Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][CH:23]=3)[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=[O:37])[N:7]([CH3:38])[C:6]1=[O:39])[CH:2]([CH3:4])[CH3:3].Br[C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[N:42]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.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>[CH3:47][C:45]1[CH:44]=[C:43]([CH3:48])[N:42]=[C:41]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:12]3[C:13]([NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[C:9]4[C:10]([N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6](=[O:39])[N:7]([CH3:38])[C:8]4=[O:37])=[N:11]3)=[CH:27][CH:26]=2)[CH:46]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc21
Reactant: Cc1cc(C)nc(Br)c1
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: C1COCCO1
Product: Cc1cc(C)nc(-c2ccc(Cn3nc4c(c3Nc3ccccc3)c(=O)n(C)c(=O)n4CC(C)C)cc2)c1
Temperature: 100 °C

Procedure:
A mixture of 7-isobutyl-5-methyl-3-(phenylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (41 mg, 0.077 mmol), 2-bromo-4,6-dimethylpyridine (14.3 mg, 0.077), tetrakis(triphenylphosphine)palladium(0) (3 mg), and 1M NaHCO3 aqueous solution (116 uL) in dioxane (350 μL) was heated at 100° C. for 4 hours, and then cooled to room temperature. The mixture was filtered through a 0.45 μm microfilter, and then purified by a semi-preparative HPLC to give pure product as a white powder. MS (ESI) m/z 509.2 [M+H]+
Reaction SMILES: I.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](SC)[NH:7][CH:6]2[CH3:15].[O:16]([CH2:23][CH2:24][NH2:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].C(Cl)Cl>C(#N)C.OO>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:25][CH2:24][CH2:23][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:7][CH:6]2[CH3:15]
Reactant: NCCOc1ccccc1
Reactant: CSC1=Nc2ccc(Cl)cc2C(C)N1
Agent: I
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC1NC(NCCOc2ccccc2)=Nc2ccc(Cl)cc21
Temperature: 170 °C
Yield: 92.9 %

Procedure:
6-Chloro-4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (106 mg, 0.30 mmol) and 2-phenoxyethyl amine (168 mg, 1.2 mmol) were dissolved in acetonitrile (0.9 ml) and heated to 170° C. in a sealed tube in a microwave oven for 30 minutes. After cooling the reaction was treated with 1N aqueous sodium hydroxide solution, methylene chloride and 5 to 7 drops of 30% aqueous hydrogen peroxide solution. After the reaction has ceased the layers were separated and the aqueous phase was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, the solvent was evaporated and the residue was purified by column chromatography (CH2Cl2:MeOH:aq conc NH3=9:1:0.1) to yield the title compound as a white solid (88 mg, 93%).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([C:7]([F:10])([F:9])[F:8])=O)=O.O.[NH2:12][NH2:13].Cl>CO>[F:8][C:7]([F:10])([F:9])[C:5]1[CH:4]=[C:2]([CH3:1])[NH:13][N:12]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc(C(F)(F)F)n[nH]1
Reaction time: 12 h
Yield: 74.5 %

Procedure:
To 1,1,1-trifluoro-2,4-pentadione (15.14 g, 98 mmol) in MeOH (200 ml) was added hydrazine monohydrate (4.92 g, 98 mmol) in MeOH (50 ml) and c.HCl (1.3 ml, 32%). The resulting clear solution was allowed to stir for 12 h. Removal of solvent by distillation up to 200° C. yielded a clear oil which crystallised on cooling. These crystals were dissolved in Et2O, dried over MgSO4, filtered and the solvent removed under reduced pressure. The resulting white solid was sublimed at 80° C. and 10−2 mbar, yielding the pure pyrazole as a white solid (10.91 g, 73 mmol, 74%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33]>>[C:32]([O:35][CH2:36][C:37]([N:29]1[CH2:30][CH2:31][CH:26]([N:24]2[CH:25]=[C:21]([C:7]3[C:6]4[C:10](=[CH:11][C:3]([F:2])=[CH:4][CH:5]=4)[N:9]([S:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)(=[O:13])=[O:14])[CH:8]=3)[CH:22]=[N:23]2)[CH2:27][CH2:28]1)=[O:38])(=[O:34])[CH3:33]
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CC(=O)OCC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 100.3 %

