Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:17]=2)[CH2:10][C:11](=[O:15])[CH:12]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][C:31]([OH:33])=[O:32]>O>[C:1]1([C:7]#[C:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:17]=2)[CH2:10][C:11](=[O:15])[CH2:12][O:33][C:31](=[O:32])[CH3:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)C=[N+]=[N-])cc1OC1CCCC1
Solvent: O
Product: COc1ccc(C(C#Cc2ccccc2)CC(=O)COC(C)=O)cc1OC1CCCC1
Yield: 63 %

Procedure:
A solution of (+/-)-1-phenyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-5-oxo-6-diazohexyne (190 mg, 0.55 mmol) in HOAc (1 ml) was heated to 70° for 30 min. The reaction was cooled, diluted with H2O, and extracted with CHCl3. The extracts were washed with H2O, 5% NaHCO3, dried, and the solvent evaporated. Purification by flash chromatography (silica gel, 50% Et2O in hexane) gave the titled compound as an oil (132 mg, 63%). 1H NMR (400 MHz, CDCl3 ) δ 7.42 (m, 2 H), 7.30 (m, 3 H), 6.96 (m, 2 H), 6.82 (d, 1 H), 4.80 (m, 1 H), 4.72 (d, 1 H), 4.56 (d, 1 H), 4.36 (t, 1 H), 3.86 (s, 3 H), 3.04 (d of d, 1 H), 2.85 (d of d, 1 H), 2.16 (s, 3 H), 1.72-2.00 (m, 6 H), 1.54-1.64 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=[CH2:13].[Li+].[Cl-]>C1(C)C=CC=CC=1.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>[F:10][C:5]1[CH:4]=[CH:3][C:2]([CH2:13][CH:12]=[CH2:11])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc(F)c(C#N)c1

Procedure:
A mixture of compound 5-bromo-2-fluorobenzonitrile (2.5 g, 12.5 mmol), allyl-tributyl-stannane (4.97 g, 12.5 mmol), LiCl (1.6 g, 37.5 mmol) and Pd(PPh3)4 (0.2 g) in anhydrous toluene was refluxed under N2 overnight. Distilled the solution under reduce pressure and the residue was purified with silica gel cloumn chromatography to give the product 2-fluoro-5-(prop-2-en-1-yl)benzonitrile.
Reaction SMILES: [CH3:1]C(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-].[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:36][CH3:37])[C:27]([NH:29][C:30]([CH2:34]O)([CH3:33])[C:31]#[CH:32])=[O:28])=[CH:20][CH:19]=2)#[CH:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.[Cl-].[Na+].O>[C:34]([C:30]([NH:29][C:27](=[O:28])[CH:26]([O:25][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:13]#[CH:14])=[CH:24]2)[S:36][CH3:37])([CH3:33])[C:31]#[CH:32])#[CH:1]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)CO)cc2c1
Reactant: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)C#C)cc2c1
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
A solution of dimethyl-1-diazo-2-oxopropylphosphonate (0.109 g) in dry methanol (2 ml) was added at room temperature to a solution of crude 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-formyl-1-methyl-prop-2-ynyl)-2-methylsulfanyl-acetamide (0.125 g) from Stage 5 in methanol (5 ml). The reaction medium was cooled down to 0° C. and potassium carbonate (0.098 g) was added portion wise. The reaction mixture was allowed to warm up to room temperature and stirred for 5.5 hours and then poured onto a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed once with brine and then dried over sodium sulphate. After filtration and concentration under reduced pressure the resulting crude mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate) of N-(1-ethynyl-1-methyl-prop-2-ynyl)-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a white solid (m.p.: 148-154° C.).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.Cl.C(Cl)Cl>CO>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])=[CH:9][CH:10]=[C:5]2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)nc31)CNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
tert-Butyl 9-methyl-2-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.14 g, 0.26 mmol) was treated with 1.25 M HCl in MeOH (6.0 mL), and the resulting suspension was stirred at ambient temperature for 18 h. To the suspension was added CH2Cl2 (1.0 mL) and 1.25 M HCl in MeOH (2.0 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was concentrated, diluted with CH2Cl2 (30 mL), washed with saturated NaHCO3 solution (2×10 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 30 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (51 mg, 46%) as a yellow powder: 1H NMR (500 MHz, DMSO-d6) δ 8.06-8.00 (m, 3H), 7.93 (d, J=8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 1H), 6.89 (d, J=1.5 Hz, 1H), 6.76 (dd, J=7.5, 2.0 Hz, 1H), 3.89 (s, 2H), 3.67 (s, 3H), 3.08 (t, J=5.5 Hz, 2H), 2.75 (t, J=5.5 Hz, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O)=[O:13].[CH2:25]=[CH:26]O>>[C:12]([OH:14])(=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O
Reactant: C=CO
Product: CCCCCCCCCCCCCC(=O)O
Temperature: 46 °C

