Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH:5]=O.[NH2:17][C:18]([NH2:20])=[O:19].Cl.CO>C(O)C>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[N:17][C:18]([OH:19])=[N:20][CH:5]=1)([O-:15])=[O:14]
Reactant: CN(C)C=C(C=O)c1ccccc1[N+](=O)[O-]
Reactant: NC(N)=O
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1-c1cnc(O)nc1
Temperature: 70 °C
Yield: 17.7 %

Procedure:
A solution of 3-(dimethylamino)-2-(2-nitrophenyl)acrylaldehyde (2.00 g, 9.08 mmol), urea (0.60 g, 9.99 mmol) and concentrated hydrochloric acid (0.50 ml) in ethanol (25 ml) was heated at 60° C. for 18 hours under a nitrogen atmosphere. An additional aliquot of concentrated hydrochloric acid (0.50 ml) was added followed by heating at 70° C. for 24 hours. The solvent was removed by evaporation under reduced pressure. The residue was crystallised from methanol yielding the title compound (0.35 g, 18% yield) as a yellow solid.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13]>O.CC(C)=O>[CH3:7][O:8][C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:12]([OH:2])=[O:13]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)O)c([N+](=O)[O-])c1OC

Procedure:
A solution of 823 g. potassium permanganate in about 8.5 liters of H2O was gradually added to a refluxing solution of 3,4-dimethoxy-2-nitrobenzaldehyde (550 g., 2.60 moles) in 5.6 liters of acetone. The reaction mixture was refluxed for four more hours, then filtered through diatomaceous earth while hot and the filter cake washed with hot water. The acetone was removed in vacuo and a small amount of unreacted solid was filtered off. The aqueous solution was acidified with 2 N hydrochloric acid (1.8 liters) to yield 505 g. (85% ) of the essentially pure title compound. Recrystallization from water afforded colorless crystals, M.P. 200°-202° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][CH2:12][CH2:11]O2)=[CH:5][CH:4]=1)#[N:2].Br[C:15]1C=[CH:19][C:18]([F:21])=[CH:17][C:16]=1COCOC>>[F:21][C:18]1[CH:17]=[CH:16][C:15]2[B:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[O:13][CH2:12][C:11]=2[CH:19]=1
Reactant: COCOCc1cc(F)ccc1Br
Reactant: N#Cc1ccc(B2OCCO2)cc1
Product: N#Cc1ccc(B2OCc3cc(F)ccc32)cc1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(4-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:3]=1.[OH2:18]>C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]2[C:6](=[O:18])[C:16]3[C:11]([S:10][C:4]=2[CH:3]=1)=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3
Reactant: O
Reactant: N#Cc1ccc(F)cc1Sc1cccc(F)c1
Solvent: CCOC(C)=O
Product: O=c1c2ccc(F)cc2sc2cc(F)ccc12
Temperature: 200 °C
Yield: 3 %