Procedure:
Following the general method as outlined in Example 89, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 368 mg; 0.80 mmol) and 2-chloro-2-oxoethyl acetate (165 mg; 1.21 mmol), 421 mg (100%) of the title compound was obtained as a yellow solid, which was used directly without further purification.
Reaction SMILES: [F:1][C:2]1([F:12])[C:5]([F:7])([F:6])[CH2:4][C:3]1([CH3:11])[C:8](Cl)=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>O1CCOCC1>[F:1][C:2]1([F:12])[C:5]([F:7])([F:6])[CH2:4][C:3]1([C:8]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH3:11]
Reactant: CC1(C(=O)Cl)CC(F)(F)C1(F)F
Reactant: NNC(N)=S
Solvent: C1COCCO1
Product: CC1(c2nnc(N)s2)CC(F)(F)C1(F)F
Temperature: 90 °C

Procedure:
A mixture of 2,2,3,3-tetrafluoro-1-methylcyclobutanecarbonyl chloride (ABCR) (2 g, 9.78 mmol) and thiosemicarbazide (Aldrich) (0.891 g, 9.78 mmol) in 10 mL of dioxane was heated at 90° C. for 12 h. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated NaHCO3. The organic extract was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on SiO2 (2% methanol in dichloromethane) to give the title compound. MS (ESI+) m/z 242 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:48])([OH:47])[CH3:46].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42]/[CH:43]=[CH:44]/[C:45]([OH:47])([CH3:48])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O)/C=C/CBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](SC/C=C/C(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.2 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (33.5 mg, 0.0577 mmol), (E)-5-bromo-2-methyl-3-penten-2-ol (41.2 mg, 0.230 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate=5:1, developed twice) to give 26.2 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from (E)-5-bromo-2-methyl-3-penten-2-ol.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([N:6]2[CH:10]=[C:9]([Br:11])[CH:8]=[N:7]2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>CC#N>[Br:11][C:9]1[CH:8]=[N:7][N:6]([CH:4]2[CH2:5][N:2]([CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH2:3]2)[CH:10]=1
Reactant: Brc1cnn(C2CNC2)c1
Reactant: BrCCOC1CCCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cnn(C2CN(CCOC3CCCCO3)C2)c1
Yield: 91.3 %

Procedure:
To 1-Azetidin-3-yl-4-bromo-1H-pyrazole hydrochloride (0.3 g, 1.26 mmol) in CH3CN (15 ml) added K2CO3(0.78 g, 5.6 mmol) followed by 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.205 ml, 1.5 mmol) reaction heated at reflux 0/N. Reaction mixture filtered, solid washed with EtOAc, filtrate concentrated under reduced pressure, residue partitioned between CH2Cl2 and H2O. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (380 mg).
Reaction SMILES: IC.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]([OH:21])=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[C:30]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:22][O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:20]([O:21][CH3:30])=[C:14]3[CH2:13]2)=[O:11])=[CH:8][CH:9]=1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(O)c2C1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(COc2ccccc2)nn2c1CN(C(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.2 %

Procedure:
Iodomethane (0.005 mL, 0.08 mmol) was added to a stirred suspension of (4-fluoro-phenyl)-(3-hydroxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (19 mg, 0.052 mmol) and Cs2CO3 (0.034 g, 0.1 mmol) in DMF (0.5 mL). The mixture was stirred at room temperature for 45 minutes and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield (4-fluoro-phenyl)-(3-methoxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (5 mg, 25% yield) as a colourless oil. C21H20FN3O3 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (br. s., 3H), 4.01 (br. s., 2H), 4.20 (br. s., 2H), 4.80 (br. s., 2H), 5.02 (s, 2H), 6.93-7.00 (m, 1H), 7.03 (d, J=7.9 Hz, 2H), 7.16 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.46-7.53 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[OH:25])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[OH:25])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccncc1O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: B
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ccncc2O)CC1

