Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])P(=O)(OC(C)C)OC(C)C.C([Li])CCC.[Si:27]([O:34][CH2:35][CH2:36][CH:37]=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CCCCCCC>[Si:27]([O:34][CH2:35][CH2:36]/[CH:37]=[CH:1]/[P:12](=[O:21])([O:13][CH:14]([CH3:15])[CH3:16])[O:17][CH:18]([CH3:19])[CH3:20])([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCCC
Product: CC(C)OP(=O)(/C=C/CCO[Si](C)(C)C(C)(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.6 %

Procedure:
To a solution of tetraisopropyl methylenebisphosphonate (2.50 g, 7.26 mmol) in n-heptane (50 ml) was added n-butyllithium (2.70 ml of 2.7M solution in n-hexanes; 7.29 mmol) and the mixture stirred at room temperature under dry nitrogen for 15 min. To the solution was added crude 3-(t-butyldimethylsilyloxy) propanal (approx. 5.85 mmol) and the mixture heated under reflux for 0.5 hr then stirred at room temperature for 64 hr. The mixture was filtered then the solvent removed. The residue was purified by column chromatography on silica gel eluting with dichloromethane-ethyl acetate (9:1, 4:1) to afford diisopropyl (E)-4-(t-butyldimethylsilyloxy)but-1-enylphosphonate as a colourless oil (1.10 g, 43%); νmax (film) 2940, 1625, 1460, 1380, 1250, 1105, 980 and 830 cm-1 ; δH (CDCl3) 0.03 (6H, s, SiCH3), 0.90 (9H, s, C(CH3)3), 1.32 (12H, dd, J 3 Hz and 6 Hz, CH(CH3)2), 2.43 (2H, m, CH2), 3.72 (2H, t, J 7 Hz, CH2O ), 4.65 (2H, m, CH(CH3)2), 5.72 (1H, dd, J 17 Hz and 20 Hz, PCH=CH), 6.75 (1H, ddt, J 7 Hz, 17 Hz and 20 Hz, PCH=CH); FABMS(thioglycerol) 351 (MH+) (Found: C, 54.76; H, 10.05%. C16H35O4PSI requires C, 54.84; H, 10.07%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[O:18])[CH2:11][NH:12][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:5][C:4]=1[C:19]#[N:20]>>[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([OH:18])[CH2:11][NH:12][C:13]([CH2:16][CH3:17])([CH3:14])[CH3:15])=[CH:5][C:4]=1[C:19]#[N:20]
Reactant: CCC(C)(C)NCC(=O)c1cc(F)c(N)c(C#N)c1
Agent: Cl
Product: CCC(C)(C)NCC(O)c1cc(F)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 172°-175° C. (decomp.)., was prepared from 4'-amino-3'-cyano-5'-fluoro-2-tert.pentylaminoacetophenone analogous to Example 49.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:6]=2[N:24]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:25])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:6]=2[N:24]=1
Reactant: COc1ccc(CN2CC(F)(F)C(=O)Nc3cnc(Cl)nc32)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)cc1
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To a solution of 0.60 g (0.0017 mole) of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-291) in 8 mL of dimethylformamide was added 0.83 g (0.0026 mole) of cesium carbonate, followed by 0.32 mL (0.0051 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water was added to the residue to give a precipitate. The solid was collected by filtration, washed with water and dried under vacuum to give 0.56 g of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-291) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:32])[C:19]([C:27]([O:29]CC)=[O:28])=[CH:20][N:21]3[CH:24]3[CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:33])[CH2:9]1)=O)(C)(C)C.[ClH:34]>C(O)(=O)C>[ClH:34].[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:32])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]3[CH:24]3[CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:33])[CH2:9]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2cc(OC3CCNC3)c(F)cc2c1=O

Procedure:
Ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3carboxylate (210 mg) was dissolved in a mixture consisting of 0.7 ml of concentrated hydrochloric acid and 2.8 ml of acetic acid. The resulting solution was heated under reflux for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol, whereby 60 mg of the title compound was obtained as crystals.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[N:17]([O-])=O.[Na+]>O>[ClH:1].[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH:15][NH2:17])[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=N[O-]
Reactant: CCCCc1csc2ccc(N)cc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCc1csc2ccc(NN)cc12
Temperature: 25 °C

