Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4OC)[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2)N=1.NC1C=CC(C2C=NN(CCCO)C=2)=C2C=1C(=O)N(C)C2>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([CH2:37][P:38](=[O:45])([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])=[CH:46][CH:47]=4)[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Agent: CN1Cc2c(-c3cnn(CCCO)c3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
This compound was prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 2C) and 7-amino-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 1C) 1H NMR (400 MHz, CD3OD) δ 8.69 (br s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.68 (d, J=8.59 Hz, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.34 (dd, J=2.4, 8.5 Hz, 2H), 4.55 (s, 2H), 4.31 (t, J=6.8 Hz, 2H), 4.01-4.12 (m, 4H), 3.57 (t, J=6.1 Hz, 2H), 3.29 (d, J=20.7 Hz, 2H), 3.17 (s, 3H), 2.10 (quin, J=6.5 Hz, 2H), 1.26 (t, J=7.1 Hz, 6H). MS (ES+): m/z 674.21 [M+H]+. UPLC: tR=1.33 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:4]=1)[C:12](=[O:11])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:1]=2
Reactant: Nc1ccc(I)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(I)cn2c1=O
Temperature: 25 °C
Yield: 32 %

Procedure:
In a 3-necked round-bottom connected to a Dean-Stark trap, a solution of 2-amino-5-iodopyridine (Preparation 1, 500 mg) and diethyl ethoxymethylenemalonate (0.92 mL) is heated at 130° C. for 2 h. The reaction is cooled to room temperature. Diphenyl ether (5 mL) is added and the reaction is heated at 250° C. for 1 h. Upon cooling the mixture to room temperature, a solid precipitates and is filtered and washed with hexanes. The crude solid is adsorbed onto silica and chromatographed eluting with CH2Cl2 (2 L). Product-containing fractions are combined and concentrated to afford a solid. The crude product is recrystallized from CH2Cl2/hexanes to yield 251 mg (32%) of the title compound as a yellow solid. Physical characteristics: m.p. 166-168° C.; 1H NMR (300 MHz, DMSO-d6) δ9.24, 8.85, 8.38, 7.62, 4.27, 1.30; IR (drift) 1747, 1611, 1558, 1506, 1473, 1355, 1345, 1291, 1266, 1258, 1152, 1140, 1118, 840, 796 cm−1; MS (ESI+) m/z 345; Anal. found: C, 38.37; H, 2.48; N, 8.11.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:13]2([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:14]3[C:19]([C:20](=[O:22])[CH:21]=[C:12]2[O:11]C1C(C)C)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.Cl>[CH2:1]([O:8][NH:9][C:13]1([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:22])[CH:21]=[C:12]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCC12C(=CC(=O)c3ccccc31)OC(C(C)C)N2OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CCC1(NOCc2ccccc2)C(O)=CC(=O)c2ccccc21
Yield: 84.9 %

Procedure:
A solution of Example 17E (1.36 g, 3.35 mmol) in tetrahydrofuran(12 mL) and 2N HCl (6 mL) was stirred at 25° C. for 2 hours. The mixture was concentrated in vacuo and the resulting oil was triturated with ethyl acetate. The white hydrochloride salt was filtered, suspended in ethyl acetate, and basified to pH 10 with 1N NaHCO3. The ethyl acetate layer was dried (Na2SO4), filtered, and concentrated in vacuo to afforded the title compound as an amber oil (1 g, 84.8%) and used for the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.34-0.51 (m, 1H), 0.63 (d, J=6.62 Hz, 3H), 0.69 (d, J=6.62 Hz, 3H), 0.72-0.89 (m, 1H), 0.92-1.09 (m, 1H), 1.16-1.31 (m, 1H), 1.46-1.77 (m, 2H), 4.23 (d, 1H), 4.30-4.40 (m, 1H), 5.71 (s, 1H), 6.84-6.95 (m, 2H), 7.06 (s, 1H), 7.19 (q, J=3.55 Hz, 3H), 7.45 (t, J=6.99 Hz, 1H), 7.61 (t, J=7.17 Hz, 1H), 7.84 (d, J=7.72 Hz, 1H), 7.87 (d, 1H), 11.78 (br.s, 1H); MS (ESI) m/z 352.0 (M+H)+.
