Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: 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.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:49][C:50]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:51]=1[C:52]([NH:54][CH3:55])=[O:53].[Cl:61][C:62]1[CH:67]=[C:66](I)[C:65]([Cl:69])=[CH:64][N:63]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:61][C:62]1[CH:67]=[C:66]([NH:49][C:50]2[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:51]=2[C:52]([NH:54][CH3:55])=[O:53])[C:65]([Cl:69])=[CH:64][N:63]=1
Reactant: CNC(=O)c1c(N)cccc1F
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNC(=O)c1c(F)cccc1Nc1cc(Cl)ncc1Cl
Temperature: 80 °C
Yield: 26 %

Procedure:
A mixture of palladium(II) acetate (53.4 mg, 0.24 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (206 mg, 0.36 mmol), cesium carbonate (3875 mg, 11.89 mmol), 2-amino-6-fluoro-N-methylbenzamide (1000 mg, 5.95 mmol) and 2,5-dichloro-4-iodopyridine (1710 mg, 6.24 mmol) in dioxane (50 mL) under an atmosphere of nitrogen was heated at 80° C. for 18 hours. The mixture was allowed to cool to room temperature, filtered and then evaporated. The residue was dissolved in EtOAc (150 mL) and the mixture washed sequentially with a saturated solution of NaHCO3 (2×100 mL), water (100 mL) and then with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford 2-[(2,5-dichloropyridin-4-yl)amino]-6-fluoro-N-methylbenzamide (486 mg, 26% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.74 (3H, d), 6.96 (1H, d), 7.15 (1H, ddd), 7.37 (1H, d), 7.54 (1H, td), 8.26 (1H, s), 8.54 (1H, m), 9.09 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =314.26 and 316.21 and 318.23.
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=2[O:9][C:10]2[CH:11]=[N:12][N:13]([CH:17]([CH2:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:18]([OH:20])=O)[C:14](=[O:16])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[N:33]=1>>[CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=2[O:9][C:10]2[CH:11]=[N:12][N:13]([CH:17]([CH2:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:18]([NH:31][C:32]3[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:39])[CH3:41])[N:33]=3)=[O:20])[C:14](=[O:16])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C2CCCCC2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C3CCCCC3)cc2=O)n1
Yield: 62 %

Procedure:
Using the method described in Example 17, 2-[4-(2-cyclohexyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (Intermediate 35) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2-cyclohexyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.82 g, 62%); ES+-HRMS m/e calcd for C31H41N5O4 [M+H+] 548.3232 found 548.3233. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.17-1.84 (m, 18H), 1.94 (m, 1H), 2.27 (m, 1H), 2.61 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=4.1, J=10.7 Hz, 1H), 5.61 (d, J=2.7 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.15-7.24 (m, 1H), 7.27-7.38 (m, 2H), 7.47 (dd, J=3.6, J=5.7 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.18 (d, J=2.7 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:23]1[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=O>>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:23]1[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27](/[CH:28]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[O:3])[CH:30]=1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 70 %

Procedure:
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 5-(1H-indol-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-61A) in a similar manner as described in Ex-22. Red solid, 70% yield, mp 185–187° C. 1H-NMR (DMSO-d6) δ 11.15 (br, s, 1H), 8.33 (s, 1H), 8.24 (d, J=8 Hz, 2H), 8.07 (d, J=15 Hz, 1H), 7.98 (d, J=8 Hz, 2H), 7.80 (d, J=15 Hz, 1H), 7.41–7.55 (m, 4H), 7.03–7.08 (m, 1H), 6.93–6.99 (m, 2H), 6.83 (s, 1H), 4.04 (s, 3H), 3.99 (s, 3H). MS m/z=463 ([M+H]+). HRMS (ES+) Calcd. for C25H22N2O5S: 463.1327. Found: 463.1316.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[S:8][CH3:9])[C:4]([NH2:6])=[O:5])#[N:2].FC(F)(F)C(O)=O.[CH:19]1([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([NH:31][NH2:32])[CH:25]=2)[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>C(O)C>[NH2:2][C:1]1[N:31]([C:26]2[CH:25]=[C:24]([C:23](=[O:33])[NH:22][CH:19]3[CH2:21][CH2:20]3)[CH:29]=[CH:28][C:27]=2[CH3:30])[N:32]=[C:7]([S:8][CH3:9])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CSc1nn(-c2cc(C(=O)NC3CC3)ccc2C)c(N)c1C(N)=O
Temperature: 65 °C

