Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[N:59]=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[N:59]=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5c[nH]nn5)cccc4c3=O)cc2)CCC1
Agent: N
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5c[nH]nn5)cccc4c3=O)cc2)CCC1
Yield: 23 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[4-oxo-2-phenyl-8-(1H-[1,2,3]triazol-4-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was subjected to flash chromatography (SiO2, gradient 0 to 20% methanolic ammonia in DCM) to afford the title compound as a white solid (7 mg, 23%, 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 8.40 (dd, J=7.6 and 1.8 Hz, 1H), 8.14 (s, 1H), 8.08 (dd, J=7.9 and 1.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.48-7.44 (m, 2H), 7.41-7.31 (m, 5H), 7.11 (d, J=8.6 Hz, 2H), 3.26 (bs, 3H), 2.37-2.27 (m, 2H), 2.08-1.88 (m, 3H), 1.66-1.54 (m, 1H). LCMS (Method E): RT=2.98 min, [M+H]+=435.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.Cl.[CH3:26][C:27]1([NH2:30])[CH2:29][CH2:28]1.C([O-])(O)=O.[Na+]>CS(C)=O>[CH3:15][C:3]1[C:2]([NH:30][C:27]2([CH3:26])[CH2:29][CH2:28]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12](=[O:14])[CH3:13])[N:4]=1
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Reactant: CC1(N)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)c1cccc2nc(C)c(NC3(C)CC3)nc12
Temperature: 85 °C

Procedure:
To a 250 mL round-bottomed flask was added 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126g) (14.5 g, 71 mmol), DMSO (100 mL), DIEA (27 mL, 156 mmol) and finally 1-methylcyclopropanamine hydrochloride (8.02 g, 92 mmol) (ChemBridge Corporation, San Diego, Calif.). The solution was heated at 85° C. for 7 h. After cooling to RT, the solution was poured into sat NaHCO3 (250 mL) and extracted with EtOAc (3×250 mL). The combined extracts were washed with H2O (3×250 mL) and brine and then dried (Na2SO4) and concentrated to afford 1-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)ethanone (611a) as a purple solid, which was used directly in the subsequent step. m/z (ESI, +ve) 256.1 (M+H)+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C(=O)([O-])[O-].[K+].[K+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[C:13]1([CH2:12][O:4][C:1](=[O:5])[C:2]#[CH:3])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#CC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a stirring mixture of propiolic acid (1.79 mL (2.04 g), 28.65 mmol) and potassium carbonate (4.87 g, 35.2 mmol) in anhydrous DMF (40 mL) was added benzyl bromide (3.78 mL (5.43 g of 99% pure), 31.4 mmol). The reaction mixture was stirred at room temperature for 16 h. The resulting heterogeneous mixture was poured into 40 mL of H2O and was extracted with ethyl ether (3×40 mL). The combined ether extracts were dried (Na2SO4). Filtration and concentration provided 12.16 g of crude product, which upon high vacuum distillation yielded 2-propynoic acid phenylmethyl ester (bp 60° C. 0.5 mm) as a clear oil (3.57 g, 22.3 mmol) in 78% yield.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.O>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 65 °C

Procedure:
KOH (8.19 g, 146 mmole), 5-chloroindole (5.0 g, 33 mmole) and piperidine-4-one hydrochloride (10.22 g, 85.7 mmole) were suspended in methanol (50 ml) and heated for 8 hours at 65° C. under argon. Water (50 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The solid thereby formed was filtered off, washed with water (3×20 ml) and recrystallised from methanol (20 ml). 5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole was obtained in a yield of 6.4 g (90%) as a yellow solid with an m.p. of 166°-168° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][NH:4][C:3]1=[S:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(O)(=O)C>C(O)C>[Cl:18][CH2:17][CH2:16][CH2:15][S:13][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=1
Reactant: ClCCCBr
Reactant: Cn1c(-c2cccnc2)n[nH]c1=S
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(SCCCCl)nnc1-c1cccnc1
Temperature: 90 °C

Procedure:
To 4-methyl-5-(3-pyridinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, preparation reported in WO 02/40471) in ethanol (6 ml) sodium ethanolate (0.85 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.31 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound as white solid (0.360 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[C:43]2[N:44]([CH:48]=[N:49][CH:50]=2)[CH:45]=[CH:46][CH:47]=1>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[CH:50]1[N:49]=[CH:48][N:44]2[CH:45]=[CH:46][CH:47]=[C:42]([C:5]3[N:4]=[C:3]4[C:8]([N:9]=[C:10]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]5)[N:2]4[CH3:1])=[C:7]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:6]=3)[C:43]=12
Reactant: Brc1cccn2cncc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cccn4cncc34)nc21
Temperature: 150 °C
Yield: 59.1 %

