Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[SH:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].CN1CCOCC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:12][CH:13]=1)[NH:6][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[N:34][C:26]=1[SH:25]
Reactant: O=C(O)c1cccnc1S
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)c1cccnc1S
Yield: 92.8 %

Procedure:
A solution of O-(2,6dichlorobenzyl)-L-tyrosine methyl ester hydrochloride (2.50 g, 6.4 mmol), 2-mercaptonicotinic acid (0.99 g, 6.4 mmol) and NMM (1.41 ml, 1.29 g, 12.8 mmol) in DMF (10 ml) was stirred at room temperature for 64 h. Solvent was removed in vacuo and the residue partitioned between DCM (30 ml) and water (25 ml). The aqueous layer was extracted with DCM (30 ml) and the combined organic layers were washed with 10% NaHCO3 solution (30 ml), dried over MgSO4 and the solvent removed in vacuo to give a brown oil which was purified by chromatography (SiO2; gradient elution, 4:1 EtOAc/hexane to 100% EtOAc) to give the title compound as a yellow foam, (2.92 g, 93%). δH (CDCl3) 8.71 (1H, dd, J 1.8, 7.6Hz), 8.05 (1H, s), 7.61 (1H, dd, J 1.8, 6.1 Hz), 7.35 (2H, m), 7.33-7.19 (2H, m), 6.94 (2H, d, J 8.7Hz), 5.22 (2H, s), 4.97 (1H, m), 3.74 (3H, s) and 3.21 (2H, m).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[C:19](I)=[CH:18][CH:17]=[CH:16][N:15]=1.[I:21][CH3:22]>C1COCC1>[F:13][C:14]1[C:19]([CH3:18])=[C:22]([I:21])[CH:17]=[CH:16][N:15]=1
Reactant: Fc1ncccc1I
Reactant: CI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1c(I)ccnc1F
Reaction time: 1 h
Yield: 88.4 %

Procedure:
n-Butyl lithium (1.6M hexane solution, 53.8 mL) was added to a solution of diisopropylamine (8.71 g) in THF (200 mL) at −10 C. After being stirred at the same temperature under nitrogen atmosphere for 1 hour, a solution of 2-fluoro-3-iodopyridine (18.3 g) in THF (70 mL) was added to the reaction mixture at −78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 1 hour. A solution of iodomethane (12.8 g) in THF (30 mL) was added to the reaction mixture at −78 C. The mixture was stirred at the same temperature under nitrogen atmosphere for 2 hours. The mixture was quenched with aqueous saturated ammonium chloride solution at 0 C and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through NH-silica and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17.2 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([N:26]([CH3:35])[CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.043 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 3.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 90% ethyl acetate in dichloromethane and then 3% and 5% methanol in ethyl acetate. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.012 g, 22%); 1H-NMR (500 MHz, DMSO-d6) 2.61 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.61 (s, 2H, NCH2CO), 3.63 (br s, 4H, piperazine N(CH2)2), 6.81 (d, J=9.00 Hz, 2H) and 8.01 (d, J=8.80 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.40 (dd, J=7.06, 3.92 Hz, 1H, pyridyl 5-H), 7.78 (d, J=8.64 Hz, 1H, pyridyl 4-H), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=4.75, 1.50 Hz, 1H, pyridyl 6-H), 8.56 (d, J=1.50 Hz, 1H, pyridyl 2-H), 13.15 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCC1)CC2

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), pyrrolidine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 295 (M+, 2), 131 (4), 85 (6), 84 (bp), 77 (3), 55 (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)Cl

