Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]([OH:36])[CH2:33][NH:34][CH3:35])[CH:29]=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]([OH:36])[CH2:33][N:34]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:22])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[CH:17]=2)[CH3:35])[CH:29]=[CH:30][CH:31]=1
Reactant: CNCC(O)c1cccc(N)c1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1cccc(N)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 57.8 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (80 mg, 0.21 mmol), 1-(3-aminophenyl)-2-(methylamino)ethanol (Zhur. Obshchei Khim. (J. Gen. Chem.) 1952, 22, 496-502)(53 mg, 0.32 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. and then diluted with 3 mL of water, left overnight) gave the title compound (62 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:23]([CH2:30][CH3:31])[CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]([CH3:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:20])[NH:13][C:14]([CH3:19])=[CH:15][C:16]=1[CH2:17][OH:18])=[O:8].CC1(C)C(C)(C)OB([C:40]2[CH:52]=[CH:51][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:30]([N:23]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:4]1[C:5]([CH3:22])=[C:6]([C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:20])[NH:13][C:14]([CH3:19])=[CH:15][C:16]=2[CH2:17][OH:18])=[O:8])[CH:21]=[C:2]([C:40]2[CH:41]=[CH:42][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:51][CH:52]=2)[CH:3]=1)[CH3:31]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(CO)cc(C)[nH]c2=O)c1C)C1CCOCC1
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
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(CO)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 20.4 %

Procedure:
To a stirred solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-(hydroxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (250 mg, 0.5 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (230 mg, 7.6 mmol) in dioxane (5 mL), aqueous 2M Na2CO3 solution (0.9 mL, 1.8 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (57 mg, 0.05 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (60 mg, 25%). LCMS: 589.35 (M+1)+; HPLC: 95.58% (@254 nm) (Rt; 3.524; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol; 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.: Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 8.22 (t, 1H), 7.57 (d, 2H, J=7.6 Hz), 7.38 (d, 2H, J=5.6 Hz), 7.36 (s, 1H), 7.21 (s, 1H), 6.16 (s, 1H), 5.28 (m, 1H), 4.52 (d, 2H, J=4.8 Hz), 4.25 (d, 2H, J=3.6 Hz), 3.81-3.83 (m, 2H), 3.57 (m, 4H), 3.48 (s, 2H), 3.01-3.09 (m, 3H), 2.36 (m, 4H), 2.23 (s, 3H), 2.15 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 1.23 (m, 2H), 0.82 (t, 3H, J=6.4 Hz).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:35][S-:36].[Na+]>C(O)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=3)[C:7]=2[CH2:6][S:36][CH3:35])=[O:24])[CH2:27][CH2:28]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CSC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (196 mg, 0.481 mmol) obtained in Example 126a), potassium carbonate (33.2 mg, 0.241 mmol, 0.5 eq.) and 15% aqueous sodium thiomethoxide solution (0.449 ml, 0.962 mmol, 2.0 eq.) were dissolved in ethanol (3.5 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (30 ml), washed twice with 2% aqueous sodium carbonate solution and with saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (160 mg, 0.445 mmol, 92.5%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[C:31][CH2:32][OH:33])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[C:31][CH2:32][O:33][S:44]([CH3:43])(=[O:46])=[O:45])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:18][CH2:19]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(C#CCO)cc34)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(C#CCOS(C)(=O)=O)cc34)CC2)cc1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