Procedure:
To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylamide 12 (100 mg, 0.574 mmol) in ethanol (5 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.183 g, 0.574 mmol) and diisopropylethylamine (0.100 ml, 0.574 mmol). The mixture was heated to 65° C. for 18 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc was added to the residue and a solid precipitated. The solid was collected on a fitted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid amide 13. HPLC (4 minute 10-90 gradient) tR 1.98 min; MS m/z 439.08 [M+H]+; 1H NMR (DMSO-d6, 500 MHz) δ 8.47 (d, J=3.7, 1 H), 7.90 (d, J=7.9, 1 H), 7.78 (s, 1 H), 7.49 (d, J=8.0, 1 H), 6.81 (bs, 2 H), 6.30 (s, 2 H), 2.86 (m, 1 H), 2.45 (s, 3 H), 2.11 (s, 3 H), 0.68 (m, 2 H), 0.57 (m, 2 H) ppm.
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([CH:11]=1)[C:9]#[N:10]>O1CCOCC1.[Cu]I>[I:1][C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: [I-]
Reactant: N#Cc1cc(Br)ccc1C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc(I)ccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
In a microwave vial 2.24 g 5-bromo-2-(trifluoromethyl)benzonitrile are dissolved in 10 ml 1,4-dioxane. 90 mg copper-(I)-iodide and 2.7 g sodium iodide are added and the mixture is purged for 5 minutes with argon. 142 μl trans-N,N′-dimethylcyclohexane-1,2-diamine and 1.9 ml hexamethyldisilazane are added and the mixture is heated for 6 hours to 110° C. The mixture is diluted in 100 ml 4 M hydrochloric acid and stirred for 10 minutes. This aqueous phase is three times extracted with dichloromethane. The combined organic phases are washed with brine and dried with magnesium sulphate. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 85:15).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[CH2:11]([C:15]([CH3:17])=O)[CH:12]([CH3:14])[CH3:13]>S(=O)(=O)(O)O>[CH3:17][C:15](=[N:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1)[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: CC(=O)CC(C)C
Agent: O=S(=O)(O)O
Product: CC(CC(C)C)=Nc1cc(O)c(Cl)cc1F
Temperature: 100 °C
Yield: 98.2 %

Procedure:
A 50-ml four-neck flask equipped with a Vigreux column (2 cmφ×25 cm) and a dehydrating column attached thereon was charged with 5-amino-2-chloro-4-fluorophenol (1.62 g), methyl isobutyl ketone (32.4 g) and concentrated sulfuric acid (50 mg). The mixture was dehydrated under reflux at 100° C. under reduced pressure (constant at 500 mmHg) for 7 hours. The concentration under reduced pressure gave 2.4 g of 5-(1,3-dimethylbutylidenamino)-2-chloro-4-fluorophenol (yield, 98%). It was found that the mass spectrum and NMR spectrum of the compound thus obtained correspond to those of the compound obtained in Example 1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 1,3-dibenzyl-5-(4-methoxy-phenyl)-2-phenyl-1H-indole (1.162 g, 2.423 mmol) was reacted with BBr3 (2.9 ml of a 1M solution in CH2Cl2) to give the product (1.105 g, 2.373 mmol, 98%) as a brown oil. 1H NMR (DMSO-d6) δ 4.05 (s, 2H), 5.33 (s, 2H), 6.79 (d, J=8.6 Hz, 2H), 6.87 (d, J=7.5 Hz, 2H), 7.08-7.23 (m, 8H), 7.30 (d, J=8.4 Hz, 1H), 7.35-7.40 (m, 5H), 7.42-7.49 (m, 3H), 7.52 (s, 1H), 9.36 (s, 1H); [ESI(+)], m/z 466 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[N:14][CH:15]=[CH:16][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>>[C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[N:14][CH:15]=[CH:16][C:10]=3[N:9]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=NNc3ccncc3N2)cc1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)N1N=C(c2ccccc2)Nc2cnccc21
Yield: 78 %

