Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[C@H:10]([O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22]([C:26]1[N:27]=[N:28][C:29](Cl)=[CH:30][C:31]=1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:34][CH:33]=1)[CH2:23][CH2:24][CH3:25].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:29]2[N:28]=[N:27][C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[C:31]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:36][CH:37]=3)[CH:30]=2)[C@H:10]([O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: COCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCOC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
To a stirred solution of (±)-cis-4-hydroxymethyl-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (4.64 mmol, 1.28 g) in DMF (5 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (13.9 mmol, 0.56 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 2.32 mmol, 0.80 g) in DMF (5 mL). After completion of addition, the reaction mixture was warmed to 50° C. for 2 hours. After cooling to room temperature, the reaction was poured into a mixture of water (100 mL) and ethyl acetate (100 mL). The mixture was shaken and separated. The ethyl acetate layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 40 g SiO2 cartridge using a gradient of ethyl acetate/hexanes to provide (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.60 g, 44%). LCMS: m/z 583.9 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[C:29]([O:33][CH2:34][CH2:35][O:36][NH2:37])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([O:33][CH2:34][CH2:35][O:36][NH:37][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1])=[O:21])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OCCON
Reactant: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)NOCCOC(C)(C)C)c(=O)n(C)c1=O
Temperature: 100 °C

Procedure:
Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23; 100 mg, 0.195 mmol, 1 eq) and O-(2-tert-butoxyethyl)hydroxylamine (See, WO05/110410; 260 mg, 1.95 mmol, 10 eq) were mixed in anhydrous THF (3 ml) and heated at 100° C. for 50 minutes in a microwave reactor. The protected product Example 24 was isolated by HPLC. [M+H] calc'd for C19H24ClIN4O5, 551; found, 551.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[CH3:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22].C(=O)(O)[O-].[Na+].O1CCOCC1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:18][C:19]1[CH:26]=[C:25]([C:2]2[N:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)[N:3]=2)[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C=O
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)ccc1C=O
Temperature: 140 °C
Yield: 54.7 %

Procedure:
3-Bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) (0.30 g, 1.0 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (CB4) (0.25 g, 1.0 mmol), sodium bicarbonate (0.25 g, 2.9 mmol), tetrakis(triphenylphosphine) palladium(0) (0.17 g, 0.15 mmol), dioxane (3.9 mL), and water (0.97 mL). in a 0.5-2.0 mL vial was capped and heated at 140° C. for 30 minutes in a Biotage Initiator® microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography using 0-20% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided the title compound as a white solid (0.19 g, 57%): 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.61 (s, 1H), 8.19 (dd, J=8.0, 1.6 Hz, 1H), 8.13 (t, J=1.1 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.86-7.78 (m, 2H), 7.45-7.37 (m, 2H), 2.77 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.01; ESIMS m/z 348 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28]S[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[N:15][N:14]=1.O[O:31][S:32]([O-:34])=O.[K+].S(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][S:32](=[O:34])(=[O:31])[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)=[N:15][N:14]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCSCC3)cc2)o1
Reactant: O=S([O-])OO
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCS(=O)(=O)CC3)cc2)o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 29.1 %

Procedure:
To a suspension of 4-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine (239 mg, 0.59 mmol) in methanol (2 mL) and water (0.5 mL) was added oxone (545 mg, 0.89 mmol) and stirred for 18 h at 60° C. and for 4 h at 50° C. After the reaction mixture was cooled to ambient temperature further oxone (331 mg, 0.54 mmol) was added and stirred for 18 h at 50° C. It was cooled to ambient temperature and aqueous sodium bisulfite (38%, 1.5 mL) was then added and stirred for 15 min. After the addition of aqueous sodium carbonate (saturated, 10 mL) the mixture was extracted with ethyl acetate (20 mL) and washed with aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:50:10:0 to 0:90:0:10) afforded the title compound (75 mg, 29%) as a white solid. MS: m/e=437.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH2:10][C:9](=O)[C:8]=2[C:7]([CH3:22])=[CH:6]1)(=[O:4])=[O:3].[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].[ClH:28].Cl.O>C(O)C>[ClH:28].[NH:26]([N:27]=[C:9]1[CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]([CH3:22])[C:8]1=2)[C:23]([NH2:25])=[NH:24]
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C1CC(=O)c2c(C)cn(S(C)(=O)=O)c2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)cn(S(C)(=O)=O)c2C1
Yield: 61.9 %

