Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:9][C:10]([OH:12])=O.[OH:18][C@@H:19]([C@@H:21]1[C@@H:24]([C@@H:25](C)[C:26](=O)N2CCSC2=S)[NH:23][C:22]1=[O:35])[CH3:20].N1C=CN=C1>O1CCCC1>[OH:18][C@@H:19]([C@H:21]1[C:22](=[O:35])[NH:23][C@@H:24]1[C@@H:25]([CH3:26])[C:10](=[O:12])[CH2:9][C:8]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:20]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1CCSC1=S
Reactant: C=CCOC(=O)CC(=O)O
Agent: CC[O-]
Agent: [Mg+2]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: C=CCOC(=O)CC(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Temperature: 60 °C
Yield: 84.4 %

Procedure:
To a stirred suspension of magnesium ethoxide (14.7 g) in tetrahydrofuran (250 ml) was added allyl hydrogen malonate (38.8 g) at 30° C. under nitrogen atmosphere. The resultant mixture was stirred at ambient temperature for 10 hours. To this mixture were added (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-oxo-2-(2-thioxothiazolidin-3-yl)ethyl]-2-azetidinone (24.7 g) and imidazole (8.8 g), and the mixture was allowed to heat to 60° C. for 1 hour. After evaporation of the solvent in vacuo, the residue was taken up into a mixture of ethyl acetate (300 ml) and brine (200 ml). After adjusting to pH 3.5 with concentrated hydrochloric acid at 5° C., the organic layer was separated and diluted with brine (200 ml). After adjusting to pH 8 with 30% aqueous potassium carbonate at 5° C., the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (600 ml) eluting with a mixture of dichloromethane and acetone (19:1-1:1 v/v) to give allyl (4R)-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (19.46 g).
Reaction SMILES: [F:1][C:2]([C:25]([F:28])([F:27])[F:26])([O:6][C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[O:11][C:12]([F:16])=[C:13]([F:15])[F:14])[C:3]([NH2:5])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]([C:25]([F:26])([F:27])[F:28])([O:6][C:7]([F:23])([F:24])[C:8]([F:21])([F:22])[C:9]([F:19])([F:20])[C:10]([F:17])([F:18])[O:11][C:12]([F:16])=[C:13]([F:15])[F:14])[C:3]#[N:5]
Reactant: NC(=O)C(F)(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#CC(F)(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F)C(F)(F)F
Temperature: 200 °C
Yield: 55 %

Procedure:
80 g of the thus prepared crude perfluoro(2-methyl-3,8-dioxa-9-decenamide) and 30 g of phosphorus pentoxide were mixed together and pulverized, and charged into a glass flask having a net capacity of 300 ml. Then, the flask was heated to 200° C. Low boiling components formed in the course of the reaction were removed from the flask by distillation through a cooling pipe. Crude residues were distilled in the presence of a small amount of phosphorus pentoxide, whereby 60 g of perfluoro(2-methyl-3,8-dioxa-9-decenonitrile) was obtained (total yield: 55%). Boiling point: 126° C., d420 : 1.2890, n020 : 1.6924
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].C(=O)(O)[O-].[Na+].Br[C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=1>CN(C=O)C.CCOC(C)=O.O>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:24]3[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)n1
Temperature: 50 °C
Yield: 49.1 %

Procedure:
4-Bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (intermediate 57, 0.41 g, 1.27 mmol), sodium bicarbonate (0.42 g, 1.78 mmol) and ethyl 2-bromo-1,3-thiazole-4-carboxylate (0.30 g, 1.27 mmol) were combined in DMF (5 ml) under nitrogen and heated at 50° C. for 18 h. The mixture was cooled to room temperature and diluted with EtOAc (75 ml) and water (10 ml). The organic layer was separated, dried over sodium sulphate, filtered and concentrated under vacuum. Purification by flash chromatography (MeOH/DCM, 10%) provided 275 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[C:15]([O:14][C:12](=[O:13])[NH:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Reaction time: 48 h
Yield: 91.4 %

