Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(Cl)Cl.N1CCCCC1.[CH:45]([C:47]1([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:49][CH2:48]1)=O>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:45][C:47]3([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:48][CH2:49]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)NC1(C=O)CC1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NC1(C=C(C#N)C(=O)N2CCC[C@@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)CC1
Yield: 29.1 %

Procedure:
To a solution of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (100. mg, 0.2100 mmol) dissolved in methanol (4 mL) and DCM (4 mL) was added piperidine (0.1 mL, 0.8500 mmol) and tert-butyl N-(l-formylcyclopropyl)carbamate (58.9 mg, 0.3200 mmol). The reaction was heated to reflux for 6 hrs and then cooled and concentrated. The residue was and dissolved in ethyl acetate (50 mL) and washed with water (50 mL) and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by Isolera (1%-8% MeOH/DCM) to provide 39 mg (13% yield) of tert-butyl N-[1-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]cyclopropyl]carbamate.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1[CH:18]=[C:17]([CH2:19]Br)[C:16]([CH2:21]Br)=[CH:15][CH:14]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:1]1([S:7]([C:10]2([C:11]#[N:12])[CH2:19][C:17]3[C:16](=[CH:15][CH:14]=[CH:13][CH:18]=3)[CH2:21]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1CBr
Reactant: N#CCS(=O)(=O)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: N#CC1(S(=O)(=O)c2ccccc2)Cc2ccccc2C1
Yield: 26.9 %

Procedure:
Similarly to Example 1(a), by reaction of 5 g (27.6 mmol) of benzenesulfonyl-acetonitrile with 8 g (30.4 mmol) of a,a′-dibromo-o-xylene, 50 ml of aqueous soda solution, 629 mg (2.8 mmol) of benzyltriethylammonium chloride. 2.1 g of 2-benzenesulfonyl-indane-2-carbonitrile is obtained in the form of a white solid. (Yield=27%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl.[S:20]([O-:24])([OH:23])(=[O:22])=[O:21].C(O)(C)C>C(#N)C>[S:20]([O-:24])([OH:23])(=[O:22])=[O:21].[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N+:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: ClCc1ccccc1Cl
Reactant: C1=NCCc2ccccc21
Agent: O=S(=O)([O-])O
Solvent: CC#N
Solvent: CC(C)O
Product: Clc1ccccc1C[N+]1=Cc2ccccc2CC1

Procedure:
The title compound is prepared analogously to Example A from 3,4-dihydroisoquinoline and 2-chlorobenzyl chloride in acetonitrile. The melting point of the hydrogensulphate is 190°-192° C. (from isopropanol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)[CH2:7][C:8]([OH:10])=O)=[O:5])[CH3:2].[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][C:33]2=[O:42])[CH2:28][CH2:27]1>>[CH2:17]1[C:18]2[C:19](=[CH:20][C:12]([CH2:11][C:6]([CH2:7][C:8](=[O:10])[N:26]3[CH2:27][CH2:28][CH:29]([N:32]4[CH2:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[NH:34][C:33]4=[O:42])[CH2:30][CH2:31]3)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:13][CH:14]=2)[CH2:15][CH2:16]1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccc2c(c1)CCC2)C(=O)OCC
Product: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1ccc2c(c1)CCC2)C(=O)OCC

