Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[CH3:20][NH:21][CH2:22][CH2:23][OH:24]>>[CH3:20][N:21]([CH2:1][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH2:22][CH2:23][OH:24]
Reactant: CNCCO
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Product: CN(CCO)C[C@@H]1Cc2ccccc2CN1

Procedure:
Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (58 mg, 0.22 mmol) and 2-(methylamino)ethanol (21.4 μL, 0.27 mmol) provided a crude oil which was used without purification in the preparation of Example 114. MS(ESI+) m/z 221.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]([NH:34][CH3:35])=[O:33])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([NH:31][C:32]([NH:34][CH3:35])=[O:33])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: CNC(=O)NC(=O)CCl
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(=O)NC)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with N-chloroacetyl-N'-methylurea according to the method of Example 2; m.p. 145°-147°.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: Cc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C#Cc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
Into a 100 ml round bottom flask was placed a mixture of 1.43 g (0.005 mole) of 1-(trimethylsilylethynyl)-4-(4-methylphenylethynyl)benzene, 1.37 g (0.01 mole) potassium carbonate, 20 ml of methanol and 20 ml of methylene chloride. The mixture was stirred at room temperature under nitrogen overnight. The dark brown suspension was filtered and the filtrate was washed twice with water (20 ml each). The aqueous layers were combined and extracted twice with methylene chloride (10 ml each). The methylene chloride layers were combined and dried over anhydrous MgSO4, filtered and concentrated. 0.7 g (73.1% yield) of brownish yellow solid was obtained. 1HNMR: 2.40 ppm (2, 3H); 3.19 ppm (s, 1H); 7.15-7.18 ppm (d, 2H); 7.43-7.46 ppm (d, 2H); 7.49 (s, 4H). The NMR indicated that there were some by-products present. It was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[CH3:22][N:23]([CH3:32])[CH2:24][CH2:25][CH2:26][C:27](=O)[C:28]([OH:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24][N:23]([CH3:32])[CH3:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: CN(C)CCCC(=O)C(=O)O
Product: CN(C)CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O

Procedure:
In the manner given in Example 13, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with 5-(dimethylamino)-2-oxopentanoic acid at room temperature to give 7-chloro-2-[[1-carboxy-4-(dimethylamino)butylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[N:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([C@@H:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[N:14][N:15]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2nnc3ccc(F)cn23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2nnc([C@@H]3CCNC3)n2c1

Procedure:
A mixture of Intermediate 90b (335 mg, 1.09 mmol) and TFA (0.812 mL, 10.9 mmol) in DCM (5 mL) was stirred at reflux for 45 min. The cooled solution was concentrated in vacuo, redissloved in MeOH (2 mL), applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH; concentration in vacuo left the title compound as a pale yellow solid (225 mg, >99%). LCMS (Method 3): Rt 0.44 min, m/z 207 [MH+].
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][C:18]=1[CH3:49])([CH3:15])[CH3:14]>O.C(OCC)(=O)C>[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][C:18]=1[CH3:49])([CH3:14])[CH3:15]
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.9 g), sodium hydrogen carbonate (2.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-isopropoxy-3-methylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.34 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.55 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.09 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]2[N:5]([CH2:9][CH2:10][N:11]=2)[C:6](=[O:8])[CH:7]=1.O.[N:17]([O-])=[O:18].[Na+]>CC(O)=O>[NH2:1][C:2]1[N:3]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]2[N:5]([CH2:9][CH2:10][N:11]=2)[C:6](=[O:8])[C:7]=1[N:17]=[O:18]
Reactant: CC(C)CN1C(N)=CC(=O)N2CCN=C21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CN1C2=NCCN2C(=O)C(N=O)=C1N
Reaction time: 0.5 h

