Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH3:20][O:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH:25]3[CH2:32][C:33](O)=[O:34])[CH2:23]1)[CH2:29]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:20][O:21][C:22]12[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH:25]3[CH2:32][C:33]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:34])[CH2:31]1)[CH2:29]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: COC12CC3CC(C1)C(CC(=O)O)C(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC12CC3CC(C1)C(CC(=O)N1CC4CC[C@](C)(C1)C4(C)C)C(C3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 29.3 μl was added to a methylene chloride 1 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 33.7 mg and stirred at 0° C. for 30 min. 5-methoxy-2-adamantyl acetic acid 36.2 mg and WSC 40.3 mg were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 20.5 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(5-methoxy-2-adamantylacetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 3 ml solution of lithium aluminum hydride 7.4 mg and refluxed under heating for 1.5 hours. The reaction mixture was cooled, then water was added thereto and then insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=20:1-10:1) to obtain the product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N+]=[N-])[CH:6]=[CH:7][CH:8]=1.[CH:24]([CH:26]=[CH2:27])=[O:25]>ClCCl.CCCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH2:27][CH:26]2[CH:24]=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: C=CC=O
Reactant: [N-]=[N+]=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=CC1CC1(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Temperature: 55 °C

Procedure:
A solution of bis[3-(trifluoromethyl)phenyl]diazomethane, prepared as in Example 84 from 3,3'-(trifluoromethyl)benzophenone hydrazone (29.9 g) and activated manganese dioxide (30 g) in dichloromethane (150 mL) was added to a solution of acrolein (9.9 mL) in heptane (90 mL) over 15 minutes at 40° C. The solution was heated at 55° C. for 5.5 hours, then the dichloromethane was distilled off and replaced with heptane (100 mL). After the mixture was heated at 90° C. overnight, the solvent was removed in vacuo and the residue was purified by HPLC (dichloromethanehexane; 1:1). Evaporation of the appropriate fractions yielded 30.5 g of 2,2-bis[3-(trifluoromethyl)phenyl]cyclopropanecarboxaldehyde. Crystallization of a portion from hexane gave the analytical sample, 106°-108° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([Cl:28])[CH:3]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.CC(C)([O-])C.[K+]>COCCOC.O.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>[Cl:28][C:4]1[CH:3]=[C:2]([C:30]2[O:29][CH:33]=[CH:32][CH:31]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:26][CH3:27])(=[O:10])=[O:9]
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccco2)cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-2-chloro-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E104) (150 mg, 0.31 mmol) and 2-furanylboronic acid (69 mg, 0.62 mmol) in DME (3 ml) was added potassium tert-butoxide (312 mg, 2.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then purified using an SCX cartridge followed by mass directed autoprep HPLC to afford the title compound (E308). MS (ES+) m/e 476/478 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([CH2:11][CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=[C:5]2[O:4][CH2:3]1.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.[O:43]1CCOCC1>>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([CH2:11][CH2:12][N:33]3[CH2:34][CH2:35][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)[CH:10]=[C:5]2[O:4][C:3]1=[O:43]
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cnc3c(c2)OCN3C)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Product: Cn1c(=O)oc2cc(CCN3CCN(c4ccccc4)CC3)cnc21
Temperature: 25 °C

Procedure:
3-methyl-6-[2-(p-toluenesulfonyloxy)ethyl]oxazolo[4,5-b]pyridin-2(3-one of Preparation 15 (210 mg, 1.2 mmol) is dissolved in 1,4-dioxane (8 ml). N-phenyl-piperazine (0.10 ml, 1.38 mmol) and triethylamine (0.18 ml, 1.3 mmol) are added in succession to the reaction mixture. Stirring is maintained at room temperature for 24 hours. After the solvent has been evaporated off under reduced pressure, the residue is taken up in water. Extraction is carried out with dichloromethane and the organic phase is dried over magnesium sulfate and filtered, and then the solvent is evaporated off. The title product is purified by chromatography on silica gel (eluant: dichloromethane/methanol: 95/5). The yield obtained is 91%. ##STR66##
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[C:24]2[S:20][C:21](=[O:26])[NH:22][C:23]2=[O:25])=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC(=O)C(=Cc2cccc(-c3ccc(OC(F)(F)F)cc3)c2)S1

