Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16]C)=[O:15])[CH2:10][CH2:9]1)=[O:7].[OH-].[Na+].Cl>CO>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)N(C)CCN(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCN(C)C(=O)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl trans-4-{[[2-(dimethylamino)ethyl] (methyl)amino]-carbonyl}cyclohexanecarboxylate (6.32 g) obtained in Reference Example 83(1) is dissolved in methanol (20 ml), and thereto is added 1 N aqueous sodium hydroxide solution (25 ml). The mixture is stirred at room temperature for 3 hours. To the reaction solution is added 1 N hydrochloric acid (25 ml) and the reaction solution is concentrated under reduced pressure. The residue is lyophilized to give the crude title compound which contains equimolar sodium chloride (6.71 g). APCI-MS M/Z: 257[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:29]2[CH2:28][CH2:27][CH:26]([O:25][CH2:24][CH:23]=[CH:22][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:31][CH2:30]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Clc1ccc(C=CCOC2CCNCC2)cc1
Product: C[C@](O)(CN1CCC(OCC=Cc2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 56.3 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 (0.217 g, 1.00 mmol) and 4-[3-(4-chloro-phenyl)-2-propenyloxy]piperidine (0.250 g, 0.995 mmol) gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-3-{4-[3-(4-chlorophenyl)-2-propenyloxy]piperidin-1-yl}-2-methylpropan-2-ol (0.263 g, yield 56%) as a brown liquid in the same manner as in Example 254.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:11]([CH:24]([CH3:26])[CH3:25])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][CH:30]=1.O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[OH:15])=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:11]([CH:24]([CH3:26])[CH3:25])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc(-c2c(C=O)c(OCc3ccccc3)nn2C(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(O)c3ccc(OC)cc3)c(OCc3ccccc3)nn2C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-4-formyl-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole (0.14 g) in tetrahydrofuran (1.8 mL) was added a solution of 4-methoxyphenylmagnesium bromide in tetrahydrofuran (0.5 mol/L, 0.96 mL) at room temperature and the mixture was stirred at room temperature for 1 hour. A small amount of water was added to the reaction mixture and the mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). Further purification by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1-2/1) gave the title compound (0.11 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.Br[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17]2.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[O:23]=[C:19]1[C:20]2[C:16](=[CH:15][C:14]([N:9]3[CH2:10][CH2:11][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:8]3=[O:12])=[CH:22][CH:21]=2)[CH2:17][CH2:18]1
Reactant: O=C1NCCN1c1cccnc1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CCc2cc(N3CCN(c4cccnc4)C3=O)ccc21
Yield: 61.7 %

Procedure:
Using the same reaction conditions as in Example 1, 1-pyridin-3-yl-imidazolidin-2-one (I-1b: 270 mg, 1.6587 mmol) was reacted with 5-bromo-indan-1-one (350 mg, 1.6587 mmol), 1,4-dioxane (10 mL), copper iodide (31.59 mg, 0.165879 mmol), trans-1,2-diamino cyclohexane (56.976 mg, 0.4976 mmol) and potassium carbonate (458.63 mg, 3.3174 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 300 mg of 1-(1-oxo-indan-5-yl)-3-pyridin-3-yl-imidazolidin-2-one (61.72% yield). Hydroxylamine hydrochloride (141 mg, 2.044 mmol) and sodium acetate (167.6 mg, 2.044 mmol) in 5 mL of water were added to a solution of 1-(3-oxo-indan-5-yl)-3-pyridin-3-yl-imidazolidin-2-one (200 mg, 0.6814 mmol) in ethanol (7 mL). The reaction mixture was heated to 90° C. and maintained for 6 hours. The reaction mixture was then cooled to room temperature and the solvent was distilled from the reaction mixture. The precipitate formed was collected, washed with chloroform and dried under reduced pressure to afford 200 mg of the product (90% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]1[CH2:20][CH:19]([CH2:21]Br)[O:18][CH2:17][CH2:16]1>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][N:10]([CH2:21][CH:19]3[CH2:20][CH2:15][CH2:16][CH2:17][O:18]3)[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrCC1CCCCO1
Reactant: O=c1[nH]ncc2ccc([N+](=O)[O-])cc12
Product: O=c1c2cc([N+](=O)[O-])ccc2cnn1CC1CCCCO1

Procedure:
Step (b) of Example 125 was repeated, except that the compound prepared in step (b) of Example 137 and tetrahydro-2H-pyran-2-methyl bromide were used as the starting compounds. Thus, 7-nitro-2-(tetrahydropyran-2-yl)methyl-2H-phthalazin-1-one was obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].CC([O-])=O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>CC(C)=O.O.CCOC(C)=O>[Cl:21][CH2:22][C:23]([NH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[OH:15])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)CCl)[C@H](O)C1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 71.6 %

