Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8](=[O:25])[C:9]([CH3:24])=[CH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[N+:21]([O-])=O)[CH3:6]>[Fe].O>[CH2:5]([O:7][C:8](=[O:25])[C:9]([CH3:24])=[CH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[NH2:21])[CH3:6]
Reactant: CCOC(=O)C(C)=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)=Cc1cc(OC)c(OC)cc1N
Yield: 73.2 %

Procedure:
Into 250 ml of glacial acetic acid, 19.0 g of 3-(4,5-dimethoxy-2-nitrophenyl)-2-methyl-2-propenoic acid ethyl ester were dissolved; and, with 15.0 g of iron powder and 20 ml of ion-exchanged water being added thereto, the mixture was refluxed under heating for 40 minutes. The resulting reaction liquid was filtered out, the filtrate was concentrated under a reduced pressure, and thus obtained residue was dissolved in ethyl acetate. The resulting solution was successively washed with water, a 5% aqueous sodium hydrogencarbonate solution, and a saturated aqueous sodium chloride solution. After this ethyl acetate solution was left on sodium sulfate anhydride for one night so as to be dried, ethyl acetate was evaporated under a reduced pressure, and the resulting residue was recrystallized from a mixed liquid of hexane/ethanol, whereby 12.5 g of the aimed product were obtained (yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[N:21][N:20]=[C:19]1[CH3:23].[CH2:25]=[O:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:19]([CH3:23])=[N:20][N:21]=[C:22]1[CH2:25][OH:26]
Reactant: C=O
Reactant: Cc1nncn1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Product: Cc1nnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 4, 2'-chloro-5-nitro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone is heated with paraformaldehyde at 125° C. to give 2'-chloro-5-nitro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[NH:20][C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](I)[CH3:33]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[N:20]([CH2:32][CH3:33])[C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCn1c(SC)nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
Under argon gas, 7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (2.46 g) was dissolved in anhydrous DME (72.5 ml)anhydrous DMF (72.5 ml) and, under ice-cooling, 60% sodium hydride-oil (255 mg) was added in two installments. The mixture was stirred for 30 minutes sand ethyl iodide (1.09 g) was added. Then, the mixture was further stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography [silica gel; dichloromethane→methanol: dichloromethane (1:49)] to provide the title compound (1.04 g).
Reaction SMILES: C[N:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][C:11]=3[CH:21]=2)[NH:3]1.[OH-].[Na+].Cl.[CH3:25]O>C1COCC1>[CH3:25][N:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[CH:21]=2)=[N:5][N:6]=[N:2]1
Reactant: COC(=O)C1=Cc2cc(C3=NNN(C)N3)ccc2OCC1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nnnc1-c1ccc2c(c1)C=C(C(=O)O)CCO2
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
In methanol (3 ml) and THF (3 ml) was dissolved methyl 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (76 mg, 0.27 mmol), and to the mixture was added 1N sodium hydroxide solution (0.8 ml). The mixture was stirred at 50° C. for 4 hours, and to the mixture was added, under ice-cooling, 1N hydrochloric acid (0.8 ml). The mixture was concentrated under reduced pressure, and to the residue was added water. Insoluble materials were filtered, which were washed with water and dried under reduced pressure to give 7-(1-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (69 mg, 0.25 mmol, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][O:12][C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][C:24]1([CH3:32])[CH2:31][C:29](=[O:30])[CH2:28][C:26](=[O:27])[CH2:25]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:10]([CH2:11][O:12][C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([CH:28]1[C:26](=[O:27])[CH2:25][C:24]([CH3:32])([CH3:23])[CH2:31][C:29]1=[O:30])=[O:6]
Reactant: Cn1nccc1OCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nccc1OCc1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CC(C)(C)CC2=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.0 g (2.9 mmol) of 2-chloro-3-[(1-methylpyrazol-5-yl)oxymethyl]-4-methylsulfonyl benzoic acid, 0.4 g (2.9 mmol) of dimedone and 0.72 g of N,N-dicyclohexylcarbodiimide in 50 ml of acetonitrile are heated at 40° C. for 4 h. After the reaction mixture has been stirred for 12 h at room temperature, 0.87 g of triethylamine and 0.57 g of trimethylsilylnitrile are added. Afterwards the reaction mixture is heated at 40° C. for 6 h, filtered, freed from the solvent under reduced pressure and the residue is purified over silica gel (eluent: toluene/tetrahydrofurane/acetic acid: 100/0/0→4/1/0.1). Yield: 0.25 g; m.p.82° C.