Procedure:
To a suspension of the so-obtained 2-methoxy-5-sulfamoyl benzoic acid in 600 parts of anhydrous tetrahydrofuran, there were added rapidly 27.5 parts of thionyl chloride. The mixture was refluxed for 2 hours. The solution was then evaporated under vacuo. The residue was treated with 500 parts of anhydrous benzene. After elmination of benzene in vacuo, there were obtained 29 parts of 2-methoxy-5-sulfamoyl benzoyl chloride, M.P. 148°-150° C, which after one recrystallization from benzene melts at 156° C.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])=[O:5]
Reactant: O=C(CCl)N1CCOCC1
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCOCC1
Yield: 34.4 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with 4-(chloroacetyl) morpholine (0.75 g, 4.61 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.34 g (35% yield) of the title compound (3) as a white solid after purification by mass-guided preparative HPLC and lyophilization. M.p.: 124 to 126° C.; 1H NMR (CDCl3, 400 MHz): δ 6.97-6.91 (m, 2H), 4.84 (s, 2H), 3.82 (s, 3H), 3.72-3.70 (m, 4H), 3.64-3.62 (m, 2H), 3.46-3.41 (m, 2H). MS (ESI): m/z 258.04 (M+H)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:16](Br)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][N:12]=1>CN(C=O)C>[NH2:10][C:11]1[C:16]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:15][C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][N:12]=1
Reactant: COc1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(N)c(Sc3ccccc3)n2)cc1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
To a cooled solution of thiophenol (0.08 mL, 0.7 mmol) in dry DMF (10 mL), sodium hydride (NaH) (0.025 g, 1.00 mmol) was added and the resulting mixture was stirred for 15 min at 5-10° C. After this time 2-amino-3-bromo-5-(4-methoxyphenyl)pyrazine 17a (0.20 g, 0.71 mmol) was added and the mixture refluxed for 6 h, cooled and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using petroleum ether-EtOAc (65:45 v/v) as eluent, to obtain 0.15 g of the title compound 18a as an orange solid (mp 89-90° C., 70% yield). 1H-NMR (CDCl3): 3.81 (s, 3H), 4.90 (br s, 2H), 6.89 (d, J=8.7, 2H), 7.33-7.39 (m, 7.45-7.50 (m, 2H), 7.69 (d, J=8.7, 2H), 8.28 (s, 1H). MS (ESI): m/z 310 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 4-fluoro-3-nitrophenol (8.1 g, 38 mmol) and 2-(chloromethyl)quinoline (6.0 g, 38 mmol) in DMF (100 mL) were added K2CO3 (21 g, 153 mmol) followed by KI (317 mg, 1.9 mmol). The mixture was stirred at 50° C. for 5 h. The mixture was cooled to RT, water (100 mL) was added, and the mixture was extracted with EtOAc (3×150 mL). The organics were combined, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by FCC to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=9, 1H), 8.15 (d, J=9, 1H), 7.87 (d, J=9, 1H), 7.80-7.72 (m, 2H), 7.65-7.56 (m, 2H), 7.32-7.26 (m, 1H), 7.23-7.16 (m, 1H), 5.44 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3[CH3:21])[N:7]([C:22]#N)[CH2:6]1)=[O:4].[CH2:24](I)[CH2:25]C>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3[CH3:21])[N:7]([CH2:22][CH2:24][CH3:25])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C#N)C1
Reactant: CCCI
Product: CCCN1C[C@H](C(=O)OC)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Yield: 54 %

Procedure:
As described at the beginning, the noncrystalline compound can be prepared from 6-cyano-2-methyl-8beta-ergoline-carboxylic acid methyl ester by reduction and alkylation with n-propyliodide in a 54% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])#[CH:20]>>[NH2:24][C:23]1[CH:22]=[C:21]([C:19]#[C:20][C:2]2[CH:3]=[C:4]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(Br)cc([N+](=O)[O-])c1
Product: CC(C)(C)NS(=O)(=O)c1cc(C#Cc2cccc(N)c2)cc([N+](=O)[O-])c1
Yield: 32 %

Procedure:
The desired compound was prepared according to the procedure of Example B5, step E using 3-bromo-N-(tert-butyl)-5-nitrobenzenesulfonamide and 3-ethynylaniline as the starting materials in 32% yield. LCMS for C18H20N3O4S (M+H)+: m/z=374.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11]>C(#N)C.C(OC)(C)(C)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C@@:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CN1C(=O)[C@@]2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21

