Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([O:24]CC4C=CC=CC=4)=[CH:18][C:19](=[O:23])[O:20]3)=[CH:15][CH:14]=2)=[C:6]([CH2:35][CH2:36][CH3:37])[C:5]=1[OH:38])(=[O:3])[CH3:2].C>CN(C=O)C>[C:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([OH:24])=[CH:18][C:19](=[O:23])[O:20]3)=[CH:15][CH:14]=2)=[C:6]([CH2:35][CH2:36][CH3:37])[C:5]=1[OH:38])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)COc2ccc3c(OCc4ccccc4)cc(=O)oc3c2)ccc(C(C)=O)c1O
Solvent: CN(C)C=O
Product: CCCc1c(OCC(O)COc2ccc3c(O)cc(=O)oc3c2)ccc(C(C)=O)c1O

Procedure:
Hydrogenation of 7-(3-[4-acetyl-3-hydroxy-2-n-propylphenoxy]-2-hydroxypropoxy)-4-benzyloxycoumarin (3.42 g; 0.0066 mole) in DMF (60 ml) at atmospheric pressure using 10% palladinized charcoal afforded the title compound; 2.86 g as a tlc pure foam. (DMSO); 9.13 (3H, t, J 6.7 Hz); 8.59 (2H, m) 7.40 (3H, s); 7.40 (2H, m); 6.30 (1H, broad exchangeable); 5.75 (5H, s); 4.75 (1H, broad exchangeable); 4.50 (1H, exchangeble) 3.30 (1H, d, J 9.3Hz); 3.01 (2H, m); 2.23 (1H, d, J 9.6 Hz); 2.15 (1H, d, J 9.3Hz); 1 low field sharp exchangeable. Molecular ion at m/e 428.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:13](Cl)=[O:14].[NH2:16][C:17]1[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19][O:20][C:21]=1[CH3:22]>N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:13]([NH:16][C:17]1[C:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:19][O:20][C:21]=1[CH3:22])=[O:14]
Reactant: Cc1onc(-c2ccccc2)c1N
Reactant: Cc1cc(C(=O)Cl)c2cc(F)ccc2n1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2c(-c3ccccc3)noc2C)c2cc(F)ccc2n1
Temperature: 70 °C
Yield: 61.9 %

Procedure:
6-Fluoro-2-methylquinoline-4-carbonyl chloride (100 mg) and 4-amino-5-methyl-3-phenylisoxazole (200 mg) were dissolved in dichlorormethane (10 mL) and pyridine (0.3 mL). The reaction solution was heated at 70° C. overnight and then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), dried, evaporated and purified by flash column chromatography (EtOAc/hexanes=1/1) to give 6-fluoro-2-methyl-N-(5-methyl-3-phenylisoxazol-4-yl)-4-quinolinecarboxamide (100 mg) as a white solid. 1H NMR (CDCl3): δ 2.58 (s, 3H), 2.76 (s, 3H), 7.14 (s, 1H), 7.44 (s, 1H), 7.49 (m, 4H), 7.67 (m, 2H), 7.82 (dd, J=2.7 and 9.9 Hz, 1H), 8.07 (dd, J=5.7 and 9.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ-111.63; LCMS: ret. time: 21.32 min.; purity: 99.44%; MS (m/e): 362.06 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:35])=O.CN(C=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16]([Cl:35])=[O:18])=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:30][CH:31]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)Cl)n21
Reaction time: 2 h

