Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14]CC)=O)[N:9]([CH2:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[C:6]2=[N:7][CH:8]=1.[NH:25]1[C:29]2=[N:30][CH:31]=[C:32]([NH2:34])[CH:33]=[C:28]2[CH:27]=[CH:26]1.C[Al](C)C>>[NH:25]1[C:29]2=[N:30][CH:31]=[C:32]([NH:34][C:12]([C:10]3[N:9]([CH2:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)[C:6]4=[N:7][CH:8]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:4]=[C:5]4[CH:11]=3)=[O:14])[CH:33]=[C:28]2[CH:27]=[CH:26]1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1nccs1
Reactant: Nc1cnc2[nH]ccc2c1
Agent: C[Al](C)C
Product: O=C(Nc1cnc2[nH]ccc2c1)c1cc2cc(C(F)(F)F)cnc2n1Cc1nccs1
Yield: 62.2 %

Procedure:
Compound 30 was prepared according to a process similar to that described in step 5.1 by reacting 186 mg (0.523 mmol) of ethyl 5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate prepared according to the protocol described in step 7.1 with 84 mg (0.628 mmol) of pyrrolo[2,3-b]pyrid-5-ylamine in the presence of 0.39 mL (0.785 mmol) of a solution of trimethylaluminium (2M/toluene). The product is collected by filtration, to give 144 mg of expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH2:23])[C:7]=2[CH:24]=1.[C:25](=O)([O:48]C1C=CC([N+]([O-])=O)=CC=1)[O:26][CH2:27][CH2:28][O:29][P:30]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=3[CH2:10][CH2:9][C@H:8]([NH:23][C:25](=[O:48])[O:26][CH2:27][CH2:28][O:29][P:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:31])[C:7]=2[CH:24]=1
Reactant: O=C(OCCOP(=O)(OCc1ccccc1)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc2c(c1)[C@@H](N)CCc1cc(OC)c(OC)c(OC)c1-2
Solvent: CC#N
Product: COc1ccc2c(c1)[C@@H](NC(=O)OCCOP(=O)(OCc1ccccc1)OCc1ccccc1)CCc1cc(OC)c(OC)c(OC)c1-2
Yield: 85 %

Procedure:
A solution of (5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-ylamine (0.329; 1 mmol) and 2-[di-(benzyloxy)phosphoryloxy]ethyl 4-nitrophenyl carbonate (0.633 g; 1.3 mmol) in acetonitrile (8 ml) was heated at 65° C., under argon atmosphere for 8 hours. After evaporation to dryness, the residue was purified by flash chromatography eluting with a 50-80% gradient of ethyl acetate/petroleum ether to give 2-[di(benzyloxy)phosphoryloxy]ethyl N-[(5S)-3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]carbamate.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:3]=2)[CH:25]=[CH:24][N:23]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Reactant: Clc1cc(I)ccn1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-iodo-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.9) (0.43 g, 1.07 mmol) and commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (263 mg, 1.1 mmol) according to the general procedure IVc protocol a. Obtained as an off-white solid (0.20 g, 48%). MS (ISP) 386.0 [(M+H)+]; mp 143.5° C.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:8]([C:9](=[O:27])[NH:10][C@@H:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]([NH:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@@H:8]1[O:7][C@H:6]1[C:4]([OH:5])=[O:3])=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)Nc1c(F)cccc1F
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)[C@@H]1O[C@H]1C(=O)O)C(=O)Nc1c(F)cccc1F
Yield: 75.3 %

Procedure:
Followed general procedure using: the corresponding peptidomimetic epoxide ethyl ester 17c (85 mg, 0.22 mmol); LiOH (5.2 mg, 0.22 mmol); after extraction afforded the desired product as a white solid (59 mg, 74.8%). 1H NMR (DMSO-d6, 400 MHz): δ 9.88 (s, 1H); 8.81-8.79 (d, 1H, J=8.21 Hz); 7.38-7.33 (m, 1H); 7.17-7.13 (t, 2H); 4.61-4.56 (q, 1H); 3.70-3.69 (d, 1H, J=1.79 Hz); 3.52-3.51 (d, 1H, J=1.79 Hz); 1.66-1.58 (m, 3H); 0.93-0.88 (dd, 6H). 13C NMR (DMSO-d6, 100 MHz): 171.35, 169.20, 165.79, 159.48 (d, J=5.16 Hz); 157.01 (d, J=5.21 Hz); 128.58 (t, 19.7 Hz); 114.63 (t, J=34.0 Hz); 112.39 (d, J=22.6 Hz); 53.05, 51.71, 51.62, 41.32, 24.71, 21.96. ESI-HRMS (m/z): [M−H]+ calcd. for C16H20N2O5: 355.3216, observed: 355.3201. HPLC Method 1: Rt=18.9 min, purity=96.5%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]=[CH:7][C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].[C:23](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH3:23])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1cnc2cc(-n3cccc3)c(F)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 60 °C
Yield: 76.4 %

