Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a stirred solution of methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (14 g, 34.3 mmol) in anhydrous toluene (400 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (12.5 mL, 13.7 mmol). The mixture was cooled to −35° C. and then a 4.17M solution of catechoborane/toluene (11.7 mL, 48 mmol) was added over the course of 10 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. At this point the reaction mixture was diluted with EtOAc (300 mL) and treated with sat.aq. Na2CO3 (50 mL). The mixture was stirred vigorously for 10 min. The organic phase was separated and washed with sat. aq. Na2CO3 (5×100 mL), 0.1N HCl (1×100 mL), and brine. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was triturated with ether to obtain 12 g (77%) of the desired (S)-methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.20 (t, J=1.8 Hz, 1H), 7.95 (dq, J=7.8, 0.8 Hz, 1H), 7.57 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 6.95 (s, 1H), 5.79 (s, 1H), 3.87 (s, 3H), 3.59 (d, J=1.8 Hz, 1H), 2.65 (s, 3H). LCMS (M+H)=410 and 412.
Reaction SMILES: [F-].[Cs+].[F:3][C:4]([F:9])([F:8])[CH2:5][NH:6][CH3:7].Br[C:11]1[N:28]([CH2:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]2)[C:14]2[C:15]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)=[N:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=2[N:12]=1>CS(C)=O.O>[Cl:27][C:25]1[CH:26]=[C:21]([C:15]2[C:14]3[N:28]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:11]([N:6]([CH3:7])[CH2:5][C:4]([F:9])([F:8])[F:3])=[N:12][C:13]=3[CH:18]=[C:17]([C:19]#[N:20])[N:16]=2)[CH:22]=[N:23][CH:24]=1
Reactant: CNCC(F)(F)F
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: CN(CC(F)(F)F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 150 °C

Procedure:
To a sealed reaction vessel was added cesium fluoride (0.085 g, 0.56 mmol). The reaction vessel was heated to 150° C. for 3 hours with stirring, under high vacuum. The vial was cooled to ambient temperature under high vacuum. The reaction vessel was backfilled with argon, and next was added a solution of 2,2,2-trifluoro-N-methylethanamine (purchased from Enamine) (0.019 g, 0.17 mmol) and 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 0.025 g, 0.056 mmol) in DMSO (0.30 mL). The reaction was heated to 100° C. for 12 hours. The reaction was cooled, diluted with H2O (2.0 mL) and extracted with EtOAc (2×5.0 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 4-(5-chloropyridin-3-yl)-2-(methyl(2,2,2-trifluoroethyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a crude residue. MS ESI calc'd. for C23H24ClF3N6 [M+H]+ 477. found 477.
Reaction SMILES: [F:1][C:2]([F:32])([C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1)[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(=O)([O-])[O-].[K+].[K+].[Br:39][CH2:40][CH:41]=[CH:42][CH2:43]Br>CN1C(=O)CCC1>[Br:39][CH2:40][CH:41]=[CH:42][CH2:43][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:2]([F:32])([F:1])[C:3]([F:23])([F:24])[C:4]([F:21])([F:22])[C:5]([F:19])([F:20])[C:6]([F:17])([F:18])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[CH:26]=1
Reactant: BrCC=CCBr
Reactant: Oc1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c1cccc(OCC=CCBr)c1
Temperature: 45 °C

Procedure:
A mixture of 3-(perfluoro-n-octyl)phenol (10.24 g), potassium carbonate (4.2 g), NMP (30 mL) and 1,4-dibromo-2-butene (12.8 g) is heated to 45° C. for 2 hr. Extraction in the normal fashion and Kugelrohr distillation of the excess dibromide (0.1 mm Hg, 80° C.) gives 1-bromo-4-[3-(perfluoro-n-octyl)phenoxy]but-2-ene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13](Cl)Cl.S(=O)(=O)(O)[OH:17]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13]=[O:17]
Reactant: Clc1cnc2c(C(Cl)Cl)c(Cl)ccc2c1
Reactant: O=S(=O)(O)O
Product: O=Cc1c(Cl)ccc2cc(Cl)cnc12

