Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.O1CCCC1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[Cl:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:46][C:45]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[CH:33]=2)=[CH:25][C:24]=1[NH:23][C:7]([C:5]1[N:6]=[C:2]([CH3:1])[O:3][C:4]=1[C:10]([F:13])([F:12])[F:11])=[O:9]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2Cl)c(C(F)(F)F)o1
Yield: 48.1 %

Procedure:
In the same manner as in Example 55 and using 2-methyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic acid (110 mg, 0.564 mmol), tetrahydrofuran (5 mL), thionyl chloride (97.2 μL, 1.12 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-chlorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (170 mg, 0.495 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (124 mg, 48%) was obtained as a white solid.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClS(O)(=O)=O.C1C(=C(C#N)C#N)C=CC(=C(C#N)C#N)C=1>[Cl:21][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([OH:20])=[O:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1
Agent: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCC(Cl)C(=O)O
Temperature: 220 °C
Yield: 69.8 %

Procedure:
In a 50 ml 3-neck round bottom flask fitted with a condenser, thermometer, and magnetic stirrer were placed 11.4 g (0.04 mole) stearic acid, 8.0 g (0.06 mole) N-chlorosuccinimide, 0.1 ml (0.0015 mole) chlorosulfonic acid, and 0.04 g (0.0002 mole) TCNQ. The flask was placed in a heating bath set at 150° C. The mixture was stirred during heating, and a homogeneous liquid phase was formed. The solution temperature continued to rise above that of the heating bath, and a sudden exothermic reaction occurred in which the reaction temperature increased to ca. 220° C. The reaction mixture was cooled and dissolved in chloroform, and the resulting solution was washed thoroughly with dilute aqueous sodium chloride solution. After drying and removal of the chloroform, the residue was recrystallized from acetonitrile to afford 8.9 g (70%) of 2-chlorostearic acid which was equivalent in purity to the product of Example I.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([O:14][C:15]2[N:20]=[C:19]([C@H:21]([OH:25])[CH2:22][C:23]#[N:24])[CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.N.CO.C(Cl)Cl>>[NH2:24][CH2:23][CH2:22][C@H:21]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:20]=1)[OH:25]
Reactant: N#CC[C@@H](O)c1cccc(OC2CCCCCC2)n1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: NCC[C@@H](O)c1cccc(OC2CCCCCC2)n1

Procedure:
LiAlH4 reduction of (R)-3-(6-(cycloheptyloxy)pyridin-2-yl)-3-hydroxypropanenitrile following the method described in Example 1 gave after flash chromatography purification (20%-30% 7N NH3/MeOH—CH2Cl2 gradient) Example 34 as a colorless oil. Yield (0.19 g, 14%); 1H NMR (400 MHz, DMSO-d6) δ 7.58 (t, J=8.0 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.51 (d, J=8.0 Hz, 1H), 5.16-5.08 (m, 1H), 4.56-4.48 (m, 1H), 2.72-2.56 (m, 2H), 1.98-1.36 (m, 14H); RP-HPLC tR=7.98 min; ESI-MS m/z 265.2 [M+H]+.
Reaction SMILES: [O:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:11][C:9]([C:6]1[N:5]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:4]2[CH:3]=[CH:2][O:1][C:8]=2[CH:7]=1)=[O:10]
Reactant: COC(=O)c1cc2occc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: COC(=O)c1cc2occc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, methyl 4H-furo[3,2-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-naphthalene to give 4-naphthalen-1-ylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 290.3 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([F:20])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:21].B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:20])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: COc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1F
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 1-chloro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (420 mg, 1.39 mmol) with boron tribromide (3.9 mL of 1.0 M solution in CH2Cl2, 3.89 mmol) according to method D to yield 330 mg (82%) of a yellowish solid: mp 195–198° C.; 1H NMR (DMDO-d6): δ 7.08 (1H, t, J=8.86 Hz), 7.32 (1H, d, J=8.89 Hz), 7.47 (1H, dd, J=8.42 Hz, J=1.52 Hz), 7.63 (1H, dd, J=12.88 Hz, J=1.98 Hz), 7.83 (1H, d, J=8.95 Hz), 7.88 (1H, dd, J=8.93 Hz, J=1.61 Hz), 8.05 (1H, d, 8.86 Hz), 8.15 (1H, d, J=1.25 Hz), 10.05 (1H, s), 10.50 (1H, s); MS (ESI) m/z 287/289 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C@@H:9]([CH2:14][CH3:15])[C:10](OC)=[O:11])[C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:21][C:10](=[O:11])[C@H:9]([CH2:14][CH3:15])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1
Reactant: CC[C@@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC[C@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
Methyl (2S)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]butanoate 41d (14.17 g, 41.33 mmol) was dissolved in 300 mL of acetic acid followed by the addition of iron powder (9 g, 0.17 mol). After exothermic reaction was completed, the reaction solution was heated to 65° C., and stirred for 1.5 hours. The reaction mixture was filtered and the filter cake was washed with dichloromethane (350 mL). The filtrate was concentrated under reduced pressure, added with 150 mL of water and filtered. The filter cake was washed with water (60 mL×3) and the mixture solvent of hexane and acetone (V/V=6:1) (140 mL) successively. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (7S)-2-chloro-8-cyclopentyl-7-ethyl-5,7-dihydropteridin-6-one 41e (10.67 g, yield: 92.0%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7](=[CH:20][C:17]1[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=1)[C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: O=Cc1ccncc1
Product: COc1ccc2c(c1)C(=O)C(=Cc1ccncc1)CO2

