Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][Cl:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[C:17]1([C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].[CH3:30]N(C=O)C>>[ClH:14].[ClH:14].[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:30][N:26]3[CH:27]=[C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:24]=[CH:25]3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Product: Cl
Product: N#Cc1ccc(Cn2cncc2CCn2cnc(-c3ccccc3)c2)cc1
Reaction time: 1 h

Procedure:
To a solution of the chloride from step E (500 mg, 1.65 mmol) in DMF (10 mL) at 0° C. was added sequentially, 4-phenyl-imidazole (238 mg, 1.65 mmol) and sodium hydride (145 mg, 60% dispersion in mineral oil, 3.62 mmol). Stirring was continued at 0° C. for 1 hour and then at room temperature for 16 hours. The reaction was quenched with water (50 mL), and extracted with CH2Cl2. The organic extracts were dried, (MgSO4), and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, 3-5% NH4OH: acetonitrile). The imidazole was converted to the hydrochloride salt by treating an EtOAc solution of the resulting material with gasseous HCl and evaporation of the solvent in vacuo.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1)=[O:4].[CH2:12]=O.[H][H]>C(O)(=O)C.O.[Pt]=O>[CH3:12][N:6]1[CH2:7][C@H:8]([OH:10])[CH2:9][C@H:5]1[C:3]([N:2]([CH3:11])[CH3:1])=[O:4]
Reactant: [H][H]
Reactant: C=O
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C
Reaction time: 1.5 h

Procedure:
To a solution of (2S,4R)-2-dimethylaminocarbonyl-4-hydroxypyrrolidine (2.0 g) in acetic acid (14.4 ml) and water (8 ml), 37% aqueous formaldehyde solution (1.27 g) and platinum oxide (38 mg) were added, and the mixture was hydrogenated at room temperature for 7 hours under an atmospheric pressure of hydrogen. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane and dried over magnesium sulfate. Potassium carbonate (3.5 g) was added thereto, and the mixture was stirred for 1.5 hours, followed by filtration. Removal of the solvent gave (2S,4R)-1-methyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([C:10]([O:12]CC)=[O:11])=[N:4]1)[CH3:2].[OH-].[Na+].C(OCC)(=O)C.O>C(O)C>[CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([C:10]([OH:12])=[O:11])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)n(CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCc1cc(C(=O)O)nn1CC
Reaction time: 8 h
Yield: 82.8 %

Procedure:
Ethyl 1,5-diethylpyrazole-3-carboxylate (20.7 g) in ethanol (250 ml) was treated with 2.5M aqueous NaOH (50.6 ml), and the mixture was stirred overnight. A further 4.2 ml of 2.5M NaOH was then added and stirring continued for a further 1 hour. The mixture was then poured into ethyl acetate/water. The mixture was shaken vigorously and the aqueous phase removed. The pH of the aqueous phase was adjusted to 2.0 using 1M aqueous HCl and saturated with NaCl. The aqueous layer was then extracted with 20% toluene/80% THF (5×100 ml). The combined organic extracts were dried over MgSO4 and evaporated in vacuo. The residue was triturated with hexane/diethyl ether to give the acid as a solid (14.69 g); υmax(CH2Cl2) 3450, 2750, 2596, 1697, cm−1; δ(CDCl3) 1.31 (3H, t, J 7 Hz), 1.44 (3H, t,J 7 Hz) 2.64 (2H, q, J 7 Hz), 4.20 (2H, q, J 7 Hz), 6.64 (1H,s) ppm.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.NCCC[CH2:35][OH:36]>>[OH:36][CH2:35][CH2:12][CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: NCCCCO
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCCCO)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-amino-1-butanol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 330 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.36 (1H, s) 8.10 (1H, t, J=5.66 Hz) 8.02 (1H, d, J=5.47 Hz) 7.77 (1H, d, J=5.27 Hz) 7.48 (1H, d, J=5.47 Hz) 7.31 (1H, dd, J=3.32, 2.54 Hz) 6.82 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.51, 1.76 Hz) 4.39 (1H, t, J=5.17 Hz) 3.36-3.43 (2H, m) 3.18-3.28 (2H, m) 1.53 (2H, dd, J=8.20, 6.83 Hz) 1.36-1.47 (2H, m)
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]([OH:12])[CH3:11])=[CH:8][C:7]([F:13])=[CH:6][C:3]=1[C:4]#[N:5].[Cr](O)(O)(=O)=O>CC(C)=O>[C:10]([C:9]1[C:2]([F:1])=[C:3]([CH:6]=[C:7]([F:13])[CH:8]=1)[C:4]#[N:5])(=[O:12])[CH3:11]
Reactant: CC(O)c1cc(F)cc(C#N)c1F
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Product: CC(=O)c1cc(F)cc(C#N)c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 59 %