Procedure:
To a stirred mixture of 249A (428 mg, 1.98 mmol) and NaOAc (325 mg, 3.96 mmol) in 2.5 mL of acetone and 0.8 mL of water under N2 at 0° C. was added dropwise chloroacetyl chloride (0.17 mL, 2.08 mmol) over 5 min. This mixture was stirred at 0° C. for 10 min and at room temperature for 25 min. The mixture was diluted with 160 mL of EtOAc and washed with water (2×40 mL), saturated NaHCO3 solution (1×30 mL) and brine (1×30 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo to give 415 mg (yield: 72%) of 249B. It had an analytical HPLC retention time=1.96 min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm) and a flow injection MS M−=291.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(N)c(C=O)cc1Br
Yield: 54.7 %

Procedure:
To a stirred solution of 2-amino-4-methoxybenzaldehyde (6 g, 39.7 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (7 g, 39.7 mmol). The reaction mixture was diluted with dichloromethane and water. The separated organic layer was dried sodium sulfate, filtered and concentrated to give the title compound (5 g, 56%) as a yellow solid. MS (ES+) C8H8BrNO2 requires: 229, 231, found: 230, 232 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1.[OH-].[Na+]>CO.O>[C:29]1([N:13]2[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=[C:12]2[O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
171 g of methyl-8-(1,4,5-triphenylimidazol-2-yloxy)-caprylate and 44 g of sodium hydroxide are dissolved in 1,000 ml of methanol and the mixture is stirred at room temperature for about 24 hours. The solvent is then stripped off in vacuo and the residue is taken up in water. The aqueous solution is washed with ether and acidified with dilute hydrochloric acid and the acid precipitated is separated off and dried.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([C:14]2[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=2)[CH2:10][CH2:11][CH2:12][OH:13])=[CH:5][C:4]=1[F:27])#[N:2].CCN(CC)CC>CS(C)=O.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:20][S:21]([C:23]([CH3:25])([CH3:24])[CH3:26])=[O:22])([C:14]2[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=2)[CH2:10][CH2:11][CH:12]=[O:13])=[CH:5][C:4]=1[F:27])#[N:2]
Reactant: Cn1cncc1C(CCCO)(NS(=O)C(C)(C)C)c1ccc(C#N)c(F)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cn1cncc1C(CCC=O)(NS(=O)C(C)(C)C)c1ccc(C#N)c(F)c1
Reaction time: 8 h

Procedure:
Sulfur trioxide pyridine complex (0.775 g, 4.866 mmol) in DMSO (5 mL) was added to a solution of (N-[1-(4-cyano-3-fluorophenyl)-4-hydroxy-1-(1-methyl-1H-imidazol-5-yl)butyl]-2-methylpropane-2-sulfinamide (0.382 g, 0.973 mmol) and Et3N (1.36 mL, 0.985 mmol) in CH2Cl2 (15 mL) at 0° C. in an ice-H2O bath, then left to come to room temperature overnight. The reaction mixture was partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution, the aqueous layer washed with CH2Cl2 (3×), the organic layers combined and dried (MgSO4), filtered and concentrated to give the crude product. Purification on an ISCO Combiflash eluting with 2-6% MeOH/CH2Cl2 gave the title compound. MS(M+1) 391.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:8][CH:7]=[CH:6][CH2:5][C@:4]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH2:3]1.Cl>CO.CCOCC>[ClH:1].[NH:2]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH2:3]1
Reactant: O=C1Nc2ccccc2[C@]12CC=CCNC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C1Nc2ccccc2C12CC=CCNC2

