Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:16][CH2:17][OH:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CO.ClCCl>ClCCl>[NH3:11].[C:1]([N:11]1[CH2:15][CH2:14][C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:16][CH2:17][O:18][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCC(CCO)(c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)OCCC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)C1
Product: N
Reaction time: 16 h
Yield: 1 %

Procedure:
Combine 1-carbobenzyloxy-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (9.6 g, 29.6 mmol) and triethylamine (8.2 mL, 59.2 mmol) in dichloromethane (150 mL). Cool in an ice-bath. Add methanesulfonyl chloride (2.5 mL, 32.6 mmol). After 16 hours, dilute the reaction mixture with dichloromethane and extract with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with methanol/dichloromethane 1/10 containing 1% concentrated aqueous ammonia to give 1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@H:13]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:19])[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1.Cl[CH2:38][CH2:39][OH:40]>>[Cl-:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:5][CH:6]1[CH2:7][CH2:8][N+:9]([CH2:38][CH2:39][OH:40])([CH2:12][CH:13]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:19])[CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:11]1
Reactant: OCCCl
Reactant: COc1cc(NC(=O)N[C@@H](CN2CCC(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc(OC)c1OC
Product: COc1cc(NC(=O)NC(C[N+]2(CCO)CCC(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc(OC)c1OC
Product: [Cl-]
Temperature: 90 °C
Reaction time: 24 h

Procedure:
1-{1-(R)-[4-(3,4-Dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3,4,5-trimethoxyphenyl)urea (0.21 g) was dissolved in 2-chloroethanol (5 mL) and the solution heated in an oil bath at 90° C. After stirring under nitrogen for 1 day, the reaction mixture was cooled and then poured directly onto a pad of silica gel. Elution with 6% methanol in methylene chloride and then 11% methanol in methylene chloride, followed by solvent removal from the appropriate fractions gave 4-(3,4-dichlorobenzyl)-1-(2-hydroxyethyl)-1-{3-methyl-2-[3-(3,4,5-trimethoxyphenyl)ureido]butyl}piperidinium chloride (41.6 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[Br:22]Br>C(O)(=O)C>[Br:22][C:16]1[CH:17]=[N:18][C:19]2[C:14]([CH:15]=1)=[CH:13][C:12]([S:11][C:8]1[N:6]3[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=1)=[CH:21][CH:20]=2
Reactant: BrBr
Reactant: Cc1ccc2nnc(Sc3ccc4ncccc4c3)n2n1
Solvent: CC(=O)O
Product: Cc1ccc2nnc(Sc3ccc4ncc(Br)cc4c3)n2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (370 mg, 1.26 mmol) in glacial acetic acid (10 mL) was added bromine (0.324 mL, 6.31 mmol) dropwise. The reaction mixture was stirred at room temperature for 5 min then at 100° C. for 2 h. The reaction was cooled to room temperature, and the mixture was concentrated in vacuo. The residue was partitioned between 10% aqueous NaOH and 10% methanol/dichloromethane. The organic layer was separated, washed with 5% aqueous Na2SO3, and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-5% methanol/dichloromethane afforded 422 mg of 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a beige solid (90% yield): 1H NMR (DMSO-d6): δ 2.53 (s, 3H), 7.41 (d, 1H), 7.70 (dd, 1H), 7.87 (d, 1H), 7.99 (d, 1H), 8.41 (d, 1H), 8.66 (d, 1H), 8.93 (d, 1H); MS (m/z) 372, 374 [M+H+]+.
