Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:30])[C:26]([NH2:29])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8](=[NH:9])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:30])[C:26]([NH:29][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a solution of 1j (50 mg, 0.117 mmol) in 0.5 mL pyridine at 0° C. was added methanesulfonyl chloride (14.8 mg, 0.129 mmol). The solution was stirred at rt for 16 h. The mixture was diluted with 50 mL EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated to afford 13 mg (22%) of intermediate 16a. MS (ESI) 505.0 (M+H+).
Reaction SMILES: [C:1]([NH:9][CH:10]([P:12]([CH:17](Br)[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:16])[O:13][CH2:14][CH3:15])Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:28]([O:35]CC)([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31]>>[C:1]([NH:9][CH:10]([P:12]([CH:17]([P:28]([O:29][CH2:30][CH3:31])([O:32][CH2:33][CH3:34])=[O:35])[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:16])[O:13][CH2:14][CH3:15])[P:28]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: CCOP(=O)(C(Br)NC(=O)c1ccccc1)C(Br)NC(=O)c1ccccc1
Product: CCOP(=O)(OCC)C(NC(=O)c1ccccc1)P(=O)(OCC)C(NC(=O)c1ccccc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the bromide 7 (195 mg; 0.38 mmol) and triethyl phosphite (130 μl; 0.76 mmol) in abs. THF (50 ml) is concentrated under reduced pressure after stirring at room temperature for 4 hours. A mixture of the diastereomeric phosphinic acid esters 14 (145 mg, 64% of theory after recrystallization from ethyl acetate) is obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])(=[O:3])[CH3:2].Cl.[CH:16]([CH:18]=[CH2:19])=[O:17]>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:19][CH2:18][CH:16]=[O:17])(=[O:3])[CH3:2]
Reactant: C=CC=O
Reactant: C=CCCCCCCCCOC(C)=O
Agent: Cl
Product: CC(=O)OCCCCCCCCCCCCC=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
To a stirred 1.0 Molar solution of borane·tetrahydrofuran complex, 90 ml (0.09 mole), was added dropwise 57 grams (0.27 mole) of 9-decenyl acetate. The reaction mixture temperature was maintained at 20°-25° C. during the addition. Upon completion of addition, the reaction mixture stirred at ambient temperature for 18 hours. After this time 2 ml of aqueous 3M hydrochloric acid was added, and the reaction mixture was stirred for five minutes. To this was then added 5.0 grams (0.09 mole) of acrolein, during which time the reaction mixture temperature rose to 35° C. The reaction mixture was concentrated under reduced pressure to a residual oil. The oil was taken up in pentane and was washed with three 30 ml portions of an aqueous solution saturated with sodium bicarbonate. The organic layer was concentrated under reduced pressure to a residual oil. Volatile materials were removed from the oil by distillation under reduced pressure yielding 4.9 grams of 13-oxotridecyl acetate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17](Br)[CH:18]=3)[NH:13][C:12](=[O:21])[C:11]=1[C:22]1[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=1)[CH2:2]2.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)[CH:18]=3)[NH:13][C:12](=[O:21])[C:11]=1[C:22]1[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=1)[CH2:2]2
Reactant: O=c1[nH]c2ccc(Br)cc2c(N[C@@H]2CN3CCC2CC3)c1-c1nc2ccccc2[nH]1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(-c2ccc3[nH]c(=O)c(-c4nc5ccccc5[nH]4)c(N[C@@H]4CN5CCC4CC5)c3c2)cc1
Temperature: 90 °C