Reaction SMILES: [C:1]([CH:4]([C:9](=[O:32])[CH:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:29]=[N:28][C:27]3[C:22](=[CH:23][C:24]([Cl:31])=[C:25]([Cl:30])[CH:26]=3)[N:21]=2)=[CH:15][CH:14]=1)[CH3:11])C(OC)=O)(=[O:3])[CH3:2].ClC1C=C2C(=CC=1Cl)N=C(OC1C=CC(OC(C)C(Cl)=O)=CC=1)C=N2.[Na].COC(=O)CC(C)=O.[Cl-].[Na+]>CS(C)=O>[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[Cl:31])[N:21]=[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:10]([CH3:11])[C:9](=[O:32])[CH2:4][C:1](=[O:3])[CH3:2])=[CH:18][CH:17]=1)[CH:29]=[N:28]2
Reactant: COC(=O)C(C(C)=O)C(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)c(Cl)cc3n2)cc1
Agent: CC(Oc1ccc(Oc2cnc3cc(Cl)c(Cl)cc3n2)cc1)C(=O)Cl
Agent: COC(=O)CC(C)=O
Agent: [Cl-]
Solvent: CS(C)=O
Product: CC(=O)CC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)c(Cl)cc3n2)cc1

Procedure:
Again, following the same procedures, methyl 2-acetyl-4-[4-(6,7-dichloro-2-quinoxalinyloxy)phenoxy]-3-oxopentanoate (XIV; X' is chloro and X" is chloro) is prepared from 2-[4-(6,7-dichloro-2-quinoxalinyloxy)phenoxy]propionic acid chloride and the sodium salt of methylacetoacetate, and is then heated with sodium chloride and DMSO to yield 5-[4-(6,7-dichloro-2-quinoxalinyloxy)phenoxy]-2,4-hexanedione (XV; X' is chloro and X" is chloro).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:11][O:12][N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][O:12][N:13]([CH3:18])[C:14]([CH:15]=[CH:16][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])=[O:17]
Reactant: C=CC(=O)N(C)OC
Reactant: NC(=O)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1cccc(C(N)=O)c1
Yield: 58 %

Procedure:
3-Iodo-benzamide compound 32 (3.0 g, 12.1 mmol), N-methoxy-N-methylacrylamide (Molander, G. G.; Stengel, P. J. Tetrahedron 1997, 53, 26, 8887-8912.) (1.8 g, 15 mmol), palladium (II) acetate (40 mg, 0.18 mmol), and triethylamine (2.1 mL, 15 mmol) were stirred in acetonitrile (12 mL) under argon in a sealed tube at 100° C. for 2.5 h. The reaction was allowed to cool, and solvent was removed. The residue was dissolved in CH2Cl2, washed with 0.1 N HCl and then with brine, dried (MgSO4), and concentrated. Recrystallization twice from methanol gave 1.64 g (58%) of 3-[2-(methoxy-methylcarbamoyl)-vinyl]benzamide 43 as a white solid. 1H NMR (CDCl3) δ 8.06 (1 H, s), 7.78 (1 H, d, J=7.8 Hz), 7.73 (1 H, d, J=16.2 Hz), 7.69 (1 H, d, J=7.8 Hz), 7.46 (1 H, t, J 7.8 Hz), 7.10 (1 H, d, J=16.2 Hz), 6.33 (1 H, br s), 5.97 (1 H, br s), 3.77 (3 H, s), 3.31 (3 H, s); IR (KBr) 3385, 3173, 1680, 1649, 1613, 1582, 1476, 1433, 1397, 1182, 1105 cm−1. Anal. (C12H14N2O3.0.33 H2O) C, H, N.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]2[S:26][C:27]([C:29]([OH:31])=O)=[CH:28][C:22]=2[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.Cl.[N:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][C:43]3([CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH2:42][CH2:41]2)=[CH:36][CH:35]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[N:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:45][CH2:44][C:43]3([CH2:46][CH2:47][N:48]([C:29]([C:27]4[S:26][C:23]5[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:21][C:22]=5[CH:28]=4)=[O:31])[CH2:49][CH2:50]3)[CH2:42][CH2:41]2)=[CH:38][CH:39]=1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)cc2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1,1′-Carbonyldiimidazole (119 mg, 0.741 mmol) and 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (200 mg, 0.706 mmol) were dissolved in dichloromethane (5 ml) and N,N-dimethylformamide (3 ml) and stirred for 1 h at room temperature. 3-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecane dihydrochloride (322 mg, 1.059 mmol), dissolved in a mixture of dichloromethane (5 ml) and triethylamine (0.293 ml, 2.118 mmol), was then added dropwise and the reaction mixture was stirred for 3 days at room temperature. The mixture was diluted with dichloromethane (50 ml) and washed with saturated sodium hydrogen carbonate solution (3×10 ml) and with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol, 5:1). Yield: 280 mg (80%)
