Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:26]CN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.[N:42]1([O:51][P+](N(C)C)(N(C)C)N(C)C)[C:46]2C=CC=CC=2N=N1>>[CH3:26][O:51][N:42]([CH3:46])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (15.8, 38 mmol), N, O-dimethyl hydroxylamine hydrochloride (11.1 mg, 114 mmol), DIEA (41 mL, 228 mmol) methyl-m-tolyl-amine (44 mg, 0.36 mmol), and BOP (69 mg, 49 mmol), were reacted according to the procedure D for the synthesis of 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-picolinic amides at 50° C. The reaction mixture was quenched with 1 (M) HCl, extracted with EtOAc, and the organic portions were washed with 1 (M) aqueous HCl, NaHCO3 and brine. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide: MS m/z: (M+H) 458.0.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]([C@H:18]([OH:20])[CH3:19])[C:15]([OH:17])=O)=[CH:5][CH:4]=1)#[N:2].[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)#[N:22].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][NH:30][C:15](=[O:17])[C@H:14]([NH:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C@H:18]([OH:20])[CH3:19])=[O:28])=[CH:31][CH:32]=1)#[N:22]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)O
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a pre-cooled (−45° C.) solution of (2R,3R)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoic acid (1.50 g, 5.55 mmol) and 4-cyanobenzohydrazide (894 mg, 5.55 mmol) in anhydrous THF (80 mL) was added 1-Hydroxybenzotriazole monohydrate (850 mg, 5.55 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (2.13 g, 11.1 mmol) at −45° C. followed by triethylamine (1.55 mL, 11.1 mmol). The reaction mixture warmed to room temperature and stirred for 24 h, then quenched with 5% aq. citric acid (300 mL). The solution was extracted with EtOAc (300 mL). The organic extract was washed with 5% aq. citric acid (2×150 mL), sat. aq. NaHCO3 (3×150 mL), H2O (2×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a light brown solid (2.12 g, 92%): 1H NMR (400 MHz, DMSO-d6, δ in ppm) 10.84 (s, 1H), 10.44 (s, 1H), 8.48 (d, J=8.8 Hz, 2H), 8.04-7.93 (m, 4H), 7.91 (d, J=8.2 Hz, 1H), 7.74 (t, J=6.8 Hz, 1H), 7.62 (t, J=7.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 5.25 (d, J=4.5 Hz, 1H), 4.32-3.97 (m, 3H), 1.32 (d, J=6.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Na].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[SH:22].[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[S:22][C:2]1[S:6][C:5]([S:7]([NH:31][CH:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)(=[O:9])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN1CCC(N)CC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Reactant: Sc1c(Cl)cncc1Cl
Agent: [Na]
Product: CN1CCC(NS(=O)(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for step B of example 17 and step B of example 44 from 5-chloro-4-nitrothiophene-2-sulfonyl chloride (0.26 g, 1 mmol), 3,5-dichloropyridine-4-thiol sodium salt (0.18 g, 1.0 mmol) and 1-methylpiperidin-4-amine (0.55 g, 5.0 mmol). The title product was obtained as oil (2.0 mg, 0.4% yield). MS m/z: 482.97, 484.97 [M+H]+.
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][CH3:15])CCC.S(=O)(=O)(O)[OH:17]>>[CH2:14]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[CH:6]=[O:17])[CH3:15]
Reactant: O=S(=O)(O)O
Reactant: CCCC/N=C/c1c(F)cccc1CC
Product: CCc1cccc(F)c1C=O

Procedure:
Prepared in analogy to Example 59(a) from butyl-[1-(2-ethyl-6-fluoro-phenyl)-meth-(E)-ylidene]-amine and aqueous sulphuric acid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH:20]([CH3:28])[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:20]([CH3:28])[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=CC(C)Br
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 6 h
Yield: 7.3 %

Procedure:
In a reactor, 100 ml of ethanol was charged and 95.3 g (0.375 mole) of 4-(4-trifluoromethylphenoxy)phenol, 85.4 g (0.412 mole) of ethyl 4-bromo-2-pentenoate and 39.0 g (0.281 mole) of potassium carbonate were added. The mixture was refluxed with stirring for 6 hours to react them. Ethanol was distilled off and 100 ml of chlorobenzene and 100 ml of water were added and the mixture was stirred at the room temperature for 30 minutes. The water phase was separated and the organic phase was washed with 5% hydrochloric acid and with water and then, chlorobenzene, ethyl 4-bromo-2-pentenoate and low boiling by-products were distilled off under a reduced pressure to obtain 10.47 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoate. The yield was 73.5%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[Li+].[Li+].S(OC)(OC)(=O)=O>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH3:29])[C:14]([S:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CCCOCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [Li+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: CC(C)c1nc(CCCOCc2ccccc2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 70 °C
Yield: 60 %

