Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH:23][C:24]([C:26]5[C:27]([Cl:32])=[N:28][CH:29]=[CH:30][CH:31]=5)=[O:25])[CH:21]=[CH:22][C:16]=4[CH2:15][CH2:14][C:13]=3[C:12]([C:33]([NH2:35])=[O:34])=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[Cl:32][C:27]1[C:26]([C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:16]3[CH2:15][CH2:14][C:13]4[C:12]([C:33]([NH2:35])=[O:34])=[N:11][N:10]([C:7]5[CH:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][CH:6]=5)[C:18]=4[C:17]=3[CH:19]=2)=[O:25])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CC(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4cccnc4Cl)ccc2CC3)cc1
Reaction time: 14 h
Yield: 50 %

Procedure:
A mixture of 1-(4-acetylphenyl)-8-{[(2-chloropyridin-3-yl)carbonyl]amino}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (200 mg, 0.41 mmol) in MeOH (3 mL) and water (0.3 mL) was added NaBH4 (10 mg, 0.25 mmol) at RT and stirred for 14 h. The mixture was separated on silica gel column (EtOAc) to give product (100 mg, 50%). 1H NMR was consistent with its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:14])[CH2:9][CH2:10][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: FC1(c2ccc(Cl)cc2)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(F)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
To a solution of the product of Step 1 (252 mg, 1.18 mmol) in isopropyl alcohol (5 mL) was added 2,6-lutidine (197 mg, 214 uL, 1.84 mmol) and potassium iodide (few mg). The resulting suspension was warmed to 80° C. Solid 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (221 mg, 0.591 mmol) was added in approximately equal portions over 2 h. Stirring was continued an additional 20 h at 80° C. The mixture was concentrated and the resulting residue purified by silica gel chromatography (methylene chloride to methylene/methanol 95:5 gradient) to afford the title compound (160 mg, 54%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:19][O:20][Si](C(C)(C)C)(C)C)[O:11][S:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[K+]>CO>[CH2:1]([O:8][CH2:9][CH:10]([CH2:19][OH:20])[O:11][S:12][CH2:13][C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CSOC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CSOC(CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
1-O-Benzyl-3-O-t-butyldimethylsilyl-2-(ethoxycarbonylmethylthio)glycerol (1 g) was added to a solvent mixture of water (8 ml) and methanol (16 ml), and potassium hydroxide (1 g) added thereto and the mixture stirred overnight at room temperature. The reaction mixture was extracted with ethyl ether twice to remove the impurities, and the pH of the extract was adjusted to 1 to 2 with 6N hydrochloric acid. Then the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product (0.6 g).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:14])=[CH:8][CH:7]=1.[Li+].[OH-]>>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:25])=[O:2])=[CH:7][CH:8]=1)=[O:14]
Reactant: COC(=O)C=Cc1ccc(NC(=O)c2ccc3ccccc3c2)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C=Cc1ccc(NC(=O)c2ccc3ccccc3c2)cc1

Procedure:
Using an analogous method (H5), the title compound was prepared from 3-{4-[(naphthalene-2-carbonyl)-amino]-phenyl}-acrylic acid methyl ester (4c) (0.940 g, 2.16 mmol) and LiOH in a form of white solid (0.757 g, 83%). 1H NMR (DMSO-d6, HMDSO), δ: 6.51 (1H, d, J=16.0 Hz); 7.44-8.22 (12H, m); 8.63 (1H, s); 10.64 (1H, s).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[O:40]1CCCC1>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:40])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(Cl)cn5)n4)c3CO)ncc2c1
Reactant: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(Cl)cn5)n4)c3CO)ncc2c1

Procedure:
1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-chloro-pyridin-2-ylamino)-1H-pyrazole-4-carbonitrile (111 mg, 0.204 mmol) and dihydrogen tris(dimethylphosphinito)hydroplatinate (10.5 mg, 0.025 mmol) were taken up in tetrahydrofuran (3.8 ml) and water (0.38 ml). The material was stirred and heated to reflux (oil bath) for 1 hour. The mixture was cooled to ambient and the volatiles were stripped (rotary evaporator). The crude remainder was purified by preparative thin layer chromatography (2 plates, eluting first with 7% methanol in methylene chloride and then re-developing again with 7% methanol in methylene chloride). The product band was collected, providing the desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-chloro-pyridin-2-ylamino)-1H-pyrazole-4-carboxylic acid amide as an off-white powder (70 mg). LC/MS calc'd for C28H25ClFN7O3 (m/e) 561.99, obs'd 562 (M+H, ES+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=C=O>>[CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:19]1([CH2:18][C:11]([NH2:10])=[O:13])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C=NCC1CCCCC1
Agent: O=C1CN(Cc2ccccc2)C(=O)N1
Product: NC(=O)CC1CCCCC1

