Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].Cl.[NH2:25][OH:26].N1C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[N:25][OH:26])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=NO
Temperature: 25 °C
Yield: 79.8 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (1.6 g, 5.19 mmol) obtained in Example 1 was dissolved in ethanol (100 mL), hydroxylamine hydrochloride (1.08 g, 15.57 mmol) and pyridine (1.64 g, 1.68 mL, 20.76 mmol) were added thereto, refluxed for 1 hr, and cooled to RT. The resulting mixture washed with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 1.34 g of the titled compound (yield: 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>>[CH3:29][N:30]([CH:32]=[C:14]1[CH2:15][CH2:16][N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[C:11]2[CH:21]=[CH:20][CH:19]=[N:18][C:12]=2[C:13]1=[O:17])[CH3:31]
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc2C1=O

Procedure:
As described for Reference Example 221, 5,6,7,8-tetrahydro-5-(4-nitrobenzoyl)-9H-pyrido[3,2-b] azepin-9-one is reacted with tert-butoxybis(dimethylamino)methane to give the product as a solid.
Reaction SMILES: [H-].[Na+].[C@@H:3]1([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[CH2:4]1.Cl[CH2:21][C:22]1[C:35]2[C:36]3=[C:37]4[C:32](=[CH:33][CH:34]=2)[CH:31]=[CH:30][CH:29]=[C:28]4[CH:27]=[CH:26][C:25]3=[CH:24][CH:23]=1.C(Cl)Cl>CS(C)=O.CO>[C:22]1([CH2:21][O:9][CH2:8][C@H:7]2[O:10][C@@H:3]([N:11]3[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]3=[O:13])[CH2:4][C@@H:5]2[OH:6])[C:35]2[C:36]3=[C:37]4[C:32](=[CH:33][CH:34]=2)[CH:31]=[CH:30][CH:29]=[C:28]4[CH:27]=[CH:26][C:25]3=[CH:24][CH:23]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: ClCc1ccc2ccc3cccc4ccc1c2c34
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COCc3ccc4ccc5cccc6ccc3c4c56)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.4 %

Procedure:
A mixture of 875 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 5 ml of dimethyl sulfoxide was stirred at room temperature for 30 minutes in an atmosphere of nitrogen, and then a solution of 2.42 g (10 mmol) of thymidine in 5 ml of dimethyl sulfoxide was added dropwise to the resulting mixture. The mixture was stirred at room temperature for 30 minutes, after which a suspension of 2.51 g (10 mmol) of 1-(chloromethyl)pyrene [Acta Chem. Scand., 10, 1362 (1936)] in 15 ml of dimethyl sulfoxide was added. The mixture was then stirred at room temperature for 90 minutes. At the end of this time, the reaction mixture was poured into 100 ml of ice-water, and the aqueous mixture was extracted with 100 ml of ethyl acetate and then with 100 ml of methylene chloride. The extract was dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 150 g of silica gel (230-400 mesh), using a gradient elution method, with mixtures of methylene chloride containing from 0 to 4% by volume of methanol as the eluent, to give 292.4 mg (yield 6.4%) of the title compound.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:22]([O:24]C)=[O:23])[S:21][C:11]1=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>CO.O>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:22]([OH:24])=[O:23])[S:21][C:11]1=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c3ccccc3n(Cc3ccccc3)c2s1
Reaction time: 8 h

Procedure:
KOH (3 g) was dissolved in methanol-water (1/1) (50 ml). (5) (3 g) was added and the mixture refluxed until the compound was in solution and subsequently 1 h in addition. After cooling the mixture was acidified with acetic acid to pH=6, and the mixture was stirred overnight. The formed precipitate was filtered off, washed with water and dried in vacuo at 50° C. The crude product (3 g) was boiled in water once more, cooled, filtered and dried again giving analytically pure (8), m.p. 194-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridyl) benzoic acid (73 mg, 0.1857 mmol) was dissolved in methylene chloride (5 ml), then p-anisidine (46 mg, 0.3739 mmol), triethylamine (75 mg, 0.7425 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (126 mg, 0.7455 mmol) were added thereto at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:4) to give the title compound (33 mg, 0.0662 mmol, 36%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][C@@H:25]1[CH3:30])(=[O:23])=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[C@@H:25]([CH3:30])[CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C[C@H]1CNCCN1S(C)(=O)=O
Agent: Cl
Product: C[C@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1S(C)(=O)=O

