Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[CH:34]=[N:35][CH:36]=[C:37](Br)[CH:38]=1)(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH2:40][CH2:41][OH:42])[S:30]([C:33]1[CH:34]=[N:35][CH:36]=[C:37]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:38]=1)(=[O:32])=[O:31]
Reactant: O=S(=O)(c1cncc(Br)c1)N(CCO)CCO
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1)N(CCO)CCO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (388 mg, 1.1 mmol) and 5-bromo-pyridine-3-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.5) (325 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (160 mg, 29%). MS (ISP) 600.2 [(M+H)+]; mp 173-178° C.
Reaction SMILES: [C:1]([C:5]1[CH:43]=[CH:42][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)[C:13](O)=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:65][CH2:66][C:67]([O:69]C(C)(C)C)=[O:68]>CN(C=O)C>[C:1]([C:5]1[CH:43]=[CH:42][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:32][CH:33]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)[C:13]([NH:65][CH2:66][C:67]([OH:69])=[O:68])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCOc1ccc(-c2nc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)O)cc3)no2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2nc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NCC(=O)O)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Prepared using General Procedures 7 and 8: To a solution of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid, Compound 2(10.0 mg, 0.017 mmol) in anhydrous DMF (1 mL) was added HOBt (3.52 mg, 0.027 mmol) and EDCI (4.88 mg, 0.027 mmol) at room temperature. After 2 h, tert-butyl 2-aminoacetate (3.49 mg, 0.027 mmol) was added and the reaction mixture stirred at room temperature for 2 h. LCMS analysis showed complete conversion to the intermediate. The reaction mixture was partitioned between NaHCO3 aqueous (5 ml) and DCM (1 mL), the organic layer was collected and concentrated by vacuum and then was re-dissolved in 1 mL of DCM and 0.1 mL of TFA. The mixture was heated to 30° C. for 3 h. The final compound was purified by HPLC to afford 9.6 mg (88%) of (S)-2-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanamido)acetic acid. LCMS-ESI (m/z) calculated for C37H44N4O6 640.3; no m/z observed, tR=11.51 min (Method 2). 1H NMR (400 MHz, DMSO) δ: 8.60 (d, J=8.4 Hz, 1H), 8.47 (t, J=5.7 Hz, 1H), 8.10 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 4.83 (d, J=8.1 Hz, 1H), 4.09 (t, J=6.4 Hz, 2H), 3.94-3.69 (m, 2H), 3.34 (s, 2H), 3.26 (d, J=13.5 Hz, 1H), 3.15-3.01 (m, 1H), 1.83-1.65 (m, 2H), 1.50-1.15 (m, 16H), 0.87 (t, J=6.7 Hz, 3H). 13C NMR (101 MHz, DMSO) δ: 175.12, 171.58, 171.13, 167.99, 166.02, 162.54, 154.10, 142.44, 131.16, 130.02, 129.89, 127.23, 126.81, 124.91, 124.25, 115.50, 115.36, 67.97, 54.23, 40.10, 37.12, 34.57, 31.19, 30.88, 28.46, 28.37, 25.36, 22.02, 13.93.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(O)=[O:28].[Na+]>C(O)=O>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([OH:28])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(F)c3)nc2N1C1CCCC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(O)c3)nc2N1C1CCCC1
Yield: 80 %

Procedure:
(R)-8-cyclopentyl-7-ethyl-2-(2-fluoropyridin-4-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 16, 100 mg, 0.28 mmol) was dissolved in 3 mL of HCOOH. This mixture was heated to reflux for 18 h, then aqueous NaHCO3 was added and the mixture was extracted with EtOAc. The combined organic phase was dried with Na2SO4, concentrated under reduced pressure and chromatographed on flash silica gel (CH2Cl2:CH3OH=6:1) to give the title compound as a white solid (80 mg, 80% yield). 1H NMR (CD3OD) δ: 8.09 (s, 1H), 8.52 (d, 1H) 7.46 (s, 1H), 7.27 (m, 1H), 4.42-4.38 (m, 2H), 3.41 (s, 3H), 2.0-1.7 (m, 10H) and 0.86 ppm (t, 3H); LCMS: 354.2 m/z (M+H)+; ret. Time: 1.36 min (Analytical Method E).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[CH:3]=1.O.O.Cl[Sn]Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cc(Cl)c1
Yield: 97.4 %

