Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[Cl:32])=[CH:9][C:8]=1[CH3:33])C.[OH-].[Na+].Cl>CCO>[Cl:32][C:15]1[CH:16]=[C:17]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:14]=1[S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:34])=[O:3])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A 1 L round-bottomed flask was charged with compound 10.6 (43.4 g, 84.9 mmol) and EtOH (386 mL). Next, 4 N NaOH (42 mL, 168 mmol) was added dropwise, and the reaction was stirred at room temperature for 30 min. The reaction was then neutralized using 343 mL of 0.5 N HCl, deposited crystals were collected, washed with 2×100 mL of water, and dried in vacuo. Recrystallization from 508 mL of AcOEt/hexanes (2/8) furnished the title compound 10 (31.1 g) as white crystals. MS APSI m/e: 481 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 12.98 (1H, brs); 7.65 (2H, d, J=8.7 Hz); 7.58 (1H, s); 7.36-7.29 (3H, m); 7.17 (2H, d, J=8.6 Hz); 6.96 (1H, d, J=8.4 Hz); 6.74 (1H, d, J=8.2 Hz); 5.14 (2H, s); 4.77 (2H, s); 2.21 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:7])=O.FS(OC)(=O)=O.C(Cl)Cl.[NH3:23]>C(O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:23])=[NH:7]
Reactant: COc1cccc(OC)c1C(N)=O
Reactant: N
Agent: COS(=O)(=O)F
Solvent: ClCCl
Solvent: CCO
Product: COc1cccc(OC)c1C(=N)N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2,6-dimethoxybenzamide (68 g.; prepared as described by P. Grammaticakis, Compt. rend., 1968, 267C,152), methyl fluorosulphonate (45 g.) and anhydrous methylene dichloride (1 l.) was stirred at room temperature for 3 hours. The solution was evaporated in vacuo, and the residue treated with anhydrous diethyl ether to give crude methyl 2,6-dimethoxybenzimidate fluorosulphonate as a white solid, m.p. 115°-137° C. This was dissolved in anhydrous ethanol (1 l.) and the solution was cooled to 0° C. Anhydrous ethanolic ammonia (350 ml.; prepared by saturation of anhydrous ethanol with anhydrous ammonia at 0° C.) was added, and the mixture kept at room temperature for 4 days. The solution was filtered, the filtrate was evaporated in vacuo, the residue was treated with an excess of 2N sodium hydroxide solution, and the precipitated solid was filtered off, washed with water and recrystallised from isopropanol to give 2,6-dimethoxybenzamidine (15 g.), m.p. 170°-174° C.
Reaction SMILES: C([Zn]CC)C.[CH:6]1([C:9]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:10]=2)[CH2:8][CH2:7]1.[Br:27][CH2:28][C:29]([C:31](Br)(Br)[Br:32])=[O:30]>CCCCCC.C1(C)C=CC=CC=1.CCOC(C)=O>[Br:27][CH:28]1[C:29](=[O:30])[CH:31]([Br:32])[CH:10]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]1[CH:13]=[C:9]2[CH:6]1[CH2:7][CH2:8]1
Reactant: O=C(CBr)C(Br)(Br)Br
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1ccc(C2CC2)c1
Agent: CC[Zn]CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1C(Br)C2C=C(C3CC3)C(C1Br)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.9 %

