Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH:22]C(=O)OC(C)(C)C)[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.ClCCCl.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(C)n1nc(NC(=O)OC(C)(C)C)nc1-c1cn2c(n1)-c1ccc(F)cc1OCC2
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(F)cc1OCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.9 %

Procedure:
tert-Butyl 5-(9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-ylcarbamate (0.200 mg, 0.47 mmol) was dissolved in 1,2-Dichloroethane (3 mL, 40 mmol) and trifluoroacetic acid (3 mL, 40 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. Complete reaction was confirmed by LCMS and the reaction mixture concentrated in vacuo. The crude solid was purified by HPLC to give 253 (18.3 mg, 12% yield)
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](B(O)O)=[CH:11][C:10]=2[CH:17]=1)[CH3:2].[C:18]([O:22][C:23](=[O:36])[N:24]([C:26]1[CH:31]=[CH:30][C:29](Br)=[C:28]([N+:33]([O-:35])=[O:34])[N:27]=1)[CH3:25])([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([O:22][C:23](=[O:36])[N:24]([C:26]1[CH:31]=[CH:30][C:29]([C:12]2[O:13][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:17][C:10]=3[CH:11]=2)=[C:28]([N+:33]([O-:35])=[O:34])[N:27]=1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOCOc1ccc2oc(B(O)O)cc2c1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Br)c([N+](=O)[O-])n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOCOc1ccc2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)nc3[N+](=O)[O-])cc2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a degassed solution of 5-ethoxymethoxy-benzofuran boronic acid (4) (0.69 g, 2.63 mmol) in ethanol (17.5 mL), (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester 12 (0.50 g, 1.51 mmol), Pd(PPh3)2Cl2 (0.14 g, 0.20 mmol) and Et3N (0.48 mL, 3.46 mmol) were added. The reaction mixture was stirred at 90° C. for 30 minutes. The reaction mixture was cooled to 0° C. and clear filtered. Volatiles were removed under reduced pressure. The residue was diluted with water and the mixture was extracted with ethyl acetate. The organic extract was washed with brine and concentrated under reduced pressure. The crude product was purified by flash column chromatography. Evaporation of solvent gave title compound 13 (58% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:33]1[CH:34]=[CH:35][C:36]([S:42](=[O:47])(=[O:46])[N:43]([CH3:45])[CH3:44])=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:33]5[CH:34]=[CH:35][C:36]([S:42](=[O:46])(=[O:47])[N:43]([CH3:45])[CH3:44])=[C:37]([C:38]([OH:40])=[O:39])[CH:41]=5)[CH:17]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)N(C)C)c(C(=O)O)c1
Temperature: 80 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (42 mg, 0.10 mmol), 5-bromo-2-(N,N-dimethylsulfamoyl)benzoic acid (31 mg, 0.10 mmol), 1 M K2CO3 (0.30 mL, 0.30 mmol), and Pd-FibreCat 1007 (8 mg, 0.004 mmol) were dissolved in DMF (1 mL) and heated at 80° C. for 3 hr in an oil bath. The mixture was filtered and purified by reverse phase HPLC to yield 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4-(N,N-dimethylsulfamoyl)-2′-methylbiphenyl-3-carboxylic acid. ESI-MS m/z calc. 522.6. found 523.5 (M+1)+; retention time 1.79 minutes.
Reaction SMILES: C([N:9]1[CH2:21][C:20](=O)[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=3)[NH:12][C:11]=2[CH2:10]1)(=O)C1C=CC=CC=1.[NH2:24]N>>[NH2:24][C:20]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=3)[NH:12][C:11]=2[CH:10]=[N:9][CH:21]=1
Reactant: O=C1CN(C(=O)c2ccccc2)Cc2[nH]c3ccc(Cl)cc3c21
Reactant: NN
Product: Nc1cncc2[nH]c3ccc(Cl)cc3c12
Temperature: 130 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Crude 2-benzoyl-6-chloro-1,2,3,9-tetrahydro-β-carbolin-4-one (4 g) was dissolved in 30 ml of anhydrous hydrazine and stirred at reflux (130° C. oil bath) under N2 for 6 hours, after which the reaction mixture was allowed to cool to room temperature and sit overnight. The precipitated yellow solids were removed by filtration and washed with water, 2×5 ml, to yield 785 mg (30%) of 4-amino-6-chloro β-carboline as an off white solid. Additional water was added to the combined filtrates until no further precipitation occurred. These solids were also removed by filtration to give 1.056 g (39%) of 4-amino-6-chloro β-carboline as yellow solids, (69% total yield). 1H-NMR (300 MHz, DMSO-d6): δ 11.48 (s, 1H), 8.44 (s, 1H), 8.13 (s, 1H), 7.77 (s, 1H), 7.42-7.52 (m, 2H), 5.86 (s, 2H). Formic acid standard conditions. DAD RT=1.68 min. M+H=218.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([NH2:28])=O)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1.N1C=CC=CC=1>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](=[S:49])[NH2:28])=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=S)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 21.7 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenamide (2.50 g), Lawesson's reagent (2.26 g) and pyridine (15 mL) was heated under reflux for 30 min. After concentration of the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenethioamide as yellow crystals (0.56 g, yield 22%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-diethyl ether gave yellow prism crystals. melting point: 129-131° C.
Reaction SMILES: [CH2:1]([N:4](C)[CH2:5][C@@H:6]([CH3:34])[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[C:21]([CH3:33])[CH:20]=1)=[N:11][CH:12]=[N:13]2)C=C>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:34][C@@H:6]([O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[C:21]([CH3:33])[CH:20]=1)=[N:11][CH:12]=[N:13]2)[CH2:5][NH:4][CH3:1]
Reactant: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Yield: 82.5 %