Procedure:
12.1 g of 3-butyl-5-aminobenzothiophene hydrochloride are mixed with 50 ml of H2O and 50 ml of concentrated HCl, and a solution of 3.6 g of NaNO2 in 40 ml of water is added dropwise at -5°. The solution obtained is added dropwise to a mixture, cooled to -15° C., of 28.4 g of S2Cl2.2H2O and 50 ml of concentrated HCl. After warming the reaction mixture to room temperature, the precipitate which has separated out is filtered off, washed with cold concentrated HCl and put into ice-water and the mixture is covered with a layer of ether and rendered alkaline with 20% strength NaOH. The ethereal phase is washed and dried and acidified with HCl/ether; the precipitate is boiled up in ethyl acetate and filtered off. Melting point: 168°-170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:5]=1[C:6]([NH:8][CH2:9][CH:10]=[O:11])=[O:7])([O-])=O.[C:20](C1C=CC2C(=O)NCC=NC=2C=1)(C)(C)C>CO.[Pd]>[C:16]([C:14]1[CH:13]=[CH:12][C:5]2[C:6](=[O:7])[NH:8][CH2:9][CH:10]([O:11][CH3:20])[NH:1][C:4]=2[CH:15]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1ccc(C(=O)NCC=O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)c1ccc2c(c1)N=CCNC2=O
Agent: [Pd]
Solvent: CO
Product: COC1CNC(=O)c2ccc(C(C)(C)C)cc2N1
Reaction time: 3 h

Procedure:
70 mg 10 wt % Pd on carbon was wetted with a small amount of methanol under argon. To this was added 717 mg (3 mmol) 2-nitro-4-tert-butyl-N-(2-oxo-ethyl)-benzamide dissolved in 20 mL methanol. The flask was evacuated and the atmosphere replaced with hydrogen gas using a balloon as ballast, and the mixture was hydrogenated for 3 hours. The reaction was filtered through celite under argon, the celite washed with ethyl acetate. Solvent was removed under vacuum to give a solid. NMR and LC/MS shows this to be a mixture of the title compound and 8-tert-Butyl-3,4-dihydro-benzo[e][1,4]diazepin-5-one as a one to one mixture, which was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](F)=[C:27]([Cl:32])[CH:26]=1)(=[O:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Cl:32][C:27]1[CH:26]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:30]=[CH:29][C:28]=1[O:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CCc1ccc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2cc(C(F)(F)F)ccc2CCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step (v) (0.6 g), the product from step (vii) (0.43 g) and potassium carbonate (0.285 g) in NMP (10 ml) was heated at 70° C. for 4 h. The mixture was partitioned between diethylether and water, the organic layer dried, and the solvent evaporated under reduced pressure. The residue was dissolved in 50% DCM/trifluoroacetic acid (20 ml) and stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue purified by RPHPLC, yield 0.175 g
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]([CH3:50])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:49])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:33](=[O:49])[NH:32][CH2:31][CH2:30][CH2:29][N:28]([CH3:50])[CH3:27])[CH:35]=2)[CH:3]=1)=[O:15]
Reactant: CN(C)CCCNC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(C(=O)NCCCN(C)C)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv), N-(3-(dimethylamino)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired compound (9% yield). LCMS: 544.20 (M+1)+; HPLC: 98.83% (@ 254 nm), (Rt; 5.258); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.00 (t, 1H), 8.70 (t, 1H), 8.64 (s, 1H), 8.39 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.92 (d, 1H, J=8 Hz), 7.64 (t, 1H, J=7.6 Hz), 5.90 (s, 1H), 5.37-5.34 (m, 1H), 4.41 (d, 2H, J=4.4 Hz), 2.28 (t, 2H, J=6.8 Hz), 2.23 (s, 3H), 2.14 (s, 6H), 2.12 (s, 3H), 1.69 (t, 2H, J=6.8 Hz), 1.55 (d, 6H, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[O:13])[CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)c1

