Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8]1([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][C:22]=2[NH2:31])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:31][C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][S:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:6]
Reactant: COCCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1NCCCCCSc1ccccc1
Solvent: c1ccncc1
Product: COCCC(=O)Nc1cnc2ccccc2c1NCCCCCSc1ccccc1
Temperature: 25 °C
Yield: 104.1 %

Procedure:
A solution of 3-methoxypropanoyl chloride (2.04 g, 16.6 mmol) in pyridine (20 mL) was slowly added to a chilled (0° C.) solution of N4-[5-(phenylthio)pentyl]quinoline-3,4-diamine (5.1 g, 15.2 mmol) in pyridine. The reaction was allowed to warm to ambient temperature. More acid chloride (1 g) was added and the reaction was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure to provide 6.7 g of 3-methoxy-N-(4-{[5-(phenylthio)pentyl]amino}quinolin-3-yl)propanamide as a sticky brown solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:36])(=[O:35])[N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[CH3:26])=[CH:20][CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC(=O)NC1(CCC2C=CC(S(N3C4C(=CC=C(OC)C=4)C(C(=O)C4C=C(OC)C(OC)=C(OC)C=4)=C3)(=O)=O)=CC=2)COC(C)(C)OC1)(C)(C)C>>[NH2:7][C:8]([CH2:9][OH:10])([CH2:13][OH:12])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH3:26])(=[O:35])=[O:36])=[CH:20][CH:19]=1
Reactant: COc1cccc(N(C)S(=O)(=O)c2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2)c1
Agent: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(CCC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(CCC(N)(CO)CO)cc2)c1
Yield: 80 %

Procedure:
When the product of Step D was substituted for tert-butyl-5-(4-(6-methoxy-3-(3,4,5-trimethoxybenzoyl)-1H-indol-1-ylsulfonyl)phenethyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 13, Step F, the similar process afforded the title compound in 80% yield, as colourless solid. 1H-NMR (CDCl3) 1.87-1.93 (m, 2H); 2.65-2.71 (m, 2H); 3.05 (s, 3H); 3.62 (s, 3H); 3.70 (5, 4H); 6.55 (tr, 1H, J=2.20 Hz); 6.62 (d, 1H, J=7.62 Hz); 6.85 (dd, 1H, J=2.41, 8.34 Hz); 7.19 (tr, 1H, J=8.22 Hz); 7.34 (d, 2H, J=8.36 Hz); 7.43 (d, 2H, J=8.31 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]([CH3:21])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: CCc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a mixture of 122a (598 mg, 2.0 mmol) in DMF (10 mL) was added NaH (64 mg, 1.6 mmol) at 0° C. and the mixture was stirred for 0.5 h. To the mixture was added iodomethane (227 mg, 1.6 mmol) in DMF dropwise at 0° C. The mixture was stirred for 0.5 h and quenched with water (20 mL). It was then extracted with dichloromethane (3×30 mL). The combined extract was concentrated under reduced pressure and the residue was purified with silica-gel column chromatography eluting with petroleum ether/ethyl acetate (5:1 to 2:1) to afford 122b (360 mg, 58%) as a light yellow solid. MS-ESI: [M+H]+ 311.1
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[NH:22])[NH:20][OH:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[CH:34](=O)[CH3:35].Cl>C(O)C.O.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[S:25]([CH3:28])(=[O:26])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19]4[NH:22][CH:34]([CH3:35])[O:21][N:20]=4)[C:8]=3[CH:23]=2)[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)N(CCCCO)c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1
Reactant: CC=O
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC1NC(c2c(-c3ccc(F)cc3)oc3cc(N(CCCCO)S(C)(=O)=O)c(C4CC4)cc23)=NO1
Temperature: 25 °C
Reaction time: 73 h
Yield: 19.9 %

