Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(Cl)Cl.[CH3:21][O:22][C:23]([O:27][Si](C)(C)C)=[C:24]([CH3:26])[CH3:25]>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:24]([CH3:26])([CH3:25])[C:23]([O:22][CH3:21])=[O:27])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OC(c1ccccc1)c1ccc2[nH]ncc2c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reaction time: 12 h
Yield: 66.7 %

Procedure:
(1H-Indazol-5-yl)(phenyl)methanol (12.1 g, 54 mmol) was dissolved in 200 mL of dry THF and 200 mL of DCM and cooled to 0 C. Added 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (43.6, 250 mmol) followed by dropwise addition of TiCl4 (60 mL of 1.0 M DCM solution, 60 mmol). After 12 h, the reaction was quenched with MeOH, poured into brine and extracted 2×DCM. The organic layers were dried over MgSO4, filtered, concentrated, and then chromatographed using 1:2 EtOAc/hexane to give 11.1 g (66% yield) of methyl 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate which was separated by chiral chromatography. MS found: (M+H)+=309.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:29]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][CH:6]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1nc2ccccn2c1-c1ccc2c(c1)CCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(C(=O)O)c1nc2ccccn2c1-c1ccc2c(c1)CCCO2
Yield: 55.7 %

Procedure:
A mixture of methyl 2-(tert-butoxy)-2-[3-(3,4-dihydro-2H-1-benzopyran-6-yl)imidazo[1,2-a]pyridin-2-yl]acetate (25e) (31 mg, 0.079 mmol) and potassium hydroxide (18 mg, 0.37 mmol) in a mixture of ethanol (3 mL) and water (1 mL) was refluxed for 1 hour. The mixture was concentrated in vacuo. Water (1 mL) was added to the residue and the aqueous layer was extracted with ethyl acetate (5 mL). The aqueous layer was acidified with 1M hydrochloric acid until pH 7 and extracted with dichloromethane (2×5 mL). The organic layer was concentrated in vacuo to provide the desired acid (17 mg, 0.044 mmol, 56%) as a beige solid.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[C:20](Cl)([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21]>O1CCCC1>[C:20]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21]
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(-n2ccnc2)cc1
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 4-(1H-imidazol-1-yl)-aniline (14 g; ~88.2 mmol) in 400 ml dry tetrahydrofuran was added dry triethylamine (14.0 ml; ~102 mmol). Ethoxalyl chloride (11.2 ml; 100 mmol) was added dropwise and the reaction mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was stirred with water to give the title compound (19.2 g; 85%). M.p. 177°-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH2:12][CH:11]=[CH:10][CH2:9]2)=[CH:5][CH:4]=1.O.[OH:16]S(O)(=O)=O.ClC1C=C(C=CC=1)C(OO)=O>CO.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:12][CH:11]3[CH:10]([O:16]3)[CH2:9]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CN2CC=CC2)cc1
Reactant: O=S(=O)(O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CC3OC3C2)cc1
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
To a solution of 4-methoxybenzyl-3-pyrroline (3.0 g, 15.8 mmol) in methanol (12 ml) cooled at 0° C., water was added (3 ml) and H2SO4 96% (1.0 ml, 19.0 mmol). The solution was stirred for 10 min. and 3-chloroperoxybenzoic acid (5.0 g, 20.5 mmol) was added in portions. The suspension was stirred at room temperature for 18 hours. Methanol was evaporated, water (15 ml) was added and the aqueous solution was neutralized with aq. NaOH 20% until pH=7. The suspension was extracted with dichloromethane and the organic phase was washed with saturated solution of NaHCO3, water and saturated solution of NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography: silica gel, gradient hexane:ethyl acetate (1:1) to neat ethyl acetate to give the titled compound (1.92 g, 59% yield) as yellow oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:24]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1C(O)=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:23])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)=[O:7])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(F)cc1
