Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:35]6[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]6)=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C1CCNCC1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(N5CCCCC5)nc4)ccc2OCC3)c(F)c1
Temperature: 150 °C
Yield: 8.5 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene, from the procedure for 249, (470 mg, 1.0 mmol), Piperidine (102 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 232 (46.2 mg, yield: 8.5%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.10 (d, J=4.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.78-7.77 (m, 2H), 7.50-7.40 (m, 1H), 7.18 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.64 (s, 4H), 3.16 (s, 2H), 1.63-1.57 (m, 4H) ESI-MS: m/z=543 [M+H+]
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1)[C:6]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]1)=[N:5]2.CO[CH:32](OC)[N:33]([CH3:35])[CH3:34]>>[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:7]2[C:6]([N:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:26]3)=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([N:1]=[CH:32][N:33]([CH3:35])[CH3:34])[CH:3]=3)[N:8]=2)[CH2:13][CH2:14]1)[CH2:19][CH3:20]
Reactant: COC(OC)N(C)C
Reactant: CCCN1CCN(c2nc3ccc(N)cc3nc2N2CCN(CCC)CC2)CC1
Product: CCCN1CCN(c2nc3ccc(N=CN(C)C)cc3nc2N2CCN(CCC)CC2)CC1
Temperature: 64 °C

Procedure:
A 6.0 g. portion of 6-amino-2,3-bis(4-propyl-1-piperazinyl)quinoxaline (prepared as in Example 5) is mixed with 3.42 ml. of dimethylformamide dimethylacetal in a reaction flask fitted with a reflux condenser. The mixture is refluxed in an oil bath at 64° C. for three hours. The condenser is removed and the distillate is allowed to boil off as the oil bath is permitted to cool overnight. The flask is stripped of solvent by water pump evacuation and the residue is dissolved in 50 ml. of acetonitrile; is treated with activated charcoal and filtered. The filtrate is cooled at -10° C. causing separation of an oil. The supernatant is decanted and the oil is air dried to yield a crystalline solid which is recrystallized from 20 ml. of hexane by cooling at -10° C. The precipitate is filtered and is air dried to give the product of the example as a yellow solid, m.p. 95.5°-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C@@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@H:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: C[C@H]1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: C[C@@H]1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(R)-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[CH:9]=1.O.CN([CH:22]=[O:23])C>>[CH3:6][O:7][C:8]1[C:17]([CH:22]=[O:23])=[CH:16][C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)OCCO2
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1C=O)OCCO2
Reaction time: 2 h

Procedure:
3.3 eq. of dry DMF are placed in a three-necked flask and then, using a dropping funnel, 1.3 eq. of phosphorus oxychloride are added at 0° C. After returning to ambient temperature, the compound obtained in Step B (4 g:20.59 mmol) is dissolved in 6.5 ml of DMF and then added to the previous solution. Heating is carried out for 2 hours at 110° C. After cooling, the mixture is hydrolysed with water and extracted with dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[C:23](Cl)(=[O:25])[CH3:24].N1C=CC=CC=1>C(Cl)Cl>[C:23]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1])(=[O:25])[CH3:24]
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)=O)c(Cl)cc1F

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and acetyl chloride with pyridine in methylene chloride there is obtained 2-chloro-4-fluoro-5-[2-methoxy -6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-phenyl acetate, m.p. 110°-112° C.;
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([C:14]#[N:15])([CH3:13])[CH2:8][CH2:9][C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[C:1]([N:5]=[N:6][C:7]([C:14]#[N:15])([CH3:13])[CH2:8][CH2:9][C:10]([Cl:18])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Reaction time: 4 h
Yield: 98.8 %