Procedure:
In 25 ml of dry acetonitrile was dissolved 5.0 g (11.5 mmol) of imidazole (101e), followed by addition of 1.7 g (23 ml) of lithium carbonate and 2.2 g (17.4 mmol) of dimethyl sulfate. The mixture was stirred under heating at 70° C. for 2 hours. The reactLion mixture was diluted with ice-water and extracted with diethyl ether. The extract was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to provide 3.1 g (yield 60%) of 2-(3-benzyloxypropyl)-5-(3,5-dichlorophenyl-thio)-4-isopropyl-1-methyl-1H-imidazole (136a) as oil.
Reaction SMILES: C[C:2]([N:5]([CH2:9][CH2:10][C:11]1([OH:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)C(=O)[O-])([CH3:4])C.CC(N(CCN1CCNCC1)C(=O)[O-])(C)C.Br[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=2)[N:38]=[CH:37][C:36]=1[F:47].BrC1C(F)=CN=C2C=1N=C(OC)C=C2.[O:62]=[C:63]1[CH2:68][O:67][C:66]2[CH:69]=[CH:70]C(C=O)=[N:72][C:65]=2[NH:64]1.O=C1CSC2C=CC(C=O)=NC=2N1>>[F:47][C:36]1[CH:37]=[N:38][C:39]2[C:44]([C:35]=1[N:14]1[CH2:13][CH2:12][C:11]([CH2:10][CH2:9][NH:5][CH2:2][C:4]3[CH:70]=[CH:69][C:66]4[O:67][CH2:68][C:63](=[O:62])[NH:64][C:65]=4[N:72]=3)([OH:17])[CH2:16][CH2:15]1)=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2
Reactant: COc1ccc2ncc(F)c(Br)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: CC(C)(C)N(CCC1(O)CCNCC1)C(=O)[O-]
Agent: CC(C)(C)N(CCN1CCNCC1)C(=O)[O-]
Agent: COc1ccc2ncc(F)c(Br)c2n1
Agent: O=Cc1ccc2c(n1)NC(=O)CS2
Product: COc1ccc2ncc(F)c(N3CCC(O)(CCNCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 26.1 %

Procedure:
The title compound (71 mg, 26%) was prepared as a yellow solid according to Example 1, except substituting the following three reagents: 1,1-dimethylethyl[2-(4-hydroxy-4-piperidinyl)ethyl]carbamate (1.5 g, 6.15 mmol) [prepared according to Example 20] for 1,1-dimethylethyl[2-(1-piperazinyl)ethyl]carbamate, 4-bromo-3-fluoro-6-(methyloxy)quinoline (1.57 g, 6.15 mmol) for 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (100 mg, 0.564 mmol) for 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS (ES) m/e 482 (M+H)+; 1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=4.6 Hz, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.33 (dd, J=2.7, 6.3 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.65 (s, 2H), 3.96 (s, 3H), 3.81 (s, 3H), 3.55-3.61 (m, 2H), 3.26-3.29 (m, 2H), 2.88-2.91 (m, 2H), 1.80-1.93 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:36](=[O:41])[C:37]([O:39][CH3:40])=[O:38].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:39][C:37](=[O:38])[C:36]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:41]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (85 mg, 0.19 mmol) and methyl 2-chloro-2-oxoacetate (35 μL, 0.38 mmol) in CH2Cl2 (1 mL) was added Et3N (53 uL, 0.38 mmol), and catalytic amount of DMAP. The reaction mixture was stirred at RT for 3 h. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (10:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolate. (18 mg, 18%)
Reaction SMILES: NC[CH2:3][CH2:4][Si:5]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[CH3:21][I:22].C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][N:30]([CH3:33])[CH:31]=O>>[I-:22].[CH3:29][N+:30]([CH3:33])([CH3:21])[CH2:31][CH2:3][CH2:4][Si:5]([O:11][Si:12]([CH3:13])([CH3:15])[CH3:14])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[O:6][Si:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)O[Si](CCCN)(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[N+](C)(C)CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.8 g of 3-aminopropyltris(trimethylsiloxy)silane, 1.8 g of methyl iodide and 1.35 g of sodium carbonate are added to 50 ml of dimethylformamide. The reaction mixture is stirred for 3 hours at room temperature. The solvent is evaporated and the residue taken in methylene chloride and water. The organic phase is then washed with water, dried and evaporated whereby compound (35) is obtained; 1H-NMR (ppm, CDCl3): 3.45-3.32 11H m, 1.68-1.58 2H m, 0.39 2H t, 0.00 27H s.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26]>>[F:12][C:11]([F:14])([F:13])[C:10]1[C:5]2[N:6]([C:2]([C:26]#[C:25][C:27]3[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=3)=[CH:3][N:4]=2)[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3n2)cc1
Product: Nc1ncc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nn23)cn1