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and (S)-1-methanesulfonyl-2-methyl-piperazine hydrochloride salt using procedure C yielded 2-chloro-6-((S)-4-methanesulfonyl-3-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12]1[O:16][CH2:15][CH2:14][O:13]1.O1CCCC1.C([Li])CCC.[CH:27]1[C:32]([CH:33]=[O:34])=[CH:31][C:30]2[O:35][CH2:36][O:37][C:29]=2[CH:28]=1>C(=O)=O.CC(C)=O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH:33]([C:32]1[CH:27]=[CH:28][C:29]2[O:37][CH2:36][O:35][C:30]=2[CH:31]=1)[OH:34]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1cc(Br)c(C2OCCO2)cc1OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1cc(C2OCCO2)c(C(O)c2ccc3c(c2)OCO3)cc1OC
Temperature: -78 °C
Yield: 30 %

Procedure:
To a flame dried four necked round bottom flask (100 mL) were added 2-(2-bromo-4,5-dimethoxyphenyl)-1,3-dioxolane (formula VII; 1.0 g, 0.9934 mole) and anhydrous tetrahydrofuran (25 ml) under nitrogen atmosphere. The flask was cooled to −78° C. in dry ice-acetone bath; n-Butyllithium (5.3 ml, 0.005 mole) was added drop wise with stirring at −78° C. and stirred for 15 minutes. A separate flame dried flask was charged with Piperonal (0.517 g, 1.0034 mole) and dry tetrahydrofuran (6 ml). The Piperonal solution was cannulated to the reaction mixture during 30 minutes and after the addition, reaction mixture was slowly warmed to room temperature and further stirred for 2.5 hours. After the consumption of all bromine compound, as confirmed by TLC (50:50, EtOAc:Hexane), reaction mixture was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (3×20 ml). All the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield 80% of crude product. The crude product was purified by column chromatography using column of 2 meter length, diameter 2.5 cm and filled with silica gel 60-120 (column chromatographic grade). Finally column eluted with EtOAC:Hexane (50:50), to get pure product (2-(1,3-Dioxolane-2-yl)-4,5-dimethoxy phenyl) (benzo(d)(1,3)dioxol-5-yl)-methanol with 30% yield. The total time required was about 7 hours.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:19])[CH2:14][S:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](F)[C:24]=1[C:30]([F:33])([F:32])[F:31].CCO>CN(C=O)C.Cl>[Cl:22][C:23]1[C:24]([C:30]([F:31])([F:32])[F:33])=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:19][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][S:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)SC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)SC[C@H](Oc1cccc(Cl)c1C(F)(F)F)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-isopropylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 mg, 0.030 μmol) was dissolved in DMF (166 μL). NaH (1.7 mg, 69.1 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorobenzotrifluoride (20.6 mg, 104 μmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight at room temperature. The product was concentrated and the crude product was dissolved in 1:1 AcOH/H2O (1.5 mL) then purified by preparative HPLC to yield the title compound as a mono-TFA salt (9.2 mg, purity 94%). MS m/z: [M+H]+ calcd for C16H21ClF3NOS, 368.10. found 368.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C-:13]#[N:14].[K+].CS(C)=O>O>[C:13]([CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])#[N:14]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCCC#N
Temperature: 90 °C
Yield: 54.3 %

Procedure:
To a 250 mL of round-bottom flask was added tert-butyl 3-bromopropylcarbamate (4.0 g, 17 mmol) (commercially available from 3B Scientific Corporation Product List Order Number 3B3-073730), potassium cyanide (1.5 mL, 20 mmol) and 100 mL of DMSO. The reaction mixture was heated at 90° C. for 16 hours. The mixture was then diluted with 100 mL of water, and extracted with 100 mL of EtOAc twice. The extracts were combined, concentrated, and purified by flash chromatography on silica gel (40% EtOAc/hexane) to give tert-butyl 3-cyanopropylcarbamate (1.7 g, 55% yield). MS m/z: 185 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 4.70 (br s, 1H), 3.25 (q, J=6.65 Hz, 2H), 2.40 (t, J=7.24 Hz, 2H), 1.84-1.91 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.Cl[CH2:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-:20].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[C:11]([O:20][CH2:15][C:16](=[O:18])[CH3:17])[CH:2]=[CH:3][C:4]=1[O:12][CH3:13]
Reactant: CC(=O)CCl
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCC(C)=O)ccc1OC
Yield: 102.1 %

