Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)c1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CCOc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a solution of 1.1 g of sodium hydride in 50 ml of DMF, 4.0 g of 2-[4-(t-butyl)phenyl]ethanol was added, and the mixture was stirred at room temperature for one hour. Then 3.6 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred at room temperature overnight. The mixture was then poured into a mixture of ice in water. The product was extracted into CH2Cl2, and the resulting solution was concentrated to dryness. TLC showed one major spot and five minor spots. The product was purified by HPLC (silica gel, CH2Cl2). The fractions containing the major product were collected and concentrated, giving 1.9 g of the title product. Yield: 28.4%. M.P. 70°-71° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:27]3[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=3[Cl:29])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Clc1ccc(Cl)c(-c2ccc(CN3CCNC(Cc4ccccc4)C3)cc2)c1
Temperature: 85 °C
Yield: 59 %

Procedure:
0.1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2,5-dichlorophenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.07 g of the title compound. Yield 59% ES MS (+) m/z 411.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][C:18]([O:24]C)=[C:19]([O:22]C)[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26](I)[CH3:27].C(=O)([O-])[O-].[K+].[K+].[BrH:35]>C(O)(=O)C.C(N(CC)CC)C.CC(C)=O>[BrH:35].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][C:18]([OH:24])=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][N:13]3[CH2:26][CH3:27])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Reactant: CCI
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCN1CCc2cc(O)c(O)cc2C1C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of 1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (7.29 g prepared as described in Example 50), ethyl iodide (1.76 ml), anhydrous potassium carbonate (5.52 g) and acetone (100 ml) was heated under reflux for 16 hours. The reaction mixture was filtered and the solvent was removed by evaporation to give a residue which was digested with a 9:1 mixture of petroleum ether and triethylamine. The solution was filtered and the solvent removed to give a residue. A sample of this residue (4 g) was heated under reflux in a nitrogen atmosphere with glacial acetic acid (40 ml) and 48% hydrobromic acid (40 ml) for 20 hours. Removal of the solvent gave a residue which was dried by azeotropic distillation with industrial methylated spirit, then with propan-2-ol and finally with a mixture of toluene and propan-2-ol to give a solid which was washed with propan-2-ol and dried in vacuo at 80° C. to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-ethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 213°-215° C.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29]>>[CH3:31][S:28]([CH2:27][CH2:26][NH:25][C:15]([C:12]1[S:11][C:10]([NH:9][C:8]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:18])=[N:14][CH:13]=1)=[O:17])(=[O:30])=[O:29]
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNC(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 75 %

Procedure:
Prepared in 75% yield (170 mg) as described in general procedure (H) from 2-(3,3-dicyclohexylureido)thiazole-5-carboxylic acid (175 mg, 0.5 mmol) and 2-aminoethylmethylsulfone (HCl salt, 80 mg, 0.5 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:24]>>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:24])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Temperature: 100 °C
Yield: 39.2 %

Procedure:
6′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 27 Step 3, 57 mg, 0.14 mmol) in ammonia (7 M in MeOH) (1.5 mL, 10.5 mmol) was heated in a microwave reactor for 40 min at 100° C. The mixture was concentrated, re-dissolved in ammonia (7 M in MeOH) (1.5 mL, 10.5 mmol) and heated with MW for 40 min at 100° C. The mixture was concentrated. Purification of the crude product by flash chromatography using a gradient of CHCl3/MeOH 40:1-30:1-20:1 gave the title compound (21 mg, 39% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15-1.29 (m, 1H), 1.47 (m, 2H), 1.61-1.73 (m, 1H), 1.73-1.97 (m, 4H), 2.18 (s, 3H), 2.98 (d, 1H), 3.08 (d, 1H), 6.67 (m, 3H), 7.26 (d, 1H), 7.37 (dd, 1H); MS (ES+) m/z 382 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:5]([CH2:18][O:19]C2CCCCO2)[CH2:4][S:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CCO>[OH:19][CH2:18][C@H:5]1[CH2:4][S:3][C:2](=[O:1])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCCCCN1C(=O)SC[C@@H]1CO
Yield: 60.1 %

