Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:28]([OH:30])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:27])[NH:8][S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10].C1CCC([N:47]=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C@H:2]([C:28]([NH2:47])=[O:30])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:27])[NH:8][S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)c(C)c2c1OC(C)(C)CC2
Solvent: CN(C)C=O
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(N)=O)c(C)c2c1OC(C)(C)CC2
Temperature: 0 °C
Reaction time: 5 h
Yield: 97.6 %

Procedure:
A] Z-Arg(Pmc)-OH (2.87 g, 5 mmoles) was dissolved in 15 ml of DMF, then added with 0.837 g (5.5 mmoles) of HOBT ammonium salt, and the reaction mixture was cooled to 0° C. After the addition of 1.135 g (5.5 mmoles) of DCC, the reaction mixture was brought to room temperature and kept under stirring for 300 minutes. After filtering dicyclohexylurea off, the solvent was evaporated under vacuum and the residue taken up in 25 ml of ethyl acetate and washed with an aqueous solution of 5% sodium hydrocarbonate, then with water till neutrality. The organic phase was anhydrified, the solvent evaporated under vacuum and the residue crystallized from ethyl ether/n-hexane. There were obtained 2.8 g of Z-Arg(Pmc)-NH2 [HPLC (gradient from 20 to 60% of B in A for 20 minutes): R.t. 15.7 min.; purity 98%].
Reaction SMILES: [CH3:1][C:2]1([CH2:13][OH:14])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:15][C:16]1[CH:17]=[N:18][C:19]([O:14][CH2:13][C:2]2([CH3:1])[O:6][C:5]3=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]3[CH2:3]2)=[N:20][CH:21]=1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(COc2ncc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
(2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)-methanol (0.10 g, 0.50 mmol), 5-bromo-2-chloropyrimidine (0.16 g, 0.82 mmol) and NaH (˜30 mg, 60% in mineral oil) were suspended in 2 mL DMF and stirred at r.t. for 2 hours. The resulting mixture was diluted with 150 mL EtOAc, washed with 100 mL NaHCO3 and 100 mL water. The aqueous layer was re-extracted with 100 mL EtOAc. The organic layer was washed with brine and dried over Na2SO4. The concentrated residue was purified by column chromatography (DCM/MeOH, 0 to 3%) to give the title compound (152 mg, 83%) as a white solid. APCI MS m/z 356.6, 358.6 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.77 (s, 2H), 8.14 (s, 1H), 4.61 (s, 2H), 4.41 (d, J=11.1 Hz, 1H), 4.20 (d, J=11.1 Hz, 1H), 1.70 (s, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH2:38][CH:37]=[C:36]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)[CH2:35][CH2:34]1>O1CCCC1.CN(C)C=O>[O:14]1[C:15]2[C:24]3[O:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:16]=2[O:25][CH2:26][CH:13]1[CH2:12][N:33]1[CH2:34][CH:35]=[C:36]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4c(c3O2)OCCC4)C1

Procedure:
To a mixture of (2R)-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-h]chromen-2-yl-methyl 4-methylbenzenesulfonate (0.30 g, 0.80 mmole) and potassium carbonate (0.22 g, 1.55 mmole) in 1:1 tetrahydrofuran/dimethylformamide (20 mL) was added 0.47 g (2.38 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H-indole. The reaction mixture was refluxed under nitrogen for 6 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure and the residue was column chromatographed on silica gel with methylene chloride to remove impurities and with 3% methanol/methylene chloride to elute the desired product as an as an oil, which was crystallized from isopropanol with the addition of a solution of oxalic acid in hot isopropanol to give 0.070 g (6%) of the (S)-enantiomer of the title compound as an orange solid, m.p. 140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[CH:14][O:15]C)[N:9]=[CH:8][CH:7]=[CH:6]2>Cl.O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH:14]=[O:15])[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COC=Cc1cc2ncccc2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2cccnc2cc1CC=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 110 %

Procedure:
1.41 g of 6-methoxy-7-(2-methoxyvinyl)quinoline was dissolved in 40 ml of 2 N hydrochloric acid-tetrahydrofuran (1:1), and the obtained mixture was then stirred at 70° C. for 2 hours. The reaction solution was cooled to a room temperature. It was diluted with ethyl acetate and then washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 1.45 g of (6-methoxyquinolin-7-yl)acetaldehyde containing triphenylphosphine oxide. This compound was used in the following reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11]CC)=O.[N:14]1([CH:20]([CH3:23])[CH2:21][NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([NH:22][CH2:21][CH:20]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:23])=[O:11]
Reactant: CC(CN)N1CCCCC1
Reactant: CCOC(=O)CN1C(=O)CCC1C
Product: CC(CNC(=O)CN1C(=O)CCC1C)N1CCCCC1

