Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].[OH-].[Na+]>C(O)(=O)C>[O:11]1[C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)NCc1ccc2c(c1)OCO2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of 3,4-methylenedioxybenzylamine (10 g, 66.2 mmol) in acetic acid (50 mL) was added acetic anhydride (15.27 g, 150 mmol). The mixture was stirred at 20° C. for 30 minutes. Then it was adjusted to PH7 with 10% NaOH. The mixture was filtered to obtain a solid which was washed water and dried in vacuum to give N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamide as a white solid (9.24 g, 77%). LC-MS: 194 [M+1]+; 1H-NMR (DMSO-d6): δ 1.84 (s, 3H), 4.12 (d, 2H, J=6.4 Hz), 5.98 (s, 2H), 6.71 (m, 2H), 6.83 (m, 2H), 8.28 (s, 1H).
Reaction SMILES: [P:1]([CH2:5][C:6]1[CH:11]=[CH:10][N:9]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=[C:8]2[N:7]=1)([OH:4])([OH:3])=[O:2].Cl>[Pd].O>[P:1]([CH2:5][CH:6]1[CH2:11][CH2:10][N:9]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=[C:8]2[NH:7]1)([OH:3])([OH:4])=[O:2]
Reactant: O=C(O)c1cn2ccc(CP(=O)(O)O)nc2n1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: O=C(O)c1cn2c(n1)NC(CP(=O)(O)O)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-phosphonomethyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid 20 (8 mg) was introduced in a Parr bottle with 0.5N HCl (2 mL), water (10 mL) and Pd on Carbon (5%, 10 mg). The bottle was evacuated, filled with hydrogen (55 psi) and shaken for 1.5 hours at room temperature. The reduction mixture was then poured onto a strongly basic ion-exchange column (OH--, Amberlite). The product was eluted with IN HCl.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:21][O:22][C:23]1[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>ClCCl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH3:21])=[O:13]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: COc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1OC
Yield: 21.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and o-anisidine (1.42 g, 11.5 mmol) in 10 mL of pyridine. The crude product was recrystallized from ethanol-ethyl acetate, then again from acetonitrile-DMF to yield 0.634 g of the title compound, mp 154°-155° C.
Reaction SMILES: Br[C:2]1([C:31]2[CH:36]=[CH:35][C:34]([CH:37]=[CH2:38])=[CH:33][CH:32]=2)[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Li+].[AlH4-].Cl>CCOCC>[C:7]1([C:6]2[CH:2]([C:31]3[CH:36]=[CH:35][C:34]([CH:37]=[CH2:38])=[CH:33][CH:32]=3)[C:3]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:4]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=Cc1ccc(C2(Br)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1
Agent: Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: CCOCC
Product: C=Cc1ccc(C2C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A suspension of 55.1 g (0.1 mol) of 5-bromo-1,2,3,4-tetraphenyl-5-p-vinylphenylcyclopenta-1,3-diene in 300 ml of ether was added in portions to a suspension of 11.5 g (0.3 mol) of Li[AlH4] in 150 ml of ether with stirring. The slightly yellow-brown suspension formed was refluxed for 2 hours to complete the reduction. After cooling to room temperature, excess Li[AlH4] was hydrolyzed first with ice water (caution: vigorous H2 evolution) and then with dilute hydrochloric acid. All volatile organic components were then distilled off from the reaction mixture using a rotary evaporator. The slightly yellow crude product was filtered off with suction and washed several times with water. For further purification, it was dried azeotropically with toluene, filtered and recrystallized (yield: 39.65 g (84%); found: C, 94.09%, H, 5.81%. calculated: C, 94.03%, H, 5.97%).
Reaction SMILES: [CH2:1]1[N:13]([C:14]2[CH:31]=[CH:30][C:17]([C:18](=[O:29])[NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[CH:16][CH:15]=2)[CH2:12][CH:11]2[N:2]1[C:3]1[C:4](=[O:33])[NH:5][C:6]([NH2:32])=[N:7][C:8]=1[NH:9][CH2:10]2.C1NC2NC(N)=NC(=O)C=2N2[C@H]1CN(C1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)C2.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C1COCC1.C=O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.Cl>O>[CH2:10]1[NH:9][C:8]2[NH:7][C:6]([NH2:32])=[N:5][C:4](=[O:33])[C:3]=2[N+:2]2[C@H:11]1[CH2:12][N:13]([C:14]1[CH:31]=[CH:30][C:17]([C:18]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:29])=[CH:16][CH:15]=1)[CH:1]=2
Reactant: Nc1nc2c(c(=O)[nH]1)N1CN(c3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc3)CC1CN2
Agent: C=O
Agent: Cl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(=O)c2c([nH]1)NC[C@@H]1CN(c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)[O-])cc3)C=[N+]21
Reaction time: 0.03 h

