Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[NH:8][C:7]=2[CH:14]=1.[H-].[Na+].I[CH2:18][CH3:19]>CN(C)C=O>[CH2:18]([N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]1=2)[CH3:19]
Reactant: COc1ccc2c(c1)NC(=O)CCC2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CCCc2ccc(OC)cc21
Yield: 94.4 %

Procedure:
8-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1.10 g, 0.00575 mol) was charged into RBF fit with stir bar, septum and under N2 atmosphere. Charged with N,N-Dimethylformamide (25 mL) and then Sodium Hydride (60% dispersion mineral oil) (0.25 g), gas evolution (H2) ensued. The mixture was stirred about 5 minutes and then treated with Iodoethane (0.63 mL, 0.0078 mol) and stirred at room temperature for 1.3 h. The mixture was quenched with ice/water and extracted with ether. The ether layer was washed with water, then with brine, dried (MgSO4), filtered and concentrated to give a 1-Ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a clear oil (1.19 g, 94%). 1H-NMR (CDCl3) δ 7.21 (t, J=8.2 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 3.84 (s, 3H), 2.25 (s, 2H), 1.7-3.5 (br pk's, 6H), 1.13 (t, J=7.2 Hz, 3H); LC/MS (ESI-pos) m/z 220.09 (M+H). M.P.=Oil. LC/MS: 220.06 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@H:14]4[CH2:16][C@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)[CH:3]=1.Cl.[F:21][CH2:22][C:23]([CH3:26])([NH2:25])[CH3:24]>>[F:21][CH2:22][C:23]([NH:25][C:17]([C:10]1[C:11]2[CH2:12][C@@H:13]3[CH2:16][C@@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:18])([CH3:26])[CH3:24]
Reactant: CC(C)(N)CF
Reactant: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Agent: Cl
Product: CC(C)(CF)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method UU using (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 1-fluoro-2-methylpropan-2-amine hydrochloride. LCMS m/z=349.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.42-0.47 (m, 1H), 1.24 (td, J=7.9, 4.8 Hz, 1H), 1.48 (s, 3H), 1.49 (s, 3H), 2.22-2.29 (m, 1H), 2.76-2.82 (m, 1H), 2.90 (d, J=16.8 Hz, 1H), 2.99 (dd, J=16.6, 6.2 Hz, 1H), 4.56 (d, J=47 Hz, 2H), 6.80 (s, 1H), 7.20 (dd, J=−5.4, 1.9 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:31][O:32][CH3:33].Cl.N1C=CC=CC=1>CCO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[N:31][O:32][CH3:33])[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CON
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(/C=C/C(=O)NO)cc21
Reaction time: 2 h
Yield: 101.7 %

Procedure:
A mixture of (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (150 mg, 0.35 mmol), NH2OCH3.HCl (63.5 mg, 0.76 mmol) and pyridine (61 μl, 0.70 mmol) in EtOH (10 ml) was heated to reflux. After 2 h, the solution was evaporated under vacuum. The crude residue was triturated with Et2O/H2O 90/10 to give (E)-3-{1′-benzyl-4-methyloxyimino-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide (150 mg) as a 90/10 mixture of the two isomers (hydrochloride salts).