Reaction SMILES: [Li].C(NC(C)C)(C)C.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:18][CH:17]=1.[CH2:28]=[O:29].Cl>C1COCC1.C(OCC)(=O)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH:24]([CH2:28][OH:29])[C:25]([OH:27])=[O:26])=[CH:20][CH:21]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: C=O
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1ccc(CCC(CO)C(=O)O)cc1
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
To a solution of lithium diisiopropylamide (prepared from diisopropylamine (16.16 g, 0.16 mol and n-butyl lithium (1.6M in hexane, 100 ml, 0.016 mol) in THF (50 ml) at -78° C., was added a solution of 4-(4-methoxyphenyl)butanoic acid (13.80 g, 0.07 mol) in THF (100 ml) over 20 min. The solution was warmed to -20° C. and stirred for 2.5 h. Formaldehyde gas generated by warming paraformaldehyde (10 g) was then passed into the reaction mixture in a stream of nitrogen. After stirring for a further 2 h. at -20° C., hydrochloric acid (2N, 500 ml) was added and the reaction mixture was diluted with ethyl acetate (800 ml). After washing with water, the organic phase was extracted with sodium hydroxide solution (0.5N, 3×200 ml). The combined aqueous extracts were acidified with hydrochloric acid and extracted with ethyl acetate (3×200 ml), the combined organic phase (MgSO4) was dried and solvent removed at reduced pressure to give the product as a colourless solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].NC(N)=O.[CH2:12](Br)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)NC(N)=O
Reactant: CCCCBr
Agent: NC(N)=O
Product: CCCCNC(=O)NC(C)C
Yield: 58 %

Procedure:
N-butyl-N'-isopropylurea was prepared in a yield of 58% as described in Example 1, but using 2.04 g of N-isopropylurea (20 mmol) as the urea and 2.74 g of butylbromide (20 mmol) as the alkylating agent.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:11])[CH:9]=[O:10].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][O:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][O:31]/[N:32]=[C:33](/[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)\[CH2:34][CH2:35]C(O)=O)=[CH:28][CH:27]=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:7][N:8]([CH3:11])[C:9](=[O:10])[CH2:35][CH2:34]/[C:33](=[N:32]\[O:31][CH2:30][C:29]1[CH:45]=[CH:46][C:26]([O:25][CH2:24][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:17][C:13]=2[CH3:12])=[CH:27][CH:28]=1)/[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)N(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Oxalyl chloride (0.156 ml) and N,N-dimethylformamide (catalytic amount) were added to a solution of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 ml) at room temperature, which was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in tetrahydrofuran (5 ml) and added dropwise to a mixture of a 40% aqueous dimethylamine (20 ml) and ethyl acetate (20 ml) at 0° C. After stirred at room temperature for 2 hours, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain E-N,N-dimethyl-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutanamide (511 mg, yield 69%) as a colorless oil from an ethyl acetate-hexane (2:1, v/v).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@H:4]([CH:12]([CH3:14])[CH3:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:16])=[O:15])[CH:12]([CH3:14])[CH3:13])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:24][CH2:23]1
Reactant: CC(C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-valinamide (973 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1764 mg) in 2-propanol (10 mL) was added piperidinium acetate (755 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (960 mg)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[CH:16]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH:29]2[CH2:31][CH2:30]2)O)=[C:23]([F:32])[CH:22]=1>ClCCl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH:29]2[CH2:31][CH2:30]2)[C:16]2[C:15]3[C:19](=[C:11]([CH2:10][S:9][CH3:8])[CH:12]=[CH:13][CH:14]=3)[NH:18][CH:17]=2)=[C:23]([F:32])[CH:22]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1F)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.13 ml (1.73 mmol) of trifluoroacetic acid was added to 256 mg (1.45 mmol) of the compound from Example 8A and 290 mg (1.45 mmol) of the compound from Example 151A in 20 ml of dichloromethane, and the mixture was stirred at RT for 2 h. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 273 mg (51% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:12]1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[N:25][C:16]=1[NH:15][C@H:13]1[CH2:14][C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=2)[CH2:12]1
Reactant: Clc1ncnc2c1ncn2[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ncnc3c2ncn3[C@H]2C[C@H](Nc3ncc4ccccc4n3)C2)cc1
Temperature: 120 °C

Procedure:
N-(Trans-3-(6-chloro-9H-purin-9-yl)cyclobutyl)quinazolin-2-amine (example 21, 0.110 g, 0.313 mmol), tetrakis(triphenylphosphine)palladium (0.018 g, 0.016 mmol), (4-methoxycarbonylphenyl)boronic acid (0.073 g, 0.406 mmol), and cesium carbonate (0.357 g, 1.094 mmol) were suspended in a mixture of dioxane (1.25 mL) and water (0.15 mL) and heated in the microwave to 120° C. for 25 minutes. The crude was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-3% methanol in dichloromethane gradient) gave the desired methyl 4-(9-(trans-3-(quinazolin-2-ylamino)cyclobutyl)-9H-purin-6-yl)benzoate (0.0531 g, 0.118 mmol, 37.6% yield). M+1: 452.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.89 (ddd, J=13.60, 8.51, 4.89 Hz, 2 H) 3.15-3.33 (m, 2 H) 3.98 (s, 3 H) 4.89-5.00 (m, 1 H) 5.44 (quin, J=7.34 Hz, 1 H) 7.30-7.35 (m, 1 H) 7.65 (d, J=8.41 Hz, 1 H) 7.69-7.81 (m, 2 H) 8.24 (d, J=8.41 Hz, 2 H) 8.45 (s, 1 H) 8.84 (d, J=8.41 Hz, 2 H) 9.01-9.14 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[H-].[Na+].[CH2:12]([N:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[C:21](Cl)[C:20]1=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([N:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([NH:1][C:2]2[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=2)[C:20]1=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: O=c1c(Cl)nc(Cl)cn1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(Nc2nc(Cl)cn(Cc3ccccc3)c2=O)c(Br)c1
Temperature: 72 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
2-Amino-3-bromo-5-methyl-pyridine (1.0 g, 5.35 mmol) was added to a solution of sodium hydride (60%, 321 mg, 8.0 mmol) in dry THF (20 mL) at r.t. under nitrogen. After 30 minutes, 1-benzyl-3,5-dichloro-2(1H)-pyrazinone (see Vekemans, et. al., J. Heterocyclic Chem., 20, (1983), 919-923) (1.36 g, 5.35 mmol) was added, and the reaction stirred at 72° C. for 4 h. The solution was concentrated in vacuo and the residue was dissolved in CH2Cl2. Organics were washed with H2O and brine, dried (MgSO4), and concentrated. Purification by silica gel chromatography (2:1:1 hexanes/EtOAc/CH2Cl2) provided the title compound as a pale yellow solid (860 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.43 (s, 1H), 7.29-7.39 (m, 5H), 5.07 (s, 2H), 2.29 (s, 3H). MS (ES) [m+H] calc'd for C17H14BrClN4O, 405, 407; found 405, 407.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C.C(OC(=O)C)(=O)C>O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:17](=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:18]([OH:20])=[O:19]
Reactant: O=Cc1cccnc1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(O)C(=Cc1cccnc1)c1ccc(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of pyridine-3-aldehyde (21.4 g), 2,4-dichlorophenylacetic acid (40.1 g), triethylamine (20 ml) and acetic anhydride (160 ml) was stirred and heated under reflux for 5 hours while maintaining a temperature of 150° C. After cooling, the reaction mixture was diluted with water (150 ml) and left to stand overnight. The crystalline solid that had separated was filtered off, washed thoroughly with water and dried. After recrystallization from ethanol (600 ml) 1 was obtained as pale yellow crystals; melting point 208-211° C.; yield 71%. The following elemental analysis results were obtained:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[NH:24]1[CH2:27][CH:26]([C:28]#[N:29])[CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:18])([CH3:19])[CH3:17])[C:13]([N:24]3[CH2:27][CH:26]([C:28]#[N:29])[CH2:25]3)=[O:14])[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 13.6 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoic acid (25 mg, 0.078 mmol) under nitrogen. THF (0.5 mL), azetidine-3-carbonitrile hydrochloride (18.45 mg, 0.155 mmol), HATU and 4-methylmorpholine (11.79 mg, 0.117 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 15-40%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow semi-solid (4.1 mg, 13.7%). 1H NMR (400 MHz, CD3OD) δ 1.17 (s, 9 H) 3.50-3.78 (m, 1 H) 4.17 (br. s., 1 H) 4.25-4.37 (m, 1 H) 4.41-4.69 (m, 2 H) 5.17-5.30 (m, 2 H) 5.44 (s, 1 H) 7.87 (br. s., 1 H) 8.25 (s, 1 H). [M+H] calc'd for C19H20ClN5O2, 386; found, 386.4.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2].[OH-].[Na+].[N+:19]([O-])([OH:21])=[O:20].OS(O)(=O)=O>>[C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCC(=O)NCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCC(=O)NCc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-Acetyl-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one (1.05 g, 4.82 mmol) was added to a 1/1 mixture of HNO3/H2SO4 (20 ml) at 0° C. The resulting solution was stirred at 0° C. for 3 h and allowed to warm to rt over 16 h. The reaction mixture was poured onto ice and neutralized with NaOH. The resulting ppt was filtered and washed with H2O to afford title compound as a pale orange solid. (600 mg, 47%). mp 253-256° C.; LCMS: m/z=264.25 (M+H+), HPLC (95% purity); 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.79 (m, 1H), 7.69 (d, J=8.6 Hz, 1H). 4.65 (m, 1H), 4.38 (m, 1H), 4.11 (m, 1H), 2.96 (m, 1H), 2.61 (m, 1H), 2.38 (m, 1H), 1.73 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[N:8]=2)[CH:2]=1.O[Li].O.Cl>C1COCC1.CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=3)[N:8]=2)[CH:2]=1