Procedure:
4′-Bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.32 g, 8.58 mmol) was resolved on a semi-preparative chiral column (CHIRALPAK-IA, Chiral Technologies, Inc.) eluted with 5% acetonitrile in tert-butylmethylether at 30 mL/min. Each run consisted of 50 mg of the racemate dissolved in acetonitrile/tert-butylmethylether (1:1). (7R)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.14 g, 86%) was the first enantiomer to elute and was obtained as a crystalline colorless solid:. mp 226-228° C. (acetonitrile/tert-butylmethylether); 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.23 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.08 (m, 1H), 6.59 (s, 1H), 6.28 (s, 1H), 5.92-5.87 (m, 2H), 4.82 (d, J=9.7 Hz, 1H), 4.67 (d, J=9.7 Hz, 1H), 3.15 (s, 3H); MS (ES+) m/z 373.8, 375.8 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:45])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[CH:6]=1.[OH-].[Na+]>CO>[C:39]1([CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][N:15]([CH2:16][C:17]2[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=2)[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:45])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of (3-{3-[(2,2-Diphenyl-ethyl)-(3,5-bis(trifluoromethyl)-benzyl)-amino]-propoxy}-phenyl)-acetic acid methyl ester (4e). (0.57 g, 0.001 mol) in methanol (7.5 mL) was treated with 2N NaOH (5 mL) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was dissolved in EtOAc (25 mL) and water was added (10 mL), the solution acidified to pH 3 with concentrated hydrochloric acid, then extracted into EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil, which was purified by flash chromatography (9:1 CH2Cl2/MeOH) to give the desired product as oil 0.49 g in 79% yield. 1H NMR (CD3OD) δ 7.70 (s, 1H), 7.66 (s, 2H), 7.23 (m, 8H), 7.14 (m, 3H), 6.82 (d, 1H), 6.58 (s, 1H), 6.54 (dd, 1H), 4.26 (t, 1H), 3.77 (s, 2H), 3.56 (t, 2H), 3.52 (s, 2H), 3.16 (d, 2H), 2.64 (t, 2H), 1.82 (t, 2H); 13C NMR (CD3OD) δ 175.6, 160.3, 145.3, 144.9, 137.3, 132.4, 130.3, 130.2, 129.4, 129.3, 127.4, 122.5, 121.5, 116.4, 113.9, 66.3, 61.0, 59.1, 51.8, 51.3, 42.1, 27.9. Anal. Calcd for C34H31F6NO3: C, 66.34; H, 5.08; N, 2.08; F, 18.52. Found: C, 66.10; H, 5.07; N, 2.21; F, 18.69.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]([C@H:8]1CCC[N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([C@H:2]1[CH2:1][CH2:6][CH2:8][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH2:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
n-Butyl lithium (1.6 M in hexanes)(27 mL, 43 mmol) was added to ice-cold hexamethyldisilazane (9.2 mL, 44 mmol) under a nitrogen atmosphere. The solution was stirred for 10 min and was then added to a suspension of methyl(triphenylphosphonium)bromide (15.5 g, 43 mmol) in 100 mL of THF at ambient temperature. After stirring for 1 h, the mixture was cooled to −78° C. and a solution of tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (7.9 g, 40 mmol) in 50 mL of THF was added. The cold bath was removed and the mixture stirred overnight at ambient temperature. The reaction mixture was then quenched with saturated NH4Cl, the phases were separated, and the organic phase was washed with saturated NH4Cl, brine, dried over Na2SO4, filtered, and concentrated to give an orange oil. The oil was purified on a Biotage 40M column eluting with heptane to give tert-butyl (2R)-2-vinylpyrrolidine-1-carboxylate (5.0 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20](=[O:37])[CH2:21][NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH2:16]1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:16][CH:17]([NH:19][C:20](=[O:37])[CH2:21][NH:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:34])([F:36])[F:35])[CH:31]=5)[N:26]=[CH:25][N:24]=4)[CH2:18]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ncccc2O)CC1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ncccc3O)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(3-hydroxy-pyridin-2-yl)-cyclohexanone (as prepared in step C, 1 eq.) and N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in the previous step, tris TFA salt, 1 eq.) in DCM was added TEA (3 eq.). After stirring at room temperature 30 minutes, NaBH(OAc)3 (3 eq) was added and the mixture was stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution and partially concentrated. Extraction with ethyl acetate followed by concentration of the organic layer in vacuo yielded a residue which was purified by flash chromatography (silica gel, 0-20% 7 N NH3-MeOH/Ethyl acetate) to afford the product as a solid, mixture of isomers.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([O:10]C)=O.CO.[CH3:14][NH2:15]>>[CH3:14][NH:15][C:8](=[O:10])[CH2:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)CCc1ccco1
Solvent: CO
Product: CNC(=O)CCc1ccco1