Yield: 75 %

Procedure:
By the same procedure as in Example 26-D), while using (2S)-1-(tert-butoxycarbonyl)-2-[2-(4-fluorophenoxy)-1-hydroxyethyl]pyrrolidine (1.90 g) and N-(tert-butoxycarbonyl)-L-proline (1.38 g), there was obtained 1.85 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH:3]=1.[C:22]([C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26])([OH:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[CH:12]1([CH2:11][NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:30]3[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])[CH:33]=[CH:32][CH:31]=3)[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][O:13]1
Reactant: COc1nc(Cl)cc(NCC2OCCc3ccccc32)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
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: COCCOC
Solvent: O
Product: COc1nc(NCC2OCCc3ccccc32)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 85 °C
Yield: 94.8 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-isochroman-1-ylmethyl-amine (141 mg, 0.46 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl-boronic acid (125 mg, 0.6 mmol), and Cs2CO3 (0.37 g, 1.15 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL) is degassed by bubbling with Ar gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium (0) (27 mg, 0.023 mmol) at room temperature. The mixture is heated at 85° C. for 3 h. The mixture is diluted with H2O (20 mL), and extracted with EtOAc (20 mL). The aqueous layer is separated, acidified to pH 2.5 with 1M HCl solution, and extracted with EtOAc (2×30 mL). The extracts are dried (MgSO4), filtered through a short pad of SiO2 to afford 2-(3-{6-[(isochroman-1-ylmethyl)-amino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (189 mg, Example 91). LCMS: RT=2.03 minutes; MS: 434 (M+H); 1H NMR (300 MHz, CDCl3) □9.8 (1H, s), 8.02 (1H, s), 7.82 (1H, d, J=6 Hz), 7.5-7.1 (6H, m), 6.43 (1H, s) 5 (1H), 4 (3H, s), 3.85-3.75 (1H, m), 3.65-3.55 (1H, m), 3.04-2.95 (1H, m), 2.75 (1H), 1.8 (6H, s). IC50=23 nM
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:15](I)[C:16]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:17]=3[N:18]=2)=[N:6]1.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33]>CN1C(=O)CCC1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:15]([NH:33][CH2:32][C:31]([F:35])([F:34])[F:30])[C:16]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:17]=3[N:18]=2)=[N:6]1
Reactant: NCC(F)(F)F
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(I)c21
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(NCC(F)(F)F)c21
Temperature: 170 °C

Procedure:
50 mg (0.09 mmol) of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 33A) was dissolved in 1 ml of absolute NMP and 336 mg (3.70 mmol) of 2,2,2-trifluoroethanamine was added. The mixture was heated in the microwave for 2 h at 150° C., 18 h at 150° C., 2 h at 160° C., 2 h at 170° C. and 5 h at 170° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 18 mg (purity 88%, 36% of theor.) of the target compound was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]2[N:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6]2.[N:17]([O-])=[O:18].[Na+].[OH-].[Na+]>CC(O)=O.O>[CH3:1][NH:2][C:3]1[C:4]([N:17]=[O:18])=[C:5]2[N:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CCOC(=O)c1c(NC)cc2ccccn12