Procedure:
Diethyl zinc (18.1 mL, 18.1 mmol of a 1M solution in hexane) was added to a solution of 3-cyclopropyl-1-(4-(trifluoromethyl)phenylsulfonyl)-1H-pyrrole (3.18 g, 10.1 mmol) and tetrabromoacetone (7.53 g, 20.1 mmol) in toluene at −10° C. The reaction mixture was stirred at room temperature for 17 h and was subsequently diluted with EtOAc and washed with saturated aqueous Na2CO3. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc, 9/1 to 7/3, v/v) to give compound 115 (3.31 g, 6.25 mmol, 62%). MS (ESI) 530.0 (M+H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.C(N(CC)CC)C.[CH3:37][N:38]1[CH:42]=[C:41]([C:43](Cl)=[O:44])[CH:40]=[N:39]1>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([C:43]([C:41]3[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=3)=[O:44])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: Cn1cc(C(=O)Cl)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)c2cnn(C)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.033 mmol) (chiral material, from Example 1, step 7, peak 1) and triethylamine (14 μL, 0.098 mmol) in methylene chloride (0.2 mL) was added 1-methyl-1H-pyrazole-4-carbonyl chloride (from Maybridge, 6.1 mg, 0.042 mmol). The resulting mixture was stirred overnight at room temperature. The solvents were evaporated and the crude material was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 7.1 mg (44%) of the product. The product was isolated as a single enantiomer. LCMS calculated for C24H28ClN8O2 (M+H)+: m/z=495.2; Found: 495.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18])[CH:10]=2)=[O:5])C.O.[OH-].[Li+]>O1CCCC1CO.O>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[CH:13][CH:12]=3)=[O:18])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: O=C(O)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
7-{[2-(4-Trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid ethyl ester (160 mg, 0.34 mmol) was dissolved in 5 ml of a 3:1:1 mixture of tetrahydrofuran-methanol-water, and lithium hydroxide monohydrate (29 mg, 0.69 mmol) was added. After 2.5 h at room temperature, the volatiles were removed under vacuum and 5 ml of water was added to the mixture, which was brought to pH 4 with 1N HCl. The resulting slurry was filtered to provide 147 mg of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.C[C@H]1O[C@H](C)CN(C2C=CC(F)=CC=2C=O)C1>>[CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C=O)C[C@H](C)O1
Agent: C[C@@H]1CN(c2ccc(F)cc2C=O)C[C@@H](C)O1
Product: CC1CN(c2ccc(F)cc2C=O)CC(C)O1

Procedure:
In a manner similar to that described in Example 1 (Step 1) cis-2-(2,6-dimethylmorpholin-4-yl)-5-fluorobenzaldehyde and trans-2-(2,6-dimethylmorpholin-4-yl)-5-fluorobenzaldehyde are obtained in 24% and 6% yields as a yellow solid and a yellow oil, respectively. Cis-isomer: 1H NMR (400 MHz, CDCl3) δ 10.37, 7.50, 7.31–7.24, 7.14, 7.12, 3.97–3.86, 3.00, 2.64, 1.24; and trans-isomer: 1H NMR (400 MHz, CDCl3) δ 10.45, 7.50, 7.14, 7.12, 4.27–4.17, 3.07, 2.76, 2.74, 1.35.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[CH3:15][N:16]([CH3:27])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH2:26])=[NH:25])=[CH:19][CH:18]=1.[OH-].[Na+]>O(CCO)C>[CH3:15][N:16]([CH3:27])[C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]2[N:26]=[C:8]([C:3]3[S:4][C:5]([CH3:7])=[N:6][C:2]=3[CH3:1])[CH:9]=[CH:10][N:25]=2)=[CH:21][CH:22]=1
Reactant: CN(C)c1ccc(NC(=N)N)cc1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N(C)C)cc3)n2)s1
Temperature: 120 °C