Procedure:
A mixture of 5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (2.25 g, 4.8 mmol) and chlorotris(triphenylphosphine)rhodium(I) (463 mg, 0.48 ml) in acetonitrile—water (17 ml:3 ml) was heated at reflux for 3 hours. After cooling, the solvents were evaporated under vacuum. The residue was purified by chromatography on silica gel (eluant: 2 to 4% methanol in DCM) to give 5-[(1R)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (1.70 g, 83%); Mass spectrum: MH+ 430.
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.CCOCC>CO>[CH3:1][O:12][C:11]([C@@H:8]1[CH2:7][C@@H:6]([OH:5])[CH2:10][NH:9]1)=[O:13]
Reactant: CC(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C

Procedure:
Acetyl chloride (7.6 ml; 107 mmol) was added slowly to MeOH (70 ml). The reaction was exothermic. (2S,4R)-4-Hydroxy-2-pyrrolidinecarboxylic acid (10 g; 76.2 mmol) was added and the mixture was refluxed for 4 hours. At this time, another portion of 3 ml of acetyl chloride in 30 ml of MeOH was added. The mixture was refluxed an additional 3 hours. The reaction was cooled to room temperature and ~750 ml of Et2O was added. The resulting colorless crystals were filtered and dried to afford 11.89 g of the title A compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([F:30])[CH:24]=1>>[F:30][C:25]1[CH:24]=[C:23]([O:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH:28]=[CH:27][C:26]=1[NH:29][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(OCc2ccccn2)cc1F
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccc(OCc4ccccn4)cc3F)c2c1
Yield: 98 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 42 which is concerned with the preparation of starting materials, 4-chloro-6-nitroquinazoline was reacted with 4-amino-3-fluorophenyl 2-pyridylmethyl ether to give 4-[2-fluoro-4-(2-pyridylmethoxy)anilino]-6-nitroquinazoline in 98% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C1COCC1>C(OCC)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:14][CH3:15])=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:19]=2)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: CCOc1ccc(B(O)O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccc(-c2cc(N)c([N+](=O)[O-])c(C#N)n2)cc1C(F)(F)F
Temperature: 150 °C
Yield: 50.7 %

