Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([N:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH:10]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>C(OCC)C>[C:19]1([CH:10]2[N:9]([NH2:7])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH2:11]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=NN1c2ccccc2OCC1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NN1c2ccccc2OCC1c1ccccc1
Reaction time: 18 h
Yield: 61 %

Procedure:
A slurry of lithium aluminum hydride (4.9 g, 130.5 mmol) in ethyl ether (100 mL) is stirred at ice bath temperature under an argon atmosphere. A solution of 4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine in ethyl ether (300 mL) is added dropwise over 1 h. The mixture is removed from the ice bath and allowed to stir for 18 h. Water (50 mL) is slowly added forming solids. The solids are collected by filtration and washed with ethyl ether. The resulting filtrates are combined and washed three times with water (200 mL), dried over magnesium sulfate, and concentrated to give 8.7 g (61%) of 3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-ylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH:17]12[CH2:22][CH:21]1[CH2:20][NH:19][CH2:18]2>>[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([C:14]([C:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:16])[CH2:18]2
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Reactant: C1NCC2CC12
Product: COc1ccc(C(=O)N2CC3CC3C2)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with 3-azabicyclo[3.1.0]hexane by following the similar procedure as described in Step-6 of Intermediate-22.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([OH:13])[C:9]([CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:8][C:7]=2[CH3:18])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CCCCCC>[Br:20][CH2:16][C:15]1([CH3:17])[O:13][C:10]2=[C:11]3[C:6](=[C:7]([CH3:18])[CH:8]=[C:9]2[CH2:14]1)[NH:5][C:4](=[O:19])[C:3]([CH2:1][CH3:2])=[CH:12]3
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)Cc1cc(C)c2[nH]c(=O)c(CC)cc2c1O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc2c3c(cc(C)c2[nH]c1=O)CC(C)(CBr)O3
Yield: 99.1 %

Procedure:
Using 3-ethyl-6-(2-methyl-2-propenyl)-5-hydroxy-8-methylcarbostyril (710 mg, 2.76 mmol) and N-bromosuccinimide (516 mg, 2.90 mmol), the procedure of Example 227 was followed (reaction, post-treatment, and recrystallization from chloroform-n-hexane) to obtain 920 mg of the title compound as pale yellow crystals (99.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:7]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CCCNCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1ccnc(Cl)c1
Yield: 76.5 %

Procedure:
Stir a solution of 2-chloroisonicotinic acid (1.0 g, 6.3 mmol), 1-hydroxybenzotriazole (850 mg, 6.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.21 g, 6.3 mmol), dipropyl amine (862 μL, 6.3 mmol), and triethylamine (1.75 mL, 12.6 mmol) in dichloromethane (63 mL ) at room temperature over the weekend. Wash the solution with 0.1 N citric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes) to give the title compound (1.16 g, 76%).
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:33](Cl)(=[O:35])[CH3:34].CS(C)=O>C1C=CC=CC=1>[C:33]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CCCCNC(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CCCCN(C(C)=O)C(c1ccccc1)c1ccccc1
Yield: 97.9 %

Procedure:
Analogously to Example 19, 9 g of ethyl 5-benzhydrylaminovalerate and 4.1 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 2.5 g of acetyl chloride. As reaction product one obtains 10 g of ethyl N-acetyl-5-benzhydrylaminovalerate as a viscous non-distillable oil. The saponification of this ester gives 7.4 g (78.7%) of N-acetyl-5-benzhydrylaminovaleric acid (M.P. 135° to 136°).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[O:12][CH3:13].C(N(CC)CC)C.ClCCl.[C:24](Cl)(=[O:26])[CH3:25]>O>[C:24]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[O:12][CH3:13])(=[O:26])[CH3:25]
Reactant: COc1cccc2cc(O)cnc12
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2cc(OC(C)=O)cnc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
175 mg of 3-hydroxy-8-methoxy quinoline [compound (V)] prepared in example 6 and 132 mg of triethyl amine were added to 10 ml of dichloromethane. After cooled to 0° C., 0.1 ml of acetyl chloride was slowly added dropwise. The solution was agitated for 1 hour, and water was added to the solution. The solution was extracted with dichloromethane and washed with water. The dichloromethane layer was dried with anhydrous magnesium sulfate. The dichloromethane was removed by vacuum distillation to give 195 mg of 3-acetoxy-8-methoxy quinoline as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:4][CH2:3]1.CO.Br>[Pt](=O)=O.O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:4][CH2:3]1
Reactant: COc1cccc2cc(C3=CCN(C)CC3)oc12
Agent: O=[Pt]=O
Agent: Br
Solvent: CO
Solvent: O
Product: COc1cccc2cc(C3CCN(C)CC3)oc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.9 %