Procedure:
Example 71 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.39–7.34 (m, 6H), 7.26 (t, 1H, J=7.2 Hz), 6.96 (d, 1H, J=7.6 Hz), 5.68 (br s, 1H), 3.26 (dd, 2H, J=6.8, 12.8 Hz), 2.88 (d, 2H, J=13.2 Hz), 2.45 (m, 1H), 2.30 (t, 2H, J=7.2 Hz), 2.19 (s, 3H), 1.96 (t, 2H, J=11.6 Hz), 1.78 (d, 2H, J=12.8 Hz), 1.65–1.58 (m, 6H), 1.02 (dd, 2H, J=3.6, 6.8 Hz); ESMS m/e: 454.2 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[CH2:27]([O:34][C:35](=[O:49])[NH:36][C@H:37]([CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35](=[O:49])[NH:36][C@H:37]([CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][I:20])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)NC[C@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H](CI)NC(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
Triphenylphosphine bound to cross-linked polystyrene resin (0.82 g, 3 mmol/g, 2.47 mmol) is suspended in dry DCM (10 ml) at ambient temperature under a nitrogen atmosphere. Iodine (0.62 g, 2.47 mmol) is added and the reaction mixture stirred for 15 minutes. Imidazole (0.167 g, 2.47 mmol) is then added and the reaction mixture is stirred for a further 15 minutes. A solution of [(R)-1-(tert-butoxycarbonylamino-methyl)-2-hydroxy-ethyl]-carbamic acid benzyl ester (0.401 g, 1.23 mmol) in dry dichloromethane (5 ml) is added and the reaction mixture is stirred at reflux for 1.5 hour. The polymer is removed by filtration, and the filtrate is first washed with aqueous 5% sodium thiosulphate solution and then water. The organic phase is dried over MgSO4 and evaporated to yield [(R)-1-(tert-butoxycarbonylamino-methyl)-2-iodo-ethyl]-carbamic acid benzyl ester. [MH]+ 435.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncccn2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ncccn2)CC1
Yield: 33 %

Procedure:
490 mg of the compound of step 2 of Example 25 was dissolved in 10 ml of ethanol, 100 mg of 10% palladium carbon was added, then the resultant mixture was agitated under hydrogen gas for 2 days. The catalyst was filtered out, the ethanol was distilled off, and the residue was refined with silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the above-referenced compound in an amount of 160 mg (yield of 33%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]([O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([O:27][CH3:28])[N:18]2C2CCCCO2)=[C:14]([NH2:29])[N:13]=1)[CH3:10]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:10][CH:9]([O:11][C:12]1[NH:13][C:14]([NH2:29])=[C:15]2[C:19]([N:20]=1)=[N:18][C:17]([O:27][CH3:28])=[N:16]2)[CH3:8]
Reactant: COc1nc2c(N)nc(OC(C)C)nc2n1C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1nc2nc(OC(C)C)[nH]c(N)c-2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Trifluoroacetic acid (1 ml, 12.98 mmol) was added to a stirred solution of 2-[(1-methylethyl)oxy]-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (568 mg, 1.848 mmol) in methanol (10 ml) and the mixture was stirred at room temperature overnight. More trifluoroacetic acid (0.2 ml) was added and the reaction mixture stirred at room temperature for a further 1.5 hours and then evaporated in vacuo. The solid residue was triturated with ethyl acetate, collected by filtration, washed with ethyl acetate and dried in vacuo overnight to give the title compound as a white solid (405 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>O1CCCC1.C1COCC1.CCCCCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)n(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 462 mg 3-methyl-indole-1-carboxylic acid tert-butyl ester in 2.5 ml anhydrous tetrahydrofuran at −78° C. under argon is 1.2 ml of a 2M LDA (Li-diisopropylamine) solution in THF/hexane and stirred at 0° C. for 30 min to complete the deprotonation. The reaction mixture is cooled to −78° C., 0.6 ml 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and stirred at 0° C. for 60 min. The reaction is quenched by the addition of 2 ml MeOH/water (1:1), diluted into water and extracted with ethylacetate. After evaporation of the solvent and purification on silica gel 385 mg of 3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15].[NH2-].[Na+].O>C1(C)C=CC=CC=1>[CH:14]([N:13]([CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9])([CH3:16])[CH3:15]
Reactant: N#CCc1ccccc1
Reactant: CC(C)N(CCCl)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Temperature: 80 °C

Procedure:
To a solution of 58 parts of α-phenylacetonitrile in 300 parts by volume of toluene is added 83 parts of 2-chloro-N,N-diisopropylethylamine dissolved in 300 parts by volume of toluene. The mixture is heated with stirring to about 80° C. and then 22 parts of sodium amide is added slowly over a period of 30 minutes. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer is separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether and the ether extract is dried over calcium sulfate, concentrated and distilled to afford α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile, as an oil boiling at about 120°-125° C. at 0.3 mm pressure. This compound is represented by the following structural formula ##STR12##
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1NC#CCC.[CH2:18]([NH:23][CH2:24][C:25]#[C:26][CH:27]([OH:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:19][CH:20]([CH3:22])[CH3:21].CO>[Pd].[Pt].C(O)C>[CH2:18]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]([OH:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:19][CH:20]([CH3:21])[CH3:22]
Reactant: CC(C)CCNCC#CC(O)c1ccccc1-c1ccccc1
Agent: [Pd]
Agent: [Pt]
Agent: CCC#CNc1ccccc1-c1ccccc1
Solvent: CCO
Solvent: CO
Product: CC(C)CCNCCCC(O)c1ccccc1-c1ccccc1