Reaction SMILES: [C:1]([CH:3]([NH:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[NH:17][C:18]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2].[H-].[Na+].Br[CH2:33][CH2:34][CH2:35][Cl:36]>CN(C=O)C>[C:1]([CH:3]([NH:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[NH:17][C:18]([C:20]1[N:21]([CH2:33][CH2:34][CH2:35][Cl:36])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2]
Reactant: ClCCCBr
Reactant: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2n1CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a stirred solution of 6-chloro-1H-indole-2-carboxylic acid [2-(1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide from Example 18 (0.428 g, 1.03 mmol) in DMF (3.5 ml) were added NaH (60% dispersion in mineral oil) (0.062 g, 1.54 mmol) at 0° C. The slurry was then stirred at room temperature for one hour followed by the addition of 1-bromo-3-chloropropane (0.13 ml, 1.34 mmol). Reaction was stirred overnight at room temperature and partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting oil was chromatographed on preparatory silica plates, eluting with 2.5% MeOH/dichloromethane, and yielding 6-chloro-1-(3-chloro-propyl)-1H-indole-2-carboxylic acid [2-(1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide (0.323 g, 64%). [M+H=492].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][NH:24][S:23]2(=[O:29])=[O:28])[CH2:17][CH2:16]1.[H-].[Na+].[CH:32](I)([CH3:34])[CH3:33]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][N:24]([CH:32]([CH3:34])[CH3:33])[S:23]2(=[O:28])=[O:29])[CH2:19][CH2:20]1
Reactant: CC(C)I
Reactant: COc1cc2ncnc(N3CCC(CN4CCCNS4(=O)=O)CC3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(CN4CCCN(C(C)C)S4(=O)=O)CC3)c2cc1OC
Reaction time: 0.75 h

Procedure:
A stirred solution of 1-(6,7-dimethoxyquinazolin-4-yl)-4-[(1,1-dioxotetrahydro-1,2,6-thiadiazin-2-yl)methyl]piperidine 1/2 CH3CH2OCOCH3 (0.7 g) (prepared as in Example 9) in dimethylformamide (4.0 cm3) was treated at room temperature with sodium hydride (100 mg. of a 50% dispersion in oil) and the mixture was stirred for 45 minutes. Isopropyl iodide (255 mg) was then added and the resulting mixture was stirred for 6 hours. The solvent was removed in vacuo and the residue was taken into chloroform (50 cm3) and water (25 cm3). The aqueous phase was extracted with chloroform (2×20 cm3) and the dried (MgSO4) extracts were evaporated to yield an oil which was chromatographed on silica (Merck 60.9385) eluting with chloroform to give a gum. Crystallisation from ethyl acetate afforded 1-(6,7-dimethoxyquinazolin-4-yl)-4-([1,1-dioxo-6-isopropyltetrahydro-1,2,6-thiadiazin-2-yl]methyl)piperidine, m.p. 158°-161° (460 mg).
Reaction SMILES: C([C:5]1[C:10]([NH2:11])=[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13]2)[CH:8]=[CH:7][N:6]=1)(C)(C)C.[NH2:26][C:27]1[C:28]([C:34](O)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1>>[NH2:26][C:27]1[C:28]([C:34]([NH:11][C:10]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[CH2:13]2)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)c1nccc(N2CCCC(O[Si](C)(C)C(C)(C)C)C2)c1N
Product: CC(C)(C)[Si](C)(C)OC1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, tert-butyl (+/−)-4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-amine was coupled to 3-amino-6-bromopicolinic acid yielding 3-amino-6-bromo-N-(4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-yl)picolinamide. LCMS (m/z): 506.2 (MH+); LC Rt=4.03 min.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2.[CH3:26]C(O)=O>C1COCC1.CCOCC>[CH3:26][O:16][C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([O:4][C:3]1[C:18]([Cl:25])=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:2]=1[Cl:1])=[CH:14]2)=[O:17]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid (94) (443 mg, 0.93 mmol) in dry THF (20 mL) was added CH2N2 in Et2O solution [Prepared from nitrosomethylurea (1.65 g) and 50% KOH (5 mL)]. This mixture was stirred at room temperature for 1 h. AcOH (1 mL) was added to the reaction mixture, which was then concentrated. Sat NaHCO3 was added to the residue, which was extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated to afford compound 95 (415 mg). 