Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1C.N1CCCNCC1>>[CH3:10][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:1]=1[N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: C1CNCCNC1
Product: Cc1cc([N+](=O)[O-])ccc1N1CCCNCC1

Procedure:
The title compound was prepared as described in Example 100A, substituting (2-fluoro-5-nitrophenyl)methanol and 1-methyl-1,4-diazepane with 1-fluoro-2-methyl-4-nitrobenzene and 1,4-diazepane (0.7 more equivalent), respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]=[C:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].[I-].[CH3:18][S+](C)(C)=O.[H-].[Na+]>>[CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]1[C:10]2([CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH2:18]1
Reactant: C[S+](C)(C)=O
Reactant: CC1=CCC(CC=C2CCCC2=O)C1(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: CC1=CCC(CC2CC23CCCC3=O)C1(C)C
Yield: 35.1 %

Procedure:
13.0 g (60 mmol) of 2-[2-(2,2,3-trimethylcyclopent-3-enyl)ethylidene]cyclopentanone was cyclopropanated with 16.2 g (74 mmol) of trimethylsulfoxonium iodide and 3.6 g (75 mmol) of 50% oil suspension of sodium hydride according to Example 11a to give 4.9 g (35% yield) of 1-(2,2,3-trimethylcyclopent-3-enylmethyl)spiro[2.4]heptan-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:12])=[O:5]
Reactant: N
Reactant: O=C(Cl)c1c(F)cccc1Cl
Product: NC(=O)c1c(F)cccc1Cl