Procedure:
To a stirred mixture of 11.6 of 2,5-difluoro-3-(1-hydroxyethyl)-benzonitrile and 290 mL of acetone is added dropwise over 1 hour 90.5 mL of Kilianis' chromic acid (Fieser and Fieser "Reagents for Organic Synthesis" Vol I p 144) at a temperature of 23°-27°. The mixture is stirred 3.5 hours at 25° C. then poured onto 1 L of ice/H2O containing 20 g of Na2S2O5 and extracted with 4×250 mL of CH2Cl2. The CH2Cl2 extracts are washed with H2O, saturated NaHCO3, H2O (250 mL each) and then evaporated in vacuo. The orange residue is stirred with 10 mL of Et2O and 40 mL of hexane for 16 hours, filtered and washed with 10 mL of hexane to give 6.85 g (59% yield) of 3-acetyl-2,5-difluorobenzonitrile, m.p. 80°-83° C. The mass spectrum has an M+1 ion at 182.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O[CH2:18][CH2:19][CH2:20]C)(=O)C>>[C:1]1([C:11]([O:13][CH2:20][CH:19]=[CH2:18])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:7]=[CH:6][C:5]1[CH:10]=[CH:1][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: CCCCOC(C)=O
Product: C=CCOC(=O)c1cccc2ccccc12
Product: C=Cc1ccccc1

Procedure:
The procedure of Example 1 is repeated with naphthalic acid in place of benzoic acid. A solution of a terpolymer of styrene allyl alcohol naphthalate in butyl acetate containing 75 weight percent of the terpolymer is obtained.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][CH2:22][CH:23](OC)[O:24]C)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>O1CCOCC1.[Cl-].[Na+].O>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][CH2:22][CH:23]=[O:24])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(CNC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NCC=O
Reaction time: 7 h
Yield: 94 %

Procedure:
To a solution of 200 mg of 8-(cyclohexylmethoxy)-N-(2,2-dimethoxyethyl)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide in 2 mL of dioxane was added 6 M hydrochloric acid, followed by stirring for 7 hours. To the reaction mixture were added saturated brine and ethyl acetate to carry out a layer separation operation. To the obtained aqueous layer was added a 1 M aqueous sodium hydroxide solution, and the resulting solid was collected by filtration and dried to obtain 165 mg of 8-(cyclohexylmethoxy)-2-methyl-N-(2-oxoethyl)imidazolo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Sn:19]([CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33])([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Sn:19]([C:32]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:33])([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)C(O)c1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)C(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 0.29 h
Yield: 36.2 %

