Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9](I)=[C:8]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:7]=1)[CH3:2].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[F-].[Cs+].O>COCCOC.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.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([F:38])([F:37])[F:26])=[CH:29][CH:30]=2)=[C:8]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(OCC(F)(F)F)c(I)c(OCC(F)(F)F)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c(OCC(F)(F)F)c1
Temperature: 100 °C
Yield: 64.9 %

Procedure:
To a solution of [4-iodo-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (0.8 g, 1.65 mmol) in DME (anhydrous, 15 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (0.4 g, 2.10 mmol), CsF (0.6 g, 3.95 mmol), and Pd(PPh3)4 (0.3 g, 0.26 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give [2,6-bis-(2,2,2-trifluoro-ethoxy)-4′-trifluoromethyl-biphenyl-4-yl]-acetic acid ethyl ester (0.54 g, 70%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.64 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 6.68 (s, 2H), 4.28-4.16 (6H), 3.63 (s, 2H), 1.29 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ 170.6, 155.3, 136.1, 135.5, 131.0, 129.4, 129.0, 124.4 (q, 3JCF=3.9 Hz), 124.2, 122.9, 119.0, 109.2 (two signals), 66.5 (q, 2JCF=35.5 Hz), 61.3, 41.5, 14.2.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]1[C:22]2([CH2:27][NH:26][CH2:25][CH2:24][NH:23]2)[CH2:21]1.CS(C)=O>C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:27][C:22]5([CH2:20][CH2:21]5)[NH:23][CH2:24][CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: C1CNC2(CC2)CN1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC4(CC4)C3)c(F)cc2c1=O
Temperature: 120 °C

Procedure:
200 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 200 mg of crude 4,7-diazaspiro[2.5]octane 25 were added to 10 ml of dimethyl sulfoxide followed by the addition of 0.3 ml of triethylamine. The mixture was heated on a bath of 120° C. for 2 hours. The solvent was then removed under reduced pressure and the residue was subjected to silica gel column chromatography, eluting with chloroform-methanol-water=15:3:1 (v/v). The crude product obtained from the fraction containing the desired compound Was recrystallized from ethanol-concentrated aqueous ammonia to give 160 mg of title compound 37.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:9]12([O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=3[O:2]1)[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: O=C1CCCC1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)OC1(CCCC1)O2
Reaction time: 18 h

Procedure:
Catechol (11 g) and cyclopentanone (9 ml) were heated under reflux in toluene (150 ml) with p-toluenesulfonic acid (0.18 g) with a water trap. After 18 hours, the mixture was concentrated and purified by chromatography (silica gel, heptane/ethyl acetate 4:1). This resulted in the product with the molecular weight of 176.22 (C11H12O2); MS(ESI): 177 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][NH2:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21].O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][NH:12][C:25](=[O:26])[CH2:24][O:23][C:20](=[O:22])[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.04 g of hydrazine carboxylic acid benzyl ester in 40 mL of dichloromethane was added 2.57 mL of triethylamine. Under ice cooling, a solution of 1.32 mL of acetoxyacetylchloride in 20 mL of dichloromethane was added dropwise over 25 minutes, and stirred at room temperature for 1 hour. The reaction solution was added with water, extracted with ethyl acetate, and the resultant organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting solid product was washed with diethyl ether and collected by filtration, to give 1.92 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:42]([NH2:45])(=[O:44])=[O:43].[C:46](Cl)(=[O:50])[CH:47]([CH3:49])[CH3:48]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:11][CH2:12][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:4][C:3]=1[S:42]([NH:45][C:46](=[O:50])[CH:47]([CH3:49])[CH3:48])(=[O:43])=[O:44]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(Cl)c(S(=O)(=O)NC(=O)C(C)C)c2)CC1
Yield: 80 %