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C@H:24]2[CH:23]=[CH:22][N:21]([S:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=3)(=[O:20])=[O:19])[C:2](=[O:1])[C@H:3]2[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:26][CH:27]=1
Reactant: CCOC(=O)/C=C/C=O
Reactant: COc1ccc(/C=C/C=NS(=O)(=O)c2ccc(OC)cc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@@H]1C(=O)N(S(=O)(=O)c2ccc(OC)cc2)C=C[C@@H]1c1ccc(OC)cc1
Yield: 81 %

Procedure:
The title compound was prepared according to the general procedure from ethyl trans-4-oxo-2-butenoate and trans-N-(4-methoxybenzenesulfonyl)-3-(4-methoxyphenyl)prop-2-en-1-imine using 10 mol % 9 as the catalyst in 81% yield as a yellow solid. [α]D20 (c 1.04, CHCl3)=+143.6; mp=107-110° C.; 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, 2H, J=7.1, 1.8 Hz), 7.13 (d, 1H, J=8.1 Hz), 7.05 (dd, 2H, J=7.1, 1.8 Hz), 6.55-6.48 (m, 4H), 5.59 (dd, 1H, J=8.0, 6.6 Hz), 4.16-4.09 (m, 2H), 3.92 (s, 3H), 3.71 (s, 3H), 3.60 (t, 1H, J=6.9 Hz), 3.52-3.47 (m, 1H), 2.58 (dd, 1H, J=17.2, 6.0 Hz), 1.95 (dd, 1H, J=17.2, 7.7 Hz), 1.22 (t, 3H, J=7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 171.8, 169.1, 164.3, 159.2, 131.4, 129.2, 128.5, 124.3, 114.3, 114.3, 113.9, 113.6, 61.0, 56.0, 55.3, 44.3, 41.2, 31.5, 14.4; IR (thin film) ν 3055, 2840, 1720, 1647, 1511, 1498, 1463, 1442, 1366, 1263, 1167, 1090, 1028 cm−1; HRMS (ESI) calcd for C23H25NO7S [M+Na]+ 482.1243, found 482.1253; >99% ee (3S,4S)-isomer as determined by HPLC (AS-H, 4:1 hexanes/i-PrOH), tr (3S,4S)=49.3 min, tr (3R,4R)=29.6 min.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[NH2:8][C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[N:11]([OH:26])[C:10]1=[O:27]>N1C=CC=CC=1>[NH2:8][C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[N:11]([O:26][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[C:10]1=[O:27]
Reactant: N[C@H]1Cc2cc(Oc3ccccc3)ccc2N(O)C1=O
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)ON1C(=O)[C@@H](N)Cc2cc(Oc3ccccc3)ccc21
Temperature: 25 °C
Yield: 63.9 %

Procedure:
Dimethylcarbamyl chloride (37 μL, 0.39 mmol) was added to a solution of (3S)-3-amino-1-hydroxy-6-phenoxy-3,4-dihydroquinolin-2(1H)-one, hydrochloride salt (93, Example 71) (100 mg, 0.33 mmol) in pyridine (2 mL). The reaction mixture was maintained at RT for 1.5 h, then concentrated in vacuo; the resulting residue was diluted with EtOAc (20 mL) and water (10 mL). The separated organic phase was washed with water (10 mL), dried over Mg2SO4, filtered, and concentrated in vacuo to provide the title compound as an oil (72 mg, 65%). LCMS m/z 253.0 [(M-dimethyl carbamic acid)+1]. 1H NMR (400 MHz, CD3OD) δ 2.94-3.02 (m, 1H), 3.02 (br s, 3H), 3.08 (dd, half of ABX pattern, J=15.5, 6.4 Hz, 1H), 3.17 (br s, 3H), 3.78 (dd, J=13.3, 6.3 Hz, 1H), 6.90-7.00 (m, 5H), 7.11 (ddt, J=7.7, 7.1, 1.1 Hz, 1H), 7.32-7.37 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound 3,5-dimethyl-4-hydroxybenzoic acid (5.04 g, 30.33 mmol) was mixed with pyridine (20 mL). Acetic anhydride (3.72 g, 36.4 mmol) was added and the mixture was stirred at room temperature for 4 h. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid in quantitative yield (6.33 g). The compound 4-acetoxy-3,5-dimethyl-benzoic acid (0.36 g, 1.73 mmol)) was dissolved in dichloromethane (5 mL) and oxalyl chloride (0.3 mL, 3.46 mmol) was added dropwise, followed by 1 drop of DMF. The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solvent was evaporated in vacuo to obtain acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester in quantitative yield (0.392 g).