Procedure:
(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (44 g, 95.8 mmol) was dissolved in CH2Cl2 (600 mL). To this solution was added oxalyl chloride (16.7 g) followed by DMF (0.3 mL). After 2 h, the volatiles were removed and the resultant residue was placed under high vacuum for 18 h to yield the title compound. The title compound was used without purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CCN(C(C)C)C(C)C.[CH2:19]([O:21][C:22](=[O:44])[C@@H:23]([CH3:43])[CH2:24][CH:25]([N:40]=[C:41]=[O:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)=[CH:29][CH:28]=1)[CH3:20]>CN(C=O)C>[CH2:19]([O:21][C:22](=[O:44])[C@@H:23]([CH3:43])[CH2:24][CH:25]([NH:40][C:41]([NH:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)=[CH:29][CH:28]=1)[CH3:20]
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)N=C=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Next, to a solution of tert-butyl 2-aminoacetate (140 mg, 1.065 mmol) in DMF (5 mL) is added DIEA (344 mg, 2.66 mmol). The solution is stirred at room temperature for 5 minutes then (S)-5-(3′-chloro-biphenyl-4-yl)-4-isocyanato-2-methyl-pentanoic acid ethyl ester (330 mg, 0.887 mmol) is added. The mixture is stirred at room temperature for 2 hours then the solvent is removed under reduced pressure to give (S)-4-(3-tert-butoxycarbonylmethyl-ureido)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester which is used directly in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6](=[CH:18][N:19]([CH3:21])[CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Yield: 97.3 %

Procedure:
To a stirred solution of 5.0 g of ethyl 2-chlorobenzoylacetate in 50 cc of benzene was added dropwise 5 cc of dimethylformamide dimethylacetal in 15 cc of benzene at room temperature. The resulting mixture was heated under reflux for 6 hours. After cooling, the solvent was distilled off to obtain 6.2 g of compound D. Yield: 97.3%.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccccc1Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1ccccc1N
Reaction time: 2 h

Procedure:
Methyl 2-(2-nitrophenoxy)benzoate (540 mg, 0.00198 mol) was dissolved in ethyl acetate (20 mL) and palladium on carbon catalyst (270 mg) was added. The mixture was hydrogenated at 57 psi for 2 h. The catalyst was filtered and the solvents were evaporated to yield the title compound. 1H NMR (250 MHz, CDCl3) δ7.83 (dd, 1H), 7.41 (m, 1H), 7.10 (m, 1H), 6.97 (m, 2H), 6.82 (m, 2H), 6.69 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:21]=1)(C(OCC)=O)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Li+].O1CCCC1>O1CCCC1>[C:22]([C:20]1[CH:21]=[C:17]([CH2:16][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][OH:7])[S:18][CH:19]=1)#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC#Cc1csc(CC(NC(C)=O)(C(=O)OCC)C(=O)OCC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1csc(CC(CO)NC(C)=O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
To a solution of diethyl (acetamido)[[4-(1-dodecynyl)-2-thienyl]methyl]propanedioate (12.3 g) in dry tetrahydrofuran (100 ml) was added 2M lithium borohydride/tetrahydrofuran (12.8 ml), and the mixture was stirred at 60° C. for 4 hrs. The solution was cooled, quenched with a 50:50:10 solution of methanol:water:acetic acid, and extracted with ethyl acetate. The organic extracts were evaporated, and the residue was chromatographed on silica gel (9:1 ethyl acetate:dichloromethane). The appropriate fractions were collected and evaporated. The residue was crystallized from ether:heptane to give 5.3 g (57%) of product, mp 55°-58° C.
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:22]=[CH:21][C:10]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:9][CH:8]=1)([O-])=[O:5]>[Rh].O1CCCC1>[OH:5][NH:4][C:7]1[CH:22]=[CH:21][C:10]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Rh]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(NO)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydrazine hydrate (containing 55% hydrazine, 1.5 mL, 26.25 mmol, 1.05 equiv.) was added dropwise over 1 minute to a mixture containing benzyl 4-nitrobenzoate (Brewster, J. H.; Ciotti, C. J., Jr. J. Am. Chem. Soc. 1955, 77, 6214; 6.43 g, 25 mmole, 1 equiv.), 5% rhodium on carbon (wet, 625 mg), and tetrahydrofuran (50 ml) at 0° C. under argon. When the addition was complete, the mixture was warmed to room temperature, stirred for 4 hours, and then was filtered through Celite®. Concentration of the filtrate gave crude benzyl 4-(hydroxyamino)benzoate as a yellow oil which was used without further purification. Pure benzyl 4-(hydroxyamino)benzoate, obtained from a separate preparation by silica gel chromatography (30% ethyl acetate/toluene) was used for characterization purposes: TLC(30% ethyl acetate/toluene) Rf 0.52; 1H NMR (250 MHz, CDCl3) δ 7.99 (d, J=8.6 Hz, 2 H), 7.26-7.55 (m, 5 H), 6.97 (d, J=8.6 Hz, 2H), 5.33 (s, 2H); IR (CHCl3) 3550, 3315, 1703, 1606, 1273, 1169, 1101, 693 cm-1 ; MS(DC/NH3) 261.2 (M+NH4)+, 245.2 (M+MH4 -16)+, 228.1 (M+H-16)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCCc1ccccc1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCc2ccccc2)CC1