A solution of 4-[6-(3-hydroxy-prop-1-ynyl)-quinazolin-4-yl]-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide (816 mg, 1.84 mmol), as prepared in Example 12, and DIEA (350 μL, 2.12 mmol) in DCM (13 mL) was treated with methanesulfonyl chloride (157 μL, 2.02 mmol) dropwise over 1 min with stirring at 0° C. under positive argon pressure. The ice bath was immediately removed, and the reaction was stirred at rt for 1 h 15 min. Flash chromatographic purification of the crude reaction mixture (1:9 hex/EtOAc→EtOAc) afforded the title compound (896 mg, 93%). 1H-NMR (300 MHz, CDCl3) δ 9.27 (s, 1H), 8.31 (d, 1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.26 (m, 2H), 6.85 (m, 2H), 6.34 (br s, 1H), 5.15 (s, 2H), 4.49 (heptet, 1H), 4.33-4.23 (m, 2H), 3.73 (m, 1H), 3.25-3.11 (m, 2H), 3.18 (s, 3H), 2.22-1.94 (m, 4H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 522.2, found 523.3 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[C:17]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].FC(F)(F)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[C:17]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[C:6]([F:9])[C:7]=1[O:8][CH2:33][C:34]([F:37])([F:36])[F:35]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(O)c(F)c3)oc2c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC(F)(F)F)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(3,5-difluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and 2,2,2-trifluoroethyl trifluoromethanesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:9][C:10]1[NH:15][C:14](=[O:16])[NH:13][C:12](=[O:17])[C:11]=1[CH:18]([CH3:20])[CH3:19].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>O.CC(C)=O>[CH:18]([C:11]1[C:12](=[O:17])[NH:13][C:14](=[O:16])[NH:15][C:10]=1[O:9][C:8]1[CH:7]=[C:6]([CH:23]=[C:22]([CH3:24])[CH:21]=1)[CH:2]=[O:1])([CH3:20])[CH3:19]
Reactant: Cc1cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)cc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C=O)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A mixture of 6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-1H-pyrimidine-2,4-dione (1.33 g, 4 mmol), PPTS (201 mg, 0.8 mmol), and water (10 drops) in acetone (20 ml) was heated under reflux for 4 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, CHCl3: methanol (95:5)) to afford 1.03 g (89%) of a white solid. m.p. 241-242° C.; 1H NMR (200 MHz, CD3OD/CDCl3) δ 1.03 (6H, d, J=7.2 Hz), 2.34 (3H, s), 2.84 (1H, m), 6.99 (1H, s), 7.17 (1H, s), 7.38 (1H, s), 9.81 (1H, s).
Reaction SMILES: [N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[N:29]=[C:28]([CH3:30])[N:27](COCC[Si](C)(C)C)[C:24]5=[N:25][CH:26]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[N:29]=[C:28]([CH3:30])[NH:27][C:24]5=[N:25][CH:26]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2cc(-c3ccc4ncnc(N5CCCc6ccccc65)c4c3)cnc2n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(-c3ccc4ncnc(N5CCCc6ccccc65)c4c3)cnc2[nH]1
Yield: 21 %

Procedure:
0.19 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazoline and 200 μl of trifluoroacetic acid in 2 ml of dichloromethane are stirred at 25° C. in a flask until the reaction is complete (HPLC check, about 48 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of preparative HPLC (gradient water:acetonitrile 1-50% in 14 min.), giving 0.03 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-(2-methyl-3H-imidazo-[4,5-b]pyridin-6-yl)quinazoline (“A5”) as white solid (yield 23%, content 99%); MS-FAB (M+H+)=393.1; Rf (polar method): 1.41 min;
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:41][CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[O:27])=[CH:24][C:23]=4[F:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)cc(F)c1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Product: COc1cc(C(=O)NC2CCN(C)CC2)cc(F)c1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-5-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the General procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (m, 4H) 1.58 (d, J=14.4 Hz, 6H) 1.75 (m, 2H) 1.93 (m, 2H) 1.99 (s, 1H) 2.16 (s, 3H) 2.78 (d, J=10.6 Hz, 2H) 3.29 (s, 3H) 3.83 (s, 2H) 3.89-4.01 (t, J=12 Hz, 2H) 4.32 (m, 1H) 7.24-7.48 (m, 2H) 8.10 (s, 1H) 8.26 (d, J=7.6 Hz, 1H) 8.53 (s, 1H). [M+H] calc'd for C27H34F3N7O3, 562. found 562.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@H:15]2[CH3:20])[CH:11]=[C:10]([CH2:21][S:22][CH3:23])[N:9]=1.S(S([O-])=O)([O-])(=O)=[O:25].[Na+].[Na+]>O.CCOC(C)=O.CO>[Cl:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@H:15]2[CH3:20])[CH:11]=[C:10]([CH2:21][S@@:22]([CH3:23])=[O:25])[N:9]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CSCc1cc(N2CCOC[C@H]2C)nc(Cl)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C[C@@H]1COCCN1c1cc(C[S@@](C)=O)nc(Cl)n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 21.7 %