Procedure:
2-chloro-6-fluoro-benzamide was prepared from 2-chloro-6-fluoro-benzoic acid chloride and ammonia by processes known from the literature. It had amelting point of 138° C. ##STR7##
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[C:5]([N:33]2[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:34]2)=[N:6][C:7]([C:10]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[N:12]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:11]=2)=[CH:8][CH:9]=1)[CH3:3].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH:2]([C:4]1[C:5]([N:33]2[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])[CH2:34]2)=[N:6][C:7]([C:10]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[N:12]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)c1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
(S)-tert-butyl 1-(3-(prop-1-en-2-yl)-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate (60.50 mg, 0.09426 mmol) and palladium hydroxide on carbon 20% (0.2:0.8, Palladium hydroxide:carbon black, 6.619 mg) in Ethanol (30 mL) in a round bottom flask was vacuumed and connected to a Hydrogen balloon. The mixture was stirred at room temperature over the weekend. The reaction mixture was filtered through Celite. The filtrate was concentrated to afford (S)-tert-butyl 1-(3-isopropyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate, which was dissolved in Trifluoroacetic Acid (3 mL) and Methylene chloride (3 mL), and treated with Trifluoromethanesulfonic acid (83.4 uL, 0.943 mmol) and Triethylsilane (150.6 uL, 0.943). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 328 as an off-white solid (8.2 mg, 21%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.31 (d, J=2.1 Hz, 1H), 9.22 (s, 1H), 9.06 (s, 1H), 8.61 (dd, J=4.7, 1.3 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.32 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.54 (dd, J=8.0, 4.8 Hz, 1H), 2.90 (d, J=9.1 Hz, 2H), 2.00 (d, J=12.6 Hz, 1H), 1.90 (d, J=13.4 Hz, 1H), 1.76 (dd, J=24.1, 11.0 Hz, 1H), 1.46-1.34 (m, 1H), 1.25 (t, J=6.9 Hz, 6H); ESI MS m/z=414.2 (M+1)
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[S:76](Cl)(=[O:78])=[O:77])([O-:69])=[O:68]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:76]([C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][C:70]=3[N+:67]([O-:69])=[O:68])(=[O:77])=[O:78])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (66 mg) in dry methylene chloride (1.4 ml) was added an excess of diisopropylethyl amine (34 μl) and o-nitrobenzenesulfonyl chloride (36 mg) followed by addition of 4-dimethylaminopyridine (24 mg). The mixture was stirred at room temperature for 18 hours at which time it was diluted with ethyl acetate, extracted from saturated sodium bicarbonate solution and washed with brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol to give the title compound (66 mg).
Reaction SMILES: [CH2:1]([C:3]1[S:20][C:6]2[NH:7][C:8](=[O:19])[N:9]([CH2:12][CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]=[C:38](C(Cl)(Cl)Cl)[O:37][N:36]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-:45].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:20][C:6]2[N:7]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[NH:39][C:38](=[O:45])[O:37][N:36]=4)=[CH:25][CH:24]=3)[C:8](=[O:19])[N:9]([CH2:12][CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1cc2c(=O)n(CCc3cccs3)c(=O)[nH]c2s1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CCc3cccs3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
A mixture of 6-ethyl-3-[2-(2-thienyl)ethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.36 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.76 g), potassium carbonate (0.32 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and acetone (5 mL). 1N Aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.32 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1.BrC[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:21]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([N:21]2[C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[CH:23][C:19]([CH2:18][CH:4]([C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]([CH3:14])[CH:6]=3)[C:3]([OH:2])=[O:15])=[N:20]2)=[CH:36][CH:35]=1.[CH3:1][O:2][C:3](=[O:15])[CH:4]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[N:21]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:20]=1
Reactant: COC(=O)Cc1cn(C)c2ccccc12
Reactant: COc1ccc(-n2nc(CCBr)cc2-c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cc(-c2ccc(C)cc2)n(-c2ccc(OC)cc2)n1)c1cn(C)c2ccccc12
Product: COc1ccc(-n2nc(CC(C(=O)O)c3cn(C)c4ccccc34)cc2-c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared by Method 2 from (1-methyl-1H-indol-3-yl)-acetic acid methyl ester (0.10 g, 0.49 mmol), 3-bromoethyl-1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazole (89 mg, 0.25 mmol), sodium hydride (19 mg, 0.49 mmol) and DMF (4.0 mL), giving 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionic acid methyl ester, which was not isolated. The ester was converted to the acid in situ by adding 2.5 mL (4.9 mmol) LiOH solution giving 57 mg (49%) of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionic acid. HPLC: Rt=3.23 (Method B). MS (ES+): mass calculated for C29H27N3O3, 465.21; m/z found 466.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.15 (br s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.32 (s, 1H), 7.17-7.10 (m, 5H), 7.05-7.03 (m, 3H), 6.93 (d, J=8.9 Hz, 2H), 6.38 (s, 1H), 4.22 (dd, J=9.1, 5.9 Hz, 1H), 3.76 (s, 6H), 3.44 dd, J=14.7, 9.2 Hz, 1H), 3.04 (dd, J=5.9, 14.7 Hz, 1H), 2.27 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.NCC([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:71])([F:70])[F:69])[CH:63]=2)[CH2:57][CH2:56]1)=O>CN(C=O)C.O>[O:27]=[C:25]([N:55]1[CH2:56][CH2:57][CH:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:69])([F:70])[F:71])[CH:63]=2)[CH2:59][CH2:60]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 16.2 %

