Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16](Br)[CH:17]=[CH:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N#N.[NH2:23]C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[NH2:23])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: Brc1cccc(-n2c3ccccc3c3ccccc32)c1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1cccc(-n2c3ccccc3c3ccccc32)c1
Yield: 90 %

Procedure:
8.5 g 9-(3-bromophenyl)-carbazole from step (1b) above, 0.12 g Pd2DBA3 0.11 g dicyclohexylphosphinebiphenyl and 50 mL dioxane were stirred in a glove box (N2). 9.2 g LiN[Si(Me)3]2 and a further 10 mL dioxane were added and the reaction brought to reflux overnight. The reaction was cooled and remove from the glove and water was added slowly. The pH of the aqueous layer was brought to 9 with carbonate and then the mixture was extracted with DCM. The DCM layer was separated and dried over magnesium sulfate then chromatographed on silica eluting with 1:1 ethylacetate:hexanes. The product elutes as a tan solution which on evaporation and addition of methanol produces a tan colored crystalline solid in ˜90% yield. 1-H nmr shows it to be the desired aniline product.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:14][C:15](=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:22]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:14][CH3:15])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H]1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-(dibenzylamino)cyclopentyl]carbamate (320 mg, 0.841 mmol) in THF (2.8 ml) at room temperature was added drop wise lithium aluminium hydride in THF (1 M, 1.3 ml, 1.261 mmol). The reaction was stirred for 1 hour and then was heated to 60° C. for 3 hours. The reaction was then cooled to room temperature and quenched by the addition of sodium sulfate decahydrate, filtered and washed with THF and ethyl acetate. The filtrate was concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)O1>>[NH:33]1[C:34]2[C:30](=[C:29]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([NH:11][CH2:12][CH2:13][OH:14])=[CH:8][C:6]=4[N:7]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: OCCNc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: OCCNc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylamino)ethanol (28 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 21 mg of 226. MS (Q1) 397 (M)+
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5](/[CH:6]=[N:7]/[C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH:23](=[O:27])[CH:24]([CH3:26])[CH3:25].O>O1CCCC1.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]2[C:24]([CH3:26])([CH3:25])[CH:23]([OH:27])[C:17]3[C:8](=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:16]=3)[NH:7]2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(C)C=O
Reactant: COC(=O)c1ccc(/N=C/c2ccc(F)c([N+](=O)[O-])c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
To a suspension of (E)-methyl 4-(4-fluoro-3-nitrobenzylideneamino)benzoate (3.62 g, 12.0 mmol) in tetrahydrofuran (24 mL), yttrium(III) trifluoromethanesulfonate (75 mg, 0.12 mmol) and isobutyraldehyde (0.87 g, 12.0 mmol) were added under nitrogen at room temperature The resultant mixture was stirred at room temperature for 20 hours (turned into clear in 10 min). Water was added to the reaction mixture and extracted with Ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. Solvent was removed and the residue was purified by column (petroleum ether/ethyl acetate=3:1, silica gel) to afford methyl 2-(4-fluoro-3-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate 3.15 g (70%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:8][C@@H:7]1[CH3:35])=[O:5])[CH3:2].N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[CH:9]([N:19]([C:42](=[O:44])[CH3:43])[CH2:20][C:21]2[CH:22]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH2:8][CH:7]1[CH3:35])=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)N1c2cc3c(cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C)CCC3
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc3c(cc2C(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)CC1C)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A solution of cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic acid ethyl ester (Example 1E) (50 mg, 0.1 mmol) and pyridine (0.15 mL, 1.85 mmol) in dichloromethane (2.5 mL) was cooled in an ice water bath as acetyl chloride (0.2 mL, 2.8 mmol) was added by syringe. After stirring overnight at room temperature, the mixture was washed with 2N HCl, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate/hexanes to afford 20 mg of the title compound. MS m/z 542.5 (M+); 1H NMR δ 1.1 (d, 3H), 2.3 (s, 3H), 6.8 (s, 1H), 7.3 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]([NH2:33])=[CH:31][C:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[N:24]1([C:27]2[C:32]([NH:33][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:18][CH2:17][CH2:16][C:15]4=[O:19])[C:3]=3[CH3:20])=[CH:31][C:30]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:29][N:28]=2)[CH2:23][CH2:22][O:21][CH2:26][CH2:25]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidin-2-one (35.0 mg, 0.120 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give 1-(4-((2,5-di-4-morpholinyl-3-pyridinyl)-amino)-5,7-difluoro-3-methyl-2-quinolinyl)-2-pyrrolidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 8.09 (1H, d, J=13.5 Hz), 7.65 (1H, d, J=2.7 Hz), 7.42 (1H, ddd, J=9.6, 2.5, 1.4 Hz), 6.97 (1H, ddd, J=13.7, 8.6, 2.5 Hz), 6.62 (1H, d, J=2.5 Hz), 4.51 (1H, br. s.), 3.92 (4H, br. s.), 3.68-3.86 (4H, m), 3.22-3.52 (3H, m), 3.15-3.22 (4H, m), 3.02 (2H, br. s.), 2.62 (2H, t, J=7.8 Hz), 2.19-2.37 (2H, m), 2.03 (3H, s). Mass Spectrum (ESI) m/e=525.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:23][C:24]([O:26][CH:27]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)C3C=CN=CC=3)=[O:25])=[CH:11][C:12]([O:15][Si](C(C)(C)C)(C)C)=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:23][C:24]([O:26][CH2:27][CH:34]3[CH2:39][CH2:38][N:37]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)[CH2:36][CH2:35]3)=[O:25])=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Nc1cc(O)ccc1NC(=O)c1ccc(Cl)cc1)OCC1CCN(c2ccncc2)CC1
Reaction time: 18 h
Yield: 124.8 %