Procedure:
Prepared analogously to Example 76c) from 3,3-bis-ethoxycarbonyl-4-indan-5-yl-butanoic acid and 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH:19][CH:7]2[CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCCN1CCC(=O)CC1
Reactant: COc1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCN1CCC(Nc2cccc(OC)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A solution of 4.5 mL (30 mmol) of N-propyl-4-piperidone, 3.4 mL (30 mmol) of m-anisidine, and 1.7 mL (30 mmol) of glacial acetic acid was stirred in 120 mL of 1,2-dichloroethane (DCE) and 9.49 g (45 mmol) of sodium triacetoxyborohydride was added. The solution was stirred at 25° C. for 3 h. The solution was washed with NaHCO3 solution and brine. It was dried and the solvent was evaporated. The m-anisidine excess was distilled off in a Kugelrohr at 100° C./0.05 Torr. There was obtained 3.5 g (47% yield) of N-(3-methoxyphenyl)-1-propyl-4-piperidinamine as a solid. MS m/z=249 (M++H). 300 MHz 1H NMR (CDCl3) δ7.1 (t, 1H); 6.15-6.35 (m, 3H); 3.75 (s, 3H ); 3.25 (m, 1H); 2.9 (m, 2H); 2.3 (m, 2H); 2.15 (m, 4H); 1.5 (m, 4H); 0.9 (t, 3H). Anal calcd. for C15H24N2O; C, 72.54; H, 9.74; N, 11.28. Found: C, 72.55; H, 9.51; N, 11.21.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][C:10](OC)=[O:11])=[C:6]([NH2:18])[N:5]=[C:4]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[N:20]=2)[N:3]=1.[OH-].[Li+].Cl>C(O)C.O>[NH2:18][C:6]1[C:7]2[N:8]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][C:10](=[O:11])[NH:1][C:2]=2[N:3]=[C:4]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[N:20]=2)[N:5]=1
Reactant: COC(=O)CN(C(=O)OC)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)N1CC(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.2 %

Procedure:
3.5 g (7.285 mmol) of the crude compound from example 55A were dissolved in ethanol (25 ml) and water (25 ml), and 174 mg (7.285 mmol) of lithium hydroxide were added. After stirring at RT for 30 min, the mixture was adjusted to pH=6 with dilute hydrochloric acid and extracted with ethyl acetate. After separation of the phases, the organic phase was washed with saturated aqueous sodium chloride solution and then dried with sodium sulfate, filtered and concentrated to dryness. The residue was slurried in acetonitrile and ethyl acetate, and insoluble constituents were filtered off. The filtrate was concentrated and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 38 mg of the title compound were obtained (1% of theory).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.ClC(OCC)=O.[NH3:29]>C(Cl)(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([NH2:29])=[O:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: N
Reactant: O=C(O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reaction time: 0.5 h

Procedure:
18 g of trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxylic acid were dissolved in 600 ml of chloroform while gassing with argon and the solution was treated dropwise at 0° C. while stirring within 3 minutes with a solution of 7.2 ml of ethyl chloroformate in 40 ml of chloroform. The reaction solution was stirred for a further 30 minutes. Ammonia gas was then conducted into the solution during 10 minutes. The mixture was stirred at 0° C. for a further 30 minutes and then extracted twice with 300 ml of water each time. The aqueous phases were back-extracted with 100 ml of chloroform each time. The combined organic phases were dried over magnesium sulfate, filtered and evaporated. Recrystallization of the brown crystalline crude product obtained (19 g) from 800 ml of methylene chloride gave 13 g of trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxamide as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.B(O[O-])=[O:16].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][NH:11][CH:12]([CH3:14])[CH3:13])=[O:16])=[CH:6][CH:7]=1
Reactant: O=BO[O-]
Reactant: CC(C)NCCSc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)NCCS(=O)c1ccc(Cl)cc1
Yield: 90.6 %

Procedure:
A solution of 15.05 g (0.066 mole) of N-[2-[(4-chlorophenyl)thio]ethyl]-1-methylethanamine and 12.0 g (0.0779 mole) of sodium perborate in 400 ml of 1M sulfuric acid was stirred at room temperature for about 18 hr. The solution was made basic with 50% sodium hydroxide and the basic solution was extracted with methylene chloride. The methylene chloride layer was dried with magnesium sulfate and the solvent removed in vacuo to give 14.7 g of solid. Nuclear magnetic resonance analysis showed a 9 to 1 ratio of sulfoxide to sulfide. The solid was recrystallized from ether-hexane to give 12.3 g (76.4%) of the free base title compound as crystalline solid, m.p. 52.5°-53.5° C.
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[NH:3][C:4]([N:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[OH:7])=[O:5].[OH-].[Na+].Cl[C:21](OCC)=[O:22]>O1CCOCC1>[Cl:15][C:10]1[CH:9]=[C:8]([N:6]2[C:4](=[O:5])[N:3]([C:2]([Cl:1])([Cl:16])[Cl:17])[C:21](=[O:22])[O:7]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CCOC(=O)Cl
Reactant: O=C(NC(Cl)(Cl)Cl)N(O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1on(-c2ccc(Cl)c(Cl)c2)c(=O)n1C(Cl)(Cl)Cl