Procedure:
A solution of Example 11D (0.10 g, 0.210 mmol) in ethanol (3 mL) and H2O (3 mL) was treated with acetaldehyde (3 mL, 53.1 mmol) and stirred in a sealed microwave tube at room temperature for 73 hours. The solvent was removed in vacuo leaving a cloudy slurry which was dissolved in ethyl acetate (50 mL) and treated with 5% aqueous HCl (5 mL). The mixture was stirred for 30 minutes at room temperature. The aqueous layer was removed and the ethyl acetate layer was washed with 10 mL 10% aqueous NaCl, dried over anhydrous sodium sulfate (solid), filtered. The solvent was removed in vacuo leaving a clear yellow oil. Purification on a silica gel column (4 g) eluting with a gradient of 99.5/0.5 dichloromethane/methanol to 94/6 dichloromethane/methanol over 25 minutes afforded the title compound (0.021 g, 20%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.56 (s, 1H), 0.84 (m, 2H), 1.07 (dd, J=6.3, 4.5 Hz, 2H), 1.37 (dd, J=5.1, 2.1 Hz, 3H), 1.32-1.48 (m, 2H), 2.37 (ddd, J=12.7, 6.9, 5.5 Hz, 4H), 3.13 (s, 3H), 3.66 (m, 2H), 4.36 (t, J=5.1 Hz, 1H), 5.74-5.80 (m, 1H), 7.22 (s, 1H), 7.30 (s, 1H), 7.42 (t, J=8.9 Hz, 2H), 7.86 (s, 1H), 8.02 (dd, J=9.0, 5.4 Hz, 2H); MS (ESI+) m/z 502 (M+H)+, (ESI−) m/z 500 (M−H)−.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>C(OC)(C)(C)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)N=Cc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
L-phenylalanine methyl ester hydrochloride (120.00 g), benzaldehyde (56.5 ml), anhydrous sodium sulfate (158.07 g) and triethylamine (77.5 ml) were added to tert-butylmethyl ether (480 ml), and the mixture was stirred overnight at 5° C. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, n-hexane was added, and the solvent was distilled off again under reduced pressure. To the concentrate was added n-hexane, and the crystallization was conducted by cooling with ice to obtain desired N-(phenylmethylene)-L-phenylalanine methyl ester (126.01 g) in a yield of 85.0%. Further, the mother liquor was concentrated under reduced pressure, and the concentrate was crystallized by cooling with ice to obtain N-(phenylmethylene)-L-phenylalanine methyl ester (13.86 g) in a yield of 9%. Thus, the crystals of N-(phenylmethylene)-L-phenylalanine methyl ester were obtained in a total yield of 94%. A part of the resulting crystals were converted into a phenylalanine methyl ester. It was analyzed by HPLC using an optically active column, and identified to have the optical purity of >99.5%e.e.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.OCC(CO)O.O.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: Cc1ccc(C)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 86.4 %

Procedure:
15 g of 2-chlorobenzonitrile, 15.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of glycerol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 24.7 mg of palladium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.2 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH3:36][C:37](O)([CH3:40])[CH2:38][OH:39]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:36][C:37]1([CH3:40])[CH2:38][O:39][C:32]2([CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:35]1
Reactant: CC(C)(O)CO
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC(C)(C)O3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 114.3 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g), 2-methylpropane-1,2-diol (0.15 g), p-toluenesulfonic acid monohydrate (0.02 g) and toluene (15 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.66 g, 100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:46]1N=N[C:48]2C=CC=[CH:52][C:47]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(C)C>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:46][CH:47]([CH3:52])[CH3:48])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NC(C)C)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and isopropylamine (7.67 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20.5 mg, 62%). LC-MS m/z 549 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH:18]=[C:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1.Cl>[Zn].C(O)C>[OH:9][C@H:8]1[CH2:10][C@@H:11]2[C@:12]([CH3:27])([CH2:13][CH2:14][C@H:15]3[C@H:16]2[CH2:17][CH:18]=[C:19]2[C@:20]3([CH3:26])[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24]2)[C@H:7]1[C@H:6]([CH3:28])[CH2:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:30][OH:29]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: C[C@@H](CO)CCC[C@@H](C)[C@H]1[C@@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 85 %

