Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=O)=[CH:5][N:4]=[CH:3]1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[OH:16][N:15]=[C:7]([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:9]1[CH:13]=[CH:12][S:11][CH:10]=1
Reactant: NO
Reactant: Cn1cncc1C(=O)c1ccsc1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cncc1C(=NO)c1ccsc1
Reaction time: 72 h

Procedure:
A solution of (1-methyl-1H-imidazol-5-yl)(3-thienyl)methanone (11.6 g, 60.0 mmol) and hydroxylamine hydrochloride (14.6 g, 210 mmol) in pyridine (60 mL) was stirred 9 h at 60° C. then left to stand for 72 h at room temperature. After removal of the solvent in vacuo, addition of water (200 mL), pH adjustment to approx 7 with aq. NaOH (1 M) induced precipitation of a solid. Filtration, sequential washings of the precipitate with water and heptane, and drying of the solid afforded a first crop of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(3-thienyl)methanimine. The combined aqueous phases were extracted with dichloromethane, the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified recrystallized from heptane to afford a second crop of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(3-thienyl)methanimine. The crops were combined and recrystallized from diisopropylether to afford final N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(3-thienyl)methanimine [9.95 g, yield 76%; HPLC/MS m/z=208 (M+H); log P(HCOOH)=0.21].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[CH:60]=[CH:59][C:37]6[N:38]=[C:39]([CH:41]7[CH:46]8[CH2:47][CH:43]([CH2:44][CH2:45]8)[N:42]7[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])[NH:40][C:36]=6[CH:35]=5)=[CH:28][CH:29]=4)[C:24](F)(F)[C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[OH2:64]>CC#N.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[CH:60]=[CH:59][C:37]6[N:38]=[C:39]([CH:41]7[CH:46]8[CH2:47][CH:43]([CH2:44][CH2:45]8)[N:42]7[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])[NH:40][C:36]=6[CH:35]=5)=[CH:28][CH:29]=4)[C:24](=[O:64])[C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(=O)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C

Procedure:
(1-{2-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (10 mg) is dissolve in MeCN (1 mL) and water (1 mL). 1 drop of TFA was added. The mixture was treated with long wavelengh UV light at room temprature for 2 hours. The reaction crude was concentrated down and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give (1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9-oxo-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DL) (3.7 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]2([CH3:24])[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[N:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([OH:35])=[C:30](B(O)O)[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.C(O)(C)(C)C.[Pd]>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([C@:8]3([CH3:24])[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[N:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[C:29]([OH:35])=[CH:28][CH:27]=1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(Br)c2)NC1=NC(=O)OC(C)(C)C
Reactant: OB(O)c1cc(Cl)ccc1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: CN1C(=O)C[C@@](C)(c2cccc(-c3cc(Cl)ccc3O)c2)NC1=NC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 50 %