Procedure:
Mix 4-fluoro-2-(3-fluoro-phenylsulfanyl)-benzonitrile (15.7 g, 63 mmol) and polyphosphoric acid (60 g), heat to 200° C. for 10 days. Dilute with H2O (300 mL) and ethyl acetate (700 mL), and filter through a pad of celite. Separate layers formed in the filtrate, and extract aqueous with two 150 mL portions of ethyl acetate. Combine organics, dry (MgSO4), filter, and concentrate to a brown solid. Purify on silica gel (0-10% ethyl acetae/hexanes)to afford 430 mg (3%) of the title compound as a yellow solid. MS [EI] 248; HPLC shows 92% purity; 1H-NMR consistent with structure. 1H-NMR (CDCl3) δ 8.67 (dd, 2H, J=9.0, 5.9 Hz), 7.26 (m, 4H).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]([OH:5])[CH3:4].[O-:12][C:13]#[N:14].[K+]>O>[OH:5][CH:3]([CH3:4])[C@@H:2]([NH:1][C:13]([NH2:14])=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#C[O-]
Reactant: CC(O)[C@@H](N)c1ccccc1
Agent: [K+]
Solvent: O
Product: CC(O)[C@@H](NC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S)-1-amino-1-phenylpropan-2-ol (0.43 g, 2 mmol) in H2O (2 mL) was added potassium cyanate (0.23 g, 2.7 mmol) and the contents were stirred at ambient temperature for 2 hr. The solid thus obtained was filtered and washed successively with H2O (2×5 mL) and dried in air to afford 1-((1S)-2-hydroxy-1-phenylpropyl)urea. MS: [M+H]+ m/z 195.
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C@H:16]([CH2:26][O:27][CH3:28])[O:15][C:14]2=[O:29])=[O:12])=CC=1)([O-])=O.[ClH:30].Cl.[NH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=2[C:44]#[N:45])[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[ClH:30].[C:44]([C:43]1[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=1[CH:39]1[CH2:38][CH2:37][N:36]([CH2:35][CH2:34][CH2:33][NH:32][C:11]([N:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C@H:16]([CH2:26][O:27][CH3:28])[O:15][C:14]2=[O:29])=[O:12])[CH2:41][CH2:40]1)#[N:45]
Reactant: N#Cc1ccccc1C1CCN(CCCN)CC1
Reactant: COC[C@@H]1OC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H]1c1ccc(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1OC(=O)N(C(=O)NCCCN2CCC(c3ccccc3C#N)CC2)[C@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-5-methoxymethyl-oxazolidine-3-carboxylic acid 4-nitrophenyl ester (195 mg, 0.48 mmol) in dry tetrahydroftirin (3 mL) was added 2-[1-(3-aminopropyl)piperidin-4-yl]benzonitrile dihydrochloride (134 mg, 0.48 mmol) (see Example 3) followed by N,N-diisopropylethylamine (167 μL, 0.96 mmol). The reaction mixture was stirred at room temperature for 20 h when the reaction was diluted with ethyl acetate (50 mL), washed with 10% aqueous sodium carbonate solution (6×25 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (2% methanol in ethyl acetate) to afford an oil. The hydrochloride salt was prepared by standard procedures to provide (4S,5R)-4-(3,4-difluorophenyl)-5-methoxymethyl-2-oxo-oxazolidine-3-carboxylic acid {3-[4-(2-cyanophenyl)piperidin-1-yl]propyl}amide hydrochloride as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([F:29])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=4)[OH:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:28]=1.[CH3:30][C:31]([OH:35])([CH3:34])[C:32]#[CH:33]>>[F:27][C:22]1[CH:21]=[C:20]([CH:18]([OH:19])[C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:29])[C:2]([C:33]#[C:32][C:31]([OH:35])([CH3:34])[CH3:30])=[CH:28][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH:25]=[C:24]([F:26])[CH:23]=1
Reactant: NC(=O)c1nc2n(c1C(O)c1cc(F)cc(F)c1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(O)c1cc(F)cc(F)c1
Yield: 45 %

Procedure:
3-((3,5-difluorophenyl)(hydroxy)methyl)-9-fluoro-10-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was prepared similarly according to General Procedure G with slight modifications. 10-bromo-3-((3,5-difluorophenyl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol to afford 25.7 mg of the titled compound (45% yield). M+1=472.1. 1H NMR (400 MHz, DMSO) δ 8.57 (d, J=8.4 Hz, 1H), 7.94 (br s, 1H), 7.47 (br s, 1H), 7.18-7.06 (m, 2H), 7.05-7.00 (m, 2H), 6.98 (d, J=10.6 Hz, 1H), 6.91-6.85 (m, 1H), 5.54 (s, 1H), 4.58-4.49 (m, 1H), 4.48-4.36 (m, 2H), 4.11-3.92 (m, 1H), 1.49 (s, 6H).
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].[CH3:14][NH:15][CH3:16].[OH-].[Na+]>>[CH2:1]([N:15]([CH3:16])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CNC
Reactant: CC(C)CCCCCCCCCCl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CCCCCCCCCN(C)C
Yield: 98.1 %