Procedure:
56 parts of 3,7-dichloro-8-dichloromethylquinoline in 250 parts of 90% strength sulfuric acid were stirred at 100° C. for 6 hours. After cooling, the solution was poured onto ice and the precipitated solid was filtered off with suction, washed neutral with water and dried. 195 parts of 3,7-dichloroquinoline-8-carbaldehyde of melting point 208° C. were obtained. The yield corresponds to 87% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:32]3[CH:31]=[N:30][C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[N:34][CH:33]=3)=[CH:14][C:6]1=2
Reactant: CN1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: CN1CCN(c2ncc(-c3cnc4c(c3)N(Cc3c(F)ccc(F)c3Cl)CCN4)cn2)CC1
Yield: 27 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 2-(4-methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester as in General Procedure 4A to give the title compound as a pale orange solid (27% yield). M.p. 194-195° C., LCMS: m/z=472.09 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.38 (s, 3H), 2.51-2.58 (m, 4H), 3.31 (t, J=4.8 Hz, 2H), 3.49-3.58 (m, 2H), 3.89-3.97 (m, 4H), 4.51 (s, 2H), 4.95 (bs, 1H), 6.96 (s, 1H), 6.99-7.08 (m, 1H), 7.10-7.18 (m, 1H), 7.57 (s, 1H), 8.45 (s, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]1[O:35][C:34]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:31])=[O:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][C:14]=2[O:13]1>C(Cl)(Cl)Cl>[CH2:12]1[O:35][C:34]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:31])(=[O:9])=[O:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][C:14]=2[O:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)c1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A solution of 0.65 g (3.8 mmol) of m-chloroperbenzoic acid in 20 ml of chloroform was dropped into a solution of 1.00 g (2.93 mmol) of the 4-(3,4-methylenedioxybenzyl)amino-6-methylsulfinylquinazoline prepared in Example 137 under stirring at room temperature. The obtained mixture was stirred at room temperature for several hours, washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and filtered. The filtrate was purified by silica gel column chromatography (ethyl acetate) and recrystallized from chloroform/n-hexane to give 0.85 g of the title compound as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([NH:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CN(C)CCCN
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1NCCCN(C)C
Yield: 55.8 %

Procedure:
Following the procedure used to prepare Example 27, 150 mg (0.34 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile is reacted with 209 mg (2.05 mmol) of N, N-dimethyl-1,3-propanediamine in 1 mL of 1-methyl-2-pyrrolidinone at 105° C. for 16 hours to yield 99 mg of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-{[3-(dimethylamino)propyl]amino}-6-methoxyquinoline-3-carbonitrile as a tan solid, mp 198-200° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:34](O)=[O:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].P(Cl)(Cl)(Cl)=O>CN(C)C1C=CN=CC=1.C(#N)C>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:34]([C:31]3([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][CH2:30]3)=[O:35])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2nonc2-c2noc(=O)n2-c2ccc(F)c(Br)c2)(c2ccccc2)CC1
Temperature: 100 °C

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.15 g, 0.44 mmol), 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (0.4 g, 1.3 mmol), and 4-dimethylaminopyridine (32 mg, 0.26 mmol) in acetonitrile (2 mL) was treated with phosphoryl chloride (0.13 mL, 1.4 mmol) and heated in the microwave at 100° C. for 10 min. The reaction mixture was concentrated and the residue was diluted with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL), dried with sodium sulfate, filtered, and concentrated to a crude residue which was purified by silica gel to give the coupled product, tert-butyl 4-[({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]-4-phenylpiperidine-1-carboxylate. This material was diluted with dichloromethane (5 mL) and treated with 4.0 M HCl in 1,4-dioxane (3 mL) and stirred for 45 min. The reaction mixture was concentrated and the crude residue was purified by preparative LCMS to give the desired product (10 mg, 4%). LCMS for C22H19BrFN6O4 (M+H)+: m/z=529.0, 531.0.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:4][CH2:3]1.Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[S:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:4][CH2:3]1
Reactant: Nc1nnc(Br)s1
Reactant: CC1CCN(Cc2cccc(OCCCN)c2)CC1
Product: CC1CCN(Cc2cccc(OCCCNc3nnc(N)s3)c2)CC1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(4-methyl-1-piperidinyl)methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28](=[O:39])[CH:27]=2)=[CH:20][N:19]=1)([O-])=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:31]=[CH:30][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:28](=[O:39])[CH:27]=3)=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccn(Cc2ccccc2)c(=O)c1
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccn(Cc3ccccc3)c(=O)c2)c(=O)[nH]1
Yield: 78 %