Procedure:
Into a 25 ml round bottom flask was weighed 5 grams (.0237 mole) of 4-t-butylazo-4-cyanovaleric acid and then 15 ml of benzene and 2 ml of thionyl chloride were added. The acid dissolved and the solution was stirred for 4 hours at 25°C ± 2°C (protected from the atmosphere by a CaCl2 tube). At the end of the starting period the benzene and excess thionyl chloride evaporated under reduced pressure leaving 5.35 grams (98.8% yield) of 4-t-butylazo-4-cyanovaleryl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH:11]([C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1)([CH3:13])[CH3:12].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:19][C:16]2[S:17][CH:18]=[C:14]([CH:11]([CH3:13])[CH3:12])[N:15]=2)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: Cc1nc(C(C)C)cs1
Reactant: N#Cc1cccc(C=O)c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1csc(C=Cc2cccc(C#N)c2)n1
Temperature: 170 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
3-Cyanobenzaldehyde (3.93 g, 30.0 mmol) was mixed with 4-isopropyl-2-methylthiazole (4.19 g, 30.0 mmol), and acetic anhydride (1.53 g, 15.0 mmol) was added. The mixture was heated under stirring at 170° C for 24 hours. After the reaction, acetic acid was distilled out under reduced pressure and the residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate=3/l) to afford the indicated compound (4.10 g) with a yield of 54%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:42](=[O:48])[O:43][C:44](Cl)(Cl)Cl)Cl.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=1)[O:55][CH2:56][CH2:57]CO>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:48])[O:43][CH2:44][CH2:57][CH2:56][O:55][C:54]1[CH:60]=[CH:61][CH:62]=[C:52]([O:51][CH3:50])[CH:53]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(OCCCO)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(OCCCOC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2Cl)c1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (107 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(3-methoxyphenoxy)-1-propanol (67 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (67 mg, yield 52%).
Reaction SMILES: [CH3:1][Mg]I.[Cl:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([C:11]([O:13]CC)=O)=[O:10])=[CH:7][CH:6]=1.[OH:18][C:19]1[C:20](=O)[O:21][C:22](C)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)C=1O>C1COCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]2([CH3:1])[O:10][C:19](=[O:18])[C:20]([O:21][CH2:22][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:11]2[OH:13])=[CH:16][CH:17]=1
Reactant: C[Mg]I
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1
Reactant: CC1(c2ccccc2)OC(=O)C(O)=C1O
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2)OC(=O)C(OCc2ccccc2)=C1O
Yield: 40 %