Procedure:
A mixture of 1-methanesulfonyl-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (0.20 g), aminoguanidine hydrochloride (0.073 g), concentrated hydrochloric acid (0.032 ml), water (0.032 ml) and ethanol (20 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was purified with silica gel column chromatography (EtOAc/MeOH). To the resulting crystals was added 1N hydrochloric acid, and the mixture was concentrated. The residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-1-methanesulfonyl-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindole hydrochloride (Compound 15) (0.16 g) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=[O:28]>C(OCC)(=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][C:27]([NH:16][C:14]1[CH:15]=[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:17])[CH3:1])[CH:4]=2)[N:11]=[CH:12][N:13]=1)=[O:28]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CN(C)c1cccc(Nc2cc(N)ncn2)c1
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(Nc2cc(NC(=O)Nc3c(Cl)cccc3Cl)ncn2)c1

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(3-dimethylamino-phenyl)-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate using ethyl acetate instead of CH2Cl2 for the work-up procedure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.O>CC(N(C)C)=O>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[CH3:23])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Cc1ccccc1CCl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccccc1COc1ccc(C(C)(C)c2ccc(OCc3ccccc3C)cc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
Under an inert atmosphere, 5.23 g Bisphenol A (BPA) (22.9 mmol) and 2.83 g potassium hydroxide (50.4 mmol) were dissolved in 50 mL dimethylacetamide. Stirring was started at 500 rpm and the contents were warmed to 70° C. After 30 minutes, 7.09 g 2-methylbenzyl chloride (50.4 mmol) dissolved in 50 mL dimethylacetamide was added to the reaction mixture. The mixture was then heated at 100° C. for 4 h until no 2-methylbenzyl chloride was noted in the GPC trace. During the course of the reaction, a white precipitate had formed. The reaction mixture was cooled to room temperature and then poured into a 1 L separatory funnel containing 200 mL deionized water. The aqueous layer immediately became opaque. The reaction flask was washed with 50 mL deionized water and this wash was added along with 150 mL toluene to the separatory funnel. The separatory funnel was shaken and the bilayer allowed to settle. The lower, aqueous layer appeared opaque while the upper, organic layer was clear and colorless. The organic layer was separated and the aqueous layer was washed 3 additional times with 100 mL toluene. The combined organic fractions were dried over 20 g magnesium sulfate and filtered into a 1 L round bottom flask. The solvent was removed from the filtered toluene solution on a rotary evaporator initially at room temperature then at 70° C. Following solvent removal, a viscous oil remained in the round bottom flask. This crude product was recrystallized at 0° C. from an acetone solution. The crystalline white solid that had formed was filtered on a 7.0 cm Büchner funnel using Whatman 540 filter paper. The crystals were pulverized into a powder and washed with cold acetone. The white powder was transferred to a 75° C. vacuum oven and dried for 24 h. For Bisphenol A bis(2-methylbenzyl) ether: 52% yield (5.2 g, 12 mmol); white powder; mp 117° C. 1H NMR (500.1 MHz, CD2Cl2, ppm, J=Hz): 7.40 (d, 7.2, 2H, Ph), 7.23 (m, 6H, Ph), 7.17 (m, 4H, Ph), 6.90 (m, 4H, Ph), 5.02 (s, 4H, -PhCH2O—), 2.37 (s, 6H, -PhCH3), 1.65 (s, 6H, —C(CH3)2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.[CH:20]1([S:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:29]3[CH2:30][CH2:31][N:26]([S:23]([CH:20]4[CH2:22][CH2:21]4)(=[O:25])=[O:24])[CH2:27][CH2:28]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=S(=O)(C1CC1)N1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Product: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde was treated with 1-cyclopropanesulfonyl-piperazine hydrochloride using General Procedure C (reductive amination) to yield 2-chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: F[C:2]1[CH:22]=[CH:21][C:5]2[N:6]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=4)[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.[I:23]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[I:23][C:2]1[CH:22]=[CH:21][C:5]2[N:6]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=4)[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: CN(C)c1ccc(-c2cn3c(n2)sc2cc(F)ccc23)cc1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)c1ccc(-c2cn3c(n2)sc2cc(I)ccc23)cc1
Yield: 15 %