Procedure:
A mixture of 1.5 g (0.005 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-4-hydroxyquinoline-3-carboxylate and 1.4 g (0.01 mol) of potassium carbonate in 10 ml of dimethylformamide is heated for 30 minutes at 60° C. and left to cool, 2.15 g (3×0.005 mol) of methyl iodide are added, the mixture is heated at 80°-90° C. for 4 hours and left to cool, 25 ml of a water/ice mixture are added and the precipitate formed is filtered off and washed with water. The precipitate is receystallized from ethanol to give 1.2 g of a solid melting at 253°-254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[NH:10][N:9]=2)=[C:4]([F:17])[CH:3]=1.S(OC)(O[CH3:22])(=O)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[N:10]([CH3:22])[N:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Fc1cc(Cl)ccc1-c1cc(OC(F)F)[nH]n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)cc2F)cc1OC(F)F
Reaction time: 1 h
Yield: 92.5 %

Procedure:
11.6 g of the 3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1H-pyrazole (purity 86%) obtained in step 1.2 were initially charged in 100 ml of toluene. 6.2 g of dimethyl sulfate were added dropwise, and the mixture was heated at reflux for 3 h. After cooling, 25 ml of saturated aqueous NH4Cl solution were added, the mixture was stirred for 1 h and the organic phase was separated off and washed with water until neutral. Drying over Na2SO4 and concentration gave 11.3 g of 3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole as an oil of a purity of 82.4% (GC). Yield: 88.6%
Reaction SMILES: C([NH:9]C(=O)C(C)=CC1C=C(OC)C(OC)=CC=1N)CC1C=CC=CC=1.NC1C=CC=CC=1[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[CH:40]=[C:41]([CH3:47])[C:42]([O:44]CC)=[O:43].[OH-].[Na+].Cl>O1CCCC1>[NH2:9][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[CH:40]=[C:41]([CH3:47])[C:42]([OH:44])=[O:43]
Reactant: CCOC(=O)C(C)=Cc1ccc(Cl)cc1-c1ccccc1N
Reactant: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=Cc1ccc(Cl)cc1N)C(=O)O
Yield: 94 %

Procedure:
Into 10 ml of tetrahydrofuran (THF), 1.24 g (5.18 mmol) of (E) ethyl 3-(2-aminophenyl-4-chlorophenyl)-2-methyl-2-propenate were dissolved; and, with 10 ml of a 1-N aqueous sodium hydroxide solution being added thereto, the mixture was reacted at 40° C. for 4 hours. After the completion of the reaction was verified by TLC, the mixture was cooled with 10 ml of 1-N hydrochloric acid being added thereto. The precipitated crystal was filtered out, whereby 1.03 g of the aimed compound were obtained (yield: 94%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)[CH:20]=[CH2:19]
Reactant: O=C1NCCc2cc(O)ccc21
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)CCNC2=O

Procedure:
To a solution of 6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (23.8 g, 146 mmol) in acetone (350 mL) is added K2CO3 (34.6 g, 219 mmol) and allyl bromide (19.3 g, 161 mmol). The reaction mixture is then heated to reflux for 24 hours. After this time the solution is filtered and subsequently concentrated in vacuo. The resulting material is washed with hexanes (1×200 mL) and Et2O (1×100 mL) to give 6-allyloxy-1,2,3,4-tetrahydroisoquinolin-1-one as a tan solid, m.p. 105°-107°.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:29])[NH:17][C:18]2([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][NH:20][CH2:19]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:30]=O>C(O)=O>[CH3:30][N:20]1[CH2:21][CH2:22][C:18]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([NH:17][C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=2)=[O:29])[CH2:19]1
Reactant: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCNC2)cc1
Reactant: C=O
Solvent: O=CO
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C)C2)cc1
Temperature: 110 °C
Yield: 35 %