Procedure:
To a solution of 3-formyl-(4′-trifluoromethoxy-1,1′-biphenyl) (0.31 g, 1.16 mmol) and 2,4-thiazolidinedione (0.164 g, 1.4 mmol) in toluene (20 mL) were added piperidine (0.015 mL, 0.152 mmol) and benzoic acid (0.021 mg, 0.175 mmol), and the reaction was refluxed for 3 h with continuous removal of water. The solvent was then distilled off and the residue was crystallized from ether-pet ether to yield titled product as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[N:12][NH:13][C:14]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:24]>C(#N)C>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[N:12][N:13]=[C:14]2[Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(=O)[nH]ncc2c1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2c(Cl)nncc2c1OCc1ccccc1
Yield: 97.4 %

Procedure:
A suspension of 5-benzyloxy-6-methoxy-2H-phthalazin-1-one (4 g, 14.17 mmoles), prepared as described in example 69, in acetonitrile (40 ml), and POCl3 (6.5 ml, 70.8 mmoles) was heated at 80° C. under stirring up to dissolution. After 30 minutes the solution was evaporated and the residue taken up in CH2Cl2 (100 ml), washed with a cold solution of NaOH (20 ml) and water (200 ml) and extracted in ethyl ether (twice) and ethyl acetate (once) checking the pH to be around 7. The organic phase was washed with a saturated NaCl solution, anhydrified and concentrated to give 4.15 g of the title compound (yield: 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10]2[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.O>CS(C)=O>[CH3:16][O:15][C:13]([C:11]1[C:10]2[C:17](=[O:22])[CH:18]([Br:23])[CH2:19][CH2:20][CH2:21][C:9]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:12]=1)=[O:14]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a solution of 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole 1,3-dicarboxylic acid 3-methyl ester 1-tert-butyl ester(1.1 g, 3.6 mmol) in DMSO(20 mL) is added 1,3-dibromo-5,5-dimethylhydantoin(1.5 g, 5.4 mmol) portion wise with the aid of a cooling bath and the resulting mixture is stirred for 18 h at RT. Water is added and the reaction mixture is extracted with ether. The combined ether layers are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (10% EtOAc/Hex to 25% EtOAc/Hex) to yield 915 mg of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a bright yellow oil (66%). 1H NMR (CDCl3) 1.59 (s, 9H), 1.72-1.84 (m, 1H), 2.12-2.25 (m, 2H), 2.43-2.58 (m, 1H), 3.05-3.14 (m, 1H), 3.40-3.49 (m, 1H), 3.80 (s, 3H), 4.75 (m, 1H), 7.79 (s, 1H) Step 2: A mixture of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(467 mg, 1.2 mmol), 4-Amidinopyridine hydrochloride(953 mg, 6.1 mmol), and NaHCO3(813 mg, 9.7 mmol) in dioxane(20 mL) is refluxed for 20 h. After cooling to RT, MeOH(5 mL) is added and the mixture is filtered. The filtrate is concentrated in vacuo and the brown residue is purified by flash chromatography on silica gel (10% MeOH/CH2Cl2) to yield 197 mg of 2-Pyridin-4-yl-4,5,6,7-tetrahydro-3H-1,3,7-triaza-cyclopenta[e]azulene-9-carboxylic acid methyl ester as a yellow solid (53%). 1H NMR (CDCl3) 2.06 (quint, 2H), 2.98 (t, 2H), 3.04 (t, 2H), 3.91 (s, 1H), 7.46 (s, 1H), 7.76 (d, 2H), 8.28 (br s, 1H)8.56 (d, 2H)
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[Na+].Cl[CH2:22][O:23][CH3:24]>CN(C=O)C>[CH3:22][O:23][CH2:24][O:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: Cc1ccc(C(=O)N[C@@H](CO)CC(C)C)cc1C