Procedure:
4-(5-Bromo-3-methylpyrid-2-yl)butylamine (0.71 gm) and 2-nitroamino-5-(1-benzyl-2-oxo-pyrid-4-ylmethyl)-4-pyrimidone (1.0 gm) were refluxed in pyridine (3 ml) for 8 hrs., an extra 0.13 gm of the amine was added and reaction was refluxed for a further 5.5 hrs. The pyridine was removed in vacuo, the residue was re-evaporated with n-propanol (2×40 ml). The residue was dissolved in warm ethanol (10 ml) ether added and on cooling a white solid was obtained which was recrystallised from acetonitrile-water (9:1) to give 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(1-benzyl-2-oxo-pyrid-4-ylmethyl)4-pyrimidone (1.18 gm) m.p. 140°-144° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:14]([O:18][C:19]([NH:21][C:22]1([C:37](O)=[O:38])[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[C:10]([C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:37]([C:22]2([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:23][CH2:24][N:25]([C:28]3[C:29]4[CH:36]=[CH:35][NH:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:26][CH2:27]2)=[O:38])[CH2:3][CH2:4][OH:5])=[CH:13][CH:12]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: N#Cc1ccc([C@@H](N)CCO)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(C#N)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
(S)-4-(1-amino-3-hydroxypropyl)benzonitrile (Intermediate 46) (195 mg, 1.11 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (400 mg, 1.11 mmol) and DIPEA (0.580 mL, 3.32 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (463 mg, 1.22 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 4-(1-(4-cyanophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (267 mg, 46.4%) as a white solid. (S)-tert-butyl 4-(1-(4-cyanophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (267 mg, 0.51 mmol) was suspended in dioxane (5.00 mL) and 4M hydrogen chloride in dioxane (0.769 mL, 22.14 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-cyanophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (70.0 mg, 15.1%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[C:3]1[C:9](=[O:13])[CH2:10][C:11]#[N:12].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[C:3]1[C:9](=[O:13])[CH:10]([C:21](=[O:22])[NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]#[N:12]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(C)n(C)c1C(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C)n(C)c1C(=O)C(C#N)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
To the suspension of 1.0 g of 1,3,5-trimethyl-β-oxo-2-pyrrolpropionitrile in 30 ml of dry toluene and 0.7 g of anhydrous triethylamine, 0.75 g of phenylisocyanate are added while stirring. The mixture is warmed for 5 minutes at the steam cone and allowed to stand at room temperature overnight. It is filtered, the residue taken up in methanol and the solution acidified with N hydrochloric acid. The precipitate formed is collected, dissolved in N aqueous sodium hydroxide, re-precipitated with 5 N hydrochloric acid and washed with water, to yield the 1,3,5-trimethyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 172°-174°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8](O)[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:24])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([F:24])[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)C(O)c1cccc(Cl)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)C(F)c1cccc(Cl)c1
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A solution of 25 g of ethyl 3-(3-chlorophenyl)-3-hydroxy-2,2-difluoropropionate in 140 mL CH2Cl2 was treated with a solution of 14 g of diethylaminosulfurtrifluoride in 10 mL CH2Cl2 at room temperature. After 3 hours, the mixture was poured into aqueous NaHCO3, extracted with ethyl acetate, dried (Na2SO4) and evaporated. The residue was distilled (0.1 mm Hg) to give 18.7 g of an oil which was used directly.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C([N:57]([CH:60]([CH3:62])[CH3:61])[CH2:58]C)(C)C.C1(NC)CC1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:57]([CH:60]1[CH2:61][CH2:62]1)[CH3:58])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: CNC1CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N(C)C3CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-cyclopropyl-methylamine in DMSO at ambient temperature.
Reaction SMILES: C1C[O:17][C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:15][OH:16])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])([CH3:4])O1.N1C=CC=CC=1[CH2:25][C:26](OC(=O)CC1C=CC=CN=1)=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[C:26]([O:16][CH2:15]/[C:8](/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])=[CH:7]\[CH2:6][CH2:5][C:3](=[O:17])[CH3:4])(=[O:27])[CH3:25]
Reactant: O=C(Cc1ccccn1)OC(=O)Cc1ccccn1
Reactant: CC(C)=CCCC(=CCCC1(C)OCCO1)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)CC/C=C(/CCC=C(C)C)COC(C)=O
Reaction time: 8 h

