Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15](O)=[O:16].ClC(OCC)=O.Cl.[CH3:32][NH:33][OH:34].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15]([N:33]([CH3:32])[OH:34])=[O:16]
Reactant: CNO
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Agent: CCOC(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C=CC(=O)N(C)O)cc(OC)c1OC
Temperature: -12 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
Triethylamine (3.07 ml, 22 mmol) was added to a stirred solution of 3,4,5-trimethoxycinnamic acid (4.76 g, 20 mmol) in N,N-dimethylformamide (30 ml). The resulting solution was cooled to -12° C., and ethyl chloroformate (2.00 ml, 21 mmol) was added dropwise with stirring. After 15 minutes, solid N-methylhydroxylamine hydrochloride (1.84 g, 22 mmol) was added, followed by triethylamine (3.2 ml, 23 mmol). The mixture was allowed to warm to room temperature, stirred overnight, and poured into 150 ml of 1% aqueous citric acid. The mixture was extracted twice with ethyl ether, and the combined extracts washed successively with water and brine, then dried over MgSO4, filtered, and evaporated. The residue was recrystallized from ethyl acetate to provide 1.82 g (34% yield) of the titled compound as colorless crystals, mp 169°-170° C.
Reaction SMILES: [CH2:1]([C@@H:8]([NH2:14])[CH:9]([O:12][CH3:13])[O:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18]>C1(C)C=CC=CC=1>[CH2:1]([CH:8]([N:14]=[CH:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[OH:18])[CH:9]([O:10][CH3:11])[O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)[C@H](N)Cc1ccccc1
Reactant: O=Cc1ccccc1O
Solvent: Cc1ccccc1
Product: COC(OC)C(Cc1ccccc1)N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.8 %

Procedure:
In a 50 ml three-necked flask equipped with a thermometer, a magnetic stirrer and a condenser, 0.14 g of optically enriched (R)-1-benzyl-2,2-dimethoxyethylamine (91% ee, determined by chiral HPLC) (0.71 mmol, 1 mol.eq.) and 0.09 g of salicylaldehyde (0.71 mmol, 1 mol.eq.) are introduced into 1 g of toluene. This medium is left to stir at ambient temperature for 2-3 h. After concentrating, a crude mass of 0.21 g of 2-[(1-benzyl-2,2-dimethoxyethylimino)methyl]phenol is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([CH2:7][CH2:8]OS(C)(=O)=O)[CH2:4][O:3]1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O>[N:15]([CH2:8][CH2:7][C@H:5]1[CH2:4][O:3][C:2]([CH3:14])([CH3:1])[O:6]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OC[C@H](CCOS(C)(=O)=O)O1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CCN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 70 h
Yield: 88.9 %

Procedure:
To a solution of methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (31.7 g, 0.14 mol) in N,N-dimethylformamide (200 mL) was added NaN3 (46 g, 0.71 mol). The reaction mixture was stirred at room temperature for 70 h. Then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine several times, dried over MgSO4, concentrated to give (S)-4-(2-azido-ethyl)-2,2-dimethyl-[1,3]dioxolane as a yellow oil (21.3 g, 88%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:20](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25](/[CH3:32])=[CH:26]/[C:27]([O:29]CC)=[O:28])=[CH:19][C:9]2[C:10]3([CH3:18])[CH:15]([OH:16])[C:14]([CH3:17])([C:8]=2[CH:7]=1)[CH2:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:5][C:6]1[C:20](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25](/[CH3:32])=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:19][C:9]2[C:10]3([CH3:18])[CH:15]([OH:16])[C:14]([CH3:17])([C:8]=2[CH:7]=1)[CH2:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)OCC)C1(C)CCCC2(C)C1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)O)C1(C)CCCC2(C)C1O