Procedure:
This example demonstrates the synthesis and purification of the acylstannane complex Bu3SnC(O)Ph. In a nitrogen-filled glove box, a 250 mL three-neck round bottom flask was charged with diisopropylamine (1.31 g, 13.0 mmol) and 40 mL dry THF. The solution was cooled to about −30° C. and 2.5 M BuLi in hexane (5.2 mL, 13.0 mmol) was added slowly by syringe. The reaction mixture was allowed to warm to room temperature. A dropping funnel containing Bu3SnCH(OH)Ph (5.00 g, 12.6 mmol) dissolved in 20 mL dry THF, a nitrogen inlet, and a glass stopper were attached to the round bottom flask. The apparatus was removed from the glove box. The reaction setup was connected to a nitrogen-filled Schlenk line. The reaction mixture was cooled to about −78° C., and the Bu3SnCH(OH)Ph/THF solution was added dropwise. After the addition, the reaction mixture was allowed to stir for 15-20 min at −78° C., during which time the color changed from yellow to light orange. The glass stopper was then removed, and 1,1′-(azo dicarbonyl)dipiperidine (3.18 g, 12.6 mmol) was quickly added as a solid. The resulting reaction mixture was allowed to stir for 20-30 min at −78° C., during which time the reaction mixture turned dark orange. The reaction mixture was allowed to warm to about 0° C., and stirred for approximately 30 min at that temperature. The reaction was quenched at 0° C. by the addition of approximately 14 mL saturated ammonium chloride; solids formed in the reaction mixture. The reaction mixture was brought into a nitrogen-filled glove-box, filtered, dried (MgSO4), and concentrated to afford an orange oil. Chromatography on silica gel using 95/5 hexane/ethyl acetate as the eluent afforded 1.80 g of Bu3SnC(O)Ph as a yellow-orange oil. 1H NMR (C6D6) δ 7.9 (2H, d, Hortho), 7.3 (3H, mult, Hmeta & Hpara), 1.8-0.9 (27H, Bu's); 119Sn NMR (CDCl3) δ 87.4 relative to SnMe4; 13C NMR (CDCl3) δ 244.8 (CO), 142.9, 132.8, 128.8, 127.7 (Caromatic), 29.1, 27.3, 13.6, 11.5 (Cbutyl).
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(O)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>ClC1C=CC=CC=1>[C:1]([NH:10][NH:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1
Reactant: NNC(=O)c1ccccc1O
Solvent: Clc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NNc1ccccc1)c1ccccc1O
Temperature: 130 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
15.2 g (0.1 mol) of salicylic acid hydrazide and 12.2 g (0.1 mol) of benzoic acid are suspended in 200 ml of chlorobenzene, 3.0 g (0.038 mol) of pyridine are added and the mixture is heated to 130° C. 13.1 g (0.11 mol) of thionyl chloride are added dropwise at this temperature. The product immediately separates as a white precipitate. After stirring for 1 hour at 130° C, the mixture is cooled and filtered and the product is washed with petroleum ether. N-Salicyloyl-N'-phenyl-hydrazine of melting point 260° C is thus obtained in 62% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(O)(CC)C>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1cc(Cl)nc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]cn2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a suspension of 6-chloro-3H-pyrimidin-4-one (˜0.23 mol) in sec-butanol (525 mL) was added ethyldiisopropylamine (49.7 mL, 0.3 mol) and BOC-piperazine (available from Aldrich; 55.9 g, 0.3 mol). The reaction was stirred at 80° C. for 8 hours, and then allowed to cool to room temperature. The crude reaction mixture was filtered, and washed with sec-butanol to give 4-(6-oxo-1,6-dihydro-pyrimidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester (47.8 g, 74%) LCMS Purity=100% (Rt=1.42). 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 5.34 (s, 1H), 3.56-3.46 (m, 4H), 3.46-3.38 (m, 4H), 1.38 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cc1ccc(COc2cccnc2N)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-amino-3-(4-methylbenzyloxy)pyridine (1.45 g, 0.0068 mol), 4chlorophenyl isothiocyanate (1.38 g, 0.008 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 1.8 g (70%), m.p. 145°-147 ° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[O:18])=[O:7])=[C:28]([CH3:35])[CH:27]=1
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCCc1ccc(O)cc1
Product: CON=C1C[C@@H](C(=O)NCCc2ccc(O)cc2)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 4-(2-aminoethyl)phenol, the title compound was obtained in 83% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(Cl)(Cl)Cl.[Pd]>[CH3:4][N:3]1[C@H:2]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:7][C:6]([C:2]4[CH:11]=[N:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=4)=[CH:5][C:19]=3[CH2:20][CH2:11]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: Clc1cnc2ccccc2n1
Agent: [Pd]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cnc5ccccc5n4)cc3CC[C@@H]12
Reaction time: 16 h
Yield: 67 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (187 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2-chloroquinoxaline (107 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. Added an additional 23 mg of the palladium reagent, and let stir an additional 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 156 mg (67%) of the title compound as a foam. mp 129°-135°. FDMS: m/e=357. α[D]589 =+72.94 (c=0.63, chloroform).
Reaction SMILES: C=O.S(=O)(=O)(O)O.[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])([OH:20])[C:12]1=[O:27])[CH:9]=[CH2:10].[C:28]([O-])(=[O:30])C.[Na+]>C(O)(=O)C.O>[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:28][OH:30])=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]([N:24]([CH3:25])[CH3:26])=[O:23])([OH:20])[C:12]1=[O:27])[CH:9]=[CH2:10]
Reactant: CC(=O)[O-]
Reactant: C=CCN1C(=O)C(O)(CC(=O)N(C)C)c2ccccc21
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCN1C(=O)C(O)(CC(=O)N(C)C)c2cc(CO)ccc21
Temperature: 80 °C
Yield: 113 %