Procedure:
1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and isocyanatomethylcyclohexane (87.8 mg, 0.63 mmol) were reacted in analogy to example 1. Yield: 36.8 mg (21%), M+H+: 330.18.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[C:28]([F:31])([F:30])[F:29])=[N:21][CH:22]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[F:31][C:28]([F:29])([F:30])[C@@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:20]1[N:19]=[CH:18][C:17]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=2)=[CH:22][N:21]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CC1(C)OB(c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cncc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A round bottom flask was charged with 6-chloropyrazin-2-amine (0.401 g, 3.09 mmol), (S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine (1.062 g, 3.09 mmol), Pd(PPh3)4 (0.358 g, 0.309 mmol) and 1,4-Dioxane (Volume: 7.74 ml). The reaction mixture was purged with nitrogen for several minutes before an aqueous 2M sodium carbonate (3.09 ml, 6.19 mmol) was added. The reaction mixture was purged for another 10 minutes under nitrogen before it was placed in a 90° C. oil bath and allowed to stir overnight. 1,4-Dioxane was removed in vacuo and the crude mixture was diluted with EtOAc. The product was wash with water (3×) and brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel using normal phase flash chromatography, eluting with CH2Cl2:MeOH to yield 0.655 g (2.11 mmol, 68.2%) of the title product; 1H NMR (300 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.26 (s, 1H), 7.83 (s, 1H), 6.55 (s, 2H), 5.16-5.02 (m, 1H), 3.77-3.60 (m, 2H), 2.29-2.01 (m, 4H); m/z [M+H]+=311.12
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][C:26]([C:30]#[N:31])=[C:27]([CH3:29])[N:28]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:38]>C(OCC)(=O)C>[ClH:38].[NH2:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][C:26]([C:30]#[N:31])=[C:27]([CH3:29])[N:28]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C#N)s3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C#N)s3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
Tert-butyl[4-butoxy-6-(5-cyano-4-methyl-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.21 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was crystallized from ethyl acetate-diisopropyl ether to give 2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carbonitrile hydrochloride (0.17 g, 94.4%) as crystals.
Reaction SMILES: [N+](C)([O-])=O.C[C:6]([O:8][CH2:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21])=O.N>[Br-].[Zn+2].[Br-].CO.O>[NH2:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH2:9][O:8][CH3:6])[CH2:19][S:18][C@H:13]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of nitromethane were added 2.72 g of 7-ACA, 8 g of zinc bromide and 0.9 g of methanol. The mixture was heated at 60° C. for 80 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture were added 10 ml of water and 5 ml of methanol. Then, the mixture was adjusted to pH 7.5 with aqueous ammonia at a temperature of from 0° C. to 5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 3.5 with 36 % hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.71 g. The yield of the desired product was 29 %.