Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@@H]1C[C@@H]([C@@](N=C=O)(OC(C)(C)C)CC(C)(C)CCOCC2C=CC=CC=2)[O:5]C1=O)C.C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(COCC=C)C1)=O)CCC.[CH2:75]([NH:79][C:80](=[O:113])[C@H:81]([CH2:111][CH3:112])[CH2:82][C@@H:83]1[O:87][C:86]([CH3:89])([CH3:88])[N:85]([C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])[C@H:84]1[CH2:97][C:98]([CH3:110])([CH3:109])[CH2:99][CH2:100][O:101]CC1C=CC=CC=1)[CH2:76][CH2:77][CH3:78].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(NC(C2CC2)=O)C1)=O)CCC>>[CH2:75]([NH:79][C:80](=[O:113])[C@H:81]([CH2:111][CH3:112])[CH2:82][C@@H:83]1[O:87][C:86]([CH3:89])([CH3:88])[N:85]([C:90]([O:92][C:93]([CH3:94])([CH3:95])[CH3:96])=[O:91])[C@H:84]1[CH2:97][C:98]([CH3:109])([CH3:110])[CH2:99][C:100]([OH:101])=[O:5])[CH2:76][CH2:77][CH3:78]
Reactant: CC[C@@H]1C[C@@H]([C@@](CC(C)(C)CCOCc2ccccc2)(N=C=O)OC(C)(C)C)OC1=O
Reactant: CCCCNC(=O)[C@H](CC)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCOCc1ccccc1
Agent: C=CCOCC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC)C1
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(NC(=O)C2CC2)Cc2ccccc21)NC(=O)OC(C)(C)C
Product: CCCCNC(=O)[C@H](CC)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O

Procedure:
Starting from 200 mg of 3(R)-ethyl-5(S)-[5-benzyloxy-1(S)-tert-butoxy- carbonylamino-3,3-dimethyl-pentyl]-2-oxo-tetrahydrofuran via 2(R)-ethyl-9-benzyloxy-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7,7-dimethyl-nonanoic acid (N-butyl)amide (Rf (A)=0.28; FAB-MS: (M+H)+ =507), 3-[N-tert-butoxycarbonyl-4(S)-(4-benzyloxy-2,2-dimethylbutyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-ethyl-propionic acid (N-butyl)amide (Rf (B)=0.46; FAB-MS: (M+H)+ =547) and 3-[N-tert-butoxycarbonyl-4(S)-(2,2-dimethyl-4-hydroxybutyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-ethyl-propionic acid (N-butyl)amide (Rf (A)=0.24; FAB-MS: MS:(M+H)+ =457) in a manner analogous to that described in Examples 74a,74b and 74c), as the pure diastereomer: Rf (P)=0.58; FAB-MS:(M+H)+ =471.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16]C)=O)=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3].N1([C:24]2[N:29]=[CH:28][C:27]([C:30](OC)=O)=[CH:26][CH:25]=2)CCOCC1>>[CH3:5][O:4][C:1]1[CH:30]=[C:27]([CH2:26][CH2:25][C:24]2[CH:9]=[C:8]([NH:13][C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[O:4][CH2:1][CH:2]=[CH2:3])=[N:13][CH:12]=3)=[O:16])[NH:7][N:29]=2)[CH:28]=[CH:3][CH:2]=1
Reactant: C=CCOC(=O)Nc1ccc(C(=O)OC)cn1
Reactant: COC(=O)c1ccc(N2CCOCC2)nc1
Product: C=CCOC(=O)Nc1ccc(C(=O)Nc2cc(CCc3cccc(OC)c3)n[nH]2)cn1
Yield: 37 %

Procedure:
Methyl 6-(prop-2-enoxycarbonylamino)pyridine-3-carboxylate, used as starting material was prepared in an analogous manner to the synthesis of methyl 6-morpholin-4-ylpyridine-3-carboxylate in Example 32, but starting with 6-(prop-2-enoxycarbonylamino)pyridine-3-carboxylic acid carboxylate (880 mg, 3.96 mmol) to give the title compound (0.35 g, 37%); 1H NMR (400.132 MHz, CDCl3) 3.93 (s, 3H), 4.75 (dt, 2H), 5.32 (dq, 1H), 5.41 (dq, 1H), 6.09-5.99 (m, 1H), 8.07 (d, 1H), 8.30 (dd, 1H), 8.97 (d, 1H), 9.45 (brs, 1H); MH+ 237.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH3:7])=[O:4].C1C=CC2N(O)N=NC=2C=1.O.Cl.