Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]3(O)[CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)=O>CO>[Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]4[CH2:15][CH2:14][N:13]([CH2:18][CH2:17]4)[CH:12]=3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2cc3cccc(Br)c3o2)CN2CCC1CC2
Solvent: CO
Solvent: O=CO
Product: Brc1cccc2cc(C3=CN4CCC3CC4)oc12
Yield: 99.3 %

Procedure:
3-(7-Bromo-1-benzofuran-2-yl)quinuclidin-3-ol (600 mg, 1.86 mmol; Intermediate 24, Step 2) was dissolved in methanol (2 mL) and formic acid (40 mL) was added to the flask. The resulting mixture was heated at reflux overnight. Concentration in vacuo furnished 562 mg (99%) of the title product. HPLC purity=90%, m/z=305 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[O:7][C:8]1[C:9]([C:23](OCC)=[O:24])=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[O:7][C:8]1[C:9]([CH2:23][OH:24])=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[N:12]=1
Reactant: CCOC(=O)c1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a solution of ethyl 5-[3-(trifluoromethoxy)phenoxy]-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole-4-carboxylate (i.e. the product of Step H, 0.39 g, 0.8 mmol) in anhydrous tetrahydrofuran (6 mL) that was cooled to 0° C. was added a solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 0.8 mL, 0.8 mmol). The reaction mixture was stirred at 0° C. for 20 min., after which the reaction was quenched with the addition of ethyl acetate (5 mL). The mixture was stirred at 23° C. for 5 min., and then water (6 drops) was added. The mixture was stirred for 5 min., and then sodium sulfate was added. The mixture was stirred for 5 min., and then the mixture was filtered and concentrated under reduced pressure to obtain the title compound (0.35 g, 100%) as a pale yellow oil. The title compound was used directly in the next step without further purification.
Reaction SMILES: [F:1][C@@H:2]1[C@H:7]([NH:8][C@@H](C2C=CC=CC=2)C)[CH2:6][CH2:5][C@@H:4]([C:17]([NH2:19])=[O:18])[CH2:3]1>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:8][C@@H:7]1[CH2:6][CH2:5][C@@H:4]([C:17]([NH2:19])=[O:18])[CH2:3][C@@H:2]1[F:1]
Reactant: C[C@@H](N[C@@H]1CC[C@@H](C(N)=O)C[C@@H]1F)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)[C@@H]1CC[C@@H](N)[C@@H](F)C1
Reaction time: 16 h
Yield: 135.5 %

Procedure:
A solution of of (e) (280 mg) in ethanol (15 ml) and 20% palladium(II) hydroxide on charcoal (80 mg) was hydrogenated at 50 p.s.i. for 16 hours. Filtration and evaporation afforded a white solid (230 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:13].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH:5]=[CH:4][C:3]=1[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[O:11][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27]
Reactant: N#CCCCCBr
Reactant: CCCc1c(O)ccc(C(=O)c2ccccc2O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCC#N)ccc(C(=O)c2ccccc2O)c1O
Temperature: 70 °C

Procedure:
A mixture of 3.6 g of (2,4-dihydroxy-3-propylphenyl)(2-hydroxyphenyl)methanone, 1.4 ml of 5-bromopentane nitrile, 100 mg of sodium iodide, and 9.12 g of potassium carbonate in 50 ml of methyl ethyl ketone was heated to 70° C. for approximately 18 hours. The mixture was cooled and partitioned between diethyl ether and water. The organic layer was separated, dried over magnesium sulfate, and evaporated to dryness. The resulting oil was purified by high pressure liquid chromatography over silica gel eluting with a 5-25% ethyl acetate in hexane gradient. Evaporation of the desired fractions and crystallization from diethyl ether/hexane provided 1.31 g of the title product, m.p. 81°-82° C.
Reaction SMILES: CN1CCOCC1.Cl.[CH3:9][CH:10]([NH:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22])[CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].O>C(Cl)Cl>[CH3:9][CH:10]([NH:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH:22][C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29])[CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(CSc1ccccc1)NC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(CSc1ccccc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 60.1 %

Procedure:
1.3 g of N-methylmorpholine was added to a suspension containing 3.0 g of N1 -(1-methyl-2-phenylthioethyl)-L-valinamide hydrochloride suspended in 80 ml of methylene chloride, at -15° C. After 1.9 g of phenyl chloroformate was added to the mixture at -15° C., the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 2.3 g of the desired product in the form of a white crystal (yield: 54%).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:20](O)(=[O:22])[CH3:21]>C(O)C.[OH-].[OH-].[Pd+2]>[C:20]([O:19][CH2:18][CH:16]1[CH2:15][NH:14][CH2:17]1)(=[O:22])[CH3:21]
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)OCC1CNC1
Reaction time: 72 h