Procedure:
A mixture of (S)-tert-butyl 4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF2; R1=R6=Me) (0.25 g, 0.6 mmol), 5-chloro-2-hydroxyphenylboronic acid (R21=5-chloro-2-hydroxyphenyl; 0.2 g, 1.2 mmol, 2 eq), Fibrecat (4.26% of Pd, 0.7 g) and 1N aq. K2CO3 (0.5 mL) in dimethoxyethane (DME, 10 mL) or tert-butanol (10 mL) in a 20 mL Smith process vial equipped with stir a bar was sealed and heated in an Emrys optimizer at 110° C. for 15 min. After cooling, the reaction mixture was transferred to a pre-packed Si-Carbonate column and eluted with MeOH/CH2Cl2 (1:1). The eluant was collected and concentrated under reduced pressure to give 0.32 g of the crude product as an oil. The crude product was purified by silica gel chromatography (20-50% EtOAc/hexanes gradient) to yield 0.13 g (0.3 mmol, 48%) of (S)-tert-butyl 4-(3-(3-chloro-6-hydroxyphenyl)-phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1H NMR (CDCl3, 300 MHz): δ 7.48-4.32 (m, 2H), 7.20 (m, 3H), 6.84 (m, 2H), 5.68 (br s, 1H), 3.28 (d, J=15.7 Hz, 1H), 3.21 (s, 3H), 2.96 (d, J=15.3 Hz, 1H), 1.68 (s, 3H), 1.53 (s, 9H). MS (ESI): MH+=443.7, 445.7; M+−56=388.0. HPLC Rt (A)=6.99 min.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:31]1[CH2:32][CH2:33][C@@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([CH3:14])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[C@H:29]([OH:34])[CH2:30]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f43) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[NH:13][CH:14]=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN(CC)CC.P(Cl)(Cl)(Cl)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([CH:12]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[N+:13]#[C-:14])[CH:3]=1
Reactant: O=CNC(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: [C-]#[N+]C(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanamine (315 mg, 1.1 mmol) in CH2Cl2 (2 mL) at 0° C. was added acetic formic anhydride (314 uL, formed by heating a 2:1 v/v ratio of acetic anhydride and formic acid at 60° C. for 2 h). The reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified on a 40 g column of silica gel, eluting with 0 to 100% EtOAc/hexane, to give N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide (327 mg, 94% yield) as a clear, viscous oil. LCMS: RT=1.37 min [M+H] 316.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 6.13 (bs, 1H), 6.34 (d, J=7.47 Hz, 1H), 7.05-7.20 (m, 5H), 7.27-7.34 (m, 2H), 8.35 (s, 1H). To a solution of N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide (327 mg, 1.04 mmol) in THF (5 mL) at 0° C. was added Et3N (0.79 mL, 5.7 mmol) followed by phosphorous oxychloride (0.125, 1.35 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ice-water (25 mL) and extracted with Et2O (3×20 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over anhydrous Na2SO4, the filtered through basic alumina. The filtrate was concentrated to give 1-fluoro-3-((4-fluorophenyl)(isocyano)methyl)-5-(trifluoromethyl)benzene (268 mg, 93% yield) as a pale brown oil. LCMS: RT=1.71 min [M−NC] 271.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); IR νmax cm−1 neat: 2139 (N═C); NMR: 500 MHz 1H (CDCl3) δ ppm 5.94 (s, 1H), 7.12 (t, J=8.52 Hz, 2H), 7.25-7.29 (m, 1H), 7.30-7.35 (m, 3H), 7.41 (s, 1H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:12][CH2:11][C@H:10]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]2[CH2:23][C@H:22]2[CH2:24][CH2:25][F:26])[CH:20]=1)=O)(C)(C)C>CCOCC.CO>[ClH:1].[NH:9]1[CH2:12][CH2:11][C@H:10]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]2[CH2:23][C@H:22]2[CH2:24][CH2:25][F:26])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@@H]2C[C@H]2CCF)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: FCC[C@@H]1C[C@H]1c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2M HCl (anhydrous) in ether (2.0 mL) was added to a stirred solution of 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(1R,2S)-2-(2-fluoroethyl)cyclopropyl]pyridine (160 mg, 0.45 mmol) in dry MeOH (2.0 mL) at 0° C. The mixture was stirred at room temperature for 12 h. The above solution was concentrated and purified by HPLC to obtain the title compound (97 mg). 1H NMR (CD3OD, 400 MHz) δ 8.40 (br s, 1H), 8.29 (br s, 1H), 7.75 (s, 1H), 4.91-4.85 (m, 1H), 4.63-4.47 (m, 4H), 4.17-4.04 (m, 2H), 2.79-2.58 (m, 2H), 2.04-1.97 (m, 1H), 1.91-1.77 (m, 2H), 1.46-1.34 (m, 1H), 1.26-1.19 (m, 1H), 1.16-1.09 (m, 1H). MS (ESI) m/z 273 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12>C(O)(=O)C.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Reaction time: 2 h

