile to obtain the title product, (m.p. 103.5°-109.5° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].[CH2:29](I)[CH3:30]>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:29][CH3:30])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCI
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.5 g of approximately 55 % sodium hydride, and the solution was stirred for 30 minutes. To this was further added 4.7 g of ethyl iodide and stirring was further continued for 1.5 hours at room temperature. After the reaction was complete, the solvent was distilled off from the mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product, which was then recrystallized from methanol to give 2.7 g of 1-(m-nitrophenyl)-3-ethylquinazoline-2,4 (1H, 3H)-dione as light brown prisms, melting at 193°-194° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][NH:11][CH2:12]3)=[CH:3][CH:2]=1>O=[Mn]=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][N:11]=[CH:12]3)=[CH:3][CH:2]=1
Reactant: c1cc2c(c(-c3ccncc3)c1)CCNC2
Agent: O=[Mn]=O
Product: C1=NCCc2c1cccc2-c1ccncc1
Reaction time: 24 h
Yield: 80 %

Procedure:
Intermediate 17B was oxidized using MnO2. After 24 h, the reaction was filtered through Celite® and concentrated to afford 75 mg (80%) of Intermediate 17 as yellow oil. MS (ESI) m/z: 209.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)(=[O:5])=[O:4].[CH2:24]=O>C(O)(=O)C>[F:23][C:2]([F:1])([F:22])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][C:13]2[N:18]3[C:19](=[CH:20][N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)[CH2:24]1)(=[O:5])=[O:4]
Reactant: O=S(=O)(NCCCCNCc1cccc2nccn12)C(F)(F)F
Reactant: C=O
Solvent: CC(=O)O
Product: O=S(=O)(NCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 6.91 g (19.72 mmol) of 5-[N-[4-(trifluoromethanesulfonamido)butan-1-yl]aminomethyl]-imidazo[1,2-a]pyridine in 20 ml of acetic acid was added 22.1 ml (295.8 mmol) of a 37% aqueous solution of formaldehyde. The mixture was heated at 100° C. for 30 minutes. The solvent was then distilled off under reduced pressure, and the residue was dissolved in 100 ml of a saturated aqueous solution of potassium hydrogencarbonate. This solution was neutralized, under ice-cooling, with 1N HCl, which was subjected to extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel chromatography (eluent: chloroform/methanol=20:1) to give 4.86 g (68.0%, pale yellow liquid product).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:17][CH3:18])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([CH3:22])([O-:21])=[O:20].C([O-])(=O)C.[NH4+]>CC(O)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([CH:12]=[CH:22][N+:19]([O-:21])=[O:20])[C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1c(C=O)cccc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1c(C=C[N+](=O)[O-])cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.46 g (18.4 mmol) 3-Benzyloxy-2-methoxy-benzaldehyde (see CN 102451178), 2.96 mL (55.2 mmol) nitromethane and 1.42 g (18.4 mmol) ammonium acetate in 30 mL AcOH are stirred at 100° C. over night. The reaction mixture is cooled to r.t. and quenched by the addition of 20 mL MeOH and 6 mL water. After stirring at r.t. for 1 h, the precipitate is filtered off and dried at 40° C.