Procedure:
An ethanol solution (75 mL) containing 1-chloro-3-methyl-5-nitro-benzene (5.0 g, 29 mmol) were mixed with SnCl2.2H2O (32.8 g, 146 mmol). The reaction mixture was refluxed for 3.0 h. The solution was concentrated under vacuum, and the residue was re-dissolved in aqueous NaOH, filtered, and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3-chloro-5-methyl-phenylamine (4.0 g) as light yellow solids in 97% yield: 1H NMR (500 MHz, CDCl3) δ 6.56 (s, 1 H), 6.48 (s, 1 H), 6.36 (s, 1), 3.66 (s, 2 H), 2.23 (s, 3 H); ESI-MS: m/z 141.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH2:11][O:10]1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)[CH2:11][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1
Reactant: Fc1ccc(C2(Cn3ccnc3)CO2)c(F)c1
Reactant: O=Cc1ccc(O)cc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(O)(Cn2ccnc2)c2ccc(F)cc2F)cc1
Reaction time: 6 h
Yield: 0.1 %

Procedure:
A mixture containing 1-[[2-(2,4-difluorophenyl)-oxiranyl]-methyl]-1H-imidazole (P2) (0.5 g, 2.1 mmole), 4-hydroxy-benzaldehyde (0.31 g, 2.5 mmole) K2CO3 (0.41 g, 2.9 mmole), 18-C-6 (25 mg) in 5 ml of DMF is stirred for 6 hours, extracted with dichloromethane, washed with 2N sodium bicarbonate, dried over Na2SO4, filtered and evaporated under reduced pressure in order to obtain 0.957 g of crude product which is purified by chromatography eluting with a CH2Cl2/MeOH mixture 97/3 in order to obtain 0.557 mg of expected product. Rf=0.12 (CH2Cl2/MeOH 97/3).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:5].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4](=[O:5])[C:6](=[CH:17][N:18]([CH3:20])[CH3:19])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CC(=O)c1ccccc1Cl
Product: COC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A mixture of methyl 2-chlorobenzoylacetate (Acros; 266 mg, 1.25 mmol) and N,N-dimethylformamide dimethylacetal (161 mg, 1.35 mmol) was stirred at rt under N2 for 2 weeks. The reaction was then concentrated in vacuo and the residue was adsorbed on silica gel and chromatographed. Elution with 3:1 EtOAc/hexanes afforded 193 mg of the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1=COCCC1
Reactant: N#Cc1ccc2[nH]cnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
A mixture of 90 (1.63 g, 11.4 mmol), 3,4-dihydro-2H-pyran (2.87 g, 34.2 mmol), and p-TsOH.H2O (196 mg, 1.14 mmol) in THF (60 mL) was stirred under nitrogen at 80° C. for 18 h. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 chromatography with eluting with petroleum ether/EtOAc (1:1) to afford 2.48 g (95.9%) of 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (92) as yellow oil: MS (ESI) m/z=228.1 [M+1]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:35])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=4)[CH:22]=3)[CH2:18][C:17](=[O:35])[NH:16][C:9]=2[CH:10]=1
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example M171) (290 mg, 0.57 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (145 mg, 65%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[CH3:27])=[O:24]
Reactant: COC(=O)Cc1ccccc1OCC(C)=O
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccccc1OCC(C)NCC(O)c1cccc(Cl)c1
Yield: 70.4 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.11 g of methyl 2-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 18), 70 ml of benzene, 60 ml of absolute methanol and 2.5 g of sodium cyanoborohydride, 3.1 g of the title compound were obtained having an Rf=0.30 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][C@H:30]([F:33])[CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][C@H:30]([F:33])[CH2:29]2)[N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2[nH]ncc2c1
Reactant: F[C@H]1CCN(CCCl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CC[C@H](F)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.4 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridin-2(1H)-one (0.51 g, 1.6 mmol) in DMSO (5.0 mL) was added (S)-1-(2-chloroethyl)-3-fluoropyrrolidine (0.24 g, 1.6 mmol) and Cs2CO3 (3.1 g, 9.5 mmol). The reaction mixture was stirred at ambient temperature for 18 h, and then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (4×20 mL). The organic extracts were washed with brine (3×20 mL) and dried (Na2SO4). Purification by flash chromatography (silica gel, CH2Cl2/80:18:2 CH2Cl2/MeOH/NH4OH, 100.0 to 0:100), followed by additional flash column chromatography (silica gel, CH2Cl2/10% MeOH in CH2Cl2, 100:0 to 10:90), followed by treatment with activated charcoal, followed by final purification by preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.2 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (58.3 mg, 8%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 8.04 (s, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.55 (d, J=9 Hz, 1H), 7.45-7.37 (m, 6H), 7.31-7.30 (m, 1H), 6.12-6.10 (m, 2H), 5.16 (dt, J=55.5, 4.5 Hz, 1H), 5.07 (s, 2H), 4.58 (t, J=7.0 Hz, 2H), 3.01 (br m, 2H), 2.97-2.93 (m, 2H) 2.92-2.90 (m, 1H), 2.56 (br s, 1H), 2.17-2.03 (m, 2H); ESI MS m/z 433 [M+H]+; HPLC (Method A)>99% (AUC), tR=13.9 min.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)[C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.[NH2:21][C:22]1[S:23][CH2:24][CH2:25][N:26]=1>CN(C=O)C.O>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]2[N:26]3[C:22]([S:23][CH2:24][CH2:25]3)=[N:21][C:2]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1)#[N:11]
Reactant: N#Cc1ccc(C(=O)C(Br)c2ccc(C#N)cc2)cc1
Reactant: NC1=NCCS1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2nc3n(c2-c2ccc(C#N)cc2)CCS3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3.8 g of 1-bromo-2-oxo-1,2-di(4-cyanophenyl)ethane, prepared as described above in part (b) and 3.8 g of 2-aminothiazoline in 70 ml of DMF was stirred at room temperature for 18 hours. The reaction mixture was diluted with cold water, and the precipitated product was filtered and dried in vacuum. The material was suspended in 200 ml of toluene, 125 mg of p-toluenesulfonic acid was added, and the mixture was refluxed for 2 hours with removal of water. After cooling, the crude product was filtered and recrystallized twice from acetic acid to afford the part (c) title compound, 1.3 g, m.p. 255°-260°; Analysis: C19H12N4S.0.5AcO; Theory; C 67.03%, H 3.91%, N 15.64%; found C: 67.03% H: 3.96%, N: 15.04%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=1)[CH2:16][CH:13]1[CH2:15][CH2:14]1)=[O:6]
Reactant: COc1cccc(C(=O)O)c1Cl
Reactant: NCC(CC1CC1)c1cnc(C(F)(F)F)nc1
Product: COc1cccc(C(=O)NCC(CC2CC2)c2cnc(C(F)(F)F)nc2)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=414.0, tR (minutes, Method F)=2.53. [α]D20=+26.3 (c=4.0 mg/mL,CHCl3)
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][C@@H:9]1[O:14][C:13]2[CH:15]=[C:16]3[C:21](=[CH:22][C:12]=2[NH:11][C:10]1=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]3)(C)(=O)=O.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:6][CH2:7][CH2:8][C@@H:9]3[O:14][C:13]4[CH:15]=[C:16]5[C:21](=[CH:22][C:12]=4[NH:11][C:10]3=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]5)[CH2:33][CH2:32]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCC[C@@H]1Oc2cc3c(cc2NC1=O)CCCC3
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cc3c(cc2O[C@H]1CCCN1CCN(c2ccc(F)cc2)CC1)CCCC3
Yield: 59.7 %