Procedure:
A solution of crude 8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-pyrido[1,2-a]indol-6(7H)-one in acetic acid (50 ml) and water (15 ml) was stirred at 45° C. for 2 hours and then at 65° C. for 2 hours. After evaporation of the solvent, the residue was diluted with water, neutralized with an aqueous sodium bicarbonate solution, and extracted three times with methylene chloride. The organic layer combined was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel column chromatography (10% methanol-methylene chloride) gave 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.0 g) as crystals.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH:1]1([NH:6][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: NC1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC1CCCC1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Cyclopentylamine (85.2 g, 1.0 mol) and triethylamine (101.2 g, 1.0 mol) were dissolved in tetrahydrofuran (750 mL) and cooled to 0°-5° C. by means of an ice-water bath. Ethyl bromoacetate (167 g, 1.0 mol) was added dropwise at 0°-5° C. to the solution. After addition the mixture was allowed to warm up to room temperature and then stirred over night at ambient temperature. The precipitated white triethylamine hydrochloride was filtered off and the filtrate concentrated to an oil which was purified over silica gel using hexane/ethyl acetate (8.2) as the eluent. The collected product was dissolved in ether and cooled by means of an ice water bath. Dry hydrogen chloride was bubbled into the solution whereby the HCL salt of the product precipitated. Filtration yielded 138 g of product as a white solid melting at 174°-176° C.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]2[O:9][CH:10]([C:13]([OH:15])=O)[CH2:11][O:12][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][NH2:29])=[CH:20][CH:19]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O1CCCC1>[C:1]([C:5]1[CH:17]=[CH:16][C:8]2[O:9][CH:10]([C:13]([NH:29][CH2:28][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:19][CH:20]=3)=[O:15])[CH2:11][O:12][C:7]=2[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc2c(c1)OCC(C(=O)O)O2
Reactant: NCc1ccnc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(c1)OCC(C(=O)NCc1ccnc3ccccc13)O2
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of 6-tert-Butyl-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (27 mg, 0.11 mmol), quinolin-4-yl-methanamine (15 mg, 0.09 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (43 mg, 0.11 mmol) in DMF (0.4 mL) was added N,N-diisopropylethylamine (82 μL, 0.47 mmol). Tetrahydrofuran (0.8 mL) was added to dilute the solution. The reaction was left to stir overnight then concentrated and attempted purification by HPLC using 20-80% acetonitrile/water. Product isolated was less than 95% pure. It was purified again using 30-60% acetonitrile/water to obtain the product (23 mg, 64%) as a solid. m/z=376.8 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ 8.89-8.81 (m, 1H), 8.76-8.72 (m, 1H), 8.16-8.13 (m, 1H), 8.04-8.02 (m, 1H), 7.80-7.75 (m, 1H), 7.66-7.61 (m, 1H), 7.11 (t, 1H, J=4.63 Hz), 6.93-6.89 (m, 2H), 4.99-4.95 (m, 1H), 4.93-4.73 (m, 2H), 4.41-4.28 (m, 2H), 1.24 (d, 9H, J=1.94 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccnc1
Yield: 75.3 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2 g, 11.9 mmol) (Alfa) was reacted with nicotinaldehyde (1.13 mL, 11.9 mmol) (Aldrich) and piperidine (1.18 mL, 11.9 mmol) in methanol to give E/Z-6-chloro-3-pyridin-3-ylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 2.3 g, 75%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:17]([O-:19])=[O:18])=[C:8]([O:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:9]=1)[CH3:2].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:20]([NH:22][C:23]([N:13]1[C:14]([CH3:16])=[CH:15][C:11]([O:10][C:8]2[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]=2[N+:17]([O-:19])=[O:18])=[N:12]1)=[O:24])[CH3:21]
Reactant: CCN=C=O
Reactant: CCOc1ccc([N+](=O)[O-])c(Oc2cc(C)[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2cc(OCC)ccc2[N+](=O)[O-])cc1C
Yield: 75.9 %

Procedure:
Reaction of 3-(5-ethoxy-2-nitrophenyloxy)-5-methylpyrazole with ethyl isocyanate was carried out in ethyl acetate in the presence of potassium carbonate in the same manner as in Example 99, to give a yellow solid of N-ethyl-3-(5-ethoxy-2-nitrophenyloxy)-5-methylpyrazole-1-carboxamide (yield: 75.9%). mp: 73-75° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.20 (t, J=7.2 Hz, 3H), 1.44 (t, J=7.0 Hz, 3H), 2.59 (d, J=0.7 Hz, 3H), 3.35 (dq, J=5.9 and 7.2 Hz, 2H), 4.09 (q, J=7.0 Hz, 2H), 5.78 (q, J=0.7 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 6.77 (dd, J=2.4 and 8.9 Hz, 1H), 6.81 (br s, 1H), 8.06 (d, J=8.9 Hz, 1H).
Reaction SMILES: C1OC1.C1OC1C.C1OC1C.C1OC1.[C:15]([OH:27])(=[O:26])[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[K+]>>[C:15]([OH:27])(=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: CCCCCCCCC=CC(=O)O
Agent: CC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CO1
Product: C=CCCCCCCCCC(=O)O
Temperature: 120 °C

