Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(O)(=O)C=C.C(O)(=O)C=C.[CH3:16][C:17](C)(C)[CH2:18][CH3:19].N(C(C)(C)C#N)=NC(C)(C)C#N>>[C:1]([O:5][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCC(C)(C)C
Reactant: C=CC(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=CC(=O)OCCCC

Procedure:
7% by weight of trimethyl propane triacrylate 14.1 g of azobisisobutyronitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24]>>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Cc1ccc(O)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 5-hydroxy-2-methylaniline (28 mg, 0.231 mmol) similar to example 185 and was isolated as a pale solid (40 mg, 75%). 1H NMR (CDCl3): 9.73 (m, 1H), 8.44-8.41 (m, 1H), 7.81-7.75 (m, 1H), 7.46 (s, 1H), 7.34-7.28 (m, 2H), 7.23 (t, J=8.1 Hz, 1H), 7.09-7.06 (m, 1H), 7.00-6.97 (m, 1H), 6.55 (d, J=0.6 Hz, 1H), 2.44 (s, 3H), 2.43 (d, J=0.6, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][S-:12].[Na+]>C(O)C>[CH3:11][S:12][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])nc1

Procedure:
5-Chloro-2-nitropyridine (8.0 grams) was added to a solution of 2.5 grams of sodium methanethiolate in 100 milliliters of ethanol at a temperature of 0°C. to which solution excess sodium methanethiolate was added portionwise. The resulting reaction mixture was then heated to reflux and refluxed for 15 hours with constant stirring. At the end of the 15 hours, the reaction mixture was filtered and allowed to concentrate to 75 milliliters. The reaction mixture was then permitted to cool and filtered again, yielding the desired 5-(methylthio)-2-nitropyridine; it was recrystallized from ethanol, m.p., 100.5-02.5°C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([CH3:43])[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]=[C:22]4[C:28]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:27][N:26](COCC[Si](C)(C)C)[C:23]4=[N:24][CH:25]=3)[CH:15]=2)[CH2:10]1)(C)(C)C.C(Cl)(=O)C>CO>[NH2:7][CH2:8][C:9]1([CH3:43])[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([C:20]3[N:21]=[C:22]4[C:28]([C:29](=[O:34])[C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:27][NH:26][C:23]4=[N:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:10]1
Reactant: CC1(CNC(=O)OC(C)(C)C)CCN(c2cccc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c2)C1
Solvent: CO
Solvent: CC(=O)Cl
Product: CC1(CN)CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
1-{2-[3-(3-Aminomethyl-3-methyl-pyrrolidin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared following a similar procedure but using (1-{3-[7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-3-methyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester as starting material. In this instance the starting material was taken into a 4/1 mixture of MeOH and acetyl chloride and the reaction mixture was stirred at RT for 2 hours before being evaporated. The residue was taken into 2 mL of concentrated HCl and stirred at RT for 1 hour before being diluted with H2O and neutralized by addition of solid NaOH. The product was obtained in 44% yield after SiO2 chromatography (DCM/[DCM/MeOH/NH4OH 60/10/1] 100-60% DCM).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12.[P:36]([O:41]C)([O:39][CH3:40])[O:37][CH3:38]>>[CH3:38][O:37][P:36]([CH2:2][CH2:3][CH2:4][Si:5]([CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12)([CH3:35])[CH3:34])(=[O:41])[O:39][CH3:40]
Reactant: COP(OC)OC
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCI
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCP(=O)(OC)OC
Yield: 76 %

Procedure:
A solution of Compound 12 (60 mg) in trimethyl phosphite (1 mL) was heated under argon at 80° C. for 10 hours. Trimethyl phosphite was removed from the reaction mixture under vacuum and the residue was eluted on a silica gel using 4% ethanol in dichloromethane to obtain the required product in 76% yield (44 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([C:14]1[N:15]=[C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][N:27]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[N:28]3)[CH2:21][CH2:20]2)[S:17][CH:18]=1)=[N:12][OH:13].[C:38](Cl)(=[O:40])[CH3:39].C(N(CC)CC)C.Cl>ClCCl>[C:38]([O:13][N:12]=[C:11]([C:14]1[N:15]=[C:16]([CH:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:37])[CH2:26][N:27]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]([F:35])([F:36])[F:34])=[N:28]3)[CH2:23][CH2:24]2)[S:17][CH:18]=1)[CH:10]=[CH:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(C=Cc3c(F)cccc3F)=NO)cs2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ON=C(C=Cc1c(F)cccc1F)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1