Procedure:
3-Phenyl-1,4-dihydropyrido[3,4-e]-as-triazine is reacted with butyryl chloride as described in Example 2 to obtain 3-phenyl-1-butyryl-1,4-dihydropyrido[3,4-e]-as-triazine with a yield of 78%; m.p.: 225°-226° C.
Reaction SMILES: C([Li])CCC.[Si:6]([C:13]1[N:14]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH:15]=[CH:16][N:17]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)#[N:25].C([O-])(O)=O.[Na+]>C1COCC1>[Si:6]([C:13]1[N:14]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:15]([CH:30]([C:29]2[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[OH:31])=[CH:16][N:17]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(C(O)c2ccc(C#N)cc2)cnc1[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
12.5 ml (19.9 mmol) of a solution of n-butyllithium (1.6M solution in hexane) are added slowly to a solution of the compound obtained in Step B (4.67 g, 18 mmol) in 40 ml of anhydrous THF that has been brought to −78° C., and then the whole is maintained at that temperature for 1 hour 30 minutes. A solution of p-cyanobenzaldehyde in 20 ml of THF, 3.3 g (25.1 mmol) is then added. The whole is stirred at −78° C. for 0.5 hour, and then hydrolysed with an aqueous saturated NaHCO3 solution. When the reaction mixture is at room temperature, it is extracted with AcOEt and then washed with a saturated NaCl solution, dried over MgSO4 and concentrated to dryness.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[C:16]1([C:15]#[C:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: C(#CC1CCNCC1)c1ccccc1

Procedure:
4-Phenylethynyl-piperidine-1-carboxylic acid tert-butyl ester was treated with TFA for 10 minutes and concentrated, lyophilized to provide the title product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].F[B-](F)(F)F.[O:16]=[N+:17]=[O:18]>C(#N)C.O>[OH:1][C:2]1[C:9]([N+:17]([O-:18])=[O:16])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10]
Reactant: O=[N+]=O
Reactant: Cc1cc(C#N)ccc1O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1O
Reaction time: 1 h
Yield: 94 %

Procedure:
A stirred solution of 4-hydroxy-3-methylbenzonitrile (3.1 g, 23.3 mmol) in 60 mL of anhydrous acetonitrile was cooled to −30° C. and treated with nitronium tetrafluoroborate (3.4 g, 25.6 mmol) in portions. After 60 minutes, the reaction mixture was diluted with 100 mL of water. The resulting light yellow precipitate was filtered, washed with water, and dried to give 3.9 g of 4-hydroxy-3-methyl-5-nitrobenzonitrile (94% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[C:11]3[S:25][C:24]([Cl:26])=[CH:23][C:12]=3[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:14][CH2:15][C:9]2=[N:8][N:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[Cl:26][C:24]1[S:25][C:11]2[N:10]3[C:6]([CH2:4][OH:3])=[N:7][N:8]=[C:9]3[CH2:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:12]=2[CH:23]=1
Reactant: CCOC(=O)c1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 0.41 g of 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-carboxylic acid ethyl ester in 6.5 ml of absolute tetrahydrofuran is added dropwise with ice-cooling and stirring to a suspension of (0.078 g) of lithium aluminium hydride in 5 ml of absolute tetrahydrofuran. After stirring for 1 hour at 5° C., there is added dropwise 0.8 ml of 0.5-N sodium hydroxide. After filtration of the solid material, the solvent is evaporated and the residue taken up in methylene chloride. The solution is washed with 0.5-N sodium hydroxide, subsequently with water and, after drying, evaporated to dryness. By crystallization of the residue from ethyl acetate, there is obtained 2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine-9-methanol, melting point 219°-221° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:30])[NH:12][C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[C:14]=2[C:27]([NH2:29])=[O:28])[CH2:3][CH2:2]1.[H][H]>CO.[Pt]=O>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[C:14]([C:27]([NH2:29])=[O:28])=[C:13]([NH:12][C:11]([NH:10][CH2:9][CH2:8][CH2:7][N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:30])[S:17][N:16]=2)=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCOCC1
Agent: O=[Pt]
Solvent: CO
Product: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Reaction time: 16.5 h
Yield: 46.5 %

