Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([NH:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=2)[CH2:34][CH2:35]1)=[O:36])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CCC(CNC(=O)OC(C)(C)C)CC2)nc(Cl)n1
Temperature: 25 °C

Procedure:
A 30 mL round-bottomed vial methyl 2,6-dichloropyrimidine-4-carboxylate (300 mg, 1 equiv.) was partially dissolved in anhydrous THF (5 mL). DIEA (278 μL, 1.1 equiv.) was added at once at 0° C. tert-Butyl(piperidin-4-ylmethyl)carbamate (311 mg, 1 equiv.) dissolved in THF (5 mL) was added at 0° C. in 5 min. The reaction mixture was warmed to RT in 3 h15. LC-MS showed mostly the desired product (2.77 min, M+1=385) and a small amount of the other regioisomer (3.28 min, M+1-isobutene=329). The solvent was evaporated and the residue was purified by biotage (SiO2, 10 g, Hex/EtOAc 9:1 to 1:1) to give the desired isomer (386.8 mg, 69.4%) as a white solid. LC-MS m/z 385 (M+1).
Reaction SMILES: O.NN.[CH3:4][N:5]1[C:9]([C:10]([NH2:12])=[O:11])=[C:8]([N+:13]([O-])=O)[C:7]([CH3:16])=[N:6]1>[Ni].C(O)C>[NH2:13][C:8]1[C:7]([CH3:16])=[N:6][N:5]([CH3:4])[C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: Cc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nn(C)c(C(N)=O)c1N
Reaction time: 1.5 h

Procedure:
1.1 ml of hydrazine hydrate are added dropwise at 60° to 75° C. to a suspension of 2.0 g of 1,3-dimethyl-4-nitropyrazole-5-carboxamide and approximately 0.2 g of moist Raney nickel in 15 ml of ethanol; the solution is kept at the boil for 1.5 hours and is filtered. The filtrate is concentrated to dryness in vacuo, and 1.3 g of the hydrochloride, mp 232° to 234° C. (dec.), are precipitated by means of an ethereal solution of hydrogen chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][CH:33]1[CH2:38][NH:37][CH2:36][CH:35]([CH3:39])[N:34]1[C:40](=[O:44])[CH2:41][O:42][CH3:43]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:38][C@H:33]([CH3:32])[N:34]([C:40](=[O:44])[CH2:41][O:42][CH3:43])[C@H:35]([CH3:39])[CH2:36]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: COCC(=O)N1C(C)CNCC1C
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COCC(=O)N1[C@H](C)CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C[C@@H]1C

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-cis-3,5-dimethyl-piperazin-1-yl]-thiazol-4-one one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2,6-dimethyl-piperazin-1-yl)-2-methoxy-ethanone following General Procedure C.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([CH:10]=[O:11])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Br:12]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:12][C:6]1[CH:7]=[C:8]([CH:10]=[O:11])[S:9][C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: BrBr
Reactant: CC(C)Cc1ccc(C=O)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Cc1sc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.2 %

