Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)=[O:20])[CH3:18])=[O:15])[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:32][I:33]>C(Cl)(Cl)Cl>[I-:33].[CH3:32][N:28]1[C:29]2[C:24](=[CH:23][C:22]([NH:21][C:19](=[O:20])[C@H:17]([CH3:18])[NH:16][C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])=[CH:31][CH:30]=2)[CH:25]=[CH:26][CH2:27]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)Nc1ccc2ncccc2c1
Reactant: CI
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)Nc1ccc2c(c1)C=CCN2C
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To 29 mg (0.06 mmol) of VII in 5 ml of chloroform was added 1 ml of methyliodide. After the mixture was stirred for 24 hours at room temperature, the solvent and alkylating agent were removed in vacuo to afford a thick orange oil. Crystallization from ethanol-ether produced 36 mg (90% yield), of a finely divided yellow powder: mp 135° C. decomposes; Rf(E)=0.06. Analysis calculated for C24H27N4O4I: C, 51.26; H, 4.84; N, 9.96. Found: C, 50.05; H, 5.23; N, 9.85. Fast atom bombardment mass spectrum: calculated for MW (435)+I-. Found: 435 (M+).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]3[C:32](=[C:33]([CH3:35])[CH:34]=2)[NH:31][N:30]=[CH:29]3)[CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:35][C:33]1[CH:34]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:27]=[C:28]2[C:32]=1[NH:31][N:30]=[CH:29]2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2cn[nH]c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2cn[nH]c12

Procedure:
60 mg (0.23 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 60 mg (0.23 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-1H-indazole and 100 μL (0.58 mmol) DIPEA in 0.8 mL DMF were stirred at RT over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous saturated NaHCO3 solution. The precipitate formed was suction filtered and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:25][CH3:26].[C:27]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>COCCOC>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:37]5[CH:38]=[CH:39][C:34]([C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:33])=[CH:35][CH:36]=5)[C:3]([CH2:25][CH3:26])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: CCc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-ethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (38 mg; 0.10 mmol) was dissolved in 1 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. 4-(tert-butoxycarbonyl)phenyl-boronic acid (29 mg, 0.13 mmol), 0.1 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 5.6 mg, 0.0048 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The organic layer was concentrated in vacuo to yield tert-butyl 4-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-ethylpyridin-2-yl)benzoate which was used without further purification.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[NH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[CH:7][C:6]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[NH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([S:17]([NH:3][CH2:1][CH3:2])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[CH:7][C:6]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: Nc1ncc(-c2cccc(S(=O)(=O)Cl)c2)cc1-c1nc2ccccc2o1
Reactant: CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cccc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)c1