Procedure:
To a solution of 3-5 (0.5 g, 2.3 mmol) in 10 mL EtOH was added p-toluene sulfonic acid (50 mg) and the resulting solution was stirred overnight at room temperature Triethylamine (0.1 mL) was added and the solution was concentrated in vacuo. The compound was purified by flash chromatography using 80% EtOAc/hexanes to yield 0.4 g of 3-6 as a colorless oil. 1H NMR (400 MHz, acetone-d6): □ 4.2 (t, 1H), 4.1 (q, 3H), 3.9 (m, 1H), 3.7 (m, 2H), 3.6 (m, 1H), 3.4 (dd, 1H), 3.3 (dd, 1H), 3.1 (m, 1H), 2.3 (t, 2H), 1.3–1.7 (m, 8H), 1.2 (t, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]1[C:33]([CH3:34])=[CH:32][C:31]([NH2:35])=[N:30]1.FC(F)(F)C(O)=O>O1CCOCC1>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:25][CH2:26]2)=[N:7][C:2]([NH:35][C:31]2[CH:32]=[C:33]([CH3:34])[N:29]([CH3:28])[N:30]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)nn1C
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)nn1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (1.52 g, 3.66 mmol) and 1,5-dimethyl-1H-pyrazol-3-amine (800.0 mg, 7.198 mmol in 1,4-dioxane (20 mL) was added trifluoroacetic acid (2.1 g, 18 mmol). The mixture was stirred at 100° C. overnight and concentrated in vacuo. The residue was dissolved in methanol (5 mL), and adjust to Ph=8˜9 with the saturated aqueous solution of NaHCO3. Then the mixture was exacted with DCM/MeOH (50 mL/10 mL) and the separated organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 10/1) to give the product as a yellow white solid (1.36 g, 95.3%).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2=[O:34])=[CH:4][CH:3]=1.[C:37]1([Mg]Br)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCOCC>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2([OH:34])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][CH:36]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 13 (36 mg, 0.071 mmol) in 0.35 mL of dry THF was cooled to 0° C. A 26 μL aliquot of a 3 M solution of phenyl magnesium bromide in ether (0.078 mmol) was added to the mixture and the reaction was allowed to warm up to room temperature. The reaction was worked up in 30 minutes when the reaction was complete as indicated by TLC. The mixture was diluted with EtOAc and washed with water. The product 14 was purified by column chromatography using 20% EtOAc-Hex solvent system to provide 33 mg (80%) of the product as a solid. 1H NMR (300 MHz, CDCl3) δ 1.20 (s, 18H), 1.52-1.68 (m, 3H), 2.95 (s, 1H), 3.93 (s, 3H), 4.08 (d, 1H, J=15 Hz), 4.77 (d, 1H, J=15 Hz), 6.85 (t, 2H, J=9Hz), 7.19-7.25 (m, 2H), 7.25-7.35 (m, 3H), 7.39-7.49 (m, 3H), 8.26 (d, 1H, J=8 Hz), 8.84 (br d, 1H, J=4 Hz); 19F NMR (282.6 MHz, CDCl3) δ −76.2, 60.7; EI MS (m/z) 587.5 [MH+], 609.4 [M+Na].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[F:11][C:12]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[F:11][C:12]1([F:17])[CH2:16][CH2:15][N:14]([CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH2:1])[CH2:13]1
Reactant: Nc1cnccc1C=O
Reactant: FC1(F)CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cnccc1CN1CCC(F)(F)C1
Reaction time: 18 h
Yield: 56.3 %