Procedure:
To a solution of 5-isobutylthiophene-2-carbaldehyde (192 mg, 1.14 mmol) in 3 mL acetic acid at room temperature was added bromine (0.07 mL, 1.36 mmol). The resulting solution was stirred at room temperature in the dark for 48 h before being poured into 35 mL saturated sodium bicarbonate. Organics were extracted with ether (2×30 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel (5% ethyl acetate in hexanes) to give 4-bromo-5-isobutylthiophene-2-carbaldehyde (147 mg, 52%). Used without further purification or characterization.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.C([O-])(=O)C>C(=O)([O-])[O-].[K+].[K+]>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Cc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.482 g (4.5 mmol) p-toluidine is stirred for 1.5 h at 90° C. under a nitrogen atmosphere. The reaction mixture is then distributed between 30 ml acetate and 20 ml of 20% aqueous potassium carbonate solution. The organic phase washed with water and dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (50:1 to 9:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV; m.p. 152-153° C.; ESI-MS: (M+H)+=327.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=O)[CH:8]=1)[CH3:2].[NH:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1>C(O)(=O)CC>[CH2:1]([O:3][C:4]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:20]3[NH:16][C:17]([C:13]([C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:8]=4)=[C:17]4[N:16]=[C:20]([C:13]([C:9]5[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:8]=5)=[C:17]5[NH:16][C:20](=[C:13]([C:9]6[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:8]=6)[C:17]6[CH:18]=[CH:19][C:20]=2[N:16]=6)[CH:19]=[CH:18]5)[CH:19]=[CH:18]4)=[CH:18][CH:19]=3)[CH:10]=[CH:11][CH:12]=1)=[O:15])[CH3:2]
Reactant: c1cc[nH]c1
Reactant: CCOC(=O)CCc1cccc(C=O)c1
Solvent: CCC(=O)O
Product: CCOC(=O)CCc1cccc(-c2c3nc(c(-c4cccc(CCC(=O)OCC)c4)c4ccc([nH]4)c(-c4cccc(CCC(=O)OCC)c4)c4nc(c(-c5cccc(CCC(=O)OCC)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
20.62 g (0.10 mol) of 3-{3-formylphenyl)-propionic acid ethyl ester (CARN 110114-05-1) is dissolved in 300 ml of propionic acid and the solution is heated to 60° C. 6.71 g (0.10 mol) of pyrrole is slowly instilled and the dark solution is stirred for 1 hour at 110° C. After cooling, it is completely concentrated by evaporation in a vacuum, the residue is taken up in dichloromethane and shaken out with saturated aqueous sodium bicarbonate solution. After the drying of the organic phase on sodium sulfate, it is filtered and concentrated by evaporation, and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane/ethanol. The residue of the product fractions that are concentrated by evaporation is recrystallized from isopropanol.
Reaction SMILES: [N:1]1([C:7]([C@@H:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C([O-])(O)=O.[Na+]>O1CCCC1>[N:1]1([CH2:7][C@@H:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C([C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1)N1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1Cc2ccccc2C[C@H]1CN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 5.3 g of the product obtained in Step A (13.9 mmol) in 278 mL of tetrahydrofuran there are added 14 mL of borane-dimethylsulphide complex (BH3Me2S) (27.8 mmol) at ambient temperature. The batch is heated for 4 hours at 80° C. It is allowed to return to ambient temperature and there are then added 7 mL (14 mmol) of BH3Me2S. The reaction mixture is again heated at 80° C. for 2 hours. The tetrahydrofuran is then evaporated off and then there is slowly added methanol and then 5.6 mL of 5M hydrochloric acid (27.8 mmol). The mixture is stirred at ambient temperature overnight, and then at 80° C. for 1 hour. Saturated aqueous NaHCO3 solution is then added to the reaction mixture placed at 0° C. until a pH of 8 is obtained, and extraction with ethyl acetate is then carried out. The organic phase is then dried over magnesium sulphate, and then filtered and evaporated to dryness. The title product is obtained in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].II.[I:14]([O-])(=O)=O.[Na+].O>C(O)(=O)C.S(=O)(=O)(O)O>[I:14][C:7]1[C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4](=[O:8])[NH:5][CH:6]=1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Reactant: [O-][I+2]([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-3-nitro-2-pyridone (2.00 g, 13 mmol) in acetic acid (12 mL) and concentrated sulfuric acid (1.6 ml,) was added iodine (1.32 g) and sodium iodate (0.55 g). The mixture was heated at 75° C. for 2.5 hours and then stirred at rt overnight. Water (100 mL) was added, and the precipitated 5-iodo-4-methyl-3-nitro-2-pyridone was collected by filtration (2.97 g, 82%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:15](=[O:16])[CH2:14][C:13]([CH3:12])=[O:17]
Reactant: C=C1CC(=O)O1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
m-Trifluoromethyl aniline (32.22 g) in benzene was dissolved in benzene and diketene added slowly with mixing. The reaction mixture was allowed to stand at 25° C. The resulting solid product was recrystallized from ethanol to yield 3'-trifluoromethyl acetoacetanilide.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CCOC(C)=O>[Pd].CO>[F:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(NCCCCN2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(NCCCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 2-fluoro-N-(4-morpholinobutyl)-4-nitroaniline (1.19 g, 4.00 mmol) in mixed solvents of EtOAc (20 mL) and MeOH (20 mL) was added catalyst Pd/C (0.30 g). The reaction was stirred at rt under H2 for 2 h, then filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/MeOH (V/V)=10:1) to give the title compound as a white solid (1.07 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C([O-])([O-])=O.[Na+].[Na+]>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>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: O=[N+]([O-])c1ccc(B(O)O)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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) in toluene (4 mL) and ethanol (2 mL) was added (4-nitrophenyl)boronic acid (160 mg, 1 mmol), 2M Na2CO3 (1.4 mL), and Pd(PPh3)4 (6 mg, 0.005 mmol), the reaction was purged with argon, and then heated at 80° C. for about 6 h. The reaction mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent to afford 1-(5-(4-nitrophenyl)pyridin-2-yl)ethanone as off white solid (105 mg, 86% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.40-8.34 (m, 3H), 8.08 (dd, 3H), 2.67 (s, 3H), LC-MS m/z calcd for [M+H]+ 243.07. found 243.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:12][C:13]([F:18])([F:17])[CH2:14][Mg]Br>>[CH3:3][C:1]([CH3:4])([O:5][C:6]([NH:7][CH2:8][CH:9]([OH:10])[CH2:14][C:13]([F:18])([F:17])[F:12])=[O:11])[CH3:2]
Reactant: FC(F)(F)C[Mg]Br
Reactant: CC(C)(C)OC(=O)NCC=O
Product: CC(C)(C)OC(=O)NCC(O)CC(F)(F)F