Procedure:
A solution of N1-(4-chlorobenzoyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbony)-4-(tert-butyldimethylsilyloxy)-1,2-benzenediamine (97 mg, 0.16 mmol) in tetrahydrofuran (2 mL) was treated with 5 N aqueous hydrochloric acid (0.5 mL) and allowed to stand at ambient temperature for 18 h. Volatile solvents were removed in vacuo and the residue diluted with dilute sodium hydrogen carbonate solution, hexane, and methylene chloride. The mixture was sonicated 5 min then filtered. The resultant material was vacuum dried to yield 48 mg (61%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[S:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[C:4]=2[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.O.[CH3:27][N:28](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[S:20][C:3]3[C:2]([C:27]#[N:28])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=4)[C:4]=3[C:18]=2[CH:24]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(CNc2ncc(Br)c3sc4ccc(Cl)cc4c23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1ccc(CNc2ncc(C#N)c3sc4ccc(Cl)cc4c23)cc1
Reaction time: 0.17 h

Procedure:
A mixture containing 4-bromo-8-chloro-N-(4-methoxybenzyl)[1]benzothieno[3,2-c]pyridine-1-amine, Zn(CN)2 (1.2 equiv) and Pd(Ph3P)4 (0.1 equiv) in DMF (0.1 M) was placed in microwave reactor at 150° C. for 10 min. The reaction was poured into H2O, filtered and washed with MeOH.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.[CH2:28]([O:35][CH2:36][C:37]1([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:42][CH2:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH2:28]([O:35][CH2:36][C:37]1([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:42][CH2:41][C:40]([C:2]2[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]3[N:25]=[CH:26][CH:27]=[C:4]3[N:3]=2)=[CH:39][CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Reactant: CCOC(=O)C1(COCc2ccccc2)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(COCc2ccccc2)CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: 90 °C
Yield: 65.8 %