Procedure:
The compound (35.7 g) obtained in Example 23-1 was dissolved in anhydrous THF (800 ml) and added with Lithium aluminum hydride (10.2 g) in an ice bath and the whole was stirred for 2 days under a nitrogen atmosphere. After completion of the reaction, methanol and then an aqueous sodium potassium tartrate solution were added thereto and the whole was stirred overnight. The resultant was subjected to extraction with chloroform and washed with saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (29.2 g) as a colorless crystal.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C.[F:27][C:28]([F:48])([F:47])[O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][C:38]3([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:37]2=[O:46])=[CH:32][CH:31]=1.[CH:49]1([CH2:53][C:54](O)=[O:55])[CH2:52][CH2:51][CH2:50]1>>[CH:49]1([CH2:53][C:54]([N:43]2[CH2:42][CH2:41][C:38]3([C:37](=[O:46])[N:36]([C:33]4[CH:34]=[CH:35][C:30]([O:29][C:28]([F:27])([F:47])[F:48])=[CH:31][CH:32]=4)[CH2:40][CH2:39]3)[CH2:45][CH2:44]2)=[O:55])[CH2:52][CH2:51][CH2:50]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(O)CC1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: O=C(CC1CCC1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 13 step A (using TBTU instead of BOP as the coupling reagent) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and cyclobutyl-acetic acid. Off-white solid. MS (ESI): 411.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8](C3CCCCO3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[C:18]([NH:23][C:24]3[C:25]4[C:29]([CH:30]=[CH:31][CH:32]=3)=[N:28][N:27](C3CCCCO3)[CH:26]=4)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl.CO>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([C:17]2[C:18]([NH:23][C:24]3[C:25]4[CH:26]=[N:27][NH:28][C:29]=4[CH:30]=[CH:31][CH:32]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1nc(-c2cccnc2Nc2cccc3nn(C4CCCCO4)cc23)c2cnn(C3CCCCO3)c2n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2cccnc2Nc2cccc3[nH]ncc23)c2cn[nH]c2n1
Reaction time: 16 h
Yield: 92.1 %

Procedure:
A solution of N-(3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (56.9 mg, 111 μmol) in DCM (1 mL) and MeOH (2 mL) was treated with (+/−)-10-camphorsulfonic acid (57 mg, 2.2 equiv.) and stirred for 16 h. LCMS indicated clean monodeprotection with only a small amount of the fully deprotected compound. Additional (+/−)-10-camphorsulfonic acid (57 mg, 2.2 equiv.) was added and the solution stirred at 60° C. for 1 h after which time reaction was complete. The mixture was concentrated and purified by SCX ion exchange chromatography washing with MeOH and eluting off with 2N NH3/MeOH to give N-(3-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-1H-indazol-4-amine (35 mg, 87% yield) as a brown solid. 1H NMR of free base thus obtained gives broad signals, so a small amount was converted to the HCl salt for better 1H NMR analysis by dissolving in MeOH containing 2 drops 2 M aqueous HCl followed by concentration to dryness. HCl salt: 1H NMR (400 MHz, d6-DMSO) δ 14.18 (br. s., 1H); 11.38 (s, 1H); 10.43 (s, 1H); 9.76 (s, 1H); 9.42 (d, 1H); 9.04 (s, 1H); 8.64 (d, 1H); 8.46 (s, 1H); 7.85-7.98 (m, 2H); 7.69 (d, J=9.54 Hz, 1H); 2.14 (s, 3H). m/z (ESI, +ve) 343.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([OH:15])[CH2:11][CH2:12][C:13]#[CH:14]>C(NCC)C.ClCCl.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15]
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: C#CCCCO
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: OCCCC#Cc1cc(Cl)ccc1Cl