Reactant: COCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COCOC[C@@H](CC(C)C)NC(=O)c1ccc(C)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of (R)—N-(1-hydroxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide (Example 71a) (0.24 mmol) dissolved in dry DMF (2 mL) was added at 0° C. powdered NaOH (0.36 mmol, 14.5 mg, 1.5 eq) and the mixture was stirred for 1 hr at 0° C. Then chloro-methoxy-methane (19.3 μl, 1 eq) was added and the reaction stirred at 0° C. for 1 hour. The reaction was quenched with water (30 mL) and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by preparative TLC (20% ethyl acetate/hexanes) to give 37.7 mg of (R)—N-(1-(methoxymethoxy)-4-methylpentan-2-yl)-3,4-dimethylbenzamide (53%). 1H NMR (500 MHz, CDCl3): δ 0.98-1.00 (t, 6H), 1.49-1.53 (m, 1H), 1.58-1.64 (m, 1H), 1.69-1.73 (m, 2H), 2.32-2.33 (d, 6H), 3.38-3.39 (t, 3H), 3.64-3.72 (ddd, 2H), 4.41-4.44 (m, 1H), 4.65-4.69 (dd, 2H), 6.37-6.39 (d, 1H), 7.19-7.21 (d, 1H), 7.50-7.52 (dd, 1H), 7.60 (sb, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].C(N(CC)CC)C.[F:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]([CH2:28][C:29](=O)[CH2:30][CH2:31][N:32]([O:34][CH3:35])[CH3:33])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[C:23]([O:22][C:21]([N:20]([CH2:28][CH:29]([NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:30][CH2:31][N:32]([O:34][CH3:35])[CH3:33])[CH2:19][C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:38][CH:37]=1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)CN
Reactant: CON(C)CCC(=O)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC(CCN(C)OC)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of glycine methyl ester (2.78 g, 22.1 mmol) in anhydrous THF (13.5 mL) was treated with triethylamine (3.03 mL, 21.6 mmol), tert-butyl 4-fluorobenzyl{4-[methoxy(methyl)amino]-2-oxobutyl}carbamate (1.50 g, 4.23 mmol) in anhydrous THF (8.5 mL), sodium triacetoxyborohydride (5.11 g, 24.1 mmol), and acetic acid (485 μL, 8.46 mmol). The mixture was stirred at ambient temperature under inert atmosphere for 42 h. Saturated aqueous NaHCO3 solution was added and the mixture was stirred until gas evolution ceased. The mixture was extracted into EtOAc, and the aqueous layer was saturated with NaCl and extracted into EtOAc again. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to a pale yellow oil. Purification by silica gel chromatography using gradient elution (hexanes to 40% EtOAc/hexanes to EtOAc) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.19 (br s, 2H), 7.02-6.98 (m, 2H), 4.56-4.37 (m, 2H), 3.72 (s, 3H), 3.49 (s, 3H), 3.39 (br s, 2H), 3.05 (br s, 1H), 2.97 (br s, 1H), 2.66 (br s, 2H), 2.55 (s, 3H), 1.68-158 (m, 4H), 1.47 (br s, 9H). ES MS (M+1)=428.4.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl.C([O-])([O-])=O.[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13][N:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1
Reactant: N#Cc1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(C#N)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.9 %

Procedure:
A flask charged with imidazole-4-carbonitrile (0.50 g, 5.2 mmol) (Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with ethyl acetate (EtOAc) (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.80 g (70%) of the title compound as a colorless oil: Mass spectrum (CI(CH4), m/z) Calcd. for C10H17N3OSi, 224.1 (M+H), found 224.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:10]=[C:5]2[C:4]([N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C:20]2=[O:32])=[CH:3]1.[ClH:33]>C(Cl)Cl.CCOC(C)=O>[ClH:33].[CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:10]=[C:5]2[C:4]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][C:20]2=[O:32])=[CH:3]1
Reactant: Cn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)c2ccc(OCc3ccccn3)nc21
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cc(N2CCNCC2=O)c2ccc(OCc3ccccn3)nc21
Temperature: 25 °C
Reaction time: 67 h

