Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:15][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([NH:1][C:30]([NH:29][C:24]3[CH:25]=[C:26]([Cl:28])[CH:27]=[C:22]([Cl:21])[CH:23]=3)=[S:31])[CH:3]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 48 h
Yield: 50.4 %

Procedure:
Prepared according to the procedure described for Example 78 using 3-amino-4-methoxy-N-(3,4-dichloro-phenyl)-benzamide from Example 4 (0.932 g, 3.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.335 g, 1.64 mmol). After 2 days, filtration afforded the product (0.426 g); m.p. 189-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10]Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)c2ccc(Cl)cc2Cl)CC1

Procedure:
1-(2,4-dichlorophenyl)-2-chloroethan-1-one(1 mmol) and methylpiperazine (4 mmol) in 8 ml DMF was stirred for 8 h at room temperature. The reaction mixture was concentrated in vacuo and extracted into ethyl acetate and the organic layer was washed with water and dried with sodium sulfate. The residue after concentration in vacuo was purified by column chromatography eluting with 10% methanol in methylene chloride to yield 1-(2,4-dichlorophenyl)-2-(4-methylpiperazinyl)ethan-1-one. The ethanone was taken up in DMF-DMA and heated to 80° C. for 6 h. The reaction mixture was cooled and concentrated in vacuo and the residue containing the enaminone was purified by column chromatography. 1 mmol of the enaminone obtained above, 1 mmol of amino{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}carboxamidine hydrochloride and 3 mmol of Cs2CO3 was suspended in DMF and heated to 90° C. for fourteen hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the layers separated. The organic layers were dried with sodium sulfate and after solvent removal were chromatographed on silica gel eluting with 5-10% methanol in methylene chloride to obtain {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-(4-methylpiperazinyl)pyrimidin-2-yl]amine as a yellow powder after lyophilization.
Reaction SMILES: C1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12]C2)CCCCC1.[F:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]=[N:24][C:23]([C:27]([OH:29])=O)=[CH:22]2.[CH2:30](N(C(C)C)C(C)C)C.OC1C2N=NNC=2C=CC=1.N12CCC(CC1)[C@H](N)C2>CN(C=O)C>[N:9]12[CH2:10][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH2:30][C@H:8]2[NH:7][C:27]([C:23]1[N:24]=[CH:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[F:16])=[O:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2cccc(F)c2cn1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N[C@@H]1CN2CCC1CC2
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CC2CCN1CC2)c1cc2cccc(F)c2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
Dicyclohexyl-carbodiimide (7.69 g, 30 mmol) is added to a solution of 8-fluoro-isoquinoline-3-carboxylic acid (5.1 g, 22.4 mmol), ethyl-diisopropyl-amine (4.6 ml, 26.88 mmol) and hydroxybenzotriazole (5.36 g, 33.6 mmol) in DMF (150 ml). The mixture is stirred for 2 hours at room temperature. (S)-(1-Aza-bicyclo[2.2.2]oct-3-yl)amine (4.46 g, 49.28 mmol) and ethyl-diisopropyl-amine (8.7 ml, 49.28 mmol) are added and the solution is stirred for another 18 hours at room temperature. The solvent is removed by evaporation and the residue is dissolved in methylenedichloride and washed with a saturated K2CO3 solution and brine. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by chromatography (CH2Cl2/MeOH/NH4OH, 92.5/7.5/0.75) to afford the desired compound (2.35 g). The product is recrystallized from ethanolic HCl to give 2 g. of the hydrochloric salt.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20]O)=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=P(Cl)(Cl)[Cl:24]>C1COCC1>[Cl:24][CH2:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(CO)c3ccccc32)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CCl)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of (1-tosyl-1H-indol-3-yl)methanol (1.0 g, 3.318 mmol) in dry THF (10 mL), POCl3 (0.661 g, 4.314 mmol) was added at 0° C. and the mixture was stirred for 10 min. The reaction mixture was allowed to warm to ambient temperature and refluxed for 3 h. The solvent was removed under reduced pressure at 45° C. and the crude reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield the title compound as a solid (1.04 g, 98%).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28]C(C(C)=C)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:37]CC1.[C:41]([OH:45])([CH3:44])([CH3:43])[CH3:42]>CC(C)=O.O>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:42]([C:41]([OH:45])([CH3:44])[CH2:43][OH:37])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C(C)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Reactant: CC(C)(C)O
Solvent: CC(C)=O
Solvent: O
Product: CC(O)(CO)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Yield: 92 %

