Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:38]([C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)[C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=1[CH2:12][CH2:13][C@H:14]1[O:19][CH2:18][C@H:17]([CH2:20][O:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[N:16]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]1)=[O:4].C(N(CC)CC)C.Cl[C:62]([O:64][CH3:65])=[O:63]>C(Cl)Cl>[CH3:65][O:64][C:62]([NH:1][C@@H:2]([C@@H:38]([C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)[C:39]1[CH:40]=[C:41]([F:46])[CH:42]=[C:43]([F:45])[CH:44]=1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=1[CH2:12][CH2:13][C@H:14]1[O:19][CH2:18][C@H:17]([CH2:20][O:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[O:23])[N:16]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:15]1)=[O:4])=[O:63]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2S,3S)-2-amino-3-(4-fluorophenyl)-3-(3,5-difluorophenyl)-N-(5-fluoro-4-(2-((2R,5R)-4-(tert-butyloxycarbonyl)-5-(2,2,2-trifluoroethylaminocarbonyloxymethyl)morpholine-2-yl)ethyl)pyridin-3-yl)propanamide (Example 90, step 5) (64 mg, 0.084 mmol) in 1 mL of CH2Cl2 was added triethylamine (0.047 mL, 0.34 mmol) and methyl chloroformate (0.013 mL, 0.17 mmol). The mixture was stirred at ambient temperature for 1 h, then diluted with CH2Cl2 and washed with aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-100% EtOc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a gum. LC MS: RT=1.38 min, M+H=816 (2 min gradient)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] (227 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (347 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:17][C:18](=[O:27])[C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.[CH:28]1([CH:31]=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(#N)C>[CH:28]1([CH2:31][NH:1][CH2:2][C@H:3]([NH:17][C:18](=[O:27])[C@H:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:8][CH:9]=2)[CH2:30][CH2:29]1
Reactant: CCCC(C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCC(C)COc1ccc([C@H](CNCC2CC2)NC(=O)[C@@H](C)c2ccccc2)cc1
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
To a stirred solution of (2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (50 mg, 0.136 mmol), prepared according to the procedure described in example 5, in acetonitrile (3 mL), was added cyclopropanecarboxaldehyde (10.23 μL, 0.136 mmol) and stirring was continued for 15 min. To this mixture, sodium triacetoxyborohydride (57.5 mg, 0.271 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA). The organic solvent was removed on the rotovapor and the aqueous mixture was frozen and placed on the lyophilizer. The product was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford (2S)-N-((1R)-2-(cyclopropylmethylamino)-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (25 mg, 43.6% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.20-7.36 (m, 5H), 6.92 (d, J=8.6 Hz, 2H), 6.73 (d, J=8.6 Hz, 2H), 6.50 (d, J=6.8 Hz, 1H), 4.99 (q, J=6.3 Hz, 1H), 3.74 (dd, J=8.8, 5.8 Hz, 1H), 3.59-3.68 (m, 2H), 2.95 (dd, J=12.2, 6.4 Hz, 1H), 2.82 (dd, J=12.2, 4.9 Hz, 1H), 2.33-2.47 (m, 2H), 2.08-2.31 (m, 1H), 1.83-1.95 (m, 1H), 1.49 (d, J=7.1 Hz, 3H), 1.26-1.48 (m, 3H), 1.13-1.25 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.1 Hz, 3H), 0.75-0.84 (m, 1H), 0.37-0.46 (m, 2H), −0.02-0.08 (m, 2H); LRMS (ESI) m/e 423.4 [(M+H)+, calcd for C27H39N2O2 423.3].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([O:21][C:24]2[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=2)=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2c3c(n(C)c12)C(=O)N(C)CC3
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3c(n(C)c12)C(=O)N(C)CC3

