Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][S:15][C:16](SC)=[N:17][C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:18]([N:17]=[C:16]([S:15][CH3:14])[NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])#[N:19]
Reactant: CSC(=NC#N)SC
Reactant: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSC(=NC#N)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A mixture of 2.02 g (10.0 mmol) of 2-nitrobenzene-sulfonamide, 1.46 g (10.0 mmol) of dimethyl N-cyanodithioiminocarbonate and 1.38 g (10.0 mmol) of powdered, anydrous K2CO3 in 16 ml of acetone was heated at reflux for 20 hours. The reaction mixture was filtered and the solid collected was washed several times with acetone. The filtrate was evaporated and the orange oily residue was triturated with ether to afford a solid. The solid was collected by filtration, washed with ether and suspended in 10 ml of IN HCl. After stirring for 1 hour the solid was collected by filtration, washed with water and dried to yield 1.65 g (55 percent) of the desired product as a cream colored solid, mp 122° C. (decomposition). IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]([N:6]1[Si:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][Si:7]1([CH3:14])[CH3:13])([CH3:5])[C:3]#[CH:4].C([Li])CCC.[CH:20](=[O:22])[CH3:21].O>O1CCCC1>[OH:22][CH:20]([C:4]#[C:3][C:2]([N:6]1[Si:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][Si:10]1([CH3:11])[CH3:12])([CH3:1])[CH3:5])[CH3:21]
Reactant: C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: -20 °C

Procedure:
1-(1,1-Dimethyl-2-propynyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (1.0 g) in dry tetrahydrofuran (10 ml) was cooled to −50° C. under an atmosphere of nitrogen with stirring and a solution of n-butyl lithium (2.0 ml, 2.5M solution in hexanes) was added dropwise over 2 minutes. The mixture was stirred for 0.25 hour at −50° C., allowed to warm to −20° C. then acetaldehyde (0.22 g) in tetrahydrofuran (2 ml) was added dropwise. The reaction was stirred at −20° C. for 1.5 hours, allowed to warm to ambient temperature over 1 hour and treated with water. The product was extracted with ethyl acetate (three times) and the extracts were combined, washed with water (twice) then dried over magnesium sulphate and evaporated under reduced pressure to give (2-hydroxy-5-methylhex-3-yn-5-yl)- 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane,1.06 g, as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[CH3:33]>N1C=CC=CC=1>[CH3:31][O:30][C:28]([C:26]1[N:27]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:9]([C:4]3[NH:5][C:6]([CH2:7][CH3:8])=[C:2]([Cl:1])[N:3]=3)=[O:11])=[C:18]([CH3:33])[CH:19]=2)[O:24][C:25]=1[CH3:32])=[O:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1nc(-c2ccc(N)c(C)c2)oc1C
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2C)nc1Cl
Yield: 77.1 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.18 g, 1.03 mmol), thionyl chloride (4 mL), methyl 4-amino-3-methylphenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (108e) (0.28 g, 1.14 mmol) and pyridine (5 mL), to obtain 0.32 g of the title compound as a colorless solid (77%).
Reaction SMILES: Br[C:2]1[CH:13]=[N:12][C:5]2[NH:6][CH2:7][C:8](=[O:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].C(N(C(C)C)CC)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([O:18][C:14](=[O:17])[CH:15]=[CH:16][C:2]1[CH:13]=[N:12][C:5]2[NH:6][CH2:7][C:8](=[O:11])[NH:9][CH2:10][C:4]=2[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1CNc2ncc(Br)cc2CN1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C=Cc1cnc2c(c1)CNC(=O)CN2
Temperature: 90 °C
Yield: 55.3 %