Procedure:
A solution of methyl 3-(furan-2-yl)propanate (4.0 g) in 40% methylamine methanol solution (50 ml) was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure to afford N-methyl-3-(furan-2-yl)propanamide (4.0 g).
Reaction SMILES: C(OC([NH:11][C:12]([CH3:50])([CH3:49])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][CH:30]=2)[C:18]1=[O:48])=[O:15])=O)C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[Pd+2].[OH-]>[C:41]([OH:43])(=[O:42])[CH3:36].[NH2:11][C:12]([CH3:50])([CH3:49])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[C:36]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)[C:18]1=[O:48])=[O:15]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)C1=O)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(N)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)C1=O
Reaction time: 4 h
Yield: 193.7 %

Procedure:
To a solution of 400 mg (0.592 mmol) of t-butyl 4'-[[3(R)[[3-benzyloxycarbonylamino-3-methyl-1-oxobutyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxylate (prepared according to the procedure of Fisher et al, U.S. Pat. No. 5,206,235) in 10 mL of methanol was added 0.034 mL (0.59 mmol) of acetic acid and 80 mg (20% w/w) palladium hydroxide. The resulting mixture was stirred under a hydrogen atmosphere for 4 hours. Catalyst was removed by filtration through Celite and the solvent removed under vacuum to afford 345 mg (97%) of the product as a white solid. 1H NMR (400 MHz, CD3OD): δ1.17 (s, 9H), 1.37 (s, 3H), 1.41 (s, 3H), 1.92 (s, 3H), 2.17 (m, 1H), 2.35 (m, 1H), 2.45-2.75 (m, 4H), 4.41 (dd; 12, 8 Hz; 1H), 4.93 (d, 15 Hz, 1H), 5.37 (d, 16 Hz, 1H), 7.12-7.52 (m, 11H), 7.66 (d, 8 Hz, 1H). FAB-MS: calculated for C33H39N3O4 541; found 542 (M+H,100%).
Reaction SMILES: [NH2:1][CH:2]([CH2:21][CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)[CH2:6]1.[C:35](Cl)([CH3:37])=[O:36]>C(Cl)Cl>[O:15]1[C:14]2[CH:19]=[CH:20][C:11]([N:7]3[CH2:6][CH:5]([CH2:4][CH2:3][CH:2]([NH:1][C:35](=[O:36])[CH3:37])[CH2:21][CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=5)[N:26]=[CH:25][CH:24]=4)[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18][CH2:17][CH2:16]1
Reactant: COc1ccc2nccc(CCC(N)CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: COc1ccc2nccc(CCC(CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)NC(C)=O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of the compound of Example 116 (0.05 g, 0.1 mmol) in DCM (1 mL) at rt was treated sequentially with TEA (0.03 mL, 2 eq.) and AcCl (1.5 eq.). The mixture was stirred at rt for 1 h, washed with water (2 mL) and purified by FC (EA, EA/MeOH 9:1) to give the title compound as a colourless foam (0.048 g, 88% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[C:19]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ccnc(Cl)c2)c1
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
Methyl 3-hydroxybenzoate (2.88 g, 18.9 mmol) was added to a mixture of 60% sodium hydride in mineral oil (0.757 g, 18.9 mmol) in DMF (20 mL). The reaction mixture was stirred for 20 minutes and then cooled in an ice bath. 2-Chloro-4-nitropyridine (3.00 g, 18.9 mmol) was added and the reaction mixture was stirred for 1 hour at 0° C., and then overnight at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed twice with water and brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 5:1 hexane:ethyl acetate to afford methyl 3-(2-chloropyridin-4-yloxy)benzoate (4.49 g, 90.0% yield) as a thick oil. 1H NMR (CDCl3) δ 8.26 (d, 1H), 7.98 (d, 1H), 7.77 (s, 1H), 7.54 (t, 1H), 7-31 (d, 1H), 6.82 (s, 1H), 6.79 (d, 1H).