Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3](=O)[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](=[O:13])([O-])[O-].[K+].[K+].[CH3:16]I.O>CN(C=O)C.C(OCC)(=O)C>[CH3:16][N:4]1[CH:3]=[C:2]([I:1])[C:10](=[O:13])[N:6]([CH3:7])[C:5]1=[O:8]
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: O=C([O-])[O-]
Reactant: CI
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(I)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.1 %

Procedure:
A mixture of 5-iodo uracil (22.2 mmol, 5.28 g) and powdered potassium carbonate (60 mmol, 10.3 g) in DMF (188 mL) was stirred for 24 h at room temperature and then methyl iodide (53.5 mmol, 3.33 mL) was added. Then, the reaction mixture was stirred for another 72 h at room temperature and was poured into water (150 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave crude solid which was crystallized from ethanol:water (3:1, 150:50 mL) and stored in the refrigerator overnight. The solids were collected by filtration and washed with ethanol:water mixture (3:1, 120 mL), water (30 mL), hexane (30 mL) and dried under vacuum to obtain 4.61 g (78%) of 1,3-dimethyl 5-iodo uracil as white needles (mp 226-228° C., Lit. 225-227° C., Synthetic communication 1988, 18, 855-867). EI-HRMS m/e calcd for C6H7IN2O2 (M+) 266.0021, found 266.0023.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]([C:18](=O)[C:19]([OH:21])=[O:20])[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(O)COCCO.O.NN.[OH-].[K+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]([OH:21])=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: CC1=CN2C(=NC(c3ccc(C)cc3)C2C(=O)C(=O)O)C=C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
In a clean round bottom flask was charged oxoacetic acid (68 mmol) from example 1, 100 ml of diethylene glycol, hydrazine hydrate (184 mmol) and potassium hydroxide (115 mmol). The reaction mixture was heated to a temperature of 120-180° C. The reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature and 100 ml of water was added. The reaction mass was further cooled to 0-10° C. and the pH was adjusted to 6-6.5 using acetic acid and stirred for 1 hour. The solid obtained was filtered, washed with water and dried in oven at 90-100° C. Yield: 16 gm of the title compound, m.p. 228-230° C. Purity 97% (HPLC).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9]([Cl:11])[N:10]=1)[CH:2]=[CH2:3].[CH2:16]([NH:19][CH2:20][CH:21]=[CH2:22])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[ClH:11].[CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9]([N:19]([CH2:20][CH:21]=[CH2:22])[CH2:16][CH:17]=[CH2:18])[N:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: C=CCNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(N(CC=C)CC=C)nc2c(C)csc12
Product: Cl

Procedure:
In a sealed tube were heated 287 mg (1.2 mmol) of 4-allylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine and 1.87 g (19.2 mmol) of diallylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 193 mg (yield: 53.7%) of a free base compound of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])[C:6]1([CH:9]1[CH:10]([O:18][CH3:19])[CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[OH:16])[CH3:8]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: C1CCNC1
Product: COC1C(O)CCC(O)(CN2CCCC2)C1C1(C)OC1CC=C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Fumagillol (500 mg) was dissolved in pyrrolidine (1 ml), and the solution was stirred at 50° C. overnight. Excess volume of pyrrolidine was distilled off under reduced pressure to leave 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol as a crude product. This crude product was dissolved in chloroform (5 ml), to which was added m-chloroperbenzoic acid (458 mg), and the mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: chloroform - methanol - ammoniacal water=15:1:0.1) to obtain 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide (554 mg: yield 84%) as colorless powder.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9](B(O)O)=[C:8]([F:16])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[C:18]1[CH:19]=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1.C1COCC1.O.O.O.O.O.O.O.O.O.O.B(O)([O-])[O-].B(O)(O)O.B(O)(O)O.B(O)(O)O.[Na+].[Na+]>O>[CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9]([C:18]2[CH:19]=[N:20][C:21]([Cl:24])=[N:22][CH:23]=2)=[C:8]([F:16])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cc(F)c(B(O)O)c(F)c1
Reactant: Clc1ncc(Br)cn1
Agent: OB(O)O
Agent: [Na+]
Agent: [O-]B([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1cc(F)c(-c2cnc(Cl)nc2)c(F)c1

