Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(=O)C1C=CC(O)=CC=1)C1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:44][CH3:45])[CH3:43])=O>>[CH2:44]([N:42]([CH2:40][C:39]1[CH:19]=[CH:18][C:17]([O:22][CH2:39][CH2:40][N:42]([CH2:44][CH3:45])[CH3:43])=[CH:16][CH:15]=1)[C:43]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:45]
Reactant: CCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 88.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-ethyl-N-methylacetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.6 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:6]=12.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH:11]([Br:20])[CH3:12])=[CH:7][C:6]=12
Reactant: CCc1ccn2ncc(Br)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccn2ncc(Br)c2c1
Temperature: 77 °C
Reaction time: 2 h
Yield: 28697.2 %

Procedure:
To a stirred solution of 3-bromo-5-ethylpyrazolo[1,5-a]pyridine (I-17, 2.1 g, 0.0094 mmol) in CCl4 (20 mL) at rt was added NBS (2 g, 0.01 mmol) followed by benzoyl peroxide (1.1 g, 0.004 mmol). The resulting reaction mixture was heated to 77° C. After 2 h, the reaction mixture was allowed to cool to rt and subsequently water (20 mL) was added followed by extraction with dichloromethane (2×20 mL). The combined organic layers were washed with water (1×20 mL), sat NaHCO3 solution (1×10 mL), brine (1×10 mL), dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography over silica gel (petroleum ether/EtOAc, 0-5% EtOAc) to afford 820 mg (29%) of 3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine (I-18) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=7.91 Hz, 1H), 7.93 (s, 1H), 7.46 (d, J=1.32 Hz, 1H), 6.90-6.92 (dd, J=1.76, 5.71 Hz, 1H), 5.19-5.24 (m, 2H), 2.08 (d, J=7.04 Hz, 3H); ESI-LC/MS (m/z): [M+H]+ 302.9, [(M+2)+H]+ 304.9, [(M+4)+H]+ 306.9, RT 2.65 min
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:16](=O)[CH3:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH3:19][C:20]([S@:23]([NH:25][CH:16]([C:4]1[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])=[C:2]([CH3:1])[CH:3]=1)[CH3:17])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)C(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)C(F)F
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (880 mg, clear colorless oil) from 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (820 mg, 3.1 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]2=[N:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][N:10]2[N:9]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]2=[N:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][N:10]2[N:9]=1)(=[O:24])[CH3:23]
Reactant: Oc1ccccc1-c1nn2cc(-c3ccccc3)nc2s1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccccc1-c1nn2cc(-c3ccccc3)nc2s1

Procedure:
4.6 g of 2-(2-hydroxyphenyl)-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazole (Example No. 28) are warmed to 150° C. in 75 ml of acetic anhydride for 1/2 an hour, excess acetic anhydride is evaporated off, the residue is stirred with water and the product is recrystallised from ethanol. 3.8 g, corresponding to 72% of theory, of colourless crystals of melting point 177° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>S(Cl)(Cl)=O.ClCCl.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]([NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])=[O:15]
Reactant: Nc1ccccc1C=O
Reactant: O=C(O)Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1NC(=O)Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of (2,6-dichloro-3-nitro-phenyl)-acetic acid (0.90 g, 3.35 mmol) in thionyl chloride (15 mL) is refluxed for one hour. The solvent is removed by concentration and dry toluene is added to thoroughly remove thionyl chloride. To the solution of acid chloride in dry dichloromethane (30 mL) is added (drop-wise) a solution of 2-aminobenzaldehyde (0.365 g, 3.02 mmol) in dichloromethane (5.0 mL). The mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc and washed with saturated K2CO3 and brine. The organic layer is dried, filtered and concentrated to give crude product (0.94 g, 88.6%).
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[OH:12].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25]OS(C)(=O)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][O:12][CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Reactant: OC1Cc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
Sodium hydride (60%) (0.6 g, 14.4 mmol) is added to a flame dried flask charged with indan-2-ol (0.965 g, 7.2 mmol) and N,N′-dimethylformamide (DMF) (20 mL), cooled to 0° C. under N2 and stirred for 30 minutes. A solution of (S)-2-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (P) (1 g, 3.6 mmol) in DMF (5 mL) is added dropwise to the reaction mixture in such a manner as to maintain 0° C. The reaction is stirred at 60° C. for one hour, cooled to 0° C., quenched with brine, diluted with EtOAc, washed repeatedly with brine (6×), dried and concentrated in vacuo. The residue is purified by chromatography on SiO2 (5% EtOAc/Hexanes) to give 0.20 g of indanyl ether (Q) as a clear colorless oil: LCMS (ES) 340.17 (MNa+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([C:20]([OH:22])=[O:21])=[CH:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:28](=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([C:20]([O:22][CH3:28])=[O:21])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2ccc(O)cc2c1=O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cn(-c2ccc(F)cc2)c2ccc(O)cc2c1=O
Yield: 74 %