Procedure:
The title compound was prepared from 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazine (example C.26 step 11) (457 mg, 1 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2) (155 mg, 1.3 mmol) according to general procedure II. Obtained as a light yellow solid (50 mg, 11%). MS (ISP) 449.2 [(M+H)+]; mp 220–221° C.
Reaction SMILES: [Br-].[CH3:2]C(C)([O-])C.[K+].[CH2:8]([O:10][C:11](=[O:32])[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:20][C:19]2=O)[CH3:9].O>O1CCCC1>[CH2:8]([O:10][C:11](=[O:32])[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][CH2:20][C:19]2=[CH2:2])[CH3:9]
Reactant: CCCCCCc1cc2c(cc1OCCCC(=O)OCC)C(=O)CC2
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCc2cc(CCCCCC)c(OCCCC(=O)OCC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.4 g (15.3 mmol) of methyltriphenylphosphate [sic] bromide are added to a suspension of 1.75 g (14.9 mmol) of potassium tert-butoxide in 20 ml of tetrahydrofuran. The reaction medium is stirred for 1 hour at 25° C. and then cooled to 0° C. A solution of 4.5 g (12.9 mmol) of ethyl4-(6-hexyl-3-oxoindan-5-yloxy)butyrate is added. The mixture is stirred for 16 hours at 25° C., poured into water and extracted with ether. The organic phase is dried (Na2SO4) and concentrated under reduced pressure (oil). Purification by flash chromatography (80/20 heptane/ethyl acetate) gives an orange oil (3.5 g; 79%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: N#Cc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1

Procedure:
The title compound was prepared from 4-cyanophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 212.5-215.7° C. 1H NMR (acetone-d6 /300 MHz) 7.96 (s, 1H), 7.90 (d, 2H, J=8.9 Hz), 7.81 (s, 1H), 7.27 (d, 2H, J=8.9 Hz), 6.96 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=7.2 Hz). FABLRMS m/z 396 (M+H). ESHRMS m/z 413.0544 (M+NH4. Calc'd 413.0516). Anal. Calc'd for C18H9ClF3NO4 : C, 54.63; H, 2.29; N, 3.54; Cl, 8.96. Found: C, 54.40; H, 2.18; N 3.30; Cl, 9.20.
Reaction SMILES: C([O:8][P:9]1[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][O:10]1)C1C=CC=CC=1.[CH2:17](I)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[CH2:17]([P:9]1(=[O:8])[O:10][CH2:11][C:12]([CH3:15])([CH3:16])[CH2:13][O:14]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)COP(OCc2ccccc2)OC1
Reactant: ICc1ccccc1
Solvent: Cc1ccccc1C
Product: CC1(C)COP(=O)(Cc2ccccc2)OC1
Reaction time: 1.5 h
Yield: 8386.1 %

Procedure:
A mixture of 2-benzyloxy-5,5-dimethyl-1,3,2-dioxaphosphorinane (100 g, 0.416 M) from Example II, benzyl iodide (1.0 g), and xylene (50 ml) was heated until the temperature reached 165° C., and then slowly dropped to 155° C. After 1.5 hrs, the mixture was allowed to cool to yield 92.4 g (92.4% yield) of pure crystalline 2-benzyl-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-one, melting point 109.5°-110.5° C. Analysis by gas-liquid chromatography showed no impurities present.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].COC(C1C2C=CSC=2C=CC=1)=O.[Cl:34]C1N=C(Cl)C(Cl)=CN=1>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:34])=[CH:18][N:17]=[C:16]([Cl:20])[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2sc(-c3ccnc(Cl)n3)cc12
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: COC(=O)c1cccc2sccc12
Product: COC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12

Procedure:
Using the method of 2-(2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methyl ester, the title compound is synthesized from benzo[b]thiophene-4-carboxylic acid methyl ester and 2,4,5-trichloropyrimidine and isolated as a solid.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[C:6]1([CH2:12][C:13]([NH:15][CH:16]2[C:32](=[O:33])[N:18]3[CH:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]([CH:23]=O)[CH2:21][S:22][C@H:17]23)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.C(OCC)(=O)C>C(OC(=O)C)(=O)C>[C:6]1([CH2:12][C:13]([NH:15][CH:16]2[C:32](=[O:33])[N:18]3[CH:19]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:20](=[CH:23][O:3][C:1](=[O:4])[CH3:2])[CH2:21][S:22][C@H:17]23)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1C(C=O)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(C)(C)C
Yield: 72.5 %