Procedure:
5 (64 mg, 1 eq) was dissolved in CH2Cl2 (5 ml) and to that was added dropwise I2 (39 mg, 1.1 eq) in 2 ml of CH2Cl2, the resulting mixture was stirred at RT for 1 h before hydrolysis with 5 ml of Na2S2O3 10%. Extraction was performed using CH2Cl2 (2×5 ml) with drying over Na2SO4 and concentrating was carried out in vacuum. Purification by flash chromatography (SiO2, hexane/AcOEt, 9/1) was used to give 6 as a white solid in 15% yield.
Reaction SMILES: OC1C=CC(C2C=CC(C3OC(=O)CC3)=CC=2)=CC=1.C[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.Br>>[OH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Agent: Br
Agent: O=C1CCC(c2ccc(-c3ccc(O)cc3)cc2)O1
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
The compound Dihydro-5-(4'-hydroxy-4-biphenylyl)-2(3H)-furanone may be prepared by treating 4'-methoxy-γ-oxo-4-biphenylbutyric acid with hydrogen bromide in acid to produce 4'-hydroxy-γ-oxo-4-biphenylbutyric acid. This in turn is treated with sodium borohydride as described above and then purified with organic solvents to produce the desired product.
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:3]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(-n2cnc(Br)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-n2cnc(Br)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-1-(4-nitrophenyl)-1H-1,2,4-triazole (0.51 g, 1.9 mmol), SnCl2-2H2O (2.14 g, 9.5 mmol) and EtOH (4 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature and basified with NaOH (2M aq.) until pH 7˜9. The resulting precipitate was filtered through Celite and washed with EtOH. The EtOH filtrate was concentrated in vacuo and the crude residue was dissolved in water and extracted with EtOAc (3×). The combined organics were dried (MgSO4) and concentrated in vacuo to provide the desired product as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.28 (s, 1H), 7.40 (d, 2H), 6.79 (d, 2H), 3.90 (br s, 2H).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C:14]3[CH:25]=[CH:24][C:17]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1>CO.[Pd]>[CH3:23][O:22][N:20]([CH3:21])[C:18](=[O:19])[C:17]1[CH:24]=[CH:25][C:14]([O:13][C:8]2[C:7]([CH:4]3[CH2:3][CH2:2][S:1][CH2:6][CH2:5]3)=[N:12][CH:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: CON(C)C(=O)c1ccc(Oc2nccnc2C2=CCSCC2)cc1
Agent: [Pd]
Solvent: CO
Product: CON(C)C(=O)c1ccc(Oc2nccnc2C2CCSCC2)cc1

Procedure:
A solution of 4-(3-(3,6-dihydro-2H-thiopyran-4-yl)pyrazin-2-yloxy)-N-methoxy-N-methylbenzamide (0.500 g, 1.399 mmol) in MeOH (10 ml) was hydrogenated at RT in 10% Pd/C (0.200 mg) in 72 h. The solid was filtered off, and the filtrate was concentrated and purified by ISCO (3% MeOH/DCM) to give the title compound. MS [M+1]: 360.1.
Reaction SMILES: C(OC(=O)[N:7]([C:14]1[C:19]([C:20](=[O:28])[NH:21][C:22]2[S:23][CH:24]=[C:25]([CH3:27])[N:26]=2)=[N:18][CH:17]=[CH:16][N:15]=1)[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(C)(C)C.[ClH:30].C(O)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:30].[ClH:30].[CH3:27][C:25]1[N:26]=[C:22]([NH:21][C:20]([C:19]2[C:14]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[N:15][CH:16]=[CH:17][N:18]=2)=[O:28])[S:23][CH:24]=1
Reactant: Cc1csc(NC(=O)c2nccnc2N(C(=O)OC(C)(C)C)c2cccnc2)n1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1csc(NC(=O)c2nccnc2Nc2cccnc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[3-(4-Methyl-thiazol-2-ylcarbamoyl)-pyrazin-2-yl]-pyridin-3-yl-carbamic acid tert-butyl ester (180 mg, 0.44 mmol) was dissolved in 5 ml ethyl acetate and 8M HCl in ethanol (2.2 ml, 17.6 mmol) was added. The reaction mixture was stirred for 3 hrs at room temperature and diluted then with 20 mL diisopropylether. The solid material was filtered off and dried at 50° C. and 15 mbar for 1 hr. The desired compound was obtained as a yellow solid (169 mg, 99%), MS: m/e=313.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[Cl-].[Li+].CCN(C(C)C)C(C)C.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][N:37]=1)CCC.[F-].[K+]>CN(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>[S:34]1[CH:35]=[CH:36][N:37]=[C:33]1[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: N#Cc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cn1)[nH]c1ncc(-c3nccs3)cc12
Temperature: 165 °C
Yield: 4.9 %