Procedure:
Compound K (383 mg, 1.28 mmol, 1.00 eq) was dissolved in methanol (6.4 mL) and concentrated sulfuric acid (0.64 mL) was added dropwise. The reaction was heated to reflux for 3 hours at which point it was cooled and neutralized with a saturated solution of sodium bicarbonate. The mixture was extracted with a solution of 3:1 CHCl3:IPA (2×) and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using 0-20% 89:10:1 DCM:methanol:NH40H afforded 296 mg (74%) of the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.36 (s, 1H), 7.72-7.68 (m, 2H), 7.61 (d, J=2.8 Hz, 1H), 7.49 (t, J=8.7 Hz, 2H), 7.11 (dd, J=9.0, 2.8 Hz, 1H), 6.84 (d, J=9.1 Hz, 1H), 3.71 (s, 3H); ES-MS [M+1]+: 314.2.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33]([O:35]C)=[O:34])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11](\[CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)/[C:12]([O:14]C)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>C(O)C.O>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33]([OH:35])=[O:34])=[CH:25][CH:24]=2)[C:7]([CH:10]=[C:11]([CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1ccc(C(=O)OC)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1ncc(C=C(Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A slurry containing 14.46 g (26.14 mmol) of methyl(E)-3-[2-n-butyl-1-{(4-carbomethoxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate, 8.38 g (2.09 mmol) of potassium hydroxide in a mixture of 165 mL of ethanol and 85 mL of water was stirred at ambient temperature for 18 hours. Concentration under vacuum and dilution with water gave 400 mL of a clear solution. Adjustment of the pH to 4.03 with hydrochloric acid gave crystals which when recrystallized from methanol gave 9.89 g (80%) of colorless crystals; mp 218°-219° C. as a partial hydrate.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[C:61](B(O)O)[CH:60]=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:61]2[CH:60]=[N:59][C:68]3[C:63]([CH:62]=2)=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2cc(F)cc(F)c2)CC1
Yield: 62 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-quinolinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(C(OC)=O)[CH:7]([CH3:8])[C:6]1([CH3:10])[CH3:9])=[S:4].O.[Br-].[Na+]>O=P1(C)CCC=C1>[CH3:1][O:2][C:3]([CH:5]1[CH:7]([CH3:8])[C:6]1([CH3:10])[CH3:9])=[S:4]
Reactant: COC(=O)C1(C(=S)OC)C(C)C1(C)C
Agent: CP1(=O)C=CCC1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: COC(=S)C1C(C)C1(C)C
Yield: 75.8 %

Procedure:
23 g (0.1 mol) of 2,2-dimethyl-3-methylthio-cyclopropane-1,1-dicarboxylic acid dimethyl ester (prepared according to J. Chem. Soc., Chem. Comm. 1972 (7), 375) were dissolved in 25 ml of 1-oxo-1-methylphospholine and 2 ml of water and the solution was heated to 180° C. with 8 g of sodium bromide for 12 hours. The mixture was then cooled, poured into water, extracted by shaking with toluene and distilled. 12 g (=69% of theory) of 2,2-dimethyl-3-methylthiocyclopropane-1-carboxylic acid methyl ester of boiling point 75° C./3 mm Hg are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccc(OC)cc2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 46.1 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.18 g of 4-methoxyphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 4-(4-methoxyphenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (31)), m.p.: 72.0° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][N:6]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:5]1=[O:21])=[N+]=[N-]>[Pd].CO>[NH2:1][CH:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][N:6]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:5]1=[O:21]
Reactant: [N-]=[N+]=NC1CC(c2ccccc2)CCN(CC2CC2)C1=O
Agent: [Pd]
Solvent: CO
Product: NC1CC(c2ccccc2)CCN(CC2CC2)C1=O
Reaction time: 18 h
Yield: 22.1 %