Procedure:
5,10-Methylenetetrahydrofolate-dehydrogenase catalyzes the reaction, 5,10-methylene-THF+NADP+ →5,10-methenyl-THF+NADPH+H+. A 0.95 mL solution containing 1 μmole THF, 10 μmoles formaldehyde (fresh), 0.6 μmoles NADP and 25 μmoles n-[2-hydroxyethyl]piperazine-N'-[ethanesulfonic acid] was pre-incubated for 2 min at 30° C. Enzyme in the extraction buffer (50 μL) was then added. After the incubation continued for 15 min at 30° C., 2 mL 1 N HCl was added to stop the reaction. After 15 min at room temperature, the absorbency was measured at 355 nm. A blank containing water was used. The 5,10-methenyl-THF formed was determined using an extinction coefficient of 24,900 M-1 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][CH:11]([C:13](=[O:36])[NH:14][C:15]1[N:16]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:17]=[C:18]([C:20]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH3:40]C([O-])=O.[Na+].[BH3-]C#N.[Na+]>CO>[CH2:1]([O:8][C:9](=[O:37])[NH:10][CH:11]([C:13](=[O:36])[NH:14][C:15]1[N:16]([C:32]([CH3:33])([CH3:35])[CH3:34])[N:17]=[C:18]([C:20]2([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:25][CH2:24][N:23]([CH3:40])[CH2:22][CH2:21]2)[CH:19]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCNCC2)nn1C(C)(C)C
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C)CC2)nn1C(C)(C)C
Reaction time: 16 h

Procedure:
A solution of 0.67 g (1.3 mmol) of {1-[2-tert-butyl-5-(4-phenylpiperidin-4-yl)-2H-pyrazol-3-ylcarbamoyl]ethyl}carbamic acid benzyl ester, 0.33 mL (4.0 mmol) of 37% aq. formaldehyde, 0.33 g (4.0 mmol) of NaOAc and 0.27 g (4.3 mmol) of NaCNBH3 in 10 mL of MeOH was stirred at rt. After 16 h, the reaction mixture was concentrated and extracted with water and EtOAc. The organic layer was dried over MgSO4, and concentrated. Purification on silica gel using 4% Et3N-MeOH as eluant afforded {1-[2-tert-butyl-5-(1-methyl-4-phenylpiperidin-4-yl)-2H-pyrazol-3-ylcarbamoyl]ethyl}carbamic acid benzyl ester.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[C:9]2[CH2:27][N:28]([S:32]([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=3)(=[O:34])=[O:33])[C:29]([CH3:31])([CH3:30])[C:8]2=[N:7]1)=O)C>CO.C(N(CC)CC)C>[F:41][C:39]1[CH:40]=[C:35]([S:32]([N:28]2[CH2:27][C:9]3[C:10]([NH:11][C:12](=[O:26])[C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]5)=[CH:15][CH:14]=4)=[N:6][NH:7][C:8]=3[C:29]2([CH3:31])[CH3:30])(=[O:33])=[O:34])[CH:36]=[C:37]([F:42])[CH:38]=1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cc(F)cc(F)c3)C4(C)C)cc2)CC1
Temperature: 60 °C
Yield: 75.4 %

Procedure:
A mixture of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (1.6 g, 3 mmol) in MeOH (60 mL) and triethylamine (5 mL) was heated at 60° C. for 2 hours. The reaction mixture was then evaporated to dryness and the crude residue crystallized from ethyl acetate, filtered, washed with diethyl ether and dried under vacuum affording the title compound as white solid (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:23]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl-].C[NH3+].[C:28]([BH3-])#[N:29].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][NH:29][CH3:28])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Agent: C[NH3+]
Agent: [Cl-]
Agent: [Na+]
Product: CNCc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Yield: 71.9 %

Procedure:
Using 5-(4-fluorophenyl)-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde (0.52 g), methylammonium chloride (1.20 g) and sodium cyanoborohydride (0.28 g), a procedure as in Example 6 was performed to give the title compound as a colorless oil (yield 0.39 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1
Reactant: NCc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc2c1