[NH2:34][C@@H:35]([C:37]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:38])[CH3:36]>CN(C=O)C.C(Cl)CCl>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([NH:34][C@@H:35]([C:37]([NH:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])=[O:38])[CH3:36])=[O:14])=[O:9])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: C[C@@H](N)C(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@H](C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a solution of Boc-Gly-Ala-Gly prepared as in Example 34B (11.0 g, 36.5 mmol) in anhydrous DMF (270 ml), was added HOBT.circle-solid.H2O (5.46 g, 40.4 mmol), EDC.circle-solid.HCl (7.74 g, 40.4 mmol), and DAla-Gly-OBzl .circle-solid.HCl prepared as in Example 34A (9.95 g, 36.5 mmol). The pH of the resulting solution was adjusted to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the reaction mixture was allowed to stir at room temperature for 12 h thereafter. The solution was concentrated in vacuo and the residue was dissolved in water (50 ml). This solution was extracted with ethyl acetate (3×100 ml). The combined ethyl acetate layers were washed with 1N sodium bisulfate (50 ml), saturated sodium bicarbonate (50 ml) and brine (50 ml). The ethyl acetate solution was dried (magnesium sulfate), filtered and allowed to sit for 12 h undisturbed. Collection of the crystals by filtration and drying at high vacuum afforded 13.4 g (70% yield) of pure product: 1H NMR (DMSO-d6) δ 1.22 (d, J=7.2 Hz, 3H), 1.23 (d, J=7.2 Hz, 3H), 1.38 (s, 9H), 3.58 (d, J=6.0 Hz, 2H), 3.73 (d, J=4.8 Hz, 2H), 3.91 (dd, J =6.0, 3.0 Hz, 2H), 4.32 (m, 2H), 5.14 (s, 2H), 6.91 (t, J=4.8 Hz, 1H), 7.38 (s, 5H), 7.97 (d, J=8.1 Hz, 1H), 8.02 (d, J=6.9 Hz, 1H), 8.19 (t, J=5.4 Hz, 1H), 8.33 (t, J=5.4 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH:27]([CH3:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9]C.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:28][CH:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]1[S:11]([C:5]1[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=1)(=[O:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
A stirred suspension of 5-[(3,4-dimethoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (988 mg, 2.5 mmol) and cyclohexene (4.11 g, 50 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (15 mL, 15 mmol). After stirring for approximately two hours at room temperature, the reaction was quenched with methanol (20 mL) and diluted with dichloromethane. The mixture was washed sequentially with an aqueous potassium carbonate solution, a saturated, aqueous, sodium chloride solution, and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and eluted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo to a crude residue (1.0 g). The crude residue was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g) with gradient elution of between 10% to 70% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min; and afforded, after evaporation of the solvent, a colorless solid. Crystallization of the colorless solid from a mixture of ethyl acetate-diethyl ether-hexane yielded the title compound (0.523 g, 1.42 mmol, 57%) as a colorless, amorphous solid, m.p. 163-165° C.;
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:22]#[N:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:24](=[O:27])([O-])[O-:25].[Na+].[Na+]>ClCCl.C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O>[CH2:2]([O:25][C:24]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:22]#[N:23])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1)=[O:27])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(CN)c2)CC1
Agent: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(CNC(=O)OCc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g of 4-(3-Aminomethyl-phenyl)-1-tert-butoxycarbonyl-piperidine-4-carbonitrile in 15 ml of dichloromethane was added a few drops of triethylamine followed by a few drops of benzyl chloroformate. The mixture was stirred for 1 hour at room temperature and was poured into aqueous sodium carbonate and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and was filtered. The filtrate was evaporated and the residue was used directly in the next step without further purification: 1H-NMR (300 MHz, CDCl3)δ (TMS) 1.39-1.52 (m, 9H), 1.80-2.16(m, 4H), 3.08-3.42(m, 4H), 4.19-4.50(m, 2H), 5.08-5.13(d, 2H), 7.28-7.79(m, 9H), MS (ESI) m/e 450 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[C:36]1(CO)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4)c(Cl)c3)c2cc1OC