Procedure:
This ester was dissolved in 7 ml of ethanol/THF=1/1 and treated under argon with 2.1 ml of 2N NaOH. The mixture was left to react at room temperature for 64 h. and then poured into ice/HCl/ethyl acetate. The organic phase was washed twice with water, dried and evaporated. Recrystallization from hexane/ethyl acetate=7/3 yielded 153 mg of (2E,4E,6E)-(5RS,9SR,10RS)-7-(3-butoxy-10-hydroxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocyclohepten-2-yl)-3-methyl-hepta-2,4,6-trienoic acid as yellow crystals of m.p. 176-178°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=1[CH3:24].O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:21]3[N:20]=[N:19][C:18]([Cl:17])=[C:23]([CH3:24])[C:22]=3[CH3:25])[CH2:15][CH2:16]2)=[N:9][CH:10]=1)=[O:4]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: COC(=O)c1cnc(N2CCNCC2)cn1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)cn1
Temperature: 190 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To the solution of 3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (250 mg, 1.07 mmol) in NMP (5 mL) is added 3,6-dichloro-4,5-dimethyl-pyridazine (237 mg, 1.33 mmol) and TEA (446 μl, 3.21 mmol), the reaction mixture is stirred at 190° C. for 60 min. Water is added to the mixture and extracted with EtOAc. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by HPLC, (acetonitrile/water: 10%˜95% with 3% 1-propanol) to give white powder (165 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)N1CCCCC1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)C)c1
Yield: 37 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-piperidin-1-ylethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.2 mg) was obtained.
Reaction SMILES: [CH:1]1([N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[C:31]([Cl:60])=[C:32]([N:38]2[CH2:43][CH2:42][C@@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:40]([O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[CH2:39]2)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Si:53]([O:52][C@H:40]1[C@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:42][CH2:43][N:38]([C:32]2[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=[C:30]([NH:29][C:7]3[N:6]=[C:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:10]4=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]4[N:8]=3)[C:31]=2[Cl:60])[CH2:39]1)([C:56]([CH3:57])([CH3:58])[CH3:59])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 50 °C
Yield: 72.8 %

Procedure:
A mixture of 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl) imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 2, 185 mg, 0.464 mmol), (+/−)-tert-butyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethyl silyl)oxy)piperidin-4-yl)carbamate (223 mg, 0.464 mmol) and cesium carbonate (302 mg, 0.927 mmol) in DMF (5 mL) was heated at 50° C. for 4 h. LCMS showed completion of reaction. The reaction mixture was diluted with ethyl acetate and the solid was filtered off. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 10-35% ethyl acetate/hexanes). (+/−)-tert-butyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (270 mg) was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4].C(N(CC)CC)C.[CH2:29]([N:31]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]1)[CH2:32][CH3:33])[CH3:30]>CN(C)C=O>[CH2:29]([N:31]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4])[CH2:32][CH3:33])[CH3:30]
Reactant: Cc1cn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Reactant: CCN(CC)CC1CCCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2c1c(C)cn2C

Procedure:
A mixture of 4-(chloroacetyl)-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-benzodiazepin-10-one (2.0 g, 0.0066 mol), dimethylformamide (30 ml), triethylamine (1 ml, 0.0071 mol) and 2-[(diethylamino)methyl]piperidine (1.7 g, 0.01 mol) is heated to 30°-40° C. for two hours with stirring. The solvent is distilled off under water jet vacuum, the residue taken up in water (10 ml), made alkline with potassium carbonate and extracted exhaustively with dichloromethane. The combined methylene chloride extracts are dried over sodium sulfate and concentrated. The crude product thus obtained is purified by chromatography on silica gel using dichloromethane/methanol (9:1 v/v). After recrystallization from ethyl acetate/methanol (95:5) the desired compound (1.4 g) is obtained in the form of colorless crystals, Mp. 176°-178° C.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23]C)[CH:19]=3)[CH:14]=2)=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C>[CH2:1]([C:8]1[O:9][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]3)=[CH:11][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(-c3cnc(Cc4ccccc4)o3)ccc2c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2cc(-c3cnc(Cc4ccccc4)o3)ccc2c1
Yield: 97.9 %