Procedure:
Dissolve 4-(4-Benzyl-phthalazin-1-yl)-5′-isopropenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (100 mg, 0.237 mmol) in acetone (1.5 mL), t-Butanol (0.7 mL) and water (0.7 mL). Add K2OsO4 (0.79 mg, 0.0024 mmol) then NMO (30.5 mg, 0.26 mmol) and stir reaction for 16 h at room temperature. Quench with saturated sodium sulfite (1 mL) and extract with EtOAc. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (100 mg, 92%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([CH2:8][OH:9])[O:6][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4]1.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:9][CH2:8][C@H:7]1[C@H:3]([CH2:2][O:1][CH2:5][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: OC[C@@H]1OC(c2ccccc2)O[C@H]1CO
Agent: [K+]
Agent: [OH-]
Product: c1ccc(COC[C@@H]2OC(c3ccccc3)O[C@H]2COCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
15 g (71.4 mMol) (4S,5S)-4,5-dihydroxymethyl-2-phenyl-1,3-dioxolan are rendered completely anhydrous by evaporating 2× with 300 ml toluene and the oil remaining in the reaction vessel is dissolved in 150 ml toluene. 30 g powdered KOH (535 mMol) and 71.5 g (418 mMol) benzyl bromide are added and the reaction mixture stirred for 15 hours at 80° C. The mixture is cooled, the remaining toluene-phase decanted, and the inorganic component removed from the residual phase by stirring 2× with 200 ml toluene and decanting. The combined toluene phases are filtered through talc, evaporated and the remaining oil filtered fraction-wise through 2 kg silica gel 60 using methylene chloride as solvent. Fractions containing benzyl bromide are disposed of. The title compound is obtained as a light yellow fluid with a rotation of [α]D20 =+10.1 (±1)° (c=1.4 in chloroform).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][CH:9]=[CH:8][C:7]=1[C:26]1[N:27]=[C:28]([NH:34][C:35]2[CH:36]=[N:37][N:38]([CH:40]3[CH2:42][CH2:41]3)[CH:39]=2)[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=1)(=O)C.C1COCC1.CC(O)C.O[Li].O>O>[CH:40]1([N:38]2[CH:39]=[C:35]([NH:34][C:28]3[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=[C:26]([C:7]4[C:6]([CH2:5][OH:4])=[C:11]([N:12]5[CH2:24][CH2:23][N:15]6[C:16]7[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=7[CH:22]=[C:14]6[C:13]5=[O:25])[CH:10]=[CH:9][CH:8]=4)[N:27]=3)[CH:36]=[N:37]2)[CH2:42][CH2:41]1
Reactant: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3cnn(C4CC4)c3)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cccc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)nc(Nc2cnn(C3CC3)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round-bottomed flask equipped with a stirring bar, 114c THF (1.25 mL), i-PrOH (1.25 mL), H2O (1.25 mL), LiOH H2O (135 mg) were added. The resulting mixture was stirred at RT for 1 hr. Removed all the solvent in vacuo and silica gel column chromatography (MeOH:DCM=10:90) gave 38.6 mg 2-(3-(6-(1-cyclopropyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-(hydroxymethyl)-phenyl)-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-1(2H)-one 114 as a yellow solid. MS (ESI+) m/z 526.3 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>CC(N(C)C)=O.C(#N)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1nc(-c2ccccc2)c2nccnc2n1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3)c3nccnc3n2)CC1

Procedure:
A mixture of 2-chloro-4-phenyl-pteridine (0.33 g, 1.36 mmol, 1.0 equiv; commercially available from Specs Research Laboratory, The Netherlands), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.41 g, 2.04 mmol, 1.5 equiv; commercially available) and triethylamine (0.28 mL, 0.21 g, 2.04 mmol, 1.5 equiv) in anhydrous DMAc (2 mL) and acetonitrile (9 mL) was heated by microwave irradiation to 120° C. for 20 min. The organic phase was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.5 g (91%) of the title compound. MS (ISP): 407.4 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10]C=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:6]([I:18])[C:5]2=[O:19].COC1C2[N:24]([C:38](=[O:49])[N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:40]=2)C=CC=1C(=O)C#CC1C=CC=CC=1>>[I:18][C:6]1[C:5](=[O:19])[C:4]2[CH:3]=[CH:2][N:24]3[C:38](=[O:49])[N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:40]=[C:10]3[C:9]=2[O:8][C:7]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1c(C(=O)C#Cc2ccccc2)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Reactant: O=c1c(I)c(-c2ccccc2)oc2ccc(F)cc12
Product: C[Si](C)(C)CCOCn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Yield: 81 %