Reaction SMILES: C([CH2:9][OH:10])=CC1C=CC=CC=1.[CH3:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=1.CO>C1(C)C(C)=CC=CC=1>[CH3:9][O:10][CH:16]([C:15]1[CH:18]=[CH:19][C:12]([CH3:11])=[CH:13][CH:14]=1)[CH3:17]
Reactant: C=Cc1ccc(C)cc1
Reactant: OCC=Cc1ccccc1
Solvent: Cc1ccccc1C
Solvent: CO
Product: COC(C)c1ccc(C)cc1

Procedure:
The RPlug reactor model of ASPEN PLUS® (Ver. 7.1) is used to model the plug flow reactor (PFR) for the reaction of styrene (A8) with methanol to form the methanol styrene ether (MSE) (i.e. 1-methoxyethylbenzene). Laboratory rate data of the reaction in xylene solvent shows an empirical relationship that is directly proportional to styrene concentration and inversely proportional to methanol concentration. It considers the effect of methanol adsorption to account for an enhanced rate at low methanol concentrations, while also accounting for inhibition of methanol at very high methanol concentrations. The reaction model also takes into account the reverse reaction by including the equilibrium constant (Keqm) which is taken from the literature (Verevkin et. al., J. Chem. Eng. Data, 46, 984-990, 2001). The NRTL-RK property method is used for vapour-liquid equilibrium calculations. Binary interaction parameters were estimated for binary pairs involving MSE and for styrene-methanol. The reaction of 4-methylstyrene (A9) and methanol to form 1-(4-methylphenyl)ethyl methyl ether (4MMSE) is modeled as a side reaction. The reaction rate was estimated from conversion data found in the literature (Zhang and Corma, Royal Society of Chemistry, 2007, Chem. Commun. 2007, 3080-3082). Since both product components (MSE and 4MMSE) are not found in the ASPEN PLUS® database, Aspen Properties using the group contribution method of GANI were used to estimate boiling point temperatures and other critical constants. In this case, the reactor is designed as a constant temperature PFR operating at 100° C. It is sized for a 1 mol/h flow of styrene in a feed mixture containing 0.2433 mass fraction of styrene in xylene. An inert, unreactive C9H12 component present at 0.1957 mass fraction is included and modeled as 1-methyl-4-ethylbenzene. FIG. 5 is a schematic representation of a 1-stage plug flow reactor 402 for methanol styrene ether synthesis. The feed 406 contains styrene, methylstyrene and inert C8 and C9 compounds. Since Methanol to feed ratio in excess of the stoichiometric requirements are used, the effluent 410 from reactor 402 is sent to distillation column 107 to separate the methanol and unreacted feed compounds 409 from product ethers 136. Stream 409 is recycled and mixed with feed 406 and methanol stream 405. The mixture 407 then enters reactor 402.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CC1C=C(C=CC=1C)C=NO.C=C1CCCCC1.C1C(=O)N([Br:44])C(=O)C1>C(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:44][CH:13]1[C:12]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[O:11][N:10]=[C:9]1[C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Br:1])[CH:3]=1