Procedure:
2-Benzyl-5-(6-methoxy-2-naphthyl)-1,3-oxazole (2.53 g, 7.59 mmol), prepared in the previous step, in 25 mL of glacial acetic acid plus 10 mL of 48% aqueous HBr was stirred under nitrogen at 120° C. for 10 h. After cooling to room temperature the HBr and the acetic acid were removed under reduced pressure. The residue was taken up in 500 mL of 90% CH3OH/CH2Cl2, extracted three times with a total of 250 mL of 5% NaHCO3, dried (MgSO4), filtered and the solvent was removed under reduced pressure to give 6-(2-benzyl-1,3-oxazol-5-yl)-2-naphthol (2.24 g, 98%) as a brown solid, mp 200-202° C. Elemental Analysis for C20H15NO2 Calc'd: C, 79.72; H, 5.02; N, 4.65. Found: C, 78.63; H, 5.15; N, 4.44.
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])=[C:11]([F:29])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[OH:30][CH2:31][C:32]([CH2:37]O)([CH2:35][OH:36])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[OH:30][CH2:31][C:32]([CH2:35][OH:36])([CH2:33][OH:34])[CH2:37][O:7][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([F:29])=[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])[C:2]=1[F:1]
Reactant: OCC(CO)(CO)CO
Reactant: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F)OCC(CO)(CO)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a stirred solution of 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetic acid (I(b)) (700 mg, 1.73 mmol, 1.0 eq) in DMF (30 mL) was added pentaerythritol (470 mg, 3.45 mmol, 2.0 eq), TEA (699 mg, 6.91 mmol, 4.0 eq) and HATU (985 mg, 2.60 mmol, 1.5 eq). The resulting mixture was stirred at room temperature overnight under N2. The reaction was diluted with water then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (DCM:MeOH=100:1-20:1) to give the title compound as a colourless oil (370 mg, 41%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]([CH3:31])[CH3:30]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH:29]([CH3:31])[CH3:30])[CH2:21][CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Reactant: CC(C)I
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[C:16](S(C)(=O)=O)[N:15]=[C:14]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:13]=2[O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])=[N:6][CH:7]=1.[CH2:45]([CH2:47][NH2:48])[OH:46].[Cl-].[NH4+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[C:16]([NH:48][CH2:47][CH2:45][OH:46])[N:15]=[C:14]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:30][CH:31]=3)(=[O:24])=[O:25])[C:13]=2[O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(S(C)(=O)=O)nc1OCCOc1ncc(Br)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(NCCO)nc1OCCOc1ncc(Br)cn1
Reaction time: 20 h
Yield: 11.7 %

Procedure:
A mixture of N-{6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]-5-(2-methoxy-phenoxy)-2-methylsulfonylpyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (500 mg), ethanolamine (172 mg) and dimethylacetamide (4 ml) is heated with stirring at 110°-120° C. for 20 hours. After cooling, to the mixture is added an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=3:1) to give the title compound (57 mg) as a powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C(N(CC)CC)C.[C:13](=[N:18][OH:19])(Cl)[C:14]([CH3:16])=O.Cl>O1CCCC1>[N:18](=[C:13]1[C:14]([CH3:16])=[N:2][CH2:3][CH2:4][S:5]1)[OH:19]
Reactant: CC(=O)C(Cl)=NO
Reactant: NCCS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=NCCSC1=NO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.27 g (0.02 mol) of cysteamine hydrochloride are suspended in 40 ml of absolute tetrahydrofuran and treated with 5.55 ml (0.04 mol) of triethylamine to free the base. The mixture is stirred for 15 minutes at room temperature and then cooled down to about -30° C. At this temperature a solution of 2.42 g (0.02 mol) of pyruvyl chloride 1-oxime in 10 ml of absolute tetrahydrofuran is added dropwise. The reaction mixture is allowed to warm to room temperature while being well stirred. After two hours ice-water and then dilute hydrochloric acid are added until a pH of 5-6 has been attained. The reaction mixture is extracted twice with ethyl acetate and the organic phase is washed with sodium chloride solution, dried over anhydrous sodium sulfate and finally evaporated. The resulting crystalline residue is treated with active charcoal. After recrystallization from hot ethyl acetate and n-hexane there is obtained pure 2-oxo-5,6-dihydro-3-methyl-2H-1,4-thiazine oxime, m.p. 197° C. (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][C:28]5[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=5)=[CH:23][CH:22]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:37][CH:38]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(C3(c4ccc(Cc5ccc([N+](=O)[O-])cc5)cc4)CCCCC3)cc2)cc1
Reactant: [H][H]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Cc2ccc(C3(c4ccc(Cc5ccc(N)cc5)cc4)CCCCC3)cc2)cc1
Yield: 82.2 %