Procedure:
DIPEA (360 mg, 2.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (200 mg, 0.8 mmol) in DMF (2 mL) followed by HOBt (131 mg, 0.97 mmol) and EDCI.HCl (187 mg, 00.97 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (200 mg, 0.8 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in CHCl3 as eluent) to afford 62 mg (16.2% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 473.17, 91%, 1H NMR (300 MHz, DMSO-d6): δ8.1 (m, 1H), 7.8 (d, 2H), 7.5 (m, 3H), 7.4 (m, 4H), 7.1 (s, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.5 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cccc(CCC(=O)O)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a mixture of ethyl 3-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (1.00 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added a 1N aqueous sodium hydroxide solution (4.2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (0.61 g, 66%) of 3-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 157-158° C.
Reaction SMILES: N[C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]=2[N:13]=1.N(OCCC(C)C)=O.[ClH:30].O>CS(C)=O.[Cu](Cl)Cl>[Cl:30][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]=2[N:13]=1
Reactant: N#Cc1c(N)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccccc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1c(Cl)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.0 g (3.04 mmol) of 7-amino-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile [Assy, M. G. et al., J. Indian Chem. Soc. 1996, 73 (11), 623-624] was dissolved in 8 ml of DMSO, 0.82 ml (713 mg, 6.09 mmol) of isopentyl nitrite and 818 mg (6.09 mmol) of copper(II) chloride were added and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled, and 6 ml of 1 N hydrochloric acid solution followed by 100 ml of water were then added. The precipitate formed was filtered off and dried under high vacuum. The product was not purified any further (purity according to LC-MS: about 82%).
Reaction SMILES: [F:1][C:2]1[C:3](/[N:9]=[CH:10]/[N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:14](Cl)(Cl)=[S:15].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>CC#N>[CH3:12][N:11](/[CH:10]=[N:9]/[C:3]1[C:2]([F:1])=[CH:7][N:6]([C:14](=[S:15])[N:20]([CH2:21][CH3:22])[CH2:18][CH3:19])[C:5](=[O:8])[N:4]=1)[CH3:13]
Reactant: S=C(Cl)Cl
Reactant: CN(C)/C=N/c1nc(O)ncc1F
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)C(=S)n1cc(F)c(/N=C/N(C)C)nc1=O
Temperature: 80 °C
Reaction time: 19 h
Yield: 16 %

Procedure:
A 25 mL screw-top vial was charged with (E)-N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformimidamide (99.7 mg, 0.541 mmol), CH3CN (5 mL) and BSA (0.0665 mL, 0.272 mmol). The resulting mixture was then agitated on a rotary shaker at 80° C. for 19 h. After cooling to room temperature, thiophosgene (0.0415 mL, 0.544 mmol) was added, and the reaction mixture was agitated at room temperature on a rotary shaker for 90 min. At this time, diethylamine (0.112 mL, 1.08 mmol) was added, and the reaction mixture was further agitated at room temperature for 1 h. The heterogenous mixture was poured into a fritted funnel, and the resulting filtrate was concentrated in vacuo. This crude material was then purified by normal phase chromatography (gradient, 0 to 100% EtOAc/Hexane) to afford (E)-4-((dimethylamino)methyleneamino)-N,N-diethyl-5-fluoro-2-oxopyrimidine-1(2H)-carbothioamide (25.9 mg, 16%) as a pale yellow solid: mp 118-123° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.41 (d, J=3.2 Hz, 1H), 3.20 (s, 3H), 3.34 (q, J=6.7 Hz, 4H), 3.09 (s, 3H), 1.17 (s, 3H), 1.08 (s, 3H); ESIMS m/z 300 ([M+H]+).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:30]=3)[C:25](O)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:43][C:44]1[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])[CH:30]=3)[C:25]([NH:43][C:44]3[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=3)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Cc1cnc(N)cn1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Reaction time: 1 h
Yield: 22.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.11 mL, 0.80 mmol) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoic acid (0.3 g, 0.62 mmol) in DCM (10 mL) and stirred for 1 hour. 2-Amino-5-methylpyrazine (135 mg, 1.23 mmol), then pyridine (0.1 mL, 1.23 mmol), were added and the mixture stirred for a further 30 mins before being reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound as a colourless oil (82 mg).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
The conditions to prepare Reference Example 34 are used with 2.0 g of 4-benzoylbenzoic acid and 30 ml of thionyl chloride to give the desired product in a solution of 30 ml of methylene chloride.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:34][NH:35][C:36]([NH2:38])=[S:37]>CO>[C:12]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[N:34][NH:35][C:36]([NH2:38])=[S:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1
Reactant: NNC(N)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NC(=S)NN=C(c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 12 h
Yield: 3.3 %

