Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=O.[CH3:14][CH:15]1[NH:21][C:20](=[O:22])[CH2:19][CH2:18][NH:17][CH2:16]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:17]2[CH2:18][CH2:19][C:20](=[O:22])[NH:21][CH:15]([CH3:14])[CH2:16]2)=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: CC1CNCCC(=O)N1
Product: CC1CN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC(=O)N1

Procedure:
In analogy to the procedure described in intermediate 1A, (E)-3,4-dichlorocinnamic acid and 3-methyl-[1,4]diazepan-5-one gave the title compound as a white solid. MS: 327.2 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].S(Cl)(Cl)=O>CC(O)C>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:14]([C:13](=[O:18])[CH3:12])[C:15](=[O:17])[CH3:16])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(C(=O)O)cc1)C(C)=O

Procedure:
To a suspension containing 3.0 g (0.02mol) of 4-carboxybenzaldehyde and 3.0 g (0.03mol) of 2,4-pentanedione in 10ml of 2-propanol was gradually added 3.0 g (0.025mol) of thionyl chloride with stirring and cooling (below 20° C). The mixture was stirred over night at 20° C. After filtering the product was washed with 2-propanol, yield 1.8 g, mp 195°-199° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[F:16])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>O.CN(C=O)C>[N:17]([CH2:6][C:7]1[C:8]([F:16])=[CH:9][C:10]([C:14]#[N:15])=[C:11]([F:13])[CH:12]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1cc(F)c(C#N)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(F)c(CN=[N+]=[N-])cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-cyano-2,5-difluorobenzyl methanesulfonate (4.5 g, 0.0182 mol; see step (iv) above) and sodium azide (2.0 g, 0.031 mol) in 20 mL of water and 40 mL of DMF was stirred at room temperature for 2 h. It was subsequently poured into 300 mL of water and extracted three times with diethyl ether. The combined ethereal phase washed several times with water, dried (Na2SO4) and evaporated. A small sample was evaporated for NMR purposes and the product crystallised. The rest was evaporated cautiously but not until complete dryness. Yield (theoretically 3.5 g) is assumed to be almost quantitative based on NMR and analytical HPLC.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[C:3](=[O:5])[CH3:4].[I-].[CH3:17][S+](C)(C)=O.[H-].[Na+]>>[CH3:1][C:2]1([C:3](=[O:5])[CH3:4])[CH2:17][CH:6]1[CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14]
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)C(C)=CCC1CC=C(C)C1(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: CC(=O)C1(C)CC1CC1CC=C(C)C1(C)C
Yield: 44.6 %

Procedure:
11.3 g (55 mmol) of 3-methyl-5(2,2,3-trimethylcyclopent-3enyl)-pent-3-en-2-one was cyclopropanated with 14.1 g (63 mmol) of trimethylsulfoxonium iodide and 3.08 g (64 mmol) of 50% oil suspension of sodium hydride according to Example 11a giving 5.4 g (45% yield) of 1-[1-methyl-2(2,2,3trimethylcyclopent-3-enylmethyl)cyclopropyl]ethanone.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]([O:17][C:18]([N:20]([C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])([CH3:16])[CH3:15].[CH2:33]([Sn:37](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1COCC1>[CH3:26][C:23]([O:22][C:21]([N:20]([C:28]1[S:29][C:30]([Sn:37]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:31][N:32]=1)[C:18](=[O:19])[O:17][C:14]([CH3:13])([CH3:15])[CH3:16])=[O:27])([CH3:24])[CH3:25]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccs1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M in hexanes, 30 mL, 0.48 mol), was added to diisopropylamine (6.7 mL, 0.48 mol) in THF (480 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins then cooled to −78° C. tert-Butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-(1,3-thiazol-2-yl)carbamate (12 g, 0.05 mol) was added and solution stirred for 30 minutes. Tributyltin chloride (16.3 mL) was added and solution stirred for 30 minutes before allowing to warm to RT. The reaction was quenched with a saturated aqueous solution of ammonium chloride (20 mL) and the product extracted with ethyl acetate. The organics were dried over sodium sulphate, concentrated in vacuo and chromatographed on silica, eluting with 5-15% ethyl acetate in hexane, to give the desired material as a clear oil (9 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH3:13])[N:3]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[F-].[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)[N:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1c(C)nc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1c(C)nc(Cl)nc1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
A mixture of methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (0.79 g, 3.57 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.595 g, 2.86 mmol) and bis(triphenylphosphine)palladium chloride (0.050 g, 0.071 mmol) in dioxane (5 mL) was stirred at RT for 10 min, after which potassium fluoride (1.038 g, 17.87 mmol) was added. The mixture was stirred under a nitrogen atmosphere and heated at 90° C. for 12 h. The reaction mixture was filtered through a bed of Celite 545, rinsed with DCM and a small amount of MeOH. Following solvent removal, the residue was dispersed in DMSO/MeOH (1/1) and purified via reverse phase preparative HPLC to give the title compound (237 mg, 25%). [M+H] calc'd for C11H11ClN4O2, 267. found, 267.
Reaction SMILES: C([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:41])(C)(C)C.[C:43](O)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[N:46][CH:45]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[O:41][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[N:46][CH:45]=1)([OH:5])=[O:42]
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Reactant: O=C(O)c1cccnc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(OC(=O)c2cccnc2)c1
Yield: 80 %