Procedure:
A mixture of 0.22 mol of 4-pentyl-2,6-difluorophenylboronic acid (prepared from 5-pentyl-1,3-difluorobenzene and trimethyl borate using n-butyllithium), 0.18 mol of 5-bromo-2-chloropyrimidine, 550 ml of THF, 75 ml of an aqueous buffer solution (pH=8), 230 ml of an aqueous disodium tetraborate decahydrate solution (4%), 200 ml of water and 2 g of tetrakis[triphenylphosphine]palladium (0) is heated at the boil for 20 hours. Customary work-up gives the product, which can be further processed without purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[OH:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([OH:3])=[O:2].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:27]([O:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH:19]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[OH:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:3])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1C(=O)O)C(O)C1CCCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(Cc1ccccc1C(=O)OCc1ccccc1)C(O)C1CCCCC1
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a solution of t-butyl 2-(2-carboxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionate (200 mg) in dimethylformamide (2 ml) were added benzyl bromide (100 mg) and potassium carbonate (270 mg) successively. After being stirred for 30 minutes the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography [silica gel, ethyl acetate - n-hexane (1:1)] to afford t-butyl 2-(2-benzyloxycarbonylphenylmethyl)-3-cyclohexyl-3-hydroxypropionate (108 mg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([Cl:27])[N:19]=1>C(#N)C>[Cl:27][C:20]1[N:19]=[C:18]([NH:16][C:15]2[C:10]([O:9][CH3:8])=[N:11][CH:12]=[CH:13][CH:14]=2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ncccc1N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ncccc1Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 14.1 %

Procedure:
Triethylamine (6.5 mL, 46.6 mmol) was added to a solution of 2-methoxypyridin-3-amine (1.0 g, 8.1 mmol) and 2,6-dichloro-3-nitropyridine (1.62 g, 8.4 mmol) in acetonitrile (30 mL) and the resulting mixture was stirred at ambient temperature for 5 days and then at 50° C. for 24 h. The precipitate formed was filtered, washed with acetonitrile and dried in vacuo. The solid was then treated with tetrahydrofuran, filtered, washed with more tetrahydrofuran and the combined filtrate and washings were concentrated to dryness under reduced pressure to yield the title compound (0.32 g, 11%) as an orange solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:12][Si](C=[N+]=[N-])(C)C.CCOCC>C1(C)C=CC=CC=1.CO>[C:1]([C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(C)=O)s1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of 5-acetylthiophene-2-carboxylic acid (3.24 g, 19.0 mmol) dissolved in a mixture of toluene (50 mL) and methanol (50 mL) cooled to 0° C. was added 2.0 M trimethylsilyldiazomethane in ether (19.0 mL, 38.1 mmol) dropwise. Upon complete addition, the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with the addition of acetic acid and the solvent was removed. The residue thus obtained was partitioned between ethyl acetate and saturated aqueous NaHCO3 and upon separation, the organic layer was dried over anhydrous magnesium sulfate and concentrated to afford the desired product (3.49 g, 100%). LC-MS: (FA) ES+ 185)
Reaction SMILES: [C:1]([C:3]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:25]#[N:26])[N:24]=3)=[O:19])=[C:13]([C:35]3[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[CH2:37][CH:36]=3)[CH:12]=2)[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.CCO>C(Cl)Cl>[C:1]([C:3]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=3)=[O:19])=[C:13]([C:35]3[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[CH2:37][CH:36]=3)[CH:12]=2)[CH2:4][CH2:5][S:6](=[O:9])(=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: CC1(C)CC=C(c2cc(C3(C#N)CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(C3(C#N)CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(4-cyano-1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (193 mg, 0.318 mmol, as prepared in the previous step) in CH2Cl2 (10 mL) was treated with TFA (2 mL) and stirred at RT for 3 h. EtOH (5 mL) was added, and the mixture was concentrated to dryness. The residue was taken up in CH2Cl2 and carefully washed with satd aq NaHCO3 (1×). The aqueous layer was extracted with CH2Cl2 (1×), and the combined aqueous layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 20-g Isolute SPE column (FlashMaster system) with 25-50% EtOAc-hexane afforded the title compound (50.4 mg, 33%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.39 (d, 1H, J=8.8 Hz), 8.01 (s, 1H), 7.53 (dd, 1H, J=8.8, 2.0 Hz), 7.42 (d, 1H, J=2.0 Hz), 5.85-5.80 (m, 1H), 3.59-3.46 (m, 2H), 2.81-2.69 (m, 2H), 2.62-2.52 (m, 2H), 2.39-2.32 (m, 2H), 2.17-2.10 (m, 2H), 1.68-1.58 (m, 4H), 1.13 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H27N5O3S, 478.2 (M+H). found 478.2.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[N:29][N:28]=[C:27]1[SH:31]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:31][C:27]3[N:26]([CH3:25])[CH:30]=[N:29][N:28]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cn1cnnc1S
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nncn3C)s2)c(C(=O)C2CCCC2)c1
Yield: 28.2 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-thiazol-2-yl]-urea (125 mg, 25%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 4-methyl-4H-[1,2,4]triazole-3-thiol (230 mg, 2 mmol) following the general procedure Y
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]([F:25])([F:26])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH:18]=[CH:19][CH:20]=1
Reactant: NCCCc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1CCCc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (1.13 g, 4.9 mmol), 3-(3-trifluoromethyl-phenyl)-propylamine (1 g, 4.9 mmol), and K2CO3 (1.13 g, 8.17 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(3-trifluoromethyl-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.658 g, 49%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.02 (m, 2H), 2.76 (t, 2H), 3.69 (t, 2H), 4.36 (s, 2H), 7.36-7.56 (m, 7H), 7.84 (d, 1H). GC-MS: m/z 319 (M)+.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[CH:15]1([N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[C:33]([F:34])=[CH:32][N:31]=[C:30]([NH:35][C:36]5[CH:41]=[CH:40][C:39]([CH2:42][CH:43]6[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]6)=[CH:38][N:37]=5)[N:29]=4)[CH:25]=[C:26]([F:27])[C:21]=3[N:20]=[C:19]2[CH3:49])[CH2:17][CH2:16]1.ClCCCl>C(O)(=O)C>[CH:15]1([N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[C:33]([F:34])=[CH:32][N:31]=[C:30]([NH:35][C:36]5[CH:41]=[CH:40][C:39]([CH2:42][CH:43]6[CH2:48][CH2:47][N:46]([CH2:1][CH3:2])[CH2:45][CH2:44]6)=[CH:38][N:37]=5)[N:29]=4)[CH:25]=[C:26]([F:27])[C:21]=3[N:20]=[C:19]2[CH3:49])[CH2:17][CH2:16]1
Reactant: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CC5CCNCC5)cn4)ncc3F)cc2n1C1CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN1CCC(Cc2ccc(Nc3ncc(F)c(-c4cc(F)c5nc(C)n(C6CC6)c5c4)n3)nc2)CC1
Temperature: 60 °C
Yield: 68.7 %