Procedure:
To a 5-liter flask were sequentially added diosgenin (40 grams, 0.0965 moles, zinc dust (900 grams, -325 mesh size) and 2 liters of absolute ethanol. The suspension was then brought to reflux and 800 ml of concentrated HCl was added dropwise over a period of 2.5 hours. The reaction was refluxed for an additional 30 minutes then immediately filtered while hot, under gravity, over Whatman no. 2 filter paper to remove the zinc particles. Two liters of water was then added to the filtrate and a white precipitate formed. The mixture was cooled at room temperature and the precipitate was collected by suction filtration (Whatman no. 2 paper) and washed three times with water, then air dried to afford 35 grams (85% yield) of compound (2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([I:39])=[CH:35][CH:34]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C.C(Cl)(Cl)Cl>C(Cl)Cl>[I:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:31]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:30])=[CH:34][CH:35]=1
Reactant: O=C(Nc1ccc(I)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(I)cc4)CC3)c2cc1OC
Temperature: 25 °C

Procedure:
To a mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (5.18 g, 19.0 mmol), prepared as described in Example 1d, and (4-iodo-phenyl)-carbamic acid 4-nitro-phenyl ester (8.00 g, 20.8 mmol), prepared as described in the preceding step, in DCM (20 mL) was added DIEA (3.44 mL, 20.8 mmol) with stirring at rt. After stirring at rt for 5 min, CHCl3 (20 mL) was added to thin the slurry, and after stirring for 4 h at rt, the greenish mixture was washed with 0.1 M NaOH (208 mL), and the resulting precipitate in the organic layer was filtered. The filter cake was dissolved in 92:8 DCM/MeOH (250 mL) and washed with water (1×50 mL) and 0.1 M NaOH (1×200 mL). The organic layer was then dried (Na2SO4), concentrated under reduced pressure, and the resulting greyish solid was triturated with hot toluene (1×20 mL) and filtered. The filter cake was washed with toluene (2×20 mL) to provide, after drying of the filter cake, the title compound as an off-white solid (7.84 g, 80%). Nmr reveals a single ˜15 mol % impurity. A sample was purified to homogeneity by flash chromatography. 1H-NMR (300 MHz, CDCl3) 9.07 (s, 1H), 7.58 (m, 2H), 7.35 (s, 1H), 7.25 (s, 1H), 7.17 (m, 2H), 6.49 (br s, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.60 (m, 1H), 3.24-3.11 (m, 2H), 2.23-2.07 (m, 2H), 2.05-1.94 (m, 2H). LC/MS (ESI): calcd mass 518.1, found 519.2 (MH)+.
Reaction SMILES: O=[C:2]1[CH:7]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:6][CH2:5][CH2:4][NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1.C(OCC)(=O)C>[NH:3]1[CH2:4][CH2:5][O:6][CH:7]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2]1
Reactant: O=C1NCCOC1CC12CC(c3ccccc31)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2c(c1)C1CC2(CC2CNCCO2)c2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 9-(3-oxo-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (100 mg) and lithium aluminum hydride (50 mg) in dioxane was stirred at 60° - 70° C. for 3 hours. Excess lithium aluminum hydride was decomposed by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 183° - 189° C. Recrystallization gave colorless crystals, M.P. 189° - 190° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C(Cl)CCl.C1C=[N:20]C2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:20])=[O:6]
Reactant: On1nnc2cccnc21
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(N)=O)cc1Br
Temperature: 25 °C
Yield: 27.7 %