Procedure:
A 4% w/w dispersion was emulsified with 0.4% Span 20 and 1% w/w Mowiol 8-88 using a Silverson mixer. These 5 μm droplets also crystallised rapidly on cooling to 46° C. but it was noticeable under the microscope that in the presence of sonication the crystallisation rate within the droplets increased (crystallised within 10 sec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[C:25]([OH:29])(=[O:28])[CH:26]=[CH2:27].C(N(CC)CC)C>CN(C=O)C.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](/[CH:27]=[CH:26]/[C:25]([OH:29])=[O:28])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C=CC(=O)O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 100 °C

Procedure:
A mixture of the title compound of Example 5 (0.913 g), acrylic acid (0.17 mL), palladium acetate (4 mg) and triethylamine (0.70 mL) in 5 mL DMF is heated to 100° C. for 24 h in a pressure-safe tube. The reaction is cooled and diluted with 50 mL of a 10% aqueous HCl solution. The resulting solid is collected, dried and recrystallized from EtOH to yield 0.564 g of the desired product as a tan solid.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:18])[CH2:5]1)=[N+:2]=[N-:3].[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>N1C=CC=CC=1>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[O:7][C@@H:6]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:18])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cnc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c1
Solvent: c1ccncc1
Product: Cc1cnc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](COC(=O)C(C)(C)C)O2)c1

Procedure:
1-(3-Azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-5-methyl-2(1H)-pyrimidinone (0.4 g, 1.59 mMol) was dissolved in dry pyridine (10 mL) at 0° C. under a nitrogen atmosphere. Pivaloyl chloride (0.588 mL; 4.78 mMol) was added with stirring and allowed to react for 72 hours. The reaction was quenched with ice then evaporated to dryness. The residue was chromatographed on silica gel eluted with 20:1 CHCl3 /MeOH (v/v) and the appropriate fractions combined and evaporated to give the title compound: mp =121°-123° C.; UV (nm): at pH 1λmax =327 (ε=5900), λmin =269 (ε=820); at pH 13λmax =322 (ε=17200), λmin =251 (ε=850); 1H NMR: (DMSO-d6) δ8.48(d, J=3.12 Hz, 1H, H4), 7.88(d, J=3.27 Hz, 1H, H6), 6.02(t, J=6.25 Hz, 1H, H1 '), 4.48-4.39(m, 1H, H3 '), 4.31-4.28(m, 2H, H5 '), 4.20-4.14(m, 1H, H4 '), 2.62-2.50(m, 1H, H2 '), 2.41-2.27(m, 1H, H2 '), 2.04(s, 3H, 5-CH3), 1.12(s, 9H, -C(CH3)3).
Reaction SMILES: [CH2:1]1[S:5](=[O:7])(=[O:6])[O:4][CH2:3][CH2:2]1.[CH3:8][C:9]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:12])=[CH2:10]>C(#N)C>[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N+:17]([CH3:19])([CH3:18])[CH2:3][CH2:2][CH2:1][S:5]([O-:4])(=[O:7])=[O:6])(=[O:12])[C:9]([CH3:10])=[CH2:8]
Reactant: C=C(C)C(=O)NCCCN(C)C
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: C=C(C)C(=O)NCCC[N+](C)(C)CCCS(=O)(=O)[O-]
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Into a round bottom flask is added 26.4 grams of anhydrous acetonitrile (available from Sigma-Aldrich) and 15.5 grams of propane sultone (available from Sigma-Aldrich), and this is stirred for 30 minutes. After the 30 minutes, a solution of 25.6 grams of DMAPMA in 56.5 grams of acetonitrile is added. The mixture is stirred and warmed to 35° C. A white precipitate quickly forms. Once the white precipitate takes up the bulk of the volume, the liquid is decanted. The solid is washed once with acetonitrile and again the liquid is removed by decanting. The solids are then washed in 2× volume diethyl ether. They are then filtered via funnel and washed with copious amounts (via filtration) of diethyl ether. The NMR structure is consistent with the structure of the target molecule SZ.
Reaction SMILES: [N:1](=[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5])[OH:2].Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C>[N:1](=[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4](=[N:13][OH:14])[NH2:5])[OH:2]
Reactant: N#CC(=NO)c1cccnc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)C(=NO)c1cccnc1