Procedure:
A mixture of 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol (135 mg, 0.20 mmol), 8-bromoimidazo[1,5-a]pyridine (44 mg, 0.22 mmol), Pd(PPh3)4 (24 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (8 mg, 20 mol %) in dioxane (2 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give 222 as a yellow solid (58 mg, 58%). LCMS (Method G): RT=4.86 min, [M+H]+ 491.4. 1H NMR (400 MHz, CHCl3-d): δ 8.42 (s, 1 H), 8.19 (s, 1 H), 8.02 (d, J=6.9 Hz, 1H), 7.95 (dd, J=6.9, 0.9 Hz, 1 H), 6.74-6.67 (m, 1 H), 4.38 (m, 4 H), 3.96 (s, 3 H), 3.91-3.87 (m, 4 H), 3.80-3.66 (m, 2 H), 2.97 (d, J=11.0 Hz, 2 H), 2.22-1.99 (m, 2 H), 1.75 (d, J=11.0 Hz, 2 H), 1.44-1.26 (m, 4 H), 1.20-1.17 (s, 6 H)
Reaction SMILES: Cl.CO[C:4](=[O:13])[CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][NH:6]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:4]([CH:5]2[CH2:10][C:9]([CH3:11])([CH3:12])[CH2:8][CH2:7][NH:6]2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C1CC(C)(C)CCN1
Reactant: C1CCNC1
Agent: Cl
Product: CC1(C)CCNC(C(=O)N2CCCC2)C1

Procedure:
5 g (0.024 moles) of 4,4-dimethyl pipecolic acid methyl ester hydrochloride were reacted with 100 ml of pyrrolidine as described in Description 22 to yield 5.4 g of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:28]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:32]2C=CC=CC=2N=N1.Cl.CN.CCN(CC)CC>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([NH:28][CH3:32])=[O:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1cc2ccccc2c(-c2ccc(I)cc2)n1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2ccccc2c(-c2ccc(I)cc2)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 1-(4-iodophenyl)-3-isoquinolinecarboxylic acid (0.2073 g, 0.55 mmol), BOP (0.2447 g, 0.55 mmol), Methylamine hydrochloride (0.096 g, 1.42 mmol), and Et3N (0.25 mL, 1.80 mmol) in DMF (8 mL) was stirred under Ar at room temperature. After stirring for 1 h , additional Et3N (0.2 ml,) was added in one portion. The mixture was stirred under Ar for 7 h, then quenched by adding H2O (8 mL). The resulting mixture was extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (Na2SO4), then filtered. The filtrate was concentrated in vacuo. The residue was purified on column chromatography (SiO2, 35% ethyl acetate in hexane, 0.1% Et3N), thereby affording the title compound as a white solid (0.1724, 81%). mp 163-164 ° C. 1H NMR (CDCl3) d 3.07, 3.09 (two s, total 3 H, N-methyl), 7.46 (d, J=8.4 Hz, 2 H, aromatic), 7.64 (t, J=7.2 Hz, 1 H, aromatic), 7.77 (t, J=6.9 Hz, 1 H, aromatic), 7.92 (d, J=8.4 Hz, 2 H, aromatic), 8.07 (t, J=7.8 Hz, 2 H, aromatic), 8.24 (br s, 1 H, NH), 8.02 (s, 1 H, aromatic). 13C NMR (CDC13) d 26.05 (q,N-methyl), 95.14 (s, C--I), 119.54 (d, aromatic), 127.02 (d, aromatic), 128.58 (d, aromatic), 128.75 (di aromatic), 130.60 (d, aromatic), 131.43 (d, aromatic), 131.56 (aromatic), 137.02 (s, aromatic), 137.40 (d, aromatic), 138.28 (s, aromatic), 142.58 (s, aromatic), 158.09 (s, aromatic), 165.12 (s, CO). HRMS calcd. for C17H13IN2O: 388.0073. Found: 388.0077.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH3:13].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:13][Br:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(OS(C)(=O)=O)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)Oc1ccc(Br)c(CBr)c1
Temperature: 80 °C