Procedure:
Following the procedure used to prepare 6-fluoro-3-iodo-2-phenyl-chromen-4-one, 8-methoxy-7-(3-phenyl-propynoyl)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one was reacted to give the title compound as a cream solid (958 mg, 81%). LCMS (Method A): RT=4.80 min, [M+H]+=536.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][CH2:19][C:20]1[N:21]([CH2:31][CH3:32])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([C:29]#[N:30])[CH:23]=2)=[O:12])C.C[Si]([N-:38][Si](C)(C)C)(C)C.[Li+].Br[CH2:45][C:46]([O:48]CC)=[O:47].O>O1CCCC1>[C:29]([C:24]1[CH:23]=[C:22]2[C:27]([CH:28]=[C:20]([CH2:19][CH2:18][C@@H:14]3[CH2:15][CH2:16][CH2:17][N:13]3[C:11]([C@H:7]3[CH2:8][CH2:9][CH2:10][N:6]3[CH:5]([C:4]([OH:3])=[O:33])[CH2:45][C:46]([OH:48])=[O:47])=[O:12])[N:21]2[CH2:31][CH3:32])=[CH:26][CH:25]=1)(=[NH:30])[NH2:38]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(C#N)cc2n1CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(CC[C@@H]2CCCN2C(=O)[C@H]2CCCN2C(CC(=O)O)C(=O)O)cc2ccc(C(=N)N)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
250 mg(0.525 mmole) of ethyl-2-[(R)-2-[[(S)-2-[2-(6-cyano-1-ethyl-indol-2-yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate was dissolved in 15 ml of tetrahydrofuran and then cooled to −78° C. 0.79 ml of lithium bis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran) was added dropwise thereto, and the reaction mixture was stirred for 30 minutes. 0.09 ml(0.787 mmole) of ethyl bromoacetate diluted with 5 ml of tetrahydrofuran was added dropwise thereto, and the resulting mixture was stirred for one hour. After water was added, the reaction solution thereby obtained was extracted with dichloromethane. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(40:1)] to obtain 180 mg (Yield: 63.9%) of the title compound as a pale yellow foam.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.Cl.[N:26]([O-])=O.[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]3[N:13]=[N:26][N:14]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(Cn2ccnc2)cc1Nc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(-n2nnc3ccc(Cn4ccnc4)cc32)cc1
Temperature: 0 °C
Yield: 49 %

Procedure:
A mixture of 1.6 parts of 4-(1H-imidazol-1-ylmethyl)-N2 -phenyl-1,2-benzenediamine, 20 parts of acetic acid and 1.08 parts of concentrated hydrochloric acid was cooled in an ice bath at 12°-16° C. A solution of 0.83 parts of sodium nitrite in 7 parts of water was added dropwise. Upon complete addition, the reaction mixture was allowed to reach room temperature while stirring. The reaction mixture was poured into alkaline ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel first using a mixture of trichloromethane and methanol, saturated with ammonia, (97.5:2.5 by volume) and then a mixture of ethyl acetate, methanol and methanol, saturated with ammonia (92:2.5:2.5 by volume) as eluents. The pure fractions were collected and the eluent was evaporated. The residue was taken up in a mixture of 2-propanone and 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 0.81 parts (49.0%) of 6-(1H-imidazol-1-ylmethyl)-1-phenyl-1H-benzotriazole; mp. 110.1° C. (compound 72).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[OH:27][C@@H:28]([CH3:43])[CH2:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[C:38]([CH:41]=O)[CH:37]=[CH:36]2.C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:41]([C:38]3[CH:37]=[CH:36][C:35]4[C:40](=[C:31]([O:30][CH2:29][C@@H:28]([OH:27])[CH3:43])[CH:32]=[CH:33][CH:34]=4)[N:39]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: C[C@H](O)COc1cccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@H](O)COc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.1 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.16 g, 0.39 mmol) and (S)-8-(2-hydroxypropoxy)quinoline-2-carbaldehyde (0.91 g, 0.39 mmol) in ethanol (2.0 mL, 0.39 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2.0 mL) and iodosobenzene diacetate (0.14 g, 0.43 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.11 g, 49%).
Reaction SMILES: CN(C=O)C.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[Cl:23].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(Cl)Cl>O>[O:27]1[CH2:28][CH2:29][N:24]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]3[Cl:23])[CH2:25][CH2:26]1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCCl
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 85 %