Procedure:
In a 1-gallon stainless steel autoclave was charged 4.5 moles of isododecyl chloride, 13.5 moles of dimethylamine (as 40% aqueous solution), and 4.5 moles of sodium hydroxide (as 50% aqueous solution). The mixture was heated at 175°-190° C. for 6 hours. The mixture was cooled. The top organic layer was collected and the residual dimethylamine evaporated. The isododecyldimethylamine was obtained in 98.1% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([Si:19]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: OCc1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a solution of (4-fluoro-phenyl)-methanol (12.16 g, 96.4 mmol, 1.0 equiv) in anhydrous DMF (50 mL) at 0° C. under Ar was added imidazole (7.22 g, 106.1 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane (15.99 g, 106.1 mmol, 1.1 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 18 h at rt. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with a sat. solution of Na2CO3 (2×100 mL) and NaCl (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure yielding a brown oil that was purified by high vacuum destillation (bp 32-35° C. at 0.1 mbar) to give 23.0 g (99%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 0.00 (s, 6H), 0.84 (s, 9H), 4.60 (s, 2H), 6.89-6.94 (m, 2H), 7.16-7.20 (m, 2H). MS (EI): 183.1 [M-tert-Bu]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:9]1[CH:22]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[C@H:9]1[CH2:22][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: Cc1c(N)ccc(C#N)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(NC[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CCCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
A mixture of 77F (660 mg, 1.92 mmol), 4-amino-2-chloro-3-methylbenzonitrile (384 mg, 2.3 mmol, 1.2 equiv) and HOAc (165 μL, 2.88 mmol, 1.5 equiv) in 1,2-DCE (10 mL) was stirred at rt for 30 min and Na(OAc)3BH (610 mg, 2.88 mmol, 1.5 equiv) was added. The reaction was stirred at rt overnight. Another 407 mg of Na(OAc)3BH (610 mg, 1.92 mmol, 1.0 equiv) was added and stirred at rt for another 24 h. The mixture was concentrated and the residue was diluted with EtOAc (30 mL), washed with saturated sodium bicarbonate solution (2×15 mL), brine (2×15 mL), dried (MgSO4) and evaporated to give the crude product. Purification of the crude product by flash chromatography (0-50% EtOAc/hexane) yield the desired product 77G (192 mg, 20%) as a white foam: Rf (30% EtOAc/hexane) 0.37; HPLC (Phenomenex Luna 5μ C18 4.6×50 mm, linear gradient over 4 min) retention time 4.6 min (100%); MS (ES) m/z 344.1 [M+1]+; HRMS calcd for C25H41N3O3SiCl 494.2606, Found 494.2613.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[N:12][C:13]([Cl:17])=[CH:14][C:15]=1Cl)=[O:9])[CH3:6].Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[N:12][C:13]([Cl:17])=[CH:14][C:15]=1[O:1][CH2:2][CH3:3])=[O:9])[CH3:6]
Reactant: CC[O-]
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(Cl)cc1OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium ethoxide (1.16 g, 17 mmol) is added to a stirred solution of 4,6-dichloropyridazine-3-carboxylic acid ethyl ester (3.73 g, 17 mmol) in THF (45 mL) cooled to 0° C. The reaction mixture is stirred at room temperature overnight and then poured into 1N HCl (20 mL). The resulting solution is then neutralized with saturated NaHCO3. EtOAc (20 mL) is added and the layers are separated. The aqueous layer is extracted twice with EtOAc (20 mL) and the combined extracts are washed with brine (25 mL), dried (Na2SO4), and evaporated. The residue is then purified by flash column chromatography (silica gel, eluted with 2:1 Hexane, EtOAc) to give the title product as a white solid. H1 NMR δ (CDCl3) 7.02 (s, 1H), 4.47 (q, 2H, J=7.2 Hz), 4.19 (q, 2H, J=7.2 Hz), 1.50 (t, 3H, J=7.2 Hz), 1.41 (t, 3H, J=7.2 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1)[CH:4]=[CH2:5].C[O:16][C:17](=[O:20])[CH2:18]Cl.O>CN(C=O)C>[C:17]([O:20][O:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=1)(=[O:16])[CH3:18]
Reactant: COC(=O)CCl
Reactant: C=CCOc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(COOC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
Sodium hydride (1.20 g; 60% dispersion in oil) was added over a period of 10 minutes to a stirred solution of 4-allyloxybenzyl alcohol (4.60 g) in DHF (20 ml) at 0° C. under an atmosphere of argon. After 0.5 hours, a solution of methylchloroacetate (3.30 g) in DMF (10 ml) was added over a period of 0.25 hours. The reaction mixture was stirred for 40 hours at ambient temperature. Water (300 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts were combined, washed with brine (2×100 ml), dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using a 9:1 (v/v) mixture of hexane/ethyl acetate to give 4-allyloxyphenylmethyloxy acetate (2.42 g) as a colourless oil; NMR(CDCl3): 3.75(3H,s), 4.07(2H,s), 4.52(4H,m), 5.36(2H,m), 6.10(1H,m), 6.88(2H,m) and 7.28(2H,m); m/z 236(H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2)=[C:2]=[O:3].[CH3:13][CH:14]([CH3:37])[CH:15]([NH:20][C:21]([C:23]1[S:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)[N:27]=1)=[O:22])[C:16]([O:18][CH3:19])=[O:17]>>[CH2:9]1[C:10]2[C:6](=[CH:5][C:4]([NH:1][C:2](=[O:3])[NH:34][C:31]3[CH:32]=[CH:33][C:28]([C:26]4[N:27]=[C:23]([C:21]([NH:20][C@@H:15]([CH:14]([CH3:37])[CH3:13])[C:16]([O:18][CH3:19])=[O:17])=[O:22])[S:24][CH:25]=4)=[CH:29][CH:30]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: O=C=Nc1ccc2c(c1)CCC2
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc4c(c3)CCC4)cc2)cs1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 23, using 2,3-dihydro-5-isocyanato-1H-indene and intermediate 3. 1HNMR (DMSO-d6, 300 MHz): δ 8.817-8.795 (d, 2H), 8.578 (s, 1H), 8.306 (s, 1H), 8.040-8.011 (d, J=8.7 Hz, 2H), 7.582-7.553 (d, J=8.7 Hz, 2H), 7.401 (s, 1H), 7.170-7.104 (m, 2H), 4.394-4.342 (t, J=7.5, 8.1 Hz, 1H), 3.700 (s, 3H), 2.863-2.773 (m, 4H), 2.343-2.274 (m, 1H), 2.087-1.981 (m, 2H), 1.001-0.953 (t, J=7.2 Hz, 6H); MS (ESI) m/z 491 (M−H), 493 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][OH:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=1>>[CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18](=[CH:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:27])([F:37])[F:38])[CH:30]=3)=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2cccc(C(F)(F)F)c2)c1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2cccc(C(F)(F)F)c2)c1

