Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.[C:18](O)(=[O:20])[CH3:19]>>[C:18]([O:1][CH:2]([CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2)(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: CCC(O)CCCCC1CCC2CC(=O)CC12
Product: CCC(CCCCC1CCC2CC(=O)CC12)OC(C)=O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The starting material from Example 3, 2-(5-hydroxyhept-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxyheptyl)-2(1H)-pentalenone} (2.5 g, 10.5 mmoles) is diluted with glacial acetic acid (10 ml) and stirred in a 70° C. water bath for 4 hours. The reaction is cooled to room temperature and partitioned between ether (50 ml) and water (50 ml). The ether layer is separated and the aqueous phase extracted with ether (2×50 ml). The organic layers are combined, neutralized with a solution of saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (2.1 g, 7.4 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:20]([O-:22])=[O:21])=[CH:5][C:6]([CH3:19])=[C:7]([N:9]2[CH2:18][CH2:17][C:12]3(OCCO3)[CH2:11][CH2:10]2)[CH:8]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].COC1C([N+]([O-])=O)=CC(C)=C(N2CCC(=O)CC2)C=1.Cl.[F:61][C@@H:62]1[CH2:66][CH2:65][NH:64][CH2:63]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(#N)C>[F:61][C@@H:62]1[CH2:66][CH2:65][N:64]([CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4]([N+:20]([O-:22])=[O:21])=[CH:5][C:6]=3[CH3:19])[CH2:18][CH2:17]2)[CH2:63]1
Reactant: COc1cc(N2CCC3(CC2)OCCO3)c(C)cc1[N+](=O)[O-]
Reactant: F[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COc1cc(N2CCC(=O)CC2)c(C)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: COc1cc(N2CCC(N3CC[C@@H](F)C3)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8-(5-Methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (INTERMEDIATE 16, 0.350 g, 1.14 mmol) and 4-toluenesulfonic acid hydrate (0.217 g, 1.14 mmol) in water (25 mL) were stirred under reflux for 6 h. The reaction mixture was allowed to cooled to RT and adjusted to pH 7 with potassium carbonate The mixture was concentrated in vacuo. The crude residue was taken up in EtOAc, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. To the resultant crude 1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-one (0.30 g, 1.14 mmol) in acetonitrile (15 mL) was added (R)-3-fluoropyrrolidine hydrochloride (0.102 g, 1.14 mmol) and sodium triacetoxyborohydride (0.481 g, 2.27 mmol) and the reaction mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo and the crude residue was taken up in EtOAc and washed with 10% aqueous sodium carbonate and brine. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give the title product which was used in the next step without further purification (0.19 g, 50%). m/z 338.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:17]=[C:16]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:15]=2)=[CH:8][C:7]=1[CH3:36].O.[OH-].[Li+].O>O1CCOCC1>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([C:16]2[CH:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:19]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[C:7]([CH3:36])[CH:8]=3)[N:15]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)COc1ccc(OCc2nc(-c3ccc(OC)cc3)cc(-c3ccc(OC)cc3)n2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)nc(COc3ccc(OCC(=O)O)c(C)c3)n2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
{4-[4,6-Bis-(4-methoxy-phenyl)-pyrimidin-2-ylmethoxy]-2-methyl-phenoxy}-acetic acid methyl ester 25 (0.14 g, 0.28 mmol) from Step D above is dissolved in dioxane (2 mL). Solid lithium hydroxide monohydrate (80 mg, 2.0 mmol) is added, followed by water (0.2 mL). After stirring at room temperature for 5 hours, the mixture is concentrated to dryness. Purification by reversed-phase HPLC afforded {4-[4,6-Bis-(4-methoxy-phenyl)-pyrimidin-2-ylmethoxy]-2-methyl-phenoxy}-acetic acid B1 as a solid. MS calculated for C28H27N2O6 (M+H+) 487.18. found 487.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[C:5]([CH3:10])=[C:4]([Cl:11])[CH:3]=1.N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1)[C:23](Cl)=[O:24].CC(C)=O.C(Cl)Cl>C(OCC)(=O)C>[Cl:9][C:6]1[C:7]([OH:8])=[C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:20]([O:19][CH3:18])[CH:21]=2)[CH:3]=[C:4]([Cl:11])[C:5]=1[CH3:10]
Reactant: Cc1c(Cl)cc(N)c(O)c1Cl
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(OC)cc(C(=O)Nc2cc(Cl)c(C)c(Cl)c2O)c1
Yield: 48 %