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.CO[C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH2:29]Br)=O)=[CH:23][CH:22]=1>CCOC(C)=O>[C:24]1([C:27]2[NH:9][C:6]3[C:7]([CH:29]=2)=[CH:8][CH:3]=[CH:4][CH:5]=3)[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: c1ccc(-c2cc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a boiling mixture of in-anisidine (1.56 ml, 20.0 minol) and N,N-dimethylaniline (3.5 ml) was added 2-bromo-4-methoxyacetophenone (1.37 g in EtOAc, 6.00 mmol) slowly by syringe. After addition, the mixture was kept at 170° C. for 1 hour. The reaction mixture was cooled to room temperature and a dark colored solid was formed. EtOAc was added along with HCI (2 N). The aqueous layer was extracted with EtOAc several times. The combined organic layers were washed with brine, and dried over MgSO4. Solvent was removed under the reduced pressure to afford a dark brown colored solid. Purification by recrystallization in EtOH afforded indole 31 as a white crystallinc material.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:15]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[C:20]([Cl:30])[CH:19]=1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN(C)C=O>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:27][C:26]([NH:25][C:21]2[C:20]([Cl:30])=[CH:19][C:18]([C:15](=[O:17])[CH3:16])=[CH:23][C:22]=2[Cl:24])=[O:29])[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(=O)c1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2C)c(Cl)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 12 parts of (1,1-dimethylethyl)-3-methyl-1-piperazinecarboxylate, 18.7 parts of N-(4-acetyl-2,6-dichlorophenyl)-2-chloroacetamide, 11.8 parts of N,N-diethylethanamine and 230 parts of N,N-dimethylformamide was stirred first for 8 hours at 70° C. and then over weekend at room temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The desired fraction was collected and the eluent was evaporated, yielding 27 parts (100%) of (1,1-dimethylethyl)-4-[2-[(4-acetyl-2,6-dichlorophenyl)amino]-2-oxoethyl]-3-methyl-1-piperazinecarboxylate as a residue (int. 21).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](O)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8](C(=O)C2C=CC=CC=2)[CH2:7]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1
Reactant: COCCCN1CCC(O)(c2ccccc2)C(C(=O)c2ccccc2)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
30 g. of 1-(3-methoxypropyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine are suspended in 225 ml. of anhydrous benzene. 50 g. of finely pulverized, anhydrous aluminum chloride are added thereto within 20 minutes, while stirring. The reaction temperature increases during said addition up to 60° C. The reaction mixture is then kept at from 50° to 55° C. for about 1 hour, is cooled to room temperature, and is added to a mixture of ice and concentrated hydrochloric acid. The benzene layer is separated from the aqueous layer by means of a separating funnel and is washed once with dilute hydrochloric acid. The combined aqueous layers are rendered alkaline by the addition of 40% sodium hydroxide solution. The precipitated base is separated by repeated extraction with ether. The combined ether extracts are dried over anhydrous potassium carbonate and the ether is distilled off. 21 g. of the crude base remain as residue. On distillation in a high vacuum, pure 1-(3-methoxypropyl)-4,4-diphenylpiperidine is obtained in the form of a light oil boiling at 130° C./0.01 mm. Hg.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:18]Br)=[CH:8][C@@H:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[P:20]([O:29]C(C)C)([O:25][CH:26]([CH3:28])[CH3:27])[O:21][CH:22]([CH3:24])[CH3:23]>>[C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:18][P:20]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:29])=[CH:8][C@@H:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)[C@@H](C=C(CBr)CCOC(C)=O)NC=O
Product: CCOC(=O)[C@@H](C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h
Yield: 32.3 %