Procedure:
3-Amino-pyridine-4-carbaldehyde (250 mg, 2.05 mmol) was dissolved in DCM (4 mL) and MeOH (4 mL), and 3,3-difluoropyrrolidine hydrochloride (353 mg, 2.46 mmol) and NaBH(OAc)3 (521 mg, 2.46 mmol) were added. The reaction mixture was stirred for 18 h, quenched with water (5 mL) and the solvents were removed in vacuo. The residue was dissolved in DCM (20 mL) and washed with sat aq Na2CO3 (5 mL). The aqueous phase was extracted with DCM (3×20 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the crude title compound as a yellow gum (246 mg, 56%). LCMS (ES+): 214.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[F:13][C:14]1[CH:19]=[C:18](F)[N:17]=[CH:16][N:15]=1>O1CCOCC1>[F:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: [H][H]
Reactant: Fc1cc(F)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ccc(Oc2cc(F)ncn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Amino-phenol (0.135 g, 1.21 mmol) is added in one portion to a suspension of NaH (60% free-flowing powder moistened with oil, 58.2 mg, 1.45 mmol, 1.2 equiv) in dioxane abs. (1.4 mL), under an argon atmosphere. When hydrogen evolution subsides, a solution of 4,6-difluoro-pyrimidine (0.141 g, 1.21 mmol) in dioxane (0.4 mL) Is added. The resulting dark mixture is stirred for 1.5 h at rt, quenched by addition of MeOH (2 mL) and concentrated in vacuo. After addition of CH2Cl2, the resulting suspension is filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography (CH2Cl2/Et2O, 90/10, then 85/15) to afford the title compound as a white solid: ES-MS: 204.0 [M+H]+; single peak at tR=4.96 min (System 2); Rf=0.30 (CH2Cl2/Et2O, 85/15).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.[Li]CCCC>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:23])([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(=O)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
tert-Butyl 1-[(3-chlorophenyl)(oxo)acetyl]-L-prolinate (2.2 g, 6.46 mmol) was dissolved in THF (10 mL) and cooled to −78° C. under a nitrogen atmosphere (Vessel A). In a separate vessel containing 3-bromopyridine (0.68 mL, 7.1 mmol) in ethyl ether (50 mL) cooled to −78° C. was added n-BuLi (2.5M in hexanes, 3.1 mL, 7.7 mmol) and the mixture was stirred for one hour (Vessel B). The contents of Vessel B were added to Vessel A via cannula at −78° C. The temperature was increased to 0° C. and the mixture stirred for 2.5 hours. The mixture was then quenched with saturated ammonium chloride solution (40 mL) and extracted with EtOAc. The EtOAc was evaporated in vacuo, and the residue dried and purified on silica gel using a 1:1 then 2:1 mixture of EtOAc to hexane as mobile phase. Pooled fractions were dried to yield: Nonpolar isomer of tert-butyl 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-prolinate (0.43 g, HPLC RT=3.01 min, Method A; LCMS m/z=417). Polar isomer of ten-butyl 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-prolinate (0.12 g, HPLC RT=2.96 min, Method A; LCMS m/z=417).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:15][CH2:14][CH2:13][N:12]2[CH:16]=[C:17]([C:19]([O:21]CC)=O)[CH:18]=[C:11]2[CH2:10]1)=[O:8].[OH-:24].[K+].Cl.[NH2:27]O.C(O)(=O)C>CO>[OH:24][NH:27][C:19]([C:17]1[CH:18]=[C:11]2[CH2:10][N:9]([C:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=3)=[O:8])[CH2:15][CH2:14][CH2:13][N:12]2[CH:16]=1)=[O:21]
Reactant: CCOC(=O)c1cc2n(c1)CCCN(C(=O)c1cccn1C)C2
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cccc1C(=O)N1CCCn2cc(C(=O)NO)cc2C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 6.5 %

Procedure:
To a vial containing crude ethyl 2-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate from Step 1 above was added potassium hydroxide (0.112 g, 2 mmol), hydroxylamine hydrochloride (0.0417 g, 0.6 mmol), and methanol (2 mL). The mixture was shaken at 80° C. for 2 h then cooled to room temperature. Acetic acid (0.114 mL, 2 mmol) was added to quench the excess base. The solvent was then completely evaporated and to the residue was added DMSO (1.2 mL). After filtration, the solution was purified via Gilson prep-HPLC to give N-hydroxy-2-(1-methyl-1H-pyrrole-2-carbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxamide (0.004 g, 6.5%). LC-MS (FA): ES+303; 1H NMR (CD3CN, 400 MHz) δ6.81 (s, 1 H), 6.40 (s, 1 H), 5.95 (m, 1 H), 5.81 (m, 1 H), 5.70 (m, 1 H), 4.27 (s, 2 H), 3.83 (m, 2 H), 3.51 (m, 2 H), 3.21 (s, 3 H), 1.85 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24](OC)=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:28]1([Mg]Br)[CH2:30][CH2:29]1.O1[CH2:37][CH2:36][CH2:35]C1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([C:24]([CH:35]2[CH2:36][CH2:37]2)([CH:28]2[CH2:30][CH2:29]2)[OH:25])=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1C
Reactant: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)(C4CC4)C4CC4)c23)c(C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
Under nitrogen atmosphere, to a solution of methyl 9-chloro-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (0.10 g, 0.26 mmol) in tetrahydrofuran (1.3 mL) was added cyclopropyl magnesium bromide (1M solution in tetrahydrofuran, 1.3 mL, 1.30 mmol) at room temperature, and the mixture was stirred at 70° C. for 1 h. The reaction mixture was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30% ethyl acetate/n-hexane mixture. The desired fractions were concentrated in vacuo. The residual oil was crystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (50.1 mg, 0.11 mmol, 44%).
Reaction SMILES: [CH2:1]([C:8]1[O:9][CH:10]=[C:11]([CH2:13][CH3:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([C:19]1[CH2:20][O:21][CH2:22][CH:23]=1)(=O)=O>>[CH2:1]([C:8]1[C:19]2[CH2:20][O:21][CH2:22][C:23]=2[C:10]([OH:9])=[C:11]([CH2:13][CH3:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)C1=CCOC1
Reactant: CCc1coc(Cc2ccccc2)n1
Product: CCc1nc(Cc2ccccc2)c2c(c1O)COC2