Procedure:
(1-Benzhydrylazetidin-3-yl)methanol (1.81 g, 7.16 mmol) was dissolved in ethanol (50 mL), and acetic acid (0.82 mL, 14.32 mmol) and 10% palladium hydroxide/carbon (1.2 g) were added at room temperature. The mixture was stirred for three days under a hydrogen stream at normal pressure. The catalyst was separated by filtration, and the reaction liquor was concentrated under reduced pressure, to obtain the title compound as an oily matter. This compound was used in the subsequent reaction without being subjected to further purification.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:37][CH:21]1[CH2:22][O:23][CH2:24][CH:25]([CH2:31][O:32][CH2:33][CH:34]1[O:36][CH2:35]1)[O:26][CH2:27][CH:28]1[O:30][CH2:29]1>>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH2:35][CH:34]([OH:36])[CH2:33][O:32][CH2:31][CH:25]([O:26][CH2:27][CH:28]([OH:30])[CH2:29][N:13]2[C:14]([CH3:17])([CH3:16])[CH2:15][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][C:12]2([CH3:19])[CH3:18])[CH2:24][O:23][CH2:22][CH:21]([OH:20])[CH2:37][N:13]2[C:12]([CH3:19])([CH3:18])[CH2:11][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:15][C:14]2([CH3:17])[CH3:16])[C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(OCC1CO1)C(COCC1CO1)OCC1CO1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1CC(O)COCC(COCC(O)CN1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)OCC(O)CN1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C

Procedure:
A mixture of 10.1 g of 4-benzoyloxy-2,2,6,6-tetramethylpiperidine and 2.6 g of glycerol tris(2,3-epoxypropyl)ether was reacted following the procedure described in Example 5 to give the desired Compound No. 115 in the form of a white vitreous solid having an Rf value of 0.87 on thin-layer chromatography on silica gel developed with a 4:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [Sn](Cl)Cl.[F:4][C:5]1[CH:6]=[CH:7][C:8]2[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[S:10][C:9]=2[CH:25]=1.O>Cl.C(O)C>[NH2:14][C:13]1[C:12]2[C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:25][C:9]=3[S:10][C:11]=2[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]=1
Reactant: N#Cc1c(Nc2ccccc2[N+](=O)[O-])sc2cc(F)ccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccccc2Nc2sc3cc(F)ccc3c21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Tin(II) chloride (50 g) was dissolved in a 18% hydrochloric acid (250 ml) solution heated to 50° C., and a suspension of 6-fluoro-2-(2-nitroanilino)benzo[b]thiophene-3-carbonitrile (20 g) in ethanol (280 ml) was added. The mixture was refluxed under heating for 4 hours. Then, the reaction mixture was cooled to 40° C. and poured into water (1 L) and the mixture was stood still for 30 minutes. The precipitated crystals were filtered by suction and washed with water (500 ml) to give 12-amino-3-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine 1 hydrochloride (15 g).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>O1CCCC1.CO>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH:14]([OH:18])[CH2:13][CH2:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2cc(OCc3ccccc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OC1CCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
2,3-Dihydro-5-(phenylmethoxy)-1H-inden-1-one (1.3 g, 5.46 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and methanol (10 mL), sodium borohydride (0.41 g, 11 mmol) was added, and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (1.16 g, yield 89%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCOCC1.CN(C=O)C>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([O:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCCN4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and N-(2-hydroxyethyl)morpholine in dioxane and DMF. ES-MS m/e (%): 500 (M+H+, 100).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=O)=[CH:10][N:9]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:12]([C:11]3[CH:10]=[N:9][C:8]([CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:14])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)nc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 82.2 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)nicotinate (108 mg) described in Preparation Example 45 and 1-(3,5-dimethylpyridin-2-yl)piperazine (77 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (141 mg) was obtained.
Reaction SMILES: [Br:1][CH:2]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[N+:10]([O-:12])=[O:11])[CH2:3]Br.CC[O-].[Na+]>CO>[Br:1][C:2]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[N+:10]([O-:12])=[O:11])=[CH2:3]
Reactant: O=[N+]([O-])c1nccn1C(Br)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: C=C(Br)n1ccnc1[N+](=O)[O-]
Yield: 55.9 %