Procedure:
2-Chloro-N-isobutyryl-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene-sulfonamide (19 mg, 80%) was obtained as amorphous solid from 2-chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide and isobutyryl chloride following the procedure outlined in example 476. 1H NMR (300 MHz, DMSO-d6, 100° C.) δ 7.85-7.76 (m, 2H), 7.60-7.50 (m, 2H), 7.42-7.28 (m, 5H), 7.26 (m, 1H), 7.18-7.12 (m, 2H), 4.76 (br, 1H), 3.36-3.08 (m, 7H), 2.53-2.27 (m, 7H), 2.04-1.82 (m, 10H), 1.69 (d, J=7.6 Hz, 2H), 0.95 (d, J=6.6 Hz, 6H). HRMS m/z (M+H)+ calcd: 716.3037, obsd: 716.3013.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=4)[N:15]=3)[NH:7][C:6]=2[CH:23]=1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34]>CS(C)=O>[NH2:22][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH2:17][CH2:18][N:19]([S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])[CH2:20][CH:21]=2)=[N:15][C:10]=1[C:8]1[NH:7][C:6]2[CH:23]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1ccc2nc(-c3nc(C4=CCNCC4)cnc3N)[nH]c2c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc2nc(-c3nc(C4=CCN(S(=O)(=O)N(C)C)CC4)cnc3N)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of 3-(6-methyl-1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (58 mg, 0.1893 mmol) and triethylamine (38.31 mg, 52.77 μL, 0.3786 mmol) in DMSO (1.450 mL) was treated with N,N-dimethylsulfamoyl chloride (35.34 mg, 26.43 μL, 0.2461 mmol). The solution was stirred at RT for 16 hours and then partitioned between EtOAc and water. The aqueous layer was separated, organics dried over MgSO4 and concentrated in vacuo to give a yellow solid which was washed with MeOH and filtered to give the desired product (47 mg, 57% Yield). 1H NMR (400.0 MHz, DMSO) d 2.46 (s, 3H), 2.77 (s, 2H), 2.80 (s, 6H), 3.48 (s, 2H), 3.96 (d, J=3.0 Hz, 2H), 6.76 (s, 1H), 7.10 (s, 1H), 7.61-7.40 (m, 3H) and 8.34 (s, 1H) ppm; MS (ES+) 414
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8](=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:9][C:5]=2[CH:4]=1.[CH3:19][I:20]>>[I-:20].[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8](=[N+:10]([CH3:19])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:9][C:5]=2[CH:4]=1
Reactant: CI
Reactant: COc1ccc2sc(=Nc3ccccc3)sc2c1
Product: COc1ccc2sc(=[N+](C)c3ccccc3)sc2c1
Product: [I-]

Procedure:
A solution of N-(5-methoxy-1,3-benzodithiol-2-ylidene)benzenamine (4.5 g) in 100 ml of methyl iodide is heated at reflux for three days. The resultant precipitate is collected by filtration and recrystallized from acetonitrile/benzene to yield 6 g of the title compound, melting point 199° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[Cl:9][C:6]1[CH:5]=[C:3]([NH2:4])[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)ccc1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
2-Bromo-5-chloroaniline (CAS#823-57-4; 5 g), 4-fluorophenylboronic acid (3.56 g) and cesium carbonate (31.6 g) were combined in THF (70 ml) and water (35 ml). The mixture was degassed by bubbling argon through the solution. After addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (886 mg) the reaction mixture was stirred 1 h at 80° C. in a sealed tube. The reaction mixture was diluted with EtOAc, washed with water, dried over Na2SO4, evaporated and purified by chromatography (silica gel, 0% to 30% EtOAc in heptane). The product was finally bulb-to-bulb distilled at 0.3 mbar and 120-130° C. oven temperature to give the title compound (5.07 g) as a light yellow liquid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:20]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:21]3[C:26]([N:27]=2)=[CH:25][N:24]=[CH:23][N:22]=3)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]3[N:20]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:21]4[C:26]([N:27]=3)=[CH:25][N:24]=[CH:23][N:22]=4)[CH2:16][CH2:17]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(CCCl)cc1
Reactant: c1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCN2CCC(Nc3nc4cncnc4n3Cc3ccccn3)CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 2 parts of 1-(2-chloroethyl)-4-methoxybenzene, 3.1 parts of N-(4-piperidinyl)-9-(2-pyridinylmethyl)-9H-purin-8-amine, 1.5 parts of sodium carbonate and 45 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.2 parts (50%) of N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-9-(2-pyridinylmethyl)-9H-purin-8-amine; mp. 144.5° C. (compound 74).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([O:12][CH2:10][CH3:11])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:11]
Reactant: CCOc1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CCOc1cccc(Nc2ncc(F)c(Nc3cccc(OCC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-ethoxyaniline were reacted to yield N2,N4-bis(3-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.96 (1H, d, J=4.8 Hz), 7.22 (m, 6H), 7.07 (t, 1H, J=1.8 Hz), 6.95 (dt, 1H, J=1.2 and 7.2 Hz), 6.77 (m, 2H), 3.88 (q, 4H, J=6.3 Hz), 1.33 (two t, 6H, J=6.3 Hz); 19F NMR (CDCl3): −46175; LCMS: ret. time: 26.86 min.; purity: 97%; MS (m/e): 369 (MH+).
Reaction SMILES: COC[N:4]1[C:9]2[C:10]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[N:11][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[S:5]1(=[O:32])=[O:31].Cl.C(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[N:21]1([C:19]([C:10]2[C:9]3[NH:4][S:5](=[O:31])(=[O:32])[C:6]4[CH:30]=[CH:29][CH:28]=[CH:27][C:7]=4[C:8]=3[N:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=2)=[O:20])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: COCN1c2c(C(=O)N3CCOCC3)nn(-c3ccccc3)c2-c2ccccc2S1(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(c1nn(-c2ccccc2)c2c1NS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 10.3 %