Procedure:
The reaction of hydroxylamine 82 (0.71 g, 2 mmol) with α,α,α-trifluoro-m-tolualdehyde (60) (0.348 g, 2 mmol) afforded, after workup, a light yellow solid. The crude product was recrystallized from ether/petroleum ether to obtain 0.80 g (1.55 mmol. 78%) of 85 as a white crystalline solid: mp 127°-129° C.; IR (CH2Cl2) 3440, 2980, 1698, 1624, 1558, 1475, 1332, 1300, 1215, 1100, 1018, 810 cm-1 ; 1H NMR (CDCl3) δ 1.14 (d, J=6.2 Hz, 3H), 1.26 (d, J=6.2 Hz, 3H), 2.29 (s, 6H), 3.65 (s, 3H), 4.97 (septet, J=6.2 Hz, 1H), 5.08 (s, 1H), 6.47 (br s, 1H), 7.28-8.76 (m, 9H); 13C NMR (CDCl3) δ 19.48, 21.99, 22.22, 39.98, 51.15, 67.31, 102.99, 103.70, 119.43, 121.55, 125.52, 125.55, 127.22, 128.56, 129.28, 130.43, 131.46, 131.92, 133.40, 144.79, 145.33, 148.92, 149.91, 167.01, 168.03. Anal. Calcd for C27H27N2O5F3 : C, 62.79; H, 5.23. Found: C, 62.68; H, 5.02.
Reaction SMILES: [Mg].[CH3:2]I.[C:4]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5].Cl>O1CCCC1.C1(C)C=CC=CC=1>[C:4]([N:8]1[C:13](=[O:14])[C:12]([CH3:2])=[C:11]([Cl:16])[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Temperature: 0 °C

Procedure:
To a solution of 6.0 g (0.25 mol) of magnesium in 50 ml of dry tetrahydrofuran was added dropwise under stream of nitrogen 35.5 g (0.25 mol) of methyl iodide to prepare a Grignard reagent. After dropwise addition of the methyl iodide, 1000 ml of dry toluene was added thereto. The resulting solution was heated at 60° to 70° C. and additional methyl iodide was added thereto until the magnesium completely disappeared. The Grignard reagent was cooled to room temperature and then added dropwise over 20 minutes with a solution of 22.1 g (0.1 mol) of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone in 200 ml of dry toluene. After dropwise addition, the resulting mixture was subjected to reaction at room temperature for 1.5 hours. The reaction liquid was poured into a solution of 100 ml of concentrated hydrochloric acid in 900 ml of ice water to effect extraction. The resulting organic layer was washed with 500 ml of a 10% sodium hydroxide solution and then with 500 ml of water, and then dried over anhydrous sodium sulfate. Solvent was distilled off therefrom under reduced pressure to give 17.2 g of a crude product. The crude product was subjected to distillation (boiling point: 60° to 62° C./0.22 mmHg) and then to column chromatography [on silica gel; eluting with hexane-acetone (15:1)] for separation and purification to obtain 4.5 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: Cl.F[C:3]1[CH:4]=[C:5]([NH:11]N)[C:6](OC)=[CH:7][CH:8]=1.[C:13](O)(=O)[CH2:14]CC(C)=O>C(O)(=O)C>[NH:11]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:3][CH:4]=2)[CH:14]=[CH:13]1
Reactant: COc1ccc(F)cc1NN
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc2[nH]ccc2c1