Procedure:
A mixture of 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (2.99 g, 6.97 mmol), ethyl 1-(benzyloxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (8.36 mmol), PdCl2(dppf)CH2Cl2 (683 mg, 0.836 mmol), and K3PO4 (5.32 g, 25.1 mmol) in dioxane/H2O (40/2 mL) was degassed and then heated at 90° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-20% EtOAc/Hexanes, Rf=0.45 in 20% EtOAc) to afford ethyl 1-(benzyloxymethyl)-4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohex-3-enecarboxylate as a pale yellow oil (3.06 g). HPLC-MS TR=3.17 min (UV 254 nm, 5 min method); mass calculated for formula C35H54N4O5Si2 666.4, observed LCMS m/z 667.3 (M+H).
Reaction SMILES: Cl.[CH2:2]([CH:9]([CH2:14][N:15]1[CH2:20][CH2:19][C:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([F:21])[CH2:17][CH2:16]1)[C:10]([O:12]C)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[ClH:28].[CH2:2]([CH:9]([CH2:14][N:15]1[CH2:16][CH2:17][C:18]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([F:21])[CH2:19][CH2:20]1)[C:10]([OH:12])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(Cc1ccccc1)CN1CCC(F)(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)CN1CCC(F)(c2ccc(Cl)cc2)CC1
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of methyl 2-benzyl-3-[4-(4-chlorophenyl)-4-fluoropiperidin-1-yl]propionate hydrochloride in methanol (2.5 mL) was added 50% aqueous sodium hydroxide solution (1 mL) and the resulting solution heated to reflux under N2 for 14 hours. After this time the reaction was cooled and concentrated. The residue was treated with 2N hydrochloric acid (6 mL) and the mixture stirred for 1 hr. The reaction was then extracted with 2-butanone (3×10 mL) and the extracts dried over magnesium sulfate, filtered and concentrated. The oily residue was re-dissolved in EtOAc (10 mL) re-filtered and concentrated. The residue was then re-dissolved in 2-butanone and concentrated to afford a yellow foam. This material was dried under high vacuum for 16 hours to afford a 55% yield of the title compound as a yellow foam.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([C@H:43]2[CH2:47][CH2:46][O:45][CH2:44]2)[C:39](=[O:48])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([C@H:43]4[CH2:47][CH2:46][O:45][CH2:44]4)[C:39](=[O:48])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1cc(Br)ccn1[C@H]1CCOC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn([C@H]3CCOC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 71 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-1-[(S)-tetrahydro-furan-3-yl]-1H-pyridin-2-one following a procedure analogous to that described in Example 1. Yield: 71% of theory; LC (method 3): tR=2.95 min; Mass spectrum (ESI+): m/z=517 [M+H]+.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=2[CH3:16])[CH:7]=[CH:8][CH:9]=1.BrCCC[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[C:24]([C:4]1[C:5]([O:17][CH2:13][CH2:12][CH3:11])=[C:6]([C:10]2[CH2:11][CH:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=2[CH3:16])[CH:7]=[CH:8][CH:9]=1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1cccc(O)c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1c(C(=O)OCC)cccc1C1=C(C)NC(=O)C(C#N)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.8 %

Procedure:
A dispersion of 337 mg (14.0 mmol) of 60% sodium hydride in mineral oil and 5 ml of DMF is treated, dropwise, with a solution of 1.60 g (7.0 mmol) of 5-(3-hydroxyphenyl)6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile. The reaction is stirred 30 min at RT, then cooled in an ice bath and 1.36 g (7.0 mmol) of ethyl 4-bromobutyrate in 5 ml of DMF is added dropwise. The reaction is allowed to slowly come to RT and stirred over night. The mixture is concentrated under vacuum, the residue is taken up in 80 ml of water, extracted with EtOAc, acidified to pH=5 with IN HCl, and the aqueous phase extracted with EtOAc (4×80 ml). The EtOAc is dried (MgSO4) and the solvent removed to leave a light yellow solid. This solid is triturated with hot ether and filtered to give 1.40 g of 5-(3-carboethoxy-propyloxyphenyl)-6-methyl-2-oxo-1,3-dihydro-3-pyridinecarbonitrile as a pale yellow solid, m.p. 168°-169° C. 1H-NMR (d6 -DMSO): δ1.20 (t,3H); 1.95 (m,2H); 2.15 (s,3H); 2.50 (t,2H); 4.03 (q,2H); 4.05 (t,2H); 6.95 (m,3H); 7.30 (m,1H); 8.10 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14].[CH3:15][O:16][C:17]1[CH:28]=[CH:27][C:20]([CH:21]([OH:26])[C:22](OC)=[O:23])=[CH:19][CH:18]=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:22](=[O:23])[CH:21]([C:20]1[CH:27]=[CH:28][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[OH:26]
Reactant: COc1ccc(CCN)c(Cl)c1OC
Reactant: COC(=O)C(O)c1ccc(OC)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)C(=O)NCCc2ccc(OC)c(OC)c2Cl)cc1
Yield: 69.4 %

Procedure:
16.86 g of (2-chloro-3,4-dimethoxyphenyl)ethylamine obtained in step 4 was reacted with 15.33 g of methyl 4-methoxymandelate obtained in step 5 at 130° to 140° C. in a nitrogen gas atmosphere for 1.5 hour. After cooling, the reaction mixture was dissolved in 30 ml of ethyl acetate and purified by silica gel chromatography. After development with ethyl acetate/n-hexane (1/1) and then with ethyl acetate, 20.6 g (69%) of N-(2-chloro-3,4-dimethoxyphenylethyl)-4-methoxymandelamide was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C[O:6][C:7]([C:9]1[C:13]([NH:14][C:15]([C:17]2[C:22]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:21][CH:20]=[C:19]([CH:30]3[CH2:32][CH2:31]3)[N:18]=2)=[O:16])=[CH:12][N:11]([CH3:33])[N:10]=1)=O>>[OH:4][CH2:3][CH2:2][NH:1][C:7]([C:9]1[C:13]([NH:14][C:15]([C:17]2[C:22]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:21][CH:20]=[C:19]([CH:30]3[CH2:32][CH2:31]3)[N:18]=2)=[O:16])=[CH:12][N:11]([CH3:33])[N:10]=1)=[O:6]
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: NCCO
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NCCO)n1
Yield: 6 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-amino-ethanol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (6%) as amorphous yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][C:16](=O)[N:17]3[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCc1ccccc1
Yield: 100.8 %