Procedure:
20.1 g of 1-(1,2-dibromoethyl)-2-nitroimidazole were heated under reflux for 1 hour in 132 ml of a 0.51N solution of sodium ethylate in methanol. The mixture was evaporated and the residue was taken up with 250 ml of ethyl acetate and 100 ml of water. The organic phase was washed with 100 ml of 10% sodium chloride solution and evaporated, and the residue was chromatographed on 300 g of silica gel using ethyl acetate/cyclohexane (4:1, v/v). After a forerun of 420 ml, there were isolated from 270 ml of further eluate 8.2 g of 1-(1-bromovinyl)-2-nitroimidazole; yield 4.6 g; m.p. 80°-82° C. (from isopropanol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[C:11](Cl)=[O:12])=[CH:4][C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH2:20]([NH2:23])[CH2:21][CH3:22]>C1C=CC=CC=1>[CH2:20]([NH:23][C:11]([CH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:2]([Cl:1])[CH:10]=2)[CH2:6][CH2:7]1)=[O:12])[CH2:21][CH3:22]
Reactant: O=C(Cl)C1CCc2cc(C3CCCCC3)c(Cl)cc21
Reactant: CCCN
Solvent: c1ccccc1
Product: CCCNC(=O)C1CCc2cc(C3CCCCC3)c(Cl)cc21

Procedure:
In 35 ml. of benzene is dissolved 2.97 g. of 6-chloro-5-cyclohexylindan-1-carbonyl chloride and to the solution is added 1.77 g. of n-propylamine under cooling and with stirring. The mixture is stirred at room temperature for 1 hour, after which time it is washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residual crystals are recrystallized from acetone. The procedure yields N-propyl-6-chloro-5-cyclohexylindan-1-carboxamide, Melting poing: 140.5 - 142.5° C.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH2:20])=[O:19])C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH2:20])=[O:19]
Reactant: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 0.75 h
Yield: 119.3 %

Procedure:
445 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was dissolved in methanol (16 mL), and 80 mg of 10% palladium-carbon (50% water content) was added, followed by stirring for 0.75 hours under hydrogen atmosphere. The catalyst of the reaction mixture was filtered through celite, and the solvent was concentrated under reduced pressure and dried under vacuum to afford 357 mg of the title compound as a colorless solid (quantitative).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH2:17])[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=2)[CH:5]=[CH:4][N:3]=1>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[C:10]([NH2:17])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cc(N)cc([N+](=O)[O-])c2)ccn1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2cc(N)cc(N)c2)ccn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
To a rt solution of 51.1B (1.10 mg, 4.8 mol) in MeOH (10 mL) was added 5% Pd/C. The heterogeneous solution was stirred at 50° C. under H2 for 4.0 hr. To the resulting mixture was added celite, solid was filtered off and washed with MeOH. The combined liquid was concentrated under reduced pressure to provide the title product 51.1C as colorless solid (865 mg, 91%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[CH:15]=[O:16])[CH:2]([CH3:4])[CH3:3].[C:17](=O)([O-])[O-].[K+].[K+].CI.O>C(#N)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:17])[N:10]=[C:9]2[CH:15]=[O:16])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)COc1ccc2[nH]nc(C=O)c2c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: CC(C)COc1ccc2c(c1)c(C=O)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A mixture of 5-iso-butoxy-1H-indazole-3-carbaldehyde (110 mg, 0.50 mmol, 1.00 equiv), potassium carbonate (209 mg, 1.50 mmol, 2.98 equiv) and methyl iodide (107.5 mg, 0.76 mmol, 1.50 equiv) in acetonitrile (4 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and the residue was filtered through a silica gel column eluted with 2-5% of ethyl acetate in petroleum ether. The crude product (70 mg) was purified by Pre-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)): Column, XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and CH3CN (18% CH3CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm to give 35 mg (30%) of 5-iso-butoxy-1-methyl-1H-indazole-3-carbaldehyde as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.1 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.07 (dd, J=8.8 Hz, 2.0 Hz, 1H), 4.08 (s, 3H), 3.74 (d, J=6.8 Hz, 2H), 2.09-2.02 (m, 1H), 0.98 (d, J=6.8 Hz, 6H) ppm. LCMS (method D, ESI): RT=2.23 min, m/z=233.1 [M+H]+ and 15 mg (13%) of 5-iso-butoxy-2-methyl-2H-indazole-3-carbaldehyde as a white solid. 1H NMR (400 MHz, CDCl3): 10.12 (s, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 7.07 (dd, J=9.2 Hz, 2.4 Hz, 1H), 4.38 (s, 3H), 3.73 (d, J=6.4 Hz, 2H), 2.10-2.05 (m, 1H), 0.99 (d, J=6.8 Hz, 6H) ppm. LCMS (method D, ESI): RT=2.24 min, m/z=233.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[NH:9][C:10](COC3C=CC(Cl)=CC=3Cl)=[N:11][C:7]=2[CH:6]=1)=[O:4].Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[NH:9]1[C:8]2[CH:22]=[CH:23][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[CH:10]1
Reactant: COC(=O)c1ccc2[nH]c(COc3ccc(Cl)cc3Cl)nc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2[nH]cnc2c1
Temperature: 10 °C
Yield: 197 %