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3].Cl.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([N:21]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)N=CC)=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1>O>[OH2:3].[CH3:1][C:2]1[N:21]([C:15]2[C:14]3[C:19](=[CH:20][C:11]([Cl:10])=[CH:12][CH:13]=3)[N:18]=[CH:17][N:16]=2)[C:25]2[C:26]([C:4]=1[CH2:5][C:6]([OH:8])=[O:7])=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2
Reactant: CC=NN(c1ccc(OC)cc1)c1ncnc2cc(Cl)ccc12
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1ncnc2cc(Cl)ccc12

Procedure:
A mixture of laevulinic acid (15g.) and acetaldehyde N1 -(7-chloroquinazolin-4-yl)-p-methoxyphenylhydrazone hydrochloride (3.3g.) was heated at 95°-100° C. for 18 hours. The mixture was poured into water (ca 300ml.), and the precipitated pale yellow solid was collected by filtration and dissolved in a mixture of water (80ml.) and ammonia solution (specific gravity 0.88, ca 5ml.). The solution was washed with ethyl acetate (2 × 25ml.). Addition of sodium chloride (ca 10g.) to the aqueous phase caused a yellow solid to precipitate. This was collected by filtration, and then dissolved in water. The solution was acidified with glacial acetic acid until precipitation was complete. The mixture was filtered to give, as solid residue, 2-methyl-5-methoxy-1-(7-chloroquinazolin-4-yl)indol-3-ylacetic acid monohydrate, m.p. 98°-100° C.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]([NH:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[CH3:40][C:41]1([CH3:57])[O:46][CH:45]([C:47]([NH:49][CH2:50][CH2:51][C:52](O)=[O:53])=[O:48])[C:44]([CH3:56])([CH3:55])[CH2:43][O:42]1>C(Cl)Cl>[C:13]([NH:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH:35][C:52](=[O:53])[CH2:51][CH2:50][NH:49][C:47]([CH:45]1[C:44]([CH3:55])([CH3:56])[CH2:43][O:42][C:41]([CH3:57])([CH3:40])[O:46]1)=[O:48])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccccc1NC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 81.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (211 mg) was added to a solution of 372 mg of 2-oleoylaminoaniline and 259 mg of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid in 30 ml of methylene chloride under ice cooling. The mixture was stirred in situ for one night. The reaction mixture was washed with water and dried over anhydrous sodium sulfate, filtered and the filtate evaporation under vacuum to obtain the crude title products. Then, the residue obtained was subjected to silica gel column chromatography to obtain 500 mg of the title compound (yield: 82%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:3]1=[O:35].Cl>O1CCCC1.CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:3]1=[O:35]
Reactant: COC(=O)CCCSc1c2c(=O)n(C)c(=O)n(CC(C)C)c2cn1Cc1cccc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)n(Cc3cccc4ccccc34)cc21
Reaction time: 1.5 h

Procedure:
The compound of Example 2, methyl 4-[(2,3,4,6-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]-pyrimidin-5-yl)thio]butanoate (400 mg), was dissolved in 3:1:1 tetrahydrofuran/methanol/1M lithium hydroxide and stirred for 1.5 h before being acidified by dropwise addition of concentrated hydrochloric acid (HCl). The mixture was then extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate (MgSO4) and evaporated to dryness in vacuo. The resultant yellow oil was chromatographed (silica), eluting with 200:10:1 dichloromethane/methanol/glacial acetic acid. The resultant red oil was dissolved in toluene and then evaporated, then similarly with trichloromethane to yield a pink foam. The foam was recrystallised from ethyl acetate/hexane to yield 129 mg of the title compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[CH3:16][CH:17]([CH3:28])[C:18](=[O:27])[CH2:19][CH2:20][C:21]1[S:25][CH:24]=[N:23][C:22]=1[CH3:26]>>[CH3:8][O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][C:18]([OH:27])([CH2:19][CH2:20][C:21]1[S:25][CH:24]=[N:23][C:22]=1[CH3:26])[CH:17]([CH3:16])[CH3:28]
Reactant: Cc1ncsc1CCC(=O)C(C)C
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Product: COC(=O)CC(=O)CC(O)(CCc1scnc1C)C(C)C

Procedure:
The title compound was prepared as described in General Method 6 from 1.00 g (8.61 mmol) of methyl acetoacetate, 0.38 g (9.50 mmol) of sodium hydride, 4.5 mL of 2.1 M nBuLi (9.45 mmol), and 1.53 g (7.75 mmol) of 4-methyl-1-(4-methyl-thiazol-5-yl)-pentan-3-one (prepared in Example C-2.) The crude compound was used without purification in the next step.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](#[N:23])[CH3:22]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:22][C:21]#[N:23])[CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(OCCCOCc2ccccc2)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCCCOCc2ccccc2)c1

Procedure:
Addition of acetonitrile to 3-(3-benzyloxy-propoxy)-benzaldehyde gave 3-(3-(3-benzyloxy-propoxy)-phenyl)-3-hydroxy-propionitrile as yellow oil. Yield (0.94 g, 54%): 1H NMR (400 MHz, CDCl3) δ 7.23-7.38 (m, 6H), 6.90-6.96 (m, 2H), 6.81-6.86 (m, 1H), 5.00 (m, 1H), 4.53 (s, 2H), 4.10 (t, J=6.2 Hz, 2H), 3.67 (t, J=6.0, 2H), 2.75 (t, J=6.4, 2H), 2.04-2.13 (m, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(=O)=O.[CH2:14]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])P(=O)(OCC)OCC.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O>O1CCCC1.C(OCC)(=O)C>[CH3:40][O:39][C:37]([C:36]1[CH:41]=[CH:42][C:33](/[CH:31]=[CH:14]/[P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])=[CH:34][CH:35]=1)=[O:38]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOP(=O)(/C=C/c1ccc(C(=O)OC)cc1)OCC
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (17 ml) is diluted with anhydrous tetrahydrofuran (81 ml) under a nitrogen atmosphere and dry ice cooling, and then a solution of tetraethyl methylenebis(phosphonate) (4.6 g) in anhydrous tetrahydrofuran (8 ml) is added dropwise thereto. The mixture is stirred under dry ice cooling for 30 minutes, and then a solution of methyl 4-formylbenzoate (2.64 g) in anhydrous tetrahydrofuran (12 ml) is added dropwise thereto. The mixture is stirred under dry ice cooling for 1.5 hours and further under ice cooling for 2.5 hours. Ethyl acetate is added to the reaction mixture. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting precipitate is filtered off to give 4.1 g (86%) of diethyl (E)-2-[4-(methoxycarbonyl)phenyl]vinylphosphonate as crystals.