Procedure:
Ethylamine (2M in methanol, 0.117 ml) was added in one portion to a solution of 3-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]benzenesulphonyl chloride (0.045 g) and N-ethyl-N-isopropylpropan-2-amine (0.030 ml) in THF (2 ml) at ambient temperature, and the resultant mixture stirred for 20 hours. The mixture was then evaporated to dryness in vacuo and redissolved in NMP (2 ml), filtered and purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-N-ethyl-benzenesulphonamide (0.007 mg); Mass Spectrum: M+H+ 395.13; RT 2.59 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5](SC)=[C:6]([CH3:8])[CH:7]=1.O[O:13][S:14]([O-:16])=O.[K+].[CH3:18]O>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:14]([CH3:18])(=[O:16])=[O:13])=[C:4]([CH3:11])[CH:3]=1
Reactant: O=S([O-])OO
Reactant: CSc1c(C)cc(Br)cc1C
Reactant: CO
Agent: [K+]
Product: Cc1cc(Br)cc(C)c1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Dissolve 5-bromo-1,3-dimethyl-2-methylsulfanyl-benzene (555 mg, 2.42 mmol) in methanol (30 mL) and treat with oxone (6.0 g, 9.8 mmol). Stir the mixture at ambient temperature for 1 hour. Filter the suspension through silica gel and elute with CH2Cl2 (100 mL). Evaporate the filtrate to give 316 mg (50%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.[CH3:29][N:30]([CH3:35])[CH:31]1[CH2:34][NH:33][CH2:32]1>>[CH3:29][N:30]([CH3:35])[CH:31]1[CH2:34][N:33]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=3)=[O:16])=[CH:4][N:3]=2)[CH2:32]1
Reactant: CN(C)C1CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Product: CN(C)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncc(F)c2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 236 using 2-chloro-5′-fluoro-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Stage 236.1) and N,N-dimethylazetidin-3-amine. The crude product was purified by preparative HPLC (Condition 14). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was removed. The aq. phase was extracted with DCM and the combined organic layers were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to afford the title product as white crystals. HPLC (Condition 10) tR=6.01 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=476.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.99 (s, 6H) 2.95-3.04 (m, 1H) 3.53 (dd, J=9.19, 5.28 Hz, 2H) 3.69-3.77 (m, 2H) 7.36 (d, J=8.99 Hz, 2H) 7.87 (d, J=8.99 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.54-8.57 (m, 1H) 8.63 (d, J=2.74 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 10.23 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(=O)OC[C@H]1CC[C@H](CCNC(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To an ice-cooled and stirred solution of the crude 26.0 g trans-acetic acid 4-(2-tert-butoxycarbonylamino-ethyl)-cyclohexylmethyl ester and 5.77 mL (92.6 mmol, 1.1 eq) of CH3I in 300 mL of DMF was added within 15 min 4.04 g (92.58 mmol, 1.1 eq) of NaH (55% in oil). After stirring at RT over night, additional 1.65 mL (26.5 mmol, 0.3 eq) of CH3I and 1.16 g (26.5 mmol, 0.3 eq) of NaH were added and the reaction mixture was then stirred at RT for another 1 h. It was then partitioned between ether, 1M HCl solution and water. The organic layer was dried over MgSO4, concentrated under reduced pressure and the residue was then chromatographed on silica gel with a 4:1 v/v mixture of n-hexane and EtOAc as the eluent giving 18.7 g (68% over 3 steps) of pure trans-acetic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester as colorless viscous oil, MS: 214 [(M-(tert-butoxycarbonyl))H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([NH2:11])=[O:10].O.[C@:22]12([CH2:32][S:33]([OH:36])(=[O:35])=[O:34])[C:29]([CH3:31])([CH3:30])[CH:26]([CH2:27][CH2:28]1)[CH2:25][C:23]2=[O:24]>CC(C)=O>[C:22]12([CH2:32][S:33]([OH:36])(=[O:34])=[O:35])[C:29]([CH3:31])([CH3:30])[CH:26]([CH2:27][CH2:28]1)[CH2:25][C:23]2=[O:24].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: NC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Yield: 35.5 %

Procedure:
A solution of 5 g (16.31 mmol) of (±)-(2-chloro-phenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl) acetamide (prepared as given in Examples 10-15) and 4.15 g (16.2 mmol) (1S)-(+)-camphor-10-sulphonic acid monohydrate in 100 mL acetone was kept warm for 20 hrs followed by storing it in temperature below 10° C. A few crystals appeared, the mother liquor was concentrated further and repeated recrystallization, followed by storage in cold condition for few days gave 3.1 g (70% yield) of (S)-2-(2-chloro-phenyl)-(4,5,6,7-tetrahydrothieno[3,2-c]pyrid-5-yl)acetamide (+)-camphor sulfonic acid salt. The salt was further purified by recrystallization in acetone, until constant specific optical rotation was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]#[N:10].[CH2:11]([N:18]1[CH2:23][CH:22]2[CH2:24][CH:19]1[CH2:20][NH:21]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH:22]2[CH2:24][CH:19]1[CH2:20][N:21]2[CH2:8][C:9]#[N:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCCl
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CCN1CC2CC1CN2Cc1ccccc1