Procedure:
A solution of 8-methoxy-2,9-dimethyl-1-oxo-1,2,3,4-tetrahydro-β-carboline-5-carboxylic acid (from step 5) (1 mmol), p-nitrophenol (1.5 mmol), EDCI (1.5 mmol) and DMAP (0.1 mmol) in dry THF was stirred at r.t. for 18 h. Minimum water was then added and the precipitated p-nitrophenylester was filtered and washed with water and dried (50-60%).
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O:12]C)=O)[CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH2:2])=[O:12])[CH:5]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 50 °C
Yield: 72 %

Procedure:
Ammonium hydroxide (2 ml) was added to methyl 4-chloropyridine-2-carboxylate (100 mg, 0.58 mmol) in MeOH (4 ml) in a sealed tube and heated at 50° C. for 4 hours. The reaction was cooled to room temperature and concentrated at reduced pressure. The residue was dissolved in dichloromethane (20 ml), washed with water (2×10 ml), dried (Na2SO4), filtered and concentrated at reduced pressure to give the title compound (66 mg, 72%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][C:6]=1[NH:7][C:8](=[O:10])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:37]1([C:43]#[CH:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>[Pd].C(O)C.[Cu]I>[C:37]1([C:43]#[C:44][C:2]2[CH:3]=[N:4][NH:5][C:6]=2[NH:7][C:8](=[O:10])[CH3:9])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)Nc1[nH]ncc1I
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)Nc1[nH]ncc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Nitrogen was bubbled through a suspension of N-(4-iodo-1H-pyrazol-5-yl)acetamide (30 g, 120 mmol), 10% palladium on carbon (50% water, 7.4 g, 3 mmol), copper(I) iodide (1.14 g, 6 mmol), triphenylphosphine (6.3 g, 24 mmol) and triethylamine (50 mL, 360 mmol) in ethanol (600 mL) for 20 min. Phenyl acetylene was added and nitrogen bubbled through the mixture for a further 25 min. The reaction mixture was then heated and stirred under reflux conditions in an atmosphere of nitrogen for 3 d and cooled to room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, iso-hexanes/ethyl acetate 9:1 to 0:1) yielding the title compound as a solid (17.6 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:15]([F:17])[F:16])[N:6]=1.[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CC(N(C)C)=O.CO>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH:15]([F:17])[F:16])=[C:7]([C:5]2[N:6]=[C:2]([N:35]3[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]3)[S:3][C:4]=2[NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[CH:12]=1
Reactant: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: CN(C)C1CCNCC1
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CN(C)C1CCN(c2nc(-c3cc(Cl)ccc3OC(F)F)c(NC(=O)c3cnn4cccnc34)s2)CC1
Temperature: 160 °C
Yield: 39.2 %

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (100 mg, 0.2 mmol) and 4-dimethylaminopiperidine (128 mg, 1 mmol) were dissolved in DMA (1 ml) and heated in a microwave at 160° C. for 1 hour. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The resulting yellow glass was purified by MDAP (Method 1). Appropriate fractions were combined and evaporated to afford a yellow solid. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH to give the title compound as a yellow-orange solid (43 mg, 39%). LCMS (Method 5) [M+H]+=548.1, RT=3.20 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.23 (s, 1H), 9.36 (dd, 1H, J=1.6, 7.0 Hz), 8.68 (s, 1H), 8.63 (dd, 1H, J=1.6, 4.2 Hz), 7.66 (d, 1H, J=2.7 Hz), 7.59 (dd, 1H, J=2.6, 8.8 Hz), 7.41 (d, 1H, J=9.0 Hz), 7.31 (dd, 1H, J=4.2, 6.7 Hz), 7.18 (t, 1H, J=73.5 Hz), 3.93 (d, 2H, J=12.7 Hz), 3.02 (dd, 2H, J=10.3, 12.3 Hz), 3.05-2.95 (m, 1H), 2.40-2.26 (m, 6H), 1.92-1.89 (m, 2H), 1.58-1.47 (m, 2H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[N:13](C(C(OCC)=O)=O)[C@@H:12]1[C@@H:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C>CO>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[C@@H:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH3:10])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)OC
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of methyl (2R)-2-[(2S,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-1-(ethoxalyl)-4-oxoazetidin-2-yl]propionate (27 mg) in methanol (1 ml) was added triethylamine (27 μl) at room temperature. After stirring for 30 minutes, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine (twice) and water, dried over magnesium sulfate and evaporated to give methyl (2R)-2-[(2S,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-4-oxoazetidin-2-yl]propionate (14 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=2)O1>>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:40][N:41]=1
Reactant: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N-methyl-isobutyramide (Example 88) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 173. NMR 400 MHz (CDCl3): 2.56 (6H, b, CH3), 2.80 (3H, d (J=4.93), CH3), 3.83 (2H, s, CH2), 3.88 (4H, m, CH2), 4.03 (4H, m, CH2), 5.19 (2H, s, NH), 7.26 (1H, s, ar), 9.28 (2H, s, ar). MH+512.37
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH:19]([F:24])[F:23])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(O)cn1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC(F)F)cn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 3.5 %