Procedure:
EXAMPLE 106 was prepared from 4-(3-hydroxy-pyridin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (which was prepared by EDC coupling of 4-amino-pyridin-3-ol and N-benzyloxycarbonyl piperidine-4-carboxylic acid) by borane-THF reduction overnight at room temperature. The reaction was quenched by slow addition of 1N HCl until pH=2, then basified to pH=10 with 10N NaOH. Extraction with chloroform yielded a crude product which was purified by preparative chromatography, eluting with 90:10 chloroform saturated with ammonia: methanol to give 4-[(3-hydroxy-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester: MS (m+1)=342.4.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH:11]1([O:16][C:17](=[O:24])[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[NH2:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:19][C:18]1([C:17]([O:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:24])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1cccc(CBr)c1
Reactant: NC1(C(=O)OC2CCCC2)CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: O=C(OC1CCCC1)C1(NCc2cccc(CBr)c2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 3-(bromomethyl)-benzaldehyde (0.467 g, 2.44 mmol) in dichloroethane (20 mL) was added cycloleucine cyclopentyl ester (0.802 g, 4.06 mmol) and sodium triacetoxyborohydride (1.18 g, 5.56 mmol). The mixture was stirred at room temperature for 3 hours, then poured into ethyl acetate (200 mL) and washed with saturated ammonium chloride solution (3 times 50 mL). The organic fraction was dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, 7:3 heptane:ethyl acetate) to yield the desired product (0.568 g, 61% yield). LC/MS: m/z 380/382 [M+H]+
Reaction SMILES: C(Cl)Cl.[N:4]1[C:14]2[O:13][C:12]3[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:18][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C1([N:30]=C=NC2CCCCC2)CCCCC1.N>C(O)(=O)C>[N:4]1[C:14]2[O:13][C:12]3[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[C:20]([NH2:30])=[O:21])=[CH:18][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1cccnc1O2
Agent: N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C(N)=O)c1ccc2c(c1)CCc1cccnc1O2
Yield: 44.2 %

Procedure:
To 10 ml of methylene chloride solution containing 50 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]oxepin-8-yl)-propionic acid and 50 mg of dicyclohexylcarbodiimide was added 5 ml of methylene chloride saturated with ammonia, and the mixture was stirred with ice-cooling for 2 hours. To this were added acetic acid and ice and the resulting mixture was extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution, then saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the residue, which was extracted with ethyl acetate and the extract was freed of the solvent. The resulting residue was chromatographed over silica gel, eluted with n-hexane/acetone (4/1-1/1), and there was obtained 22 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]oxepin-8-yl)-propionamide as white crystals. These were recrystallized from ethyl acetate to give colorless crystals having a melting point of 162°-165° C.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1>C(OCC)(=O)C>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:4]([C:5]#[N:1])=[C:9]([CH3:8])[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc2nonc12
Solvent: CCOC(C)=O
Product: CC1=C(C#N)C(c2cccc3nonc23)c2c[nH]nc2N1

Procedure:
The title compound was prepared from ethyl acetate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:14]([C:15]3[C:16]([CH3:22])=[N:17][O:18][C:19]=3[CH2:20][OH:21])=[CH:13][N:12]([CH3:23])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:31][S:32]([O:21][CH2:20][C:19]1[O:18][N:17]=[C:16]([CH3:22])[C:15]=1[CH:14]1[CH2:13][N:12]([CH3:23])[N:11]=[C:10]1[C:8](=[O:9])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1noc(CO)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(COS(C)(=O)=O)c1C1CN(C)N=C1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of (4-chlorophenyl)(4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)methanone (0.05 g, 0.15 mmol) in DCM (10 mL), was added triethylamine (0.1 mL) and methane sulfonyl chloride (0.05 mL) at room temperature. The mixture was stirred for 2 h at room temperature. DCM (50 mL) and saturated sodium bicarbonate solution (20 mL) were added. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the titled product as yellow oil (0.035 g, 56%). LC/MS m/z 409 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.Br[CH:34]([CH3:38])[C:35]([NH2:37])=[O:36]>>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C@@H:34]([CH3:38])[C:35]([NH2:37])=[O:36])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(Br)C(N)=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN([C@@H](C)C(N)=O)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine and 2-bromopropionamide were reacted to give a racemic mixture. The enantiomers were separated by SFC to give 546. LCMS m/z: 252.7 (2M+H+)
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][CH:12]1[CH2:26][CH2:25][O:24][C:23](=[O:27])[CH2:22][CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][C:16]#[C:15][CH2:14][CH2:13]1>C(O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:11][CH:12]1[CH2:26][CH2:25][O:24][C:23](=[O:27])[CH2:22][CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][CH2:13]1
Reactant: CC1CCC#CCCCC=CCC(=O)OCC1
Agent: [Pd]
Agent: CC1CC/C=C\CCC/C=C/CC(=O)OCC1
Agent: CC1CCC#CCCC/C=C/CC(=O)OCC1
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CC1CCC=CCCCC=CCC(=O)OCC1
Reaction time: 3.5 h