Procedure:
A mixture of 5-(3-(3-morpholinopropyl)ureido)-3-(4-nitrophenyl)isothiazole-4-carboxamide (110 mg, 0.25 mmol) and platinum oxide (25 mg, 0.11 mmol) in 15 mL MeOH was hydrogenated under 60 PSI hydrogen. After 16.5 hours, the mixture was filtered and rotary evaporated to an off-white solid. Then an additional 16 mg of impure product from another reaction was combined and this material chromatographed eluting with gradient 5% to 15% MeOH in CHCl3 to give the title compound as an off-white solid (47 mg, 40%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH:6]([C:29]1[CH:30]=[N:31][CH:32]=[N:33][CH:34]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=1)[CH3:2].C=O.[C:38](O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH:6]([C:29]1[CH:30]=[N:31][CH:32]=[N:33][CH:34]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH3:38])[N:14]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cncnc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CC(C=CCCCCc1cccc(N(C)Cc2ccc(OC)cc2)n1)c1cncnc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of 6-10 (1.6 g, 3.37 mmol) in methanol (30 mL) was added paraformaldehyde (0.80 g) and acetic acid (0.96 mL, 16.8 mmol). After stirring at 50° C. for 15 minutes, NaCNBH3 (0.275 g, 4.38 mmol) was added and the mixture stirred for an additional 30 minutes at 50° C. Evaporation of the solvents and purification on silica gel (5% MeOH/CHCl3) afforded 6-10 in 75% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[N:27][CH:28]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:22][C:23]1[CH:28]=[N:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: COc1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 87.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 18 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (20.0 g) and 5-amino-2-methoxypyridine (8.72 g), as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (23.9 g) was obtained.
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([CH:20]1[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(C3CCCN(C(=O)OC(C)(C)C)C3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(C3CCCNC3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)piperidine-1-carboxylate (620 mg) in DCM (15 mL) was added TFA (1.2 mL). The resulting solution was stirred at ambient temperature for 1 hr. The volatiles were removed to give the crude title compound that was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[CH:12]=[C:11]([CH2:30][CH2:31][O:32][CH3:33])[N:10]=1)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[C:5]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([NH:29][C:1](=[O:3])[CH3:2])[CH2:27][CH2:28]3)[CH2:17][CH2:16]2)[CH:12]=[C:11]([CH2:30][CH2:31][O:32][CH3:33])[N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(=O)Cl
Reactant: COCCc1cc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)nc(C(C)(C)C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1cc(N2CCN(CC[C@H]3CC[C@H](NC(C)=O)CC3)CC2)nc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of acetyl chloride (181 mg, 2.308 mmol), trans-4-(2-{4-[2-tert-Butyl-6-(2-methoxy-ethyl)-pyrimidin-4-yl]-piperazin-1-yl}-ethyl)-cyclohexylamine (690 mg, 1.539 mmol) and triethylamine (778 mg, 7.69 mmol) in DCM (15 ml) was stirred at room temperature for about 3 h. The solution was concentrated to dryness. The residue was transferred neat onto a 50×250 mm silica gel column and eluted with 5% MeOH/CH2Cl2. Fractions were collected and the solvent removed under reduced pressure to provide the title compound (468 mg, 1.040 mmol, 67.6% yield) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3]([O:5][CH3:6])=[O:4]>[Rh]>[C:3]([O:5][CH3:6])(=[O:4])[C:2]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH2:1]
Reactant: COC(=O)CC(C)C(=O)OC
Agent: [Rh]
Product: C=C(CC(=O)OC)C(=O)OC

Procedure:
The hydrogenation is carried out by a method similar to example G2 using the rhodium complex of example F5. The conversion is quantitative, and the optical yield ee of the hydrogenation product (dimethyl methylsuccinate) is greater than 98%.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:16][C@H:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][C@H:13]2/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:7][CH:6]=1)(=O)C.Cl.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:16][C@H:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH2:14][C@H:13]2/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(CN2C[C@H](NS(=O)(=O)c3ccc(Cl)cc3)C[C@H]2/C=C\CCCC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(CN2C[C@H](NS(=O)(=O)c3ccc(Cl)cc3)C[C@H]2/C=C\CCCC(=O)O)cc1
Yield: 51.7 %

Procedure:
A solution of (2S,4R)-1-[(4-acetylaminophenyl)methyl]-2-[(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)pyrrolidine (200 mg) in 6N-hydrochloric acid (5 ml) was refluxed for 4 hours. The mixture was cooled in an ice bath and adjusted to pH 7 with 1N-sodium hydroxide. The precipitated solid was collected by filtration to give (2S,4R)-1-[(4-aminophenyl)methyl]-2-[(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)pyrrolidine (95 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][C@H:40]1[CH2:48][OH:49]>CN(C=O)C>[OH:49][CH2:48][C@@H:40]1[CH2:41][C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:39]1[C:16]1[C:17]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:8][CH:9]=2)[N:15]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: OC[C@@H]1Cc2ccccc2N1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N4c5ccccc5C[C@H]4CO)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Yield: 26.2 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). (S)-indolin-2-ylmethanol (67.3 mg, 0.45 mmol) was added and the reaction mixture was heated at 85° C. overnight. The reaction was allowed to reach room temperature, the solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography using dichloromethane and methanol as eluent and gave (S)-tert-butyl 4-(2-(hydroxymethyl)indolin-1-yl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (65.3 mg, 26.2%). MS (ES+) m/z 554.4 (M+H)+