Procedure:
The title compound was prepared according to the procedure in Example 25, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.500 g, 0.749 mmol), nicotinic acid (0.092 g, 0.749 mmol), 2-chloro-1-methylpyridinium iodide (0.230 g, 0.899 mmol) and triethylamine (0.251 mL, 1.80 mmol). Purification on Biotage KP-Sil eluting with 20% EtOAc/hexane gave 0.460 g, (80%) of the title compound. 1H NMR (DMSO-d6) 6 1.34 (s, 9 H), 1.55 (s, 3 H), 2.16 (s, 6 H), 2.36 (s, 3 H), 7.19 (s, 2 H), 7.45-7.46 (m, 2 H), 7.61-7.71 (m, 2 H), 8.12-8.25 (m, 4 H), 8.50 (ddd, 1 H), 8.94 (d, 1 H), 9.29 (s, 1 H).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)[N:10]=[C:9]([C:49]([F:52])([F:51])[F:50])[N:8]=1)(=O)=O.[CH3:53][NH:54][CH3:55]>O1CCCC1>[CH3:53][N:54]([CH2:6][C:7]1[N:8]=[C:9]([C:49]([F:51])([F:52])[F:50])[N:10]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]3[CH2:21][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:44])([CH3:45])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:23]3)[CH2:16][CH2:15]2)[CH:12]=1)[CH3:55]
Reactant: CNC
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(COS(C)(=O)=O)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Solvent: C1CCOC1
Product: CN(C)Cc1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[6-[(cis-4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-2-(trifluoromethyl)pyrimidin-4-yl]methyl methanesulfonate (450.0 mg, 0.5906 mmol) was dissolved in tetrahydrofuran (10.00 mL) and 2.0 M dimethylamine in tetrahydrofuran (4.00 mL, 8.00 mmol) was added. The reaction were stirred at 25° C. for 16 hours at which time LCMS analysis showed that the reaction was completed. The solvent was then removed and the product was used in the next reaction without purification. MS (ES): 711(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc2[nH]c(C)cc12
Reactant: BrCc1ccccc1
Solvent: O
Product: COc1cccc2c1cc(C)n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
4-Methoxy 2-methyl-1H-indole (1 g, 6.2 mmol) was added to 248 mg (6.2 mmol)) of 60% sodium hydride/mineral oil (washed with hexane before adding DMF) in 15 mL of DMF and after stirring for 0.5 hour, 0.74 mL (6.2 mmol) of benzyl bromide was added. The mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.3 g (84% yield) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole, melting at 96-116° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][NH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:49]([N:48]([CH3:47])[C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[O:11])=[CH:20][CH:19]=2)=[O:23])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N(C)Cc4ccccc4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), methylbenzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][C:3]=1[O:10][CH3:11].[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH3:18][O:17][CH:12]([O:15][CH3:16])[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([O:10][CH3:11])[CH:4]=1
Reactant: COc1cc(C=O)ccc1Cl
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(OC)OC)ccc1Cl
Yield: 86 %