Procedure:
Prepared according to Procedure H using (2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)methanamine (0.080 g, 0.279 mmol), 6-chloropurine (0.065 g, 0.42 mmol, 1.5 eq) and DIEA (0.56 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=225 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.49 (s, 1H), 8.14 (s, 1H), 8.03-8.10 (m, 2H), 7.66-7.73 (m, 2H), 7.47-7.56 (m, 2H), 7.43-7.44 (m, 1H), 7.33-7.40 (m, 1H), 4.10-4.18 (m, 2H), Mass Spectrum (ESI) m/e=405 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[O:10][CH:11]=1)(=O)=O.C([O-])(=O)C.[Na+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:45]1[N:50]=[CH:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[O:10][CH:11]=[C:7]([C:45]3[N:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[N:8]=2)=[CH:13][CH:14]=1
Reactant: Brc1ncccn1
Reactant: O=S(=O)(Oc1coc(-c2ccc(F)cc2)n1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(-c2nc(-c3ncccn3)co2)cc1

Procedure:
A stirred solution of 2-(4-fluorophenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate (3.8 g, 12.21 mmol), Fe(dppf)2 (0.338 g, 0.611 mmol), Pd(dppf)Cl2 (0.447 g, 0.611 mmol), sodium acetate and bis(pinacolato)diboron (4.03 g, 15.87 mmol) in 50 ml of dioxane was heated at 100° C. for 3 h. Then 2-bromopyrimidine (2.91 g, 18.32 mmol), Pd(PPh3)2Cl2 (0.857 g, 1.221 mmol) and sodium carbonate (12.2 ml, 2 M, 2.42 mmol) were added. The resultant mixture was then heated at 95° C. overnight, diluted with H2O and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated. The resulting residue was purified by flash chromatography (silica gel column, EtOAc/hexane) to give the title compound. LC-MS m/z 241.11 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])C.[OH-].[Na+]>>[C:40]([CH2:39][CH2:38][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:45])=[O:3])([OH:42])=[O:41]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc(F)cc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)cc2)c1
Yield: 99.3 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-ethoxy-4′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (150 mg, 0.24 mmol) and 1.0 N aqueous sodium hydroxide (2.4 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-ethoxy-4′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (135 mg, 99%) as a light brown waxy solid: ES(+)-HRMS m/e calcd for C33H39FO7 (M+Na)+ 589.2572. found 589.2573.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1.Cl.O1CCOCC1>CC(O)C>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cc(C)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1cc(C)ccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Temperature: 130 °C
Yield: 59.1 %

Procedure:
3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (76 mg, 0.34 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-5,N-dimethyl-benzamide (120 mg, 0.38 mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (95 μL, 0.38 mmol, 1.1 eq) was added and the reaction was heated at 130° C. in a microwave for 20 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5,N-dimethyl-benzamide as a yellow solid (99.4 mg, 59%). m.p.=210-212° C.; LCMS (m/e) 495 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.87 (s, 1H), 8.51 (d, 1H, J=8.5 Hz), 8.05 (d, 1H, J=1.0 Hz), 7.35 (s, 1H), 7.30-7.15 (m, 3H), 7.01 (d, 1H, J=8.1 Hz), 6.86 (s, 1H), 6.23-6.10 (m, 1H), 3.54 (t, 2H, J=5.4 Hz), 3.37 (s, 3H), 3.02 (d, 3H, J=5.0 Hz), 2.96-2.84 (m, 5H), 2.80-2.66 (m, 6H), 2.36 (s, 3H).
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]#[N:17])[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([OH:31])=[O:30].Cl>[Cl-].C[N+](C)(C)C.CC(C)=O.O>[N:1]1([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:28][C:29]([OH:31])=[O:30])=[C:11]([C:16]#[N:17])[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCl
Reactant: N#Cc1cc(C(=O)NN2CCOCC2)ccc1O
Agent: C[N+](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cc(C(=O)NN2CCOCC2)ccc1OCC(=O)O
Temperature: 30 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
3-Cyano-4-hydroxybenzoic acid (4-morpholinyl)amide (10 g, 43.1 mmol), sodium iodide (3.2 g, 21.3 mmol), potassium carbonate (17.9 g, 129 mmol) and tetramethylammonium chloride (0.47 g, 4.29 mmol) are suspended in acetone (125 mL) and water (15 mL), and the mixture is refluxed for 1 hour. After cooling to 30° C., chloroacetic acid (8.1 g, 86.2 mmol) is added. The mixture is refluxed for 5 hours, cooled to 30° C., and thereto are added potassium carbonate (11.9 g, 86.2 mmol) and chloroacetic acid (8.1 g, 86.2 mmol) successively. The mixture is refluxed for 3 hours, cooled to 30° C., and thereto are added potassium carbonate (11.9 g, 86.2 mmol) and chloroacetic acid (8.1 g, 86.2 mmol) successively. The mixture is refluxed for 3 hours, and thereto is added water (140 mL, 14 V), followed by addition of conc. hydrochloric acid (35 mL, 0.40 mol) at 40° C. or below. The mixture is stirred at 20° C. for one hour. The precipitated crystals are collected by filtration, and dried with a conical dryer to give 3-cyano-4-carboxymethoxybenzoic acid (4-morpholinyl)amide (11.6 g, 93.0%, content: 96.6%). Mp: 205-206° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36](Br)(Br)([Br:38])[Br:37]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=[C:36]([Br:38])[Br:37])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C=C(Br)Br)COC1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
To a stirred, cooled (0° C.) solution of (R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (4.30 g; CAS 95715-87-0 and triphenylphosphine (9.15 g) in dichloromethane (100 ml) was added portionwise carbon tetrabromide (6.94 g). The mixture was stirred at 0° C. for 20 min and then at r.t. for 2 h. The mixture was concentrated in vacuo to ca 20 ml, then diluted with hexane (100 ml) and concentrated in vacuo to half-volume. The residue was stirred at 0° C. for 15 min, then the mixture was filtered and the filtrate was concentrated in vacuo to afford (S)-4-(2,2-dibromo-vinyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (6.18 g, 92%) as a colourless oil. MS (EI): 330.9 ([{81Br}M—C4H8]+), 328.9 ([{81 Br79 Br}M—C4H8]+), 326.9 ([{79 Br}M—C4H8]+).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([OH:8])=[O:7])[CH:2]=[CH2:3].C1(C)C=CC=CC=1.[CH2:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([O:4][CH2:5][C:6]([O:8][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=[CH2:16])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCCCCCCCCO
Reactant: C=CCOCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCCCCCCCCOC(=O)COCC=C
Yield: 56.6 %