Procedure:
3-bromo-4-methylbenzoic acid (3.12 g, 14.5 mmol) was dissolved in DMF (26 ml) and EDC (3.51 g, 18.3 mmol), HOAt (2.79 g, 20.5 mmol), ammonium chloride (3.05 g, 57.0 mmol), and diisopropylethylamine (7.5 ml, 43.1 mmol) were added. The reaction was stirred at room temperature over the weekend, and then poured into water (100 ml), and diluted with more water. The resultant precipitate was filtered, washed with water, collected as a solution in EtOAc, and concentrated to give title compound (858.7 mg, 28%). MS (ESI pos. ion) m/z: 214 (M+H). Calc'd Exact Mass for C8H8BrNO: 213.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:11]([O:13]C)=O)=[O:8])=[CH:4][CH:3]=1.[OH-].[Li+].[CH3:23][N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>>[CH3:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])[C:11](=[O:13])[NH:35][C:32]1[CH:33]=[CH:34][C:27]2[CH2:26][CH2:25][N:24]([CH3:23])[CH2:30][CH2:29][C:28]=2[CH:31]=1
Reactant: COCCOCC(NC(=O)c1ccc(Cl)s1)C(=O)OC
Reactant: CN1CCc2ccc(N)cc2CC1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: [Li+]
Agent: [OH-]
Product: COCCOCC(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc2c(c1)CCN(C)CC2

Procedure:
The title compound is prepared from methyl 2-(5-chlorothiophen-2yl)carbonylamino-3-(2-methoxyethyloxy)propionate by lithium hydroxide saponification and subsequent reaction with 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine with EEDQ analogously to Example 58(c).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([OH:39])[CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccnc(O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccnc(O)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.49 g, 1.1 mmol) was reacted with 4-amino-pyridin-2-ol (Molbridge) (0.14 g, 1.3 mmol), HATU (0.72 g, 1.9 mmol) and iPr2NEt (0.46 mL, 2.6 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-pyridin-4-yl)-amide as a off white solid (20 mg, 3.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([CH2:47][CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:18](=[O:46])[CH2:19][CH2:20][C@H:21]([NH:28][CH2:29][C:30]2[C:35]([N+:36]([O-])=O)=[CH:34][N:33]=[C:32]([O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:31]=2)[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>CO.[Zn]>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:12][CH2:13][C@@H:14]([N:17]([C:18](=[O:46])[CH2:19][CH2:20][C@H:21]([NH:28][CH2:29][C:30]2[C:35]([NH2:36])=[CH:34][N:33]=[C:32]([O:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:31]=2)[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:47][CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCOCC1)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cnc(Oc2ccccc2)cc1CN[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1

Procedure:
Zinc dust (21.4 g, 330 mmol) was carefully added into a solution of 4-{(2-benzyloxy-ethyl)-[4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-amino}-cis-cyclohexanecarboxylic acid benzyl ester (1.85 g, 2.4 mmol) and NH4Cl (2.6 g, 48 mmol) in MeOH (300 mL). The resulting mixture was refluxed 4 hours. The MeOH was removed before EtOAc (300 mL) was added. The resulting solution washed with aq. NaHCO3 and aq. NaCl. The organic layer was dried with MgSO4, filtered, and evaporated to yield 4-[[4-[(5-amino-2-phenoxy-pyridin-4-ylmethyl)-amino]-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-(2-benzyloxy-ethyl)-amino]-cis-cyclohexanecarboxylic acid benzyl ester as a light brown oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[C:26]([CH3:27])=[C:25]([CH3:28])[C:14]2[O:15][C:16]([CH2:20][C:21](OC)=[O:22])([CH3:19])[CH2:17][CH2:18][C:13]=2[C:12]=1[CH3:29])(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[OH:10][C:11]1[C:26]([CH3:27])=[C:25]([CH3:28])[C:14]2[O:15][C:16]([CH2:20][CH2:21][OH:22])([CH3:19])[CH2:17][CH2:18][C:13]=2[C:12]=1[CH3:29]
Reactant: COC(=O)CC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCO)O2
Reaction time: 1 h
Yield: 98 %

Procedure:
Lithium aluminum hydride (LAH) (8.0 g) was suspended in ether (500 ml). A solution of methyl 2-(6-acetoxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl)acetate (12.16 g) in ether (200 ml) was added dropwise to the suspension. The mixture was stirred for 1 hour. A saturated aqueous solution of sodium sulfate was added dropwise to the reaction solution at room temperature to decompose excess LAH. The solution was filtered. The filtrate was evaporated to give the title compound (9.31 g) having the following physical data.