Procedure:
1-Trichloromethyl-3-(3',4'-dichlorophenyl)-3-hydroxyurea (16.9 grams; 0.05 mol) is dissolved in dioxane (75 ml) and mixed with 2N aqueous sodium hydroxide (30 ml). Ethyl chloroformate (5.7 ml; 0.06 mol) is then added dropwise to the mixture with stirring, resulting in the formation of a precipitate. The precipitate is recovered by filtration, washed with water and dried to yield 2-(3', 4'-dichlorophenyl)-4-trichloromethyl-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[N:22][NH:23]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.Br[CH:29]([CH3:35])[C:30]([O:32]CC)=[O:31].FC1C(F)=CC(C2C=CC(OCC3C=C4C(C=NN4CC(O)=O)=CC=3)=CC=2)=C(OC)C=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[N:22][N:23]4[CH2:35][CH2:29][C:30]([OH:32])=[O:31])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cn[nH]c3c2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cnn(CC(=O)O)c3c2)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cnn(CCC(=O)O)c3c2)cc1

Procedure:
3-[6-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-propionic acid was prepared from 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole (0.1 g, 0.221 mmol) and ethyl bromopropionate (40 mg, 0.221 mmol), as described above for [6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-acetic acid, to yield 81 mg (83.6%) of product. LC-MS (ES) calculated for C24H20F2N2O4, 438.43; found m/z 439 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:11]([CH2:16][NH:17][C:18](=[O:20])[O-:19])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[C:4]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:39]1(B(O)O)[CH2:43][CH2:42][CH2:41][CH:40]=1>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.CN1C(=O)CCC1>[C:39]1([C:2]2[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]3[C:11]([CH2:16][NH:17][C:18](=[O:20])[O:19][C:5]([CH3:21])([CH3:6])[CH3:4])=[N:12][CH:13]=[CH:14][CH:15]=3)=[O:7])=[C:4]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[N:3]=2)[CH2:43][CH2:42][CH2:41][CH:40]=1
Reactant: OB(O)C1=CCCC1
Reactant: O=C([O-])NCc1ncccc1CNC(=O)c1ccc(Cl)nc1NCCc1cccc(F)c1
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: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCc1ncccc1CNC(=O)c1ccc(C2=CCCC2)nc1NCCc1cccc(F)c1

Procedure:
A mixture of (3-((6-chloro-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate (0.10 g, 0.19 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mmol), K2CO3 (0.081 g, 0.59 mmol), cyclopenten-1-yl boronic acid (0.026 g, 0.23 mmol) and NMP (0.2 mL) was sealed in a tube and microwaved at 150° C. for 30 min. The reaction mixture was filtered through a silica plug with EtOAc, washed with H2O, brine, dried (Na2SO4) and concentrated to give tert-butyl (3-((6-cyclopentenyl-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate. LC/MS (M+H+) m/z 546.2.
Reaction SMILES: C[PH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[K].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([C:19]([O-:21])=[O:20])[NH2:18].[Na+].[CH3:23]O>COCCOC>[CH3:23][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[PH:2][C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]=1)([C:19]([OH:21])=[O:20])[NH2:18]
Reactant: CO
Reactant: CPc1ccccc1
Reactant: NC(C(=O)[O-])c1ccccc1F
Agent: [K]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1PC(N)(C(=O)O)c1ccccc1
Temperature: 80 °C