Procedure:
A mixture of alpha-oximino-3-pyridylacetonitrile (41.0 g, 279 mmol), hydroxylamine hydrochloride (21.5 g, 310 mmol) and sodium acetate (50.8 g, 620 mmol) in ethanol (99.9%, 500 ml) was refluxed for 4 h. After cooling, the precipitate was collected by filtration and dried. The precipitate contained the wanted product and sodium acetate (85 g, 168%); M+ : 180.
Reaction SMILES: ClC1C=CC2SN=C(O)C=2C=1.C([S:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23])C1C=CC=CC=1>>[Cl:29][C:27]1[CH:26]=[CH:25][C:21]2[C:22]([OH:23])=[N:24][S:19][C:20]=2[CH:28]=1
Reactant: NC(=O)c1ccc(Cl)cc1SCc1ccccc1
Agent: Oc1nsc2ccc(Cl)cc12
Product: Oc1nsc2cc(Cl)ccc12

Procedure:
A method similar to the preparation of 5-chlorobenzo[d]isothiazol-3-ol (see pages 17 and 18 above) was followed using 2-benzylsulphanyl-4-chlorobenzamide (350 mg, 1.26 mmol). The title compound was isolated as a white solid (150 mg, 64%).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27]([O:34][CH3:35])=[CH:26][C:16]=2[CH2:17][N:18]2[C@H:22]([CH2:23][OH:24])[CH2:21][CH2:20][C:19]2=[O:25])=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.[Pd]>[C:30]([C:28]1[C:27]([O:34][CH3:35])=[CH:26][C:16]([CH2:17][N:18]2[C:19](=[O:25])[CH2:20][CH2:21][C@H:22]2[CH2:23][OH:24])=[C:15]([C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1cc(CN2C(=O)CC[C@H]2CO)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COc1cc(CN2C(=O)CC[C@H]2CO)c(-c2ccc[nH]c2=O)cc1C(C)(C)C
Reaction time: 2 h

Procedure:
step 4—A mixture of 108 (100 mg) and 10% Pd/C (15 mg) in MeOH (20 mL) under 1 atmosphere of H2 at RT was stirred for 2 h. The catalyst was filtered off and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 10% MeOH to afford 44.3 mg (55%) of I-72.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]12([CH2:28][NH2:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[C:18]12([CH2:28][NH:29][C:9](=[O:11])[CH2:8][S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:25][CH:24]3[CH2:23][CH:22]([CH2:21][CH:20]([CH2:26]3)[CH2:19]1)[CH2:27]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)CSc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CSc1ccccc1)NCC12CC3CC(CC(C3)C1)C2
Reaction time: 2 h