Procedure:
7-Bromo-1,2,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-3-one (145 mg, 0.6 mmol) and tert-butyl acrylate (307 mg, 2.4 mmol) were dissolved in DMF (3 mL) and the reaction vessel was purged with argon for 5 min. Tri-σ-tolylphosphine (37 mg, 0.12 mmol) and palladium acetate (14 mg, 0.06 mmol) were added and the solution was degassed with argon. Diisopropylethylamine (0.23 mL, 1.32 mmol) was added and the solution was degassed with argon, sealed and heated to 90° C. for 16 h. The reaction was cooled to room temperature and filtered through a bed of celite. The filter cake was washed with ethyl acetate (50 mL) and the filtrate was washed with H2O (5 mL) and brine (5 mL), dried over MgSO4 and concentrated to a brown oil. The oil was subjected to silica gel chromatography (5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) to yield the title compound as a yellow solid (96 mg, 52%). 1H NMR (300 MHz, DMSO-d6) 8.18 (t, J=5.7 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 7.37 (d, J=15.8 Hz, 1H), 7.35 (t, J=5.3 Hz, 1H), 6.24 (d, J=15.8 Hz, 1H), 4.28 (d, J=5.7 Hz, 2H), 3.98 (d, J=5.1 Hz, 2H), 1.45 (s, 9H); ESI MS m/z 290 [C15H19N3O3+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[N:7]=[CH:8][C:9]([C:11]3[C:12]4[N:13]([N:17]=[C:18]([NH2:20])[N:19]=4)[CH:14]=[CH:15][N:16]=3)=[CH:10][C:2]=12.Cl[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>C(O)(C)(C)C>[O:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:26]=[CH:27][C:22]([NH:20][C:18]3[N:19]=[C:12]4[C:11]([C:9]5[CH:8]=[N:7][C:3]6=[N:4][CH:5]=[CH:6][N:1]=[C:2]6[CH:10]=5)=[N:16][CH:15]=[CH:14][N:13]4[N:17]=3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1
Reactant: Clc1ccc(N2CCOCC2)cc1
Reactant: Nc1nc2c(-c3cnc4nccnc4c3)nccn2n1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CC(C)(C)O
Product: c1cn2nc(Nc3ccc(N4CCOCC4)cc3)nc2c(-c2cnc3nccnc3c2)n1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
8-Pyrido[2,3-b]pyrazin-7-yl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine, 4-(4-chloro-phenyl)-morpholine (1.1 eq.), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl]2-(2-aminoethyl)phenyl)Pd(II) (0.25 eq), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl; BrettPhos (0.25 eq.) are combined and suspended in t-butanol. The suspension is purged with N2 and lithium bis(trimethylsilyl)amide, (3 eq; 20% (ca 1.06M) solution in THF/ethylbenzene) is added. The vessel is sealed under N2 and heated to 65° C. for 2 h and then to 110° C. for 2 h. The mixture is filtered and concentrated. Purification via prep. HPLC gives the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[N:28]1([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([C:43]3[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=3)=[O:42])=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]3[CH:22]=[CH:23][C:24]4[NH:25][C:47]([C:46]5[CH:49]=[CH:50][C:43]([C:41](=[O:42])[NH:40][C:37]6[CH:38]=[CH:39][C:34]([N:28]7[CH2:29][CH2:30][O:31][CH2:32][CH2:33]7)=[CH:35][CH:36]=6)=[CH:44][CH:45]=5)=[N:1][C:4]=4[CH:5]=3)=[O:21])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 195 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholin-4-ylbenzoyl)aniline and 4-(4-morpholinylphenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C35H34N6O4: 603.26; found: 603.36.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.OP([O-])(O)=O.[K+].[C-:22]#[N:23].[K+]>CN(C=O)C.O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([OH:15])[CH2:14][C:22]#[N:23])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1coc(-c2ccc(F)cc2)n1
Reactant: [C-]#N
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC(O)c1coc(-c2ccc(F)cc2)n1
Temperature: 80 °C
Yield: 21.2 %

Procedure:
A solution of 1-(2-(4-fluorophenyl)oxazol-4-yl)ethanone (250 mg, 1.22 mmol) in DMF-H2O (7 mL; 2:5 v/v) was cooled to 0° C. and KH2PO4 (327 mg, 2.4 mmol) was added, followed by KCN (116 mg, 1.8 mmol). The reaction mixture was stirred at 80° C. 10 h and then diluted with water. The organic product was extracted with EtOAc and the combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 8-12% EtOAc in petroleum ether) to afford 3-(2-(4-fluorophenyl)oxazol-4-yl)-3-hydroxypropanenitrile (60 mg, yield 21%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=0.7 Hz, 1H), 8.03-7.98 (dd, J=8.9 Hz, 5.4 Hz, 2H), 7.40-7.34 (t J=8.9 Hz, 2H), 6.13-6.12 (d, J=5.3 Hz, 1H), 4.93-4.87 (m, 1H), 2.98-2.93 (dd, J=8.9 Hz, 5.8 Hz, 2H). MS (ESI) m/z: Calculated for C12H9FN2O2: 232.06. found: 233.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:18](=[O:19])[CH2:17][C:16]([CH3:15])=[O:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCCN(Cc2ccccc2)C1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OC1CCCN(Cc2ccccc2)C1
Yield: 62.7 %

