Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][C:30]([NH:1][C:2]2[C:3]([C:7]3[NH:23][C:10]4=[CH:11][C:12]5[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=5[CH:17]=[C:9]4[N:8]=3)=[N:4][NH:5][CH:6]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(O)CC1CCCC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)CC4CCCC4)nc3cc21

Procedure:
2-Cyclopentyl-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and cyclopentylacetic acid (111 μl, 0.89 mmol). The title compound was obtained as yellow powder (74 mg, 22%).
Reaction SMILES: [Cl-].C[Al+]C.C([O:7][C:8]([C:10]1[CH:14]=[CH:13][N:12]([CH:15]([CH3:17])[CH3:16])[C:11]=1[CH:18]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)=O)C>>[Cl:34][C:30]1[C:29]([F:35])=[C:28]([N:27]2[C:8](=[O:7])[C:10]3[CH:14]=[CH:13][N:12]([CH:15]([CH3:16])[CH3:17])[C:11]=3[CH:18]2[C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cccc(Cl)c1F)c1ccc(C#N)cc1
Agent: C[Al+]C
Agent: [Cl-]
Product: CC(C)n1ccc2c1C(c1ccc(C#N)cc1)N(c1cccc(Cl)c1F)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Step H1, but dimethylaluminium chloride (1M in hexanes) [1184-58-3] was used instead of trimethylaluminium chloride, and 2-[(3-chloro-2-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step I2) was used instead of 2-[(4-chloro-phenyl)-(4-hydroxy-cyclohexylamino)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester to afford the title compound as a yellow foam. tR: 5.18 min (HPLC 4); ESI-MS: tR=1.11 min, [M+H]+ 394/396 (LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16].[C:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:39]3[C:34]([CH:35]=[N:36][C:37](O)=[N:38]3)=[CH:33][CH:32]=2)[CH:26]=1)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:39]3[C:34]([CH:35]=[N:36][C:37]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH2:10][CH:11]5[CH2:15][CH2:14][CH2:13][N:12]5[CH3:16])[CH:4]=4)=[N:38]3)=[CH:33][CH:32]=2)[CH:26]=1)(=[O:23])=[O:24])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CN1CCCC1COc1cc(N)ccc1Cl
Product: CN1CCCC1COc1cc(Nc2ncc3ccc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)n3n2)ccc1Cl

Procedure:
Prepared by following a procedure analagous to Example 1255c by using 4-Chloro-3-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine and N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide. 1H-NMR (DMSO) δ 9.8 (brs, 1H), 9.7 (s, 1H), 9 (s, 1H), 8.6 (s, 1H), 8.3 (d, J=8.0 Hz, 1H), 7.8 (d, J=8.0 Hz, 1H), 7.7 (t, 1H), 7.6 (s, 1H), 7.5 (d, J=8.7 Hz, 1H), 7.4 (m, 2H), 7.2 (d, J=4.7 Hz, 1H), 7.0 (d, J=4.7 Hz, 1H), 4.2 (m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.1 (m, 1H), 3.0 (s, 3H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H), 1.6 (m, 1H); LC/MS (ESI+): 569 (M+H).