Procedure:
From 9.3 g. of ethyl 2-methyl-5-oxo-1-pyrrolidineacetate and 10.7 g. of 2-(1-piperidinyl)propylamine (J. Chem. Soc. 1947, 1511), following the procedure of Example 9, there is obtained (±)-2-methyl-5-oxo-N-[2-(1-piperidinyl)propyl]-1-pyrrolidineacetamide; m.p. 111°-112° C. after recrystallization from heptane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and aniline.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:13]=[C:12]([CH3:23])[CH:11]=1)(=O)C.[ClH:24]>CO>[ClH:24].[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:10]([NH:9][C:5]3[NH:6][CH2:7][CH2:8][N:4]=3)=[CH:11][C:12]([CH3:23])=[N:13]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2nc(C)cc2NC2=NCCN2C(C)=O)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-n2nc(C)cc2NC2=NCCN2)cc1

Procedure:
1-Acetyl-2[1-(4-methoxyphenyl)-3-methyl-5-pyrazolyl]amino-2-imidazoline (13.1 g.) was treated with HCl in methanol as described in Example II to give 7.9 g. of product as the HCl salt, mp 197°-198°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:23][C:20]([F:21])([F:22])[C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96 %

Procedure:
To a clear solution of 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in anhydrous dichloromethane (15 mL) was added TFA (8 mL) dropwise. The yellow solution was stirred at room temperature for 2.5 hour. Reaction was complete as determined by TLC. TFA was removed under reduced pressure. The residue was redissolved in dichloromethane (50 mL), and washed with sat. K2CO3 solution first, then washed with brine and dried over Na2SO4, filtered and concentrated down to give 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine as a light yellow oil (1.19 g, 96.0% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccccc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.068 mMol) benzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 346(M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[N:6]=[C:5]2[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[N:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1
Reactant: CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccc(Br)cc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2n[nH]c3ccc(Br)cc23)CC1
Reaction time: 6 h

Procedure:
To a stirred solution, under N2, 5-bromo-3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole (4.4 g, 0.01 mol) of Example 4c in THF (70 ml), was added, dropwise, lithium aluminum hydride [20 ml of a 1M solution in tetrahydrofuran (THF)]. The reaction was then stirred for 6 hours at reflux. The reaction was cooled in an ice bath, water was added cautiously and then the reaction was filtered. The filter cake was washed with THF and then methanol, and the filtrate was concentrated to yield 5-bromo-3-(4-methyl-1-piperazinyl)-1H-indazole.
Reaction SMILES: C([NH:8][C@@H:9]([C:13](O)=O)[C@@H:10]([CH3:12])[OH:11])(OC(C)(C)C)=O.[CH3:16][CH:17]([C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1)[CH3:18]>>[NH2:8][C@@H:9]([C:13]1[NH:25][C:22]2[CH:23]=[CH:24][C:19]([CH:17]([CH3:18])[CH3:16])=[CH:20][C:21]=2[N:26]=1)[C@H:10]([OH:11])[CH3:12]
Reactant: CC(C)c1ccc(N)c(N)c1
Reactant: C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)c1ccc2[nH]c([C@H](N)[C@@H](C)O)nc2c1

Procedure:
The title compound was prepared according to Method 4 using N-Boc-D-allo-threonine (Preparation 55) and 4-(1-methylethyl)-1,2-benzenediamine. The residue was purified using preparative HPLC using the following conditions:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13].[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.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>[CH3:25][N:9]1[C:8](=[O:26])[C:7]([C:6]2[CH:5]=[CH:4][S:3][C:2]=2[C:32]2[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)=[C:12]([CH3:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:10]1=[O:24]
Reactant: Cc1c(-c2ccsc2Br)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(B(O)O)cc1
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: O
Solvent: C1CCOC1
Product: Cc1c(-c2ccsc2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 91.9 %

Procedure:
To a solution of 5-(2-bromothiophen-3-yl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 200) (17.0 mg), 4-cyanophenylboronic acid (11.2 mg) and sodium carbonate (20.2 mg) in tetrahydrofuran (1.0 ml)/water (0.2 ml) was added tetrakis(triphenylphosphine)palladium (4.4 mg) and the resulting mixture was stirred with heating under reflux for twelve hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[3-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]thiophen-2-yl]benzonitrile (16.4 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:27]([CH:24]([CH3:26])[CH3:25])[C:28]2=[O:29])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: CC(C)N=C=O
Product: COc1cccc2c1ncc1c(=O)n(C(C)C)c(=O)n(C3CCCC3)c12
Yield: 53.8 %

Procedure:
1-Cyclopentyl-3-isopropyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and isopropyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 354 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 7.78 (d, 1H), 7.57 (t, 1H), 7.24 (d, 1H), 5.21 (p, 1H), 4.93 (m, 1H), 4.14 (s, 3H), 3.83 (m, 2H), 2.38 (m, 2H), 2.08 (m, 4H), and 1.15 (d, 6H) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.FC(F)(F)S(O[C:15]1[C:16]2[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[CH:24][CH:23]=2)[N:20]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:15]2[C:16]3[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:32][CH:31]=[N:30][CH:29]=4)=[CH:26][CH:27]=3)[N:20]=2)[CH2:2]1
Reactant: OCC1CCCNC1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N3CCCC(CO)C3)c2C1
Yield: 34.6 %

