Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH:8][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccnc1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cccnc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Alanine t-butyl ester (0.454 g, 2.50 mmol) was dissolved in 15 ml of CH2Cl2, then Et3N (0.252 g, 2.50 mmol) was added and the mixture was stirred for 10 minutes at room temperature. Then nicotinic acid (0.31 g, 5.0 mmol) in 8 ml of DMF and HOBt (0.43 g, 3.20 mmol) in 5 ml of DMF were added, followed by DCC (0.52 g, 3.0 mmol) in 10 ml of CH2Cl2. The mixture was stoppered and stirred overnight at room temperature. The DCU which formed was removed by filtration and the solvent was removed in vacuo. The residue was dissolved in 25 ml of CHCl3 and washed successively three times with 5% acetic acid/H2O, three times with 7% NaHCO3 /H2O and once with saturated NaCl solution. The organic layer was dried over anhydrous Na2SO4 for one hour, then the solvent was removed in vacuo to give nicotinoyl-alanine t-butyl ester. That product was dissolved in 25 ml of 1:1 TFA/CHCl3 and was stirred at room temperature for 30 minutes. The solvent was removed in vacuo, the residue was triturated three times with Et2O and then recrystallized from Et2O to give nicotinoyl-alanine (27). TLC showed one spot, Rf =0.42 in 1:9 CH3OH/CHCl3. Mass spectrum showed one major peak centered at m/z=195 (M+H+) which matched the calculated molecular weight. The product was obtained in 53% overall yield (0.257 g, 1.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:2]=1[F:1]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (16.0 g, 0.046 mol) and NH4Cl (6.0 g, 0.11 mol) in EtOH/H2O (150 mL, v/v=4:1) was added iron powder (12.4 g, 0.22 mol) at rt. The reaction mixture was heated to reflux for 2 h, then cooled down to rt. Celite (10 g) was then added and stirring for 30 min. The mixture was filtered and the solid was washed with MeOH (20 mL×3) and DCM (20 mL×3). The filtrate was washed with 30 mL of saturated NaHCO3 aqueous. The aqueous phase was extracted with DCM (20 mL×3). The combined organic phases were washed with brine (20 mL×3), dried over Na2SO4, and concentrated in vacuo to give a yellow solid (0.9 g, 98%).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9][C:8]=2[CH:19]=1)=[O:3].[NH3:20]>O1CCCC1>[O:14]=[C:13]1[CH2:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[S:9][C:8]2[CH:19]=[C:4]([C:2]([NH2:20])=[O:3])[CH:5]=[CH:6][C:7]1=2
Reactant: N
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1CC2=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1CC2=O

Procedure:
Dissolve the acid chloride from Step 1 in 20 ml. of dry tetrahydrofuran and add this solution dropwise with stirring to a cooled (ice-bath) saturated solution of ammonia in 60 ml. of tetrahydrofuran. Pass ammonia through the reaction for 15 minutes. Stir at room temperature for an additional 15 minutes and evaporate the reaction mixture to dryness. Add a mixture of 12 ml. of ethanol and 60 ml. of water to the residue and stir at room temperature for an additional 30 minutes. Separate the solid by filtration and wash with water, then with ethanol and then with ether. Dry in vacuo to obtain the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccn(-c2ccccc2)c1C
Yield: 52.1 %

Procedure:
A solution of 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (388 mg, 2.53 mmol), iodobenzene (619 mg, 3.04 mmol), copper(I) iodide (24 mg, 0.127 mmol), N,N′-dimethyl-ethane-1,2-diamine (54 μL, 0.506 mmol), potassium phosphate (1.128 g, 5.31 mmol) in dry toluene (2.5 mL) was irradiated with microwave at 130° C. for 2 h; then the solids were filtered off, the filtrate was concentrated, the resulted residue was purified on column to give the title product (302 mg); The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=7.5-7.2 (m, 5H), 6.51 (s, 2H), 4.28 (q, 2H, J=7.4 Hz), 2.44 (s, 3H), 1.36 (t, 3H, J=7.4 Hz).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([CH3:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH3:28])C1C=CC=CC=1.C(O)(=O)C>CO>[CH3:27][C:14]1([N:11]2[CH2:12][CH2:13][NH:8][C@@H:9]([CH3:28])[CH2:10]2)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]1
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1
Reaction time: 18 h
Yield: 99.7 %