Procedure:
A solution of 1,4-dichloro-2-iodobenzene (20.0 g, 73.3 mmol), 4-pentyn-1-ol (6.17 g, 73.3 mmol), bistriphenylphosphine(Pd II) chloride (1.03 g, 1.47 mmol), and copper(I) iodide (0.14 g, 0.733 mmol) in 400 ml of diethylamine was stirred under nitrogen for three days. This was diluted with dichloromethane and the oily layer was adsorbed onto silica gel and eluted with hexanes-ethyl acetate (5:1) to give 5-(2,5-dichlorophenyl)-pent-4-yn-1-ol, 13.7 g (82%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:29][O:30][C:31](=[O:51])[C@H:32]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.C(OCC)(=O)C>[CH3:29][O:30][C:31](=[O:51])[C@H:32]([N:42]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[C:11]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])=[O:13])[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)[C@@H](COCc1ccccc1)NCc1ccc(F)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](COCc1ccccc1)N(Cc1ccc(F)cc1)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To a solution of N-t-butoxycarbonyl-D-alanine (5.6 g, 30 mmol, [α]D+23° (c=2, CH3CO2H)) in anhydrous tetrahydrofuran (150 mL) under N2 at 0° C. was added N-methylmorpholine (3.0 g, 30 mmol), followed by the addition of isobutylchloroformate (3.7 mL, 30 mmol), resulting in the formation of a white solid. The resulting suspension was stirred at 0° C. for 15 minutes, and then at ambient temperature for 1 hour. A solution of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)-amino)propanoic acid methyl ester (7.5 g, 24 mmol, in 50 mL of anhydrous tetrahydrofuran) was added to the mixture and the resulting mixture was stirred at ambient temperature. After 15 hours, the mixture was filtered through Celite (tetrahydrofuran). The filtrate was concentrated in vacuo to afford a yellow liquid, which was dissolved in ethyl acetate, washed with water and then with brine. The organic phase was separated then dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 7.3 g (63% yield) of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)-N-(((1S)-1-(t-butoxy-carbonylamino)ethyl)carbonyl)amino)propanoic acid methyl ester, a compound of formula (Q), as a clear oil; NMR (CDCl3) 7.4-7.2 (m, 7), 7.0 (dd, 2), 5.3 (d, 2), 4.9-4.3 (m, 5), 4.1-3.7 (m, 4), 1.6 (s, 9), 1.0 (d, 3) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH:5]=[CH2:6].[Cl:8][C:9]([Cl:14])(Cl)[C:10](Cl)=[O:11]>COCCOC.C(OCC)C.[Cu].[Zn]>[CH3:1][O:2][C:3](=[O:7])[CH2:4][CH:5]1[CH2:6][C:10](=[O:11])[C:9]1([Cl:14])[Cl:8]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCC(=O)OC
Agent: [Cu]
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOCC
Product: COC(=O)CC1CC(=O)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 138.8 %

Procedure:
To a mixture of but-3-enoic acid methyl ester (1.00 g, 10 mmol) and zinc-copper couple (1.97 g) in 1,2-dimethoxyethane (4.89 ml) and diethyl ether (37 ml), trichloroacetyl chloride (2.98 ml, 26.7 mmol) is added at room temperature under nitrogen. The mixture is stirred at room temperature for 3 days. The mixture is filtrated and washed with diethyl ether. The filtrate is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography to give (2,2-dichloro-3-oxo-cyclobutyl)-acetic acid methyl ester (2.93 g, quant.); TLC (hexane/AcOEt, 3:1) Rf 0.35, 1H NMR (400 MHz, chloroform-d) δ ppm 2.68-2.74 (m, 1H), 2.94-3.00 (m, 1H), 3.06-3.13 (m, 1H), 3.33-3.41 (m, 1H), 3.51-3.57 (m, 1H), 3.75 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[H][H]>[Pd].CO>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:10][C:4]=1[NH2:1]
Reactant: COCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc(N)c(N)c1

Procedure:
A mixture of 3.5 g. of 2-nitro-4-methoxymethoxyaniline, 1 g. of 5% palladium-on-charcoal catalyst and 120 ml. of methanol is hydrogenated at ambient conditions. After the uptake of hydrogen is complete, the mixture is filtered and 1,2-diamino-4-methoxymethoxybenzene is obtained by evaporation of the solvent.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH2:12][C:13]3[C:17]=2[N:16]=[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=32)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:13]3[C:17]=2[N:16]=[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=32)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=CC(OCc2ccccc2)=C2N=C3CCCCC3=C2C1
Reactant: CCCCCCCCBr
Product: CCCCCCCCC1C=CC(OCc2ccccc2)=C2N=C3CCCCC3=C21
Yield: 86.8 %