Procedure:
A solution of 3-(2,6-difluorophenyl)-1-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolyl]-2-propen-1-one 1-oxime (i.e. the product of Example 2, Step B) (0.10 g, 0.189 mmol), acetyl chloride (0.017 g, 0.22 mmol) and triethylamine (0.022 g, 0.22 mmol) in dichloromethane (5 mL) was stirred for 2 hr and shaken with 1 mL of 1 N hydrochloric acid. The mixture was poured onto a Celite® extraction tube, eluted with dichloromethane and concentrated to give 0.11 g of crude material which was purified via silica gel chromatography (hexanes-ethyl acetate gradient) to provide 0.11 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[O:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([N:25]5[CH2:28][CH:27]([C:29]([O:31]CC)=[O:30])[CH2:26]5)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(O)(=O)C(O)=O>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[O:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([N:25]5[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]5)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1CN(C2CCCc3oc(-c4noc(-c5ccc(CC(C)C)cc5)n4)cc32)C1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Cc1ccc(-c2nc(-c3cc4c(o3)CCCC4N3CC(C(=O)O)C3)no2)cc1
Yield: 55.1 %

Procedure:
The title compound (13 mg) was synthesized in a yield of 50% as a white crystalline solid by conducting the similar reaction to that mentioned in Example 3 (3e) using ethyl 1-{2-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-4,5,6,7-tetrahydro-1-benzofuran-4-yl}azetidine-3-carboxylate (25 mg, 0.056 mmol) that was obtained in Example 7 (7f), a 1N aqueous solution of sodium hydroxide (0.17 ml, 0.17 mmol), and oxalic acid (3 mg, 0.028 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29](O)=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[N:4]=1.[CH:42]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH2:44][CH2:43]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:48][S:45]([CH:42]5[CH2:44][CH2:43]5)(=[O:47])=[O:46])=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[N:4]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1cccc(-c2cc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)c1
Product: COc1cccc(-c2cc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)nc(OC)n2)c1
Yield: 63.4 %

Procedure:
The acid 25 (150 mg, 0.26 mmol) was reacted with cyclopropane sulphonamide (64 mg, 0.53 mmol) according to the procedure described in Example 16 step g, which gave the title compound (110 mg, 62%), MS [M+1] 668.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:31][CH3:32])([C:27]([O:29]C)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O>CO>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:31][CH3:32])([C:27]([OH:29])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Br)ccc12)C(=O)OC
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Br)ccc12)C(=O)O
Temperature: 25 °C
Yield: 56.9 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-bromo-4′-[5-chloro-2-(1-ethyl-1-methoxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.2 g, 1.8 mmol), LiOH.H2O (1.5 g, 36 mmol), H2O (3 mL) and methanol (10 mL) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated. The water phase was acidified to “pH” 2-3 by addition of concentrated HCl solution and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was washed with methanol to give the title compound (660 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29](=[O:31])[CH3:30])=[CH:26][C:25]=2[CH:32]=1>CC#N>[C:29]([C:27]1[O:28][C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:8]3[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:32][C:25]=2[CH:26]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)c1cc2cc(N)ccc2o1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc3oc(C(C)=O)cc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Reaction time: 1 h
Yield: 29393388 %

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (300 mg, 0.90 nmol) and 1-(5-amino-1-benzofuran-2-yl)ethanone (387 mg, 2.21 mmol) in dry MeCN (4.5 mL) was heated in a microwave reactor at 130° C. for 1 h, then at 130° C. for 1 h, then at 140° C. for 1 h and finally at 140° C. for 1.5 h. The mixture was purified using preparative HPLC (Kromasil-column C8, 0.1M NH4OAc/MeCN, gradient) to give the title compound (116 mg, 28%); 1H NMR (400 MHz, CD3CN): δ 7.86 (bs, 1H), 7.34-7.32 (m, 1H), 7.26-7.22 (m, 1H), 7.03-7.15 (m, 7H), 3.76 (t, 2H), 1.78-1.87 (m, 2H) 1.43-1.54 (m, 2H), 1.05 (t, 3H); Mass Spectrum: M−H+ 437
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>C(OCCO)C>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCCO
Solvent: O
Product: Cc1ccccc1Nc1cc(C(=O)O)ccc1C(=O)O
Temperature: 150 °C
Reaction time: 6 h