Procedure:
1-(2-phenylethyl)-4-piperidone is prepared from 4-piperidone and (2-chloroethyl)benzene essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([C:11]#[N:12])[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)=[CH:17][CH:16]=1
Reactant: N#Cc1cc(Br)cn2ccnc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Yield: 59.7 %

Procedure:
Prepared from 6-bromo-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23 step 2) (1.6 g, 7 mmol) and commercially available 4-trifluoromethylphenylboronic acid (1.505 g, 36 mmol) as described in example C.20 step 2. Obtained the title compound as a white solid (1.2 g, 46%). MS (ISP) 288.0 [(M+H)+].
Reaction SMILES: O1CCO[CH:2]1[C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26].Cl.CNC.C([BH3-])#N.[Na+]>O.C(O)C>[CH3:24][N:25]([CH2:2][C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1)[CH3:26]
Reactant: CNC
Reactant: CNC(=C[N+](=O)[O-])NCCSCc1ccc(C2OCCO2)o1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.9 %

Procedure:
To a stirred solution of N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (1.65 g) and dimethylamine hydrochloride (16.3 g) in water (3.74 ml) and ethanol (6.2 ml) was added 2 N hydrochloric acid (3.74 ml). After 15 min. at room temperature, a solution of dimethylamine in water (40%) (0.85 ml) was added followed by a solution of sodium cyanoborohydride (0.156 g) in water (1 ml). After 1h, the solution was evaporated in vacuo and to the oily residue was added acetic acid (0.5 ml). After 10 min., tetrahydrofuran (100 ml) and an excess of anhydrous sodium carbonate were added, the mixture heated to boiling and allowed to cool to room temperature. After standing for 3 h, the mixture was filtered and the combined filtrate and washings evaporated to low bulk in vacuo. Decolourising charcoal was added to the hot solution and after 1h, the mixture was filtered. The filtrate was evaporated to give an oil (1.7 g) which was chromatographed on silica using methanol:0.88 ammonia (79:1) to give an oil which was dissolved in ethanol. The solution was filtered and evaporated to give an oil (0.75 g) which was crystallised from methyl isobutyl ketone to yield the title compound (0.27 g), m.p. 68°-69.5° which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent Specification No. 1,565,966.
Reaction SMILES: [NH3:1].C(O[C:5](=[O:29])[CH2:6][N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:15]=[C:14]2[CH3:27])=[CH:9][C:8]1=[O:28])C>CO>[CH3:27][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][N:7]([CH2:6][C:5]([NH2:1])=[O:29])[C:8](=[O:28])[CH:9]=2)[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[N:15]=1
Reactant: N
Reactant: CCOC(=O)Cn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Solvent: CO
Product: Cc1cccc(C#Cc2cn(-c3ccn(CC(N)=O)c(=O)c3)c(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2 ml of a 7M solution of ammonia in methanol were added 60 mg (0.16 mmol) of [4-(2-methyl-4-m-tolylethynyl-imidazol-1-yl)-2-oxo-2H-pyridin-1-yl]-acetic acid ethyl ester (Example 13). The reaction vessel was closed and the yellow solution was stirred for 16 h at room temperature. The solution was then evaporated to dryness yielding 45 mg of the title compound as a light brown solid, MS: m/e=347.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]([OH:17])=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:44][CH2:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([Br:54])=[CH:50][CH:49]=1)=[O:47].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH:14]([C:15](=[O:17])[NH:44][CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([Br:54])=[CH:50][CH:49]=2)=[O:47])[CH2:13][C:10]2([CH2:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-tert-butyl ester (350 mg, 1.45 mmol) was mixed with HATU (551 mg, 1.45 mmol) in DMF (5 mL) and the mixture was stirred at room temperature for 30 minutes. 2-Amino-1-(4-bromo-phenyl)-ethanone bis HCl salt (416 mg, 1.45 mmol) in 2 mL DMF was added, followed by DIEA (3.5 eq., 0.88 mL) dropwise at 0° C. The reaction was stirred at 0° C. for 40 minutes. The reaction mixture was diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 67%). LCMS-ESI−: calc'd for C20H25BrN2O4: 437.33. Found: 460.1 (M+Na+).
Reaction SMILES: [S-2:1].[Na+].[Na+].[S].Cl[CH2:6][CH2:7][CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>C(O)C>[CH2:11]([O:10][Si:9]([CH2:8][CH2:7][CH2:6][S:1][S:1][CH2:6][CH2:7][CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: [S-2]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: [Na+]
Agent: [S]
Solvent: CCO
Product: CCO[Si](CCCSSCCC[Si](OCC)(OCC)OCC)(OCC)OCC
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
17.8 kg of virtually anhydrous sodium sulfide are mixed with 190 l of ethanol and added to an enameled 500 l capacity reactor. This is followed by the addition through a fine nozzle of 13.85 kg of sulfur in molten form. The mixture is heated to 50° C. and 190 l of 3-chloropropyltriethoxysilane are metered in within 10 minutes. On account of the exothermic reaction the temperature of the reactor contents rises to 74° C. A further 4.45 kg of virtually anhydrous sodium sulfide are added at this temperature. Three further portions of sodium sulfide are added at 5 minute intervals (i.e. each 5 minutes), the temperature of the reactor contents rising to 82° C. After completion of the sodium sulfide addition the reaction mixture is kept for 1.5 hours at 82-83° C. and the sodium chloride that has precipitated is separated after cooling the mixture. A yellow product is obtained after evaporating the reaction mixture in vacuo and renewed fine filtration. HPLC analysis confirms the presence of a product with a mean polysulfane chain length of 2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Temperature: 60 °C
Yield: 138.4 %