Procedure:
21.2 g (63.1 mmol) of ethyl 6-acetoxy-4-bromomethyl-2(R)-formylamino-hex-3-enoate and 69.1 ml (252.2 mmol) of 90% triisopropyl phosphite are heated to 80° C. and the mixture is stirred for 18 hours under a pressure of 100-150 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is purified by flash chromatography on silica gel with ethyl acetate/ethanol (19:1), giving 8.6 g of ethyl 6-acetoxy-2(R)-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate a yellowish-orange oil. ee=92.5%; αD -90.2°±0.4° (c=2.84 CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24](Br)=[N:23][CH:22]=[C:21]([Cl:26])[N:20]=2)(=[O:17])=[O:16])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24]([O:8][CH2:7][C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[N:23][CH:22]=[C:21]([Cl:26])[N:20]=2)(=[O:17])=[O:16])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Nc1nc(Cl)cnc1Br)c1ccc(Cl)s1
Reactant: Cc1cc(CO)no1
Product: Cc1cc(COc2ncc(Cl)nc2NS(=O)(=O)c2ccc(Cl)s2)no1

Procedure:
Prepared by the method of Example 20b using (5-methyl-3-isoxazolyl)methanol and 5-chloro-N-(3-bromo-6-chloro-2-pyrazinyl)-2-thiophenesulphonamide.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)CCC.C(OC([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)C)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH:29]1[CH:33]=[C:32]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=[N:30]1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 1000 mL round bottom flask was charged with 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (10.00 g, 35.23 mmol), 1-butanol (25.0 mL), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.66 g, 52.85 mmol), water (25.0 mL) and potassium carbonate (12.17 g, 88.08 mmol). This solution was degased 4 times, filling with nitrogen each time. To the solution was added tetrakis(triphenylphosphine)palladium(0) (4.071 g, 3.523 mmol). The solution was degased 4 times, filling with nitrogen each time. The mixture was stirred overnight at 100° C. After being cooled to room temperature, the mixture was filtered through a bed of celite and the celite was rinsed with ethyl acetate (42 mL). The filtrate was combined, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined and concentrated under vacuum with a bath temperature of 30-70° C. to give the final compound 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine. Yield: 78%. LC-MS: 316.2 (M+H)+.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][C:2]=1[C:10]1[C:11]([NH2:27])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=NN(C3CCNCC3)[CH:20]=2)[CH:15]=1.[CH3:28][C:29]1(C)[C:33](C)(C)OB(C2C=CC(O)=CC=2)[O:30]1.[F-].[Cs+]>CO.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:27][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH:20]=[CH:33][C:29]([OH:30])=[CH:28][CH:17]=2)=[CH:15][C:10]=1[C:2]1[O:3][C:4]2[C:9]([N:1]=1)=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccnc2o1
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: Nc1ncc(-c2ccc(O)cc2)cc1-c1nc2cccnc2o1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 1460.8 %

Procedure:
A mixture of 5-bromo-3-oxazolo[5,4-b]pyridin-2-yl-pyridin-2-amine (1 g, Example 9 starting material), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.794 g), bis(triphenylphosphine) palladium(II) chloride (0.121 g) and caesium fluoride (1.56 g) in methanol (17 ml) was heated at 120° C. for 20 min in a microwave oven. The reaction was repeated and the reaction mixtures were combined. The resulting mixture was concentrated, then diluted with water (400 ml) and stirred for 30 min. The resulting solid was filtered, washed with water (4×150 ml), dried, washed with diethyl ether (4×150 ml) and dried overnight to give 4-(6-amino-5-oxazolo[5,4-b]pyridin-2-yl-3-pyridyl)phenol (12.3 g) as a solid. NMR Spectrum: (DMSOd6) 6.88 (d, 2H), 7.50-7.57 (m, 3H), 7.72 (bs, 2H), 8.28 (dd, 1H), 8.37-8.42 (m, 2H), 8.53 (d, 1H), 8.55 (bs, 1H); Mass spectrum: M+H+ 355
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.P([S-])(OCC)(OCC)=[S:24]>C(OCC)(=O)C.Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[C:11](=[S:24])[NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(C#N)CCc2cccc(Br)c2)cc1
Reactant: CCOP(=S)([S-])OCC
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(CCc2cccc(Br)c2)C(N)=S)cc1
Yield: 73 %

Procedure:
By a reaction in the same manner as in Example 178a and using the compound (3.94 g, 11.0 mmol) obtained in Example 181a, 4M hydrogen chloride-ethyl acetate solution (40 mL) and O,O-diethyl dithiophosphate (2.43 mL, 14.5 mmol), the title compound (3.15 g, 73%) was obtained as a colorless oil.
Reaction SMILES: C([Li])CCC.[I:6]I.Br[C:9]1[CH:10]=[C:11]([Cl:16])[C:12]([Cl:15])=[N:13][CH:14]=1>C(OCC)C.CCCCCC>[Cl:15][C:12]1[C:11]([Cl:16])=[CH:10][C:9]([I:6])=[CH:14][N:13]=1
Reactant: Clc1cc(Br)cnc1Cl
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Clc1cc(I)cnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In one embodiment of the present invention, 5-bromo-2,3-dichloropyridine is dissolved in ethyl ether and cooled to about -78° C. A slight excess molar quantity of n-butyl lithium, dissolved in hexane, is slowly added to the reaction mixture with mild agitation. After about 0.5 hour of stirring, a slight excess molar quantity of I2, dissolved in ethyl ether, is added to reaction mixture with mild agitation. After about 0.5 hour of stirring, the reaction mixture is allowed to warm to room temperature and the 2,3-dichloro-5-iodopyridine is isolated employing standard separatory and purification techniques.