Procedure:
Bromoterephthalic acid (12.2 g), ortho-toluidine (10.7 ml), anhydrous K2CO3 (13.8 g), catalytic Cu powder (0.2 g) in 2-ethoxy-ethanol (17.5 ml) were stirred together while heating under reflux conditions in an oil bath at 150° C. After 6 hours, water (200 ml) was added and, when all salts had dissolved, the solution was clarified and crude product precipitated by acidification to pH 2. The collected diacid was well washed with boiling water then recrystallised from 50% ethanol, pure product being obtained as yellow needles of mp 318° C. (dec).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:3].[NH2:27][C:28]1[N:33]=[C:32](Cl)[C:31]([C:35]#[N:36])=[C:30]([CH3:37])[N:29]=1.C(N(CC)CC)C>CS(C)=O>[NH2:27][C:28]1[N:33]=[C:32]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH3:3])[C:31]([C:35]#[N:36])=[C:30]([CH3:37])[N:29]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 85 °C
Yield: 83.3 %

Procedure:
To a 50 mL pear flask were added tert-butyl (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (0.85 g, 2.37 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.638 g, 3.78 mmol) in DMSO (12 mL). Triethylamine (1.65 mL, 11.8 mmol) was added to the mixture which was then heated to 85° C. for three hours. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, 25-100% EtOAc/heptane gradient) to give the title compound as an off-white solid (0.97 g, 83%). ESI-MS m/z [M+H]+ calc'd for C25H33N9O2, 492. found 492.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[CH:30]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH:30]1([C:34]([NH:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:17]=4)=[N:7][N:6]3[CH:29]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CCC5)cn4n3)ccc2C)n(C)n1
Yield: 77.1 %

Procedure:
In the same manner as in Example 264 and using N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol), cyclobutanecarbonyl chloride (86 mg, 0.73 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (170 mg, 76%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:57])([Cl:56])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:34](=[O:48])[N:35]([CH:45]3[CH2:47][CH2:46]3)[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=3[Cl:44])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][O:26][Si](C(C)(C)C)(C)C)[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[Cl:56][C:2]([Cl:1])([Cl:57])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:34](=[O:48])[N:35]([CH:45]3[CH2:47][CH2:46]3)[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=3[Cl:44])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:13]2)=[O:8])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCO[Si](C)(C)C(C)(C)C)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCO)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Yield: 160.4 %

Procedure:
A sol. of compound E5 (728 mg, 0.800 mmol) and TBAF (1.0 M in THF, 1.00 mL, 1.00 mmol) in THF (20 mL) was stirred at 0° C. for 3.5 h. The mixture was diluted with EtOAc and was washed with brine (4×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4→1:2→1.1→EtOAc) yielded the title compound (1.02 g, 96%). LC-MS: tR=1.17 min, ES+: 795.31.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH:12]([CH3:14])[CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:3].Cl.Cl.[NH2:17][C:18]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:19]=1[O:20][CH2:21][CH2:22][OH:23].N>O.C(O)C>[ClH:1].[NH2:28][C:26]1[C:25](=[N:11][C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:2][CH3:3])[CH:12]([CH3:13])[CH3:14])=[CH:6][CH:7]=2)[CH:24]=[C:19]([O:20][CH2:21][CH2:22][OH:23])[C:18](=[NH:17])[CH:27]=1
Reactant: CCN(c1ccc(N)cc1)C(C)C
Reactant: Nc1ccc(OCCO)c(N)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CCN(c1ccc(N=C2C=C(OCCO)C(=N)C=C2N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 13.5 %