Procedure:
A catalytic amount of p-toluenesulfonic acid was added to a solution of 1,4 dibenzoylbenzene 1 (0.286 g, 1 mmol) in anhydrous methanol (10 mL). After stirring at reflux for 10 min, thiosemicarbazide (0.182 g, 2 mmol) was added to the reaction mixture and stirred for 12 h under an inert atmosphere of nitrogen gas. After 12 h, methanol was removed under reduced pressure and 10 mL of water was then added. The products were extracted with ethyl acetate (2×20 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 70:30) afforded 4-benzoyl benzophenone thiosemicarbazone 4 (0.012 g, 0.033 mmol) in a 3.3% yield. HRMS (ESI) calculated for C21H17N3OSH+ (M+H)+ 360.11651, found 360.11649.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Cl)=[N:6][OH:7])[CH3:2].[C:10]([CH:14]1[CH2:19][CH2:18][C:17](=[CH2:20])[CH2:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:5]1[CH2:20][C:17]2([CH2:18][CH2:19][CH:14]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:15][CH2:16]2)[O:7][N:6]=1)=[O:9])[CH3:2]
Reactant: C=C1CCC(C(C)(C)C)CC1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=NOC2(CCC(C(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-chloro-2-hydroxyiminoacetic acid ethyl ester (2.2 g, 14.6 mmol) in DCM (20 ml) was slowly added dropwise at 0° C. to a solution of 1-tert-butyl-4-methylenecyclohexane (740 mg, 4.86 mmol) in DCM (20 ml). Subsequently, a solution of triethylamine (1.5 ml) in DCM (10 ml) was slowly added dropwise at 0° C. and the resulting mixture was stirred overnight at RT. The reaction mixture was diluted with water. The aqueous phase was extracted several times with DMC. The combined organic phases were dried and the solvent was removed under vacuum. After purification of the residue (silica gel, hexane/ether 2:1) by column chromatography, the desired product 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid ethyl ester was obtained as a yellowish liquid (1.21 g, 93% of the theoretical amount).
Reaction SMILES: CCN(C(C)C)C(C)C.C(OC(=O)[CH:14]([C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22](F)[C:21]=1[F:29])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.CS(C)=O.[Cl:35][C:36]1[CH:37]=[C:38]([C:42]([F:46])([F:45])[CH2:43][NH2:44])[CH:39]=[CH:40][CH:41]=1>C([O-])(O)=O.[Na+]>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22]([NH:44][CH2:43][C:42]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([Cl:35])[CH:37]=2)([F:45])[F:46])[C:21]=1[F:29])[CH3:19]
Reactant: NCC(F)(F)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(C#N)ccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2cccc(Cl)c2)c1F
Temperature: 110 °C
Reaction time: 69 h
Yield: 64.1 %

Procedure:
To a solution of DIPEA (1.38 mL, 7.9 mmol), 2-(6-cyano-2,3-difluorophenyl)malonic acid diethyl ester (1.35 g, 6.00 mmol), as prepared in the preceding step, and DMSO (1.7 mL) was added 2-(3-chlorophenyl)-2,2-difluoroethylamine (1.44 g, 7.51 mmol), as prepared in Example 2d. The reaction was stirred under argon at 110° C. for 69 h and then allowed to cool to room temperature. The mixture was diluted with saturated NaHCO3 (15 mL) and extracted with ether (2×15 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel (3:1 hexane/EtOAc) to afford the title compound (1.525 g, 64%) as a tan crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.51-7.41 (m, 2H), 7.40-7.36 (m, 2H), 7.30 (dd, J=8.6 Hz, 1.3 Hz, 1H), 6.63 (t, J=8.2 Hz, 1H), 4.67 (br, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.84 (d, J=2.0 Hz, 2H), 3.81 (dt, J=13.3 Hz, 6.9 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H). LC/MS (ESI) calcd for C21H20ClF3N3O2 (MH+.MeCN) 438.1. found 438.2.