Reaction SMILES: C(O)C.[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]#[N:20])=[N:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[OH:22][NH3+:23].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([NH:23][OH:22])=[NH:20])=[N:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [NH3+]O
Reactant: N#CCc1ccc(OCc2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(Cc1ccc(OCc2ccccc2)cn1)NO
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
To an ethanol (30 mL) solution of (5-benzyloxy-pyridin-2-yl)-acetonitrile (1.77 g, 7.89 mmol) described in Manufacturing Example 127-1-4 were added hydroxylammonium chloride (848 mg, 11.8 mmol) and potassium carbonate (2.18 g, 15.8 mmol), which was stirred for 11 hours and 20 minutes at 70° C. The mixture was then stirred for another 5 hours and 45 minutes under reflux. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (550 mg, 27%).
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Cl:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:15]=1[NH2:16].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:16]/[C:15]1[C:17]([Cl:24])=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=1[Cl:13])=[N+:2]=[N-:3]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (3.00 g, 18.07 mmol) and 2,6-dichloro-4-nitroaniline (3.74 g, 18.07 mmol) in DCM (60 mL) was cooled to 0° C., under an atmosphere of nitrogen. Triethylamine (7.56 mL, 54.2 mmol) was added, followed by dropwise addition of titanium (IV) chloride solution (1 N in DCM, 10.8 mL, 10.8 mmol). The reaction mixture was stirred at 0° C. for 3 hours, then allowed to reach room temperature over 1 hour. The resultant mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the crude title compound as a yellow/brown solid (5.89 g, 92% yield). LCMS (Method C): RT=4.08 min, m/z: 327 [M+H+−N2].
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1.C1(N[S:33]([C:36]([F:39])([F:38])[F:37])(=[O:35])=[O:34])C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[S:33]([O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][N:13]([C:8]3[CH:7]=[C:6]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:25])[CH:11]=[CH:10][C:9]=3[CH3:12])[C:14]2=[O:24])=[CH:19][CH:18]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1=O
Temperature: 120 °C

Procedure:
N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (250 mg), N-phenyltrifluoromethanesulfonamide (267 mg) and potassium carbonate (311 mg) were stirred in THF (6 ml) and heated under microwave irradiation (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 120° C. for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed with water (2×), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography with a gradient of iso-hexane to 70% ethyl acetate/iso-hexane yielded 2-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1-oxo-1,2-dihydroisoquinolin-7-yl trifluoromethanesulfonate as a cream coloured solid (264 mg); NMR Spectrum: (DMSOd6) 0.53 (m, 2H), 0.67 (m, 2H), 2.10 (s, 3H), 2.83 (m, 1H), 6.87 (d, 1H), 7.49 (m, 2H), 7.76 (s, 1H), 7.86 (d, 1H), 7.93 (d, 1H), 8.00 (d, 1H), 8.19 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+Na+ 489.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]#[N:14])[N:4]=1.[OH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[C:13]([C:5]1[N:4]=[C:3]([CH2:2][O:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]2)[C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)#[N:14]
Reactant: N#Cc1cc2ccccc2c(CBr)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](OCc2nc(C#N)cc3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 1-(bromomethyl)isoquinoline-3-carbonitrile (0.150 g, 0.607 mmol) in DCM (6 mL) was added (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.114 g, 0.607 mmol) and AgOTf (0.016 g, 0.061 mmol). The suspension was stirred for 15 minutes at RT and then heated at 45° C. overnight. The reaction mixture was subsequently cooled, absorbed onto silica and eluted with a gradient of 0-5% MeOH in DCM. The enriched fractions were concentrated in vacuo to give the title compound as a yellow residue which was used without further purification (54.6 mg, 25.4%). ESI-MS m/z [M+H-tert butyl]+ 298.6.