Procedure:
A mixture of methanesulfonic acid 4-bromo-3-methylphenyl ester, as described above in Step B, (14.3 g, 53.9 mmol), N-bromosuccinimide (14.4 g, 80.9 mmol), and 2,2′-azobisisobutyronitrile (1.34 g, 8.16 mmol) in CCl4 was heated at 80° C. for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with a gradient of hexane—5% to 20% EtOAc, to yield the titled product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(OCC)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]=1)[CH2:8][NH:9][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cc(Br)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NCc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
To a solution of compound 13 (2.5 g, 10.82 mmol) in pyridine (20 mL) was added acetic anhydride (2 mL, 21.60 mmol) and the mixture was stirred at room temperature for 12 h. The reaction was added ethyl acetate (30 mL) and the organic layer was washed sequentially with H2O (20 mL), 1N HCl (15 mL×3), brine (15 mL) and dried over Na2SO4 and evaporated to get the title compound as an off-white solid (2.89 g, 98%). IR (KBr) νmax. cm−1: 3419 (NH), 3062 (Ar—H), 2925 (Alph-H), 1695 (C═O), 1604, 1564 (C═C), 1520, 1435 (NO2), 1232 (C—N), 1168 (C—O). 1H NMR (500 MHz, CDCl3) δ=2.19 (s, 3H, CH3); 5.50 (s, 2H, CH2); 7.63 (dd, 1H, J=2.3, 8.6 Hz, H-4); 7.75 (d, 1H, J=2.3, H-6), 8.00 (d, 1H, J=8.6 Hz, H-3). 13C NMR (125.7 MHz, CDCl3) δ=20.78 (CH3), 62.27 (CH2), 126.58 (C-3), 129.03 (C-1), 131.73 (C-6), 131.82 (C-4), 134.34 (C-5), 145.33 (C-2), 170.10 (CO). Calculated (%) for C9H9BrN2O3 (271.98); C, 39.58; H, 3.32; N, 10.26. found (%); C, 39.52; H, 3.36; N, 10.20.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[OH:8].NC1C(O)CCOC1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O>[CH2:27]([O:26][C:24](=[O:25])[NH:1][C@H:2]1[CH2:7][CH2:6][O:5][CH2:4][C@@H:3]1[OH:8])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC1CCOCC1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: NC1COCCC1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N[C@H]1CCOC[C@@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a crude 5:1 mixture of rac-(3R,4S)-4-aminotetrahydro-2H-pyran-3-ol and rac-(3R,4S)-3-aminotetrahydro-2H-pyran-4-ol (see Example 8, 3.50 g, 29.9 mmol) in 150 mL of water at 0° C. was added sodium carbonate (3.80 g, 35.9 mmol) followed by benzyl chloroformate (5.12 mL, 35.9 mmol) dropwise. After 30 min, the mixture was warmed to rt, and after 4 h, a solid precipitate was collected via filtration and recrystallized from ethyl acetate/hexanes to provide benzyl[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]carbamate that gave a proton NMR spectra consistent with theory. The filtrate was concentrated and the resultant residue was subjected to purification via silica gel chromatography, eluting with 30-70% ethyl acetate in hexanes to provide a mixture of benzyl[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]carbamate and benzyl [(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]carbamate. The two enantiomers were separated via chiral chromatography to provide pure benzyl[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]carbamate and benzyl[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]carbamate. The semi-preparative separation was performed on a 5 cm id by 50 cm length, 20 μm, AD column run at 85 mL/min in a mixture of 60% ethanol/40% heptane with 0.1% DEA added to both components.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]3[CH:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(#N)C.C(O)C>[CH3:25][O:24][C:19]1[C:20]([O:22][CH3:23])=[CH:21][C:16]2[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:34](=[O:35])[CH2:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:3][CH:4]=3)[C:17]=2[CH:18]=1
Reactant: COc1cc2c(cc1OC)C1CN(C)CCC1N=C2c1ccc(N)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NC(=O)Cc2ccccc2)cc1

Procedure:
30g of 6-(4-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine and 6,0 g of phenylacetic acid chloride are heated to the boil under reflux in 70 ml of acetonitrile for 7 hours. After working up in a manner analogous to that described in Example 31, and upon adding dilute hydrochloric acid in ethanol to the crude product, the dihydrochloride form of the title compound slowly crystallizes (melting point 240°-245°).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:9]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: Nc1ccccc1
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)OC

Procedure:
A solution of 5.6 g (15 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester and 5.5 ml (60 mmol) of aniline in 60 ml of glacial acetic acid is boiled under reflux for 4 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The crude product is recrystallized from ethanol, yielding the title compound in the form of yellow crystals, m.p. 178°, FAB-MS: 377 [M+ +H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH3:38]>>[CH2:36]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:37][CH3:38]
Reactant: CCCBr
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Product: CCCOc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1OC