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (0.95 mmol, 0.19 g) and N-(4-dimethylamino-phenyl)-guanidine (2 mmol) in 2-methoxylethanol (5 mL) was added NaOH (40 mg). The reaction mixture was heated at 120° C. for 18 h. The solvent was evaporated and the residue was purified by chromatography, using EtOAc/PE to afford N,N-dimethyl-N′-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,4-diamine {119} (74 mg) as a reddish-brown solid. 1H-NMR (300 MHz, d6-DMSO) δ2.62 (s, 3H, CH3), 2.65 (s, 3H, CH3), 2.86 (s, 6H, CH3), 6.73 (m, 2H, Ph-H), 6.97 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.56 (m, 2H, Ph-H), 8.44 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 9.33 (s, 1H, NH). DE MALDI-TOF MS: {M+H}+=329.51 (C17H19N5S requires 325.43).
Reaction SMILES: C1COCC1.[Al+3].[Cl-].[Cl-].[Cl-].[N-:10]=[N+:11]=[N-:12].[Na+].[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([C:35]#[N:36])([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([N:21]1[CH2:22][CH2:23][C:24]([C:35]2[NH:36][N:12]=[N:11][N:10]=2)([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:25][CH2:26]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1(Nc2ccccc2F)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccccc1NC1(c2nnn[nH]2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To 250 ml of stirring dry THF in a 500 ml r.b. flask at 0° C. under N2, AlCl3 (23.0 g, 172 mmol) was added in small portions. Subsequently, NaN3 (47.4 g, 729 mmol) and 1-benzyl-4-cyano-4-(2-fluoroanilino)piperidine (21.8 g, 70 mmol) were added. The resulting mixture was refluxed for 20 hours. It was cooled to room temperature and poured onto stirring water (300 ml). The THF layer was separated and the aqueous layer was extracted with additional THF (3×500 ml). The combined THF layers were dried over MgSO4 and filtered. The filtrate was kept at 0° C. for 15 hours. After a filtration, the desired compound (17.1 g, 49 mmol) as white powder was obtained: m.p. 195°-198° C.; IR (nujol) 3360 cm-1 ; NMR (270 MHz, DMSO-d6) δ2.29, 2.46 and 2.67 (3 m, 8H, piperidine CH2 's), 3.53 (s, 2H, benzyl CH2), 6.12, 6.61, 6.72 and 6.98 (4m, 4H, anilinophenyl H's), 7.2-7.4 (m, 5H, benzylphenyl H's). Anal. Calcd. for C19H21FN6 : C, 64.75; H, 6.01; N, 23.85. Found: C, 64.52; H, 5.94; N, 23.56. ##STR21##
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS[C:28](=[NH:33])[NH:29][N+:30]([O-:32])=[O:31].C(#N)C>CO>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:28]([NH2:33])=[N:29][N+:30]([O-:32])=[O:31])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: COc1ccc(N)cc1CNC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(NC(N)=N[N+](=O)[O-])cc1CNC(=O)OC(C)(C)C
Yield: 32.7 %

Procedure:
A mixture of the compound (130 mg) obtained in Example 119, triethylamine (0.09 ml), S-methyl-N-nitroisothiourea (84 mg), acetonitrile (3 ml) and methanol (1 ml) was heated under reflux for 20 h. The reaction mixture was distilled under reduced pressure and the residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=1:1) to give 57.2 mg of the titled compound (yield, 33%).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=1>CN(C)C=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>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[N:18][CH:19]=2)[CH:8]=[CH:7][C:6]=1[O:9][CH3:10]
Reactant: COc1ccc([Sn](C)(C)C)cc1OC
Reactant: COc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(OC)c(OC)c2)cn1
Temperature: 90 °C