Procedure:
A stirred mixture 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (1 g, 5.04 mmol), 4-ethoxy-3-trifluoromethylphenylboronic acid (1.33 g, 6.04 mmol), tetrakis-(triphenylphosphine)palladium(0) (˜500 mg,10 mol %), potassium carbonate (2.09 g, 15.12 mmol) and THF (10 ml) was degassed under a stream of nitrogen before heating in the “Smith” microwave at 150° C. for 10 minutes. The crude mixture was concentrated under reduced pressure to remove THF before partitioning between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give a dark brown oil. Trituration with diethylether gave a light brown solid which was filtered and dried under a stream of air to afford 4-amino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-3-nitro-pyridine-2-carbonitrile (900 mg). 1H NMR (DMSO): δ 8.25-8.1 (m, 3H), 7.63 (s, 1H), 7.44 (d, 2H), 4.27 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[NH:14][C:13](=[O:15])[O:12][C:10](=[O:11])[C:9]2=[CH:16][CH:17]=1)([O-:5])=[O:4].[CH3:18]I.Cl>CN(C=O)C>[CH3:18][N:14]1[C:13](=[O:15])[O:12][C:10](=[O:11])[C:9]2[CH:16]=[CH:17][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]1=2
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 86.7 %

Procedure:
To a suspension of 0.1656 g (4.14 mmoles) of sodium hydride (60% in mineral oil) in 20 mL DMF was added a solution of 0.6584 g (3.16 mmoles) of 4-nitroisatoic anhydride in 20 mL DMF. After stirring a few minutes at room temperature, a clear orange solution formed. 0.2615 g (3.2 mmoles) of methyl iodide was added to the reaction, and the mixture was stirred at room temperature for 4 hours. The reaction was poured into 50 mL of cold 1 N HCl, and the resulting bright orange precipitate was filtered and washed sequentially with water and ether to give 608.3 mg (86%) of product. 1H NMR (CO(CD3)2, 400 MHz,) δ 3.69 (s, 3H, —NCH3—), 8.12 (dd, J=8.8 Hz, 2 Hz, 1H, ArH), 8.2 (d, J=2 Hz, 1H, ArH), 8.34 (d, J=8.4 Hz, 1H, ArH).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[F:32]>C1COCC1.O>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[C:31]([F:32])[CH:30]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)cc1F
Yield: 69 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′ (1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3,4-difluorophenyl boronic acid (1.6 g, 5.2 mmol of a 50% solution of acid in THF/water) according to Example 45 procedure A. The product was purified by flash silica gel chromatography (eluant: 10:0.5 hexane:ethyl acetate) to give the desired product (0.75 g, 1.7 mmol, 69%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.41-1.78 (8H, m) 1.95-1.99 (2H, q) 5.00 (2H, s) 6.82 (1H, d) 7.28-7.46 (8H, m) 7.58 (1H, q) 7.67-7.71 (1H, m) 9.61 (1H, s); MS (ESI(−ve)) m/z 417 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:27][CH:26]=1)#[N:24]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C#N)cc3)c(F)cn2c1=O
Yield: 103 %

Procedure:
Ethyl 8-(4-cyano-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (151 mg, 0.47 mmol) and 4-cyano-phenyl-boronic acid (82 mg, 0.56 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH, 1:0 to 9:1) afforded the title compound as a yellow solid (189 mg, 100%). ESI-MS m/z: 391 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:25][CH2:24][CH2:23][C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[C:16]=3[N:17]=[C:18]([NH2:20])[N:19]=2)[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:25][CH2:24][CH2:23][C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[C:16]=3[N:17]=[C:18]([NH2:20])[N:19]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(N)nc3c2CCCc2ccccc2-3)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2c(c(N3CC[C@@H](N)C3)n1)CCCc1ccccc1-2
Reaction time: 16 h