Procedure:
A mixture of 5-chlorosalicylaldehyde (20.02 g, 0.128 mole) and ethyl 4,4,4-trifluorocrotonate (23.68 g, 0.14 mole) was dissolved in anhydrous DMF, warmed to 60° C. and treated with anhydrous K2CO3 (17.75 g, 0.128 mole). The solution was maintained at 60° C. for 20 hours, cooled to room temperature, and diluted with water. The solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 54.32 g of an oil. The oil was dissolved in 250 mL of methanol and 100 mL of water, whereupon a white solid formed that was isolated by filtration, washed with water and dried in vacuo, to afford the ester as a yellow solid (24.31 g, 62%): mp 62-64° C. 1H NMR (CDCl3 /90 MHz) 7.64 (s, 1H), 7.30-7.21 (m, 2H), 6.96 (d, 1H, J=Hz), 5.70 (q, 1H, J=Hz), 4.30 (q, 2H, J=7.2 Hz), 1.35 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:18](=O)[CH:17]2[NH:20][C:21](=O)[CH:12]1[CH2:13][CH:14]=[CH:15][CH2:16]2.CC(C[AlH]CC(C)C)C>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:18][C@@H:17]2[NH:20][CH2:21][C@H:12]1[CH2:13][CH:14]=[CH:15][CH2:16]2
Reactant: O=C1NC2CC=CCC1N(c1ccc3ccccc3c1)C2=O
Agent: C1=C\C[C@@H]2CN[C@H](C/1)CN2c1ccc2ccccc2c1
Agent: CC(C)C[AlH]CC(C)C
Product: C1=CC[C@@H]2CN[C@H](C1)CN2c1ccc2ccccc2c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
7-Naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene-8,10-dione (130 mg, 0.45 mmol) and DiBAl-H (6 mL, 1M, 6 mmol) were placed in a μW tube under argon vent. The reaction mixture was then heated to 130° C. for 900 sec. The reaction was quenched with Rochelle's salt and diethyl ether mixture (1:1, 200 mL) and then stirred overnight. The organic eas layer separated and dried with magnesium sulfate, filtered and solvent evaporated under reduced pressure to yield the title compound as a residue.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH2:28][C:29]3[S:30][C:31]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)=[CH:32][N:33]=3)=[CH:20]2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.C[O-].[Na+]>CO>[O:35]1[CH:36]=[CH:37][CH:38]=[C:34]1[C:31]1[S:30][C:29]([CH2:28][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]3)[CH:20]=2)=[N:33][CH:32]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ncc(-c4ccco4)s3)c3ccccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cc(Cc3ncc(-c4ccco4)s3)c3ccccc32)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a solution of acetate 79 (195 mg, 0.32 mmol) in MeOH (15 mL) were added sodium methoxide (25 wt. % in MeOH, 1 mL) at room temperature. The mixture was stirred at room temperature for 1 hours. The amberlite IR-120H resin was added to the mixture to acidify the mixture. The mixture was filtered off and the filtrate was concentrated in vacuo. The residue was purified by prep HPLC (C18) to provide the titled compound 80 (25 mg, 18%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[NH2:14][OH:15].Cl.C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:15][N:14]=[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])[NH2:2]