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with propyl bromide
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11](=[O:24])/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:8]=2)[CH:3]=[N:2]1.C1COCC1.[N:30]([CH3:33])=[C:31]=[O:32]>CCOC(C)=O>[C:20]([C:17]1[CH:16]=[CH:15][C:14](/[CH:13]=[CH:12]/[C:11]([NH:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][N:1]3[C:31](=[O:32])[NH:30][CH3:33])=[CH:5][CH:6]=2)=[O:24])=[CH:19][CH:18]=1)([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3cn[nH]c3c2)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)n1ncc2ccc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask, equipped with a magnetic stir bar, was added (2E)-N-(1H-indazol-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide, Example 155, (61 mg, 0.19 mmol), THF (8 mL) and isocyanatomethane (54 mg, 0.96 mmol, Carbolabs). The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water (8 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (40:20:1 hexane:EtOAc:MeOH) provided the title product as an off-white solid. MP 208-209° C. MS (ESI, pos. ion) m/z: 377 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.Cl.[Br:19][C:20]1[C:21]([C@H:28]([NH2:38])[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:19][C:20]1[C:21]([C@H:28]([NH:38][C:13](=[O:15])[CH2:12][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:17])[F:16])=[N:4]2)[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reactant: CSc1ncc(Br)c([C@H](N)Cc2cc(F)cc(F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-(3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (124 mg, 0.5 mmol) and 11F (200 mg, 0.5 mmol) were dissolved in 3 mL of DMF and cooled down to 0° C. To it were added N,N-diisopropylethylamine (435 μL, 2.5 mmol) and HATU (228 mg, 0.6 mmol). The reaction mixture was stirred at 0° C. for 5 minutes, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in methylene chloride and to it added hexanes. The precipitate was collected by vacuum filtration and dried under high vacuum overnight to afford the title compound 11G. MS (m/z) 592.25 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH:14]=[C:13]2[C@@H:8]([CH2:9][C:10]3[C:11]4[C:18]([NH:19][CH:20]=3)=[CH:17][CH:16]=[CH:15][C:12]=42)[NH:7][CH2:6]1)=[O:4].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.CO.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH:14]=[C:13]2[C@@H:8]([CH2:9][C:10]3[C:11]4[C:18]([NH:19][CH:20]=3)=[CH:17][CH:16]=[CH:15][C:12]=42)[N:7]([C:28](=[O:29])[NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6]1)=[O:4]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2NC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C(=O)Nc2ccccc2)C1

Procedure:
To a 100 ml round-bottom flask containing a solution of (6aR,9R)-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carboxylic acid methyl ester (0.89, 2.98 mmol) in dichloromethane (20 ml) is added phenylisocyanate (0.45 ml, 4.5 mmol, 1.5 eq.). The reaction mixture is stirred at room temperature for 16 hours by which time TLC in 10% methanol/DCM showed conversion of starting material to give product as a mixture of diastereomers. The volatiles are concentrated in vacuo and purified directly using Normal Phase Flash column chromatography (Biotage Flash 40, 90 g cartridge) using 30% ethyl acetate/hexane to isolate the product as a 1:1 diastereomeric mixture.
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13]#[N:14])=[C:6]2[CH:7]=[N:8][CH2:9][CH2:10][O:11][C:5]2=[C:4]([CH:15]([OH:17])[CH3:16])[CH:3]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[C:12]([C:13]#[N:14])=[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][O:11][C:5]2=[C:4]([CH:15]([OH:17])[CH3:16])[CH:3]=1
Reactant: CC(O)c1cc(Cl)c(C#N)c2c1OCCN=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)c1cc(Cl)c(C#N)c2c1OCCNC2
Reaction time: 1 h
Yield: 41 %

Procedure:
The crude 7-chloro-9-(1-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepine-6-carbonitrile was taken up in ethanol (30 mL) cooled in an ice bath and the sodium tetrahydroborate (0.16 g, 4.4 mmol) was added. The reaction was allowed to stir for 1 h, and water was added to quench the remaining hydride and the reaction was concentrated to remove most of the ethanol. The residue was dissolved with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated to give 7-chloro-9-(1-hydroxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile as an oil (0.45 g, 41%). LCMS calculated for C12H14ClN2O2(M+H)+: m/z=253.1; found: 253.0.