Procedure:
A total of 3.4 mL (10.2 mmol) of 3.0M methylmagnesium iodide was added to a solution of 2.34 g (10 mmol) of ethyl 4-chlorobenzoylformate in THF in an analogous manner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior to hydrogenolysis 1.3 g (40% yield) of 5-(4-chlorophenyl)-4-hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone as a yellow oil: 1H NMR (CDCl3) δ 7.37-7.21 (m, 9H), 5.10 (s, 2H), 1.73 (s, 3H).
Reaction SMILES: [N:1]#[C:2][NH2:3].CC(C)([O-])C.[K+].[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[CH:24][CH:23]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)=[O:34]>C(#N)C.C(O)(C)(C)C.O>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29]3[S:30][C:32]([C:33](=[O:34])[C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)=[C:2]([NH2:3])[N:1]=3)=[CH:26][CH:27]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(N=C=S)cc2)C1
Reactant: N#CN
Reactant: O=C(CBr)c1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(Nc3nc(N)c(C(=O)c4cccc(F)c4)s3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyanamide (46.2 mg, 1.1 mmol) was suspended in acetonitrile (5 mL). To the stirred suspension, potassium tert-butoxide (123 mg, 1.1 mmol) in 2 mL of tert-butanol was added followed by isothiocyanate (Example 19, 306 mg, 1 mmol). The mixture was stirred for 30 minutes at room temperature followed by the addition of 2-bromo-1-(3-fluoro-phenyl)-ethanone (TCl, 216 mg, 1 mmol). After being stirred for 2 hours at room temperature, the mixture was poured into water and the new mixture was extracted with ether. The extract was dried (Na2SO4) and concentrated to give the desired product as a yellow solid, 480 mg, 99%. MS (ES) MH+=485.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CO.CC(C)=O.[OH-].[K+]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:40])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-benzoic acid tert-butyl ester (1.07 g, 1.82 mmol) in a 1:1 MeOH/acetone solution (40 mL total) was added 4 mL of a 50% KOH (aq) solution. The reaction mixture was stirred for 20 hours at ambient temperature. Glacial acetic acid was added dropwise until the solution had a pH=6. The product was extracted into ethyl acetate and dried over Na2SO4. The material was adsorbed onto silica gel and purified by flash chromatography in an ethyl acetate and hexane gradient, affording 3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid tert-butyl ester as a colorless oil that started to crystallize into a white solid (1.97 g, quantitative yield). 1H NMR (500 MHz, CDCl3) δ 11.34 (s, 1H), 8.50 (s, 2H), 8.21 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.75 (m, 2H), 7.55 (m, 2H), 7.40 (t, J=6.0 Hz, 1H), 7.10 (m, 2H), 3.88 (s, 3H), 1.25 (s, 9H). MS: m/e 401.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[C:13]([C:31](=[NH:34])[NH:32][NH2:33])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.Cl[C:44](Cl)([O:46]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[C:13]([C:31]3[NH:34][C:44](=[O:46])[NH:33][N:32]=3)[CH:12]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)C(=O)c1ccc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)c(C(=N)NN)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)c(-c3n[nH]c(=O)[nH]3)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3′-(N-aminocarbamimidoyl)-4′-[3-(3-trifluoromethyl-phenyl)-ureido]-biphenyl-4-carboxylic acid dimethylamide (322 mg) and triethylamine (212 microliters) dissolved in dichloromethane (5 ml) at -50° C. was treated with a solution of triphosgene (236 mg) in dichloromethane (5 ml). The mixture was stirred for 2.5 hrs at ambient temperature and poured into water. After adjusting to pH 7 with aq. sodium bicarbonate, the mixture was extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated. Column chromatography on silica afforded 3′-(5-Oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-4′-[3-(3-trifluromethyl-phenyl)-ureido]-biphenyl-4-carboxylic acid dimethylamide as a white solid. Mp.=212° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]12[CH2:11][CH:10]1[CH2:9][NH:8][CH2:7]2)(=[O:3])[CH3:2].[CH2:12](N(CC)CC)[CH3:13].Cl[C:20]1[N:29]=[C:28]2[C:23]([C:24](=[O:41])[C:25]([C:38]([OH:40])=[O:39])=[CH:26][N:27]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])=[CH:22][C:21]=1[F:42].N1C2C(=CC=CN=2)C=CC=1>C(#N)C>[C:1]([NH:4][CH2:5][C:6]12[CH2:11][CH:10]1[CH2:9][N:8]([C:20]1[N:29]=[C:28]3[C:23]([C:24](=[O:41])[C:25]([C:38]([O:40][CH2:12][CH3:13])=[O:39])=[CH:26][N:27]3[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])=[CH:22][C:21]=1[F:42])[CH2:7]2)(=[O:3])[CH3:2]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NCC12CNCC1C2
Reactant: CCN(CC)CC
Agent: c1cnc2ncccc2c1
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4CC4(CNC(C)=O)C3)c(F)cc2c1=O

Procedure:
A mixture of 1-[(N-acetyl)aminomethyl]-3-azabicyclo[3.1.0]hexane (115.5 mg, 0.75 mmol) and triethylamine (312 μl, 2.25 mmol) in acetonitrile (20 ml) was treated with the ethyl ester of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (283 mg, 0.74 mmol) and heated to 80° for 20 hours. Additional 1-(N-acetyl)-aminomethyl-3-azabicyclo[3.1.0]hexane (97 mg) was added portionwise over 2.5 hours until thin layer chromatography indicated the absence of starting naphthyridine. The reaction mixture was concentrated in vacuo, and the residue chromatographed on silica gel (eluant: 189:10:1 chloroform:methanol:concentrated ammonium hydroxide). The title product was obtained as a colorless oil (280.3 mg, 0.56 mmol, 76% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]1[C:16](=[O:17])[CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][C:13]1=[O:25].C(N(C(C)C)C(C)C)C.Cl[C:36]([S:38][CH:39]([CH3:41])[CH3:40])=[O:37]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:16](=[O:17])[CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][C:13]=1[O:25][C:36]([S:38][CH:39]([CH3:41])[CH3:40])=[O:37]
Reactant: CC#Cc1cc(C)c(C2C(=O)CC(Cc3ccccn3)C2=O)c(C)c1
Reactant: CC(C)SC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC#Cc1cc(C)c(C2=C(OC(=O)SC(C)C)CC(Cc3ccccn3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To a solution of the 2-(2,6-dimethyl-4-prop-1-ynyl-phenyl)-4-(2-pyridylmethyl)cyclopentane-1,3-dione (0.100 g, 0.302 mmol) in dichloromethane (3.02 mL) was added N-ethyl-N-isopropyl-propan-2-amine (1.51 mmol, 0.265 mL). The reaction was then cooled in the freezer for 30 minutes before addition of S-isopropyl chlorothioformate (0.075 ml, 0.603 mmol), and then the reaction mixture was stirred overnight at room temperature. The reaction was then washed with water, dried and reduced in vacuo. The crude product was then purified by column chromatography, eluting with acetonitrile and dichloromethane, to give the desired product (23 mg, 18%). The product was characterised by HPLC, as follows.
Reaction SMILES: O[C:2]1([C:23]([F:26])([F:25])[F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:23]([F:25])([F:26])[F:24])[N:3]=[C:4]2[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccncc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccncc2)cc1
Yield: 40.8 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (0.85 g, 2.2 mmol) and p-toluenesulfonic acid monohydrate (0.12 g) in toluene (150 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture was chromatographed on silica gel using ethyl acetate/acetone (96/4) to give pure 4-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (330 mg, 41%) as a white solid: mp (DSC) 197° C. Anal. Calc'd. for C16H12N3SO2F3 : C, 52.30, H, 3.29, N, 11.44, S, 8.73. Found C, 52.19, H, 3.26, N, 11.25, S, 8.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)C(C)(C)Cn1ncc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(cnn4CC(C)(C)C(=O)O)c3)no2)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 3.1 %