Procedure:
To 5-hydroxypyrazine-2-carboxylic acid methyl ester (2.0 g, 13 mmol) in a glass tube reaction vessel in DMF (26 mL) was added potassium carbonate (5.3 g, 39 mmol) and sodium 2-chloro-2,2-difluoroacetate (4.0 g, 26 mmol). The reaction vessel was capped and warmed to 100° C. The reaction was stirred for 30 minutes and cooled to room temperature. The reaction was filtered washing with EtOAc. The filtrate was concentrated in vacuo. The residue was taken up into EtOAc and washed with brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hex) to give methyl-5-(difluoromethoxy)pyrazine-2-carboxylate (0.09 g, 0.46 mmol) (0.40 g, 20%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Product: CCOC(=O)COc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
The subtitle compound was prepared by the method of example 1 step (iv) using ethyl bromoacetate and 4-chloro-2-nitrophenol Yield 1.4 g
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[CH3:13][C:14]([NH:16][CH:17]1[C:27]2[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]=2[C:25]2[C:20](=[CH:21][C:22]([O:37][CH3:38])=[C:23]([O:35][CH3:36])[C:24]=2[O:33][CH3:34])[CH2:19][CH2:18]1)=[O:15]>C1COCC1>[C:9](=[O:10])([O:11][CH3:12])[O:32][C:29]1[CH:30]=[CH:31][C:26]2[C:25]3[C:24]([O:33][CH3:34])=[C:23]([O:35][CH3:36])[C:22]([O:37][CH3:38])=[CH:21][C:20]=3[CH2:19][CH2:18][C@H:17]([NH:16][C:14](=[O:15])[CH3:13])[C:27]=2[CH:28]=1
Reactant: COC(=O)Cl
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc2c(c1)[C@@H](NC(C)=O)CCc1cc(OC)c(OC)c(OC)c1-2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Triethylamine (70 μl; 0.5 mmol) and methyl chloroformate (39 μl; 0.5 mmol) were added to a solution of N-acetyl-colchicinol (0.178 g; 0.5 mmol) in THF (3 ml). The mixture was stirred at ambient temperature for 90 minutes. After removal of the insoluble material by filtration the residue was purified by flash chromatography eluting with dichloromethane/ethanol (98/2) to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl methyl carbonate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[C:14]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][O:21][NH2:22])=[CH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][O:21]/[N:22]=[C:10](/[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)\[CH3:11])=[CH:18][CH:17]=1)#[N:15]
Reactant: COc1ccc(C(C)=O)cc1O
Reactant: N#Cc1ccc(CON)cc1
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2ccc(C#N)cc2)cc1O
Yield: 50.3 %