Procedure:
0.3557 g (0.00936 mol) of lithium aluminum hydride was suspended in 40 ml of THF under argon. A solution of 3.01 g (0.00936 mol) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenethyl-2H-benzo[e]indol-2-one in 40 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 2 hours. 10 ml of ethyl acetate and a saturated aqueous Na2SO4 solution were cautiously added dropwise thereto in succession until a complete white precipitate had resulted. After filtration and concentration there were obtained 2.9 g (100%) of oily rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenethyl-1H-benzo[e]indole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30]C1C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][CH3:30])=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1ccc(CCCc2cc(CO)ccc2OCc2ccccc2)cc1
Solvent: CO
Product: COCc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)OC)cc2)c1
Yield: 66.2 %

Procedure:
To a solution of methyl 4-[3-(2-benzyloxy-5-hydroxymethylphenyl) propyl]benzoate (5.31 g) in methanol (100 ml) was added 4-methylbenzenesulphonic acid (3.11 g). The reaction was heated at reflux for 18 hours, the solvent evaporated, the residue dissolved in EtOAc, washed with brine and the solvent evaporated to give methyl 4-[3-(2-benzyloxy-5-methoxymethylphenyl)propyl]benzoate (3.64 g).
Reaction SMILES: [F:1][C:2]([F:23])([P:13](=[O:22])([O:18]C(C)C)[O:14]C(C)C)[P:3](=[O:12])([O:8]C(C)C)[O:4]C(C)C.C[Si](Br)(C)C.C(N(CCCC)CCCC)CCC>C(#N)C.CN(C=O)C>[F:23][C:2]([F:1])([P:3](=[O:4])([OH:12])[OH:8])[P:13](=[O:14])([OH:18])[OH:22]
Reactant: CC(C)OP(=O)(OC(C)C)C(F)(F)P(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=P(O)(O)C(F)(F)P(=O)(O)O
Temperature: 41 °C
Reaction time: 24 h
Yield: 300.4 %

Procedure:
To a stirred solution of tetraisopropyl difluoromethylenediphosphonate (2.0 g, 5.26 mmol) in anhydrous acetonitrile (30 mL) was added dropwise trimethylsilyl bromide (4.17 mL, 31.58 mmol). The resulting solution was stirred at 40-42° C. for 24 h, concentrated to dryness, and coevaporated with anhydrous acetonitrile once. The residue was re-dissolved in an acetonitrile/water mixture, and then coevaporated with DMF. The residue was dissolved in a DMF solution of tributylamine (1.93 g, 2.48 mL, 10.43 mmol), transferred into multiple small flasks, concentrated to dryness, and coevaporated with anhydrous DMF three times. The residue was dried in a vacuum oven at 40° C. for 4 h to give a slightly yellow residue (3.35 g).
Reaction SMILES: [CH2:1]([C@:17]12[CH2:25][CH2:24][C:23]3[C:26]4[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[CH:30][C:31]=4[CH2:32][CH2:33][C:22]=3[C@@H:21]1[CH2:20][CH2:19][C:18]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:1]([C@:17]12[CH2:25][CH2:24][C:23]3[C:26]4[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[CH:30][C:31]=4[CH2:32][CH2:33][C:22]=3[C@@H:21]1[CH2:20][CH2:19][C@@H:18]2[OH:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCCCCCCCCCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O
Reaction time: 2 h

Procedure:
Stir a solution of 13β-cetyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (0.60 g.) and sodium borohydride (0.20 g.) in ethanol (110cc.) for 2 hours and leave overnight. Reflux with stirring for 2 hours, cool, and add an excess of 50% aqueous acetic acid. Evaporate the mixture to dryness under reduced pressure and partition the residue between ether and water. Work up in the usual manner to get an ether solution of the title product as a gum; infrared absorption peak at 3.37 μ (hydroxyl) with no band in the 5.71-5.88 mμ region; ultraviolet absorption peak at 278 mμ.