Procedure:
To a suspension of para-formaldehyde (36.2 g, 1.13 mol) in 150 ml of glacial acetic acid, sulfuric acid (22.2 g, 0.226 mol) is added and the mixture heated at 80° C., until a clear solution has been formed. To this, during 45 minutes a solution of 2-(1-allyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (example 26) (62 g, 226 mmol) in a mixture of glacial acetic acid (350 mL) and water (10 mL) is added. The red reaction mixture is stirred for another hour at 80° C., and by then all of the starting material is consumed (HPLC). Sodium acetate (46.3 g, 564 mmol) is added, and after stirring for 5 minutes an orange suspension forms. The solvent is removed on the rotavapor, and to the residue water (about 250 mL) is added. Extraction with chloroform (2×200 mL), drying the organic layer and removal of the solvent leaves the crude title product (77.7 g, quant.) as a red oil. After chromatographic purification white crystals, mp=125° C. 1H-NMR (CDCl3, 300 MHz) δ 2.71, 2.94 (AB, 2H, 2J=16.1 Hz, CH2CONMe2); 2.83, 2.84 (2 s, 3H each, N(CH3)2); 4.19, 4.25 (ABAtlyl, 2H, 2J=16.4 Hz, 3J=5.3 Hz, NCH2); 4.47 (s, 2H, CH2OH); 5.12 (dd, 1H, 2J=1.2 Hz, 3J=10.3 Hz, cis CH═CH2), 5.51 (dd, 1H, 3J=17.3 Hz, trans CH═CH2); 5.75 (ddtr, 1H, CH═CH2); 6.21 (br s, 1H, OH); 6.70 (d, 1H, 3J=7.9 Hz, H-7); 7.15 (dd, 1H, 4J=1.5 Hz, H-6); 7.37 (d, 1H, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.71, 37.84 (N(CH3)2); 38.87 (CH2CONMe2); 42.67 (NCH2); 64.80 (CH2OH); 74.46 (C-3); 109.36 (C-7); 117.73 (CH═CH2); 123.43 (C-4); 128.63 (C-6); 131.00 (C-9); 131.33 (CH═CH2); 136.35 (C-5); 141.89 (C-8); 170.53 (C-11); 176.36 (C-2).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:13][C:12]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:11]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:13][C:12]([C:26]([F:32])([F:31])[C:27]([F:28])([F:29])[F:30])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(N3CCNCC3)s2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[5-(piperazin-1-yl)-thiophen-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.07 mmol) prepared in Step 1, triethylamine (47.0 uL, 0.34 mmol) and methanesulfonyl chloride (11.6 mg, 0.10 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Br-:1].[CH3:2][C:3]1[CH2:11][CH2:10][N+:9]2[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(C)=O.[Br-].C(CC[N+]1C2C=CC=CC=2SC=1C)(=O)C.[Br-].CC1C=C[N+]2C3C=CC=CC=3SC=2C=1>C(O)C.CCOCC>[Br-:1].[CH3:2][C:3]1[CH:11]=[CH:10][N+:9]2[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1=C(c2ccccc2)c2sc3ccccc3[n+]2CC1
Agent: CC(=O)CC[n+]1c(C)sc2ccccc21
Agent: Cc1cc[n+]2c(c1)sc1ccccc12
Agent: [Br-]
Solvent: CCO
Solvent: CCOCC
Solvent: CS(C)=O
Product: Cc1cc[n+]2c(sc3ccccc32)c1-c1ccccc1