Procedure:
A solution of t-butyl 4-[(3S)-4-benzyl-3-methylpiperazin-1-yl]-4-methylpiperidine-1-carboxylate (45.5 g, 0.118 mol) in methanol (320 mL) and acetic acid (35 mL, 5 equiv) in a 2.25 L Parr bottle was charged with H2 to 60 psi and the mixture shaken for 18 hr. The reaction mixture was filtered through a pad of Celite and the pad was washed with methanol. The filtrate was concentrated under vacuum. The residual oil was dissolved in DCM (500 mL) and washed with aqueous sodium hydroxide (300 mL). The aqueous phase was back-extracted with methylene chloride (200 mL). The combined organic solution was washed with brine (500 mL), dried with sodium sulfate and the solvent was removed under vacuum to give 35 g (100%) of product as a pale yellow viscous oil that slowly crystallized. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.44 (m, 2H), 3.36 (m, 2H), 2.97 (dt, 1H), 2.84 (dd, 1H), 2.78 (m, 1H), 2.71 (brd, 2H), 2.16 (dt, 1H), 1.81 (t, 2H), 1.76 (m, 1H), 1.45 (s, 9H), 1.34 (m, 3H), 1.03 (d, 3H), 0.90 (s, 3H); MS (EI) 298.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:13][CH:14]([CH3:32])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[N:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19]>>[CH3:13][CH:14]([CH3:32])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[N:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3[N+](=O)[O-])CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-nitrobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (72% yield). 1H NMR (500 MHz, CDCl3) δ 8.24, 8.07, 7.84, 7.76, 7.63, 7.44, 7.01, 4.12-4.26, 3.75-3.95, 3.50, 3.41, 1.65-1.76, 1.52, 0.94. MS (ES+) m/z 427 (M+1).
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:13]([CH:14](O)[CH2:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S([O-])(O)(=O)=O.[K+]>C(O)C>[CH2:2]([N:9]1[C:13]([CH:14]=[CH:15][CH2:16][CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:12][N:11]=[CH:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OC(CCC(c1ccccc1)c1ccccc1)c1cncn1Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: C(=Cc1cncn1Cc1ccccc1)CC(c1ccccc1)c1ccccc1

Procedure:
1-benzyl-5-(1-hydroxy-4,4-diphenylbutyl)-1H-imidazole hydrochloride (5,0 g) and 30,0 g of anhydrous potassium hydrogen sulphate are heated at 150° C. for 4 hours. The mixture is cooled, 90 ml of ethanol is added to dissolve the product. The mixture is then filtered and the filtrate is evaporated to minor volume. Water is added and the mixture is made alkaline with sodium hydroxide. The product is extracted in methylene chloride, washed with water and evaporated to dryness. The product is then made to hydrochloride salt with dry hydrochloric acid in dry ethylacetate. Yield is 2,9 g. M.p. 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.II.Br[CH:13]([F:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C1C=CC=CC=1.[Zn].C(OCC)(=O)C.O>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([F:19])[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:7])[CH3:18]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)Br
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)C(O)c1ccc(Cl)cc1
Reaction time: 2.5 h
Yield: 47.4 %

Procedure:
Zinc powder (1.96 g) was added to 4-chlorobenzaldehyde (141 mg) dissolved in benzene (20 mL), and a catalytic amount of iodine was added to the mixture while refluxing by heating. Ethyl bromofluoroacetate (185 mg) in benzene (2.5 mL) was added dropwise thereto, followed by stirring for 2.5 hours. The reaction mixture was cooled by ice, 1N hydrochloric acid (12.5 mL) was added thereto, and the resultant mixture was stirred at room temperature for 1.5 hours. Water and ethyl acetate were added thereto for partiton. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, and dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=3:1), to thereby give the title compound (diastereomer mixture) (117 mg) as a colorless oil.
Reaction SMILES: Cl.C(O)(=O)C.[OH:6][N:7]=[C:8]([C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1)[C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:26][N:25]1[C:21]([C:8]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)[O:6][N:7]=2)=[CH:22][CH:23]=[N:24]1
Reactant: Cn1nccc1C(C#Cc1ccc(C(F)(F)F)cc1)=NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1nccc1-c1cc(-c2ccc(C(F)(F)F)cc2)on1
Yield: 75.6 %

Procedure:
Concentrated hydrochloric acid (0.50 mL) was added to an acetic acid (5.0 mL) solution of N-hydroxy-1-(1-methyl-1H-pyrazol-5-yl)-3-[4-(trifluoromethyl)phenyl]prop-2-yn-1-imine (303 mg) at a room temperature, and the obtained solution was then heated to reflux for 30 minutes. Thereafter, water was added to the reaction solution, and the obtained solution was then neutralized with potassium carbonate, followed by extraction with chloroform. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=3:2), so as to obtain the title compound (229 mg) in the form of a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:16]C(=O)OCC1C=CC=CC=1)[CH2:13][CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:16][C@H:12]([CH2:13][CH2:14][OH:15])[CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CCO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@H](N)CCO
Reaction time: 15 h