Procedure:
DMF (3 lt), 6-(3-chloropropoxy)-7-methoxy-4-chloro quinazoline (200 gm) and morpholine (210 gm), were heated to 70-75° C. for 6-8 hours. The reaction mass was cooled to room temperature, and methylene chloride (2.5 lt) and water (2.5 lt) were charged. The layers separated and the aqueous layer extracted with methylene chloride twice (500 ml). The combined methylene chloride layer was washed with water, dried over sodium sulphate (10 gm) and concentrated completely at 35-40° C. to yield the title compound (200 gm, 85% yield).
Reaction SMILES: [C:1]([C:5]1ON=[C:7]([C:10]([NH2:12])=O)[CH:6]=1)([CH3:4])(C)C.CN.[C:15](N)(=[O:19])CCC.[NH2:21][C:22]1C=CC=[CH:24][CH:23]=1>>[CH2:22]([NH:21][C:15]([NH:12][C:10]1[CH:4]=[CH:1][CH:5]=[CH:6][CH:7]=1)=[O:19])[CH2:23][CH3:24]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)c1cc(C(N)=O)no1
Reactant: CCCC(N)=O
Agent: CN
Product: CCCNC(=O)Nc1ccccc1
Yield: 46.7 %

Procedure:
The procedures of Example 1 were repeated except that 5-t-butyl-3-isoxazolylcarboxamide and methylamine were replaced with n-butyramide and aniline, respectively, to give N-propyl-N'-phenylurea in 46.70% yield.
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:7]2[C:6]3[S:19][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=3[C:10](=[O:11])[N:9]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:18])=[CH:27][CH:26]=1)#[N:35]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1cc2c(=O)n(C(C)C(=O)OC)c(=O)[nH]c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(C(C)C(=O)OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A mixture of methyl 2-(6-ethyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)propanoate (9.9 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (11.5 g), potassium carbonate (9.7 g) and acetonitrile (500 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (15 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[OH:13][CH:14]([CH2:18][CH2:19]Br)[CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[OH:13][CH:14]1[CH2:18][CH2:19][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:16][CH2:15]1
Reactant: Nc1ccc2[nH]c(=O)ccc2c1
Reactant: OC(CCBr)CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2cc(N3CCC(O)CC3)ccc2[nH]1
Temperature: 100 °C

Procedure:
A mixture of 6-aminocarbostyril, 1.6 g (0.01 mole), crude bromopentanes from step c, 3.1 g, anhydrous sodium carbonate, 2.0 g (0.020 mole), and dimethylformamide, 15 mL, was heated for 4.5 hours at 100° C. with occasional stirring. The mixture was then cooled and diluted with water, 150 mL, to give a pasty precipitate which was filtered off and washed with water to give a sticky solid (2.9 g). The solid was taken up in hot methanol and the insoluble material filtered off (0.6 g, mp 270°-280° C.). Further treatment with hot methanol gave 0.4 g of the desired product, mp 280°-283° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12].S(=O)(=O)=O.N1C=CC=CC=1.OS([O-])(=O)=O.[K+]>CS(C)=O>[F:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: COc1ccc(CO)c(F)c1
Agent: O=S(=O)([O-])O
Agent: O=S(=O)=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1ccc(C=O)c(F)c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Triethylamine (0.92 ml, 6.60 mmol) was added to a solution of 2-fluoro-4-methoxybenzylalcohol (346.9 mg, 2.22 mmol) in DMSO (8 ml). Pyridine sulfur trioxide (1.0501 g, 6.60 mmol) was added portionwise to the mixture checking raise of the temperature. The mixture was stirred for 0.5 hours. The mixture was added to 5% KHSO4 aqueous solution, extracted three times with ethyl acetate and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ether=5/1) to give the title compound (301 mg; 88%).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[N:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34](B(O)O)=[CH:33][N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34]([C:2]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]3[CH:10]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[N:11]([C@H:14]4[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]4)[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:33][N:32]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)cc1)N([C@H]1CC[C@H](O)CC1)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N([C@H]2CC[C@H](O)CC2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 4-[2-bromo-5-(trans-4-hydroxy-cyclohexyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate AV) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 5.54 min (HPLC 2); ESI-MS: tR=0.86 min, [M+H]+ 502 (LC-MS 1); TLC: Rf=0.11 (EtOAc).