Procedure:
A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (100 mg, 0.366 mmol) and lithium chloride (46.6 mg, 1.10 mmol) in DMF (0.63 mL) was treated with DIPEA (159 uL, 0.915 mmol) and 2-(tri-n-butylstannyl)thiazole (345 uL, 1.10 mmol), and then degassed by the bubbling of nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (21.2 mg, 18.3 umol, 5.0 mol %) was added and the mixture heated at 165° C. for 15 hours. The mixture was allowed to cool and treated with saturated aqueous potassium fluoride solution at ambient temperature. The resulting solids were removed by filtration and washed with 20% methanol in DCM and water. The filtrate was filtered through a pad of celite, washing with 20% methanol in DCM. The layers were separated, the aqueous phase extracted into 20% methanol in DCM, and the combined organic phases concentrated in vacuo. The residue was dissolved in AcOH with sonication and heating, filtered hot and allowed to cool. The resulting suspension was treated with water and then filtered to collect the off-white solid. This solid was purified by preparative HPLC [0-30% MeCN/water modified with 0.1% formic acid] to afford an off-white solid powder (5.0 mg, 18%). 1H NMR (400 MHz, DMSO-D6): 9.26 (s, 1H), 9.24 (s, 1H), 9.01 (s, 1H), 8.94 (s, 1H), 7.96 (d, J=3.2 Hz, 1H), 7.80 (d, J=3.2 Hz, 1H). LCMS (Method D): RT=9.31 min, M+H+=278.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[Cl:16])(=O)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>O.C1(C)C=CC=CC=1.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>[Cl:16][C:8]1[CH:9]=[C:10]([C:13](=[O:15])[CH3:14])[CH:11]=[CH:12][C:7]=1[C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: OB(O)c1ccc(F)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: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc(F)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
19.7 g of 4-acetyl-2-chlorophenyl trifluoromethanesulphonate (compound Va.1), 10 g of 4-fluorobenzeneboronic acid, 2 g of tetrakis(triphenylphosphine)palladium, 17.9 g of sodium carbonate in 84.5 ml of water, 591 ml of toluene, 200 ml of ethanol and 5.51 g of lithium chloride are stirred under an inert atmosphere at 60° C. for 8 hours. The reaction mixture is then stirred for 12 hours at room temperature. The resulting mixture is filtered and the solvents are evaporated from the filtrate under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a 97/3 (v/v) cyclohexane/ethyl acetate mixture; yield=94%.
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[CH3:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19][C:20]2=O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH2:19][CH:20]2[NH2:10])=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: NC1CCCc2occc21
Product: COc1ccc2c(c1)C(N)CCC2

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 7-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 6.99, 6.75, 3.95, 3.82, 2.74, 2.05, 1.96, 1.71, 1.67, 1.56; 13C NMR (100 MHz, CDCl3) δ 158.28, 142.62, 130.30, 129.19, 113.44, 112.88, 55.73, 50.12, 34.17, 29.12, 20.26.
Reaction SMILES: [C:1](O[C@@H](C(N)(C)[C@H](O)C)C)(=[O:3])[CH3:2].[CH:13]([C:16]([N+:21]([O-])=O)([CH2:19][OH:20])[CH2:17][OH:18])([CH3:15])[CH3:14]>>[C:1]([O:18][CH2:17][C:16]([NH2:21])([CH:13]([CH3:15])[CH3:14])[CH2:19][OH:20])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)C(C)(N)[C@@H](C)O
Reactant: CC(C)C(CO)(CO)[N+](=O)[O-]
Product: CC(=O)OCC(N)(CO)C(C)C
Yield: 98 %

Procedure:
Using the procedure in 5D, 2-isopropyl-2-nitro-1,3-propanediol (11A) gave 98% yield of 2-amino-2-isopropyl-1,3-propanediol acetate mp 155°-155.5°. H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337 (1975) report the synthesis of this compound as the free base (mp 70°-72°)).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:22]1[C:30]2[C:25](=[C:26]([CH2:31][S:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)(=O)=O>CN(C=O)C>[CH3:33][S:32][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[NH:24][CH:23]=[C:22]2[CH:11]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=1)[CH2:10][CH2:9][C:1]#[N:2]
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(C(F)(F)F)cc3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
28.5 g (0.44 mmol) of potassium cyanide were added to 100 mg (0.22 mmol) of the compound from Example 51A in 5 ml of DMF. The mixture was stirred at 80° C. for 2 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient with addition of 0.1% formic acid) resulted in 77 mg (91% of theory) of the title compound.