Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1>CN(C=O)C>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][CH2:23][CH2:22][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: BrCCOC1CCCCO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a solution of 4-pyrazole boronic acid pinacol ester (2.0 g, 10.3 mmol) in anhydrous DMF (20 mL) was added cesium carbonate (4.03 g, 12.4 mmol) and the mixture stirred at RT for 10 minutes. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (1.87 mL, 12.4 mmol) was added in two portions and the mixture was heated to 70° C. After heating for 18 hours the mixture was allowed to cool to RT and partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was washed with EtOAc (3×20 mL) and the combined organic layers washed with water (3×100 mL) followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (2.15 g, 65%). LCMS: RT=3.97 min, [M+Na]+=345
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Br)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1)[CH3:19]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: CCOC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Analogously to the method described in Example 5, the use of p-(1-adamantyl)-phenol and 4-bromobutyric acid ethyl ester as starting materials gives 4-[4-(1-adamantyl)-phenoxy]butyric acid ethyl ester of boiling point 150°C (0.03 mm).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: OB(O)c1cccc(Cl)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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2cccc(Cl)c2)oc1C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 3-chlorophenylboronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 92%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:9]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:27])[CH2:22][CH2:21]4)[CH:8]=2)[CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([O:33][CH2:34][CH:35]=O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([O:33][CH2:34][CH2:35][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=4)=[C:9]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[C:23](=[O:27])[CH2:22][CH2:21]5)[CH:8]=3)[CH2:5][CH2:6]2)=[CH:31][CH:30]=1
Reactant: O=CCOc1ccc(Cl)cc1
Reactant: O=C1CCc2cc(-c3cc(C4CCNCC4)oc3-c3ccncc3)ccc21
Product: O=C1CCc2cc(-c3cc(C4CCN(CCOc5ccc(Cl)cc5)CC4)oc3-c3ccncc3)ccc21
Yield: 65 %

Procedure:
The title compound (0.140 g, 65%) was prepared from the product of Example 31 Step 5 and (4-chlorophenoxy)acetaldehyde (Maguire et al, J. Chem. Soc., 1954, 3669) using the method of Example 32; MS(ES+) m/e 513 [M+H]+.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][C:16]1[CH:15]=[CH:14][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=3[CH:2]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[CH2:3][C:4]=2[CH:17]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(C)ccc1O2
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(C)ccc1O2

Procedure:
In a manner analogous to that described in the preceding paragraph, by reacting 10-chloro-10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin with 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone there is obtained 3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone having a melting point of 175°-176° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:12][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(F)c(C(=O)O)cc1N
Temperature: 60 °C

Procedure:
2-Fluoro-4-methyl-5-nitrobenzoic acid (900 mg, 4.52 mmol) in MeOH (70 ml) was treated with ammonium formate 1 (425 mg, 22.60 mmol) and Pd (Carbon) (144 mg, 1.356 mmol). The mixture was degassed thoroughly refilling with nitrogen and heated to 60° C. for 2 hrs. The mixture was filtered through silica and washed with MeOH. The filtrate was passed through SCX-2 resin (30 g 0.67 mmol/g) eluting with MeOH (250 ml) followed by 2M ammonia in MeOH (250 ml). The ammonia/MeOH washings were evaporated to dryness and the resulting crude residue was purified by recrystallisation from MeOH to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cccc([N+](=O)[O-])c2)c(OC)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cccc(N)c2)c(OC)c1

Procedure:
Following a similar procedure to that described in Example (1b), 720 mg of isorner B of N-[1-(3,4-difluorophenyl)ethyl]-N-[(2,4-dimethoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 799 mg of nickel chloride hexahydrate, 254 mg of sodium borohydride and 80 ml of methanol were reacted, to obtain 580 mg of isomer B of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[CH3:17][O:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(C)n1ccc2ccc(CO)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc2ccn(C(C)C)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
A solution of 6-hydroxymethyl-1-(2-propyl)indole (0.214 g, 1.13 mmole) in 2 mL of anhydrous N,N-dimethylformamide was added dropwise to a slurry of 95% NaH (35.2 mg, 1.36 mmole) in 6 mL of anhydrous N,N-dimethylformamide at 0° C. under argon and the reaction mixture was stirred at 0° C. for 1 h followed by addition of methyl iodide (84.7 mL, 1.356 mmole). The reaction was then stirred at 20° C. under argon for 17 h. It was poured into ice-water (50 mL) and extracted with ethyl acetate. The ethyl acetate layers were dried over anhydrous magnesium sulfate and evaporated. Purification by flash chromatography using ethyl acetate (2-5%)/hexanes gave 107 mg of 6-methoxymethyl-1-(2-propyl) indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[CH3:30][O:31][CH2:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]([C:34](=[O:35])[CH2:33][CH2:32][O:31][CH3:30])[CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:5][CH:4]=1
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Reactant: COCCC(=O)Cl
Product: COCCC(=O)N(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide and 3-methoxy-propionyl chloride, the title compound was prepared as light yellow crystals (46% yield). MS: m/e=499(M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[CH2:36]([NH2:38])[CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:36]([NH:38][CH2:34][C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH3:37]
Reactant: CCN
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCNC[C@@H]1CNC[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Reaction time: 8 h