Procedure:
By the method of Example 1, 6-methoxy-4-chromanone (26.7 g, 0.15 mol) and pyridine-4-carbaldehyde were converted to present title product, 13.5 g; m.p. 170-171.5° C.; IR (KBr) 1675, 1616, 1598, 1552 cm-1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.[C-]#N.[K+].[I-].[K+].[CH3:25][N:26](C)C=O>O>[C:25]([CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)#[N:26]
Reactant: O=C(OCc1ccccc1)N1CCOC(CCCl)C1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: O
Product: N#CCCC1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(2-chloroethyl)-4-benzyloxycarbonylmorpholine (16 g), potassium cyanide (6.3 g), potassium iodide (1 g), and dimethylformamide (50 ml) is heated at 100° C. with stirring for 5 hours. After cooling, the reaction mixture is diluted with water and extracted with diethyl ether. The organic layer is dried over sodium sulfate and evaporated. The residue is crystallized from diethyl ether-hexane to give the title compound (10.7 g), mp 59°-60° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][C@@H:15]1[CH:19]([OH:20])[CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.O1CCOCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=[C:2]([NH:14][C@H:15]2[C@H:19]([OH:20])[CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)[CH:11]=1
Reactant: Cc1ccc2nc(Cl)cc(C)c2c1
Reactant: CC(C)(C)OC(=O)N1CC(O)[C@@H](N)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3O)cc(C)c2c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a mixture of 2-chloro-4,6-dimethylquinoline (0.40 g), Pd2(dba)3 (0.095 g), (±)-BINAP (0.20 g), (S)-t-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (0.51 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.60 g) under nitrogen atmosphere, and the mixture was stirred at 70° C. for 1 h. The reaction mixture was diluted with ethyl acetate and water, the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the solids were washed with ethyl acetate and diisopropyl ether to obtain (3R,4R)-t-butyl 3-(4,6-dimethylquinolin-2-ylamino)-4-hydroxypyrrolidine-1-carboxylate (0.39 g). (2) (3R,4R)-t-Butyl 3-(4,6-dimethylquinolin-2-ylamino)-4-hydroxypyrrolidine-1-carboxylate (0.39 g) was dissolved in 4 M HCl in 1,4-dioxane (5 mL), and the mixture was stirred at room temperature for 2 h. To the reaction suspension was added diisopropyl ether, the mixture was stirred, and then the solids were collected by filtration to obtain (3R,4R)-4-(4,6-dimethylquinolin-2-ylamino)pyrrolidin-3-ol di hydrochloride (0.32 g).
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([N:7]([C:26]2[CH:31]=[CH:30][C:29](OC)=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:3][CH:2]=1.Cl.N1C=CC=CC=1.N1C=CC=CC=1.[F:53][C:54]([F:67])([F:66])[S:55]([O:58]S(C(F)(F)F)(=O)=O)(=[O:57])=[O:56]>>[F:53][C:54]([F:67])([F:66])[S:55]([O:58][C:29]1[CH:28]=[CH:27][C:26]([N:7]([C:4]2[CH:3]=[CH:2][C:1]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:6][CH:5]=2)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:31][CH:30]=1)(=[O:57])=[O:56]
Reactant: COc1ccc(N(c2ccc(-c3ccccc3)cc2)c2c(-c3ccccc3)cccc2-c2ccccc2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(N(c2ccc(-c3ccccc3)cc2)c2c(-c3ccccc3)cccc2-c2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 14 h
Yield: 71.5 %