Procedure:
Quinoline (4.86 μL, 0.0411 mmol) and 10% Pd/BaSO4 (0.88 mg, 0.00824 mmol) were added to a stirred solution of (4E)-13-methyloxacyclopentadec-4-en-9-yn-2-one (48.2 mg, 0.206 mmol) in ethanol (2.0 mL). The reaction flask was flushed with argon followed by hydrogen, and the reaction mixture was stirred under hydrogen atmosphere at room temp. and ambient pressure. After 3.5 h, GC-monitoring indicated complete conversion, upon which the catalyst was filtered off through a pad of Celite and washed with ethanol. The solvent was removed under reduced pressure, and the resulting residue purified by chromatography on silica gel [20 g; pentane-Et2O (10:1); Rf=0.78 in pentane-Et2O (5:1)] to furnish (4E,9Z)-13-methyloxacyclopentadeca-4,9-dien-2-one (44.8 mg, 92%) as a colourless odoriferous liquid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[C:6]=1[CH3:7]>CO.O1CCCC1.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH2:14])[C:6]=1[CH3:7]
Reactant: Cc1ncn(-c2cccc([N+](=O)[O-])c2)c1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncn(-c2cccc(N)c2)c1C
Yield: 98.2 %

Procedure:
A suspension of 4,5-dimethyl-1-(3-nitrophenyl)imidazole (130 mg) in methanol (2 ml) and tetrahydrofuran (2 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 50 mg) under hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(4,5-dimethyl-imidazol-1-yl)aniline (110 mg, 98.2%).
Reaction SMILES: O.[OH-].[Na+].[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>CO>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]([C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Reactant: O=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)C(=Cc1cccnc1)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.2 %

Procedure:
100 ml of water, followed by 28 ml of 10% strength aqueous sodium hydroxide solution, were added to a stirred solution of 22.6 g (0.1 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one and 21.4 g (0.2 mol) of 3-pyridinealdehyde in 500 ml of methanol. The solution was subsequently stirred at room temperature for 4 days, the methanol was removed in vacuo and the aqueous residue was taken up in ether. The aqueous phase was separated off, the organic phase was extracted three times with 1 N hydrochloric acid and the hydrochloric acid extracts were neutralized with solid sodium bicarbonate and extracted three times with ethyl acetate. 22.8 g (72% of theory) Of 2-(4-chlorophenoxy)-4,4-dimethyl-1-pyridin-3-yl-1-penten-3-one of melting point 74°-76° C. were obtained from the ethyl acetate phase.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:15][C:16]([N:18]1[C@@H:22]([C@H:23]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:24]([N:34]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:25][C:26]2[CH:31]=[C:30](F)[CH:29]=[C:28]([F:33])[CH:27]=2)[CH2:21][O:20][C:19]1([CH3:58])[CH3:57])=[O:17])([CH3:14])([CH3:13])[CH3:12].[Cl-].[NH4+]>CN1CCCC1=O.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[C@@H:22]([C@H:23]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C@@H:24]([N:34]([CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:25][C:26]2[CH:27]=[C:28]([F:33])[CH:29]=[C:30]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:31]=2)[CH2:21][O:20][C:19]1([CH3:58])[CH3:57])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(OCc3ccccc3)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.6 %

Procedure:
Add NaH (12.5 g, 60% mineral oil suspension, 312.5 mmol) in portions to a solution of benzyl alcohol (32 mL, 309.2 mmol) in N-methylpyrrolidinone (1 L). Stir the reaction mixture at r.t. until no gas evolution is detected. Add (R)-4-[(1R,2S)-3-(3,5-difluorophenyl)-1-benzyloxy-2-dibenzylaminopropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (130 g) to the mixture and warm it up to 90° C. After 45 min, allow to cool to room temperature and add saturated aqueous ammonium chloride. Dilute with ethyl acetate (2 L) and wash with saturated aqueous sodium chloride (2×1.5 L). Dry the organic layer on MgSO4, filter and concentrate. Subject residue to silical gel chromatography, eluting with 2-4% ethyl acetate in hexanes, to provide 139.45 g (94%) of the desired compound as a white solid.