1H NMR (300 MHz, DMSO-d6) δ 3.89 (3H, s), 5.75 (2H, br s), 6.76 (2H, s), 7.73 (1H, d, J=2.9 Hz), 8.09 (2H, s), 8.67 (1H, s), 8.94 (1H, d, J=2.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:18][C@@H:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.BrC1C=C(C=CC=1C)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[C:20]1([C@H:19]([NH:26][C:5]([C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([Br:1])[CH:3]=2)=[O:7])[CH3:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(C(=O)Cl)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)N[C@H](C)c2ccccc2)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a solution of 3-bromo-4-methylbenzoic acid (5.0 g, 0.023 mol) in CH2CH2 (100 mL) was added oxalyl chloride (8.67 g, 0.069 mol). After 10 minutes, 1.0 mL of DMF was added slowly and the mixture was continued to stir at RT for 2 hours. The volatile was removed in vacuo. The residue was re-dissolved in CH2CH2 (100 mL) and transferred to a 125 mL additional funnel. To a 500 mL Erlenmeyer flask equipped with a stir bar was added 100 m]L of sat. aq. NaHCO3 solution followed by 2.79 g of (R)-α-methylbenzylamine (0.023 mol) in 100 mL of CH2CH2. 3-Bromo-4-methylbenzoyl chloride in CH2Cl2 (from above) was added dropwise to the Erlenmeyer flask and the reaction mixture was continued to stir at RT for 16 hours. The organic phase was diluted with 50 mL of CH2CH2, separated from aqueous phase, dried over Na2SO4 and concentrated in vacuo. The residue was washed with 50 mL of Et2O and dried in an oven at 40 C overnight to afford light yellow solid (7.0 g, 0.022 mol, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[N:3]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1
Reactant: COc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A solution of 4-chloro-6-fluoro-2-(2-methoxyphenyl)quinazoline (3.0 g, 10.39 mmol) in CH2Cl2 (15 mL) was cooled to −78° C. To it was added a 1.0 M BBr3 solution in CH2Cl2 (52 mL, 52 mmol) dropwise. The reaction was allowed to warm to room temperature. It was neutralized with a saturated aqueous NaHCO3 solution, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 5-20% CH2Cl2/hexanes gave 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (1.68 g, 60%). LC/MS: m/z 275.3 (M+H)+ at 3.39 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH2:11]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:11]([CH:19]1[CH2:20][CH2:21][N:22]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH2:23][CH2:24]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: c1ccc(CCC2CCNCC2)cc1
Product: Nc1ccc(N2CCC(CCc3ccccc3)CC2)nc1

Procedure:
Intermediate B-22 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 4-phenethylpiperidine as starting materials. MS (M+1): 312.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH2:14][CH2:13][S:12][C:11]1=[CH:16][N+:17]([O-:19])=[O:18])(=[O:9])=[O:8])=O>ClCCl.CO>[OH:3][CH2:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH2:14][CH2:13][S:12][C:11]1=[CH:16][N+:17]([O-:19])=[O:18])(=[O:8])=[O:9]
Reactant: O=COCCCS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)CCCO

Procedure:
2 g of 1 was elected through a column of 200 g of neutral alumina, using a 19:1 v:v mixture of dichloromethane and methanol as eluent. The fractions containing 2 were stripped of solvent under reduced pressure and the combined residue was triturated with ether, to give 2, as a solid, m.p.: 80°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][CH:6]1[NH:11][C:10](=O)[CH2:9][NH:8][C:7]1=O.COCCOC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][CH:6]1[CH2:7][NH:8][CH2:9][CH2:10][NH:11]1
Reactant: COc1cccc(CC2NC(=O)CNC2=O)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1cccc(CC2CNCCN2)c1OC
Temperature: 60 °C
Yield: 86.1 %

Procedure:
A suspension of 3-(2,3-dimethoxybenzyl)-2,5-piperazinedione (1.26 g) in a mixed solvent of tetrahydrofuran (50 ml) and 1,2-dimethoxyethane (50 ml) was heated at 60° C. with stirring and lithium aluminum hydride (0.905 g) was added thereto portionwise carefully. After the reaction mixture was heated at 70° C. with stirring for 3 hours, lithium aluminum hydride (0.20 g) and tetrahydrofuran (30 ml) were added thereto again and the suspension was stirred at the same temperature for 12 hours. After being cooled with ice-water, the mixture was quenched by sequential addition of water (1.3 ml), 15% aqueous sodium hydroxide (1.3 ml), water (3.8 ml) and the whole was stirred at room temperature for 2 hours. The resulting insoluble materials were removed by filtration and the filtrate was dried over sodium sulfate, and evaporated under reduced pressure to give light yellowish oil of 2-(2,3-dimethoxybenzyl)piperazine (0.97 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:16][C@@H:17]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[CH3:18]>>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[C@@H:17]([CH3:18])[CH2:16][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH3:1])[CH:9]=2)=[N:11]1
Reactant: C[C@@H](CBr)N1C(=O)c2ccccc2C1=O
Reactant: Cc1cc(-c2cc[nH]n2)ccc1C#N
Product: Cc1cc(-c2ccn(C[C@H](C)N3C(=O)c4ccccc4C3=O)n2)ccc1C#N
Yield: 25.4 %

Procedure:
2-Methyl-4-(1H-pyrazol-3-yl)benzonitrile (2.35 g, 12.2 mmol) was reacted with (S)-2-(1-bromopropan-2-yl)isoindoline-1,3-dione (3.61 g, 13.5 mmol) using the method of Example 27(a). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane) to yield 1.15 g (25%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.59 (d, 3H), 2.47 (s, 3H), 4.41 (m, 1H), 4.83 (m, 2H), 6.46 (d, 1H), 7.39 (m, 2H), 7.47 (m, 2H), 7.69 (m, 2H), 7.78 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH2:55]([O:57][C:58]([C:60]1[S:64][C:63]([NH2:65])=[N:62][CH:61]=1)=[O:59])[CH3:56]>C(Cl)Cl>[CH2:55]([O:57][C:58]([C:60]1[S:64][C:63]([NH:65][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:62][CH:61]=1)=[O:59])[CH3:56]
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Yield: 98 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (300 mg, 1.01 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (717 mg, 1.62 mmol), triethylamine (420 μL, 3.03 mmol), and 2-amino-thiazole-5-carboxylic acid ethyl ester: (279 mg, 1.62 mmol) in methylene chloride (10 mL) was stirred at 25° C. under nitrogen for 14 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 10/11 hexanes/ethyl ether) afforded 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester (448 mg, 98%) as a white solid: mp 100–103° C.; EI-HRMS m/e calcd for C21H26N2O5S2(M+) 450.1283, found 450.1285.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3](Cl)=[N:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:27]([O:29][CH:30]([O:33][CH2:34][CH3:35])[C:31]#[CH:32])[CH3:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C.[Cu]I.O>[CH2:27]([O:29][CH:30]([O:33][CH2:34][CH3:35])[C:31]#[C:32][C:3](=[N:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]([F:26])([F:25])[F:1])[CH3:28]
Reactant: FC(F)(F)C(Cl)=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CC(OCC)OCC
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: CCOC(C#CC(=NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F)OCC
Temperature: 60 °C

Procedure:
In a typical reaction, 2,2,2-trifluoro-N-(trityl)ethanimidoyl chloride and a slight excess of 3,3-diethoxyprop-1-yne are mixed with about 0.3 equivalents of copper (I) iodide and slight excesses of potassium phosphate and potassium iodide in anhydrous acetonitrile. The mixture is heated at about 60° C. under a nitrogen atmosphere until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude N-(5,5-diethoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-1,1,1-triphenylmethanamine.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:43])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18](C3CCCCO3)[N:17]=[C:16]4[C:28]3[NH:42][C:31]4[CH:32]=[N:33][CH:34]=[C:35]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[C:30]=4[N:29]=3)[CH:10]=[N:9][CH:8]=2)[CH2:3][CH2:2]1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:4][NH:5][C:6](=[O:43])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][N:17]=[C:16]4[C:28]3[NH:42][C:31]4[CH:32]=[N:33][CH:34]=[C:35]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[C:30]=4[N:29]=3)[CH:10]=[N:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(NCC1CC1)c1cncc(-c2ccc3c(c2)c(-c2nc4c(-c5cccnc5)cncc4[nH]2)nn3C2CCCCO2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CC1)c1cncc(-c2ccc3[nH]nc(-c4nc5c(-c6cccnc6)cncc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
