Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[NH:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[NH2:21]Cl.O>CN(C=O)C.CCOCC>[NH2:21][N:8]1[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc(C(C)C)[nH]c1C(=O)OCC
Reactant: NCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(C)C)n(N)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 1B (2.53 g, 10 mmol) in dry DMF (40 ml) was added NaH (60%, 550 mg, 13.75 mmol) in one portion. After H2 evolution subsided, NH2Cl in ether (85 ml) was added dropwise via additional funnel. The reaction mixture was stirred at room temperature for 1 h. Water was added, the mixture was extracted with ether (×3), the combined ether layers were washed with brine, dried over MgSO4, concentrated in vacuo to give 1C (2.50 g, 93%) as an oil. Compound 1C had an analytical HPLC retention time=2.893 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=269+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[C:30](C)[CH:29]=1.[C:38]([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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[C:28]([O:27][CH3:26])=[N:33][CH:32]=[C:31]([CH3:38])[CH:30]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1cc(C)c(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Temperature: 120 °C
Yield: 81.5 %

Procedure:
To a mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.550 g, 1.5 mmol) and 6-methoxy-4-methylpyridin-3-ylboronic acid (0.376 g, 2.25 mmol) in DME (10 mL) and Na2CO3 (2 M, 1.5 mL, 3.0 mmol) was added Pd(PPh3)4 (0.087 g, 0.075 mmol). The mixture was heated in microwave oven at 120° C. for 30 minutes. The reaction was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (0-20% EtOAc-Hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (0.554 g, 81%). ESI-MS m/z calc. 453.44. found 454.2 (M+1)+. Retention time 2.08 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([NH:33][C:34]2[N:35]=[CH:36][C:37]3[CH2:43][CH2:42][NH:41][CH2:40][C:38]=3[N:39]=2)[CH:30]=[CH:29][N:28]=1)[CH3:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][C:17]([N:41]2[CH2:42][CH2:43][C:37]3[CH:36]=[N:35][C:34]([NH:33][C:31]4[CH:30]=[CH:29][N:28]=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=4)=[N:39][C:38]=3[CH2:40]2)=[O:18])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@@H](N)c1ccc(Cl)c(Cl)c1
Reactant: CCOc1cc(Nc2ncc3c(n2)CNCC3)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Nc2ncc3c(n2)CN(C(=O)N[C@H](C)c2ccc(Cl)c(Cl)c2)CC3)ccn1
Reaction time: 0.5 h

Procedure:
A vial was charged with 185 (0.105 g, 0.553 mmol), CDI (0.0896 g, 0.553 mmol) and DCM (2 mL) and stirred for 30 min. To the solution was added 186 (0.150 g, 0.553 mmol) and DIPEA (0.193 ml, 1.11 mmol) and the resulting reaction stirred for 3 d. The reaction was washed with brine (4 mL), and the organic phase concentrated and loaded on to a preparative SiO2 plate (1.0 mm thickness) which was developed with EtOAc/MeOH (95:5) and eluted to afford 0.038 g (13%) of I-35: 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.96 (d, 1H), 7.73 (s, 1H), 7.44 (m, 1H), 7.35 (d, 1H), 7.29 (m, 1H), 7.20 (m, 1H), 6.95 (m, 1H), 5.40 (d, 1H), 5.00 (m, 1H), 4.49 (s, 1H), 4.36 (q, 2H), 3.68 (m, 2H), 2.72 (d, 2h), 1.49 (d, 3H), 1.39 (t, 3H); m/z (APCI-pos) M+1=487.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C@@H:32]([CH3:35])[CH2:33][OH:34]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12]([NH:31][C@@H:32]([CH3:35])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: C[C@H](N)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@@H](C)CO)nc2c1ccc(=O)n2-c1ccccc1F
Temperature: 23 °C
Reaction time: 18 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and (S)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 23° C. for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-20% EtOAc/CH2Cl2 gave the title compound as an off-white amorphous solid. mp 114-120°, LC MS m/z=423 (MH+) Retention time=2.0 min.