Procedure:
To a solution of 5.00 g. (0.024 mole) of the product of Procedure 30 in 15 ml. H2O and 4 ml. HOAc (0°) was added (portionwise) 1.72 g. (0.024 mole) NaNO2. The mixture was stirred at 24° for 30 min., cooled to 0° and filtered to yield 4.44 g. (72%) of a purple solid, mp 203°-205°d.
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(CC)CC.Cl.Cl.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C=O)C>[NH3:5].[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][N:42]([C:1]([O:2][CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]2)=[O:22])[CH2:41][CH2:40]1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Cc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(C(=O)OCCN2CCN(C)CC2)CC1
Product: N
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 866 mg, 2.8 mmol) was dissolved in DMF (20 mL). NEt3 (1.5 mL, 10.8 mmol) and 4-(2-methyl-phenyl)piperazine dihydrochloride (704 mg, 2.8 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 mL) and washed with 1 M aq Na2CO3 solution (5×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 200:8:1 mixture of DCM:EtOH:NH3) to give 2-(4-methylpiperazin-1-yl)-ethyl 4-(2-methylphenyl)piperazine-1-carboxylate (308 mg, 32%) as a yellow oil.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([CH2:20][O:21][CH:22]([F:24])[F:23])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]([CH2:20][O:21][CH:22]([F:24])[F:23])[C:10]([OH:12])=[O:11]
Reactant: O=C(OCc1ccccc1)[C@@H](COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@H](COC(F)F)C(=O)O
Yield: 79.4 %

Procedure:
Benzyl (2R) 2-dibenzylamino-3-difluoromethoxy-propionate (3.1 g, 6.28 mmol) was stirred with Pd(OH)2 in methanol under H2 overnight. The reaction mixture was filtered and the filtrate concentrated to dryness, then triturated with diethyl ether to give (2R)-2-amino-3-(difluoromethoxy)propanoic acid (773 mg, 68.4%) as a white solid. 1H NMR (300 MHz, MeOD): (ppm) 6.49 (wt, 1H), 4.33 (dd, 1H), 4.22 (dd, 1H), and 3.88 (dd, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1(=[O:12])[O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>[Zn].O>[OH:12][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:1][CH2:2][CH2:3][SH:4])=[O:11]
Reactant: O=C1CCCCCO1
Reactant: NCCS
Agent: [Zn]
Solvent: O
Product: O=C(CCCCCO)NCCS
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture, under an inert atmosphere, of 5 g of cysteamine and 7.2 cm3 of ε-caprolactone is stirred for 6 hours at ambient temperature. It is then left to stand overnight, after which the mixture is heated for 4 hours at a temperature of about 60° C. At the end of this time all the ε-caprolactone is transformed. The mixture is then poured into 100 cm3 of water to which 10 g of acid resin, "Dowex 50" are added and then 3 g of powdered zinc. The whole is stirred for 4 hours at ambient temperature. The water is then removed under reduced pressure and there are obtained 10 g of 6-hydroxy N-(2-mercaptoethyl) caproamide in the form of a viscous liquid at ambient temperature whose NMR'H spectrum and thiol dosages and residual amine correspond to the expected structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[C:19](=[O:28])[NH:20][C:21]3[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:12]2.[CH3:29][O:30][C:31]1N=[CH:35][C:34]([CH:37]=O)=[CH:33][N:32]=1.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:37][C:34]1[CH:35]=[CH:39][C:31]([O:30][CH3:29])=[N:32][CH:33]=1)[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[C:19](=[O:28])[NH:20][C:21]3[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:12]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ncc(C=O)cn1
Reactant: COCCNCCOc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1
Agent: [Na+]
Solvent: ClCCCl
Product: COCCN(CCOc1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1)Cc1ccc(OC)nc1

Procedure:
A solution of 3-(5-{2-[(2-methoxyethyl)amino]ethoxy}-1H-indol-2-yl)-2(1H)- quinolinone 2-1 (150 mg, 0.4 mmol), 2-methoxypyrimidine-5-carboxaldehyde (110 mg, 0.8 mmol) and sodium triacetoxyborohydride (168 mg, 0.8 mmol) in DCE (25 mL) was stirred under ambient conditions for 18 h. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was suspended in ethyl ether with the aid of sonication, then filtered and air dried to provide 3-[5-(2-{(2-methoxyethyl)[(2-methoxy-5-pyrimidinyl)methyl]amino}ethoxy)-1H-indol-2-yl]-2(1H)-quinolinone (2-2) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ11.05 (s, 1H), 9.60 (s, 1H), 8.53 (s, 2H), 8.33 (s, 1H), 7.68 (d, 1H, J=8 Hz), 7.52 (t, 1H, J=8 Hz), 7.34 (d, 1H, J=8 Hz), 7.27 (t, 1H, J=8 Hz), 7.22 (d, 1H, J=8 Hz), 7.05 (s, 1H), 6.96 (s, 1H), 6 J=8, 2 Hz), 4.13 (t, 2H, J=6 Hz), 4.01 (s, 3H), 3.80 (s, 2H), 3.53 (t, 2H, 3.34 (s, 3H), 3.01 (t, 2H, J=6 Hz), 2.84 (t, 2H, J=6 Hz).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[N:5][C:4]=1[S:25][CH3:26])#[N:2].C(=O)([O-])[O-:28].[K+].[K+]>C(O)C>[C:1](/[C:3](/[C:8]([NH:7][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:9])=[C:4](/[NH:5][C:6](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)\[S:25][CH3:26])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CSc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccc(C)cc2)cc1
Agent: [K+]
Solvent: CCO
Product: CS/C(NC(=O)c1ccc(SC)cc1)=C(\C#N)C(=O)Nc1ccc(C)cc1
Temperature: 60 °C
Yield: 80.9 %