Procedure:
1-(4-(3-(hydroxymethyl)piperidin-1-yl)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (25.7 mg, 34.6%) was prepared from piperidin-3-ylmethanol and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (example 88a) according to the general procedure for amine substitution of tosylate on pyrimidines.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][N:28]4[C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCCCN3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCCCC1c1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Reaction time: 16 h
Yield: 9.8 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.22 mmol), N,N-dimethylglycine (27 mg, 0.26 mmol), EDCl (46 mg, 0.24 mmol), HOBt (32 mg, 0.24 mmol), and N,N-diisopropylethylamine (114 μL, 0.65 mmol) in DMF (1.5 mL) was stirred at it for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 11 mg (10%) of the desired product. NMR (400 MHz, CD3OD) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.80 (d, 1 H), 7.55-7.68 (m, 1 H), 7.25-7.42 (m, 5 H), 7.16 (s, 1 H), 6.08 (d, 1 H), 5.65 (s, 2 H), 3.59-4.46 (m, 2 H), 2.99-3.26 (m, 1 H), 2.63-2.85 (m, 1 H), 2.25-2.42 (m, 1 H), 1.97 (s, 6 H), 1.54-1.82 (m, 3 H), 1.29-1.53 (m, 1 H), 1.22 (s, 2 H); ES-MS m/z 509.26 [M+H]+, HPLC RT (min) 2.16.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[NH2:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:13][CH2:14][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11]2)[CH:3]=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cccc(Cl)n1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)n2)CC1
Temperature: 140 °C
Yield: 27.6 %

Procedure:
A mixture of 6-chloropyridin-2-amine (10 g, 78 mmol) and tert-butyl piperazine-1-carboxylate (29 g, 156 mmol) was refluxed at 140° C. for 3 days. The reaction mixture was purified by silica gel column chromatography (elute: petroleum ether/ethyl acetate=2:1) to give tert-butyl 4-(6-aminopyridin-2-yl)piperazine-1-carboxylate (6 g, 28%). LCMS (M+H) m/z: calcd 278.17. found 279.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:50])[CH2:43][CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:50])[CH2:43][CH:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CN(CC1CCOCC1)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CC2CCOCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 59.3 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-ylmethyl)acetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.9 mg) was obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([O:38][CH2:39][C:40]([NH:42][CH3:43])=[O:41])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([O:38][CH2:39][C:40]([NH:42][CH3:43])=[O:41])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CNC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To 2 mL of a chloroform solution containing 87 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-((methylamino)carbonylmethyloxy)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 49 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)-N-methylacetamide as a pale yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(Br)cc1
Yield: 27.9 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and cyclopropylamine (0.27 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclopropylbenzenesulfonamide (0.12 g) was provided after purification. MS (ESI) m/z 276. HPLC purity 100.0% at 210-370 nm, 8.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][C:11]2=[O:16].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[N:17]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][NH:10][C:11]3=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: O=C1NCCc2c(OCCCCl)cccc21
Solvent: CCO
Product: O=C1NCCc2c(OCCCN3CCCCC3)cccc21
Yield: 61 %

Procedure:
A mixture of 0.6 g (2.5 mmol) of 5-(3-chloropropoxy)-3,4-dihydro-1(2H)-isoquinolinone and 0.6 ml (10 mmol) of piperidine in 30 ml of ethanol was refluxed for 40 hours. The mixture was concentrated, dissolved in chloroform and washed with saturated sodium bicarbonate. The organic layer was dried and concentrated. The solid was recrystallized from water to provide 0.44 g (61%) of the desired product; mp 112°-114°.
Reaction SMILES: [C:1](C1C=C(C)C=C(C)N=1)(=O)C.[Br:12][CH2:13][C:14]([C:16]1[CH:21]=[C:20]([CH2:22]C)[CH:19]=[CH:18][N:17]=1)=[O:15]>>[Br:12][CH2:13][C:14]([C:16]1[C:21]([CH3:1])=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1)=[O:15]
Reactant: CC(=O)c1cc(C)cc(C)n1
Reactant: CCc1ccnc(C(=O)CBr)c1
Product: Cc1ccnc(C(=O)CBr)c1C

Procedure:
* 2-Bromoacetyl-3,4-dimethylpyridine was prepared from 2-acetyl-4,6-dimethylpyridine (Sundberg et al., J. Am. Chem. Soc., 1969, 91, 658) according to the procedure for preparing 2-bromoacetyl-4-ethylpyridine described in Example 57.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccc2ncnc(O)c2c1
Product: COCCOc1ccc2ncnc(Cl)c2c1
Yield: 71 %

Procedure:
4-hydroxy-6-(2-methoxyethoxy)quinazoline (870 mg, 3.9 mmol) was reacted with POCl3 as described in Example 4A Step 2 to give 4-chloro-6-(2-methoxyethoxy)quinazoline (662 mg, 2.8 mmol, 71%). LC-MS (ESI) m/z 239 (M+H)+.