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(NC)c(N=O)c2ccccn12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ethyl 2-(methylamino)-3-indolizinecarboxylate 6 (4.45 g, 20.4 mmol) was dissolved in CH3COOH (40 mL) and cooled to 0° C., before a solution of sodium nitrite (1.7 g, 24.0 mmol) in water (10 mL) was added. After being stirred at 0° C. for 3 h, the reaction mixture was basified with a 2 M solution of NaOH (pH=8-9) and extracted with CH2Cl2 (3×50 mL). The combined extracts were dried over anhydrous magnesium sulphate, filtered and then concentrated under vacuum. The residue was chromatographed on silica gel with an elution gradient of 1/1 to 4/1 of ethyl acetate/petroleum ether, to give, following removal of the solvents, 3.89 g of green microcrystals of ethyl 2-(methylamino)-1-nitroso-3-indolizinecarboxylate 7, m.p.: 156-157° C. 1H NMR (DMSO-d6): δ 1.40 (t, J=7.0 Hz, 3H), 3.47 (d, J=5.4 Hz, 3H), 4.38 (q, J=7.0 Hz, 2H), 7.35 (t, J=7.0 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.79 (br s, 1H), 8.38 (d, J=8.1 Hz, 1H), 9.27 (br s, 1H). 13C NMR (DMSO-d6): δ 14.5, 34.5, 59.7, 98.8, 116.2, 120.0, 123.5, 128.1, 135.2, 149.4, 149.8, 160.9.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([N:15]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]2[C:17]([N:18]([CH3:33])[C:19](=[O:32])[N:20]([CH3:31])[C:21]2=[O:30])=[CH:16]1)[CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[N+]1([O-])CC[O:40]CC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:8][C:9]([N:10]([N:15]1[C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:22]2[C:17]([N:18]([CH3:33])[C:19](=[O:32])[N:20]([CH3:31])[C:21]2=[O:30])=[CH:16]1)[CH2:11][CH2:12][C:13]([OH:40])=[O:14])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(N(CCCO)C(=O)OCc3ccccc3)cc2n(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)c2c(-c3ccccc3)n(N(CCC(=O)O)C(=O)OCc3ccccc3)cc2n(C)c1=O
Reaction time: 0.5 h

Procedure:
Tetrapropylammonium perruthenate (0.152 g, 0.432 mmol) was added to a solution of (1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-(3-hydroxy-propyl)-carbamic acid benzyl ester (step 2) (2 g, 4.32 mmol) and N-methylmorpholine oxide monohydrate (commercial) (2.92 g, 21.62 mmol) in Acetonitrile (40 ml). The mixture was stirred at room temp. for 30 mins. The reaction mixture was quenched with isopropanol (50 mL) and stirred for 20 mins. The mixture was then evaporated under reduced pressure. Purification of the residue by chromatography on silica, eluting with EtOAc followed by 1% acetic acid/EtOAc afforded the title compound as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]2[O:22][C:17]2([O:23][CH3:24])[C:18]([F:21])([F:20])[F:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]2[O:22][C:17]2([O:23][CH3:24])[C:18]([F:19])([F:20])[F:21])=[CH:13][CH:14]=1
Reactant: COC1(C(F)(F)F)OC1Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC1(C(F)(F)F)OC1Cc1ccc(O)cc1
Yield: 99.4 %

Procedure:
A solution of (2S*, 3R*)-4-(4-benzyloxyphenyl)-2-methoxy-1,1,1-trifluoro-2,3-epoxy-butane (957 mg, 2.8 mmol) in ethyl acetate (30 ml) was hydrogenated at atmospheric pressure over palladium hydroxide/carbon (20%, 290 mg) for 1 hour. The mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and chromatographed on silica gel (hexane:ethyl acetate=7:1-5:1) to give the title compound (691 mg, 97%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([OH:9])[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH2:16][NH:15][C:14]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[N:22][C:13]2=3)[CH2:4]1.CO>C(Cl)Cl.O=[Mn]=O>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([OH:9])[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[N:15][C:14]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[N:22][C:13]2=3)[CH2:4]1
Reactant: COc1ccc2c(n1)N(CCN1CC[C@@H](O)[C@@H](CN)C1)C(=O)CN2
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CC[C@@H](O)[C@@H](CN)C3)c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-{2-[(3S,4R)-3-(aminomethyl)-4-hydroxy-1-piperidinyl]ethyl}-6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (170 mg; 0.508 mmol) in DCM:MeOH: 10:1 was added MnO2 (156 mg; 1.52 mmol). The reaction mixture was stirred at ambient temperature under N2 for 2 days, filtered, and concentrated to obtain the product (142 mg; 84%).