Procedure:
t-Butyl-N-(2-oxoethyl)carbamate is treated with 1,1,1-trifluoroethyl magnesium bromide to give (R/S)-1-[(1,1-dimethylethoxycarbonyl)]amino4,4,4-trifluoro-2-butanol. The procedures and methods used in this synthesis are the same as those listed in Example 3, except that (R/S)-1-[(1,1-dimethylethoxy)carbonyl]amino-4,4,4-trifluoro-2-butanol is used instead of (S)-1-[(benzyloxycarbonyl)amino]-2-propanol, to give the title compound.
Reaction SMILES: [H-].[Na+].[CH:3](Br)([CH3:5])[CH3:4].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24]>CN(C)C=O>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]([C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])[CH:3]([CH3:5])[CH3:4]
Reactant: Clc1cccc(Cl)c1Nc1nc2ccccc2[nH]1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(c1nc2ccccc2[nH]1)c1c(Cl)cccc1Cl
Yield: 7.3 %

Procedure:
In analogy to example 1, (1H-benzoimidazol-2-yl)(2,6-dichlorophenyl)amine (250 mg) was dissolved in dimethylformamide (3 ml), deprotonated with sodium hydride (43 mg) and alkylated with isopropyl bromide (111 mg) in a closed vessel at 100° C. for one hour. Workup and chromatography resulted in 21 mg of the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[H][H]>[Pt](=O)=O.C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(O)C=Cc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)CCC1CCNCC1

Procedure:
50 g (0.335 mol) of 3-(4-pyridyl)-acrylic acid are hydrogenated in 800 ml of 50% strength acetic acid with the addition of 10 g of platinum dioxide as the catalyst at room temperature under a hydrogen pressure of 50 psi until the uptake of hydrogen has ended. After the catalyst has been filtered off, the filtrate is concentrated to dryness in vacuo and the residue which remains is crystallized from a little methanol, after addition of ether.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9](Cl)[N:10]=2)[CH:7]=1.[CH3:23][S:24][CH2:25][CH2:26][CH2:27][NH2:28]>>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:28][CH2:27][CH2:26][CH2:25][S:24][CH3:23])[N:10]=2)[CH:7]=1
Reactant: CSCCCN
Reactant: Cc1c(Br)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Product: CSCCCNc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Temperature: 155 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-bromo-2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (Int. 29, 125 mg, 0.32 mmol) in IMS (5 mL) was added 3-methylsulfanyl-propylamine (215 μL, 1.92 mmol) and the reaction mixture was heated under microwave irradiation at 155° C. for 2 hrs. After this time more 3-methylsulfanyl-propylamine (490 μL) was added and heating continued for 3 hrs then a further portion of 3-methylsulfanyl-propylamine (490 μL) was added and heating continued for 7 hrs. The resultant residue was loaded onto an SCX-2 cartridge and eluted with MeOH and then further purified by flash chromatography, eluting with a gradient of 0-50% EtOAc in cyclohexane to give the title compound as a colourless glass (57 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]2[CH2:13][CH2:12]C2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:13]([CH3:12])[CH3:18])=[O:8])[CH:3]1[C:14]([OH:16])=[O:15]
Reactant: CC1(C)C(C=CC(=O)OC2CCC2)C1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)C=CC1C(C(=O)O)C1(C)C

Procedure:
Into 20 cm3 of toluene are introduced 2.1 g of tertbutyl (1R cis, ΔZ) 2,2-dimethyl 3-(3-isobutoxy 3-oxo 1-propenyl) cyclopropane-1-carboxylate and 0.1 g of paratoluene sulphonic acid, the whole is taken to reflux and maintained there for 20 minutes, concentrated to dryness by distillation under reduced pressure and chromatographed on silica eluting with a mixture of hexane and ethyl acetate (7:3) containing 1% of acetic acid and 1.53 g of (1R cis, ΔZ) 2,2-dimethyl 3-(3-isobutoxy 3-oxo-1-propenyl) cyclopropane-1-carboxylic acid are obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15].CCOCC>C1COCC1>[C:14]([O:18][C:19](=[O:22])[CH2:20][C:10]1([OH:12])[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CC1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 5 h