Procedure:
The corresponding enantiomer N-((3S,4R)-4-Ethylaminomethyl-pyrrolidin-3-ylmethyl)-N-isopropyl-4-methoxy-3-(3-methoxy-propoxy)-benzamide is obtained as follows: A solution of (3S,4R)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.27 g, 2.58 mmol) and gaseous ethylamine (0.704 g, 15.5 mmol; Fluka 02940) in 1,2-dichloroethane (10 mL) is stirred at room temperature for 30 min, then sodium triacetoxyborohydride (1.37 g, 6.45 mmol) is added in one portion and the mixture is stirred overnight. The organic phase is washed with saturated aqueous NaHCO3 solution, the water layers are re-extracted with CH2Cl2, and the combined organics are dried (Na2SO4) and evaporated to dryness to give the title compound. MS: 522.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([NH:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Yield: 78.8 %

Procedure:
A mixture of 2-chloro-5-nitro-pyridine (3.4 g, 0.021 mol), (S)-(−)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (4 g, 0.021 mol), and potassium carbonate (14.5 g, 0.105 mol) in acetonitrile (50 mL) was heated at reflux for 24 h. The reaction was monitored by LCMS and additional (S)-(−)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester was added until the reaction was driven to completion. The reaction mixture was then filtered and concentrated to give (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.1 g, 78.6%) as a yellow solid. LCMS calcd for C14H20N4O4 (m/e) 308, obsd 307.1(M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]([F:32])([F:31])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([F:32])([F:31])[F:18])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=445.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([O:21]C)=O)[CH:16]=[CH:17][CH:18]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:23]>>[OH:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:13]=1[N:14]=[C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[NH:23][C:19]2=[O:21]
Reactant: COC(=O)c1cccc2oc(-c3ccc([N+](=O)[O-])cc3)nc12
Reactant: N
Product: O=c1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc2c(O)cccc12
Reaction time: 20 h

Procedure:
Methyl 2-(4-nitrophenyl)benzoxazole-4-carboxylate (0.20 g) obtained as described in Example 19 (2nd stage) was dissolved in liquid ammonia (30 ml) and sealed in an autoclave. The reaction mixture was left at 55° C., 20 bar for 20 hours. Under these conditions, the expected 2-(4-nitrophenyl)benzoxazole derivative apparently rearranged to give the corresponding quinazolinone derivative. Once the reaction was complete the ammonia was removed and the resulting solid recrystallised from boiling ethyl acetate and petrol (84%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:22][C:23]([CH3:29])([CH3:28])[C:24]([NH:26][CH3:27])=[O:25]>>[CH3:28][C:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24](=[O:25])[NH:26][CH3:27])[CH3:29]
Reactant: O=C(O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1
Reactant: CNC(=O)C(C)(C)N
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(N2CCC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (Example 78 b) and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (EI): m/e=397.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][OH:7].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]([C@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:50]([C:57](=[O:65])[C:58]3[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=3)[C@@H:49]([CH3:66])[CH2:48]2)[C:44](=[O:46])[CH3:45])=[CH:39][CH:38]=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:44]([N:43]([C:40]1[CH:39]=[CH:38][C:37]([Cl:36])=[CH:42][CH:41]=1)[C@H:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([C:57]([C:58]2[CH:63]=[CH:62][C:61]([O:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[C:3]([O:2][CH3:1])=[O:16])=[CH:60][CH:59]=2)=[O:65])[C@@H:49]([CH3:66])[CH2:48]1)(=[O:46])[CH3:45]
Reactant: COC(=O)C(CCO)NC(=O)OC(C)(C)C
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ester was dissolved in 20 ml toluene at room temperature with PPh3 (0.94 g, 3.6 mmol), then added N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (0.31 g, 0.71 mmol) and stirred for 5 min. DEAD (0.626 g, 3.6 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by silica gel chromatography (45% CH2Cl2/55% EtOAc) to afford crude methyl 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2-[(tert-butoxycarbonyl)amino]butanoate (0.47 g).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[C:2]#[C:3][C:4]([OH:6])=[O:5].[CH2:9](O)[CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)O>>[C:2]([C:1]([O:8][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])#[C:3][C:4]([O:6][CH2:9][CH2:10][CH2:11][CH3:12])=[O:5]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCO
Agent: O=S(=O)(O)O
Product: CCCCOC(=O)C#CC(=O)OCCCC