Reaction SMILES: C(OC([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[NH2:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O
Product: CC(C)(N)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a solution of 502 mg (1.34 mmol) of 3-t-butoxycarbonylamino-3-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Example 1, Step I) in 3 mL of methylene chloride at 0° C. was added 0.160 mL (1.47 mmol) of anisole followed by 3 mL of trifluoroacetic acid. The mixture stirred at room temperature for 3 hours. All volatiles were removed under vacuum to give an oil which was dissolved in 10 mL of water. To this solution was added 268 mg (6.7 mmol) of sodium hydroxide and the resulting mixture was stirred until all the solids were dissolved. The solution was transferred to a separatory funnel and the aqueous layer was extracted with chloroform (3×50 mL). The combined organic extracts were washed with brine, dried over sodium surf ate and filtered. The solvent was removed under vacuum to afford 368 mg (100%) of the product as a white solid. 1H NMR (200 MHz, CDCl3): δ 1.27 (s, 6H), 1.95-2.30 (m, 2H), 2.37-2.75 (m, 3H), 2.80-3.02 (m, 1H), 3.48 (s, 2H), 4.52 (m, 1H), 6.97 (m, 1H), 7.1-7.27 (m, 3H), 7.98 (s, 1H), 8.29 (d, 7 Hz, 1H). FAB-MS: calculated for C15H21N3O2 275; found 276 (M+H, 100%).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C@@H:14]([C@H:23]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)OS(C)(=O)=O)[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+]=[N-]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:7]([O:6][C@H:5]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:23]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:1][CH2:4]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)O[C@@H](COCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](CN=[N+]=[N-])OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
1-Azido-1-deoxy-4-O-methanesulfonyl-2,3,5-tri-O-benzyl-L-xylitol (4.5 g, 7.98 mmol) is dissolved in a 1:1 mixture of ethanol and ethyl acetate (30 mL) and Palladium black (0.234 g) is added. The mixture is stirred under hydrogen at atmospheric pressure overnight. The catalyst is filtered off and the solvents evaporated under reduced pressure. Flash chromatography on silica gel and elution with a 95:5 mixture of ethyl acetate and methanol yield 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino-D-arabinitol (2.76 g, 86%) as an oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[Br:1][CH2:2][CH2:3][O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: OCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
To a solution of 2-bromoethanol (15 g, 0.12 mol) in DCM (150 mL) was added PPTS (891 mg, 3.6 mmol), then dihydropyran (10.6 g, 0.126 mol) was added dropwise at 0° C. The mixture was stirred at room temperature for 4 h. It was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (50:1) to give 2-(2-bromoethoxy)tetrahydro-2H-pyran (18.0 g, 72.0% yield) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36]([CH:38]1[O:40][CH2:39]1)Br>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:36][CH:38]1[CH2:39][O:40]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 453) (50 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (54 mg) and epibromohydrin (0.03 ml) were added to the suspension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (58 mg, yield 100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:31])[C:9]1[S:10][C:11]([S:29][CH3:30])=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:18]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:30][S:29][C:11]1[S:10][C:9]([C:8]([NH2:31])=[NH:7])=[CH:13][C:12]=1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:18]=1)(=[O:16])=[O:15]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(N2CCCCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(N2CCCCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of 5-methylsulfanyl-4-(3-piperidin-1-yl-benzenesulfonyl)-thiophene-2-carboxamidine (10 mg, 0.020 mmol, Example 286: step h) in 1 mL of CH2Cl2 under Ar at 0° C. was added 5 drops (˜200 ul) of TFA. The mixture was stirred at 0° C. for 1 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5% MeOH/CH2Cl2) gave 7.5 mg (77%) of product as colorless oil: 1H-NMR (CD3OD, 400 MHz) δ 8.25 (s, 1H), 7.76 (dd, 1H, J=1.6, 1.6 Hz), 7.62 (ddd, 1H, J=7.5, 1.6, 1.6 Hz), 7.56 (ddd, 1H, J=7.5, 1.6, 1.6 Hz), 7.51 (dd, 1H, J=7.5, 7.5), 3.31–3.30 (m, 4H), 2.54 (s, 3H), 1.57–1.56 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C17H21N3O2S3, 396.1 (M+H), found 396.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][S:12][CH3:13])[C:3]=1[NH2:14].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:3]=1[N:14]=[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15])[N:9]2[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CSCCNc1nc(C)nc(Cl)c1N