Procedure:
10% palladium on carbon (30 mg) was added to a solution of 3-azido-1-(cyclopropylmethyl)-5-phenylazepan-2-one (0.3 g, 1.05 mmol) in methanol (4 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the reaction was filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→93% dichloromethane/7% (10% ammonium hydroxide/methanol)] gave the title compound (60 mg). The racemic product was resolved on a chiralpak AS (250×20 mm) column using 20% propanol/hexanes→50% propanol/hexanes (0.1% diethylamine in hexanes) to give four enantiomerically pure isomers. MS 259 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13].ClC1C=CC(OC[C@@H](C)CCl)=CC=1.ClC1C=CC(O)=CC=1>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1ccccc1F
Agent: C[C@@H](CCl)COc1ccc(Cl)cc1
Agent: Oc1ccc(Cl)cc1
Product: C[C@@H](CCl)COc1ccccc1F

Procedure:
Prepared by Procedure U and Scheme AK using 2-fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane. 1-CHLORO-4-{[(2R)-3-CHLORO-2-METHYLPROPYL]OXY}BENZENE: Prepared by Procedure U and Scheme AK using 4-chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 38.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (31 mg, 38.8%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[CH2:9][CH2:8][C:3]21[O:7][CH2:6][CH2:5][O:4]2>C(Cl)Cl>[CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][C:3]21[O:4][CH2:5][CH2:6][O:7]2
Reactant: CC1CC(O)CCC12OCCO2
Solvent: ClCCl
Product: CC1CC(=O)CCC12OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a 200 mL round bottom flask containing the product of Example 32C (1.50 g, 8.71 mmol) and DMP (4.06 g, 9.58 mmol) (Aldrich) was added methylene chloride (100 mL) and the reaction mixture was stirred for 1 hr at room temperature. The reaction mixture was quenched with saturated NaHCO3 and extracted with EtOAc (200 mL), dried (NaSO4), filtered, and concentrated in vacuo. The residue was purified on SiO2 with hexane/ethylacetate 0-20% to afford a colorless oil (1.12 g) in 76% yield. 1H NMR (300 MHz, CDCl3) δ ppm 4.20-3.95 (m, 4H), 2.63-1.97 (m, 6H), 1.94-1.74 (m, 1H), 1.04-0.83 (m, 3H). MS (DCI+) M/Z 171 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].CS[C:17](=[NH:19])[NH2:18].O.[OH-].[Na+]>C(O)C>[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].[C:1]1([CH2:7][CH2:8][NH:9][C:17]([NH2:19])=[NH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][CH2:8][NH:9][C:17]([NH2:19])=[NH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSC(=N)N
Reactant: NCCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N=C(N)NCCc1ccccc1
Yield: 127 %

Procedure:
2-Phenylethylamine (8.49 g, 70.1 mmol) and S-methylisothiourea sulfate (9.43 g, 33.9 mmol) was dissolved in 100 ml destilled water. Air was passed over the reaction mixture and through 50% NaOH (500 ml) and then through 5% cuprous sulfate (250 ml). The reaction mixture was heated at reflux for 5 hours. Evaporation of the solvent yielded a white powder. The product was isolated by crystallisation from 96% ethanol, washed with cold acetone and diethyl ether and dried in a desicator. After three crystallisations, the product contained only minor amounts of starting material. The reaction yielded 61.5% (9.14 g) 2-phenylethylguanidine hemisulfate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:16][C@H:17]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:24])[CH2:19][NH:18]1.[Cl-].[NH4+]>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:18]2[CH2:19][C@H:20]([CH3:24])[CH2:21][CH2:22][CH2:23][C@@H:17]2[CH3:16])[CH:7]=1
Reactant: C[C@@H]1CCC[C@H](C)NC1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: C[C@@H]1CCC[C@H](C)N(c2cc(Cl)ncn2)C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
Into 4 ml of acetonitrile were added 0.3 g of 4,6-dichloropyrimidine, 0.83 g of potassium carbonate and 0.43 g of cis-2,6-dimethylhexahydro-1H-azepine hydrochloride, and the mixture was stirred for 4 hours at 60° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.3 g of 1-(6-chloropyrimidin-4-yl)-cis-2,6-dimethylhexahydro-1H-azepine.
Reaction SMILES: [ClH:1].Cl.Cl.[CH2:4]([O:6][C:7](=[O:28])[CH2:8][C@H:9]([NH:16][C:17](=[O:27])[CH2:18][NH:19]C(OC(C)(C)C)=O)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH3:5]>CCOC(C)=O>[ClH:1].[ClH:1].[CH2:4]([O:6][C:7](=[O:28])[CH2:8][C@H:9]([NH:16][C:17](=[O:27])[CH2:18][NH2:19])[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH3:5]
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)c1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](NC(=O)CN)c1cccnc1
Reaction time: 0.25 h