Procedure:
A room temperature solution of (phenylsulfanyl)acetic acid (1.68 g, 10.0 mmol) in dichloromethane (10 mL) was treated with 2M oxalyl chloride in dichloromethane (8 mL, 16.0 mmol) and DMF (1 drop), stirred for 2 hours, concentrated, dissolved in dichloromethane (10 mL), treated with 1-adamantylmethylamine (1.65 g, 10.0 mmol) and N,N-diisopropylethylamine (2.1 mL, 12.0 mmol), and stirred for 1 hour. The mixture was filtered through a pad of silica gel (20 g) and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([O:21][CH2:22][CH3:23])[C:16]([O:18]CC)=[O:17])=[CH:10][C:9]=1[O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].C1COCC1.S([O-])(O)(=O)=O.[K+]>O.C(O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([O:21][CH2:22][CH3:23])[C:16]([OH:18])=[O:17])=[CH:10][C:9]=1[O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(Cc2ccccc2)c(OCCc2ccc(OS(C)(=O)=O)cc2)c1)OCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(Cc1ccc(Cc2ccccc2)c(OCCc2ccc(OS(C)(=O)=O)cc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 3-[4-benzyl-3-({4-[(methylsulfonyl)oxy]phenethyl}oxy)phenyl]-2-ethoxypropanoate (0.48 g), LiOH (0.024 g), THF (10 ml), ethanol (2 ml) and water (2 ml) were added to a reaction flask. The solution was stirred 4 h at room temperature. Aqueous solution, 1 M, of potassium hydrogen sulfate (2 ml) was added to the reaction flask. The solvent was evaporated. The residue was extracted twice by ethyl acetate. The organic phase was dried by magnesium sulfate and filtered. The solvent was evaporated and the product isolated (0.4 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=1)=[O:7])(=[O:4])=[O:3].[C:31](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.O>[CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]([CH3:31])[C:16]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=1)=[O:7])(=[O:3])=[O:4]
Reactant: Cc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccccc3)[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccccc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 37.1 %

Procedure:
To a solution of N-methanesulfonyl-6-(6-methyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxamide (100 mg) in N,N-dimethylformamide (1.2 mL) were added cesium carbonate (155 mg) and methyl iodide (0.023 mL), and this mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (38.3 mg). 1H-NMR (DMSO-d6) δ ppm: 2.43 (3H, s), 3.38 (3H, s), 3.57 (3H, s), 4.21 (2H, s), 6.82-6.89 (1H, m), 7.24-7.33 (2H, m), 7.37 (1H, d, J=8.0 Hz), 7.43-7.58 (5H, m), 7.81-7.90 (2H, m), 10.90-11.55 (1H, br). ESI-MS (m/z): 434 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[Br:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1>C(#N)C>[Br:12][C:13]1[C:14]2[N:15]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:19]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ncccc1Br
Solvent: CC#N
Product: Oc1ccc(-c2cn3cccc(Br)c3n2)cc1
Temperature: 110 °C
Yield: 63.2 %

Procedure:
432 mg (corresponding to 2.01 mmol) of 2-bromo-4′-hydroxyacetophenone and 348 mg (corresponding to 2.01 mmol) of 3-bromo-2-aminopyridine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 6 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 8 mL of water and 8 mL of methanol. Then, about 8 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 368 mg (corresponding to 1.27 mmol) of 8-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 13, Step 2).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10]1([N:16]=[C:17]=[S:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)(=O)C.CCOCC>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:17](=[S:18])[NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2]2
Reactant: S=C=Nc1ccccc1
Reactant: OC1CN2CCC1CC2
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: S=C(Nc1ccccc1)OC1CN2CCC1CC2
Yield: 29 %