Procedure:
620 mg (1.69 mmol) of benzyl [(1S)-4-[(tert-butoxycarbonyl) -amino]-1-(2-hydroxyethyl)butyl]-carbamate (Example Z2) are dissolved in 60 ml of ethanol. 100 mg of palladium on activated carbon (10%) are added thereto, and the mixture is hydrogenated under atmospheric pressure at RT for 15 h. The reaction mixture is filtered through prewashed kieselguhr, washed with ethanol, and the filtrate is concentrated on a rotary evaporator. The product is reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH3:24][C:25]1(C)[C:29](C)(C)OB(C(C)=C)O1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][C:11]1[S:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=1[C:6]1[N:5]([CH3:17])[N:4]=[CH:3][C:2]=1[C:25]([CH3:29])=[CH2:24]
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1cnn(C)c1-c1cc(C(=O)OC)sc1C
Yield: 61.1 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (300 mg, 0.95 mmol), potassium carbonate (658 mg, 4.76 mmol), bis(tri-t-butylphosphine)palladium(0) (24.32 mg, 0.05 mmol) and 4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (0.18 ml, 0.95 mmol) in 1,4-dioxane (5.3 ml) and H2O (1.0 ml) was stirred at 80° C. in a sealed tube for 12 h. The reaction contents were partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-methyl-4-[1-methyl-4-(1-methylethenyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate (171 mg, 0.58 mmol, 61% yield) as a yellow oil: LCMS (ES) m/z=276 (M+H)+.
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C:5]3[C:10]([C@H:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3.C(#[N:13])C.ClCCl.S(=O)(=O)(O)O>O>[NH2:13][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:1]
Reactant: c1ccc2c(c1)C[C@H]1O[C@@H]21
Reactant: CC#N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: -30 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Into a 300 ml four-neck flask, 10.0 g (75.8 mmol) of cis-(±)-1,2-epoxyindan (VI), 50 ml of acetonitrile, and 40 ml of dichloromethane were introduced. This mixture was cooled to -30° C. in a dry ice/acetone bath. To this mixture, 11.14 g (113.6 mmol) of 100% sulfuric acid (prepared from 97% sulfuric acid and fuming sulfuric acid) was dropwise added at -30° to -27° C. in a period of 1 hour. When left for 1 hour to return to room temperature, the mixture became white and turbid to form a slurry. An HPLC analysis of the contents revealed that 46.8% of cis-oxazoline derivative (IV: R=CH3) had been generated. No cis-amide derivative (III: R=CH3) was detected. As the mixture was heated while 72 ml of water being added thereto, 100 ml of an azeotrope of acetonitrile/dichloromethane/water was distilled off in a period of 1 hour. The remaining mixture was cooled to room temperature, washed twice with 100 ml of dichloromethane, and then subjected to liquid separation. The water phase was adjusted to a strongly alkali state by an addition of 25% sodium hydroxide. The crystal deposited thereby was filtered off under reduced pressure, washed with water, and then dried to yield 7.53 g (yield: 66.8%) of cis-(±)-1-aminoindan-2-ol (V) as a white crystal. Its purity determined by an HPLC was 95.5%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.I[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: OCC1CCCNC1
Reactant: CCCCCCI
Product: CCCCCCN1CCCC(CO)C1
Yield: 93.6 %

Procedure:
3-Piperidine methanol (2.30 g, 20 mmol) and 1-iodohexane (1.5 mL, 10 mmol) were converted to product by the procedure of Preparation 1 to yield 1.866 g (47%) of the title compound which was used without further purification. 1H NMR consistent with desired product.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:12]=[C:11]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[C:10]([CH3:26])=[CH:9][C:8]=2[C:7]([CH3:28])([CH3:27])[CH2:6][CH:5]=1)([CH3:3])[CH3:2].[CH:29](=O)[CH3:30]>>[CH2:29]([N:14]([C:11]1[C:10]([CH3:26])=[CH:9][C:8]2[C:7]([CH3:28])([CH3:27])[CH2:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]=2[CH:12]=1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CC=C3C(C)C)cc1
Reactant: CC=O
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)(C)CC=C3C(C)C)cc1
Yield: 50.1 %

