Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]=[CH:25][C:26](OCC)=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]=[CH:25][CH2:26][OH:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=CCOC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC=CCO)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 10 h
Yield: 56 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-[{3-(ethoxycarbonyl)-2-propenyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (10 g) in tetrahydrofuran (120 ml) was added dropwise 1.0 M solution of diisobutylaluminum hydride in toluene (56.6 ml) at -40° C. and the mixture was allowed to warm to 0° C. and stirred for 10 hours at the same temperature. The reaction mixture was added dropwise 1N hydrochloric acid (50 ml), and the resulting precipitate was filtered off. The filtrate was dissolved in a mixture of ethyl acetate (200 ml) and water (100 ml). The organic layer was separated, washed with brine (100 ml), dried over magnesium sulfate and treated with active carbon. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl acetate (1:4 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-(4-hydroxy-2-butenyl)oxymethyl-4-methanesulfonyloxypyrrolidine (5.07 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([Cl:10])[N:4]=1.[CH3:11][NH:12][CH3:13]>O1CCOCC1.O>[CH3:1][S:2][C:3]1[N:4]=[C:5]([Cl:10])[CH:6]=[C:7]([N:12]([CH3:13])[CH3:11])[N:8]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CNC
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(Cl)cc(N(C)C)n1
Yield: 97.9 %

Procedure:
To a solution of 46 g 2-methylthio-4,6-dichloropyrimidine in 250 ml dioxane, were added at room temperature and over a period of 10 minutes, 65.6 ml of 40% dimethylammonia-solution in water and the mixture was stirred for one hour. The solvent was evaporated and the residue purified on silica gel with toluene as eluent to give 57.0 g (97.9%) of 2-methylthio-4-chloro-6-(N,N-dimethylamino)-pyrimidine of m.p. 102° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([C:23]6[CH:28]=[CH:27][C:26]([C:29]7([C:32]([OH:34])=O)[CH2:31][CH2:30]7)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:35]([NH2:37])[CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:35]([NH:37][C:32]([C:29]1([C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[N:22][C:17]4[N:18]([C:14]([C:11]5([C:7]6[CH:6]=[C:5]7[C:10](=[CH:9][CH:8]=6)[N:1]=[CH:2][CH:3]=[CH:4]7)[CH2:13][CH2:12]5)=[CH:15][N:16]=4)[CH:19]=3)=[CH:28][CH:27]=2)[CH2:31][CH2:30]1)=[O:34])[CH3:36]
Reactant: O=C(O)C1(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2)CC1
Reactant: CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C1(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-{4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl}cyclopropanecarboxylic acid (20 mg, 0.045 mmol), ethylamine (2.4 mg, 0.054 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (24 mg, 0.054 mmol), and N,N-diisopropylethylamine (23 μL, 0.13 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at RT for 2 h. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=474.1.
Reaction SMILES: [CH2:1]([C@@:4]12[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:20])[CH2:6][CH2:5]2)[CH:2]=[CH2:3].B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([C@@:4]12[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:20])[CH2:6][CH2:5]2)[CH:2]=[CH2:3]
Reactant: C=CC[C@]12CCC(=O)C=C1CCc1cc(OC)ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC[C@]12CCC(=O)C=C1CCc1cc(O)ccc12
Temperature: 0 °C
Yield: 77.4 %

Procedure:
To a solution of (4aR)-4a-allyl-7-methoxy-4,4a,9,10-tetrahydro-3H-phenanthren-2-one (15.0 grams, 55.9 mmol) in methylene chloride (350 mL) at −78° C. was added dropwise boron tribromide (10.6 mL, 112 mmol). The mixture was allowed to warm to 0° C. over 5 hours and was then poured onto a mixture of ice and water. Solid sodium bicarbonate was carefully added to neutralize the mixture which was then extracted with ethyl acetate. After washing with brine, the organic extract was dried (MgSO4) and concentrated under vacuum. The title compound (11.0 grams, 53%) was isolated by flash chromatography eluting with 5 to 10% ethyl acetate in methylene chloride. 1H NMR (CDCl3): δ 7.14 (d, J=8.5 Hz, 1H), 6.72 (dd, J=2.7, 8.5 Hz, 1H), 6.58 (d, J=2.7 Hz, 1H), 5.94 (s, 1H), 5.62-5.54 (m, 1H), 5.03-4.98 (m, 2H), 4.85 (br s, 1H), 2.95-2.91 (m, 1H), 2.85-2.63 (m, 5H), 2.53-2.40 (m, 3H), 2.08-1.99 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>Cl.CC(O)C>[F:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: CN1CCNCC1
Reactant: Cc1ccc(-c2ccnc(Cl)c2)cc1F
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc(-c2ccnc(N3CCN(C)CC3)c2)cc1F
Temperature: 180 °C