Reaction SMILES: [CH3:1][C:2]([NH2:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:18][C:2]([NH:19][S:28]([CH3:27])(=[O:30])=[O:29])([CH3:1])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])cnc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CNc1c([N+](=O)[O-])cnc2ccccc12)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Under a nitrogen atmosphere, a suspension of 2-methyl-N1-(3-nitroquinolin-4-yl)propane-1,2-diamine (93 g, 358 mmol) and triethylamine (100 mL, 717 mmol) in anhydrous dichloromethane (1 L) was cooled to 0° C. Methanesulfonyl chloride (27.7 mL, 358 mmol) was added over a period of 20 minutes. The reaction was allowed to warm to ambient temperature and stirred overnight. Additional methanesulfonyl chloride (9.2 mL) was added over a period of five minutes, and the reaction was stirred for an additional day. Additional methanesulfonyl chloride (2.0 mL) was added, and the reaction was stirred for two hours. The solvent was removed under reduced pressure, and the residue was triturated with water (800 mL) at 50° C., isolated by filtration, and washed with water to provide 116 g of N-{1,1-dimethyl-2-[(3-nitroquinolin-4-yl)amino]ethyl}methanesulfonamide as a yellow powder.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[O:29][C:28](=[O:30])[CH:27]=[CH:26][C:25]=3[CH:31]=2)[C:3]1=[O:32].[CH3:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[O:29][C:28](=[O:30])[CH:27]=[CH:26][C:25]=3[CH:31]=2)[C:3](=[O:32])[CH:2]([NH:1][C:41]([NH:40][C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([CH3:33])[CH:35]=2)=[O:42])[N:8]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(Cc2ccc3oc(=O)ccc3c2)C1=O
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(Cc3ccc4oc(=O)ccc4c3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-1H-1,4-benzodiazepin-2-one (214 mg) in dry methylene chloride (20 ml) was added dropwise a solution of 3-methylphenyl isocyanate (73 mg) in dry methylene chloride (10 ml) under nitrogen atmosphere at cooling in an ice-bath. The mixture was stirred under the same temperature for 1 hour and at ambient temperature overnight. The resultant precipitates were collected by filtration to afford a crude product. The crude product was purified by column chromatography on silica gel with eluents of chloroform and a mixture of chloroform and ethyl acetate to afford N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-oxo-2H-1-benzopyran-6-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea as a colorless crystalline solid (200 mg).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.Br[C:17]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O>>[N+:25]([C:24]1[CH:23]=[CH:22][CH:21]=[C:18]2[C:17]=1[C:12]1[CH:11]=[CH:10][CH:9]=[C:4]3[C:5](=[O:7])[O:14][C:1](=[O:13])[C:2](=[CH:19]2)[C:3]=13)([O-:27])=[O:26]
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1Br
Product: O=C1OC(=O)c2cc3cccc([N+](=O)[O-])c3c3cccc1c23

Procedure:
As described in example 50, the following compounds were prepared from dimethyl homophthalate and 2-bromo-3-nitrobenzaldehyde (Rahman, L. K. A.; Scrowston, R. M. J. Chem. Soc. Perkin Trans. 1 1984, 385):
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)/[CH:7]=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2].C(N(CC)CC)C>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[N+:1]([C:4]1[CH:5]=[C:6]([C@H:7]2[C@@H:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][NH:8]2)[CH:16]=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCC/N=C/c1cccc([N+](=O)[O-])c1