Procedure:
A mixture of 1-methyl-4-(7-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (58.0 g), methanol (1.5 l), water (200 ml), 48% HBr (42.0 g), and platinum dioxide were shaken under hydrogen at room temperature for 6 hours. The mixture was filtered; the filtrate was concentrated in vacuo to the aqueous phase, neutralized with 5% Na2CO3 and extracted with CH2 Cl2. The organic phase was washed with water, dried (Na2 SO4) and concentrated in vacuo to give 59 g of the crude product, which was crystallized from methanol/water, m.p. 74°-75° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([CH3:21])[NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][N:34]=[C:35]=[S:36].O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:20][C:35]([NH:34][CH2:33][C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[S:36])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: S=C=NCc1ccco1
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=S)NCc1ccco1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Yield: 76.8 %

Procedure:
(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (50 mg, 0.14 mmol), as described in Example 1, is dissolved in 0.89 mL dichloromethane and furylmethylisothiocyanate (19.3 mg, 0.14 mmol) is dropwise added. After stirring for 90 min at r.t. water (5 mL) is added and the reaction mixture extracted once with ethyl acetate (50 mL). The organic phase is washed with water (10 mL) and dried over Na2SO4. After filtration the solvent is removed and the residue purified by chromatography (silicagel, eluents: hexane/ethylacetate). 53.8 mg (77.7%) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[CH2:15][S:14][C:13]2=[O:18])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:20][CH:21]=O>C(O)C>[N:1]1[CH:20]=[CH:21][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]3[C:16](=[O:17])[CH2:15][S:14][C:13]3=[O:18])[C:2]=12
Reactant: O=CCCl
Reactant: Nc1ncccc1OCCCN1C(=O)CSC1=O
Solvent: CCO
Product: O=C1CSC(=O)N1CCCOc1cccn2ccnc12

Procedure:
To a solution of 4.01 g (15 mmol) of 3-[3-(2-aminopyridin-3-yloxy)propyl]thiazolidine-2,4-dione in 40 ml of ethanol, 15 ml of a 40% chloroacetaldehyde solution was added at 60° C., followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 2.92 g (66.8%, white powder) of the desired product.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH2:25][CH3:26]>>[CH2:25]([N:24]([CH2:16][C:15]1[CH:18]=[CH:19][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:13][CH:14]=1)[CH2:23][CH2:22][O:21][CH3:20])[CH3:26]
Reactant: CCNCCOC
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CCN(CCOC)Cc1ccc(C(=O)N2CCN(C(C)C)CC2)cc1

Procedure:
Prepared from the product of Example 15 and (2-methoxy-ethyl)-ethyl-amine.
Reaction SMILES: [CH3:1][C@@:2]1([NH:17]C(=O)OC(C)(C)C)[CH2:6][CH2:5][C@H:4]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])[C:3]1([CH3:16])[CH3:15].[ClH:25]>C(OCC)(=O)C>[ClH:25].[NH2:17][C@:2]1([CH3:1])[CH2:6][CH2:5][C@H:4]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])[C:3]1([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@]1(C)CC[C@H](C(=O)N2CCCCC2)C1(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)[C@@H](C(=O)N2CCCCC2)CC[C@@]1(C)N
Reaction time: 2 h

Procedure:
A mixture of intermediate 6 (0.27 g. 1.0 mmol), 1,1′-Carbonyldiimidazole (0.19 g, 1.2 mmol) and piperidine (0.10 g, 1 mmol) in dichloromethane was stirred at room temperature for 8 h. The reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous Na2SO4 and concentrated. Crude material was purified by column chromatography to obtain tert-butyl (1R,3S)-1,2,2-trimethyl-3-(piperidine-1-carbonyl)cyclopentylcarbamate. To the solution of tert-butyl (1R,3S)-1,2,2-trimethyl-3-(piperidine-1-carbonyl)cyclopentylcarbamate in ethyl acetate was added hydrochloride solution in ethylacetate and stirred for 2 h to afford ((1S,3R)-3-amino-2,2,3-trimethylcyclopentyl)(piperidin-1-yl)methanone hydrochloride. 1H NMR (400 MHz, D2O) δ ppm: 0.98 (s, 3H), 1.11 (s, 3H), 1.31 (s, 3H), 1.54-1.60 (m, 6H), 1.94-2.20 (m, 4H), 3.47-3.48 (m, 1H), 3.54-3.57 (m, 2H), 3.65-3.66 (m, 2H). m/z (M+H): 239.2.
Reaction SMILES: [Na].C(O[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH2:12]([C:16](C)=[O:17])[CH:13]([CH3:15])[CH3:14]>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C:16](=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:10]
Reactant: CC(=O)CC(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)CC(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 116.1 %