Procedure:
Then, 11.8 g of the 1-benzyl-3-hydroxypiperidine and 5.6 g of diketene were reacted similarly as in Reference Example 1, and the reaction product was purified by silica gel column chromatography (eluent:chloroform:methanol=9:1 v/v), to obtain 10.65 g of acetoacetic acid-N-benzyl-3-piperidinyl ester (yield: 62.5%). This was used in the reaction of Example 4 without distillation.
Reaction SMILES: [CH2:1]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CS(O)(=O)=O.O.[CH2:32]([C:38]1([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[C:50]2[CH:49]=[C:48]([C:51]3(O)[C:63]4[CH:62]=[C:61]([Br:64])[CH:60]=[CH:59][C:58]=4[C:57]4[C:52]3=[CH:53][C:54]([Br:65])=[CH:55][CH:56]=4)[CH:47]=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>ClCCl>[CH2:20]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]([C:51]3([C:48]4[CH:47]=[CH:46][C:45]5[C:44]6[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=6)[C:38]([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:50]=5[CH:49]=4)[C:63]4[CH:62]=[C:61]([Br:64])[CH:60]=[CH:59][C:58]=4[C:57]4[C:52]3=[CH:53][C:54]([Br:65])=[CH:55][CH:56]=4)[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccccc21
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccc(C3(O)c4cc(Br)ccc4-c4ccc(Br)cc43)cc21
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2ccc(C3(c4ccc5c(c4)C(CCCCCC)(CCCCCC)c4ccccc4-5)c4cc(Br)ccc4-c4ccc(Br)cc43)cc21

Procedure:
In a 2 L round-bottom flask, 50 g of the compound (1) and 200 g of 9,9-dihexylfluorene were dissolved in 1000 ml of dichloromethane, and then the temperature was decreased to 0° C. The reaction solution was slowly added with a s olution of 10 ml of methane sulfonic acid dissolved in 100 ml of dichloromethane with stirring, followed by further stirring for 2 hours. The resulting reaction solution was poured into water, after which an extraction was performed using diethyl ether. The solvent was evaporated using a rotary evaporator. A column chromatography separation resulted in 60 g (58%) of (9,9-di(9,9-dihexylfluoren-2-yl)-2,7-dibromofluorene) (2).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])[CH:2]=[CH2:3].[SH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16]>>[OH:17][CH:14]([CH2:15][OH:16])[CH2:13][S:12][CH2:3][CH2:2][CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11]
Reactant: OCC(O)CS
Reactant: C=CCc1cccc(C)c1O
Product: Cc1cccc(CCCSCC(O)CO)c1O

Procedure:
In the same manner as in Synthetic example 1, 2-allyl-6-methylphenol and 3-mercapto-1,2-propanediol were reacted to obtain 2-[3-(2,3-dihydroxypropylthio)propyl]-6-methylphenol.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1.[Br-].C(N[C@H]1CCCC[C@@H]1NCC1C=CC=CC=1)C1C=CC=CC=1.C(N[C@H]1CCCC[C@@H]1NCC1C=CC=CC=1)C1C=CC=CC=1.[Ni+2].[Br-]>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C@@H:6]([CH:14]([C:13]([O:20][CH3:21])=[O:19])[C:15]([O:17][CH3:18])=[O:16])[CH2:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Reactant: COC(=O)CC(=O)OC
Agent: [Ni+2]
Agent: [Br-]
Agent: c1ccc(CN[C@H]2CCCC[C@@H]2NCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 7 h
Yield: 75 %

Procedure:
This hydrated coarse crystal of 4-chloro-β-nitrostyrene was dissolved in toluene (19 ml), the aqueous phase was separated by a liquid-separation operation, and the organic phase was azeotropically dehydrated under reduced pressure, to distill off 9.5 ml. A catalyst prepared according to a method described in non-patent document 2 (nickel(II)bis[(S,S)—N,N′-dibenzylcyclohexane-1,2-diamine]bromide) (58 mg, 0.072 mmol) and dimethyl malonate (2.3 g, 17 mmol) were added, and the mixture was heated up to 50° C. and stirred at the same temperature for 7 hours. After completion of the reaction, the reaction solution was washed with 0.1 mol/L hydrochloric acid (5 ml) and water (5 ml) each once. The organic phase was concentrated under reduced pressure, and crystallized in a toluene/heptane solvent, to obtain 4.2 g (13 mmol) of a title compound. Yield 75%. The spectrum data corresponded to the value in non-patent document 3. The optical purity of the resultant title compound was measured by HPLC to find a value of 94% ee.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[Si:22]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][CH:7]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccc2[N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
2-(3-Hydroxyphenyl)nitrobenzene, as described above in Step B, (8.07 g, 37.52 mmol), imidazole (7.66 g, 112.56 mmol) and tert-butyldimethylsilyl chloride (6.22 g, 41.27 mmol) were dissolved in DMF (30 mL) and stirred for 0.75 hour. The DMF was removed in vacuo and the resulting residue was taken up in water and dimethyl ether and extracted with dimethyl ether (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of 0%→4% EtOAc in hexanes, to yield the above-titled compound.
Reaction SMILES: C([O:8][C:9]1[C:10]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:21]=[C:20]([C:33]([O:35][CH3:36])=[O:34])[C:11]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)C1C=CC=CC=1.Br>C(O)(=O)C.ClCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[CH:21]=[C:20]([C:33]([O:35][CH3:36])=[O:34])[C:11]3[N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]4=[C:9]([OH:8])[C:10]=3[C:23]2=[O:24])=[CH:31][CH:30]=1
Reactant: COC(=O)c1cn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cn(Cc2ccc(F)cc2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O