Reaction SMILES: [CH2:1]1[C@:6]2([OH:10])[C:7]([O:9][C@@H:4]([CH2:5]2)[C@@H:3]([OH:11])[C@H:2]1[OH:12])=[O:8].C1C[O:16]CC1>Cl>[CH2:5]1[C@@H:4]([OH:9])[C@@H:3]([OH:11])[C@H:2]([OH:12])[CH2:1][C@@:6]1([C:7]([OH:16])=[O:8])[OH:10]
Reactant: C1CCOC1
Reactant: O=C1O[C@H]2C[C@]1(O)C[C@H](O)[C@@H]2O
Agent: Cl
Product: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1

Procedure:
A mixture of 10 g (9.6 mmol) 1,4-O-dicarbotrichloroethoxy-3-O-dicarbotrichloroethoxycaffeoyl quinide is stirred for 5 days at ambient temperature in 65 ml THF and 8 ml concentrated HCl. After separation of the THF and saturation with NaCl, the aqueous phase is extracted with 3×40 ml ethyl acetate. The combined extracts are then washed with brine and dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with a mixture of 1 volume dichloromethane to 10 volumes hexane gives 9.5 g 1,4-O-dicarbotrichloroethoxy-3-O-dicarbotrichloroethoxycaffeoyl quinic acid (yield 93%) in the form of an amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[C:11]3C=CC=C[C:12]=13)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1cc2cn[nH]c2c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 25 °C

Procedure:
A suspension of 5-nitrobenzoindazole (8.16 g, 50 mmol), 3-fluorobenzyl bromide (10.4 g, 55 mmol) and potassium carbonate (13.8 g, 100 mmol) in acetone (200 mL) was refluxed overnight. After reaction cooled to room temperature, the reaction mixture was diluted with dichloromethane (100 mL), filtered through silica gel (about 100 g), and rinsed with 1:1 ethyl acetate:dichloromethane (about 100 mL). The residue after concentration was purified with column chromatography eluting with 0-30% ethyl acetate in dichloromethane to give the title compound as a white crystalline solid (the first fraction, 5.69 g, 42%). LCMS ESI(+) m/z: 272 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[Cu][C:11]#[N:12].C(OCC)(=O)C.[OH-].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([C:11]#[N:12])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: N#C[Cu]
Reactant: Cc1cnc(N)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(N)c(C#N)c1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
To a solution of 2-amino-3-bromo-5-methylpyridine (3.74 g) in DMF (30 mL) was added copper(I) cyanide (4.48 g), and the mixture was stirred under microwave irradiation at 180° C. for 30 min. To the reaction mixture were added ethyl acetate and water, 1N aqueous sodium hydroxide solution (50 mL) was added and the mixture was stirred. Insoluble material was filtered off through celite. The aqueous layer and organic layer were separated, and the aqueous layer was extracted with ethyl acetate. The extract was collected, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (357 mg) as a colorless solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].[C:35]([O:38][CH2:39][C:40](Cl)=[O:41])(=[O:37])[CH3:36]>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:40]([CH2:39][O:38][C:35](=[O:37])[CH3:36])=[O:41])[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
(1S,2R,3S,5R)-3-Amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (Intermediate GA3) (3.0 g, 5.6 mmol) is dissolved in dry THF (100 mL) and TEA (2.8 g, 28 mmol). Acetoxyacetylchloride (0.76 g, 5.6 mmol) is dissolved in dry THF (4 mL) and is added to the reaction mixture dropwise.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([C@@H:10]([C@H:14]([CH2:20][CH3:21])[CH2:15][C:16]([F:19])([F:18])[F:17])[C:11](O)=[O:12])=[N+]=[N-]>C1COCC1>[NH2:7][C@@H:10]([C@H:14]([CH2:20][CH3:21])[CH2:15][C:16]([F:17])([F:18])[F:19])[CH2:11][OH:12]
Reactant: CC[C@H](CC(F)(F)F)[C@H](N=[N+]=[N-])C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](CC(F)(F)F)[C@H](N)CO
Temperature: 25 °C

Procedure:
To a gray slurry of lithium aluminum hydride (LAH—110.6 mg, 2.91 mmol) in THF (2 mL) at 0° C. was added dropwise over 5 min (2S,3R)-2-azido-3-ethyl-5,5,5-trifluoropentanoic acid (130 mg, 583 mmol). The resulting slurry was allowed to warm to 25° C. for 19 h. The reaction was quenched by sequential addition of H2O (0.5 mL), 1N NaOH (1.5 mL) and H2O (0.5 mL) at 0° C. The white precipitate that formed after 5 h was filtered off, the organic solvent was dried over MgSO4, filtered and concentrated to obtain (2S,3R)-2-amino-3-ethyl-5,5,5-trifluoropentan-1-ol as a crude oil (120 mg, 96%). Mass Spectrum (+ESI): 186 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19](=[O:31])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:22][CH:21]=1)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19](=[O:31])[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:24][CH:25]=1)=[O:8]