Procedure:
1,1-bis[4-(4-nitrobenzyl)phenyl]cyclohexane 98.93 g was dissolved in 1100 ml of tetrahydrofuran, a Pd--C catalyst (5% purity, water content 55.9%) 9.8 g was added, and the mixture was cooled with water at atmospheric pressure and contacted with hydrogen gas with stirring. After the absorption of hydrogen stopped, the catalyst was filtered off and the solution was concentrated. The concentrate was recrystallized with toluene solvent to obtain 71.71 g of 1,1-bis[4-(4aminobenzyl)phenyl]cyclohexane which is a diamino compound of the present invention. The melting point was 154.4°-155.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[C:17]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:23]=4)=[O:21])[CH:16]=[CH:15][C:14]=3[CH3:34])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:35][CH3:36].C1(C)C=CC(S(O[CH2:47][CH2:48][N:49]2[CH:53]=[CH:52][N:51]=[N:50]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:36][O:35][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:47][CH2:48][N:49]1[CH:53]=[CH:52][N:51]=[N:50]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:18]=[C:17]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:16]=[CH:15][C:14]=1[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Reactant: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCCn1ccnn1
Temperature: 100 °C
Yield: 21.4 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-[2-methyl-5-(2-morpholinopyridine-4-carboxamido)anilino]quinazoline (184 mg), 2-(1,2,3-triazol-1-yl)ethyl 4-toluenesulphonate (101 mg), cesium carbonate (370 mg) and N,N-dimethylacetamide (4 ml) was stirred and heated to 100° C. for 1 hour. After cooling the reaction mixture to ambient temperature, the reaction mixture was partitioned between water and methylene chloride. The organic phase was dried with brine and sodium sulphate and evaporated. The material so obtained was purified by column chromatography on silica using a 10:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (47 mg); NMR: 2.14 (s, 3H), 3.51 (t, 4H), 3.72 (t, 4H), 3.91 (s, 3H), 4.59 (t, 2H), 4.87 (t, 2H), 7.09 (d, 1H), 7.2 (s, 1H), 7.22 (d, 1H), 7.27 (d, 1H), 7.58 (m, 1H), 7.74 (s, 2H), 7.83 (s, 1H), 8.18 (s, 1H), 8.24 (d, 1H), 8.26 (s, 1H), 9.39 (s, 1H), 10.28 (s, 1H); m/s: M+H+ 582.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](O)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21].C1C=[C:26]2[N:28]=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:28][CH3:26])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-fluoro-2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylic acid (73 mg, 0.252 mmol), methylamine, HCl (25.5 mg, 0.377 mmol), HOBT hydrate (65.5 mg, 0.428 mmol) and EDC hydrochloride (87 mg, 0.453 mmol) at r.t. under N2 was added N,N-diisopropylethylamine (0.220 mL, 1.258 mmol). The mixture was stirred at r.t. for 16 hours. After concentration, the mixture was added with 5 ml 1N HCl, and then 14 ml H2O. The white solid was filtered and washed with 3×5 ml H2O and dried (64 mg). 1H NMR (500 MHz, CD3OD) δ 7.89 (dd, J=8.09, 5.34, 2H), 7.25 (t overlapping with dd, 2H), 7.23 (dd, 1H), 6.99 (t, J=8.55, 1H), 2.96 (s, 3H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH—90% H2O—0.1% TFA, Solvent B=90% MeOH—10% H2O—0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=304.06, HPLC Rt=1.262 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:14][N:15]=2)[NH:10][N:9]=1.C(Cl)(Cl)(Cl)[Cl:27]>>[Cl:27][C:14]1[N:15]=[C:16]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][NH:10][C:11]2=[N:12][C:13]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Fc1ccc(Oc2cnc3c(-c4ccccc4Cl)n[nH]c3n2)c(F)c1
Product: Fc1ccc(Oc2nc3[nH]nc(-c4ccccc4Cl)c3nc2Cl)c(F)c1

Procedure:
A suspension of 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-1H-pyrazolo[3,4-b]pyrazine (2.70 g, 7.5 mmol) in 500 mL carbon tetrachloride was bubbled with chlorine gas for 16 hours at room temperature while stirring. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (methylene chloride/hexanes 2:3 to 1:0) to give 1.21 g of 5-Chloro-3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyrazine. Mass spec. M+1=394.