Procedure:
(S)-Spiro[indoline-3,3′-(1,3,4,7-tetrahydro-2H-azepin)]-2-one Hydrochloride The material from the second peak from STEP C (47 mg) was dissolved in methanol (5 ml) and treated with HCl in ether (1.5 ml) at room temperature overnight. The title compound was obtained upon removal of solvents. MS (TSP+) m/z [M+H]+: 215. 13C NMR: (CD3OD): 181.0, 142.1, 132.7, 132.2, 130.4, 125.7, 124.8, 123.8, 111.6, 53.8, 47.6, 47.5, 35.4 ppm.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:9]([NH:8][C:5]4[O:4][N:3]=[C:2]([CH3:1])[C:6]=4[CH3:7])=[O:16])[CH2:33][CH2:34]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(Cl)c4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 41.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (226 mg, 0.786 mmol), 1-[4-(3-chlorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.715 mmol) and diisopropylethylamine (0.249 ml, 1.43 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 124 mg (41.4%) of the desired product as a solid. mp 201-202° C.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8](=[O:11])[CH2:9]Cl)(=O)C.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[S:21])[S-:20].C([NH+](CC)CC)C>O>[OH:11][C:8]1([CH2:7][OH:6])[CH2:9][S:21][C:19](=[S:20])[N:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: CC(=O)OCC(=O)CCl
Reactant: S=C([S-])Nc1ccccn1
Agent: CC[NH+](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC1(O)CSC(=S)N1c1ccccn1
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
A 5.5 N aqueous solution of sodium hydroxide (36 cc) is added in the course of 5 minutes, at 22°-23° C., to a suspension of 3-chloro-2-oxopropyl acetate (29.9 g) in distilled water (500 cc). The hydrolysis reaction is allowed to proceed for 15 minutes at 22° C. and triethylammonium pyrid-2-yldithiocarbamate (53.6 g) is then added in the course of 5 minutes at a maximum of 23° C. The reaction is allowed to proceed for 2 hours at 20°-23° C. The crystals which have appeared are filtered off, washed with distilled water (50 cc) and then with ethyl ether (50 cc) and dried under reduced pressure (0.1 mm Hg) at 45° C. 4-Hydroxy-4-hydroxymethyl-3-(pyrid-2-yl)-thiazolidine-2-thione (12.0 g), which melts at 134°-135° C., is thus obtained.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:13](=[O:14])[C:12]([C:15](O)=[O:16])=[CH:11][C:10]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:9]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br.[NH2:25][CH:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31].C(N(CC)CC)C.CCCCCC.C(OCC)(=O)C>C1COCC1>[O:31]=[C:27]1[CH:26]([NH:25][C:15]([C:12]2[C:13](=[O:14])[N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:9]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:10]=3[CH:11]=2)=[O:16])[CH2:30][CH2:29][O:28]1
Reactant: O=C(O)c1cc2c(n(CC3CCCCC3)c1=O)CCCCCC2
Reactant: NC1CCOC1=O
Agent: Br
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NC1CCOC1=O)c1cc2c(n(CC3CCCCC3)c1=O)CCCCCC2
Reaction time: 0.5 h
Yield: 77 %

Procedure:
1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydro-cycloocta[b]pyridine-3-carboxylic acid (AA01, 250 mg, 0.788 mmol) which had been obtained in Example 1 was made to be the acid chloride according to the conventional method, and the acid chloride was dissolved in THF. Then, the solution was dropped into the DMF (2 mL) mixed liquid of 3-amino-dihydro-furan-2-one hydrobromide (187 mg, 1.03 mmol) and triethylamine (0.38 mL, 2.36 mmol) while cooling with ice. After that, the mixture was stirred at the same temperature for 30 minutes, and further stirred continuously at room temperature for 3 hours. The mixture was subjected to the same after-treatment as described above, and then refined with silica gel column chromatography (hexane-ethyl acetate (40 to 60%)), and I-072 was obtained as a colorless solid (242 mg, 77%, mp: 136-140° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([NH:7][CH3:8])[CH3:6].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([N:7]([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[CH3:8])[CH3:6]
Reactant: C=CC(=O)OC
Reactant: CNC(C)CC(=O)OC
Product: COC(=O)CCN(C)C(C)CC(=O)OC
Yield: 57.9 %

Procedure:
3-Methylamino-butyric acid methyl ester (7.6 g, 58 mmol, 1.0 equiv) was added neat to methyl acrylate (7.5 g, 87 mmol, 1.5 equiv). The resulting solution was refluxed for 16 h. The reaction was cooled and diluted with hexanes (200 mL) and an insoluble polymer separated out. The hexane solution was decanted and the polymer was washed 2×100 mL hexanes with vigorous stirring. The combined hexane solutions were then concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 using pure CH2Cl2 as an eluent. The pure product was isolated as a clear colorless oil (7.3 g, 58%); MS, m/z 218=M+1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cccnc1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cccnc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 3-ethynylpyridine (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 87.59 (s, 1H), 7.63 (ddd, J=8.0, 5.1, 0.8 Hz, 1H), 8.19 (ddd, J=9.3, 2.8, 1.8 Hz, 1H), 8.36 (dt, J=7.9, 2.0 Hz, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.68 (dd, J=5.2, 1.6 Hz, 1H), 8.99 (t, J=1.6 Hz, 1H), 9.12 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[Cl:23][C:24]1[C:32]([C:33]#[N:34])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH:40]([F:42])[F:41])[N:28]2[CH2:35][C:36]([NH:38][NH2:39])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>CC#N>[Cl:23][C:24]1[C:32]([C:33]#[N:34])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH:40]([F:41])[F:42])[N:28]2[CH2:35][C:36]1[O:10][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[N:39][N:38]=1
Reactant: O=C(O)c1cccc(F)n1
Reactant: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)NN)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CC#N
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2nnc(-c3cccc(F)n3)o2)c1Cl
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
To a solution of 6-fluoro-2-pyridinecarboxylic acid (0.006 g, 0.043 mmol) in MeCN (2 mL), under N2, was added EDCl (0.0085 g, 0.044 mmol). After 5 min, 2-[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetohydrazide (0.012 g, 0.040 mmol) was added. After 1 h, additional 6-fluoro-2-pyridinecarboxylic acid (0.003 g, 0.02 mmol) and EDCl (0.0077 g, 0.040 mmol) were added. After another 15 min, additional 6-fluoro-2-pyridinecarboxylic acid (0.0014 g, 0.01 mmol) and EDCl (0.0046 g, 0.02 mmol) were added. After another 10 min, TsCl (0.009 g, 0.048 mmol) and P-BEMP (loading 2.2 mmol/g, 0.073 g, 0.16 mmol) were added and the mixture was heated at 120° C. for 20 min. Upon cooling, additional TsCl (0.0046 g, 0.024 mmol) and P-BEMP (0.037 g, 0.08 mmol) were added and the mixture was heated at 120° C. for another 20 min. Upon cooling, the resin was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.005 g, 31% yield): MS (ES) m/z 404 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([OH:27])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.O>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([O:27][CH:8]([CH3:10])[CH3:9])[CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)I
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Temperature: 50 °C