Reactant: COCCOc1ccc(C(=O)NNC(C)C)cc1
Reactant: O=C(O)COc1ccc(F)cc1Br
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc(C(=O)NN(C(=O)COc2ccc(F)cc2Br)C(C)C)cc1
Yield: 63.3 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (164 mg, 0.66 mmol) and 4-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (200 mg, 0.79 mmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.29 mL, 1.65 mmol) and PyBroP (462 mg, 0.99 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 45-60% ethyl acetate/hexanes gradient to afford the product as a solid (202 mg, 63%).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([NH:10][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.[Pd]>[C@H:11]1([NH:10][C:7]2[O:8][CH2:9][C:4]3[CH:3]=[C:2](/[CH:22]=[CH:23]/[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:21]=[CH:20][C:5]=3[N:6]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: Brc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: C=Cc1ccccc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C(=C/c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2)\c1ccccc1
Yield: 16 %

Procedure:
A stirred mixture of (6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (Example 32) (200 mg, 0.58 mmol), styrene (91 mg, 0.87 mmol), tri(o-tolyl)phosphine (14.2 mg, 0.047 mmol), triethylamine (295 mg, 2.91 mmol) and palladium actetate (5.23 mg, 0.023 mmol) in acetonitrile (5 ml) was heated under reflux conditions for 23 h, evaporated and purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/heptane) to yield the title compound as white solid (34 mg, 16%). MS (ISP): m/e=367.2 (M+H+); m.p. 162° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH2:20][C:21]2[CH:25]=[CH:24][O:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[C@H:26]1([CH2:36]O)[C@@H:35]2[N:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:29][CH2:28][CH2:27]1>>[C@H:26]1([CH2:36][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[NH:11][C:12]4[C:17]([CH:18]=3)=[C:16]([O:19][CH2:20][C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)[CH:15]=[CH:14][CH:13]=4)=[O:9])[CH2:3][CH2:2]2)[C@@H:35]2[N:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:29][CH2:28][CH2:27]1
Reactant: O=C(NC1CCNCC1)c1cc2c(OCc3ccoc3)cccc2[nH]1
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3ccoc3)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid piperidin-4-ylamide, 165 (preparation see below) and (1R,9aR)-1-(octahydro-quinolizin-1-yl)-methanol analogously to the method described in example 127.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:36]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([F:25])=[CH:27][CH:28]=2)=[O:37])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OCC(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OCC(F)(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(2,2,2-trifluoroethoxy)phenyl)-1-propanol (181 mg, 0.53 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (206 mg, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:5][C:6]1[C:7]2[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][C:8]=2[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:36][CH2:37][CH2:38][CH2:39]1)[CH2:5][C:6]1[C:7]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:8]=2[S:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2c(Cc3ccc(CN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCS
Solvent: O
Solvent: CC(Cl)Cl
Product: Oc1ccc2c(Cc3ccc(CN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