Procedure:
Using the procedure of Example 9, 37.4 g of 1,2,3,4-tetrahydro-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole from Example 56 was alkylated with 1-bromooctane (27.9 g; 0.145 mol) giving 45.6 g (86.8%) of 1,2,3,4-tetrahydro-6-phenylmethoxy-9-octyl-9H-dibenzo-[b,d]pyrrole as a yellow oil after chromatographic purification.
Reaction SMILES: [CH:1]([C:4]1[C:5]2[CH:6]=[C:7]([CH3:28])[C:8]([NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[CH:9][C:10]=2[C:11]([CH3:15])([CH3:14])[CH2:12][CH:13]=1)([CH3:3])[CH3:2].[CH:29](=O)[CH2:30][CH3:31]>>[CH2:29]([N:16]([C:8]1[C:7]([CH3:28])=[CH:6][C:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:9]=1)[C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=1)[CH2:30][CH3:31]
Reactant: CCC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C(C)C)=CCC3(C)C)cc1
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1C)C(C(C)C)=CCC2(C)C
Yield: 64.2 %

Procedure:
Following General Procedure D, ethyl 4-(5-isopropyl-3,8,8-trimethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 48, 0.10 g, 0.26 mmol) was reacted with propionaldehyde (0.20 mL, 2.6 mmol) to give 0.070 g (68%) of the title compound as a clear oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([OH:10])[CH:7]=[CH:6]1)(=[O:3])[CH3:2].C(OC1CC(=O)C=C1)(=O)C.[Cr](O)(O)(=O)=O>>[C:1]([O:4][C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH:7]=[CH:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C=C[C@@H](O)C1
Agent: O=[Cr](=O)(O)O
Agent: CC(=O)OC1C=CC(=O)C1
Product: CC(=O)O[C@@H]1C=C[C@H](O)C1

Procedure:
The trans-3-acetoxy-5-hydroxycyclopent-1-ene obtained by using baker's yeast and whose absolute configuration was determined to be of R-configuration was converted to 4-acetoxycyclopent-2-en-1-one by oxidation with chromic acid. When the specific rotation of this compound was found to be +74°.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Mg+2:5].[O-2].[Mg+2].C(=O)=O>O>[C:1](=[O:2])([OH:4])[O-:3].[Mg+2:5].[C:1](=[O:2])([OH:4])[O-:3]
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: O=C([O-])O
Reaction time: 2 h

Procedure:
A light-burned magnesia, made from calcination of magnesium carbonate (Si 2.5 wt %, Fe 0.9 wt %, Al 0.5 wt %) at 750-850° C. for 5 hours, is hydrated for 2 hours at 80° C. The weight ratio of water to magnesium oxide is 1:1. Then water is added into the mixture to prepare slurry at a weight ratio of water to magnesium oxide of 40:1. After that, carbon dioxide (90 vt %) is introduced into the slurry to react for 30 minutes at 20° C. Subsequently, a pure magnesium bicarbonate solution (MgO: 23 g/L, Fe: 1.1 ppm, Al: 1.0 ppm) is obtained after clarification and filtration
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[O:23])[C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:24][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][NH:21][C:20]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (82 mg, 0.241 mmol) in dichloromethane (4 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 241.0 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][NH:33][C:16]1[N:15]=[C:14]2[NH:13][C:12](=[O:24])[N:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[CH2:20][C:19]2=[CH:18][N:17]=1)[CH3:26]
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)=O)nc3NC2=O)c1
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNc1ncc2c(n1)NC(=O)N(c1cc(OC)cc(OC)c1)C2
Yield: 40 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1121 g (0.861 mmol) of diethylaminopropylamine were reacted. The residue was chromatographed eluting with acetonitrile/ethanol/triethylamine (8:1:0.5 v/v/v) to give 0.0476 g (40%) of the title compound: HPLC=89% pure.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=5)=[CH:23][CH:22]=4)[C:13](=[O:20])[N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7][N:6]1[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])=[O:4].Cl.[CH3:44][O:45][C:46](=[O:64])[CH:47]([NH2:63])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[CH:40]([O:39][C:37]([N:6]1[CH:5]([C:3](=[O:4])[NH:63][C@H:47]([C:46]([O:45][CH3:44])=[O:64])[CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[CH:57][CH:56]=3)=[CH:53][CH:54]=2)[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:21]4[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=5)=[CH:25][CH:26]=4)[C:13](=[O:20])[N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7]1)=[O:38])([CH3:41])[CH3:42]
Reactant: COC(=O)C(N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-isopropyl ester 7-methyl ester (204 mg) was hydrolyzed and coupled to 2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester-hydrochloride according to general procedures A and B to provide (S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid isopropyl ester (161 mg, LC/MS: m/z 862).
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])=[O:4].CCN(C(C)C)C(C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]([O:1][NH:2][C:3]([CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=[O:7])=[O:4])=[O:27]
Reactant: CC(C)CC(C(=O)O)C(=O)NO
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CC(C(=O)O)C(=O)NOC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 55.3 %