Procedure:
To a suspension of 5-Cyano-1-(4-methylphenyl)-4-(methylthio)-2-[4-(methylthio)phenyl]-6-oxo-1,6-dihydropyrimidine (2.5 g, 6.59 mmol) in ethanol (30 ml) was added anhydrous potassium carbonate (1.3 g, 9.4 mmol) under continuos stirring, and at an ambient temperature. The suspension was heated slowly to 60° C. under stirring for 5 hours. Subsequently the reaction mixture was filtered, and washed with water then with ethanol and dried under vacuum to yield the title compound (2.12 g, 80.8%, m.p.: 173-175° C., purity 91.6% by HPLC). 1H-NMR (CDCl3)δ (ppm): 2.34 (s, 3H), 2.53 (s, 3H), 2.69 (s, 3H), 7.16-7.18 (d, 2H), 7.26-7.37 (m, 4H), 7.92-7.94 (d, 2H), 14.0 (s, 1H, D2O exchangeable). IR (KBr) cm−1: 3311, 2201, 1702 (—C═O). MS m/z: 398.5 (M++1).
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[NH:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH:3]=1.Cl.[NH2:14][C@@H:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([N:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1)=[O:17]>>[CH2:23]([C@H:15]([NH:14][C:9]([C:7]1[NH:6][C:5]2[S:12][C:2]([Br:1])=[CH:3][C:4]=2[CH:8]=1)=[O:11])[C:16]([N:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1)=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1cc2cc(Br)sc2[nH]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1)c1cc2cc(Br)sc2[nH]1