Procedure:
A solution of 2.11 g (17.0 mmol) of methylphenylphosphine in 20 ml of 1,2-dimethoxyethane was admixed with 0.67 g (17.0 mmol) of potassium metal. After the metallation reaction was complete, 3.0 g (15.7 mmol) of sodium 2-(2-fluorophenyl)glycinate were added and the reaction mixture was heated at 80° C. for 0.5 hour. Subsequently, excess potassium phenylmethylphosphide was hydrolyzed by addition of 10 ml of methanol and the volatile constituents were taken off from the reaction mixture under reduced pressure (80° C., 0.01 mbar). The residue was extracted with 50 ml of ether, dissolved in 500 ml of water and the pH was adjusted to about 4 by addition of 10% strength hydrochloric acid. The 2-(methylphenyl)phosphino-α-phenylglycine obtained as colorless precipitate was filtered off and dried under reduced pressure. The yield was 3.46 g (81%). For further purification, the product was recrystallized from methanol/water (1:1).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:36]1[O:46]C2C(=C(C=CC=2)C=O)[O:37]1>>[CH3:1][N:2]([CH3:35])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1[C:7]2[O:46][CH2:36][O:37][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Reactant: O=Cc1cccc2c1OCO2
Product: CN(C)C(=O)OC(c1cccc2c1OCO2)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 97 but using 2,3-(methylenedioxy)benzaldehyde in place of benzaldehyde. Pale yellow oil (65 mg, 82%);
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C.Cl>[CH2:1]([O:8][N:9]([CH3:25])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCNC(=O)NOCc1ccccc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCNC(=O)N(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of decyl isocyanate (19.6 g, 0.11 mol) in 1,2-dichloroethane (100 ml) was added a solution of benzyloxyamine (0.114 mol) in methylene chloride (100 ml). The solution was refluxed for 20 minutes, evaporated, and the residue triturated with pentane to give N-benzyloxy-N'-decylurea as a white solid (22.36 g, 67% yield). This urea (2.95 g, 10 mmol) was dissolved in DMF (30 ml) at 40° C. Sodium hydride (425 mg of a 60% dispersion in oil) was added. Within 15 minutes, a precipitate formed. After 30 minutes, methyl iodide (0.64 ml) was added, and the mixture was stirred for one hour at room temperature. The resulting solution was poured in 1% HCl, and the resulting solid was washed with water, collected by filtration, and air-dried. Recrystallization from pentane provided N-benzyloxy-N-methyl-N'-decylurea as a white solid (2.25 g, 73% yield). Hydrogenolysis as in Example 2 above, and recrystallization from ethanol-water, provided the title compound as a white solid (1.43 g, 91% yield), mp 74°-76° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13]2)#[N:2].[ClH:28]>O1CCOCC1.C(#N)C>[ClH:28].[CH2:13]1[C:14]2[C:9](=[C:8]([O:7][CH2:6][C:5]3[CH:4]=[C:3]([CH:27]=[CH:26][CH:25]=3)[C:1]#[N:2])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:11][NH:12]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2OCc2cccc(C#N)c2)C1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: N#Cc1cccc(COc2cccc3c2CCNC3)c1
Reaction time: 2 h

Procedure:
tert-Butyl 5-(3-cyanobenzyloxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.040 g) was taken up in 4 M HCl in dioxane (2 mL) at r.t. After stirring for 2 h. the reaction was complete and this was concentrated under reduced pressure to give a residue. This was taken up in acetonitrile and reconcentrated under reduced pressure two times to give crude 3-[(1,2,3,4-tetrahydroisoquinolin-5-yloxy)methyl]benzonitrile HCl salt (0.040 g) as a solid residue. Analytical LCMS (M+H)+: m/z=265.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:22][C:21]1[C:3]2[C:2](=[CH:20][CH:19]=[CH:18][C:4]=2[O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:1]=[C:24]([CH3:31])[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)C(=O)NC1CCCCC1Oc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3NC(=O)C(C)C)c2c1N