Procedure:
A vial was charged with the hydrochloride salt of 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-yl)-6-bromoquinolin-2(1H)-one (1.0 equivalent) and 4-methoxyphenyl boronic acid (1.3 equivalents). To this solution was added DME and 2 M aqueous Na2CO3 (10%). The mixture was degassed by bubbling argon through the solution for 5 minutes. Pd(dppf)2Cl2.CH2Cl2 (0.2 equivalents) was then added to the degassed solution. The mixture was heated at 90° C. for 16 hours, and the top organic layer was separated and filtered. The solvent was removed, and the residue was purified by reverse phase HPLC affording the desired product. MS m/z 492.6 (M+H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[CH2:22]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:21]=[CH2:20]
Reactant: COC(=O)CNCc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN(CC(=O)OC)Cc1ccccc1
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of methyl 2-(benzylamino)acetate (21.30 g, 119.2 mmol, 1.0 eq) in DMF (150 mL) was added anhydrous K2CO3 (8.02 g, 143.02 mmol, 1.2 eq) followed by allyl bromide (12.37 mL, 143.02 mmol, 1.2 eq) at room temperature. The mixture was stirred for 4 h, quenched with water and extracted with EtOAc (100 mL×3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) PE/EtOAc) to afford the title compound as colorless oil (18.30 g, 70%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ: 3.27 (2H, d, J=6.4 Hz), 3.32 (2H, s), 3.68 (3H, s), 3.78 (2H, s), 5.19 (2H, m), 5.88 (1H, m), 7.23-7.35 (5H, m) ppm.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2].[CH3:26]OS(OC)(=O)=O>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[C:15]([N:17]([CH3:26])[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCN1CCCC1CNC(=O)c1cc(NS(=O)(=O)CC)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCCC1CNC(=O)c1cc(N(C)S(=O)(=O)CC)ccc1OC
Yield: 26.8 %

Procedure:
To a solution of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-ethanesulfonamidobenzamide (266 mg) in dry acetone (7 ml), potassium carbonate and dimethylsulfate (100 mg) are added, and the resultant mixture is refluxed for 30 minutes. After evaporating the acetone, the residue is mixed with water and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is dissolved in methylene chloride, and the resultant mixture is chromatographed on a column of alumina, which is eluted with methylene chloride. After evaporating the eluate to remove the methylene chloride, the residue is washed with isopropyl ether and recrystallized from ethyl acetate/isopropyl ether in that order to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-(N-methylethanesulfonamido)benzamide (74 mg) as crystals melting at 85° to 87° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:30]Br>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:11]([Br:30])[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (5.0 g, 15.2 mmol; Example 32, step 5) and sodium bicarbonate (19.2 g, 228 mmol) in dichloromethane (150 mL) at 0° C., a solution of bromine in dichloromethane (0.5 M, 32 mL, 16 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with a hexane-ethyl acetate gradient to provide the titled product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][O:24][CH3:25]>CN(C=O)C.O>[CH3:25][O:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 60 °C
Yield: 76.4 %

Procedure:
To methyl 5-hydroxy-2-nitrobenzoate (1.08 g, 5.5 mmol) in DMF (50 mL) was added potassium carbonate (1.52 g, 11 mmol) followed by 1-bromo-2-methoxyethane (1.55 mL, 16.4 mmol) and the mixture heated at 60° C. overnight. After cooling to room temperature, the reaction was diluted with H2O, extracted with EtOAc, and the organic layer washed with H2O and brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (12-100% EtOAc/hexanes) to give methyl 5-(2-methoxyethoxy)-2-nitrobenzoate (1.08 g, 4.2 mmol, 77%). 1H NMR (300 MHz, DMSO-d6) δ 8.13 (d, 1H), 7.31 (s, 1H), 7.29 (d, 1H), 4.29 (dd, 2H), 3.86 (s, 3H), 3.68 (dd, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 256 (M+H)+.
Reaction SMILES: CO[C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:21][C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[CH3:31][O-:32].[Na+]>>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:29])[C:22]=1[N:21]1[C:7]2[N:8]=[C:9]([O:32][CH3:31])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]1=[O:30]
Reactant: COC(=O)/C=C/c1c(Nc2c(F)cccc2F)nc(SC)nc1-c1ccccc1F
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(-c2ccccc2F)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(2,6-difluoro-phenyl amino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and sodium methoxide to afford the title compound 8-(2,6-difluoro-phenyl)-4-(2-fluoro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.82 (s, 3H), 6.56 (d, 1H, J=9.6 Hz), 7.08 (m, 2H), 7.26-7.59 (m, 6H). LC MS (m/e)=384 (MH+). Rt=2.22 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[S:13])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[N:14]=[C:12]([C:11]2[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][CH:10]=2)[S:13][CH:5]=1
Reactant: Cc1ccc(C(N)=S)cc1
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc(CCl)cs2)cc1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
To a solution of 1,3 dichloroacetone (0.84 g, 6.62 mmol) in toluene (5 ml) was added 4-methylthiobenzamide (0.50 g, 3.31 mmol) and the reaction mixture was heated at 120° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 15% EtOAc-Hexane) to get the desired product (0.49 g, 67%). The other derivatives were also prepared by the same general method.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10](=[O:15])[CH:11]=[C:12](C)[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.CC(C)(C=CC)CC(=[O:21])C>>[CH3:1][C:2]12[O:21][C:3]1([C:10](=[O:15])/[CH:11]=[CH:12]\[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7]2
Reactant: CC(C)=CC(=O)C1C(C)=CCCC1(C)C
Reactant: CC=CC(C)(C)CC(C)=O
Product: C/C=C\C(=O)C12OC1(C)CCCC2(C)C