Procedure:
K2CO3 (9.62 g, 69.6 mmol) and 2-iodopropane (2.00 mL, 20.00 mmol) were added successively to a stirred solution of 4-benzyloxy-2-hydroxybenzaldehyde (3.65 g, 16.0 mmol) in dry DMF (20.0 mL) at 25° C. under N2. The reaction was heated at 50° C. overnight. The reaction was diluted with water (50 mL) and extracted with Et2O (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford 4-(benzyloxy)-2-isopropoxybenzaldehyde. LCMS calc.=293.1; found=292.9 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>O.O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)C=Cc1ccc2cc[nH]c2c1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Temperature: 90 °C
Reaction time: 6 h
Yield: 19.4 %

Procedure:
A mixture of 3-(1H-indol-6-yl)-acrylic acid methyl ester XXX (1.0 g, 5.0 mmol), 2-methoxyphenyl boronic acid (1.1 g, 7.2 mmol), [RhCl(cod)]2 (110 mg, 0.25 mmol) and TEA (5 mmol) in H2O (14 ml) and 1,4-dioxane (1 ml) was stirred at 90° C. in a sealed vial for 6 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc; The combined organic layers were dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/acetone) to provide 3-(1H-indol-6-yl)-3-(2-methoxy-phenyl)-propionic acid methyl ester XXXVII (300 mg, 20% yield) as a yellow film.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.Cl>[Fe].CO>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([S:11][CH:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[CH:3]=1
Reactant: CN1CCC(Sc2cc(F)cc([N+](=O)[O-])c2)CC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CN1CCC(Sc2cc(N)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.8 %

Procedure:
Combine 4-(3-Fluoro-5-nitro-phenylsulfanyl)-1-methyl-piperidine (preparation 75, 0.31 g, 1.15 mmol), iron dust (0.21 g, 3.79 mmol), methanol (10 mL) and aqueous 1M hydrochloric acid (0.35 mL, 0.35 mmol), stir and heat at reflux. After 20 h, cool to ambient temperature and concentrate. Partition residue between ethyl acetate (50 mL) and 1M sodium hydroxide (20 mL). Separate the organic layer, dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain 0.11 g (40%) of the title compound: mass spectrum (electrospray): m/z=241.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6]([CH3:8])([CH3:7])[CH2:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:3]1.[CH:22](=O)[CH2:23][CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.ClCCCl>[CH2:22]([N:18]1[CH2:17][CH2:16][N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:4]2[CH2:3][C:2]([CH3:21])([CH3:1])[C:6]([CH3:7])([CH3:8])[CH2:5]2)[CH2:20][CH2:19]1)[CH2:23][CH3:24]
Reactant: CCC=O
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2ccccc2C2CC(C)(C)C(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.2 %

Procedure:
To a solution of the 1-[2-(3,3,4,4-tetramethylcyclopentyl)phenyl]piperazine (20 mg, 0.0698 mmol) produced in Example (55b) in tetrahydrofuran (1 mL) were added propionaldehyde (0.0065 mL, 0.0908 mmol), sodium triacetoxyborohydride (19.2 mg, 0.0908 mmol) and acetic acid (0.0076 mL, 0.133 mmol), followed by stirring for 3 hours at room temperature. After further adding propionaldehyde (0.0065 mL, 0.0908 mmol), sodium triacetoxyborohydride (19.2 mg, 0.0908 mmol) and 1,2-dichloroethane (1 mL) to the reaction mixture, stirring was continued for 18 hours and 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The obtained organic layers were concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1.2 mg of 1-propyl-4-[2-(3,3,4,4-tetramethylcyclopentyl)phenyl]piperazine as a colorless oil.