Procedure:
HCl gas was passed through a solution of 24-1a (0.84 g, 2.4 mmol) in EtOAc (24 mL) at 0° C. for 15 min and the reaction mixture stirred for an additional 15 min. The reaction mixture was concentrated and the residue triturated with ether to give 24-2 as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1)[CH3:2].O.O.[Sn](Cl)Cl>C(OCC)C.Cl>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([N:3]([CH2:13][CH3:14])[CH2:1][CH3:2])=[N:5][CH:6]=1
Reactant: CCN(CC)c1ccc([N+](=O)[O-])cn1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOCC
Solvent: O
Product: CCN(CC)c1ccc(N)cn1
Yield: 191.5 %

Procedure:
Following procedures similar to those disclosed in Artland, et al., J. Heterocyclic Chem., Vol. 14, 129-134 (1977), the reaction of 10.0 g (0.0512 mole) of 2-diethylamino-5-nitropyridine with 147.0 g (0.659 mole) of tin (II) chloride dihydrate in diethyl ether and concentrated hydrochloric acid produced a residue. This reaction was repeated, and the residues were combined, giving a total of 20 g. The combined residue was purified by column chromatography on silica gel, eluting with acetone to yield 16.2 g of 5-amino-2-diethylaminopyridine as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:5][N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[ClH:42].O1CCCC1.[OH-].[Na+]>O.C(OCC)(=O)C.CO>[ClH:42].[ClH:42].[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:5][NH:4][N:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(-c3ccccn3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1n[nH]cc1-c1ccc2nccc(-c3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 33 mg 6-(3-methyl-1-trityl-1H-pyrazolyl)-4-(2-pyridyl)quinoline obtained in Example 154, 0.48 mL of 5 N hydrochloric acid, 3 mL tetrahydrofuran, and 3 mL methanol was stirred overnight at room temperature. The reaction solution was cooled with iced water and basified with 5N aqueous sodium hydroxide, then ethyl acetate and water were added thereto, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, and 0.15 mL of 4 N hydrochloric acid/ethyl acetate was added thereto. The reaction solution was evaporated, then ethyl acetate was added to the residue, and the formed crystals were separated by filtration to give 19 mg of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([C:4]1([C:20]([O:22][CH3:23])=[O:21])[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)[CH:2]=C.C1C=C[NH+]=CC=1.[O-:30][Cr](Cl)(=O)=O>C1COCC1.C(Cl)Cl.CCOCC>[O:30]=[CH:2][CH2:1][C:4]1([C:20]([O:22][CH3:23])=[O:21])[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:6][CH2:5]1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: C=CCC1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1(CC=O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl 4-methyl 4-allylpiperidine-1,4-dicarboxylate from Step B (4.45 g, 14.0 mmol) in THF (70 mL) at 0° C. was added borane-methyl sulfide complex (28.0 mL of a 2M solution in THF, 56.1 mmol). The reaction mixture was slowly warmed to ambient temperature and stirred for 16 h, then quenched with water and concentrated in vacuo. The residue was dissolved in CH2Cl2 (140 mL) and added drop wise to a solution of PCC (6.65 g. 30.8 mmol) and 4 Å molecular sieves (6.65 g) in CH2Cl2 (50 mL) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 16 h, then diluted with ether (200 mL) and filtered through a pad of celite. Additional ether was used to wash the celite. The combined organics were concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=356 (M+Na).