Procedure:
MS: M+ = 208 (0.1); m/e: 193 (1); 175 (0.1); 165 (0.1); 151 (15); 135 (2); 123 (9); 111 (6); 95 (4); 81 (2); 69 (100); 55 (18); 41 (26) 29 (3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[C:20]([N:26]=[C:27]=[S:28])=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:27](=[S:28])[NH:26][C:20]1[C:19]([Cl:18])=[CH:24][C:23]([Cl:25])=[CH:22][N:21]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ncc(Cl)cc2Cl)c1NCCCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.1 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (3.13 g, 12.1 mmol) and 3,5-dichloro-2-isothiocyanatopyridine (3.23 g, 15.7 mmol) in tetrahydrofuran (40 mL) was stirred at room temperature for 3 days. The mixture was concentrated in vacuo, and the residue was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (3.43 g, 7.4.0 mmol, 61%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)=[O:2].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:35].[K+]>O>[C:9]([N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[S:7][C:3]([C:1]([OH:35])=[O:2])=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C=O)s1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C(=O)O)s1

Procedure:
25 g of N-(5-formyl-thien-2-yl)-N-hexadecylacetamide are dissolved in 20 cc. of pyridine. A solution of 6.7 g of potassium permanganate in 90 cc. of pyridine and 40 cc. of water is added with stirring and cooling such that the temperature of the reaction mixture does not rise above -3° C. Stirring is continued until all of KMnO4 has been reacted. Thereafter, the solvents are distilled off, the residue is triturated with dilute hydrochloric acid and the mixture is extracted with chloroform. The chloroform layer is separated, washed with water and dried over Na2SO4. The solvent is evaporated and the resulting crude product is purified chromatographically on a column of silicic acid gel using chloroform as eluant.
Reaction SMILES: O[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P(Cl)(Cl)([Cl:13])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:13][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(O)c1cccnc1Cl
Reaction time: 12 h