Procedure:
Sodium meta-periodate (64.7 g, 302.69 mmol) was added in one portion to (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (82.87 g, 302.69 mmol) in water (500 ml), EtOAc (1000 ml) and MeOH (500 ml). The resulting solution was stirred at 20° C. for 16 hours. Sodium metabisulfite (50 g) was added and the mixture stirred for 30 minutes. The reaction mixture was filtered and then partially evaporated to remove the MeOH. The organic layer was separated, dried over MgSO4, filtered and then evaporated. The aqueous layer was washed with DCM (3×500 ml). The organic layers were combined, dried over MgSO4, filtered and then evaporated. The residues were combined and dissolved in DCM (400 ml) and purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Fractions containing product were evaporated and the residue was dissolved in DCM (400 ml) and then divided into four 450 ml bottles. An aluminium foil cap was placed over the top of each bottle and a few holes made in each cap. The bottles were placed in pairs in a large dish containing Et2O (1000 ml), and then covered and sealed with a second glass dish and left for 11 days. The resultant white needles were collected by filtration and dried under vacuum. The crystals were dissolved in DCM (200 ml) and placed into a 450 ml bottle. An aluminium foil cap was placed over the top of the bottle and a few holes made in the cap. The bottle was placed in a large dish containing Et2O (1500 ml) and then covered and sealed with a second glass dish and left for 6 days. The resultant crystals were collected by filtration and dried under vacuum to afford (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (16.53 g, 19%); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 2.61 (3H, s), 3.29 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 3.99 (1H, dd), 4.02 (1H, s), 4.31 (1H, s), 6.41 (1H, s). Chiral HPLC: (HP1100 System 5, 20 μm Chiralpak AD-H (250 mm×4.6 mm) column eluting with Hexane/EtOH/TEA 50/50/0.1) Rf, 12.192 98.2%.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][O:42][CH:43]([CH3:45])[CH3:44])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][O:42][CH:43]([CH3:45])[CH3:44])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1
Reactant: CC(C)OCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CC(C)OCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 87.8 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 191 mg (0.287 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-isopropoxymethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 60-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 135 mg of the title compound was obtained as a white solid. (Yield: 88%)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[CH:17]([OH:19])=[O:18]
Reactant: COC(=O)c1cccc(-c2ccc3c(c2)[C@H](Nc2cccnc2)C[C@H](C)N3C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(-c3cccc(C(=O)O)c3)cc2[C@H](Nc2cccnc2)C[C@@H]1C
Product: O=CO
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 85 %

Procedure:
To a stirred solution of methyl 3-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (for a preparation see Example 175) (14.5 mg, 0.035 mmol) in methanol (1 mL) was added NaOH (2M in water, 0.5 mL, 1.000 mmol) and the resulting mixture was stirred at room temperature for 100 min then was concentrated under a stream of nitrogen. The residue was dissolved in water (0.2 mL) and methanol (0.8 mL) before being purified by MDAP (modifier: formic acid) to give 3-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid:formic acid 1:3 (14.3 mg, 85% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: OCCc1ccncc1F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccncc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