Procedure:
To a solution of 4-(methoxymethyl)-3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazine 5,5-dioxide (85 mg; 0.19 mmol; 1.00 eq.) in 1,4-dioxane (3 mL) is added HCl (0.75 mL; 1 M; 0.75 mmol; 4.00 eq.) after which reaction mixture is stirred at 100° C. for 90 min under microwave irradiation (*2). DCM is added to the reaction mixture that is neutralized to pH 6 with NaHCO3, extracted with DCM, dried over MgSO4 and purified by MD-Autoprep to give 8 mg (10%) of the title compound as an off white solid. 1H NMR (300 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.00-7.91 (m, 1H), 7.71-7.50 (m, 7H), 6.99-6.86 (m, 1H), 3.83-3.55 (m, 8H). HPLC (max plot) 97.4%; Rt 3.27 min. MS (ESI+) 411.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][NH:8][C:9]2[S:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=[C:17]4B3OC(C)(C)C(C)(C)O3)=[N:12][N:13]=2)=[CH:5][CH:4]=1.Br[C:45]1[N:50]=[C:49]([N:51]2[CH2:56][CH2:55][N:54]3[C:57]([CH3:60])=[N:58][N:59]=[C:53]3[CH2:52]2)[CH:48]=[CH:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[S:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][CH:18]=[C:17]4[C:45]3[CH:46]=[CH:47][CH:48]=[C:49]([N:51]4[CH2:56][CH2:55][N:54]5[C:57]([CH3:60])=[N:58][N:59]=[C:53]5[CH2:52]4)[N:50]=3)=[N:12][N:13]=2)=[CH:42][CH:43]=1
Reactant: Cc1nnc2n1CCN(c1cccc(Br)n1)C2
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(B3OC(C)(C)C(C)(C)O3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(-c5cccc(N6CCn7c(C)nnc7C6)n5)c4c3)s2)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A glass microwave reaction vessel was charged with N-(4-methoxybenzyl)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (90.0 mg, 0.146 mmol) and 7-(6-bromopyridin-2-yl)-3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (64.4 mg, 0.219 mmol) in p-dioxane/H2O (3:1, 2.0 mL) followed by potassium carbonate (40.3 mg, 0.292 mmol) and Pd(PPh3)4 (8.43 mg, 7.30 μmol). The reaction was stirred and heated in a microwave at 100° C. for 15 min, then 120° C. for 15 min. The mixture was diluted with DCM and washed with brine, dried, filtered and concentrated to give the crude material. MS (ESI, pos. ion) m/z: 550 (M+1).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][C:6](=O)[CH3:7])[CH3:2].[OH2:9].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:18]O>C(O)C>[CH2:1]([S:3][CH2:4][CH2:5][C:6](=[N:18][OH:9])[CH3:7])[CH3:2]
Reactant: CCSCCC(C)=O
Reactant: NO
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCSCCC(C)=NO
Yield: 99.8 %