Procedure:
A mixture of (S)-6,7,8,9-tetrahydro-2-(3-mesyloxypropyl)-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one (1.02g), 1-(4-fluorophenylpiperazine (0.83g), triethylamine (0.43 ml) and dimethylformamide (15 ml) was stirred at 70° C. for 2 hours. The solvent was distilled off and the residue was purified by column chromatography on silica gel (60 g) with ethyl acetate-hexane (3:1, v/v) to yield crystals of (S)-(-)-2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one (0.76 g, 59.6%). Repeated recrystallization from MeOH gave colorless crystals, m.p. 155.5°-156.6° C. [α]D26 -19.9° (c=1.2, CHCl3).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:35][C:36]1([F:40])[CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][C:36]([F:40])([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: FC1(F)CNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CC(F)(F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3,3-difluoroazetidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.94 (m, 1H), 7.66 (2H), 7.05 (1H), 4.57 (m, 4H), 3.49 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 446 [M+H]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[C@@H:17]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][NH:26][C@@H:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCc2ccccc21
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Solvent: CN1CCCC1=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CN[C@H]1CCc2ccccc21
Temperature: 85 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole (0.180 g, 0.64 mmol) and (S)-indan-1-ylamine (0.171 g, 1.29 mmol) were mixed in N-methylpyrrolidone (4.0 mL) and then heated to 85° C. over 2 nights while monitoring with analytical LCMS. The reaction was submitted to standard aqueous workup then purified via preparatory HPLC to afford the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[Cl:21][C:22]1[CH:29]=[C:28](F)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>C(COC)OC>[Cl:21][C:22]1[CH:29]=[C:28]([CH:27]=[CH:26][C:23]=1[C:24]#[N:25])[O:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
Potassium tert-butoxide (5.57 g, 49.68 mmol) was added to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g, 24.84 mmol) in glyme (100 ml) and the mixture stirred for 30 min. before addition of 2 chloro-4-fluoro-benzonitrile (7.73 g, 49.68 mmol). The reaction was stirred at room temperature overnight and then partitioned between ethyl acetate (250 ml) and water (200 ml). The organic layer was separated, dried over magnesium sulfate and the solvent evaporated. The residue was purified by flash chromatography eluting with ethyl acetate:isohexane (4:1) to give the subtitle compound as a colourless solid (3.45 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>CN(C=O)C.C(Cl)Cl>[CH2:16]([C:7]1([CH2:5][CH2:4][CH2:3][CH:11]=[CH2:10])[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12])[CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCCCC1(CCCC=C)Cc2cc(OC)ccc2C1=O
Reaction time: 6 h