Procedure:
A solution of ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoate (D111) (100 mg, 0.21 mmol) in Ethanol (2 ml) was treated with a 2M sodium hydroxide aqueous solution (1 ml) and heated at 80° C. with stirring for 4 hours. The reaction mixture was cooled to room temperature and diluted with water (5 ml). The aqueous solution was acidified with glacial acetic acid, and extracted with EtOAc (2×10 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the residue by MDAP gave the desired product (3 mg, 3%) as a colourless solid. MS (ES): C22H22ClN5O4 requires 455; found (MH+) 456.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]([CH3:11])[C:7](=[O:12])[CH:6]=1)=O.O.[NH2:14][NH2:15]>C(O)C.C(OCC)C>[CH3:11][N:8]1[CH:9]=[CH:10][C:5]([C:3]([NH:14][NH2:15])=[O:2])=[CH:6][C:7]1=[O:12]
Reactant: COC(=O)c1ccn(C)c(=O)c1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: Cn1ccc(C(=O)NN)cc1=O
Temperature: 78 °C
Yield: 78 %

Procedure:
The title compound from example 30.1 (4 g, 24 mmol) was dissolved in ethanol and stirred at 78° C. Hydrazine hydrate (5.8 mL, 120 mmol) was added via a syringe and the reaction was stirred for 3 h at 78° C., at which time the starting material was no longer visible by TLC. The reaction mixture (clear solution) was then cooled to room temperature, and diluted with diethyl ether to precipitate the product which was collected by vacuum filtration to yield the title compound as a pale yellow solid (3.13 g, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH:22]=O)=[CH:7]2.[CH2:24]([NH2:33])[C:25]1[CH:32]=[CH:31][C:28]([O:29][CH3:30])=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:30][O:29][C:28]1[CH:31]=[CH:32][C:25]([CH2:24][NH:33][CH2:22][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:26][CH:27]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3C(F)(F)F)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2ccccc2C(F)(F)F)cc1

Procedure:
Prepared according to Procedure F using 8-methyl-2-(2-(trifluoromethyl)phenyl)-quinoline-3-carbaldehyde (1 g, 3.17 mmol), DCE (16 mL), PMBNH2 (0.62 mL, 4.75 mmol, 1.5 eq), and NaBH(OAc)3 (2.0166 g, 9.52 mmol, 3 eq). After purification, N-(4-methoxybenzyl)(8-methyl-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methanamine was obtained as light yellow syrup. 1H NMR (DMSO-d6) δ ppm 8.48 (1 H, s), 7.87 (2 H, t, J=7.2 Hz), 7.64-7.77 (2 H, m), 7.48-7.62 (3 H, m), 7.14 (2 H, d, J=8.6 Hz), 6.81 (2 H, d, J=8.6 Hz), 3.71 (3 H, s), 3.44-3.62 (4 H, m), 2.61 (3 H, s), 2.54 (1 H, s). Mass Spectrum (ESI) m/e=437.2 (M+1).