Procedure:
Stir a mixture of methyl 4-hydroxy-2-methoxybenzoate (Danishefsky et al., J. Med. Chem. 1979, 101, 7001-7008, 0.54 g, 3 mmol), chloroacetone (6 mmol, Aldrich Chemical Company), potassium carbonate (9 mmol) and dimethylformamide at 50° C. overnight. Cool the reaction to room temperature, dilute with ethyl acetate, wash with saturated NaHCO3 solution and saturated brine. Dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the residue by column chromatography (silica gel, step gradient elution with 10% ethyl acetate in hexane to 30% ethyl acetate in hexane) and concentrate the appropriate fractions to afford 0.73 g of 2-methoxy-5-(2-oxo-propoxy)-benzoic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[CH3:19][O:20][C:21]1[C:22]([CH3:28])=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].C(O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([O:20][CH3:19])[C:22]=1[CH3:28]
Reactant: COc1cccc(N)c1C
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(OC)c3C)c2cc1OC
Temperature: 100 °C
Yield: 72 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 3-methoxy-2-methylaniline (0.036 g, 0.26 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 2.5 h. After cooling, the mixture was diluted with water (15 ml) and made alkaline with saturated NaHCO3. The resulting gummy precipitate was collected and crystallized from methanol-water to give the title compound (45 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH3:10].[C:18]1([C:24]#[C:25][C:26]([O:28]CC)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-:31].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[ClH:31].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:25][C:26](=[O:28])[C:9]=1[CH3:10].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:25][C:26](=[O:28])[C:9]=1[CH3:10]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CCC(=Nc1ccccc1)c1ccccc1Br
Reactant: [Cl-]
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2Br)n(-c2ccccc2)c(-c2ccccc2)cc1=O
Product: Cl
Temperature: 60 °C
Yield: 13.6 %

Procedure:
to 300 ml of toluene were added 6.4 g (0.022 mole) of 1-(2-bromophenyl)-N-phenylpropaneimine, 3.9 g (0.022 mole) of ethyl phenylpropiolate and 3.6 g (0.027 mole) of aluminum chloride. The reaction mixture was then heated at 60° C. hours. After cooling, the reaction mixture was poured into 500 ml of 2N sulfuric acid, followed by extraction with methylene chloride. After washing the organic layer (the extract) with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). The resultant crystals were then recrystallized from a 2:1 mixed solvent of acetone and hexane to obtain 1.3 g of 2-(2-bromophenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone hemihydrochloride having a melting point of 236°-238° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:16]=[C:15]3[NH:40][C:41](=[O:68])[C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)=[CH:44][C:43]=2[N:55]([CH:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)[C:56](=[O:61])[C:57]([F:60])([F:59])[F:58])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>O1CCOCC1.CO>[F:8][C:6]1[CH:5]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[NH:40][C:41](=[O:68])[C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]3)=[CH:44][C:43]=2[N:55]([CH:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)[C:56](=[O:61])[C:57]([F:59])([F:60])[F:58])(=[O:10])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(S(=O)(=O)c5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A mixture of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide (2.4 g, 2.53 mmol), 4N hydrochloric acid in 1,4-dioxane (35 mL), methanol (50 mL) and 1,4-dioxane (15 mL) was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure and the residue dissolved in dichloromethane, washed with water, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/acetone 1:1 as the eluant affording the title compound as a pale yellow solid (1.43 g, 80% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1([C:48]2[S:49][CH:50]=[C:51]([CH2:53]O)[N:52]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:53][C:51]5[N:52]=[C:48]([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[S:49][CH:50]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: OCc1csc(-c2ccccc2)n1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 113.3 %