Procedure:
To a stirring solution of N-Boc-3-azetidinone (0.45 g, 2.64 mmol) in THF (5 mL) was slowly added a 0.5 M solution of 2-tert-butoxy-2-oxoethyl-zinc chloride in Et2O (10 mL, 5.0 mmol), and the reaction mixture was stirred for 5 h. The reaction was then quenched with sat. aq. NH4Cl (10 mL), and the aqueous layer was separated and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with 5% aq. NaHCO3 (2×10 mL), brine (15 mL), dried over Na2SO4, filtered and concentrated to dryness to yield tert-butyl-2-(N-Boc-3-hydroxy-azetidin-3-yl)-acetate (MS m/e [M+H]+ calcd 288.2. found 287.7).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[NH3:33]>O1CCOCC1>[NH2:33][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=1
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCOCC1
Reactant: N
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
(S)-4-Amino-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (108 mg, 0.237 mmol) in dioxane (3 mL) was combined with 0.5 M ammonia in dioxane (1.419 mL, 0.710 mmol) to give a yellow solution, which was stirred overnight at 60° C. The product was purified by LC/MS using a 5-30% CH3CN gradient in H2O with 0.035% formic acid. The pure fractions were combined and lyophilized to give a formic acid salt of the title compound as a white solid (14 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.59 (m, 3 H), 2.74-2.87 (m, 2 H), 3.03-3.17 (m, 2 H), 3.70-3.99 (m, 8 H), 5.76-5.91 (m, 1 H), 6.52-6.69 (m, 1H), 7.45-7.48 (br s, 2 H), 7.52-7.62 (m, 1 H), 7.75-7.79 (br s, 2 H), 7.82-7.91 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O, 394.4; found 394.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH:9]=O)=O.C(=O)(O)O.[NH2:15][NH:16][C:17]([NH2:19])=[NH:18]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:18]=[C:17]([NH2:19])[N:16]=[N:15][CH:9]=1
Reactant: N=C(N)NN
Reactant: O=CC(=O)c1ccccn1
Agent: O=C(O)O
Solvent: CCO
Product: Nc1nncc(-c2ccccn2)n1
Yield: 19.7 %

Procedure:
5-(Pyridin-2-yl)-1,2,4-triazin-3-amine (1.5 g, 8% over 2 steps) was prepared from a crude sample of 2-pyridylglyoxal (8.0 g) and aminoguanidine hydrogen carbonate (6.0 g, 44 mmol). The reagents were refluxed in EtOH (100 mL) for 4 hours. The reaction mixture was then cooled, concentrated under reduced pressure and purified by gradient flash chromatography (eluting with 0-30% ethyl acetate/hexane). The sample contained a mixture of isomers at this stage and was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-:24].[K+].[K+].OO.O>CS(C)=O>[NH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:24])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(N)CCc1ccc(Oc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(N)CCc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
4-(4-(3-Amino-3-methylbutyl)phenoxy)benzonitrile hydrochloride (1.04 g, 32.8 mmol) was dissolved in DMSO (30 ml) and treated with potassium carbonate (0.68g, 49.2 mmol, 1.5 eq.) with stirring. After 10 minutes, hydrogen peroxide (7 ml, 30% aqueous solution) was added dropwise slowly. The mixture was allowed to stir for 16 hours and then added to 300 ml of water, causing a white precipitate. The material was filtered and dried to give a white solid (908mg, 93%). NMR, MS.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[C:15]([NH2:16])=[CH:14][C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12]2)[CH:6]=1)[CH3:2].[Cl:22][C:23]([Cl:47])([Cl:46])[CH2:24][O:25][C:26](=[O:45])NC1N(C2C=CC=C(CO)C=2)N=C(C(C)(C)C)C=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[C:15]([NH:16][C:26]([O:25][CH2:24][C:23]([Cl:47])([Cl:46])[Cl:22])=[O:45])=[CH:14][C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:12]2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1

Procedure:
The title compound was prepared from Intermediate 29a using an analogous procedure to that described for Intermediate 29c. LCMS (Method 3): Rt 4.67 min, m/z 462, 464 [MH+].