Procedure:
Into a 500 ml 3-necked round bottom flask, equipped with a stir bar, addition funnel, and N2 inlet, was placed 10 g (52 mmoles) of 6-amino-2,4-dichloro-3-methylphenol and 150 ml of ethyl acetate. With stirring a solution resulted. To this solution was added 4.53 g (57.2 mmoles) of pyridine. This solution was stirred for 5 minutes during which time 10.95 g (54.6 mmoles) of 3,5-dimethoxybenzoyl chloride (Aldrich Chemical Co., CAS RN 17213-57-9) was dissolved in 75 ml of ethyl acetate and placed in an addition funnel. This solution was added dropwise to the reaction vessel over a 30 minute period. A precipitate formed almost immediately. After complete addition the reaction mixture was allowed to stir overnight. Thin layer chromatography (5/95 acetone/CH2Cl2) analysis of the reaction mixture indicated no starting material and primarily one new spot and a spot at the origin. The reaction mixture was poured into a separatory funnel and washed 2 times with a cold 10% hydrochloric acid solution followed by 2 times with a saturated sodium chloride solution and the organic layer was dried over sodium sulfate. The sodium sulfate was collected on a gravity filter and the filtrate was concentrated to a salmon colored solid. This solid was recrystallized from refluxing ethanol. The resulting crystals were collected on a medium sintered glass funnel, and dried by sucking air through for three hours. 8.9 g of desired product was obtained, a 48% purified yield.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=O)[CH3:2].BrCC(C1OC2C(OC)=CC=CC=2C=1)=O.[CH2:30]([C:34]([NH2:36])=[O:35])[C:31]([NH2:33])=[NH:32].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.O>[NH2:33][C:31]1[NH:32][C:1]([C:4]2[O:5][C:6]3[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=3[CH:8]=2)=[CH:2][C:30]=1[C:34]([NH2:36])=[O:35]
Reactant: COc1cccc2cc(C(C)=O)oc12
Reactant: N=C(N)CC(N)=O
Agent: COc1cccc2cc(C(=O)CBr)oc12
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2cc(-c3cc(C(N)=O)c(N)[nH]3)oc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
Phenylrimethylammonium tribromide (2.0 g, 5.3 mmol) was added to a solution of 2-acetyl-7-methoxybenzofuran (1.0 g, 5.3 mmol) in anhydrous tetrahydrofuran (25 mL), and the mixture was stirred at room temperature for 4 hours. After the insoluble solid was filtered out, the filtrate was concentrated in vacuo to give a mixture including 2-bromoacetyl-7-methoxybenzofuran. Malonamamidine hydrochloride (1.5 g, 11 mmol) and potassium carbonate (1.5 g, 11 mmol) were added to a solution of this mixture in anhydrous N,N-dimethylformamide (40 mL) and the whole was stirred at 60° C. overnight. After cooling, the reaction mixture was diluted with water (200 mL), and the whole was extracted with ethyl acetate (100 mL, twice). The organic layer was washed with brine (100 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the obtained residue was purified by silica gel column chromatography to give the title reference compound (0.33 g) as a dark green solid (Yield 23%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:23]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:40]>C(OCC)(=O)C>[ClH:40].[N:11]1([C:14]2[CH:15]=[C:16]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:23]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:35])([F:36])[F:37])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(N3CCNCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-[3-(4-BOC-piperazin-1-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (760.0 mg, 1.6 mmol) prepared in Example 95 was added to a saturated solution of hydrochloric acid in ethyl acetate (10.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 700.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.C(N(CC)CC)C.Br.[S:38]1[CH2:41][CH:40]([NH2:42])[CH2:39]1.O>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7](=[O:27])[NH:42][CH:40]2[CH2:41][S:38][CH2:39]2)[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:24])([F:25])[F:26])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: NC1CSC1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NC2CSC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Yield: 41 %