Procedure:
Prepared as in Example 2a from N-(2-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide (Example 39b) and ethyl 3-oxobutanoate as a yellow solid (63%). MS 414 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:45]=[CH:44][C:19]([CH2:20][NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:25]=[C:24]([NH:34][C:35]3[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=3)[N:23]=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:46][C@@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:49][C@H:48]1[C:59]([OH:61])=[O:60].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[C:55]([O:54][C:52]([N:50]1[CH2:51][C@@H:47]([NH:46][C:39](=[O:40])[C:38]2[CH:37]=[CH:36][C:35]([NH:34][C:24]3[N:23]=[C:22]([NH:21][CH2:20][C:19]4[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[CH:45][CH:44]=4)[N:27]=[C:26]([O:28][CH2:29][C:30]([F:31])([F:33])[F:32])[N:25]=3)=[CH:43][CH:42]=2)[C@H:48]([C:59]([OH:61])=[O:60])[CH2:49]1)=[O:53])([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](C(=O)O)C1
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCCCCOc1ccc(CNc2nc(Nc3ccc(C(=O)N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12 %

Procedure:
To a solution of 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (200 mg), trans-4-amino-1-Boc-pyrrolidine-3-carboxylic acid (72.6 mg) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (121 mg) was added iPr2NEt (0.22 mL). The mixture was stirred at room temperature for 4 hours. The mixture was purified by preparative HPLC to give trans-1-(tert-butoxycarbonyl)-4-(4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-3-carboxylic acid (32 mg).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:31][CH:30]4[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]5[C:27]([C:33](O)=[O:34])([NH:28][C:29]4=[O:32])[CH2:26]5)[CH2:15]3)[CH:10]=[C:9]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:44]1([S:47]([NH2:50])(=[O:49])=[O:48])[CH2:46][CH2:45]1.CCN=C=NCCCN(C)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:31][CH:30]4[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]5[C:27]([C:33]([NH:50][S:47]([CH:44]6[CH2:46][CH2:45]6)(=[O:49])=[O:48])=[O:34])([NH:28][C:29]4=[O:32])[CH2:26]5)[CH2:15]3)[CH:10]=[C:9]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC2C1=O
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC2C1=O
Yield: 62.4 %

Procedure:
The acid 17f (240 mg, 0.41 mmol) was reacted with cyclopropane sulfonamide (63 mg, 0.52 mmol), EDAC (105 mg, 0.55 mmol) and DBU (182 mg, 1.2 mmol) in dry DCM according to the procedure described in Example 13 step f. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the title compound, (175 mg, 62%), (M+H)+684.
Reaction SMILES: O1[C:3]23[C@H:16]([CH2:17][CH2:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@:7]24[CH2:22][C@H:8]2[CH2:9][C@H:10]([OH:21])[C@:11]4([CH2:13][CH2:14]1)[CH3:12])[CH2:5][CH2:4]3.[ClH:23].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:23][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@H:16]2[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@@:7]31[CH2:22][C@H:8]3[CH2:9][C@@H:10]2[OH:21]
Reactant: C[C@]12CC[C@@H]3[C@H]4CCC(=O)C5OC54CC[C@H]3[C@@]13C[C@H]3C[C@@H]2O
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C(Cl)C(=O)CC[C@@H]43)[C@@]13C[C@H]3C[C@@H]2O

Procedure:
The epoxide mixture of step 1 (2 g) is dissolved in 200 ml of acetone and treated at 5° C. with 12 ml of concentrated hydrochloric acid. After 2 house, the mixture is neutralized with sodium carbonate solution and the acetone is removed. The residue is extracted with dichloromethane. The organic extracts are dried and concentrated, After crystallization from ethanol, 4-chloro-17β-hydroxy-14α,15α-methylenestr-4-ene-3-one is obtained.