Procedure:
Acetophenone 12 (30 mg, 0.181 mmol) was condensed with O-(4-cyanobenzyl)hydroxylamine hydrochloride (35) (37 mg, 0.200 mmol) according to the general procedure II-B defined above. After being heated for 3 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing solid was filtered off and washed with cold isopropanol (3.0 mL) to afford the title compound CP30283 (27 mg, 51%) as a white solid, m.p. 125.9-129.7° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29]>C1COCC1>[OH:29][CH2:28][C:27]([NH:26][C:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:25]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:24])([CH3:31])[CH3:30]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Reactant: CC(C)(N)CO
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)NC(C)(C)CO)cc1OCC2

Procedure:
Following the same procedure as for 133, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (20 mg, 0.06 mmol) was reacted with 2-amino-2-methyl-1-propanol (11 mg, 0.12 mmol) in THF to provide N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide 163. LC/MS (ESI+): m/z 411 (M+H). 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=8.4, 1H), 7.95 (d, J=22.3, 2H), 7.64-7.45 (m, 3H), 5.86 (dt, J=13.1, 6.5, 1H), 4.88 (t, J=6.0, 1H), 4.63-4.44 (m, 4H), 3.58-3.45 (m, 3H), 1.49 (d, J=6.6, 6H), 1.32 (s, 6H)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][N:22]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2][N:25]2[CH2:24][CH2:23][N:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]([CH3:20])[CH2:26]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)N1CCNCC1C
Reactant: Fc1ccc(C(CCCCCl)c2cccnc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(CCCCC(c2ccc(F)cc2)c2cccnc2)CC1C
Temperature: 70 °C
Reaction time: 40 h
Yield: 96.7 %

Procedure:
A mixture of 14 parts of 3-[5-chloro-1-(4-fluorophenyl)pentyl]-pyridine, 7.75 parts of ethyl 2-methyl-1-piperazinecarboxylate, 8.7 parts of N,N-diethylethanamine, 0.1 parts of potassium iodide and 198 parts of N,N-dimethylformamide was stirred for 40 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in a mixture of water and sodium carbonate. The aqueous layer was extracted with trichloromethane. The extract was washed with a sodium carbonate solution in water and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18 parts (96.7%) of ethyl 4-[5-(4-fluorophenyl)-5-(3-pyridinyl)pentyl]-2-methyl-1-piperazinecarboxylate as a residue (int. 38).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]([CH2:18][C:19]1[CH:27]=[C:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]3[N:20]=[C:19]([CH2:18][O:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:27]=[C:22]3[CH2:23]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccc(OCc2cc3n(n2)CCNC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
4-Fluorobenzoyl chloride (0.14 mL, 1.2 mmol) was added to a stirred solution of 4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.3 g, 1.0 mmol) and pyridine (0.16 mL, 2.0 mmol) in DCM (13 mL) under N2 at 0° C. The reaction was stirred at room temperature for 1 hour, diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo. The desired product was triturated with DIPE to yield 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.21 g, 59% yield) as a white solid. C20H18FN3O2 1H NMR (500 MHz, CDCl3) δ ppm 4.07 (br. s., 2H), 4.27 (br. s., 2H), 4.81 (br. s., 2H), 5.05 (s, 2H), 6.16 (br. s., 1H), 6.96 (dd, J=7.5, 7.2 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 7.15 (t, J=8.5 Hz, 2H), 7.29 (dd, J=8.1, 7.8 Hz, 2H), 7.49 (dd, J=8.5, 5.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28](O)=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.[CH3:41][NH:42][CH3:43].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28](=[O:29])[N:42]([CH3:43])[CH3:41])([CH3:26])[CH3:27])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)N(C)C)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 23.3 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.07 mmol), dimethylamine hydrochloric salt (8.2 mg, 0.1 mmol), EDC.HCl (20 mg, 0.1 mmol), and HOBt (14 mg, 0.1 mmol) in THF (5 mL) was added DIPEA (0.018 mL, 0.2 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 10 mg).