Procedure:
Sodium pellets (4.6 g, 200 mmol) were dissolved in ethanol (165 ml) under nitrogen at room temperature and a solution of diethyloxalate (13.5 ml, 100 mmol) in isobutylmethyl ketone (30 ml, 200 mmol) was added dropwise at room temperature over 20 minutes. The reaction was heated to 60° C. and stirred at this temperature for one hour. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (4×200 ml). The combined organic extracts were washed with water, dried over MgSO4 and concentrated under reduced pressure to give 5-methyl-3-oxo-hexanoic acid ethyl ester (20 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=14.40-14.70 (1H, brs), 6.27 (1H, s), 4.25-4.32 (2H, quart), 2.26-2.31 (2H, d) (1H, m), 1.29-1.34 (3H, t), 0.89-0.94 (6H, d) ppm. LRMS (thermospray): m/z [M+NH4]+ 218.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]2[N:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]=[C:16]([CH3:17])[C:3]=12.[ClH:24].C([OH:27])C>>[ClH:1].[ClH:24].[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[F:13])[NH:5][C:4]1[N:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]=[C:16]([CH3:17])[C:3]=1[C:2]2=[O:27]
Reactant: Cc1nn(-c2cccnc2)c2nc3cc(F)c(F)cc3c(Cl)c12
Reactant: CCO
Agent: Cl
Product: Cc1nn(-c2cccnc2)c2[nH]c3cc(F)c(F)cc3c(=O)c12
Temperature: 25 °C
Yield: 33 %

Procedure:
To a solution of 4-chloro-6,7-difluoro-3-methyl-1-(3-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (0.70 g, 2.12 mmol) in ethanol (40 mL), 6N hydrochloric acid (2 mL, 12.0 mmol) was added, and the mixture was heated under reflux for 2.5 days. The solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and air dried to give the title compound (0.27 g, 33% yield).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: O=C(NN1CCCCC1)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 1-amino-piperidine (CAN 2213-43-6; 76.9 mg, 0.51 mmol) as starting materials, and isolated (17 mg, 12.57%) as white solid; (UV peak area, ESI) 100%, 316.6 (M+H).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[CH3:29][N:30]1[C:34](=[O:35])[N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:32]([C:44]2[CH:49]=[CH:48][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:46][CH:45]=2)=[N:31]1>>[CH3:29][N:30]1[C:34](=[O:35])[N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:32]([C:44]2[CH:49]=[CH:48][C:47]([C:2]3[N:7]4[CH:8]=[C:9]([CH2:11][CH2:12][C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)=[CH:46][CH:45]=2)=[N:31]1
Reactant: Cn1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)n(COCC[Si](C)(C)C)c1=O
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Product: Cn1nc(-c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2)n(COCC[Si](C)(C)C)c1=O
Yield: 45.7 %

Procedure:
Compound 3a (350 mg, 0.760 mmol) was subjected to Suzuki coupling conditions with 1-methyl-3-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-[[2-(trimethylsilyl)ethoxy]methyl]-4,5-dihydro-1H-1,2,4-triazol-5-one (983 mg, 2.28 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 10e as a yellow solid (230 mg, 43% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C36H42N8O3S: 633.3 (M+H). Found 633.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10](C(=O)C)[CH:11]=2)[CH2:6]1.ClC1C=CC=[C:21]([C:25]([O:27]O)=[O:26])C=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:27][C:25](=[O:26])[CH3:21])[CH:11]=2)[CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CC1Cc2ccc(C(C)=O)cc2C1
Solvent: ClCCl
Product: COC(=O)CC1Cc2ccc(OC(C)=O)cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
11.0 g (47.0 mmol) of methyl(5-acetylindan-2-yl)acetate was dissolved in 200 ml of methylene chloride, to which was added 14.6 g (67 mmol) of m-chloroperbenzoic acid and stirred for 4 hours at room temperature, followed by refluxing for 17 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and water in this order, dried and then the solvent was removed. The residue was purified by silica gel column chromatography (chloroform) to obtain 11.3 g of an oily product. Yield: 97%
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Na+].[C:6]1([CH3:15])[C:7]([S:12]([O-:14])=[O:13])=[CH:8][CH:9]=[CH:10][CH:11]=1>CN(C=O)C>[C:6]1([CH3:15])[C:7]([S:12]([CH2:2][C:3]#[N:4])(=[O:14])=[O:13])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccccc1S(=O)[O-]
Reactant: N#CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)CC#N
Reaction time: 1 h
Yield: 51.6 %

Procedure:
2.2 ml (34.5 mmol) of chloroacetonitrile were added to a suspension of 4.5 g (28.8 mmol) of toluene-2-sulphinic acid sodium salt in 100 ml of DMF and stirred at 1000 for 1 hr. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was washed three times with CH2Cl2. The combined organic phases were washed once with H2O, dried (MgSO4). filtered and evaporated. Chromatography (SiO2, CH2Cl2) yielded 2.9 g (50%) of (toluene-2-sulphonyl)-acetonitrile as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I>C1COCC1>[CH3:15][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[N:9]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h