Procedure:
2-Bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid and (2S)-amino-1-(3-hydroxy-azetidin-1-yl)-3-phenyl-propan-1-one hydrochloride were coupled according to Procedure B.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:29])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:20][CH:19]=2)[CH2:13][CH2:12]1.[CH3:30][O:31][CH:32]([O:35][CH3:36])[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C(OCC)(=O)C>[CH3:30][O:31][CH:32]([O:35][CH3:36])[CH2:33][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:29])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:20][CH:19]=2)[CH2:13][CH2:12]1
Reactant: COC(C=O)OC
Reactant: Nc1ccccc1C(=O)CCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCCl
Product: COC(CNc1ccccc1C(=O)CCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound prepared in Example 309 (0.613 g) was suspended in 1,2-dichloroethane (30 mL). 2,2-Dimethoxyacetaldehyde solution in water (60% by weight) (2.28 mL) and beaded molecular sieves were added and the reaction mixture stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (2.62 g) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 2% (9:1 methanol/concentrated ammonium hydroxide)/dichloromethane) to furnish the title compound (0.555 g) with the following physical properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:34][NH:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][N:35]([CH3:34])[C:30](=[O:31])[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: CNCCO
Product: CN(CCO)C(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 59.7 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (200 mg, 0.45 mmol) was reacted with 2-(methylamino)ethanol (0.219 ml, 2.73 mmol) to give the title compound as a white solid (130 mg, 59%), except that the reaction was run at 45° C. for 18 hours. NMR Spectrum (2 rotamers, ratio 2/1) 2.97 and 3.08 (s, 3H), 3.62-3.43 (m, 4H), 4.73 and 4.99 (t, 1H), 5.16 and 5.23 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.37-7.18 (m, 3H), 7.75-7.69 (m, 3H), 7.90 (m, 1H), 8.15 (s, 1H), 8.53 (m, 2H), 8.57 (s, 1H), 11.20 and 11.21 (br s, 1H); Mass spectrum MH+ 484.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:16][C:15]=1[N+:30]([O-:32])=[O:31])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.[BH4-].[Li+]>C(COC)OC>[CH2:23]([O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:14]([CH:4]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]#[N:13])=[CH:10][CH:11]=2)[CH2:3][OH:2])=[C:15]([N+:30]([O-:32])=[O:31])[CH:16]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: COCCOC
Product: COc1cc(C(CO)Nc2ccc(C#N)cc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
4-{2-propanesulfonylamino-1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-benzamidine was prepared similarly to Example 2, except propanesulfonyl chloride was substituted for benzenesulfonyl chloride in the reaction with 4-{2-amino-1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-benzonitrile. MS(M+H)=545. 4-Benzyloxy-5-methoxy-2-nitrobenzaldehyde (12.2 g 42 mmoles) and 4-aminobenzonitrile (5 g, 42 mmoles) were dissolved in methanol (165 ml) and stirred for two hours and then heated to 60° C. for 30 minutes. The reaction was allowed to cool to room temperature and benzyl isonitrile (5 g. 42 mmoles) added. The reaction was cooled to 0° C. and boron trifluoroetherate (16 ml, 126 mmoles) added dropwise over five minutes. The reaction was stirred at 0° C. for 20 minutes and then allowed to come to room temperature and then stirred at ambient temperature for two hours. Water (4 ml) was added and the mixture stirred at room temperature overnight. A yellow precipitate was evident the next morning and the solid filtered off. The solid was washed with methanol and air dried to yield 8 grams of the desired product. The solvent from the filtrate was removed in vacuo and replaced with ethyl acetate. The solution was washed with water and saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and the solvent removed. The crude material was submitted to flash chromatography (hexanes: ethyl acetate, 1:1) to yield an additional 7 g of the desired product (4-Benzyloxy-5-methoxy-2-nitro-phenyl)-(4-cyano-phenylamino)-acetic acid methyl ester. 1HNMR(CDCl3): 7.68 (s, 1H), 7.4 (m, 7H), 7.0 (s, 1H), 6.61 (d, 2H), 6.2 (s, 1H), 5.2 (s,2H), 3.87 (s, 3H), 3.75 (s, 3H). (4-Benzyloxy-5-methoxy-2-nitro-phenyl)-(4-cyano-phenylamino)-acetic acid methyl ester (4.5 g, 10 mmole) was dissolved in dimethoxyethane and lithium borohydride (0.210 g, 10 mmole) added. The reaction was heated to reflux for three hours and cooled to room temperature. The reaction was quenched with water containing acetic acid and diluted with ethyl acetate. After transferring to a separatory funnel, the organic layer was washed with water several times. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed. The crude material was then submitted to flash chromatography to yield 3.1 g of 4-[1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-hydroxy-ethylamino]-benzonitrile (74%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22].Cl.[NH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19])=[CH:7][C:3]=1[C:4]([NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=1)=[O:6]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(O)ccc1Cl
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)c2cc(OC(=O)C(C)(C)C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-5-hydroxybenzoic acid (1.0 g, 5.8 mmol) in DCM (10 ml) was treated with triethylamine (2.5 eq, 2.0 ml, 14.5 mmol) and 2,2-dimethylpropanoyl chloride (2.0 eq, 1.43 ml, 11.6 mmol). Mixture stirred at room temperature for 2 hours. A solution of methyl 4-(aminomethyl)benzoate hydrochloride (1.5 eq, 1.75 g, 8.7 mmol) and triethylamine (2.0 eq, 1.6 ml, 11.6 mmol) in DCM (10 ml) was then added and the mixture stirred at room temperature for another 2 hours. The mixture was diluted with DCM (300 ml) and aqueous sodium bicarbonate (100 ml), layers separated and aqueous layer extracted again with DCM (200 ml). Organic layers combined, washed with brine, dried over magnesium sulphate and evaporated. Residue purified by column chromatography (Biotage SP4) eluting with 0-30% EtOAc in Hex to give the title compound as a white solid. MS (ES+) m/z 404 [M+H]+ (C21H2235ClNO5). 1H-NMR (400 MHz, d6-DMSO) δ 1.30 (9H, s), 3.85 (3H, s), 4.51 (2H, d, J 6), 7.24 (1H, dd, J 8.8, J 2.8), 7.29 (1H, d, J 2.8), 7.51 (2H, d, J 8.8), 7.56 (2H, d, J 8.4), 7.95 (2H, m).