Procedure:
The biphenylyl alkynylamine next is reduced to yield the corresponding biphenylyl alkylamine of the invention. Such exhaustive reduction typically is carried out by hydrogenation in the presence of a catalyst such as palladium or platinum. For example, a biphenylyl butynylamine such as N-isopentyl-4-hydroxy-4-(1,1'-biphenyl-2-yl)-2-butynylamine is dissolved in a suitable organic solvent such as methanol or ethanol and stirred for about two to four hours at about 20 to about 50° C. under a hydrogen atmosphere of about 20 to about 80 psi, in the presence of a hydrogenation catalyst such as palladium suspended on carbon. The reduced product, for instance N-isopentyl-4-hydroxy-4-(1,1'-biphenyl-2-yl)butylamine, is isolated by filtering the reaction mixture to remove the catalyst and then evaporating the reaction solvent from the filtrate. The amine thus formed can be further purified if desired by standard methods such as acid and base extraction, crystallization from solvents such as diethyl ether or Skelly-B, salt formation, chromatography and the like.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[OH-].[Na+]>C(O)CO>[CH3:19][O:18][C:16]([CH:11]1[CH2:10][N:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13][C:12]21[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: COC(=O)C1CN(Cc2ccccc2)CCC12CCCC2
Temperature: 70 °C
Yield: 207.6 %

Procedure:
A mixture of 20.0 gm (70.4 mMol) 1-benzyl-3-methoxycarbonyl-4-oxopiperidine hydrochloride in 60 mL ethylene glycol was cooled in an ice bath as 24 gm hydrogen chloride were added. The slurry was heated at 70° C. for 2 hours and was then poured into 200 mL ice water. The pH was adjusted to about 8 with 5N sodium hydroxide and the resulting mixture extracted well with diethyl ether. The organic extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure to provide 21 gm 8-benzyl-8-azaspiro[4,5]decane-6-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:53])[C@H:10]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:11][C:12](=[O:48])[C@H:13]([C:44]([CH3:47])([CH3:46])[CH3:45])[NH:14][C:15](=[O:43])[C@H:16]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42])[NH:17]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:53])[C@H:10]([CH2:49][CH:50]([CH3:51])[CH3:52])[NH:11][C:12](=[O:48])[C@H:13]([C:44]([CH3:45])([CH3:46])[CH3:47])[NH:14][C:15](=[O:43])[C@H:16]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42])[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccccc1C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Yield: 99.8 %

Procedure:
A solution of 10 g (13.95 mmol) of N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 30 ml of piperidine and 120 ml of dichloromethane was stirred for 30 minutes at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly 20% ethyl acetate in hexane and then 10% methanol in dichloromethane for the elution. Evaporation gave 6.9 g of N-[N-[2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in the form of an oil which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([F:15])[CH:2]=1.[OH2:16]>O=[Mn]=O>[F:15][C:3]1[CH:2]=[CH:1][C:6]([C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:16])=[CH:5][CH:4]=1
Reactant: Fc1ccc(Cc2ccc(F)cc2)cc1
Reactant: O
Agent: O=[Mn]=O
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 95 %

Procedure:
The procedure of Example 1 was used except that 20 g 4,4'-difluorodiphenylmethane, 30 g water, 31 g MnO2 and 50 g H2 SO4 were used. 20 g off-white solids, after toluene removal, afforded 95% pure 4,4'-difluorobenzophenone in a 90% yield.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[Cl:27])[CH:20]=[C:19]([C:28]#[N:29])[N:18]=1>C1COCC1>[Cl:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[N:18][C:19]([C:28]#[N:29])=[CH:20]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: N#Cc1cc2cccc(Cl)c2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3cccc(Cl)c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (126 mg, 0.674 mmol) in THF (5 mL) was added NaH (26.8 mg, 0.677 mmol) at 0° C. The mixture was stirred for 30 minutes. Next, 1,8-dichloroisoquinoline-3-carbonitrile was added and the reaction mixture was warmed to RT for 4 hours. The reaction was quenched with H2O (2 mL) and the mixture was extracted with EtOAc (3×10 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by preparative TLC to give the title compound (120 mg, 73.2%).