Procedure:
In a 4 l multi-necked flask, 1829.9 g (0.7 mol) of an α,ω-dihydroxypoly(ethylene oxide-propylene oxide) copolymer having a hydroxyl number of 41.5 (mg KOH)/g with 50% by mass propylene oxide content and with ethylene oxide end blocks were heated with 249.4 g (1.4 mol) of undecenoic acid (molar mass: 184.3 g/mol, acid number: 304.4 mg KOH/g) to 70° C. with stirring and then 41.6 g of Novozym® 435 (2% by mass based on the total batch) were added. At 4 mbar and with further continual stirring, and also with the introduction of a gentle stream of nitrogen (˜2000 ml/h), the reaction mixture was reacted for 23 hours. During this time the initial acid number of the reaction mixture fell from originally 35.8 mg KOH/g solids to 1.4 mg KOH/g solids. Following filtration and 2-hour heat treatment at 120° C., the α,ω-bis-undecenoato-poly(ethylene oxide-propylene oxide) copolymer was ready for use for the subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:18])[CH2:13][O:14][CH2:15][CH2:16]Cl)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C:12]2=[O:18])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1cc(NC(=O)COCCCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Nc1cc(N2CCOCC2=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
22.2 5.2 g (0.016 mol) of N-(3-amino-4-nitrophenyl)-2-(2-chloroethoxy)acetamide are suspended in 250 ml of acetonitrile, and 6.6 g (0.02 mol) of caesium carbonate are added. The mixture is stirred at room temperature for 18 h. The batch is poured into about 250 ml of water and extracted 3× with 200 ml of ethyl acetate each time. The entire organic phases are dried using anhydrous sodium sulfate, filtered, and the solvent is stripped off in a Rotavapor to a residual volume of about 150 ml. The crystals deposited during evaporation in the rotary evaporator are separated off and dried, giving 4-(3-amino-4-nitrophenyl)morpholin-3-one, HPLC-MS [M+H]+ 238.1.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].Br[C:68]1[C:69]([CH3:82])=[C:70]([CH3:81])[C:71]2[O:75][C:74]([CH3:77])([CH3:76])[C:73](=[O:78])[C:72]=2[C:79]=1[CH3:80]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:76][C:74]1([CH3:77])[C:73](=[O:78])[C:72]2[C:79]([CH3:80])=[C:68]([N:4]3[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]3)[C:69]([CH3:82])=[C:70]([CH3:81])[C:71]=2[O:75]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Cc1c(C)c2c(c(C)c1Br)C(=O)C(C)(C)O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C)c(N2CCCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2=O
Temperature: 25 °C
Yield: 13.5 %

Procedure:
tert-butyl 1,4-diazepane-1-carboxylate (2.50 g, 12.5 mmol), palladium acetate (70.0 mg, 0.312 mmol), BINAP (579 mg, 0.901 mmol) and sodium tert-butoxide (1.79 g, 18.6 mmol) were added to a solution of toluene (20 mL) containing 5-bromo-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one (1.77 g, 6.25 mmol) synthesized in Reference Example 36, and the mixture was heated to reflux under argon atmosphere for 29 hours. After cooled to room temperature, the mixture was diluted with water and extracted using ethyl acetate. It was dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate: 100:0 to 95:5) to give 340 mg of the title compound (yield: 14%).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[CH:25](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:25]=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: COC(OC)OC
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(CC)Oc1cc(C)nc2c1ncn2-c1c(C)cc(C)cc1C

Procedure:
A mixture of 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine, trimethyl orthoformate, p-toluenesulfonic acid monohyrate in toluene was heated at reflux using Dean-Stark apparatus for 24 hours. The mixture was heated at reflux overnight. The mixture was quenched with water, sat. NaHCO3, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was isolated. Anal. For C21H29N3O.¼H2O calc. C, 73.76; H, 8.10; N, 12.29; found: C, 73.22; H, 7.96; N, 12.42.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1\[C:10](=[O:29])[NH:11][C:12]2[C:17]\1=[C:16]([C:18]#[C:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:15]([N+:26]([O-])=O)=[CH:14][CH:13]=2.[NH4+].[Cl-].CN(C=O)C>O.CO.[Zn]>[NH2:26][C:15]1[C:16]([C:18]#[C:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:29])/[C:9]/2=[CH:8]\[C:4]1[NH:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#Cc3cccnc3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(C#Cc3cccnc3)c21
Temperature: 90 °C

Procedure:
Using Method L above, (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one (0.1 g, 0.26 mmol) (from Example 68 above) was reduced with Zn (0.15 g, 2.33 mmol) and NH4Cl (30.6 mg, 0.57 mmol) in 10% water in methanol (10 mL) with a trace of DMF and heating at 90° C. for 5 h, to yield (Z)-5-amino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 28 mg, 30%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(O)(C(F)(F)F)=O>CO.CCOC(C)=O>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][CH2:9][NH:8][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C1CCCCC1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCCCNC1CCCCC1
Reaction time: 24 h
Yield: 46 %

Procedure:
A solution of cyclohexanone (6.0 eq) and tert-butyl (3-aminopropyl)carbamate (1.0 eq) in MeOH (1.5 M) was stirred at RT for 2 h and treated with NaBH3(CN) (6.0 eq). TFA was added until pH 6, and stirring was continued for 24 h at RT. The reaction mixture was diluted with EtOAc, washed sequentially with sat. aq. NaHCO3 solution and brine. The solution was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with EtOAc to afford the title compound EE1 (46% yield). 1H-NMR (500 MHz, DMSO-d6, 300K) δ: 8.12 (1H, br. s), 3.04-2.91 (3H, m), 2.91-2.82 (2H, m), 2.00-1.91 (1H, m), 1.78-1.53 (5H, m), 1.37 (9H, s), 1.24-1.12 (6H, m). MS (ES) C14H28N2O2 required: 256, found: 257 (M+H)+.