Procedure:
Heat a mixture consisting of 24.4 g of 2-hydroxy nicotinic acid and 42 ml. of phosphorous oxychloride to 100°-108° C and hold for 1 hour. Add 36.4 g of phosphorous pentachloride and heat the resulting mixture at reflux for another hour. Remove the excess phosphorous oxychloride in vacuo and pour the viscous residue on ice with stirring. Age the resulting slurry at room temperature for about 12 hours. The slurry is filtered, washed and dried to yield 2-chloro-nicotinic acid, m.p. 190° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[NH2:16]Cl>CN(C=O)C.CCOCC>[N:1]1([NH2:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: NCl
Reactant: c1cnc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
A solution of pyrrolo[2,3-b]pyridine (16.9 mmol) and potassium tert-butoxide (33.8 mmol) in DMF (76 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (169.2 mL) is added drop-wise at rt and the reaction mixture is stirred at rt for 2 h. The reaction mixture is quenched with 5% Na2S2O3 aqueous solution (100 mL), and extracted with ether for three times. The combined organic layer is washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 60-80% EtOAc in heptane to afford pyrrolo[2,3-b]pyridin-1-ylamine (703 mg, 31%) as a solid. MS: 134 (M+H); 1H NMR (300 MHz, CDCl3): δ 5.04 (br, 2N—H), 6.35 (d, H), 7.09 (m, H), 7.35 (m, H), 7.91 (m, H), 8.34 (d, H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:17][C:18]=3[O:23][CH:24]([CH3:26])[CH3:25])[N:13]=2)=[CH:7][C:6]=1[CH3:31].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN(C=O)C>[CH3:31][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:17][C:18]=3[O:23][CH:24]([CH3:26])[CH3:25])[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: Cc1cc(-c2nc3cc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCBr
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nc3cc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one (0.39 g, 0.79 mmol) in DMF (10 mL) was added pyrrolidine (0.45 g, 6.37 mmol). The reaction mixture was stirred at room temperature for 4 hours. Then, water was added and product was extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Solvent was evaporated to give the title compound as a white solid. Yield: 0.32 g (83%). MP 65-68° C. 1H NMR (400 MHz, CDCl3): δ 9.05 (br s, 1H), 7.63 (s, 2H), 6.78 (s, 1H), 6.42 (s, 1H), 4.70 (m, 1H), 4.63 (m, 1H), 3.94 (m, 2H), 2.94 (m, 2H), 2.64 (br s, 4H), 2.38 (s, 6H), 1.84 (m, 4H), 1.46 (m, 3H), 1.42 (m, 3H). MS (ES) m/z: 480.29 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11](=[O:20])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.C[Si]([I:32])(C)C.II>C(Cl)Cl>[I:32][CH:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[NH:12][C:11]1=[O:20]
Reactant: COc1ccc(C2CC(=O)Nc3ccccc3C2)cc1
Reactant: C[Si](C)(C)I
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2Cc3ccccc3NC(=O)C2I)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (-20° C.) solution of 500mg (1.87mmole) of 2,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1H-1-benzazepin-2-one in 10 mL of methylene chloride was added triethylamine (1.04g, 9.35 mmol, 5eq.) followed by trimethylsilyl iodide (749mg, 3.74mmol, 2eq.). After 15 minutes, 950 mg (3,74 mmol, 2eq) of iodine was added and the brown mixture was stirred at 0° C. for one hour. The reaction mixture was diluted with methylene chloride, washed with aqueous sodium bisulfite solution, water and brine and then dried (MgSO4). Filtration followed by evaporation of the solvent under vacuum gave the product as a mixture of cis and trans isomers (675 mg,92%). FAB-MS: calculated for C17H16NO2I 393; found 393 (100%), 394 (20%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([O:31][CH2:32]Cl)=[CH:29][CH:28]=1>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:32][O:31][C:30]3[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=3)[C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: ClCOc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(COc2ccc(Cl)cc2)c(=O)c2c1ncn2Cc1ccccc1
Reaction time: 1 h

Procedure:
2.59 g (19.0 mmol) of potassium carbonate were added at 60° C. to a suspension of 3.0 g (12.0 mmol) of 7-benzyl-3-methylxanthine (prepared according to Example 1a) in 50 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 2.69 g (15.0 mmol) of 4-chlorophenoxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 8 hours. The crude mixture was then filtered, the filtrate was concentrated under reduced pressure, the residue was taken up in dichloromethane, and the solution was washed once with 1 N sodium hydroxide solution and twice with water. The organic phases were dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19.8/0.2) Yield: 4.15 g (87% of theory); melting point: 96° C.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:29][N:30]1[CH2:34][CH2:33][C@@H:32](O)[CH2:31]1>C(Cl)(Cl)Cl>[CH3:29][N:30]1[CH2:34][CH2:33][C@@H:32]([O:16][C:15]([CH:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:17])[CH2:31]1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: CN1CC[C@@H](O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN1CC[C@@H](OC(=O)C2c3ccccc3Oc3ccccc32)C1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
2 g of 9H-Xanthene-9-carboxylic acid (0.0088 mol) were dissolved in 30 ml of CHCl3 (ethanol free). The solution was cooled at 0° C. and 1.08 ml (0.0123 mol) of oxalyl chloride and a drop of DMF was added. The mixture was stirred and allowed to warm to room temperature. After an hour at this temperature the solvents were evaporated and the residue was dissolved in CHCl3 and evaporated again. This procedure was repeated two times. The solid obtained (2.19 g) was dissolved in 20 ml of CHCl3 and added to a solution of 0.975 g (0.0097 mol) of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19) in 15 ml of CHCl3 cooled at 0–5° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in toluene and extracted with HCl 2N. The aqueous layer was basified with K2CO3 and extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to yield 2.53 g (93%) of the title product as an oil.