Procedure:
To a solution of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (500 mg, 1.13 mmol) [prepared according to WO 02/48115, example 2D] in tetrahydrofuran (10 ml) is added triethylamine (0.4 ml, 2.87 mmol) and 3-thietanamine hydrobromide salt [the product of step 2] (250 mg, 1.47 mmol), and the mixture is heated to reflux overnight. The cooled reaction mixture is poured into water, extracted with ethyl acetate, the combined organic layers washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product is purified by flash chromatography (ethyl acetate/hexane 1:2) to afford 250 mg (41%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Yield: 79 %

Procedure:
2-Amino-3-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(5,7-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one. 1-(4,6-dichloro-3-methoxy-2H-indazol-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part a to d except using 3,5-dichloro-2-nitrobenzaldehyde (2.1 g) and decaborane (0.41 g) in part a to yield [2-(tert-butyldimethylsilanyloxy)propyl]-(3,5-dichloro-2-nitrobenzyl)amine (1.2 g, 32%). 3,5-Dichloro-2-nitrobenzaldehyde (2.2 g, 79%) was prepared by nitration of 3,5-dichlorobenzaldehyde (2.2 g) in a mixture of nitric acid (1.5 mL) and sulfuric acid (8 mL) at 0° C. for 30 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a solution of 5-bromo-1H-indazole (5 g, 25.38 mmol) in DCM (50 mL), 3,4-dihydro-2H-pyran (4.26 g, 50.76 mmol) and PTSA (2.41 g, 12.69 mmol) were added and the reaction was stirred at room temperature for 3 h. Solvent was removed under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with water (20 mL), brine (20 mL), and dried over sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by flash chromatography using hexane/ethyl acetate to give 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as colorless liquid (6.95 g, 97%). 1HNMR: 400 MHz, DMSO-d6: δ 1.57-1.62 (m, 2H), 1.74-1.76 (m, 1H), 1.96-2.06 (m, 2H), 2.37-2.40 (m, 1H), 3.72-3.78 (m, 1H), 3.87-3.90 (m, 1H), 5.85-5.86 (m, 1H), 7.53-7.54 (m, 1H), 7.74 (d, J=9.20 Hz, 1H), 8.04 (d, J=1.60 Hz, 1H), 8.11 (s, 1H). LCMS: RT 2.033 min; LCMS (ES-API), m/z 283 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:8]=1)[CH3:2].[C:19]([OH:22])(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:11][C:12]=1[O:22][C:19](=[O:21])[CH3:20])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)C=Cc1ccc(N(CC)CC)cc1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(N(CC)CC)cc1OC(C)=O

Procedure:
3-(4-Diethylaminophenyl)-2-propenic acid ethyl ester (1 g, 3.80 mmol) was dissolved in 5 ml of pyridine. To this was added 0.8 ml of anhydrous acetic acid and it was allowed to react at room temperature for 24 h. After the solvent was removed in vacuo, purification was carried out by silica gel column chromatography (toluene/ethyl acetate 93:7 as a developing solvent) to give 1.2 g of the desired product in a quantitative yield.
Reaction SMILES: [Cl:1][C:2]([Cl:10])=[CH:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][OH:9].[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:13]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:13]=1[O:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH:3]=[C:2]([Cl:10])[Cl:1]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCOCC=C(Cl)Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 4.7 %