Procedure:
To a microwave tube was added 2-chloro-4-(3-fluoro-4methyl-phenyl)-pyridine (30 mg, 0.14 mmol), 1-methylpiperazine (50 mg, 0.5 mmol), 2-propanol (0.6 mL) and 1 drop concentrated HCl. The resulting mixture was heated at 180° C. for 60 minutes using the microwave instrument. The resulting mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].C(N(CC)CC)C>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:9][C:6]1[CH:5]=[N:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: C#Cc1cnc(N)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cnc(N)cn1
Reaction time: 6 h
Yield: 84 %

Procedure:
To a stirred solution of 5-ethynyl-2-aminopyrazine (18 mg; 0.151 mmol), in ethyl acetate (500 μL) was added triethylamine (63 μL; 0.45 mmol) and Pd(OH)2 (0.01 mmol; 20% wt on carbon). The reaction was placed under a hydrogen atmosphere at 45 psi and shook for 6 hours. The reaction was filtered and concentrated under reduced pressure to yield an off white solid (84% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1)[CH3:2].N12CCCN=C1CC[CH2:31][CH2:30][CH2:29]2.C(Br)C=C>C(O)C>[CH2:31]([O:26][C:20]1[CH:19]=[C:18]([C:15]2[O:16][CH:17]=[C:13]([CH2:12][CH2:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[O:27])[N:14]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH:30]=[CH2:29]
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCO
Solvent: C=CCBr
Product: C=CCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC)co2)ccc1OC
Reaction time: 3 h

Procedure:
A 0.3 g quantity of 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 101 was suspended in 10 ml of ethanol, 0.37 g of 1,8-diazabicyclo[5,4,0]undec-7-ene and 0.14 ml of allyl bromide were added thereto, and stirring was conducted for 3 hours while heating and refluxing. After distilling off ethanol under reduced pressure, water was added, ethyl acetate extraction was performed, followed by drying over anhydrous magnesium sulfate and distilling the solvent off. The residue was subjected to silica gel column purification (n-hexane:ethyl acetate=3:1), thereby yielding 0.2 g of white powdery 3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: CC1C=CC(C([O:8][CH2:9][C@@H:10]2[CH:14]([O:15]C(C3C=CC(C)=CC=3)=O)[CH2:13][C@H:12]([N:25]3[C:29]4=[N:30][C:31]([NH2:36])=[N:32][C:33]([O:34][CH3:35])=[C:28]4[C:27]([I:37])=[N:26]3)[O:11]2)=O)=CC=1.C[O-].[Na+].C(O)(=O)C>CO>[NH2:36][C:31]1[N:30]=[C:29]2[N:25]([C@@H:12]3[O:11][C@H:10]([CH2:9][OH:8])[CH:14]([OH:15])[CH2:13]3)[N:26]=[C:27]([I:37])[C:28]2=[C:33]([O:34][CH3:35])[N:32]=1
Reactant: COc1nc(N)nc2c1c(I)nn2[C@H]1CC(OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc(N)nc2c1c(I)nn2[C@H]1CC(O)[C@@H](CO)O1
Temperature: -10 °C