3-Fluoro-4-(2-hydroxyethyl)pyridine (4.0 g, 28.3 mmol) and triethylamine (8.3 mL, 60 mmol) were dissolved in CH2Cl2 (40 mL) and cooled to 0° C. To this solution, methanesulfonyl chloride (2.0 mL, 31.2 mmol) was added dropwise. The mixture stirred at 0° C. for 1 h. The mixture was diluted with water, and the layers separated. The water layer was extracted with CH2Cl2. The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum to provide 3-fluoro-4-(2-methanesulfonyloxyethyl)pyridine (5.2 g, 83%) as a pink oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(OC([Cl:19])=O)C.[NH2:20][CH:21]1[CH2:25][N:24]([CH:26]([CH3:28])[CH3:27])[N:23]([CH3:29])[CH2:22]1.Cl>>[ClH:11].[ClH:19].[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:20][CH:21]2[CH2:25][N:24]([CH:26]([CH3:28])[CH3:27])[N:23]([CH3:29])[CH2:22]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)N1CC(N)CN1C
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CN(C)N(C(C)C)C1

Procedure:
The title compound was prepared as described in Example 11 of U.S. Pat. No. 4,207,327 from 4-amino-5-chloro-2-methoxybenzoic acid, ethylchlorocarbonate and 4-amino-1-isopropyl-2-methylpyrazolidine and hydrogen chloride, m.p. 182°-186° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@:5]3([CH2:20][O:19]C(=O)[NH:17]3)[C:4]=2[CH:3]=1.[OH-].[K+]>CO.O1CCOCC1>[NH2:17][C@@:5]1([CH2:20][OH:19])[C:4]2[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][C:8]([I:16])=[CH:9][CH:10]=2
Reactant: O=C1N[C@@]2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@]1(CO)c2cc(Br)ccc2Oc2ccc(I)cc21
Reaction time: 24 h
Yield: 37 %

Procedure:
In a 350-mL resealable vessel, the (S)-2′-bromo-7′-iodospiro[oxazolidine-4,9′-xanthen]-2-one (11 g, 24.02 mmol) was dissolved in 1:1 MeOH-dioxane (160 mL). Aqueous KOH (5 M, 48.0 mL, 240 mmol) was added. The vessel was sealed and placed in a 105° C. oil bath. After 24 h, the reaction was concentrated to remove the MeOH and most of the dioxane. The residue was diluted with water (200 mL) and the aqueous phase was extracted with 5% MeOH-DCM (4×200 mL). The organics were combined, washed with dilute brine (35 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (1.5% MeOH/DCM) to afford (S)-(9-amino-2-bromo-7-iodo-9H-xanthen-9-yl)methanol (3.84 g, 8.89 mmol).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:20]C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[Cl:12][C:13]1[C:18]([Cl:19])=[C:17]([C:1](=[O:10])[C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:16]=[CH:15][C:14]=1[OH:20]
Reactant: COc1cccc(Cl)c1Cl
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccc(O)cc1)c1ccc(O)c(Cl)c1Cl
Temperature: 5 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
A mixture of 15.4 g of p-anisoyl chloride and 17.7 g of 2,3-dichloroanisole in 80 ml of dry benzene is cooled at 5° C. After adding 13.3 g of anhydrous aluminum chloride in portions at 5° to 10° C. over a period of five minutes, the cloudy greenish mixture is warmed up to room temperature and then stirred for 48 hours. It is then cooled at 15° C. and 25 ml more of dry benzene is added, followed by the addition of 26.6 g of anhydrous aluminum chloride in portions at 15° C. over a period of five minutes. After the addition is completed, the mixture is stirred at room temperature for 21/2 hours, heated to 45° C. for 90 minutes and to 75° C. to 80° C. for one hour. The reaction mixture is then treated with ice and concentrated hydrochloric acid. The organic phase is separated, and the solid residue is washed with boiling dichloroethane to yield 15 g (53% of theory) of crude 2,3-dichloro-4-(4-hydroxybenzoyl)phenol, melting at 208° to 210° C.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[NH:14][CH3:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(=O)NC)CC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(8-methoxy-3-methylcarbamoylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-ethyl-3-fluoro-benzamide was prepared from 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (52 mg, 25%). LCMS (m/e) 556 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 7.47 (s, 1H), 7.40-7.24 (m, 4H), 6.59 (s, 1H), 6.31-6.23 (m, 1H), 3.84 (s, 3H), 3.45-3.35 (m, 2H), 3.11 (s, 2H), 2.88 (d, 3H, J=4.8 Hz), 2.86-2.78 (m, 2H), 2.71-2.64 (m, 2H), 2.63-2.55 (m, 4H), 1.13 (t, 3H, J=7.3 Hz).