Yield: 71.2 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (134 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, phenylmethanol (49 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (100 mg, yield 72%).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[C:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:36])[CH3:35]>>[C:34]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[C:22]([O:23][CH3:24])=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)=[CH:39][CH:38]=1)(=[O:36])[CH3:35]
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccc(C(C)=O)cc1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 51 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used 4-acetylphenyl boronic acid. The title compound (83 mg) was obtained as a pale green solid, (yield=51%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[CH2:8][N:9](C)[CH2:10][CH2:11][CH:12]=2)=[N:4][S:5][N:6]=1>ClCCCl>[ClH:1].[Cl:1][C:2]1[C:3]([C:7]2[CH2:8][NH:9][CH2:10][CH2:11][CH:12]=2)=[N:4][S:5][N:6]=1
Reactant: CN1CCC=C(c2nsnc2Cl)C1
Solvent: ClCCCl
Product: Cl
Product: Clc1nsnc1C1=CCCNC1
Temperature: 40 °C

Procedure:
To a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (670 mg, 3.1 mmol) in 1,2-dichloroethane (20 ml) was added a solution of 1-chloro-methyl-chloroformate (440 mg, 3.1 mmol) in 1,2-dichloroethane at 0° C. The reaction mixture was heated to 40° C. for 2 h and evaporated. The residue was dissolved in methanol and heated to reflux for 1 h. After cooling to room temperature the precipitate was collected by filtration to yield 320 mg (41%). (M.p. 224° C.; M+ : 201 and 203; Compound 17).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:18]=3)[C:13]([C:34]#[N:35])=[CH:12]2)=[CH:7][C:6]=1[O:36]COC)C.C(O)C.O.[OH-].[Li+].Cl>O.O1CCCC1>[CH2:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([C:13]([C:34]#[N:35])=[CH:12][N:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:40])=[O:3])=[C:6]([OH:36])[CH:7]=2)=[CH:15][CH:16]=1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCNC(=O)OCc4ccccc4)cc32)cc1OCOC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cn(-c2ccc(C(=O)O)c(O)c2)c2cc(OCCNC(=O)OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To a solution of 4-[6-(2-benzyloxycarbonylaminoethyloxy)-3-cyanoindol-1-yl]-2-methoxymethoxybenzoic acid ethyl ester (0.14 g) in a mixed solvent of ethanol (2.5 mL), tetrahydrofuran (5 mL), and water (2.5 mL) was added lithium hydroxide mono hydrate (0.03 g), and this mixture was stirred at room temperature for 3 hours. To this reaction mixture was added 2 mol/L hydrochloric acid (0.75 mL), and this mixture was stirred at 50° C. for 5 hours. This reaction mixture was treated 1 mol/L hydrochloric acid (5 mL), and this mixture was concentrated under reduced pressure until this solvent volume became one-third. The precipitated solid was collected by filtration, and washed with water, methanol and ether to give the title compound (0.097 g)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][NH:39][C:40]2[CH:44]=[CH:43][S:42][C:41]=2[C:45](O)=[O:46])=[CH:30][CH:29]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][NH:39][C:40]2[CH:44]=[CH:43][S:42][C:41]=2[C:45]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][N:8]3[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=2)=[O:46])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc21