Procedure:
To a suspension of 15 (32.4 g, 50.40 mmol) in 600 mL of methanol was added 12.5 mL of 1M sodium methoxide in methanol. The reaction mixture was stirred at reflux for 18 h. and then cooled in a freezer (−10° C.). The crystals of 3 that formed were filtered and rinsed with ice-cold methanol: 10.95 g yield. Acetic acid (12.5 mL) was added to the filtrate and the volume was reduced to about 300 mL. The solution was allowed to sit in the freezer overnight and another crop of crystals (3.95 g) was collected. The filtrate was evaporated to dryness and the residual oil was triturated in ether. The solid that formed was filtered, dried and recrystallized from boiling water: 2.03 g. Total yield=16.93 g (83%); TLC (10% methanol in ethyl acetate), Rf=0.23; 1H NMR (DMSO-d6) δ 7.02 (2H, br s, 6-amino), 6.33 (1H, t, J=6.1 Hz), 5.24 (1H, d, J=4.4 Hz, 3′-OH), 4.73 (1H, t, J=5.6 Hz, 5′-OH), 4.36 (1H, m, 3′-H), 3.99 (3H, s, 4-methoxy), 3.75 (1H, m, 4′-H), 3.51–3.32 (2H, m, 5′-Hs), 2.79 and 2.17 (2H, 2×m, 2′-Hs). Anal. Calcd. For C11H141N5O4 0.3H2O; C, 32.02; H, 3.57; N, 16.98. Found C, 32.13; H, 3.35; N, 16.77.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[CH3:34]>>[OH:41][CH2:40][C:39]([NH:38][S:35]([C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:29]=1)(=[O:37])=[O:36])([CH3:43])[CH3:42]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1N
Product: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-4-methyl-benzenesulfonamide (example B. 11) according to general procedure II. Yellow solid. MS (ISP) 614.2 [(M−H−]; mp 240° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][NH:18][CH3:19])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:20])[CH2:17][N:18]([C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=1)[CH3:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: Cl
Product: Cc1cc(N(C)CC(=O)OC(C)(C)C)nc(Cl)n1
Yield: 52 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-6-methylpyrimidine and sarcosine tert-butyl ester hydrochloride. The title compound was isolated as a slightly yellow oil in a yield of 52%. MS ISP (m/e): 272.2 & 274.0 (25 & 10) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=6.23 (s broad, 1H), 4.21 (s broad, 2H), 3.10 (s broad, 3H), 2.36 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[O:21][CH2:20]3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:29]1([CH2:35][CH2:36][NH2:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([OH:21])[CH2:20][NH:37][CH2:36][CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(CCCN2CCN(CC3CO3)CC2)c2ccc(F)cc2)cc1
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CNCCc1ccccc1)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 9.8 %

Procedure:
3.86 g (0.01 mol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine and 1.2 g (0.01 mol) of 2-phenylethylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[O:12])[CH2:6][CH2:7][C:8](=[O:10])[OH:9].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([C:35](O)=[O:36])[S:32][C:31]=2[CH:38]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([C:35]([NH:4][C@@H:5]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH2:17][CH2:18]3)=[O:12])[CH2:6][CH2:7][C:8](=[O:9])[OH:10])=[O:36])[S:32][C:31]=2[CH:38]=1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)CCC(=O)O)CC2)CC1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](CCC(=O)O)NC(=O)c3cc4ccc(Cl)cc4s3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-(D-glutamyl)-4-(1-methylpiperidin-4-yl)piperazine trihydrochloride and 6-chlorobenzo[b]thiophene-2-carboxylic acid (41%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:6]=1[NH2:7].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]([CH3:15])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[C:6]=2[NH2:7])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccccc1-n1nc(C)c(Br)c1N
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: CN(C)C=O
Product: Cc1ccccc1-n1nc(C)c(-c2ccc(F)cc2)c1N
Temperature: 110 °C

Procedure:
4-Bromo-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (2 g, 7.52 mmol), 4-fluorophenylboronic acid (2.10 g, 11.3 mmol), and Pd(PPh3)4 (434 mg, 0.38 mmol) were dissolved in DMF (20 mL), and Na2CO3 (saturated aq solution, 18 mL) was added. The mixture was degassed for 10 min and then heated at 110° C. for 2 h. The reaction mixture was diluted, and the solid was filtered off. The solvent was concentrated under reduced pressure, and the residue purified by silica gel flash chromatography using 10 to 40% ethyl acetate in hexanes to give 1.2 g (90% pure, 51%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 7.25-7.34 (m, 6H), 7.08 (t, 2H), 3.62 (s, 2H), 2.20 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]([NH2:12])(=[S:11])[CH3:10]>C(O)C>[CH3:10][C:9]1[S:11][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[N:12]=1
Reactant: CC(N)=S
Reactant: O=C1CCCCC1Cl
Solvent: CCO
Product: Cc1nc2c(s1)CCCC2