Reactant: Cc1ccc(C2=NOC3(CCCCC3)C2)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: C=C1CCCCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1ccc(C=NO)cc1C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2=NOC3(CCCCC3)C2Br)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a solution of 3-(3-bromo-4-methylphenyl)-1-oxa-2-azaspiro[4.5]dec-2-ene (2.0 g, 6.49 mmol, 1.0 eq) (prepared by following the procedure described for step-2 of the intermediate 27 by the reaction of 3-methyl-4-methylbenzaldehyde oxime with methylenecyclohexane) in chloroform (20 mL) was added NBS (1.15 g, 6.49 mmol, 1.0 eq) followed by catalytic amount of AIBN (21 mg, 0.13 mmol, 0.02 eq). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with chloroform (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, ethyl acetate and hexane) to afford 600 mg of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 7.97 (d, J=2.0 Hz, 1H), 7.65 (dd, J=8.0, 2.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 5.14 (s, 1H), 2.43 (s, 3H), 2.13-2.10 (m, 1H), 2.01-1.99 (m, 1H), 1.82-1.76 (m, 4H), 1.65-1.62 (m, 1H), 1.52-1.45 (m, 3H); ESI-MS (m/z) 386, 388, 390 [(MH)+ Br79,81].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]([O:28][CH2:29][O:30][CH3:31])[CH2:14][N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][C:16]1=[O:27].C(N(CC)CC)C>ClCCl>[CH3:31][O:30][CH2:29][O:28][CH:13]([CH2:14][N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][C:16]1=[O:27])[CH:12]=[O:11]
Reactant: COCOC(CO)Cn1c(=O)cnc2ccc(OC)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC(C=O)Cn1c(=O)cnc2ccc(OC)cc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.032 ml, 0.374 mmol) was dissolved in dichloromethane (2 ml). A solution of dimethyl sulfoxide (0.053 ml, 0.748 mmol) in dichloromethane (0.5 ml) was added to this solution at −78° C. and the mixture was stirred for 30 minutes. While maintaining the temperature at −78° C., a solution of 1-[3-hydroxy-2-(methoxymethoxy)propyl]-7-methoxyquinoxalin-2(1H)-one (100 mg, 0.340 mmol) in dichloromethane (3 ml) was further added and the mixture was stirred for 40 minutes. While maintaining the temperature at −78° C., triethylamine (0.261 ml, 1.870 mmol) was added and the mixture was stirred for 30 minutes. The temperature was raised to 0° C., the reaction solution was stirred for 2 hours, then diluted with dichloromethane and washed with water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to yield 109 mg (quantitative) of the title compound in the form of an orange oily product. The product was used as such for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:11].[OH-].[Na+].O.[CH:15]([Cl:18])(Cl)[Cl:16]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:16][C:15]1([Cl:18])[CH2:10][CH:9]1[C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[O:2][CH3:1]
Reactant: ClC(Cl)Cl
Reactant: C=Cc1cccc(C)c1OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1c(C)cccc1C1CC1(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
In chloroform (12 mL) was dissolved 304 mg (2.05 mmol) of 2-methoxy-1-methyl-3-vinylbenzene, 5 mL (63 mmol) of 50% aqueous sodium hydroxide solution was added dropwise to the solution, then, 59.9 mg (0.263 mmol) of benzyl(triethyl)ammonium chloride was added to the mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with chloroform. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=4:1) to obtain 390 mg (1.69 mmol, Yield: 82.4%) of 1-(2,2-dichlorocyclopropyl)-2-methoxy-3-methylbenzene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[C:9]([Cl:17])[CH:8]=2)=[O:4].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH2:15][Br:24])=[CH:11][CH:10]=[C:9]([Cl:17])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(C)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A solution of 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (1.6 g, 4.88 mmol), N-bromosuccinimide (869 mg, 4.88 mmol) and benzoyl peroxide (118 mg, 488 μmol) in carbon tetrachloride (50 mL) was heated at 100° C. for 5 h. At this time, the reaction was cooled to 25° C. The resulting solids were collected by filtration to afford 3-bromomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (1.7 g, 85.6%) as a white solid. The material was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](N1C=CN=C1)=[O:12].[NH2:18][CH2:19][C:20]#N.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:12])[CH2:20][C:19]#[N:18]