Procedure:
A mixture of the 4-ethylsulfanyl-butan-2-one (13.6 g, 0.1 mol), sodium acetate trihydrate (68 g, 0.5 mol) and hydroxylamine hydrochloride (34.7 g, 0.5 mol) in 500 mL of ethanol was heated to refluxed for 3 hours. The mixture was cooled and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate (2×200 mL). The organic solution was then washed with Brine, dried, filtered and concentrated in vacuo to afford 14.7 g of the oxime.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([N:23]2[CH2:28][C:27]3([CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][O:37][C:38]4[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=4)[CH:41]=O)[CH2:30][CH2:29]3)[O:26][CH2:25][CH2:24]2)=[O:22])[N:20]=1.[NH2:46][CH2:47][C@@H:48]([C:57]1[CH:66]=[CH:65][C:64]([OH:67])=[C:63]2[C:58]=1[CH:59]=[CH:60][C:61](=[O:68])[NH:62]2)[O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51].C(O)(=O)C>CO>[Si:50]([O:49][C@H:48]([C:57]1[CH:66]=[CH:65][C:64]([OH:67])=[C:63]2[C:58]=1[CH:59]=[CH:60][C:61](=[O:68])[NH:62]2)[CH2:47][NH:46][CH2:41][C:40]1[CH:43]=[CH:44][CH:45]=[C:38]([O:37][CH2:36][CH2:35][CH2:34][N:31]2[CH2:32][CH2:33][C:27]3([O:26][CH2:25][CH2:24][N:23]([C:21]([C:19]4[N:20]=[C:16]([CH3:15])[S:17][CH:18]=4)=[O:22])[CH2:28]3)[CH2:29][CH2:30]2)[CH:39]=1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCCOc4cccc(C=O)c4)CC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCOc4cccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (0.113 g) was added in one portion to a stirred solution at 0° C. of 3-(3-(4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)propoxy)benzaldehyde (example 95, step b) (0.157 g), (R)-5-(2-amino-1-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxyquinolin-2(1H)-one (WO2004106333) (0.118 g) and acetic acid (0.020 mL) in methanol (7 mL). The resulting mixture was stirred at 20° C. for 2 hours. Most of the methanol was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and aqueous phosphate buffer (pH=7.2), the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 8% methanol and 1% ‘880’ aqueous ammonia in dichloromethane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.160 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C.O1CCOCC1>[NH4+].[Cl-].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(c2ncccc2C(F)(F)F)CC1
Temperature: 200 °C
Yield: 63.6 %

Procedure:
A mixture of the amine from Step 7D (200 mg, 0.68 mmol), 2-chloro-3-(trifluoromethyl)pyridine (200 mg, 1.36 mmol), DIEA (0.36 mL, 2.04 mmol), and 1,4-dioxane (0.10 mL) was heated in the Emrys Creator microwave to 200° C. for 1 h. The mixture was diluted with sat. NH4Cl (20 mL) and EtOAc (50 mL). The organic phase washed with 10% HCl (25 mL), H2O (3×25 mL), and brine (25 mL), dried (MgSO4), and concentrated. The resulting yellow oil was purified by SiO2 chromatography (elution with 10 to 30% EtOAc-hexanes), and lyophilized to afford the title compound (0.19 g), a white solid, 64%.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COc1cccc(N=C=O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-methoxyphenyl isocyanate (0.160 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 133 mg (41.4%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])[CH3:17]>C(N(CC)CC)C>[CH3:29][C:26]([C:21]1[CH:22]=[C:23]([S:25][CH2:6][CH2:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[O:7])[CH:24]=[C:19]([C:16]([CH3:18])([CH3:17])[CH3:15])[C:20]=1[OH:30])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)N(CC)Cc1ccncc1
Solvent: CCN(CC)CC
Product: CCN(Cc1ccncc1)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared according to the method of Example 4 from N-ethyl-N-(4-pyridinylmethyl)-2-propenamide (1.5 g, 0.00788 mole,), 2,6-bis(1,1-dimethyl-ethyl)-4-mercaptophenol (2.06 g, 0.00867 mole,) and triethylamine (1 ml) to provide 3.0 g of product, m.p. ca. 121°-123° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:10]#[CH:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C#CCN1CCCC1
Reactant: Brc1ccc(I)cc1
Product: Brc1ccc(C#CCN2CCCC2)cc1

Procedure:
Prepared according to general working method I from 4-bromo-iodobenzene (10.9 g, 38.5 mmol) and 1-prop-2-ynyl-pyrrolidine (4.20 g, 71% purity, 27.3 mmol).