Procedure:
5.00 g (37.7 mmol) of 2-chlorocyclohexanone and 2.83 g (37.7 mmol) of thioacetamide are heated in 25 ml of ethanol at the reflux temperature overnight. After cooling, the volatile components are removed in a rotary evaporator, and the remaining residue is taken up in 2 N sodium carbonate solution. It is extracted three times with dichloromethane, and the combined organic phases are dried with magnesium sulfate. The solvent is removed in a rotary evaporator, and the residue is then purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 7:3). 3.35 g (58% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH2:4][CH:5]2[CH:26]([NH:27]S(C(C)(C)C)=O)[CH:8]([CH2:9][C:10]=1/[CH:11]=[CH:12]/[C:13]1[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:15]([CH3:25])[N:14]=1)[CH2:7][CH2:6]2>CO>[Cl:2][C:3]1[CH2:4][CH:5]2[CH:26]([NH2:27])[CH:8]([CH2:9][C:10]=1/[CH:11]=[CH:12]/[C:13]1[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:15]([CH3:25])[N:14]=1)[CH2:7][CH2:6]2
Reactant: Cn1nc(/C=C/C2=C(Cl)CC3CCC(C2)C3NS(=O)C(C)(C)C)cc1-c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: Cn1nc(/C=C/C2=C(Cl)CC3CCC(C2)C3N)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Hydrochloric acid (in dioxane, 4M, 50 ml) was added into a solution of the product of Step 5 (5.71 g, 12 mmol) in methanol (100 ml) at 0° C. The solution was stirred at 0° C. for 1 hr and then at ambient temperature for a further 1 hr. The reaction mixture was concentrated in vacuo, diluted with saturated sodium hydrogen carbonate and extracted with ethyl acetate (3×100 ml). The organic extract were washed with brine, dried over MgSO4 and concentrated in vacuo, then eluted through an SCX cartridge (50 g) with methanol (100 ml) and then with ammonia in methanol (2M, 50 ml). The fraction containing the product was concentrated in vacuo, to afford (3-chloro-4-{(E)-2-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl]vinyl}bicyclo[4.2.1]non-3-en-9-yl)amine (3.76 g, 84%). δH (400 MHz, CDCl3) 1.33-1.61 (4H, m), 1.74-1.92 (2H, m), 2.15-2.23 (1H, br), 2.30-2.39 (1H, br), 2.54-2.69 (3H, m), 3.12 (1H, d, J 18.0), 3.34 (1H, t, J 6.5), 3.82 (3H, s), 6.47 (1H, s), 6.65 (1H, d, J 16.5), 7.15 (2H, t, J 8.5), 7.37-7.41 (2H, m), 7.47 (1H, d, J 16.5)
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)([CH3:4])[CH3:3].[I-].[Mg+2].[I-].[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[CH:24]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]1=[O:30]>>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[CH:24]1[C:25](=[O:30])[CH:26]2[CH:27]([CH:10]3[O:9][CH:8]2[CH:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:11]3)[C:28]1=[O:29]
Reactant: C[Si](C)(C)C#Cc1ccoc1
Reactant: Cc1cc(C)c(C2C(=O)C=CC2=O)c(C)c1
Agent: [I-]
Agent: [Mg+2]
Product: Cc1cc(C)c(C2C(=O)C3C4CC(C#C[Si](C)(C)C)C(O4)C3C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-(Trimethylsilylethynyl)furan (10.0 g, 61 mmol) and magnesium iodide (1.11 g, 4 mmol) are added to 2-(2,4,6-trimethylphenyl)cyclopent-4-ene-1,3-dione (4.34 g, 20 mmol) and the mixture is stirred at room temperature for 3 days. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7RS)-4-(2,4,6-trimethylphenyl)-8-trimethylsilylethynyl-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: O=[C:2]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:26][C:27]1[C:28]([NH2:33])=[N:29][NH:30][C:31]=1[NH2:32].Cl>CO>[NH2:32][C:31]1[C:27]([CH2:26][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:24])([F:23])[F:25])[C:16]=2[CH3:15])=[C:28]2[N:33]=[C:2]([CH:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[CH:3]=[C:4]([OH:6])[N:29]2[N:30]=1
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Reactant: Cc1c(Cc2c(N)n[nH]c2N)cccc1C(F)(F)F
Agent: Cl
Solvent: CO
Product: Cc1c(Cc2c(N)nn3c(O)cc(C4CCOCC4)nc23)cccc1C(F)(F)F
Temperature: 65 °C