Procedure:
2.5 g of crude 2-allyloxyacetic acid are introduced into 40 ml of toluene, and 4.7 g (30 mmol) of 9-decen-1-ol and 0.38 g (2.0 mmol) of p-toluenesulfonic acid are added. The mixture is then heated with a water separator until visible amounts of water no longer separate out. The mixture is then cooled, and the organic phase is washed once with saturated NaHCO3 solution, dried over Na2SO4 and filtered, and the product is freed from the solvent. Flash chromatography (cyclohexane/EtOAc=20:1, Rf=0.29) gives 3.1 g (62%) of dec-9-enyl 2-allyloxy-acetate as a colorless oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28]O)[C:21](=[O:27])[NH:22]2>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=1)[C:21](=[O:27])[NH:22]2
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Reactant: O=C1Nc2cccc(F)c2C1=CO
Product: O=C1Nc2cccc(F)c2C1=CNc1ccc(OCCN2CCCCC2)cc1
Yield: 62.6 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (600 mg, 1.2 equiv.) and 4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (407 mg, 2.27 mmol, 1 equiv.) (4-Fluorooxindole may be prepared as described in Synthesis 1991, 10, 871) are reacted to give the named compound as a yellow solid (542 mg, 63%).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:19][O:20][C:21](=[O:24])[CH:22]=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[CH3:19][O:20][C:21](=[O:24])[CH:22]=[CH:23][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:12])=[CH:5][C:6]=1[CH3:11]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(CO)cc1C
Temperature: 0 °C

Procedure:
A mixture of methyl-4-bromo-3-methylbenzoate (5.7 g, 24.88 mmol), lithium aluminum hydride (29 mL, 29 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (100 mL) is stirred in ice/water for 1 hr. The reaction is quenched with aqueous hydrochloric acid (50 mL, 1 M). The product is extracted into ethyl acetate (3×100 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product is taken up in propionitrile (100 mL). Methylacrylate (10 mL, 121.5 mmol), palladium acetate (1.12 g, 5 mmol), tri-o-tolylphosphine (3.0 g, 10 mmol), and N,N-diisopropyl ethylamine (8.7 mL, 50 mmol) are sequentially added and the resulting reaction mixture is heated to 110 deg C. 3 hr. The mixture is concentrated, and the residue diluted with aqueous hydrochloric acid (100 mL, 1M). The product is extracted with dichloromethane (2×100 mL) and ethyl acetate (100 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered, concentrated, and purified via silica chromatography eluting with 7:3 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to afford the pure product as a yellow oil, 4.7 g, 91%. MS M++1 207. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]4[O:9][CH:8]([CH3:10])[CH2:7][C:6]=4[C:11]=3[CH3:12])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)C2
Product: COc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 56.3 %

Procedure:
By using 5-bromo-7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (542 mg, 2.0 mmol) synthesized in Reference example 83 and 1-(4-fluorophenyl)piperazine (720 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 417 mg (yield 56%). Melting point was 114 to 116° C. (ethanol-water).