Procedure:
Finely ground potassium carbonate, as well as 1.3 mL of freshly distilled chloroacetonitrile were added to a solution of 3 g of 2-benzyl-2,5-diazabicyclo[2.2.1]heptane in 40 mL of anhydrous toluene and refluxed for 10 hours with vigorous stirring. The solution was cooled, filtered and evaporated. Bulb tube distillation (boiling point: 110°-120° C. at 0.01 mbar) resulted in 3.57 g of 140 as a colorless oil (97% of the theoretical yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[C:14]1([C:20]2[C:21]3[C:26]([C:27]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:28]4[C:33]=2[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29]4)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=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.C(=O)([O-])[O-].[Na+].[Na+]>[C:14]1([C:20]2[C:33]3[C:28]([C:27]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:26]4[C:21]=2[CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:3]=2)[CH:24]=[CH:25]4)=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
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+]
Product: c1ccc(-c2cccc(-c3ccc4c(-c5ccccc5)c5ccccc5c(-c5ccccc5)c4c3)n2)cc1
Yield: 84.6 %

Procedure:
2-Bromo-6-phenylpyridine 2.5 g (11 mmol), 9,10-diphenylanthracene-2-boronic acid 4.9 g (13 mmol) and tetrakis(triphenylphosphine)palladium 0.25 g (0.22 mmol) were dissolved in 60 mL of 12-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 30 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the solution was filtered, and a solid matter obtained was washed with water, methanol and toluene to obtain 4.5 g (yield: 84%) of a greenish white solid matter. Mass spectral analysis of the above solid matter resulted in confirming that the measured value m/e was 483 versus a molecular weight of 483.20 and that it was the aimed compound 1
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:31]2[CH2:30][CH2:29][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:33][CH2:32]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropylethylamine (4.00 ml) was added to a solution of 4-bromobenzenesulfonyl chloride (3.00 g) and 1-(tert-butoxycarbonyl)piperazine (2.40 g) in methylene chloride (50 ml) at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1→1:1), followed by reprecipitation in a hexane—methylene chloride system, whereby the title compound (4.47 g) was obtained as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH:17]=3)[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH+]1C=CC=CC=1.O>CN(C)C=O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:12]1[CH:11]=[CH:10][C:6]2[C:7](=[O:9])[CH:8]=[C:3]([C:1]3[NH:36][N:35]=[N:34][N:2]=3)[O:4][C:5]=2[CH:13]=1
Reactant: N#Cc1cc(=O)c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(-c2nnn[nH]2)oc2cc(COc3cccc(OCc4ccc5ccccc5n4)c3)ccc12
Temperature: 100 °C

Procedure:
0.72 g of 2-cyano-7-(3-(quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran, 0.54 g of sodium azide and 0.96 g pyridinium chloride are combined in 20 ml of dimethylformamide and heated for 3 hours at 100° C. The mixture is poured into water and the precipitate filtered off. This crude product is recrystallized from dimethylformamide to give 5-(7-(3-(quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran-2-yl)tetrazole; m.p. 246° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(OCCCCCl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COc1ccc(OCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(4-chlorobutoxy)-4-methoxybenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[N:27]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:33]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)(=[O:35])=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)N1CCCCC1
Yield: 29 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (200 mg, 0.510 mmol) and 1-piperidinesulfonyl chloride (0.201 mL, 1.531 mmol) the title compound of Step A was obtained as a yellow foam (193 mg, 41% and 29% yield, repeated twice). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (s, 1H), 8.15-8.44 (m, 1H), 7.45-7.67 (m, 1H), 7.22-7.42 (m, 2H), 6.61 (d, J=5.4 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.52 (t, J=4.7 Hz, 4H), 3.03 (t, J=5.0 Hz, 4H), 1.24-1.66 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[C:15]([O:17]C)=O.[CH3:19][N:20]=[C:21]=[S:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:8]([N:5]1[CH2:6][CH2:7][C:2]2[NH:1][C:21](=[S:22])[N:20]([CH3:19])[C:15](=[O:17])[C:3]=2[CH2:4]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN=C=S
Reactant: COC(=O)C1=C(N)CCN(Cc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1c(=S)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Temperature: 20 °C