Procedure:
To a mixture of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.2 g, 0.999 mmol) and 4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazole-3,5-diamine (0.270 g, 0.999 mmol) was added Methanol (4 mL) and hydrochloric acid (0.4 mL, 0.500 mmol) in methanol (1.25 N). The reaction vessel was sealed and heated at 65° C. for 6 days. The reaction mixture was concentrated to 1 mL. The solid was filtered and wash with methanol (2 ml×3) and dried (0.19 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.84 (m, 4H) 2.47 (s, 3H) 2.58-2.75 (m, 1H) 3.34-3.39 (m, 2H) 3.85 (s, 2H) 3.93 (dd, J=11.24, 3.16 Hz, 2H) 5.28 (s, 2H) 5.41 (d, J=1.52 Hz, 1H) 7.01 (d, J=7.83 Hz, 1H) 7.28 (m, 1H) 7.54 (d, J=7.83 Hz, 1H) 11.18 (s, 1H); LC/MS: MS (ES+) m/e 407.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][N:5]([C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])[C:6](Cl)=[O:7].O>O1CCCC1>[CH2:1]([NH:3][C:6]([N:5]([CH3:4])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:7])[CH3:2]
Reactant: CN(C(=O)Cl)C(=O)Nc1ccccc1
Reactant: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 80 %

Procedure:
In 50 ml of anhydrous tetrahydrofuran, 9.0 g (0.2 mol) of ethylamine was dissolved, and under cooling below 0° C. with stirring, a solution prepared by dissolving 21.3 g (0.1 mol) of 2-methyl-4-phenylallophanoyl chloride into 50 ml of anhydrous tetrahydrofuran was added by drop-wise. The reaction was continued at a room temperature for 1 hour, the solvent was then removed by distillation under a reduced pressure. To the residue thus obtained was added water and the precipitate thus formed was separated by filtration and dried, and recrystallized from ether-petroleum ether to obtain 17.7 g (yield 80%) of 1-ethyl-3-methyl-5-phenylbiuret having a melting point of 80.5°-81.5° C.
Reaction SMILES: [N:1]1C=CC=CC=1.N.[NH2:8][C:9]1[C:10]([F:35])=[CH:11][C:12]([F:34])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([N+:27]([O-:29])=[O:28])=[C:22](F)[C:23]=3[CH3:25])[C:18](=[O:30])[C:17]([C:31]([OH:33])=[O:32])=[CH:16]2)[CH:14]=1>C(OCC)C>[NH2:1][C:22]1[C:23]([CH3:25])=[C:24]2[C:19]([C:18](=[O:30])[C:17]([C:31]([OH:33])=[O:32])=[CH:16][N:15]2[C:13]2[CH:14]=[C:9]([NH2:8])[C:10]([F:35])=[CH:11][C:12]=2[F:34])=[CH:20][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: Cc1c(F)c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: c1ccncc1
Agent: N
Solvent: CCOCC
Product: Cc1c(N)c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Pyridine (1.0 ml) and 28% aqueous ammonia (100 mg) were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-8-methyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was stirred at 50° C. for 2 days. Additional 28% aqueous ammonia (0.5 ml) was added, and the mixture was further stirred overnight at 50° C. Diethyl ether was added to the reaction mixture, followed by stirring. A supernatant liquid was removed, and ethanol was added to the residue. Solids deposited were collected by filtration and washed with ethanol to obtain the title compound (59 mg) as a yellow powder.