Procedure:
To a mixture of 1.30 g of 3-(3,3-dichloro-2-propenyloxy)propanol, 2.02 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 1.89 g of triphenylphosphine and 20 ml of tetrahydrofuran was slowly added dropwise 1.42 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.15 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(3,3-dichloro-2-propenyloxy)propyloxy)benzene (yield, 4.7%), nD18.5 1.5530.
Reaction SMILES: [Na].[CH3:2][O-].[Na+:4].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([CH3:14])[N:7]=1.[Cl-].[NH4+]>CO.C1COCC1>[CH3:10][O-:11].[Na+:4].[Cl:5][C:6]1[N:7]=[C:8]([CH3:14])[C:9]([C:10]#[CH:2])=[CH:12][CH:13]=1
Reactant: Cc1nc(Cl)ccc1C=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(Cl)nc1C
Temperature: -78 °C

Procedure:
A 4.37 M sodium methoxide solution was prepared by dissolving sodium metal (2.10 g, 91.4 mmol) in dry methanol (20 ml). In a separate flask, Bestmann's reagent (2.11 ml, 13.5 mmol) was taken up in THF (44.3 ml) and cooled to −78° C. The sodium methoxide solution (3.09 ml, 13.50 mmol) was added dropwise to the reaction mixture over 30 minutes. A solution of 6-chloro-2-methylnicotinaldehyde (1.00 g, 6.43 mmol) in THF (20 ml) and then added dropwise to the reaction over 30 minutes and the reaction was allowed to warm slowly to −10° C. and maintained at −10° C. for 90 minutes. Saturated aqueous ammonium chloride was added, the layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O)(=S)[CH3:2].C([O-])(=O)C.[Na+].Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][C:28]=1[CH3:35]>O1CCOCC1.C(O)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([CH:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]3)=[N:4][C:1]([CH3:2])=[N:34]2)=[CH:29][C:28]=1[CH3:35]
Reactant: Cc1cc(NN)ccc1Cl
Reactant: CC(=S)NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)n(-c2ccc(Cl)c(C)c2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
The product from step A (3.09 g, 10.79 mmol), sodium acetate (0.879, 10.7 mmol) and (4-chloro-3-methylphenyl)hydrazine hydrochloride (2.24 g, 11.6 mmol) were mixed in dioxane (25 mL) and acetic acid (25 mL). The reaction mixture was warmed at 90° C. with stirring for 16 h, cooled to rt and the volatiles were removed. Purification of the residue on SiO2 (5 to 60% ethyl acetate, hexanes) afforded the title compound, which was used without further purification. HPLC/MS: 335.0, 337.0 (M-55), Rt=3.40 (LC4).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:7]([O:6][C:4](=[O:5])[C:3]1[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:2]=1[F:1])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(N)cc1F
Temperature: 95 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Tert-butyl 2-fluoro-4-nitrobenzoate (24.2 g, 0.100 mol) was added to a warm (95° C.) solution of ammonium chloride (53.5 g, 1.00 mol), dissolved in ethanol (300 ml) and water (150 ml). Iron powder (325 mesh, 16.8 g, 0.300 mol) was added with stirring in small portions over about 1 h. The reaction mixture was stirred and heated at 95° C. for another 30 minutes and then filtered while still warm. The filter cake was washed thoroughly with excess ethanol. The filtrate and washings were diluted with water (1 L) and extracted with ether (3×150 ml). Combined ether extracts were washed with water and brine, dried (MgSO4), and evaporated to give the product as an off-white solid (21.1 g, 98%); mp 100-101° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:16][C:12]3([CH2:15][O:14][CH2:13]3)[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CCO.[Pd]>[CH2:13]1[C:12]2([CH2:11][N:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[NH2:1])[CH2:16]2)[CH2:15][O:14]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(N2CC3(COC3)C2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(N2CC3(COC3)C2)c1
Yield: 89.1 %