Procedure:
A heterogenous mixture of methanol (2 ml), CH2Cl2 (3 ml), 4-chloro-3-methoxybenzaldehyde (2 g, 11.7 mmol; prepared essentially as described by R. M. Riggs et al., J. Med. Chem., 30 1887, 1987.), trimethyl orthoformate (1.7 ml, 15.5 mmol) and a large crystal of p-toluenesulfonic acid was stirred at room temperature for one hour. Additional MeOH (1 ml) and a crystal of p-toluenesulfonic acid were added and the solution was warmed until homogenous. Upon completion of the reaction, the solution was stirred 5 min with excess solid NaHCO3 and rotory evaporated to remove solvents. The paste was dissolved in 40 ml EtOAC, partitioned against dilute NaHCO3 solution, and evaporated to yield a light brown oil. The reaction was repeated with another 2 g of 4-chloro-3-methoxybenzaldehyde and both product oils were combined to give 4.37 g (86%) of dimethyl acetal 3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].CCOC(C)=O>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 5-bromo-3-iodopyridin-2-amine (B-7-1) (20 g, 66.9 mmol) in Et3N (200 mL) was added CuI (1.27 g, 6.69 mmol), and the resulting mixture was degassed with N2 for 2 minutes. Then Pd(PPh3)2Cl2 (1.4 g, 20.1 mmol) was added and the mixture was degassed again. Then ethynyl-trimethyl-silane (7.2 g, 73.6 mmol) was added dropwise into the mixture at 0° C. The mixture was stirred at room temperature for 4 hours. TLC (Petroleum ether: EtOAc=5:1) showed that the reaction was complete. The mixture was evaporated under reduced pressure to give crude mixture which was purified via a silica gel column eluted with petroleum ether/EtOAc (20:1) to afford 5-bromo-3-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (B-7-2) (10 g, 55.6%) as a white solid.
Reaction SMILES: O[Li].O.[CH:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:17])=[CH:14][C:15]=2[F:16])=[CH:8][C:7]([C:18]([OH:20])=[O:19])=[C:6]([OH:21])[CH:5]=1.[CH2:22]1COCC1.Cl>CO.O>[F:16][C:15]1[CH:14]=[C:13]([F:17])[CH:12]=[CH:11][C:10]=1[C:9]1[CH:4]=[CH:5][C:6]([O:21][CH3:22])=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc(F)cc2F)cc1C(=O)O
Yield: 93 %

Procedure:
LiOH.H2O (60 mg, 1.43 mmol) was added to a solution of fully methylated diflunisal (140 mg, 0.50 mmol) in MeOH:THF:H2O (4.5 mL 1:1:1), and stirred at rt for 4 h. Upon completion, the reaction was acidified with 30% HCl, extracted with ethyl acetate (3×5 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (2:1 ethyl acetate:hexane, 1% acetic acid) to afford 33 (122 mg, 93%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 10.77 (br s, 1H), 8.31 (dd, 1H, J=2.5, 0.9 Hz), 7.75 (dt, 1H, J=8.6, 2.1 Hz), 7.41 (dt, 1H, J=8.9, 6.6 Hz), 7.15 (d, 1H, J=8.8 Hz), 6.94 (m, 1H), 4.13 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 177.7, 161.4, 158.2, 135.7, 133.9, 131.4, 129.0, 123.5, 118.1, 112.2, 112.0, 104.6, 56.9. HRESIMS calculated for C14H10F2O3 (M−H) 263.0520, found 263.0514. Normal phase HPLC retention time: 21.6 min. Reverse phase HPLC retention time: 11.9 min. >99% pure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:27])[NH:20][C:21]([CH3:26])=[CH:22][C:23]=2[CH2:24][CH3:25])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[Na].[CH:29]1([S:32]([OH:34])=[O:33])[CH2:31][CH2:30]1>>[CH:29]1([S:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:27])[NH:20][C:21]([CH3:26])=[CH:22][C:23]=3[CH2:24][CH3:25])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)(=[O:34])=[O:33])[CH2:31][CH2:30]1
Reactant: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: O=S(O)C1CC1
Agent: [Na]
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(S(=O)(=O)C2CC2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared from 6-bromo-N-[(4-ethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (70 mg, 0.162 mmol) and the sodium salt of cyclopropanesulfinic acid (41.9 mg, 0.325 mmol) in the same manner as described for example 91. The product was collected an off-white solid (52 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.16 (m, 5H), 1.19-1.27 (m, 2H), 1.50 (d, J=6.57 Hz, 6H), 2.15 (s, 3H), 2.58 (m, 2H), 2.97 (m, 1H), 4.41 (d, J=4.80 Hz, 2H), 5.26 (m, 1H), 5.94 (s, 1H), 8.01 (d, J=1.26 Hz, 1H), 8.43 (s, 1H), 8.53 (s, 1H), 8.83 (m, 1H), 11.58 (s, 1H); LCMS: (M+H)+=457.0
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][N:5]=[C:6]1[C:10](=O)[CH2:9][CH2:8][S:7]1(=[O:13])=[O:12]>O.CO>[OH:4][N:5]=[C:6]1[C:10](=[N:2][OH:3])[CH2:9][CH2:8][S:7]1(=[O:13])=[O:12]
Reactant: NO
Reactant: O=C1CCS(=O)(=O)C1=NO
Agent: Cl
Solvent: CO
Solvent: O
Product: O=S1(=O)CCC(=NO)C1=NO
Yield: 49.7 %