Procedure:
A solution of 2.00 g (6.64 mmol) of 4-trimethylstannylveratrole, 2.49 g (13.2 mmol) of 2-methoxy-5-bromopyridine and 370 mg (0.332 mmol) of Pd (PPh3)4 in 30 mL of dry dimethylformamide is flushed thoroughly with nitrogen and heated to 90° C. for 12 hours. The reaction mixture is partitioned between ethyl acetate (150 mL) and water (100 mL). The aqueous layer is back extracted with ethyl acetate (100 mL) and the combined organics are washed with brine (75 mL), dried (MgSO4) and evaporated to give a crude yellow oil. The oil is chromatographed on silica gel (eluting with 95:5 hexane/ethyl acetate and then with 9:1 hexane/ethyl acetate) which gives 5-(3,4-dimethoxy-phenyl)-2-methoxypyridine m.p 83°-84° C.)
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine-2HCl (70 mg, 0.206 mmol), (3-fluorophenyl)acetic acid (31.8 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at rt for overnight. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The white solid was filtered to give the product. LC/MS (ES) m/z=403.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.26 (t, J=8.46 Hz, 2H), 3.93 (s, 5H), 4.25 (t, J=8.46 Hz, 2H), 7.11 (s, 1H), 7.13-7.17 (m, 2H), 7.39 (d, J=6.82 Hz, 1H), 7.44 (d, J=8.34 Hz, 1H), 7.51 (s, 1H), 8.18 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [Na].Cl.[C:3](=[NH:8])(OCC)[CH3:4].[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1>C(O)C>[NH:8]=[C:3]([N:16]([C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:19][CH:18]=1)[NH2:17])[CH3:4]
Reactant: CCOC(C)=N
Reactant: Cc1ccc(C(=O)NN)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(=N)N(N)C(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 15.7 %

Procedure:
1.65 g (72 mmol) sodium are dissolved in 80 mL ethanol. 8.89 g (72 mmol) ethyl acetimidate hydrochloride in 160 mL ethanol are added at ambient temperature and the precipitated sodium chloride is filtered off. The filtrate is combined with 6.00 g (40 mmol) 4-methyl-benzoic acid hydrazide and stirred overnight. The reaction mixture is evaporated down and cooled. The precipitated solid is filtered off and washed with cold ethanol and diethyl ether (5.7 g white solid). A further 1.2 g solid are obtained from the filtrate after distillation of the solvents and recrystallisation from ethanol.
Reaction SMILES: [K].CCOCC.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH2:14][CH2:13][CH2:12]2.[N:20](OCCCC)=[O:21]>C(O)(C)(C)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[N:20][OH:21])[CH2:14][CH2:13][CH2:12]2
Reactant: CCCCON=O
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [K]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)CCCC2=NO
Reaction time: 0.5 h
Yield: 12 %

Procedure:
In 60 ml of refluxing t-butanol was dissolved 3.84 g (0.0985 mole) of potassium. Ether (150 ml) was added followed by 15.87 g (0.09 mole) of 6-methoxy-1-tetralone. Butyl nitrite (11.1 g, 0.0932 mole) was added dropwise with stirring over a period of 30 minutes. The insoluble salts were filtered and washed with ether. They were slurried with 180 ml of water and then 15 ml of Concentrated HCl was added. The initially formed oil solidified. The solid was filtered and washed with water. Recrystallization of the still damp product from 250 ml of ethanol gave 8.86 g. Concentration of the filtrate to 1/3 volume gave 2.06 g additional material. Total yield 10.92 g (59%). A second recrystallization gave an analytical sample, mp 168°-171° dec.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C(Cl)Cl.CO>[Cl:16][C:11]1[CH:10]=[C:9]([C:4]2[N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:21]4[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]4)=[CH:31][CH:30]=3)[N:7]=[C:6]([NH2:8])[CH:5]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Nc1cc(-c2ccc(F)c(Cl)c2)nc(Cl)n1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3nc(N)cc(-c4ccc(F)c(Cl)c4)n3)cc2)CC1
Yield: 84 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-6-(3-chloro-4-fluorophenyl)pyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 84% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). MS (ESI): 214.2 [M+2H]2+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([O:15][C:16](=[O:25])[CH2:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22]Cl)[CH3:14].II.[CH:28]1C=CC=CC=1>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:28][N:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:3]=1)[CH3:14]
Reactant: CCOC(=O)CC(=O)CCCCCl
Reactant: Nc1cccc(-n2ccnc2)c1
Reactant: c1ccccc1
Agent: II
Product: CCOC(=O)C=CC1CCCCN1c1cccc(-n2ccnc2)c1
Reaction time: 16 h
Yield: 8 %