A solution of N-(cyclopropylmethyl)-5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXII) (125 mg, 0.22 mmol) and Et3SiH (87 μL, 0.55 mmol) in DCM (5 mL) was slowly added TFA (2.5 mL). The reaction was stirred at r.t. for 3 h. The reaction was evaporated under vacuum and the residue was treated with water, basified with aq. ammonia. The solids were filtered, washed with cold water and dried. The crude product was heated in MeOH and filtered hot to remove impurities. The hot MeOH solution was allowed to slowly cool to r.t. to produce N-(cyclopropylmethyl)-5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)nicotinamide (3) as a off-white solid (48 mg, 0.10 mmol, 44% yield). 1H NMR (DMSO-d6) δ ppm 0.28 (d, J=4.28 Hz, 2H), 0.42-0.58 (m, 2H), 1.09 (br s, 1H), 3.25 (t, J=6.06 Hz, 2H), 7.50-7.70 (m, 1H), 7.79-8.11 (m, 2H), 8.48-8.68 (m, 1H), 8.69-8.82 (m, 1H), 8.81-8.97 (m, 3H), 9.00-9.18 (m, 2H), 9.46 (br s, 1H); ESIMS found C28H22N8O m/z 487 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[N:3]=1.II.[F:14][C:15]([F:34])([F:33])[CH2:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:23]=1)=O>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:22]2[CH:23]=[C:19]([C:17]3[N:11]=[C:9]([NH:8][C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)[S:10][C:16]=3[C:15]([F:34])([F:14])[F:33])[CH:20]=[N:21]2)=[CH:30][CH:29]=1
Reactant: Cc1ccnc(NC(N)=S)n1
Reactant: COc1ccc(Cn2cc(C(=O)CC(F)(F)F)cn2)cc1
Agent: II
Solvent: c1ccncc1
Product: COc1ccc(Cn2cc(-c3nc(Nc4nccc(C)n4)sc3C(F)(F)F)cn2)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
According to Scheme 9 Step 3: To a solution of 1-(4-methylpyrimidin-2-yl)thiourea (0.79 mmol, 133 mg) in pyridine (1 mL) was added iodine (0.79 mmol, 200 mg). The solution was stirred at 80° C. for 15 minutes and then 3,3,3-trifluoro-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)propan-1-one (0.79 mmol, 235 mg) was added. The reaction mixture was stirred for 2 hours at 80° C. The solvent was removed under reduced pressure. The crude mixture was partitioned between AcOEt and a saturated aqueous solution of Na2CO3. The aqueous layer was extracted with AcOEt. The combined organic layers were dried over MgSO4, were filtered and were evaporated under reduced pressure. The resulting crude product was purified by flash chromatography over silica gel using DCM/MeOH (99:1) to afford 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)-5-(trifluoromethyl)thiazol-2-amine (0.40 mmol, 180 mg, 51%).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][CH:14]([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:17]1(B(O)O)[CH2:19][CH2:18]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:17]1([C:2]2[C:3]([O:12][CH2:13][CH:14]([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:19][CH2:18]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cnc(OCC(F)F)c(Br)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(OCC(F)F)c(C2CC2)c1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A mixture of methyl 5-bromo-6-(2,2-difluoroethoxy)nicotinate (900 mg, 3.0 mmol, Step-2 of Amine-74), cyclopropylboronic acid (780 mg, 9.1 mmol), palladium(II) acetate (34 mg, 0.15 mmol), tricyclohexylphosphine (0.60 mL, 0.30 mmol, 0.5M in toluene) and potassium phosphate (1.6 g, 7.6 mmol) in toluene/water (10:1, 33 mL) is stirred at reflux temperature overnight. After cooled to room temperature, the mixture is filtered through a pad of celite, washed with ethyl acetate. The filtrate is extracted with ethyl acetate and dried over sodium sulfate. The organic solvent is removed under reduced pressure and then the residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (15:1) to give 630 mg (81% yield) of the title compound as a pale yellow solid.