Reactant: O=Cc1ccccc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CSCCn1c(-c2ccccc2Cl)nc2c(Cl)nc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Heat a mixture of 6-chloro-2-methyl-N4-(2-methylsulfanylethyl)pyrimidine-4,5-diamine (1.63 g, 0.007 mol), 2-chlorobenzaldehyde (1.96 g, 0.014 mol), and 15% FeCl3 on SiO2 (4.89 g) in 1,4-dioxane (15 mL) to 100° C. for 16 h. Cool the reaction and remove the silica by filtration through diatomaceous earth. Concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in dry dichloromethane (10 mL) and add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.58 g, 0.007 mol) at 0° C. Stir the reaction mixture at room temperature for 2 h. Dilute the reaction mixture with dichloromethane, and wash with 1 N aqueous sodium hydroxide solution, water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with ethyl acetate:hexane (15:85) to give the title compound (1.9 g). ES/MS m/z 353 (M+1).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([OH:18])(=[S:17])[CH3:16]>C(OCC)C>[C:15]([S:17][CH:10]([CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:18])[CH3:16]
Reactant: CC(O)=S
Reactant: COC(=O)C=CC(=O)c1ccccc1
Solvent: CCOCC
Product: COC(=O)C(CC(=O)c1ccccc1)SC(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.90 g of methyl 3-benzoylacrylate was dissolved in 30 ml of diethyl ether, and 0.8 ml of thioacetic acid was added thereto. The mixture was stirred for 5 hours at room temperature. The reaction solution was washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. The diethyl ether was removed from the solution by evaporation, and the residue was purified by silica gel column chromatography using a mixture of hexane and diethyl ether as an eluent, and then recrystallized from the same mixture to give 2.42 g of methyl 2-acetylthio-3-benzoylpropionate.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:13]([F:18])[CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(Br)cc1F
Solvent: ClCCl
Product: Fc1cc(Br)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred mixture of phenylboronic acid (1.20 g, 9.85 mmol) and 4-bromo-2-fluorophenol (0.94 g, 4.92 mmol) in DCM (50.00 mL) was added cupric acetate (1.34 g, 7.39 mmol), powdered 4 A molecular sieves and TEA (3.43 mL, 24.6 mmol) at rt. The resulting mixture was then stirred at rt for 24 h at ambient atmosphere. The solvent was then removed under reduced pressure and the resulting residue was purified by flash chromatography (5% EtOAc in hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][C:14]([C:27]([F:30])([F:29])[F:28])=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][C:14]([C:27]([F:30])([F:28])[F:29])=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(C(F)(F)F)ccc23)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(C(F)(F)F)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
To (4-fluorophenyl) (4-(5-methyl-1H-pyrazol-3-ylamino)-7-(trifluoromethyl)quinazolin-2-yl) methanone (500 mg, 1.2 mmol) in a 1:1 mixture of MeOH/THF (10 mL) at 0° C. was added NaBH4 (68 mg, 1,79 mmol). After 10 min of stirring at 0° C., 10 drops of water were added. The solvents were removed under vacuum and the residue was dissolved in a mixture of 1:1 of water EtOAc (20 mL), washed with brine and dried over sodium sulfate. The crude product (360 mg) was purified on reverse-phase preparative HPLC (elution gradient of 40-90% acetonitrile in water with 0.05% acetic acid) to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(trifluoromethyl)quinazolin-2-yl)methanol as white solid (140 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.2 (s, 3 H) 5.9(s, 1H) 6.55 (s, 1 H) 7.35-7.5(m, 3H) 7.9-8.0(m, 1H) 8.05-8.3 (m, 4H) 11.1 (br. s, 1 H) 12.25 (br. s., 1 H) LC-MS (ESI) m/z 418 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[CH2:17]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:17]([O:24][C:25](=[O:38])[C@@H:26]([O:35][CH2:36][CH3:37])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:15][C:14](=[O:16])[CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:30][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCO[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (3.29 g, 15.2 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (4.56 g, 15 2 mmol) in dry DCM (70 mL) was added EDCxHCl (3.49 g, 18.22 mmol) and DMAP (0.37 g, 3.03 mmol) under nitrogen atmosphere. After stirring for 1 h at ambient temperature the mixture was extracted with saturated aq. NaHCO3, aq. HCl (0.05N) and with saturated aq. NaHCO3 again. The organic layer was dried and the remaining crude product purified by HPLC. The title compound was obtained as an oil (4.15 g, 54.7%). 1H NMR (400 MHz, CDCl3): δ 7.99-7.80 (d, 2H), 7.25-7.43 (m, 8H), 7.18-7.20 (d, 2H), 6.99-7.01 (d, 2H), 5.12 (s, 2H), 4.01-4.04 (m, 1H), 3.80 (s, 2H), 3.57-3.61 (m, 1H), 3.31-3.35 (m, 1H), 2.98-3.00 (m, 2H), 2.41 (s, 3H), 1.11-1.15 (t, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:11]=[CH:12][C:5]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