Procedure:
To a solution of tert-butyl 4-[1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-oxopiperazine-1-carboxylate (0.278 g, 0.653 mmol) in DCM (10 mL) is added a saturated solution of hydrogen chloride in EtOAc (6 mL) at room temperature, and the reaction mixture stirred at room temperature for 67 h. The solvent is carefully decanted off and the residue triturated with Et2O/MeOH. The solvent is again decanted off and the residue further triturated with Et2O/MeOH. The resultant residue is dried in vacuo for 3 h. to give the title compound (0.217 g, 0.580 mmol) as a pale yellow solid. MS (m/z): 338 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=O)[C:4]=2[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:49][C:50]([C:52]1([NH2:61])[CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1)=[O:51])[CH3:48]>CO.C(Cl)Cl.C(Cl)Cl>[CH2:47]([O:49][C:50]([C:52]1([NH:61][C:9]([C:8]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=3[S:6][CH:7]=2)=[O:11])[CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1)=[O:51])[CH3:48]
Reactant: O=C(O)c1csc2ccc(Cl)cc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2csc3ccc(Cl)cc23)Cc2ccccc2C1
Yield: 96.3 %

Procedure:
To a 40 mL vial containing a stirring bar, 5-chloro-benzo[b]thiophene-3-carboxylic acid (518 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) and DIPEA (0.95 mL, 8.0 mmol) are added. Then 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added. The reaction is allowed to stir for 20 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.64 g of off white solid. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 20% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% over 8 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 7 through 31 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.94 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[C:14](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of 2-chloro-5-nitroisonicotinic acid (Intermediate 25A) (0.64 g, 3.17 mmol) in DMF (15 mL) under nitrogen was added sodium carbonate (1.0 g, 9.51 mmol). Reaction cooled in an ice bath and methyliodide (1.35 g, 9.51 mmol) was added dropwise. After complete addition, reaction allowed to warm to room temperature and stirred overnight under nitrogen. The reaction mixture was filtered and concentrated. The resultant crude material was purified by a 20 g silica column eluting with 40% ethylacetate in hexane to afford methyl 2-chloro-5-nitroisonicotinate (0.62 g, 2.86 mmol).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:41]=[CH:40][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22](OS(C(F)(F)F)(=O)=O)=[N:21]2)=[CH:17][CH:16]=1.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C:22]2[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][N:20]([CH2:19][C:18]3[CH:40]=[CH:41][C:15]([O:14][CH2:13][C:3]4[N:4]=[C:5]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)[O:6][C:2]=4[CH3:1])=[CH:16][CH:17]=3)[N:21]=2)=[CH:46][CH:45]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccc(OC)cc1
Yield: 24.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (790 mg) was added to a mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-trifluoromethanesulfonyloxy-1H-pyrazol-4-yl]propionate (2.00 g), 4-methoxyphenylboronic acid (0.77 g), 2N aqueous sodium carbonate solution (5.0 ml), ethanol (5 ml), and toluene (100 ml). This mixture was refluxed under an argon atmosphere for 13 hours. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-(4-methoxyphenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (450 mg, yield: 24%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](OC(=O)C)(=O)[CH3:14]>C(O)(=O)C>[CH3:13][C:14]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cnc2ccccc2c1S
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2cnc3ccccc3c2s1

Procedure:
A suspension of 3-aminoquinoline-4-thiol (about 12 g) in a mixture of acetic anhydride (150 mL) and acetic acid (300 mL) was heated at reflux overnight. The reaction mixture was filtered to remove a fine solid. The filtrate was evaporated under vacuum. The residue was diluted with ethanol then refluxed for 30 minutes. The solution was concentrated under vacuum and the residue diluted with water. The aqueous residue was made basic with sodium hydroxide and then extracted with diethyl ether. The ether extracts were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated to provide 12.8 g of crude product. A sample (800 mg) was recrystallized from hexane to provide 2-methylthiazolo[4,5-c]quinoline as yellow needles, m.p. 95.5-97.5° C.