Procedure:
5.4 g (77 mmol) of hydroxylamine hydrochloride, dissolved in 15 ml of water, are added to a solution of 11.4 g (70 mmol) of 2-hydroxyimino-3-oxotetrahydrothiophene dioxide in 100 ml of methanol. After 2 hours at room temperature the batch is completely concentrated and the residue is recrystallised from ethanol. 6.2 g (50%) of 2,3-dihydroxyiminotetrahydrothiophene dioxide, m.p. 181° C., are obtained.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:10][CH:11](O)[CH:12]=[CH2:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:13][CH:12]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]#[N:9])[CH:11]=[CH2:10]
Reactant: N#Cc1ccccc1O
Reactant: C=CC(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(C)Oc1ccccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
To a mixture of salicylonitrile (2.0 g, 16.8 mmol) and but-3-en-2-ol (1.5 ml, 16.8 mmol) in tetrahydrofuran (100 ml) was added triphenylphosphine (4.4 g, 16.8 mmol), followed by diisopropyl azodicarboxylate (3.3 ml, 16.8 mmol) in tetrahydrofuran (15 ml), added dropwise ensuring the reaction temperature did not rise above 20° C. The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. To the residue was added diethyl ether (20 ml) and the solution was washed with aqueous sodium hydroxide solution (1N), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica) with gradient elution, diethyl ether:cyclohexane [1:9 to 1:1]. The appropriate fractions were combined and concentrated to give the title compound (1.9 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[CH2:9]Br.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28](=[O:34])[C@H:29]([CH:31]([CH3:33])[CH3:32])[NH2:30].O>C(#N)C>[CH3:32][CH:31]([CH3:33])[CH:29]([N:30]1[CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[C:5]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[CH:4]=2)[CH2:9]1)[C:28]([O:27][CH3:26])=[O:34]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(CBr)c(CBr)c2)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1

Procedure:
The compound of example 671 (3 g, 7.79 mmol) was taken in acetonitrile and to the reaction mixture, potassium carbonate (3.25 g, 23.37 mmol) was added followed by the addition of valine methyl ester (1.56 g, 9.35 mmol). The reaction mixture was refluxed for about 16 h and water was added to quench the reaction. The aqueous mixture was extracted with ethyl acetate to obtain a crude material, which was purified using column chromatography (silicagel, 30% ethyl acetate in petroleum ether).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(NC(C)C)(C)C.[Li].[Br:21]C(F)(F)C(Br)(F)F>O1CCCC1>[Br:21][C:11]1[S:12][C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=2[Cl:1])[CH:10]=1
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1cnc2cc(Br)sc2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) in tetrahydrofuran (5.0 mL) is slowly added lithium diisopropylamine (0.7 mL, 1.40 mmol, 2M in tetrahydrofuran) at −78° C. over 5 minutes. After 30 minutes, 1,2-dibromo-1,1,2,2,-tetrafluoroethane (0.16 mL, 1.3 mmol) is added slowly to the solution of the anion. The temperature is maintained at −78° C. for 4 hours then warmed to room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo to afford a dark solid residue. The residue is purified by flash column chromatography eluting with a gradient of 2% ethyl acetate in hexane to 8% ethyl acetate in hexane to provide 103 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as an off white solid, mp 190–191° C.; 1H NMR (DMSO-d6) δ 8.13 (s, 1H), 9.12 (s, 1H); MS 272.8, 274.8, 276.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][C:3]=1F.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:22][S:23]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:25])=[O:24]>CS(C)=O.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][C:3]=1[N:31]1[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][S:23]([CH3:22])(=[O:24])=[O:25])[CH2:33][CH2:32]1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
1-Methyl-2-fluoro-4-(ethyloxy)-5-nitrobenzene (Example 215, step A) (5.74 g, 28.8 mmol) was dissolved in DMSO (60 mL). K2CO3 (11.9 g, 86.4 mmol) and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, step B) (9.85 g, 43.2 mmol) were added and the reaction mixture was heated to 100° C. and allowed to stir overnight. The mixture was cooled to rt then diluted with DCM and filtered. The filtrate was poured into H2O and extracted with DCM. The combined organics were dried with MgSO4, filtered, and concentrated in vacuo to give the title compound of Step A (9.70 g, 26.1 mmol, 90%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 6.51 (s, 1H), 4.11 (q, J=7.0 Hz, 2H), 3.16 (t, J=6.5 Hz, 2H), 3.03 (s, 3H), 3.00-2.91 (m, 6H), 2.72-2.62 (m, 4H), 2.21 (s, 3H), 1.44 (t, J=7.0 Hz, 3H).