Procedure:
Anhydrous sodium acetate (1.0 g.) was added to a solution of t-butyl 7-(2-phenylacetamido)-3-formylcepham-4-carboxylate (2.0 g.) in acetic anhydride (5 ml.) and stirred at 65° to 70° C. for an hour. To the resultant solution were added water (200 ml.) and ethyl acetate (200 ml.), and adjusted to pH 8.0. The organic layer was separated, washed with aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give t-butyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (1.6 g.), mp. 178° to 183° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.750 g, 4.00 mmol) in DCM (10 mL) was cooled to 0° C. and charged with triethylamine (0.67 mL, 4.8 mmol), methanesulfonyl chloride (0.34 mL, 4.4 mmol), and 4-dimethylaminopyridine (0.005 g, 0.04 mmol) and stirred at ambient temperature for 6 h. The reaction mixture was partitioned between CHCl3 and sat. NaHCO3 and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were washed with sat. NaHCO3 (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a pale yellow oil. This material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 2.05-2.36 (m, 2H), 3.05 (s, 3H), 3.43-3.74 (m, 4H), 5.24-5.30 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([OH:14])=[O:13])[C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:15][C:9]1([CH3:16])[C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:11][C@H:10]1[C:12]([O:14][CH2:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a stirred solution of (1R,3S)-3-(tert-butoxycarbonyl)-2,2-dimethylcyclobutanecarboxylic acid (step 2, 0.200 g) in DMF (5 ml) Cs2CO3 (0.371 g) was added at about 0° C. under nitrogen atmosphere. After 30 minutes, BnBr (0.11 ml) was added by drop wise to the reaction mixture and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give crude product which upon column chromatography afforded the title compound (150 mg, 53.9% Yield). 1H NMR (300 MHz, CDCl3): δ 7.37-7.34 (5H, m), 5.12 (2H, d, J=3.9 Hz), 2.80 (1H, t, J=8.1 Hz), 2.768-2.52 (2H, m), 2.0 (1H, m), 1.44 (9H, m), 1.32 (3H, s), 0.953 (3H, s); Mass: [M+Na]+ 341.2 (100%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][N:32]=2)=[CH:27][CH:26]=1>COC(C)(C)C>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]=[CH:2][O:3][CH3:4])=[CH:33][N:32]=2)=[CH:29][CH:30]=1
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)nc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: COC=Cc1ccc(-c2ccc(Br)cc2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 29.0 g of methoxymethyl-triphenylphosphonium chloride in 200 ml of t-butyl methyl ether in a sulphonation flask fitted with a mechanical stirrer is treated while gassing with argon at -10° C. within 3 minutes with 9.7 g of potassium t-butylate. The orange suspension is stirred at about 0° C. for a further 1 hour, then treated dropwise at -10° C. within 10 minutes with a solution of 14.76 g of 2-(p-bromophenyl)-5-pyridinecarboxaldehyde in 90 ml of t-butyl methyl ether and stirred at 0° C. for a further 45 minutes. The reaction mixture is subsequently partitioned three times in diethyl ether/water. The organic extracts are washed twice with water, dried over magnesium sulphate, filtered and evaporated. In order to separate triphenylphosphine oxide, the residue is dissolved in ethyl acetate and the solution is diluted with petroleum ether, filtered and evaporated. Purification of the residue by chromatography on silica gel gives 2-(p-bromophenyl)-5-(2-methoxyvinyl)pyridine.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([Br:9])=[C:7]([N+:10]([O-:12])=[O:11])[C:6]([Br:13])=[N:5]1)[CH2:2][CH3:3].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCO>[CH2:14]([NH:21][C:8]1[N:4]([CH2:1][CH2:2][CH3:3])[N:5]=[C:6]([Br:13])[C:7]=1[N+:10]([O-:12])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:9][C:8]1[C:7]([N+:10]([O-:12])=[O:11])=[C:6]([Br:13])[NH:5][N:4]=1
Reactant: CCCn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: NCc1ccccc1
Solvent: CCO
Product: CCCn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Product: O=[N+]([O-])c1c(Br)n[nH]c1Br

Procedure:
A mixture of 1-propyl-3,5-dibromo-4-nitropyrazole (19.4 g, 62 mmol), EtOH (500 ml) and benzylamine (40 g, 373 mmol) was refluxed for 15 hours. The reaction medium was concentrated to the maximum under reduced pressure. The residue was suspended in EtOAc (100 ml ), the insoluble part was separated out by filtration and the filtrate was evaporated to dryness. The black oil obtained was purified by column chromatography (eluent: EtOAc/hexane) to give the benzyl(5-bromo-4-nitro-2-propyl-2H-pyrazol-3-yl)amine in the form of a yellow solid (9 g; 29%) from 3,5-dibromo-4-nitropyrazole.