Procedure:
N-([1,1′-biphenyl]-4-yl)-N-(4-methoxyphenyl)-[1,1′:3′,1″-terphenyl]-2′-amine (13.6 g, 27.0 mmol) and pyridine hydrochloride (31.1 g, 270.0 mmol) were purged with nitrogen for overnight. The mixture was refluxed for 2 h. After cooling, the precipitate was filtered and washed by excess water. The solid dissolved in DCM was filtered through a silica pad and washed with DCM. The solvent was removed in vacuo. The residue was dissolved in DCM (100 mL) and cooled down to 0° C. After that, pyridine (8.7 mL, 108.0 mmol) and trifluoromethanesulfonic anhydride (9.1 mL, 54.0 mmol) were added at 0 0° C. The mixture was stirred for 14 h from 0° C. to room temperature. The reaction mixture was quenched by the addition of saturated K2CO3 solution and extracted with DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by re-crystallization in 20% toluene/heptane to afford 4-([1,1′-biphenyl]-4-yl([1,1′:3′,1″-terphenyl]-2′-yl)amino)phenyl trifluoromethanesulfonate (12.0 g, 72% yield over 2 steps) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[C:8]2[O:27][CH:28]([F:30])[F:29]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid methyl ester (0.017 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.20 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue diluted with water. The pH of the resulting mixture was adjusted to 5 by the addition of sodium dihydrogenphosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient of acetonitrile in water (30% to 95% of organic modifier) gave title compound, 0.010 g.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[CH3:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1)([CH3:15])[C:13]#[N:14].C(=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>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([C:18]3[CH:17]=[C:16]([C:12]([CH3:15])([CH3:11])[C:13]#[N:14])[CH:21]=[CH:20][CH:19]=3)=[C:3]2[CH:10]=[N:9]1
Reactant: CC(C)(C#N)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Ic1ccnc2[nH]ncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C#N)c1cccc(-c2ccnc3[nH]ncc23)c1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A suspension of 4-iodo-1H-pyrazolo[3,4-b]pyridine (50 mg, 0.204 mmol), 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanenitrile (66 mg, 0.245 mmol), 2 M aqueous solution of sodium carbonate (0.31 ml, 0.612 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mol %, 12 mg, 0.01 mmol), in ethylene glycol dimethyl ether (2.5 ml) was heated under microwave irradiation at 150° C. for 30 minutes. The mixture was cooled down to room temperature, filtered through a path of celite and evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (28.4 mg, 53% yield).
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[C:5]1[CH:6]=[C:7]([CH:25]=[CH2:26])[C:8](=[O:24])[N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[CH2:2][CH3:3]>CO.[Pd]>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[CH:6]=[C:7]([CH2:25][CH3:26])[C:8](=[O:24])[N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:28][CH3:29]
Reactant: C=Cc1cc(N(CCC)CCC)c2cccc(-c3c(C)cc(C)cc3C)n2c1=O
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)c1cc(CC)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Reaction time: 1 h
Yield: 100.3 %

Procedure:
1-(Dipropylamino)-6-mesityl-3-vinyl-4H-quinolizine-4-one (9.4 mg, 0.024 mmol) was dissolved in methanol (1 mL) 10 mg of 10% Pd/C was added. The solution was evacuated and filled with a hydrogen balloon at room temperature. After 1 h, the solution was filtered and concentrated. Flash chromatography (5% ethyl acetate/hexanes) gave 9.4 mg (100% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14]([CH2:22][C:23]#C)[CH2:15]2)=[N:6][CH:7]=1.C(Cl)(=[O:38])C>>[C:22]([N:14]1[CH2:13][CH:12]2[CH2:21][CH2:20][CH:16]([C:17]3[C:11]2=[CH:10][C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:25][C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([NH:30][CH3:31])=[O:29])[C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:19][CH:18]=3)[CH2:15]1)(=[O:38])[CH3:23]
Reactant: C#CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Reactant: CC(=O)Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(C)=O)C2)ncc1Cl

Procedure:
2-[2-(10-Acetyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 2-[5-chloro-2-(10-prop-2-ynyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide and acetyl chloride in an analogous manner to Example 282. Product isolated as a yellow foam (30 mg, 91%). LCMS (m/e) 491 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 11.08 (s, 1H), 8.61 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.56-7.38 (m, 3H), 7.32-7.21 (m, 1H), 7.13-7.01 (m, 2H), 6.95 (s, 1H), 6.26 (bs, 1H), 4.34-4.20 (m, 1H), 3.80-3.69 (m, 1H), 3.43-3.30 (m, 1H), 3.28-3.18 (m, 1H), 3.15-2.99 (m, 2H), 3.03 (d, 3H, J=1.9 Hz), 2.07 (s, 3H), 2.02-1.92 (m, 2H), 1.84-1.67 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[C@H:38]1[CH2:43][CH2:42][C@H:41]([N:44]([CH3:58])[S:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH2:40][CH2:39]1>C(Cl)Cl.[N+](C)([O-])=O.CCOC(C)=O.OS([O-])(=O)=O.[K+]>[CH3:7][O:6][C:4](=[O:5])[CH2:3][CH2:2][O:1][C@H:38]1[CH2:39][CH2:40][C@H:41]([N:44]([CH3:58])[S:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH2:42][CH2:43]1
Reactant: COC(=O)CCO
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: COC(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 2.5 h