Procedure:
The above synthesis may be carried out as follows: To benzene (20 mL) was added 1-(3-aminophenyl)imidazole (755 mg, 4.7 mmol), 7-chloro-3-oxoheptanoic acid ethyl ester (982 mg, 4.7 mmol), Na2HPO4 (667 mg, 4.7 mmol), I2 (60 mg, 0.23 mmol), and 4 Å molecular sieves (500 mg). After refluxing for 6 hours, more I2 (60 mg) was added. After stirring for 16 hours, the reaction was filtered, the solvent was removed in vacuo, and the residues chromatographed (CH2Cl2/MeOH, 98/2) to give 120 mg (8%) of 1-[3-(1H-imidazol-1-yl)phenyl]piperidine-2-acrylic acid ethyl ester (1H NMR (CDCl3) δ 7.85 (s, 1), 7.05-7.50 (m, 6), 4.80 (s, 1), 4.15 (q, 2), 3.45 (t, 2), 2.4 (t, 2), 1.5-1.8 (m, 6), 1.30 (t, 3)). This ester (120 mg, 0.38 mmol) was dissolved in MeOH (20 mL) and reacted with 10% Pd/C (60 mg) and 1 atm of H2. After reacting for 60 hours, the reaction was filtered, the solvent removed in vacuo, and the residue chromatographed (ethyl acetate/hexanes, 1/1) to give 24 mg of 1-[3-(1H-imidazol-1-yl)phenyl]piperidine-2-acetic acid ethyl ester (compound of formula (XV)). This ester (24 mg, 0.076 mmol) was dissolved in 5% methanolic NaOH. After stirring for 16 hours, the reaction was acidified with methanolic HCl, the solvent removed in vacuo, and the residue dissolved in DMF. Piperonylamine (1 eq), Hünig's base (2 eq) and HATU (1 eq) were added. After reaction completion the reaction mixture was partitioned with water and ethyl acetate. The organic layer was separated, washed with water, and dried. The solvent was removed in vacuo and the residue was chromatographed (ethyl acetate/MeOH, 98/2) to give 6 mg of the compound of formula (Ibb), N-[(1,3-benzodioxol-5-yl)methyl]-1-[3-(1H-imidazol-1-yl)phenyl]piperidine-2-acetamide: 1H NMR (CDCl3) δ 7.80 (s, 1), 7.10-7.30 (m, 4), 6.50-6.70 (m, 5), 5.90 (s, 2), 4.20-4.35(m, 2, 3.85 (br s, 1), 3.50 (t, 2), 2.95 (d, 1), 2.35-2.55 (m, 2), 1.4-1.9 (m, 6); MS: (419 M+H)+.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[O:19]([CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:28]1[CH2:29][CH2:30][CH:26]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1ccc(OC2CCNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC(Oc4ccccc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-phenoxypyrrolidine hydrochloride (28 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a pale yellow solid. This solid was triturated in methanol, filtered, washed with methanol, acetone and diethyl ether then dried to give the title compound (30 mg, 68%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH3:61])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:44][CH:43]([NH2:59])[C:42]2=[O:60])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>O1CCCC1>[C:32]1([CH3:61])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:58])[C:54]([CH3:55])([CH3:56])[CH3:57])[CH2:44][CH:43]([NH:59][C:14]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=3)=[O:16])[C:42]2=[O:60])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)C(C)(C)C
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 188.3 %

Procedure:
Methyl 5-amino-2-fluorobenzoate (241 mg) was dissolved in tetrahydrofuran (43 ml), under ice-cooling triphosgene (142 mg) was added and triethylamine (123 μl) were added five times every 3 minutes, a solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (528 mg) in tetrahydrofuran (20 ml) was added thereto, and the mixture was allowed to come to room temperature and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water (50 ml) was added, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 543 mg of the titled compound (Yield: 69.3%).