Procedure:
To a solution of 5-methoxy-1-indanone (2.5 g, 15.4 mmol) in DMF (20 mL) at rt was added NaH (1.8 g, 61% in oil, 46.2 mmol) and 5-bromo-1-pentene (5.48 mL, 46.2 mmol). After 6 h at rt, the solution was diluted with CH2Cl2 and quenched with saturated aqueous NH4Cl. The slurry was dried with MgSO4 and filtered through a plug of silica and rinsed with 10% EtOAc in hexanes. The filtrate was concentrated and provided crude 2,2-di(4-pentenyl)-5-methoxy-1-indanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9]Br.[CH3:11][C:12]([O-:14])=[O:13].[Na+]>CN(C)C=O>[C:12]([O:14][CH2:9][C:3]1[C:4]([Br:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:13])[CH3:11]
Reactant: CC(=O)[O-]
Reactant: BrCc1c(Br)cccc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(Br)cccc1Br
Temperature: 100 °C
Reaction time: 1.75 h
Yield: 95 %

Procedure:
A mixture of 1,3-dibromo-2-(bromomethyl)benzene (27.6 g, 84 mmol), NaOAc (35.5 g, 5 eq.) and dimethylformamide (DMF) (150 mL) was stirred at 100° C. (hot oil bath temperature) for 1.75 h, allowed to cool, and then partitioned between heptane (500 mL) and water (200 mL). After removing the organic layer, the aqueous layer was extracted with heptane (200 mL). The combined organics were washed with H2O (2×300 mL), dried (Na2SO4), filtered, and evaporated to give 24.57 g (yield of 95%) of title product as a colorless oil. This oil contained 13% unreacted starting material but was successfully used without further purification. 1H NMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 5.41 (s, 2H), 7.08 (t, 1H), 7.58 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].[CH2:12]([O:14][C:15](=[O:24])[C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([OH:23])[CH:17]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:9]2[C:8]([F:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[F:1])[CH:17]=1)[CH3:13]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Product: CCOC(=O)c1cc(O)cc(Oc2c(F)cc(C#N)cc2F)c1
Yield: 39.4 %

Procedure:
Using 1.5 g (9.55 mmol) of 3,4,5-trifluoro-benzonitrile and 3,5-dihydroxy-benzoic acid ethyl ester (1.73 g, 9.55 mmol) and following the procedure of Example 42(a) afforded 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.28 (3H, t), 4.27 (2H, q), 6.67 (1H, t), 6.92 (1H, s), 7.18 (1H, s), 8.08 (2H, d), 10.20 (1H, brs).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1
Reactant: O=[N+]([O-])c1ccc2occc2c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2occc2c1

Procedure:
To a solution of all of the 5-nitrobenzofuran in 90% ethanol (50 ml) kept at reflux were added small portions of Fe powder (in total 2.5 g) and concentrated HCl (in total 0.1 ml) during 10 min. The mixture was refluxed for another hour. The inorganic precipitates were filtered off and the mixture was poured onto brine and ethyl acetate (250 ml). Work-up of the organic phase afforded 1 g of crystalline 5-aminobenzofuran derivative.