Procedure:
At 0° C. to a solution of 0.62 g (5.9 mmol) of methyl beta-hydroxypropionate in 4.5 mL of CH2Cl2 was added 1.4 mL (6.4 mmol, 2.4 eq) of 2,6-di-tert-butylpyridine, followed by 1.03 mL (6.2 mmol, 2.4 eq) of trifluoromethane sulfonic acid anhydride. The solution was stirred at that temperature for 2.5 h, was concentrated, and the residue was dissolved in 5 mL of nitromethane. To this solution 1 g (2.96 mmol) of trans-N-(4-hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide and 1.3 mL (5.9 mmol, 2.0 eq) of 2,6-di-tert-butylpyridine in 10 mL of nitromethane were added. The solution was stirred at 60° C. for 3 h, diluted with EtOAc and 1M KHSO4. The inorganic phase was extracted with EtOAc, the combined organic phases were washed with a saturated aqueous solution of NaHCO3, brine and were dried over Na2SO4 and evaporated. Column chromatography on silica gel with EtOAc/n-hexane 1:3 gave 1.2 g (95%) of trans-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid methyl ester as light yellow oil, MS: 424 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=3[C@H:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:3][CH2:2]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:70]1[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[CH:71]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[F:76][C:72]1[CH:71]=[C:70]([N:23]2[CH2:24][CH2:25][CH2:26][C@@H:22]2[C:10]2[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[C:14]3[C:9]=2[O:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]3=[O:17])[CH:75]=[CH:74][CH:73]=1
Reactant: COC(=O)c1cc([C@H]2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: Fc1cccc(Br)c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
Diacetoxypalladium (3.3 mg, 0.01 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-[(2R)-pyrrolidin-2-yl]chromene-6-carboxylate (121 mg, 0.34 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (16.61 mg, 0.03 mmol), 1-bromo-3-fluorobenzene (0.047 mL, 0.42 mmol) and cesium carbonate (165 mg, 0.51 mmol) suspended in 1,4-dioxane (3.3 mL). The resulting suspension was degassed with argon and then stirred at 100° C. for 20 h. The reaction mixture was allowed to cool to room temperature, and the crude product was purified by flash chromatography on silica gel eluting with 0 to 7% propanol in DCM. The solvent was evaporated to dryness to afford methyl 8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylate (120 mg, 79%) as a yellow oil which solidified on standing. Mass Spectrum: m/z [M+H]+=453.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([O:20][CH2:21][C:22](O)=O)[CH3:19]>>[CH3:16][C:14]([CH3:15])([OH:17])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:19]1[CH2:18][O:20][CH2:21][CH3:22]
Reactant: CCOCC(=O)O
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Yield: 6 %

Procedure:
Using the general method of Example 91, 3-amino-4-(2-hydroxy-2-methylpropylamino)quinoline (46.2 g. 0.20 mol) was reacted with ethoxyacetic acid (62.5 g, 0.6 mol) to provide 53.6 g of crude product as a greyish solid. A small amount was recrystallized from toluene to provide 3.6 g of a colorless solid, m.p. 117°-120° C. Analysis: Calculated: % C 68.2; % H, 7.1; % N, 14.0; Found: % C, 68.5; % H, 7.1; % N, 14.0.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:19])[CH:6]([OH:18])[CH:7]([NH:11]C(=O)OCC=C)[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1.CN1C(=O)CC(=O)N(C)C1=O>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.C(Cl)Cl>[NH2:11][CH:7]([CH2:8][CH2:9][CH3:10])[CH:6]([OH:18])[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:19]
Reactant: C=CCOC(=O)NC(CCC)C(O)C(=O)NC1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: CCCC(N)C(O)C(=O)NC1CC1
Reaction time: 8 h

Procedure:
Allyl 1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate bound resin M1B (30 g, 1.0 eq.) was swollen with DCM. 1,3-Dimethylbarbituric acid (24.17 g, 12 eq.) and tetrakis(triphenylphosphine)palladium (1.49 g, 0.1 eq.) were added and the mixture shaken overnight. The mixture was filtered and washed with DMF and DCM to yield the resin M1D.