Procedure:
Add sodium triacetoxyborohydride (720 mg) to a mixture of [4-(3-cyclopropyl-7-fluoro-2-methyl-3H-benzoimidazol-5-yl)-5-fluoro-pyrimidin-2-yl]-(5-piperidin-4-ylmethyl-pyridin-2-yl)-amine (110 mg), 1,2 dichloroethane (1.14 mL) and acetic acid (2709 μL). Heat at 60° C. for 1 h. Remove the solvent under vacuum. Purify by strong cation exchange cartridge (SCX) eluting with methanol and then methanol-NH3 2M followed by silica gel column chromatography eluting with DCM/methanol-NH3 2M (3%) to afford 80 mg of the title compound. MS (ES+): m/z=504 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([N:14]2[CH2:17][CH:16]([NH:18][CH2:19][CH2:20][CH3:21])[CH2:15]2)[S:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:3])[CH3:2].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([N:18]([CH2:19][CH2:20][CH3:21])[CH:16]2[CH2:17][N:14]([C:6]3[S:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH2:15]2)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCCNC1CN(c2nc(C(C)C)c(C(=O)OCC)s2)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CN(c2nc(C(C)C)c(C(=O)OCC)s2)C1
Yield: 61.2 %

Procedure:
The same operation as in Example (221c) was performed using ethyl 4-isopropyl-2-[3-(n-propylamino)azetidin-1-yl]-1,3-thiazole-5-carboxylate obtained in Example (229b) (91 mg, 0.29 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (51 mg, 0.29 mmol), WSC hydrochloride (168 mg, 0.88 mmol), 1-hydroxybenzotriazole (39 mg, 0.29 mmol) and N-methylmorpholine (0.06 mL, 0.58 mmol), to obtain 83 mg of the title compound as a colorless oily substance (61%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH2:16])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:19]OC(OC)N(C)C.COCCOC.Cl.[CH:34]([NH:37][NH2:38])([CH3:36])[CH3:35]>C(O)(=O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:37]([CH:34]([CH3:36])[CH3:35])[N:38]=[CH:19][N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(C)NN
Reactant: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Solvent: CC(=O)O
Solvent: COCCOC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 65 °C
Yield: 38.4 %