Procedure:
Condensation of hydrazine hydrochloride (2) with levulinic acid (3) in acetic acid results in the formation of two regioisomeric indole derivatives 4 and 5 in a 1:7 ratio. The major regioisomer 5 can be isolated in pure form by crystallization of the reaction mixture. Alternatively, the indole mixture can be esterified with an alcohol such as 2-trimethylsilylethanol to afford the corresponding esters that can then be separated by a number of means, for example by chromatography.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:14]1[N:19]=[C:18]2[N:20]([C@@H:24]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[C:21](=[O:23])[NH:22][C:17]2=[CH:16][CH:15]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:6][C:14]1[N:19]=[C:18]2[N:20]([C@@H:24]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[C:21](=[O:23])[NH:22][C:17]2=[CH:16][CH:15]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3[nH]c(=O)n([C@H](C)c4cccnc4)c3n2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1cccnc1)n1c(=O)[nH]c2ccc(N)nc21

Procedure:
A solution of (R)-tert-butyl 2,4-dimethoxybenzyl(2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)carbamate in methylene chloride (15 mL) was treated with TFA (15 mL) and triethylsilane (1.0 mL) for one hour. The mixture was concentrated to provide the intermediate (R)-5-amino-3-(1-(pyridin-3-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (68), which was dissolved in acetonitrile (50 mL) and stirred vigorously with di-tert-butyl dicarbonate (1.0 g) and potassium carbonate (3.0 g) for 2 h. Methylene chloride (200 mL) and water (100 mL) was added and the organic layer was separated. The aqueous layer was extracted with another 100 mL of methylene chloride. The combined organic layers were separated, dried over sodium sulfate, filtered, and concentrated. Column chromatography (2→3→4% MeOH in methylene chloride) provided 235 mg (R)-tert-Butyl 5-amino-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (69).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CC1C=CC(S(O[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:30]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:29]([CH2:28][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]2=[O:14])[CH2:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(Cc3ccccc3)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC2CCCN(Cc3ccccc3)C2)C(=O)C1
Reaction time: 48 h
Yield: 19.6 %

Procedure:
To a solution of tert-butyl-3-oxopiperazine-1-carboxylate (250 mg) in dimethylformamide (10 mL) was added sodium hydride (55 mg) at room temperature under argon. The mixture was stirred at room temperature 15 minutes before a solution of (1-benzylpiperidin-3-yl)methyl 4-methylbenzenesulfonate (492 mg) in dimethylformamide (5 mL) was added. The mixture was stirred overnight at room temperature before sodium hydride (60 mg) was added and the mixture was stirred for 48 hours. A further quantity of sodium hydride (60 mg) was added and the mixture was stirred for 5 hours and then quenched by the addition of water. The mixture was then partitioned between water and ethyl acetate. The layers were separated and the organic layer washed twice with water and once with brine. The organic layer was then dried over sodium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 70% ethyl acetate in hexane to give the title compound as a colourless oil (95 mg, 20%).
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[OH-].[K+].C1C[O:17][CH2:16]C1.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl>O.CCOC(C)=O>[O:11]1[C@@H:3]2[CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C@@H:2]2[NH:1][C:16]1=[O:17]
Reactant: C1CCOC1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1N[C@H]2c3ccccc3C[C@H]2O1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
To a solution of (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (500 mg, 3.35 mmol) in water (20 mL) at 0° C. was added potassium hydroxide (1128 mg, 20.1 mmol) followed by THF (20 mL) and the reaction was stirred at 0° C. for 20 minutes. Bis(trichloromethyl) carbonate (995 mg, 3.35 mmol) was added and the reaction was stirred at 0° C. for 2 hours. The reaction was poured into EtOAc and the organic phase washed with 1N HCl, 1N NaOH and brine. After drying over MgSO4, concentration yielded (3aS,8aR)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (574 mg, 97.8% yield) as a white solid.