Procedure:
To a solution of 6-(3-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane (130 mg, 0.59 mmol) in 5 mL of EtOH was added 10% Pd/C (20 mg), the mixture was stirred for 15 hours at room temperature in a hydrogen atmosphere. Insoluble matters were removed and the filtrate was concentrated in vacuo to give 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)aniline (100 mg, 98%). LC-MS: 191 [M+H]+, tR=0.99 min.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].[C:10]([C:13]1[CH:14]=[C:15](/[CH:18]=[C:19]2\[C:20](=[O:30])[NH:21][C:22]3[C:27]\2=[C:26](I)[C:25]([F:29])=[CH:24][CH:23]=3)[NH:16][CH:17]=1)(=[O:12])[CH3:11]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[C:10]([C:13]1[CH:14]=[C:15](/[CH:18]=[C:19]2\[C:20](=[O:30])[NH:21][C:22]3[C:27]\2=[C:26]([C:2]#[C:1][C:3]2([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[C:25]([F:29])=[CH:24][CH:23]=3)[NH:16][CH:17]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#CC1(O)CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#CC4(O)CCOCC4)c32)c1

Procedure:
Using Method C above, 4-Ethynyl-tetrahydro-pyran-4-ol (0.16 g1 1.26 mmol) (Example 85A) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.2 g, 0.50 mmol) (Example 90B above) using (Ph3P)4Pd (58.4 mg) and Cul (9.6 mg) as catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 85° C. for 18 h. (Yield 102 mg, 52%).
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].[C:6](Cl)(=[O:10])[CH:7]=[CH:8][CH3:9].C=CC1C=CC=CC=1>C(Cl)Cl.Cl[Cu]>[C:6]([NH:2][C:1](=[O:5])[O:3][CH3:4])(=[O:10])/[CH:7]=[CH:8]/[CH3:9]
Reactant: CC=CC(=O)Cl
Reactant: COC(N)=O
Agent: Cl[Cu]
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: C/C=C/C(=O)NC(=O)OC
Temperature: 114 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a mixture of methyl carbamate (1.0 g, 8.54 mmol) and 2-butenoyl chloride (2.4 mL, 25.0 mmol) was added styrene (30 mL), followed by CuCl (0.1 g). The reaction mixture was stirred at 114° C. for 16 h. It was then cooled to room temperature and evaporated to give a white residue, which was dissolved in DCM and washed with water, brine and dried over MgSO4. The solution was concentrated and the addition of pentane to the residue furnished the product as a white precipitate. Yield 76% (0.93 g). m.pt. 149–150° C. 1H NMR: δ 1.94 (dd, 1H, CH3CH, 2JHH=6.8 Hz, 3JHH=1.4 Hz); 3.78 (s, 3H, OCH3); 6.84 (dd, 1H, COCH, 2JHH=15.0 Hz, 3JHH=1.3 Hz); 7.10–7.20 (m, 1H, CH3CH); 7.89 (s, br, 1H, NH). 13C NMR: δ 18.4 (CH3CH), 53.0 (OCH3), 122.7 (COCH), 146.6 (CH3CH), 152.4 (CO2), 166.1 (COCH). m/z (HR-EIMS) Expected 143.0582 (M+), observed 143.0577. Anal. calcd for C9H9NO3: C, 50.35; H, 6.34; N, 9.79%. Found: C, 50.44; H, 6.59; N, 9.94%.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][NH2:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19]1>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][NH:17][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][OH:23])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCC1c2ccccc2CCc2ccccc21
Reactant: O=C1CCCO1
Product: O=C(CCCO)NCC1c2ccccc2CCc2ccccc21

Procedure:
10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-methylamine (8.5 g) and γ-butyrolactone (3.7 g) are heated at 150° C. (internal temperature) for 1 hour. After cooling, the solid residue is recrystallized from benzene to give N-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl]-4-hydroxybutyramide, (III, Alk = CH2CH2CH2 and Y = OH), m.p. 103°-105° C.