Reactant: O=C(O)c1sccc1NCc1ccnc2ccccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(NC(=O)c3sccc3NCc3ccnc4ccccc34)cc21
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 6-aminoindoline-1-carboxylate (3.2 g, 13.68 mmol) in CH2Cl2 (135 mL) was added iPr2NEt (14 mL), 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylic acid hydrochloride (5.27 g, 16.42 mmol), EDC (3.93 g, 20.5 mmol), DMAP (0.81 g, 6.63 mmol), and HOAt (5.5 mL. 0.5M in DMF). The resulting mixture was then heated to reflux under N2 atmosphere. After 8 h the reaction was cooled to rt and then washed with 50% NaCl solution. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to yield a residue that was purified by silica gel chromatography (80% EtOAc in Hexanes 100% EtOAc) to yield tert-butyl 6-({[3-[(quinolin-4-ylmethyl)amino]thien-2-yl]carbonyl}amino)indoline-1-carboxylate as a yellow solid. MS (ES+): m/z 501 [M+1]. 1H NMR (d6-DMSO, 400 MHz): δ1.48 (s, 9H), 2.99 (t, J=8.4 Hz, 2H), 3.90 (t, J=8.4 Hz, 2H), 5.06 (d, J=6.0 Hz, 2H), 6.78 (brs, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.40 (d, J=4.4 Hz, 1H), 7.56 (d, J=5.6 Hz, 1H), 7.66 (t, J=6.8 Hz, 1H), 7.78 (t, J=6.8 Hz, 1H), 8.04 (m, 2H), 8.21 (d, J=8.0 Hz, 1H), 8.82 (d, J=4.4 Hz, 1H), 9.35 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CCN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:43]([NH:50][C:19]([C:15]1[S:14][C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][CH2:2][CH:7]3[CH2:6][CH2:5]3)[C:9]2=[O:22])=[N:17][C:16]=1[CH3:18])=[O:21])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 15 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-cyclopropylethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 15% yield: mp 137-138° C.; 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 5.88 (s, 1H), 4.54 (d, J=5.7 Hz, 2H), 4.09 (t, J=7.8 Hz, 2H), 3.58 (t, J=8.7 Hz, 2H), 3.37 (t, J=7.8 Hz, 2H), 2.60 (s, 3H), 1.46 (m, 2H), 0.70-0.58 (m, 1H), 0.46-0.37 (m, 2H), 0.13-0.03 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.4, 155.3, 153.0, 137.9, 128.7, 127.8, 127.6, 44.8, 44.0, 42.5, 42.0, 32.4, 17.1, 8.4, 4.3; MS (ES+) m/z 385.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2cccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2cccs2)=NC1c1ccc(F)cc1Cl
Yield: 42.5 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.7 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.33 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C1C2C(=CC=CC=2)C=[N:3][N:2]=1.[N+:11]([C:14]1[CH:15]=[C:16]2[C:21](=O)[O:20][C:18](=[O:19])[C:17]2=[CH:23][CH:24]=1)([O-])=O.NN>C(O)(C)C>[NH2:11][C:14]1[CH:15]=[C:16]2[C:17](=[CH:23][CH:24]=1)[C:18]([OH:19])=[N:3][N:2]=[C:21]2[OH:20]
Reactant: c1ccc2cnncc2c1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: NN
Solvent: CC(C)O
Product: Nc1ccc2c(O)nnc(O)c2c1

Procedure:
The synthesis of phthalazine derivatives of general formulas 13-20 may be achieved as outlined in Scheme II. In general, a mixture of 4-nitrophthalic anhydride 9 and hydrazine may be refluxed in a suitable solvent, e.g., isopropyl alcohol, to provide 6-amino-phthalazine-1,4-diol 10 in almost quantitative yield. Compound 10 may then be treated with phosphorus oxychloride and N,N-diisopropylethylamine to form 1,4-dichloro-phthalazin-6-ylamine 11. Reduction of compound 11 with a suitable reducing agent, e.g., iron, may be used to produce the amino derivative 12. Alkylation or acylation of the amino group of compound 12 using A-B-X (where, for example, A is alkyl, aryl, arylalkyl, arylheteroalkyl, B is absent, CO, SO2, and X is a suitable leaving group, such as, Cl, Br, I, OTosyl, etc.) may be used to provide the dichloro derivative of general formula 13. Treatment of compound 13 with a nucleophile of general formula R1R2NH affords two isomers of general formulas 17 and 18. Alternatively, compound 13 may be treated with NaI and HI in, e.g., acetone to obtain the di-iodo derivative 14. Compound 14 may then be reacted with an appropriate nucleophile (e.g., of general formula R1R2NH) to produce compounds 15 and 16. Compounds 15 and 16 may then be treated with CuCN to produce the corresponding cyano derivatives 19 and 20.