Procedure:
To a solution of 6-nitroindazole (8 g) in THF (200 ml) was added NaH (2.5 g) at 0° C. The reaction was stirred for 30 min and MeI (3.7 ml) was added and stirred at RT overnight. The reaction was quenched with water and extracted with EtOAc twice, then was further purified by column chromatography to give 1-methyl-6-nitro-1H-indazole which was hydrogenated with an H2 atmosphere in the presence of Pd/C (400 mg) to give 1-methyl-6-amino-1H-indazole.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:7](O)=[O:8]>COCCOCCOC>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH2:7][OH:8]
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: OCc1cc(F)cc(Br)c1
Temperature: 25 °C

Procedure:
Sodium borohydride (1.68 g) was added to diethylene glycol dimethyl ether (40 ml). While the mixture was stirred at room temperature, 3-bromo-5-fluorobenzoic acid (9.72 g) was added portionwise (six portions). After the crystals were completely dissolved, trifluoroborane ether complex (8.40 g) in diethylene glycol dimethyl ether (10 ml) was added dropwise thereto. The mixture was stirred for 5 hours, and poured into ice/water. The mixture was extracted with ether (200 ml), and washed with water, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→5:1), to thereby yield a mixture of the target compound and diethylene glycol dimethyl ether. The thus-obtained mixture was analyzed by NMR to determine the content of diethylene glycol dimethyl ether. The content and the yield of the target compound as determined by NMR were 7.70 g and 84.6%, respectively.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])[C:13](=[O:19])[C:14]3([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH:2]=1.C(O)(C(F)(F)F)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:13](=[O:19])[C:14]3([CH3:17])[CH3:18])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(-c3cccnc3)cc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(-c3cccnc3)cc21
Yield: 59.5 %

Procedure:
1,1-Dimethylethyl N-((7-(3-pyridyl)-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (184 mg, 436 μmol) was stirred in TFA (2 mL, 26924 μmol) at room temperature for 30 minutes. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the desired product as a yellow solid (95 mg). MS (m/e)=367.2 (M+H)+. Calculated for C21H19NO5 366.12.
Reaction SMILES: [O:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:14](O)=[O:15].C(N1C=CN=C1)(N1C=CN=C1)=O.[H-].C([Al+]CC(C)C)C(C)C.CC1C=CC=CC=1>O1CCCC1.O.CO>[O:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH:14]=[O:15]
Reactant: O=C(O)C1CCc2ccc3c(c2O1)CCC3
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=CC1CCc2ccc3c(c2O1)CCC3
Temperature: -80 °C
Yield: 53.9 %

Procedure:
A mixture of intermediate (4-a) (0.11 mol) in tetrahydrofuran (250 ml) was stirred under nitrogen flow. 1,1'-Carbonylbis-1H-imidazole (0.11 mol) was added and the reaction mixture was stirred for 2 hours at room temperature. Then, it was cooled to -80° C. A solution of diisobutylaluminum hydride in methylbenzene (20%) (0.33 mol) was added dropwise and the reaction mixture was stirred for 2 hours at -80° C. The mixture was decomposed with methanol, then poured out into water. The mixture was acidified, then extracted with 1,1'-oxybisethane. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated, yielding 12 g of (±)-2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-carboxaldehyde (interm. 5-a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](I)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:17][C:18]1[S:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Br:17][C:18]1[S:22][C:21]([C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:14]=[C:13]([CH3:15])[N:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(I)n1
Reactant: OB(O)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Br)s2)n1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-2-iodo-6-methyl-pyridine (example A.52) (1.0 g, ca. 80% pure, ca. 2.75 mmol) and commercially available 5-bromthiophene-2-boronic acid (0.568 g, 2.75 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.480 g, 46%). MS (ISP) 397.9 [(M+H)+], 400.0 [(M+2+H)+], 402.1 [(M+4+H)+] and 404.2 [(M+6+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH2:25]([N:28]=[C:29]=[O:30])[CH:26]=[CH2:27].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:29]([NH:28][CH2:25][CH:26]=[CH2:27])=[O:30])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: C=CCN=C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCNC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 44 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine is reacted with 1.2 eq of allyl isocyanate in dioxane/water (1:1) in the presence of sodium acetate (2.5 eq). The crude product is purified by column chromatography (silica, 3:7 ethyl acetate:methylene chloride). Recrystallization from methylene chloride:hexane, and then from methanol:water gives pure 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(2-propenylamino) carbonyl]-lH-indole-3-methanamine (44%); mp 148°-149° C.