Procedure:
Following General Procedure D, ethyl 4-[(8-isopropyl-3,5,5-trimethyl-5,6-dihydronaphthalen-2-yl)amino]benzoate (Compound 17, 0.48 g, 1.28 mmol) was reacted with acetaldehyde (0.9 mL, 12.8 mmol) to give 0.26 g (50%) of the title compound as a clear oil.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:12][CH:11]2[CH2:13][CH:8]([CH:9]=[CH:10]2)[C:7]1=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd].C(O)(C)C>[CH2:1]([CH:6]1[CH2:12][CH:11]2[CH2:13][CH:8]([CH2:9][CH2:10]2)[C:7]1=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCC1CC2C=CC(C2)C1=O
Agent: [Pd]
Solvent: CC(C)O
Product: CCCCCC1CC2CCC(C2)C1=O
Temperature: 100 °C
Yield: 53.3 %

Procedure:
3-Pentylbicyclo[3.2.1]oct-6-en-2-one (130 g, synthesized as above) was placed in a stainless steel autoclave with isopropanol (30 g) and Pd/C (1.5 g). The mixture was placed under 300 psi of hydrogen gas, and heated at 100° C. until gas uptake ceased. The resulting material was then removed from the autoclave, filtered, and distilled to yield 3-pentylbicyclo[3.2.1]octan-2-one 70 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N(C(=O)c2ccc(Br)cc2)c2ncccc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of Preparation 1 (R)-tert-butyl 3-((3-chloropyridin-2-yl)amino)piperidine-1-carboxylate (100 g, 321 mmol) and 4-bromobenzoyl chloride (73.7 g, 336 mmol) in dry THF (500 mL) was added 1 M lithium bis(trimethylsilyl)amide (362 mL, 362 mmol) dropwise at 0° C. The reaction mixture was warmed and stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc (3×1000 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel to give afford the title compound as a yellow solid (100 g, 63%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:8])[CH:5]=[CH:6][N:7]=1.[C:9]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[NH:15]1)([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:9]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]1[CH2:2][C:3]1[N:4]([CH3:8])[CH:5]=[CH:6][N:7]=1)([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)n1[nH]c(=O)c2ccccc21
Reactant: Cn1ccnc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)n1c2ccccc2c(=O)n1Cc1nccn1C
Temperature: 80 °C
Yield: 66.7 %

Procedure:
2-Chloromethyl-1-methylimidazole (0.91 g) was added portionwise to a stirred mixture of 1,2-dihydro-1-carboethoxy-3H-indazol-3-one (1.03 g), caesium carbonate (5.4 g) and N,N-dimethylformamide (DMF, 5 ml). The mixture was heated to 80° C. for 4 hours under an atmosphere of argon, cooled to ambient temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate. The solid was washed with ethyl acetate. The organic solutions were combined, washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The oil residue crystallised on trituration under diethyl ether. There was thus obtained a mixture (1 g, 67% of 1,2-dihydro-1-carboethoxy-2-(1-methylimidazol-2-yl)methyl-3H-indazol-3-one and 1-carboethoxy-3-(1-methylimidazol-2-yl)methoxy-1H-indazole (starting material for Ex. 145).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].C1(CN)CCCCC1.[O:15]=[C:16]1[C:24]2([CH2:28][O:27][C:26]3[CH:29]=[C:30]4[C:34](=[CH:35][C:25]2=3)[CH2:33][CH2:32][O:31]4)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:37]([CH2:36][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3([CH2:28][O:27][C:26]4[CH:29]=[C:30]5[C:34](=[CH:35][C:25]3=4)[CH2:33][CH2:32][O:31]5)[C:16]2=[O:15])=[CH:38][CH:39]=1)[CH3:2]
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: CCOCCN
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCOCCNC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-ethoxyethylamine to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-ethoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (48%) as a colorless solid: mp 84-85° C.; 1H NMR (300 MHz, CDCl3) δ7.80-7.73 (m, 2H), 7.44-7.38 (m, 2H), 7.23-7.15 (m, 2H), 7.07-7.00 (m, 1H), 6.77-6.71 (m, 1H), 6.58-6.50 (m, 1H), 6.47 (s, 1H), 6.43 (s, 1H), 5.00 (ABq, 2H), 4.85 (ABq, 2H), 4.60-4.50 (m, 2H), 3.68-3.48 (m, 6H), 3.11-2.91 (m, 2H), 1.21 (t, J=7.0, Hz, 3H); 13C NMR (75 MHz, CDCl3) δ177.9, 166.9, 161.8, 161.3, 141.8, 139.2, 134.2, 132.6, 128.7, 127.6, 127.5, 124.0, 123.6, 120.0 (2C), 118.8, 109.1, 93.2, 80.6, 72.4, 68.9, 66.5, 57.7, 43.8, 39.8, 29.0, 15.1; MS (ES+) m/z 485.1 (M+1).