Reactant: NO
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(C(N)=NO)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A mixture of methyl 3-cyano-4-methylbenzoate (compound 1.7, 8 g, 43.38 mmol, 1.00 equiv, 95%), NH2OH.HCl (3.785 g, 54.86 mmol, 1.20 equiv), and N,N-Diisopropylethylamine (DIEA, 17.7 g, 136.95 mmol, 3.00 equiv) in tetrahydrofuran (100 mL) was stirred overnight at 70° C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was taken up in water and the pH was adjusted to 2-3 with hydrogen chloride (aqueous, 1 M). After washing the mixture with 3×40 mL of ethyl acetate, the pH of the aqueous layer was adjusted to 8-9 with NaOH (aqueous, 2 M) followed by extraction with 3×30 mL of ethyl acetate. The combined organic layers were dried over (Na2SO4) and concentrated under reduced pressure to yield 2.76 g (29%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.C([O:23][C:24]1[C:29]([CH2:30]Cl)=[C:28]([CH3:32])[CH:27]=[C:26]([CH3:33])[N:25]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:30][C:29]1[C:24](=[O:23])[NH:25][C:26]([CH3:33])=[CH:27][C:28]=1[CH3:32])[CH2:7]2
Reactant: CC(C)Oc1ccc2c(c1Cl)C(=O)NC2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2Cc3ccc(OC(C)C)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
A mixture of 7-chloro-6-isopropoxy-2,3-dihydro-isoindol-1-one (133a, 120 mg, 0.532 mmol), 2-benzyloxy-3-chloromethyl-4,6-dimethyl-pyridine (Cpd Z, 139 mg, 0.532 mmol), cesium carbonate (260 mg, 0.798 mmol), and potassium iodide (132 mg, 0.798 mmol) in DMF (6 mL) was stirred at 100° C. overnight. The solution was cooled to room temperature and the reaction mixture partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, heptanes/EtOAc) and the residue concentrated under vacuum. The residue was treated with TFA at room temperature overnight. Excess TFA was removed under vacuum and the resulting residue was partitioned between ethyl acetate (50 mL) and sodium bicarbonate (50 mL). The organic phase was separated, washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, MeOH/EtOAc, 1/10) to give the title compound (Example 133, 20 mg, 12% yield over two steps) as a solid. 1H NMR (400 MHz, chloroform-d) δ 12.09 (br. s., 1H), 7.08-7.13 (m, 1H), 7.02-7.07 (m, 1H), 5.94 (s, 1H), 4.66 (s, 2H), 4.44-4.55 (m, 1H), 4.31 (s, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 1.36 (d, J=6.06 Hz, 6H): MS 361 [M+H].