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[N:11][N:10]=2)[CH2:4][O:3]1.C(O)(C(F)(F)F)=O>ClCCl>[F:28][C:22]1[CH:23]=[C:24]([I:27])[CH:25]=[CH:26][C:21]=1[NH:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:12]1[O:13][C:9]([NH:8][CH2:7][CH:5]([OH:6])[CH2:4][OH:3])=[N:10][N:11]=1
Reactant: CC1(C)OCC(CNc2nnc(-c3ccncc3Nc3ccc(I)cc3F)o2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCC(O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(4-{5-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-[1,3,4]oxadiazol-2-yl}-pyridin-3-yl)-(2-fluoro-4-iodo-phenyl)-amine (100 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL) and TFA (3 mL) was added. The reaction mixture was stirred at RT for 4 hrs. The solvent was evaporated, and the residue was dissolved in Ethyl acetate, and washed with 1N aqueous NaOH. After solvent evaporation a residue was collected and dissolved in methanol. The product crystallized out the methanolic solution and filtered (63 mg). LC/MS (Method A) [6.61 min; 472(M+1)].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CN([CH:30]=[O:31])C>O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:22]([CH3:24])[CH3:23])[C:14]=2[CH:30]=[O:31])=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 3 °C
Reaction time: 1.5 h

Procedure:
5.77 g (78.96 mmol) of DMF are weighed into a 100 ml three-necked round-bottomed flask, equipped with a magnetic stirrer, thermometer, dropping funnel, reflux condenser and nitrogen delivery line, and cooled, with stirring, to 3° C. 12.11 g (78.96 mmol) of phosphorus oxychloride are then slowly added dropwise so that the internal temperature does not exceed 10° C. The reaction mixture is then heated to 80° C. and 10 g (39.48 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, dissolved in 10 ml of DMF, are added dropwise in the course of 30 min. Stirring is subsequently carried out for 1.5 hours at that temperature. Cooling and dilution with 10 ml of DMF are then carried out. The reaction mixture is transferred into a dropping funnel and, with stirring, slowly added dropwise at 40° C. to 10 g (0.25 mol) of sodium hydroxide in 200 ml of water. The aqueous phase is extracted four times with 50 ml of toluene and the combined organic phases are washed six times with 100 ml of water. Subsequently, 10 g of silica gel are added, the mixture is stirred for 1 hour and filtration is carried out, followed by washing three times with 50 ml of toluene and concentration by evaporation. 10.17 g of a brown oil are obtained, which is dissolved in 100 ml of hexane under reflux. 10 g of silica gel are added, and filtration is carried out while hot, followed by washing three times with 50 ml of hot hexane. The filtrate is concentrated by evaporation and the residue is recrystallised from 94% ethanol. Slightly beige crystals having a melting point of from 89.5 to 91° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH3:21])=[C:13]([Cl:20])[C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:15]1[C:14]2[C:13]([Cl:20])=[C:12]([CH3:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: CCOC(=O)c1c(N)sc(C)c1Cl
Reactant: N#Cc1ccncc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl

Procedure:
With the procedure of Example 477, the reaction of 4-cyanopyridine and 2-amino-4-chloro-5-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.