Reactant: N#CCN
Reactant: O=C(Nc1nc2ccccc2s1)n1ccnc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: C1CCOC1
Product: N#CCC(=O)Nc1nc2ccccc2s1
Temperature: 30 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
0.3 g of benzothiazole was dissolved in 50 ml of tetrahydrofuran, and then 0.32 g of carbodiimide was added thereto in a dropwise manner in ice-bath. The obtained reaction mixture was stirred at room temperature for 10 hours. The produced white solid was filtrated, to obtain N-(benzo[d]thiazole-2-yl)-1H-imidazole-1-carboxamide (0.261 g, 54%). N-(benzo[d]thiazole-2-yl)-1H-imidazole-1-carboxamide (30 mg) was dissolved in 5 ml of tetrahydrofuran, and 11.1 mg of 2-aminoacetonitrile and then 29 μl of acetic were added thereto in a dropwise manner. The obtained reaction mixture was stirred at 30° C. for 18 hours, to produce N-(benzo[d]thiazole-2-yl)-2-cyanoacetamide (10 mg) in a light brown solid phase
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[C:46]([O:45][C:44](=[O:50])[NH:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:36][C:33]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([O:13][CH3:14])[C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:22]=2[CH3:32])=[O:34])[CH2:38][CH2:39]1)([CH3:47])([CH3:49])[CH3:48]
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=1.C(N(CC)CC)C.[CH3:21][C:22]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>ClCCl.C(OCC)(=O)C>[CH3:21][C:22]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:33])([CH3:32])[C:29]([NH:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)[CH:8]=1)=[O:30]
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Cl)c1
Reactant: Cc1nnc(-c2cccc(N)c2)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc(-c3nnc(C)o3)c2)c1
Yield: 7.4 %

Procedure:
To a solution of 7.05 g (0.04 mol) of 3-(5-methyl-1,3,4-oxadiazol-2-yl)benzenamine and 10 ml of triethylamine in 300 ml of dichloromethane is added 11 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride (U.S. Pat. No. 4,285,951). The mixture is worked up, the crude product slurried in ethyl acetate and filtered through silica gel. The solvent is evaporated to give 1.2 g of 5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]pentanamide after recrystallization from 2-propanol; mp 90°-92° C.
Reaction SMILES: [CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[CH:12]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[N:17]=2)[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:3])[CH3:2].[CH3:46][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[C:12]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[N:17]=2)([CH3:46])[C:11](=[O:26])[N:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3nn(C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 165 mg (0.27 mmol) of N-Isopropyl-N-(4-methoxy-phenyl)-2-[3-(1-methyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]acetamide, prepared as in Example 49, in 5 mL of DMF at 0° C. is added 0.82 mL (0.82 mmol, 3.0 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and 51 μL (0.82 mmol, 3.0 equiv) of methyl iodide is added. The resulting solution is stirred for 4 h at RT, warmed to 50° C. for 16 h, and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel MPLC on an Si60 column using hexane/EtOAc 4/3 as eluent followed by lyophilization in acetonitrile/H2O afforded 124 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.48-6.95 (m, 16H), 6.71 (d, 1H, J=7.3), 4.78 (m, 1H), 4.21 (s, br, 2H), 3.95 (s, 3H), 3.74 (s, 3H), 2.79 (d, 2H, J=5.9), 1.20 (s, 3H), 0.93 (m, 6H); low resolution MS (FAB)m/e 616 (MH+).