Procedure:
A mixture of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.800 g, 2.52 mmol), triphenylphosphine (0.992 g, 3.78 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 0.555 g, 2.90 mmol) in a 200 mL flask fitted with an addition funnel was maintained under vacuum for ten minutes. The mixture was then flushed with nitrogen and charged with dry tetrahydrofuran (60 mL, distilled over lithium aluminum hydride). The solution was warmed to ˜50° C. and then sonicated for 5 min. The cooled heterogeneous mixture was then treated at 22° C. with a solution of diisopropyl azodicarboxylate (0.663 g, 3.28 mmol) in tetrahydrofuran (15 mL), added dropwise over 2.5 h. The reaction was homogeneous (pale yellow) at the end of the addition. The mixture was then stirred for another 2.5 h (total 5 h). The reaction mixture was then diluted with dichloromethane (400 mL), washed with saturated sodium bicarbonate (20 mL), brine and dried (anhydrous magnesium sulfate). Evaporation gave a white solid which was chromatographed on silica gel (3×12 cm, elution dichloromethane-ethyl acetate 98.5:1.5 to 97:3). The fractions were collected and evaporated to give the desired compound (1.40 g) as a white solid, contaminated with hydrazide by tlc. Crystallization in ethyl acetate (40 mL) gave the pure title material (0.838 g, 68%) as a white solid. The mother liquors (0.475 g) were chromatographed on silica gel (3×12 cm, elution dichloromethane-ethyl acetate 98.5:1.5 to 97:3) to give after crystallization from ethyl acetate (30 mL) to provide additional desired compound (0.160 g, 13%, total 81%) as a white solid. LC (Method C): 2.480 min. HRMS (ESI) calcd for C24H19N4O4S2 [M+H]+ m/z 491.0842. found 491.0865. 1H NMR (CDCl3, 400 MHz) 3.85 (s, 3H) 4.21 (s, 3H) 5.33-5.55 (m, 2H) 6.48 (d, J=1.96 Hz, 1H) 6.72 (dd, J=1.96, 0.78 Hz, 1H) 7.12 (s, 1H) 7.36-7.39 (m, 1H) 7.41-7.50 (m, 3H) 7.86 (s, 1H) 7.95-8.02 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][C@@H:9]([NH:11][C:12](=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH3:10].N(CCO)(CCO)CCO.O>C1COCC1>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][NH:11][C@@H:9]([CH3:10])[CH2:8][OH:7])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(CC(=O)N[C@@H](C)CO)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: OCCN(CCO)CCO
Solvent: C1CCOC1
Product: COc1ccc(CCN[C@@H](C)CO)cc1OC
Reaction time: 1.5 h
Yield: 34.7 %

Procedure:
To a suspension of 12.6 g (0.33 mole) lithium aluminum hydride (LAH) in 150 mL of dry THF under argon was added dropwise a suspension of 21.0 g (0.083 mole) (S)-N-(2-hydroxy-1-methylethyl)-3,4-dimethoxybenzeneacetamide in dry THF. The reaction mixture was heated under reflux for 4 hr. An additional 1.0 g of LAH was added and refluxed another 3 hr. An additional 3.0 g of LAH was added and the reaction was refluxed overnight. To the reaction was added 69 mL (0.48 mole) of triethanolamine over 1 hr. After stirring for 90 min, 16 ml of water was added and this was stirred overnight. An additional 12 ml of water was added. The solid that formed was filtered off and the filter cake was washed three times with ether and once with THF. The filtrate was washed with brine and dried (K2CO3). The solvent was removed in vacuo. The residue was dissolved in ether/acetonitrile, the undissolved solid was filtered off and the filtrate was evaporated in vacuo. The residue was treated with ethereal hydrogen chloride and the solid was collected. Three recrystallizations from acetonitrile gave 6.9 g of (S)-2-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-propanol (38%) mp, 120°-123° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.C=O.[CH:27](O)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH3:27])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: O=CO
Reactant: Fc1cccc(F)c1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CC[C@H]2[C@@H](C1)c1cc(-c3c(F)cccc3F)cc3c1N2CCC3
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of (7aS,11aR)-2-(2,6-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.050, 0.15 mmol), HCHO (0.20 mL, 2.9 mmol) and formic acid (1.0 mL, 2.9 mmol) was heated at 80° C. for 4 h and cooled to room temperature. Water (5.0 mL) was added and the solution was basified with saturated Na2CO3 until pH>8. The mixture was extracted with CH2Cl2 (3×10 mL), dried (Na2SO4) and flash column chromatography (1–5% MeOH in CHCl3) gave the title compound (0.032 g, 62%) as a white foam. 1H NMR (CDCl3, 300 MHz) δ 2.00–2.20 (m, 5H), 2.20–2.50 (m, 4H), 2.55–2.68 (m, 1H), 2.68–2.82 (m, 3H), 2.86–2.98 (m, 1H), 3.28–3.42 (m, 3H), 6.90–7.08 (m, 4H), 7.14–7.25 (m, 1H) ppm. MS (ESI): 341 (base, M+H).