Procedure:
3-Quinuclidinol and phenyl isothiocyanate were used. The reaction solution was heated at reflux under nitrogen for 6 days. The reaction solution was chromatographed using silica gel and elution with 10% methanol in methylene chloride followed by a solution of methylene chloride/methanol/ammonium hydroxide (9:1:0.1) to afford a white foam. This foam was dissolved in ethyl acetate/ether (1:9, 10 mL/g of foam), and the resulting cloudy solution was filtered through diatomaceous earth. The resultant filtrate was evaporated under reduced pressure, and the residual foam was crystallized from ethyl acetate/hexanes (1:3) to afford the title compound (29%) as a white solid: mp 132.0-133.0° C.; FAB LRMS m /z (relative intensity, %) 263 (MH+, 14), 110 (100).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=O)[CH:4]=[C:5](SC)[S:6]C.O.[NH2:14][NH2:15]>C(O)C>[C:2]([C:3]1[N:14]=[N:15][C:5](=[S:6])[CH:4]=1)([CH3:12])([CH3:11])[CH3:1]
Reactant: CSC(=CC(=O)C(C)(C)C)SC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1=CC(=S)N=N1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a stirred solution of 4,4-dimethyl-1,1-bis(methylthio)-1-penten-3-one (18.4 g) in ethanol, was added dropwise with stirring hydrazine hydrate (5.3 g), keeping the temperature below 25°. The reaction mixture was stirred briefly at room temperature, then refluxed for 2 hours. Evaporation of the solvent, and trituration with ether, afforded 3-t-butylpyrazole-5-thione (7.8 g, 20% yield), of melting point 147°-8°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2[NH:14][C:15](=[O:23])[C:16](C(OCC)=O)=[CH:17][C:12]=2[CH:11]=[N:10]1.O.[OH-].[Li+].C1C(=O)N([Br:34])C(=O)C1.C([O-])(O)=O.[Na+]>O.CC#N>[Br:34][C:16]1[C:15](=[O:23])[NH:14][C:13]2[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:10]=[CH:11][C:12]=2[CH:17]=1
Reactant: CCOC(=O)c1cc2cnn(-c3c(F)cccc3F)c2[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1[nH]c2c(cnn2-c2c(F)cccc2F)cc1Br
Temperature: 90 °C
Reaction time: 1 h
Yield: 8787.3 %

Procedure:
Ethyl 1-(2,6-difluorophenyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (9.40 g, 0.29 mmol) was treated with 80 mL CH3CN and 80 mL water and lithium hydroxide monohydrate (3.10 g, 74 mmol). The resulting suspension was then heated to 90° C. for 1 h. The solution was allowed to cool to 35° C. and treated with N-bromosuccimide (5.20 g, 29 mmol) in one portion. It was allowed to stir for 1 h at RT then treated with another equiv. of N-bromosuccimide (5.20 g, 29 mmol) in one portion. After stirring for an additional 1 h at RT, it was treated with a saturated solution of NaHCO3 and extracted with 2×150 mL EtOAc. The combined organic solution was washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound (8.31 g) as an orange foam in ca. 90% purity. No further purification was carried out prior to use in the next step. MS (ESI, pos.ion) m/z: 326.0/327.9 (M+1). For a related reference, see: Chowdhury, S.; Roy, S. J. Org. Chem. 1997, 62, 199-200.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[O-].[Na+].[C:27](OC(=O)C)(=[O:29])C.O>CO.C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:29][CH3:27])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(OCCCCCCBr)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COCCCCCCOc1ccc(N2CCN(C(C)=O)CC2)cc1
Reaction time: 6 h

Procedure:
A solution of crude 1-acetyl-4-[4-(6-bromohexyloxy)phenyl]piperazine (10.52 g) in methanol (105 ml) was treated with 28% sodium methoxide in methanol (105 ml), and the solution was refluxed for 7 hours. After cooling, the precipitate was removed by filtration. The filtrate was added to a mixture of methylene chloride and water. The organic layer was taken, dried over magnesium sulfate, filtered and evaporated to give a crude oil. This oil in methylene chloride (20 ml) was treated with acetic anhydride (6.4 ml) under ice-cooling. After 6 hours, the solution was added to a mixture of methylene chloride and water. The organic layer was taken, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with a mixed solvent of methylene chloride-methanol (from 0% to 3% gradient elution) to give 1-acetyl-4-[4-(6-methoxyhexyloxy)phenyl]piperazine (5.38 g) as a pale red solid.