3-[3-Bromo-4-[(1-pyrrolidinyl)methyl]benzyl]-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (0.32 g; 0.53 mmol)(Part A) was dissolved in 9.0 mL of dichloroethane under an argon atmosphere and cooled in an ice-water bath. To this was added ethanethiol (0.78 mL; 10.56 mmol) and 0.70 g (5.28 mmol) of aluminum chloride, and the mixture was stirred in the cold bath for 1 h. Brine (80 mL) was added to the mixture, and stirring was continued while warming to room temperature for 1 h. Extraction was carried out with dichloromethane (4×75 mL). The combined organics were dried by passage through sodium sulfate. The title compound (0.23 g; 74% yield) was isolated as a white crystalline solid by flash chromatography on silica gel eluting with a gradient of EtOAc(100-85%)/Et3N(0-5%)/MeOH(0-10%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:14][CH2:13]1.[CH3:29]N(C)C=O.[H-].[Na+].IC>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH3:29])[C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:14][CH2:13]1
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)OCC(CN1CCC(CNc3nc4ccccc4s3)CC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(CC1CCN(CC2COc3ccccc3O2)CC1)c1nc2ccccc2s1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 11.85 parts of N-[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinylmethyl]-2-benzothiazolamine in 72 parts of N,N-dimethylformamide were added portionwise 1.5 parts of a sodium hydride dispersion 50%. Upon completion, stirring was continued for 30 minutes. A solution of 4.6 parts of iodomethane in 18 parts of N,N-dimethylformamide was added dropwise. The whole was stirred overnight at room temperature. The reaction mixture was poured into water and the product was extracted twice with 4-methyl-2-pentanone. The combined organic layers were dried, filtered and evaporated. The residue was separated by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 1,1'-oxybisethane, yielding 1 part of N[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N-methyl-2-benzothiazolamine; mp. 125.4° C. (compound 62).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])(OCC)=O>O>[CH:29]1[CH:28]=[C:25]2[C:26]([N:1]([C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([NH2:6])=[O:7])[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=1)=[O:27]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a stirred solution of L-glutamine (43.8 g, 300 mmoL) and sodium carbonate (33.4 g, 315 mmoL) in 750 mL of water is rapidly added N-carbethoxyphthalimide [65.8 (97% pure, 67.8 g), 300 mmoL] as a solid. After 1 hour, the reaction mixture is filtered to remove unreacted N-carbethoxyphthalimide. The pH of the stirred filtrate is adjusted to 3-4 with 4N hydrochloric acid. The mixture is then seeded with N-phthaloyl-L-glutamine and the pH adjusted to 1-2 with 4 N hydrochloric acid. The resulting slurry is stirred for 1 hour. The slurry is filtered and the solid washed with copious amounts of water. The solid is air-dried and then dried in vacuo (60° C.,<1 mm) overnight to afford 49.07 g (59%) of N-phthaloyl-L-glutamine, which can be alternatively named as 2-phthalimidoglutaramic acid, as a white powder.
Reaction SMILES: [I:1]I.Br[C:4]1[CH:5]=[C:6]2[C:19]3[CH:9]([CH2:10][C@@H:11]4[C@@H:16]([C:17]=3[CH:18]=1)[CH2:15][C@H:14]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][N:12]4[CH3:28])[CH2:8][N:7]2[Si](C(C)(C)C)(C)C>>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([NH:20][C@H:14]1[CH2:15][C@H:16]2[C@@H:11]([CH2:10][CH:9]3[C:19]4[C:6](=[CH:5][CH:4]=[C:18]([I:1])[C:17]2=4)[NH:7][CH2:8]3)[N:12]([CH3:28])[CH2:13]1)=[O:27])[CH3:24]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3C(C[C@H]2N(C)C1)CN4[Si](C)(C)C(C)(C)C
Reactant: II
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(I)ccc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
With iodine and 3-(13-bromo-1-tert-butyldimethylsilyl2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:11])[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1c[nH]c(=O)c(Br)c1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2c[nH]c(=O)c(Br)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylic acid (500 mg, 2.294 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (1044 mg, 2.75 mmol) in DMF (6 mL) was added 1-methylpiperazine (0.382 mL, 3.44 mmol). The mixture was stirred at room temperature for 2 hours and was purified via preparative HPLC, eluting with a gradient of 10-50% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA). The product-containing fractions were dried under vacuum to give the title compound.