Agent: [Ti+4]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CCN[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To the imine 15A (1.0 g, 2.84 mmol) and triethylamine (0.39 mL, 2.84 mmol) in dichloromethane (50 mL) at −10° C. was added titanium chloride (11.3 mL, 1.0 M in dichloromethane) dropwise under argon. The reaction was stirred at rt for 4 h and then quenched with saturated potassium carbonate. The mixture was filtered through celite and the aqueous layer was extracted with dichloromethane (2×). The organic extracts were combined, washed with brine and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by preparative HPLC equipped with a YMC ODS S5 (30×100 mm) column. The separation was performed using a linear gradient (solvent A: 10% acetonitrile-90% water-0.1% TFA; solvent B: 90% acetonitrile-90% water-0.1% TFA; 0 to 100% B in 12 min with a flow rate of 40 mL/min to give 0.32 g of 15B as a solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 2.53 (m, 2H) 3.47 (s, 3H) 3.62 (m, 1H) 3.79 (m, 2H) 5.14 (d, J=6.85 Hz, 1H) 7.76 (m, 2H) 8.33 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]([C:8]1[N:9]=[CH:10][C:11]([N:14]2[CH2:18][C@@:17]3([CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][N:26]4[C:30]5[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=5[N:28]=[CH:27]4)([CH3:24])[CH2:19]3)[O:16][C:15]2=[O:37])=[N:12][CH:13]=1)([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[CH3:47][P:48](Cl)([CH3:50])=[O:49]>ClCCl>[CH3:47][P:48]([CH3:50])(=[O:49])[O:1][CH2:2][CH2:3][O:4][C:5]([C:8]1[CH:13]=[N:12][C:11]([N:14]2[CH2:18][C@@:17]3([CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][N:26]4[C:30]5[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=5[N:28]=[CH:27]4)([CH3:24])[CH2:19]3)[O:16][C:15]2=[O:37])=[CH:10][N:9]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(OCCO)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reactant: CP(C)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(OCCOP(C)(C)=O)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reaction time: 2 h
Yield: 8.4 %

Procedure:
To a solution of 1-(((5S,7S)-3-(5-(2-(2-hydroxyethoxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (60 mg, 0.119 mmol) in dichloromethane (DCM) (1127 μl) was added DIEA (62.3 μl, 0.357 mmol) and dimethylphosphinic chloride (40.1 mg, 0.357 mmol) at RT. The mixture was stirred for 2 hours, concentrated and reconstituted in DMSO/MeOH and filtered. The solution was purified by reverse phase HPLC (Waters Sunfire 30×150 mm Acetonitrile: Water TFA 30-70%, 50 mL/min, 15 min.). The product was free based with PL-HCO3 resin SPE to yield 2-((2-(5-((5S,7S)-7-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-3-yl)pyrazin-2-yl)propan-2-yl)oxy)ethyl dimethylphosphinate as a white solid (5.8 mg, 8%). 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J=1.51 Hz, 1H), 8.60 (d, J=1.26 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.83 (d, J=8.53 Hz, 1H), 4.12-4.21 (m, 2H), 3.94-4.03 (m, 2H), 3.88 (dd, J=23.09, 10.04 Hz, 2H), 3.42 (t, J=4.77 Hz, 2H), 2.00 (d, J=13.30 Hz, 1H), 1.88 (d, J=14.05 Hz, 1H), 1.59-1.78 (m, 3H), 1.30-1.56 (m, 15H), 1.07 (s, 3H). MS (m/z) 581.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[NH:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16].C(N(CC)CC)C.CO.C(Cl)(Cl)Cl>ClC(Cl)C.CN(C1C=CN=CC=1)C.ClCCl>[CH3:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[NH:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1)=[O:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc2nc(N)[nH]c(=O)c2[nH]1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc2nc(NC(=O)C(C)(C)C)[nH]c(=O)c2[nH]1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a 250-mL round-bottomed flask was added 8 (1.37 g, 8 mmol), suspended in 40 mL of dichloroethane; then trimethylacetyl chloride (1.99 mL, 16 mmol), DMAP (0.13 g, 1 mmol) and triethylamine (2.68 mL) were added. The mixture was stirred overnight at 50° C. The resulting mixture was cooled, diluted with dichloromethane (50 mL), washed with brine (40 mL×2), dried over Na2SO4 and concentrated in vacuo. To this solution were added methylene chloride (30 mL) and silica gel (5 g) and the solvent evaporated. The silica gel plug obtained was loaded onto a silica gel column and eluted with 9:1 ethyl acetate/n-hexane The fractions containing the product (TLC) were pooled and the solvent was evaporated to afford 1.33 g (67%) of9 as a white solid: TLC Rf0.47 (MeOH/CHCl3, 1:10); mp 156-157° C.; 1H NMR (DMSO-d6) δ 1.19 (s, 9 H), 2.29 (s, 3 H), 5.97 (s, 1 H), 10.72 (s, 1 H), 11.78 (s, 1 H), 11.87 (s, 1 H). Anal. (C12H16N4O20.15CH3COCH3) C, H, N.