Procedure:
First, dibutyl acetylenedicarboxylate was prepared. A mixture of 2-butynedioic acid (5.0 g, 44 mmol), n-butyl alcohol (162 g, 2.19 mol), and sulfuric acid (0.86 g, 9 mmol) was heated at reflux for 6 hours. The mixture was cooled to ambient, washed with 10% aqueous NaHCO3 then with brine, dried (Na2SO4), concentrated, and the resulting crude product distilled under reduced pressure (bp 65-70° C./0.08 mm). Dibutyl acetylenedicarboxylate was obtained as a colorless oil (8.5 g, 86% of theory). 1H NMR (CDCl3): δ 1.90 (t, 6H), 1.38 (m, 4H), 1.65 (m, 4H), 4.20 (t, 4H).
Reaction SMILES: [OH:1][CH:2]([CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH:6]1[O:22][Si](C(C)(C)C)(C)C)[CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C.Cl>[OH:1][CH:2]([CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH:6]1[OH:22])[CH2:3][CH3:4]
Reactant: CCC(O)C1C(O[Si](C)(C)C(C)(C)C)CCC12CCN(C(=O)OC(C)(C)C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)C1C(O)CCC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 1-(1-hydroxyprop-1-yl)-2-(tert-butyldimethylsilyloxy)-8-azaspiro[4.5]decane-8-carboxylate (0.248 g, 0.58 mmol) in THF (15 mL) was added 1M tetrabutylammonium fluoride in THF (2.3 mL, 2.3 mmol). The solution was stirred at room temperature for 4 h and was then diluted with ethyl acetate, poured into IN HCl, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 50% ethyl acetate in hexanes to afford the title compound (0.18 g) as a mixture of isomers.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:33]=[C:32]([C:34](O)=[O:35])[O:31][N:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([C:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: Cc1cc(C(=O)O)on1
Agent: Cl
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)on1

Procedure:
The title compound, off-white solid (62 mg, 71%), MS (ISP) m/z=440.4 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 3-methylisoxazole-5-carboxylic acid.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([F:16])([F:14])[F:15])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:5]1
Reactant: [N-]=[N+]=NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 3-azido-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-benzo[e][1,4]diazepine-2-one (crude from above) in 1.3 L THF was added triphenylphosphine (109 g, 0.417 mol) and water (150 mL). This was stirred overnight at ambient temperature. The reaction was then concentrated under reduced pressure, taken up in 1N HCl (1500 mL), and extracted with ethyl ether (2×500 mL). The combined organics were back extracted with 1N HCl (1×300 mL). The combined aqueous layers were back extracted with ethyl acetate (100 mL) and then basefied with sat. NaHCO3 (100 mL) and 50% NaOH until pH=10. This was extracted with ethyl acetate (2×500 mL). The combined ethyl acetate fractions were dried over Na2SO4, evaporated under reduced pressure and crystallized from ethyl ether to give the title compound as a powder. MP=141°-143° C.;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:13]([C:17]1[CH:18]=[C:19]([C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[C:20]([OH:25])=[C:21]([CH:24]=1)[CH:22]=O)([CH3:16])([CH3:15])[CH3:14].[BH4-].[Na+]>CO>[C:13]([C:17]1[CH:18]=[C:19]([C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)[C:20]([OH:25])=[C:21]([CH:24]=1)[CH2:22][NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCNCc1cc(C(C)(C)C)cc(-c2ccc(C(F)(F)F)nc2)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
tert-Butyl N-(3-aminopropyl)carbamate (0.404 g, 2.32 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (from Example 47 Step 1) (0.5 g, 1.55 mmol) in methanol (5 mL) and the reaction mixture stirred at room temperature under nitrogen for 4 hours. Sodium borohydride (234 mg, 6.19 mmol) was then added and the reaction mixture stirred at room temperature for 2.5 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (5 mL), the mixture stirred vigorously for 10 minutes then partitioned between ethyl acetate (80 mL) and saturated aqueous ammonium chloride solution (80 mL). The organic phase was separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 6% methanol (containing 1% aqueous ammonium hydroxide) in dichloromethane to give tert-butyl (3-((5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzyl)amino)propyl)carbamate (0.755 g, 100% yield) as a yellow syrup.