NaH (0.177 g, 4.42 mmol) was added to 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.450 g, 2.95 mmol) in dimethylformamide (“DMF”; 5 mL) at 0° C. The reaction was then warmed to room temperature and stirred for 1 hour. The reaction was then cooled to 0° C. Chlorotriisopropylsilane (0.945 mL, 4.42 mmol) was added to the mixture. The reaction mixture was warmed to 70° C. and stirred for 2 hours. Next, the reaction was poured into water (50 mL) and extracted with DCM (3×50 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated. The resulting residue was purified by column chromatography (10:1 hexanes:DCM) to give 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.55 g, 60.4% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([P:17](Cl)(Cl)=[O:18])[CH3:16]>>[CH2:15]([P:17]1(=[O:18])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:16]
Reactant: CCP(=O)(Cl)Cl
Reactant: c1ccc(CNc2ccccc2)cc1
Product: CCP1(=O)c2ccccc2CN1c1ccccc1
Yield: 6 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and ethyl phosphonic dichloride. The reaction of the dilithio compound and the ethyl phosphonic dichloride was conducted at -76° C. to yield 1-ethyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.45 g, 6% yield) as a pale yellow solid having a melting point of 116°-120° C. and the following analysis:
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:9])=[C:5]1[CH2:10][CH2:11][CH:12]=[O:13])([CH3:3])=[CH2:2].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1.CCOCC>[OH:13][CH:12]1[CH2:11][CH2:10][C:5]2[CH:4]([CH2:8][CH2:7][C:6]=2[CH3:9])[C:1](=[CH2:3])[CH2:2]1
Reactant: C=C(C)C1CCC(C)=C1CCC=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C1CC(O)CCC2=C(C)CCC12
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution, cooled to 0°, of 57 g of 3-isopropenyl-1-methyl-2-(3-oxopropyl)-1-cyclopentene in 3 l of absolute benzene and 800 ml of absolute ether were added dropwise under a nitrogen atmosphere within 30 minutes 900 ml of a 0.5 M solution of tin tetrachloride in benzene. The mixture was stirred for a further 30 minutes at 5°, whereby it became red coloured, then treated at 0° with saturated sodium carbonate solution up to an alkaline reaction and suction filtered. The benzene solution was washed with saturated sodium carbonate solution and water, dried with anhydrous sodium sulphate and evaporated under reduced pressure. The crude product obtained was fractionated on a short column with the addition of 2 g of anhydrous potash. There were obtained 41 g (yield 72%) of 6-hydroxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.5 90°-92°; nD 20 = 1.5233; IR(film):νmax = 3450, 3090, 1640,1450, 1440, 1380, 1200, 1155, 1098, 1080, 1060, 1030, 942, 890, 775 cm-1. The compound has a flowery, camphorous, woody odour.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[OH:36]>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH3:10])[N:7]=2)[CH:24]=[CH:23][C:22]=1[OH:36]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: COc1ccc([C@H](C)Nc2cncc(Cl)n2)cc1
Product: COc1ccc([C@H](C)Nc2cncc(-c3ccc(O)c(OC)c3)n2)cc1
Yield: 35.4 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(15)-1-(4-methoxyphenyl)ethyl]pyrazin-2-amine (149.4 mg, 0.57 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (156 mg, 0.62 mmol) furnished the product (71 mg, 35%).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:50]([F:53])([F:52])[F:51])=[C:13]([N:15]2[C:19](=[O:20])[N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[S:34](=[O:44])(=[O:43])[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:24][C:23]=3[F:45])[C:17]([CH2:46][CH2:47][CH2:48][CH3:49])=[N:16]2)[CH:14]=1>>[C:39]([O:38][C:36]([NH:35][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:18]2[C:17]([CH2:46][CH2:47][CH2:48][CH3:49])=[N:16][N:15]([C:13]3[CH:14]=[C:9]([NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH:10]=[CH:11][C:12]=3[C:50]([F:52])([F:53])[F:51])[C:19]2=[O:20])=[C:23]([F:45])[CH:24]=1)(=[O:44])=[O:43])=[O:37])([CH3:40])([CH3:41])[CH3:42]
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)Nc1ccc(C(F)(F)F)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)OC(C)(C)C)cc3F)c2=O)c1
Yield: 91 %

Procedure:
Valeryl chloride was reacted with 2-[5-amino-2-(trifluoromethyl)phenyl]-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 33, Step D) according to the procedure of Example 26 to give a 91% yield of the title compound as a white solid, mp 179°-182° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 754 (M+Li)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])C.Cl.ClC(OC1C=[CH:32][C:31]([Cl:34])=[CH:30]C=1)=O>CO.O>[Cl:34][C:31]1[CH:32]=[CH:3][C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:15]2)[CH3:8])=[CH:4][CH:30]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN(C[C@H]1CC[C@H](OCCCCO)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(C[C@H]1CC[C@H](OCCCCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the sequence described in examples 1.5 and 1.7, trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester was treated with hydrogen chloride solution in methanol/water followed by acylation with 4-chlorophenyl chloroformate giving trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 370 (MH+, 1Cl).