Procedure:
9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (4.93 g, 16.0 mmol) was taken up in 1,1-dimethoxy-N,N-dimethylmethanamine (25 mL, 0.18 mol) and 1,2-dimethoxyethane (66.5 mL, 0.640 mol). The heterogeneous mixture was stirred very vigorously and heated at 65° C. for 1 h. LC/MS showed complete consumption of starting material at the end of this period. The reaction mixture was concentrated in vacuo and carried on to the subsequent reaction with no further purification steps applied. The crude product from the previous reaction (5.8 g, 16.0 mmol) was suspended in glacial acetic acid (53.2 mL) and isopropylhydrazine hydrochloride (4.36 g, 39.4 mmol) was added. The mixture was heated at 100° C. for 2 h. The reaction vessel was cooled to room temp and the solvent was removed in vacuo. The resultant residue was dry loaded onto silica gel and purified by ISCO chromatography (120 g column, 100% EtOAc). In total, 2.3 g (39% yield) of 95 was isolated over the two steps. LC/MS (ESI+): m/z 376 (M+H, with halide isotope). 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.6, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.36 (dd, J=8.7, 2.0, 1H), 7.30 (d, J=2.0, 1H), 5.85 (dt, J=13.3, 6.6, 1H), 4.55 (d, J=15.5, 4H), 1.48 (d, J=6.6, 6H)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].C(Cl)(=O)C(Cl)=O.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]([C:6]([C:5]3[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=3)=[O:8])[CH2:23][C:22]=12
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
To a stirred mixture of 4-bromo-3-methyl benzoic acid (21.5 g, 100 mmol) and N,N-dimethylformamide (0.251 mL, 3.00 mmol) in anhydrous dichloromethane (200 mL) was added dropwise oxalyl chloride (9.16 mL, 105 mmol). The mixture was heated to reflux for 1.5 hours, then cooled to room temperature and the solvent evaporated. Fresh anhydrous dichloromethane (200 mL) was added and the resulting solution concentrated and the residue was dried in vacuo. The crude acid chloride thus obtained and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (17.5 g, 95.0 mmol) were combined in anhydrous dichloromethane (200 mL), followed by addition of N,N-diisopropylethyl amine (19.2 mL, 110 mmol). After stirring at room temperature for 18 hours, the reaction mixture was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to afford the crude amide which was recrystallized from ethyl acetate to provide slightly orange crystals (34.8 g) of the title compound, m.p. 175–176° C.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([Cl:11])=[CH:7][CH:8]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:18]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br)#[N:19]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:10]([CH2:23][C:22]2[CH:21]=[C:20]([CH:27]=[CH:26][CH:25]=2)[C:18]#[N:19])[C:9]2[C:4](=[N:5][C:6]([Cl:11])=[CH:7][CH:8]=2)[CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Clc1ccc2[nH]c(Br)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1

Procedure:
2-Bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (2.0 g, 8.6 mmol, prepared as in Example 103, Step 1) in DMF (20. mL) was treated with K2CO3 (1.8 g, 13 mmol) and m-cyanobenzyl bromide (1.9 g, 9.5 mmol, Aldrich) overnight. The reaction mixture was diluted with EtOAc and washed sequentially with water and brine. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The solid obtained was triturated with hexanes/diethyl ether and isolated by filtration. Yield: (2.3 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][C@H:16]3[O:21]C(=O)C(C)(C)C)([CH3:14])[C@@H:12]([O:28]C(=O)C(C)(C)C)[CH2:11][CH2:10]4)[CH2:7][C:6](=[O:35])[C:5]=2[CH:4]=1.[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][C@H:16]3[OH:21])([CH3:14])[C@@H:12]([OH:28])[CH2:11][CH2:10]4)[CH2:7][C:6](=[O:35])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2[C@H](OC(=O)C(C)(C)C)C[C@]2(C)[C@@H](OC(=O)C(C)(C)C)CC[C@@H]12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C(=O)C[C@@H]1[C@@H]2[C@H](O)C[C@]2(C)[C@@H](O)CC[C@@H]12
Reaction time: 3.5 h
Yield: 84.3 %

Procedure:
The keto-diester (16) (30 mg, 0.06 mmole) was added to a degassed 10% solution of potassium hydroxide in methanol-water (19:1) (4 ml), and the solution was boiled for 3.5 h under nitrogen. The solvent was removed by evaporation under reduced pressure, and the residue was dissolved in ether. The residue was washed in succession with dilute hydrochloric acid and water, dried, and evaporated to give a residue which was chromatographed on silica (1 g) eluted with ether to give the product (5) (16 mg, 82%), m.p. 113°-4° C. (from ether-light petroleum), νmax 3400 (OH) and 1675 cm-1 (CO), δ (400 MHz) 8.08 (1 H, dd, J 8.5 and 1 Hz, 1-proton), 7.54 (1 H, d, J 3 Hz, 4-proton), 7.12 (1 H, dd, H 8.5 and 3 Hz, 2-proton), 4.27 (1 H, dt, H 10 and 5 Hz, 11-proton), 3.85 (3 H, s, OCH3), 3.79 (1 H, t, J 8 Hz, 17-proton), 2.78 (1 H, dd, J 17 and 2,5 Hz, 12-proton), 2.45 (1 H, t, J 10 Hz, 9-proton), 2.35 (1 H, A portion of ABX system, J 12 and 5 Hz, 7-proton), 2.35 (1 H, B portion of ABX system, J 12 and 5 Hz, 7-proton), 2.18 (2 H, m), 1.96 (1 H, qt, J 14, 10, 5, and 3.5 Hz, 8-proton), 1.86 (2 H, br s, OH), 1.56-1.27 (5 H, m), 0.8 (3 H, s, 18-CH3);