Procedure:
A solution of the product from Example 4D (68 mg, 0.17 mmol) in CH2Cl2 (3 mL) was treated with trifluoroacetic acid (0.2 mL) and stirred for 16 hours. The mixture was diluted with CH2Cl2, washed H2O, dried, concentrated and chromatographed on silica gel eluting with eluting with NH4OH/MeOH/CH2Cl2 (0.8/8/92) to provide the title compound.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:20]#[N:21])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([Cl:19])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>C[O-].[Na+].CO>[Cl:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:20]#[N:21])=[N:9][C:8]([C:6]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:7])=[C:17]2[OH:18]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Cl)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Cl)ccc12
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of 6-chloro-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (99 mg, 0.33 mmol) and glycine (1.84 g, 24.49 mmol) in 0.5 M sodium methoxide/methanol (32.6 mL) was refluxed for twenty-one hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (40 mL) and the solution washed with dichloromethane (3×50 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl. The suspension was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a white solid (84 mg): MS: (+) m/z 306.27 (M+1); (−) m/z 304.26 (M−1).
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH:13][CH2:14][CH2:15][C:16]1[CH:45]=[CH:44][CH:43]=[CH:42][C:17]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:41][CH2:40][C:24]2([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]3[N:33]=[C:34]([CH:37]([CH3:39])[CH3:38])[S:35][CH:36]=3)=[O:31])[CH2:25]2)[CH2:23][CH2:22]1.[C:46]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])(=[O:49])[CH:47]=[CH2:48]>C1(C)C=CC=CC=1>[CH:37]([C:34]1[S:35][CH:36]=[C:32]([C:30]([N:26]2[CH2:25][C:24]3([CH2:40][CH2:41][N:21]([CH2:20][CH2:19][O:18][C:17]4[CH:42]=[CH:43][CH:44]=[CH:45][C:16]=4[CH2:15][CH2:14][O:13][CH2:48][CH2:47][C:46]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:22][CH2:23]3)[O:29][CH2:28][CH2:27]2)=[O:31])[N:33]=1)([CH3:39])[CH3:38]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCO)CC3)C2)cs1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccccc4CCOCCC(=O)OC(C)(C)C)CC3)C2)cs1
Yield: 68.2 %

Procedure:
benzyltrimethylammonium hydroxide (0.2 mL) was added to (9-(2-(2-(2-hydroxyethyl)phenoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (0.60 g) (example 178 step b) and tert-butyl acrylate (0.244 g) in toluene (1 mL) and the reaction mixture stirred vigorously. Afire 16 h, more benzyltrimethylammonium hydroxide (0.2 mL) and tert-butyl acrylate (0.244 g) was added. After a further 48 h the reaction mixture was evaporated in vacuo and applied to a silica gel column eluting with 5% methanol in DCM. Yield as a gum 0.52 g.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OC(=O)N(C)C)cc(Cl)c21
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (60 mg, 0.22 mmol) in DMF (3 mL) was slowly added NaH (27 mg, 0.66 mmol) at 0° C. The mixture was stirred for 20 min and N,N-dimethylcarbamic chloride (29 mg, 0.27 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature and quenched with ice water. The resulting mixture was extracted with EtOAc (2×15 mL) and the combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step reaction without further purification. MS (ESI) m/z=342 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:25])[C:11]([OH:16])([C:17]3[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:12]([F:15])([F:13])[F:14])=[C:2]([Cl:1])[C:7]=2[Cl:8])=[CH:28][C:27]=1[F:26]
Reactant: CC(c1ccc(O)c(Cl)c1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2Cl)cc1F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2,3-dichloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 197, step 5) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=546.2 [M−H+].
Reaction SMILES: Cl[CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([NH:4][CH2:3][CH:2]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([C:17]([F:16])([F:25])[F:26])[CH:19]=2)[CH3:15])[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(Cl)CNc1cccc(C(F)(F)F)c1
Product: CC(CNc1cccc(C(F)(F)F)c1)Nc1cccc(C(F)(F)F)c1
Yield: 76.6 %

Procedure:
N-(β-chloropropyl)-3-trifluoromethyl-aniline is reacted with 3-trifluoromethylaniline as described in Example 16, point (c) to obtain 1,2-bis(3'-trifluoromethylphenyl-amino)propane with a yield of 76.6%. The dihydrochloride of this base melts at 116°-120° C.