Procedure:
Intermediate (3d) (12.7 g, 73.2 mmol, 1.0 eq) was dissolved into 180 mL DCM and cooled to 0° C. DIPEA (13.4 mL, 76.9 mmol, 1.05 eq) was added, followed by pivaloyl chloride (9.5 mL, 76.9 mmol, 1.05 eq). The mixture was warmed to room temperature and stirred for 12 hours. The mixture was concentrated under reduced pressure, dissolved into 300 mL EtOAc, washed 2×200 mL 1M H3PO4, 100 mL saturated aqueous NaCl, dried over MgSO4, and evaporated. The material was triturated with hexanes, filtered and dried the to yield the title compound (10.5 g, 55%). 1H NMR (DMSO) δ (ppm): 0.7 (m, 6H), 1.2-1.4 (m, 1H), 1.4-1.6 (m, 2H), 2.9 (t, 1H), 3.3 (quart, 1H), 8.9 (br s, 1H), 10.5 (br s, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:6][CH:5]=1.[CH3:13]I.O>O1CCCC1.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH2:10][CH2:11][O:12][CH3:13])[N:9]=1
Reactant: OCCc1cccc(Br)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of sodium hydride (59 mg, 1.49 mmol) in tetrahydrofuran (2 ml) was cooled to 0° C. in an ice bath. 2-(6-Bromopyridin-2-yl)ethanol (Example 235 Step 3) (100 mg, 0.49 mmol) in tetrahydrofuran (2 ml) was added dropwise and the reaction was allowed to warm to room temperature. After 45 minutes at room temperature, the reaction was cooled to 0° C., followed by the addition of methyl iodide (0.09 ml, 1.49 mmol). The reaction was then allowed to warm to room temperature. Upon completion, the reaction was cooled to 0° C. and water was added dropwise. Ethyl acetate was then added and the layers were separated. The organic layer was then dried over sodium sulfate, filtered and concentrated. Purification of the crude residue by silica gel chromatography afforded the title compound.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]([NH2:14])[CH3:13])=[CH:4][CH:3]=1.[O:15]=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@@H:18]([CH2:26][CH:27]=O)[CH2:17]1.C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]([NH:14][CH2:27][CH2:26][C@@H:18]2[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16](=[O:15])[CH2:17]2)[CH3:13])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(F)c2ccccc12
Reactant: O=CC[C@H]1CC(=O)c2ccccc2C1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C[C@@H](NCC[C@H]1CC(=O)c2ccccc2C1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a stirred solution of (R)-1-(4-fluoronaphthalen-1-yl)ethanamine (1.206 g, 6.38 mmol) in methanol (5 mL) was added (S)-2-(4-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetaldehyde (1.2 g, 6.38 mmol) at 0° C. Acetic acid (0.365 mL, 6.38 mmol) was added and reaction was stirred for 5 min. Reaction was warmed to RT and stirred for 20 min. Again reaction was cooled to 0° C. Sodium cyanoborohydride (0.401 g, 6.38 mmol) was added to the reaction mixture and stirred for overnight (16 h). To the reaction solution were added NaHCO3 solution (5 mL) and water (10 mL) and the mixture was extracted with ethyl acetate (20 mL×2). The extract was washed with saturated brine solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude title compound (2.0 g, 5.53 mmol, 87% yield).