Procedure:
788 g of methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate from a) were dissolved in 2.5 l of toluene, and 447 g of methyl isothiocyanate and 625 ml of triethylamine were added, with stirring. After stirring for 24 h at an internal temperature of 100° C., the mixture was allowed to cool to 20° C. and the precipitate was filtered off with suction and washed with toluene. After drying, this gave 420 g of crude 6 benzyl-3-methyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrido[4,3-d]pyrimidin-4-one, which was reacted further in c).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[ClH:17].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1)=[O:21]
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccccc3Cl)n2)CC1
Product: Cl
Yield: 172.4 %

Procedure:
Prepare according to procedure in Example 66 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol), 2-chlorobenzoyl chloride (126 μL, 0.998 mmol), and 1,4-dioxane (10 mL) to yield 340 mg (95%) of the title compound: mass spectrum (ion spray): m/z=359.3 (M+1); Analysis calc'd for C19H24N4OCl2.0.5H2O: C, 56.44; H, 6.23; N, 13.86. Found: C, 56.21; H, 5.91; N, 14.23. mp 90–2° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[CH:22]=[CH:21][O:20][CH:19]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[CH:22]=[CH:21][O:20][CH:19]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1ccoc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccoc1
Yield: 66.1 %

Procedure:
8.0 g of ethyl 3-(4-fluorobenzoylamino)-3-(3-furylcarbonyl)propionate, 40 ml of chloroform and 20 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 5.0 g of ethyl 2-[2-(4-fluorophenyl)-5-(3-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 65.8%
Reaction SMILES: I[C:2]1[C:3]([NH2:14])=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:29](=O)([O-])[O-:30].[Cs+].[Cs+]>CO.[Cu]I>[CH3:29][O:30][C:2]1[C:3]([NH2:14])=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(-c2ccccc2)ncc1I
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1cnc(-c2ccccc2)cc1N
Temperature: 130 °C
Yield: 44.7 %

Procedure:
A stirred suspension of 6.20 g (20.9 mmol) 5-iodo-2-phenyl-pyridin-4-ylamine, 319 mg (1.68 mmol) copper(I) iodide, 453 mg (2.51 mmol) 1,10-phenanthroline and 13.6 g (41.9 mmol) cesium carbonate in 40 ml methanol was heated at 130° C. for 20 min in a microwave oven. The resulting mixture was then cooled to room temperature and concentrated in vacuo. The residue was resuspended in 500 ml dichloromethane and extracted three times with 200 ml portions of 1 M aq. hydrochloric acid. The combined acid extracts were then made basic by addition of 5 N aq. sodium hydroxide solution and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (methanol/dichloromethane 3/97-5/95) afforded 1.87 g (45%) 5-methoxy-2-phenyl-pyridin-4-ylamine as a dark red oil. ES-MS m/e (%): 201 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1.[BH4-].[Na+].Cl>COCCOC.O1CCCC1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1
Reactant: Cc1cccc(C)c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1cccc(C)c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 83.5 %

Procedure:
2′,6′-Dimethylbiphenyl-3-carbaldehyde (18.5 g, 88.0 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (100 mL) and tetrahydrofuran (100 mL), and sodium borohydride (1.66 g, 44.0 mmol) was added under ice-cooling and the mixture was stirred at the same temperature for 3 hrs and then at room temperature for 3 hrs. Dil. hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-50% ethyl acetate/hexane) to give the title compound (15.6 g, yield 83%) as a colorless oil.