Procedure:
1,2-Dihydro-3-methyl-4-phenylpyrido[2,1-b]benzothiazolium bromide is prepared by reacting 3-(2-acetylethyl)-2-benzylbenzothiazolium bromide (1.0 g.) dissolved in 25 ml. of dimethyl sulfoxide. The reaction mixture is heated to reflux for several minutes and cooled. The resulting tan solid precipitate is filtered, washed with ether and dried to give 0.7 g. (72% yield) of product having a melting point of 208°-210° C. 1,2-Dihydro-3-methyl-4-phenylpyrido[2,1-b]benzothiazolium bromide (1.0 g.) is heated in 15 ml. of dimethylsulfoxide to 160° C and held for several minutes. As the mixture cools, 5 ml. each of ether and ethanol are added, precipitating some of the starting material. The addition of more ether causes the slow crystallization of the product, which on recrystallization from ethanol, is obtained in 30% yield (0.3 g.). The product has a melting point of 285°-287° C with decomposition. The NMR spectrum verifies a completely aromatic ring system. When this example is repeated, except that 3-(2-acetylethyl)-2-methylbenzothiazolium bromide is used as the starting material, there is obtained, in somewhat lower yield, 3-methylpyrido[2,1-b]benzothiazolium bromide, which is a useful intermediate in preparing dyes in accordance with this invention.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][CH3:22])[CH2:16]3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)(Cl)Cl>[CH:11]1[C:12]2[CH:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([N:21]([C:30](=[O:32])[CH3:31])[CH3:22])[CH2:16]3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNC1CCCN(C2c3ccccc3Oc3ccccc32)C1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N(C)C1CCCN(C2c3ccccc3Oc3ccccc32)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1.0 g. of 1-(9-xanthenyl)-3-methylaminopiperidine and 2.0 g. of triethylamine in 25 ml. of dry chloroform is treated at 0°C. with 0.5 g. of acetic anhydride in 2 ml. of dry chloroform. The mixture is refluxed with stirring for two hours and then poured into ice water. The chloroform layer is washed with water, dried over potassium carbonate, and the solvent is removed in vacuo to give 1-(9-xanthenyl)-3-(N-acetyl-N-methylamino)-piperidine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[OH:10][C@H:11]([CH3:15])[C:12](O)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:12]([C@H:11]([OH:10])[CH3:15])=[N:9][N:8]=2)[N:3]=1
Reactant: C[C@@H](O)C(=O)O
Reactant: NNc1ccc(Cl)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)c1nnc2ccc(Cl)nn12

Procedure:
A mixture of 3-chloro-6-hydrazinopyridazine (1.44 g, 9.96 mmol), (R)-2-hydroxypropanoic acid (0.90 g, 10 mmol, i.e. D-lactic acid) and p-TsOH.H2O (2.37 g, 12.4 mmol) in toluene was refluxed overnight. Some oil was formed at the bottom of the flask. LC-MS of this oil showed the desired product was formed. Toluene was poured off, and the oil residue was suspended in water (10 mL), then basified with 3 N aq. NaOH to pH=10. This aqueous solution was extracted with EtOAc (3×30 mL), and the combined organic phases were washed with brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation under reduced pressure afforded the title compound as an off-white solid. MS (ES+): 199/201 (3/1) [MH+]. 1H NMR (400 MHz, CDCl3): δ=1.88 (d, J=6.8 Hz, 3H), 2.97 (d, J=6.8 Hz, 1H, —OH), 5.51 (m, 1H), 7.15 (d, J=9.6 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H).