Procedure:
9.4 g (50 millimoles) of 2-benzyl-4-ethyloxazole and 29.6 g. (200 millimoles) of 3-methylsulfonyl-2,5-dihydrofuran are heated for 15 hours at 150°. Unconverted sulfone is distilled off in a high vacuum. The residue is digested in methylene chloride, the undissolved constituent is filtered off, and the filtrate is extracted with 150 ml of 10% strength sodium hydroxide solution. The alkaline solution is neutralized and extracted with methylene chloride. On concentrating the methylene chloride solution, 6.2 g of 4-benzyl-6-ethyl-1,3-dihydro-furo[3,4-c]pyridine-7-ol remain. Melting point, after recrystallization from nitromethane: 148° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20](=[O:27])[C:21]2[S:25][CH:24]=[CH:23][C:22]=2[CH3:26])[C:3]1=[O:28].[C:29]([OH:39])(=[O:38])[C@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:31]>ClC1C=C(Cl)C=C(C=O)C=1O.C(#N)C>[NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20](=[O:27])[C:21]2[S:25][CH:24]=[CH:23][C:22]=2[CH3:26])[C:3]1=[O:28].[C:29]([O-:39])(=[O:38])[C@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:31]
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: Cc1ccsc1C(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: O=Cc1cc(Cl)cc(Cl)c1O
Solvent: CC#N
Product: Cc1ccsc1C(=O)CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Product: O=C([O-])[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.8 %

Procedure:
A mixture of 4.28 g 3-amino-1,3-dihydro-1-(3-methyl-2-thenoyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 1.59 g (S)-mandelic acid, 63 mg 3,5-dichlorosalicylaldehyde and 110 ml acetonitrile was stirred at room temperature for three days. The crystals which separated out were collected by filtration and washed with 100 ml acetonitrile, thus giving 5.13 g of (R)-3-amino-1,3-dihydro-1-(3-methyl-2-thenoyl)methyl-5-phenyl-2H-1,4-benzodiazepin-2-one·(S)mandelate as white crystals.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:39])[NH:20][C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:39])[NH:20][C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.56 g), sodium hydrogen carbonate (2.35 g) and dimethyl sulfoxide (14 mL) was stirred at 40° C. for 30 min, 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.20 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.48 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.46 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.37 g, 31%).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12](=[N:16][OH:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:18]([NH:22][C:23]([O:17][N:16]=[C:12]1[C:13](=[O:15])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: O=C1C(=NO)c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)ON=C1C(=O)c2ccccc2-c2ccccc21
Yield: 99.3 %

Procedure:
22.3 g (0.1 mole) of 9,10-phenanthrene-dione-9-oxime are reacted with 12 ml (0.11 mole) of n-butyl isocyanate in 100 ml of chloroform in the presence of 0.2 ml of triethyl amine for an hour. The reaction mixture is heated to boiling for half an hour and evaporated in vacuo. Thus 32 g of 9,10-phenanthrene-dione-9-(n-butyl-aminocarbonyl)-oxime are obtained in the form of a yellowish brown oil, yield 99%.