Procedure:
A mixture of 2-(2,4-dichlorophenoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (110 mg, 0.31 mmol), acetic acid (60 mL) and coned HCl (60 mL) was heated under reflux for 3 h. At the end of the reaction period, the mixture was cooled to 10° C., neutralized with aqueous sodium bicarbonate solution, filtered, washed with ethyl acetate (10 mL), water (50 mL) and dried to afford 2-2,4-chloro-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid as a colorless powder (0.099 g, 94.28% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:7]=2[N:29]=1.C(O)(C(F)(F)F)=O.NC1CCN(CCN2C3C(=CC(C#N)=CC=3)N=CC2=O)CC1>>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:29][C:7]2=3)[CH2:20][CH2:19]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1

Procedure:
tert-Butyl {1-[2-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 203, 0.213 g) was deprotected with TFA as described for Intermediate 197 to give the crude free base of the product, 0.15 g.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9](OCC)=O)=[CH:7][N:6]=[C:5]2[NH:14][N:15]=[CH:16][C:4]=12)[NH2:2].C(N1C2=[N:24][CH:25]=[C:26](C(OCC)=O)[C:27](NN)=[C:22]2C=N1)C>>[CH2:5]([NH:6][C:9]1[C:8]2[CH:7]=[N:6][C:5]3[NH:14][N:15]=[CH:16][C:4]=3[C:3]=2[N:1]2[N:2]=[C:27]([CH3:22])[CH:26]=[C:25]2[N:24]=1)[CH2:4][CH2:3][CH3:8]
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1NN
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Product: CCCCNc1nc2cc(C)nn2c2c1cnc1[nH]ncc12

Procedure:
By substituting an equivalent amount of 4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in the procedure of Example 1 a and continuing as in parts b, c and d, 5-chloro-2-methyl-8H-pyrazolo[1,5a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine and N-butyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5-amine respectively, are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[I-].[CH3:16][S+](C)(C)=O.[OH-].[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1.O>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:16]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 80 °C
Yield: 86.4 %

Procedure:
A solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.00 g), trimethylsulfoxonium iodide (2.43 g) and tetrabutylammomium bromide (0.048 g) in toluene (20 mL) was added a solution of sodium hydroxide (5.02 mL) in water (6.3 mL) dropwise at room temperature. The resulting mixture was heated at 80° C. for 4 hours. The organic phase was separated and the aqueous layer was extracted with toluene. The combined extracts were washed with water, brine, dried and evaporated in vacuo and further dried under high vacuum to obtain the title compound (1.85 g) having the following physical data.
Reaction SMILES: [C:1]([N:4]([CH2:13][CH2:14][C:15]([OH:17])=O)[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])(=[O:3])[CH3:2].[CH2:18]([C:20]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:19]>>[C:1]([N:4]([CH2:13][CH2:14][C:15]([N:22]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]1[C:31]([CH2:35][CH3:36])=[CH:32][CH:33]=[CH:34][C:20]=1[CH2:18][CH3:19])=[O:17])[C:5]1[C:6]([CH3:12])=[CH:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCNc1c(CC)cccc1CC
Reactant: CC(=O)N(CCC(=O)O)c1c(C)cccc1C
Product: CCOC(=O)CCCN(C(=O)CCN(C(C)=O)c1c(C)cccc1C)c1c(CC)cccc1CC

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-acetyl-3-(2,6-dimethylanilino)propionic acid and ethyl 4-(2,6-diethylanilino)butyrate and suitable processing produces ethyl N-[N-acetyl-3-(2,6-dimethylanilino)propionyl]-4-(2,6-diethylanilino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-acetyl-3-(2,6-dimethylanilino)propionyl]-4-(2,6-diethylanilino)butyric acid (M.P. 110° to 111°).
Reaction SMILES: [C:1]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>ClCCl.CCOC(C)=O>[C:1]12([C:6]([O:8][CH3:9])=[O:7])[O:18][CH:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: COC(=O)C1=CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C12CCCC1O2
Reaction time: 2 h
Yield: 142 %

Procedure:
Methyl cyclopent-1-ene-1-carboxylate (30.0 g, 237.8 mmol) was dissolved in 20 mL of dichloromethane and 3-chloroperbenzoic acid (64.4 g, 373.3 mmol) was added. The reaction was allowed to stir vigorously for 2 hours. The reaction mixture was diluted with EtOAc and washed with 0.5 N NaOH. The organic layer was dried over sodium sulfate, filtered and concentrated to give 48.0 grams of methyl 6-oxabicyclo[3.1.0]hexane-1-carboxylate.