Procedure:
7.2 g of the alcohol thus obtained was acetylated with anhydrous pyridine-acetic anhydride in the usual way and dissolved in 70 ml of methanol. To this solution was added 70 mg of p-toluenesulfonic acid, and the mixture was allowed to stand overnight at room temperature. The resultant was neutralized with an aqueous sodium hydrogencarbonate solution and extracted with n-hexane. There was obtained 7.2 g of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16]1([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]1)[C:17](=[O:28])[N:18]2[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]2([C:32]4=[CH:33][C:34]5[O:38][CH2:37][O:36][C:35]=5[CH:39]=[C:31]4[O:30][CH2:29]2)[C:17](=[O:28])[N:18]3[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5][CH:4]=1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: CN(C)c1ccc(B(O)O)cn1
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: C1COCCO1
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(-c3ccc(N(C)C)nc3)cccc21
Temperature: 25 °C

Procedure:
To an oven-dried flask was charged with [6-(dimethylamino)pyridin-3-yl]boronic acid (37.0 mg, 0.17 mmol), Pd(PPh3)4 (13.5 mg, 0.012 mmol) followed by flashing with nitrogen. To the flask was added a solution of 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (50.0 mg, 0.12 mmol) in anhydrous dioxane (2.00 mL) followed by the addition of 2.0 M Na2CO3 (0.24 mL). The reaction mixture was heated at reflux for 48 h. After cooling down to ambient temperature, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (2.00 mL), washed with saturated ammonium chloride (2.00 mL), and concentrated in vacuo to dryness. The residue was subjected to column chromatography to yield the title compounds: 1H NMR (300 MHz, CDCl3) δ 7.77 (d, 1H), 7.32 (t, 1H), 6.87 (dd, 2H), 6.71 (dd, 1H), 6.23 (d, 1H), 6.20 (s, 1H), 5.88 (d, 2H), 4.56 (ABq, 2H), 3.89-3.80 (m, 1H), 3.69-3.59 (m, 1H), 3.05 (s, 6H), 1.78-1.69 (m, 2H), 1.39-1.35 (m, 4H), 0.90 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.9, 158.3, 156.1, 148.8, 147.3, 142.9, 142.0, 137.8, 137.2, 129.9, 128.9, 125.6, 122.0, 121.0, 107.6, 104.3, 102.5, 101.5, 93.6, 77.8, 58.5, 40.5, 38.2, 29.1, 27.2, 22.4, 14.0; MS (ES+, m/z) 472.0 (M+1).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:8])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)C1CCCCC1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3CCCCC3)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use cyclohexanecarbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white solid (58% yield). 1H NMR (300 MHz, CDCl3) δ 8.06, 7.99, 6.99, 3.88, 3.79, 3.68, 3.56, 2.50, 1.67-1.84, 1.48-1.60, 1.24-1.34, 0.76, 0.47, 0.10. MS (ES+) m/z 386 (M+1).