Reactant: COC(=O)c1ccc(CNc2nccc(-c3cccnc3)n2)cc1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CNc2nccc(-c3cccnc3)n2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a stirred solution of 41 (3.68 g, 11.5 mmol) in a mixture of THF (23 ml) and MeOH (23 ml) was added a solution of LiOH—H2O (1.06 g, 25.3 mmol) in water (11.5 ml) at room temperature. The reaction mixture was stirred at 40° C. overnight, cooled to the room temperature, and an aqueous solution of HCl (12.8 ml, 2N) was added (pH˜4-5). The mixture was concentrated to dryness; the formed solid was triturated with water, filtered off, washed with minimum H2O and dried to afford the title compound 42 (3.44 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 12.83 (bs, 1H), 9.23 (bs, 1H), 8.73-8.66 (m, 1H) 8.46-8.36 [m, included at 8.42 (d, J=5.1 Hz), 2H], 8.02 (t, J=6.3 Hz, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.60-7.40 (m, 3H), 7.28 (d, J=5.1 Hz, 1H), 4.67 (d, J=6.3 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24][CH2:25][C:26](Br)=[O:27]>C(OCC)(=O)C.CCCCCC>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:26](=[O:27])[CH2:25][Br:24])[C:10]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccc(Cl)cc2N1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccc(Cl)cc2N1Cc1ccccc1
Yield: 50 %

Procedure:
Using (3aR*,10aS*)-9-benzyl-7-chloro-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one and bromoacetyl bromide, the titled compound was synthesized in substantially the same manner as in Working Example 122 in a yield of 50%, m.p. 163°-164° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[O:6]1[CH2:10][CH2:11][O:12][CH:5]1[C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Brc1cccc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromobenzaldehyde (15.87 g, 85.78 mmol), 1,2-ethyleneglycol (8.01 g, 128.7 mmol) and p-toluenesulfonic acid hydrate (100 mg ) in benzene (200 ml) was refluxed at 110° C. under nitrogen for 3 hours, and the water formed in the reaction was collected through a Dean Stark trap. The resulting solution was cooled to room temperature, and washed with 10% sodium hydroxide (2×100 ml), water (4×100 ml) and brine (1×100 ml), and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave the title compound as an oily material (16.8 g, 86%).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH2:23]([C:26]1([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:28][CH2:27]1)[CH2:24][CH3:25]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4](=[O:21])[NH:32][S:29]([C:26]2([CH2:23][CH2:24][CH3:25])[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[CH:19][CH:18]=1
Reactant: CCCC1(S(N)(=O)=O)CC1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CCCC1(S(=O)(=O)NC(=O)C(O)=CC(=O)N(Cc2ccc(F)cc2)OC)CC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 1-propyl-cyclopropanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. MS (M−H) calcd for C18H22FN2O6S: 413.1. Found: 413.0. 1H NMR (500 MHz, CDCl3) δ: 0.92 (t, 3, J=8), 1.00 (m, 2), 1.54 (m, 2), 1.74 (m, 2), 1.84 (m, 2), 3.68 (s, 3), 4.79 (s, 2), 6.54 (s, 1), 7.04 (m, 2), 7.29 (m, 2), 8.79 (s, 1). Anal calcd for C18H23FN2O6S: C, 52.16; H, 5.59; N, 6.76. Found: C, 52.20; H, 5.69; N, 6.66.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.COC(OC)[N:24]([CH3:26])C.O.[NH2:30]N>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)=[CH:26][NH:24][N:30]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: NN
Reactant: COc1cc(C)cc(C(=O)Cc2ccnc(SC)n2)c1
Reactant: COC(OC)N(C)C
Solvent: O
Product: COc1cc(C)cc(-c2n[nH]cc2-c2ccnc(SC)n2)c1
Yield: 78.6 %

Procedure:
1-(3-Methoxy-5-methylphenyl)-2-(2-(methylthio)pyrimidin-4-yl)ethanone was heated with N,N-dimethylformamide dimethylacetal (34.46 mL, 258.6 mmol) at 90° C. for 20 hours with stirring. Excess N,N-dimethylformamide dimethylacetal was removed by vacuum distillation, and the reaction mixture was dissolved in anhydrous ethanol (55 mL). To this solution was dropwise added hydrazine hydrate (2.59 mL, 51.72 mmol), and stirred at room temperature for 12 hours. After completion of the cyclization, the solvent was removed by vacuum distillation. The concentrate was treated in water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under vacuum. Purification by column chromatography gave the title compound (6.35 g, 78.6%).