Procedure:
To a solution of 2.14 g (0.01 mol) of N-ethyl-N-isopropyl-4-aminoaniline hydrochloride and 2.41 g (0.01 mol) of 2-(2,4-diaminophenoxy)ethanol dihydrochloride in 10 ml of water and 10 ml of ethanol, brought to pH 9.5 with 20% aqueous ammonia, are added dropwise 5.7 g of 30% aqueous peroxide hydrogen solution (0.05 mol). After stirring for 6 hours at room temperature, a gum forms. The supernatant is removed and the residual gum is washed with four times of water and then taken up in dichloromethane in order to perform a chromatography (eluent: dichloromethane/methanol 98/2 v/v). 510 mg of 2-{4-amino-3-[4-(ethylisopropylamino)phenylimino]-6-iminocyclohexa-1,4-dienyloxy}ethanol hydrochloride 66 are thus obtained in the form of a black powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([CH3:15])([CH3:14])[CH:12]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:10]/[C:11]([CH3:15])([CH3:14])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(C)C=O
Solvent: ClCCl
Product: CC(C)(C)/C=N/CC(=O)OC(C)(C)C
Yield: 100.4 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with trimethylacetaldehyde (Aldrich) (0.42 g, 5 mmol) in CH2Cl2 at room temperature for 20 h to give [2,2-dimethyl-prop-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.0 g, 100%).
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:50])[C@@H:14]([CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH:15][C:16](=[O:41])[C@@H:17]2[CH2:21][C@@H:20]([NH:22][C:23](=[O:33])[CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:19][N:18]2C(OC(C)(C)C)=O)[CH:3]=1>O1CCOCC1.CO>[ClH:1].[ClH:1].[ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:50])[C@@H:14]([CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:15][C:16](=[O:41])[C@@H:17]2[CH2:21][C@@H:20]([NH:22][C:23](=[O:33])[CH2:24][NH2:25])[CH2:19][NH:18]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N[C@H](CCc2ccccc2)C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)N[C@H](CCc2ccccc2)C(=O)Nc2cnc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 4 N hydrogen chloride in 1,4-dioxane (10 mL) was added to a solution of trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-prolyl-D-homophenylalanine 3-quinolylamide (C, 162 mg) in methanol (10 mL) at 0° C. After stirring at 0° C. for 5 min and at room temperature for 3 hr, the solution was concentrated in vacuo. The residue was purified by HPLC(Shiseido, Capcell Pak C18 UG120, 3 cm×25 cm, 0.02 N hydrochloric acid: methanol=65:35, v/v) and freeze-dried from water to afford the title compound (90 mg) as a pale yellow powder: 1H NMR (400 MHz, D2O) δ 2.18-2.43 (m, 3H), 2.43-2.57 (m, 1H), 2.74-2.96 (m, 2H), 3.40 (dd, J=12.2,4.4 Hz, 1H), 3.76-3.87 (m, 3H), 4.45-4.60 (m, 2H), 4.61-4.73 (m, 1H), 7.01-7.17 (m, 1H), 7.17-7.31 (m, 4H), 7.86 (t, J=7.8 Hz, 1H), 8.00 (t, J=7.8 Hz, 1H), 8.04-8.19 (m, 2H), 8.81 (s, 1H), and 9.15 (s, 1H); IR (KBr) 3388, 3205, 3037, 1685, 1681, 1610, 1571, 1552, 1496, 1486, and 1454 cm−1; mass spectrum (EI+) m/e 474 (M+); (FAB+) m/e 475 (M+1); Anal. Calcd for 26H30N6O3.3HCl.3H2O: C, 48.95; H, 6.16; N, 13.17. Found: C, 49.16; H, 5.90; N, 13.15.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[CH3:36][O:35][CH2:34][CH2:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:37][CH2:38][CH2:39][O:40][CH3:41])[N:25]=[CH:24][N:23]=[C:22]2[O:20][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCOC
Temperature: 70 °C

Procedure:
According to the procedure described in Example 13B Step 1, a mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (0.688 g, 2.5 mmol), 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline from the previous step (0.782 g, 2.5 mmol), and Cs2CO3 (0.977 g, 3 mmol) in isopropanol (15 mL) was heated at 70° C. for 7 hours, to afford 1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-(5-tert-butylisoxazol-3-yl)urea as solid. 1H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.98 (s, 1H), 8.55 (s, 1H), 7.58 (m, 2H), 7.42 (s, 1H), 7.40 (t, 1H), 7.25 (d, 1H), 6.97 (d 1H), 6.47 (s, 1H), 4.34 (m, 4H), 3.77 (m, 4H), 3.38 (s, 3H), 3.36 (s, 3H), 1.27 (s, 9H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([OH:25])=[C:20]([Cl:26])[CH:19]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([OH:25])=[C:20]([Cl:26])[CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-2,6-dichlorophenol (ABCR), the title compound was obtained as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.