Procedure:
A solution of methyl 10-(benzyloxy)-2-(4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido[3′,4′:4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylat (30 mg, 0.06 mmol) and hydrogen bromide in acetic acid (0.7 mL, 30% solution) in dichloromethane (10 mL) was stirred at room temperature for 6 hr. The reaction mixture was concentrated under vacuum, and the residue subjected to reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provided the title product.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(O)(C)C.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[CH2:7][C@H:27]2[N+:28]([O-:30])=[O:29])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)O
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t-BuOH (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10 min a solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et2O (3×10 mL); the organic layers were washed with brine (2×15 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual orange oil was purified by column chromatography on silica gel (5% EtOAc/hexanes) affording 0.16 g of 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene [Rf=0.5 (20% EtOAc/hexanes), white solid, 26% yield].
Reaction SMILES: C(S[C:4](=[O:23])[CH:5]([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)C.O.[NH2:25][NH2:26]>CCO>[F:20][C:19]([F:22])([F:21])[CH:5]1[CH2:6][C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:26][NH:25][C:4]1=[O:23]
Reactant: NN
Reactant: CCSC(=O)C(CC(=O)c1ccc(C(F)(F)F)cc1)C(F)(F)F
Solvent: O
Solvent: CCO
Product: O=C1NN=C(c2ccc(C(F)(F)F)cc2)CC1C(F)(F)F
Temperature: 23 °C
Yield: 99.1 %

Procedure:
A mixture of 4-oxo-2-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-thiobutyric acid S-ethyl ester (example C.26 step 4) (16.0 g, 45 mmol) and hydrazine monohydrate (2.39 mL, 49 mmol) in EtOH (250 mL) was refluxed for 18 h under nitrogen atmosphere. Cooled to 23° C., the solvents were evaporated to leave the title compound as a brown solid (13.83 g, 100%), which was used without further purification [according to Synthesis 2003, (3), 436.]. MS (ISP) 311.1 [(M+H)+]; mp 135-136° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:11]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>>[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)c1Br
Yield: 60 %

Procedure:
3,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3,4-dichlorobenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 144-146° C., yield 60%.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9](F)[N:8]=[C:7]([NH:16][CH3:17])[N:6]=1>CO>[Cl:4][C:5]1[C:10]([O:11][CH:12]([F:14])[F:13])=[C:9]([O:2][CH3:1])[N:8]=[C:7]([NH:16][CH3:17])[N:6]=1
Reactant: CNc1nc(F)c(OC(F)F)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1nc(Cl)c(OC(F)F)c(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At 0° C. and over a period of 10 minutes, 4.7 g (0.026 mol) of 30% strength sodium methylate was added, while stirring, to 6.0 g (0.0263 mol) of 4-chlorodifluoromethoxy-6-fluoro-2-methylaminopyrimidine in 100 ml of methanol. The mixture was stirred for 1 hour at 0° C. and for 1 hour at 25° C. Conventional working up gave 6.3 g (100% of theory) of the title compound of melting point 49°-53° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:28]([F:31])([F:30])[F:29])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([OH:27])=O)[N:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:28]([F:29])([F:31])[F:30])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:27])[N:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NCC(F)(F)F
Reactant: O=C(O)Cn1ncc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc2c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1ncc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc2c1=O)NCC(F)(F)F
Reaction time: 18 h
Yield: 63.8 %

Procedure:
To a stirred solution of (E)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl)acetic acid (0.15 g, 0.31 mmol) in CH2Cl2 (20.0 ml) was added 2,2,2,-trifluoroethanamine (0.03 g, 0.31 mmol), PyBOP (0.17 g, 0.34 mmol) and DIPEA (0.15 ml, 0.93 mmol) at ambient temperature, and the reaction was stirred for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with 3N HCl (2×20 mL), NaHCO3 (2×20 mL) and brine solution (2×). The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.11 g): mp 172-175° C.; 1H NMR (400 MHz, CDCl3) δ 8.83 (t, J=6.6 Hz, 1H), 8.42 (t, J=14.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (t, J=6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m, 1H), 7.01-6.93 (m, 1H), 4.96-4.81 (m, 3H), 4.00-3.88 (m, 2H); ESIMS m/z 554.0 ([M−H]−).