Procedure:
To a solution of ethyl 2-(3-(3-(4-octylphenyl)ureido)pyrrolidin-3-yl)acetate (84 mg, 0.2 mmol) in formic acid (2 mL) was added formalin (15 μL, 0.16 mL). The solution was heated to 110° C. for 2 h. The mixture was concentrated and dissolved into CH2Cl2 (25 mL) and washed with sat. bicarbonate (2×5 mL), H2O (5 mL), dried over MgSO4 and concentrated to dryness to give the title compound as a brown oil (29 mg, 35%) MS ESI 418.4 [M+H]+, calcd for [C24H39N3O3+H] 418.30.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:10]([O:9][CH2:8][C:7]1[C:2]([C:17]#[N:18])=[N:3][CH:4]=[CH:5][CH:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1C#N
Temperature: 120 °C
Yield: 82 %

Procedure:
A mixture of 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 100.0 mmol, 1 eq.) and Zn(CN)2 (23.5 g, 200.0 mmol, 2.0 eq.) in DMF (100.0 mL) was purged with N2 for 5 min and added Pd(PPh3)4 (5.78 g, 5.0 mmol, 0.05 eq.). The mixture was heated at 120° C. for 2 h under N2, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)picolinonitrile (20.4 g, 82%) as a colorless oil. LRMS (M+H+) m/z 249.1.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH3:23])[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])(=O)=O.[I-:24].[Na+]>CC(C)=O>[I:24][CH2:6][CH2:7][C:8]1([CH3:23])[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22]
Reactant: COC(=O)C1C=CCN2C(=O)C(C)(CCOS(C)(=O)=O)C(=O)N12
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C1C=CCN2C(=O)C(C)(CCI)C(=O)N12
Yield: 80.5 %

Procedure:
A mixture of 7.6 g (22 mmol) of methyl 2,3,5,8-tetrahydro-2-(2-methanesulfonyloxyethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate and 6.6 g (44 mmol) of sodium iodide in 100 ml of acetone was heated under reflux for 16 hours. The resulting suspension was filtered and the filtrate was evaporated to dryness. The residue was partitioned between dichloromethane and water. The organic solution was washed with 10% aqueous sodium thiosulfate, dried over magnesium sulfate and evaporated to give 6.7 g (80%) of methyl 2,3,5,8-tetrahydro-2-(2-iodoethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylate having a melting point of 86°-87° C. (from diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[CH:13]=[C:14]([NH:21][C:22]([C:24]2([CH3:27])[CH2:26][O:25]2)=[O:23])[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:27][C:24]([OH:25])([CH3:26])[C:22]([NH:21][C:14]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:12]([CH3:11])[CH:13]=2)=[O:23])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(C#N)c(F)c2)ccc1[N+](=O)[O-]

Procedure:
3-(4-Cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 2-fluoro-4-hydroxybenzonitrile and 2-methyl-oxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. 1H NMR (DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4.11 (1H, d, J=10.1 Hz), 4.371 (1H, d, J=10.1 Hz), 6.33 (1H, bs), 6.96 (1H, m), 7.18 (1H, m), 7.80 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.91 (1H, d, J=2.1 Hz), 8.03 (1H, d, J=9.0 Hz), 10.21 (1H, s).
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[C:11]([NH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CO>[C:11]([NH:18][CH2:19][C:20]1[CH:21]=[C:22]([NH:23][C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])[CH:24]=[CH:25][CH:26]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CO
Product: CSC(Nc1cccc(CNC(=O)OC(C)(C)C)c1)=C(C#N)C#N

Procedure:
A mixture of 102.1 g (600 mmol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile, 133.3 g (600 mmol) of 3-(N-Boc-aminomethyl)-aniline (WO 93/00095) and 1100 ml of methanol is heated under reflux for 6.5 hours and then concentrated by evaporation in vacuo. Crystallization of the residue from ethyl acetate, filtration and washing the filtration residue with ethyl acetate yield 3-[3-(N-Boc-aminomethyl)-phenylamino]-2-cyano-3-methylmercapto-acrylonitrile; m.p. 150-151° C.
Reaction SMILES: C(C1SC=C([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C=1)=O.[CH:24]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>>[CH:24]([C:26]1[S:30][C:29]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:28][CH:27]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C=O)c1
Reactant: O=Cc1ccc(B(O)O)s1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc(C=O)s1
Yield: 47 %

Procedure:
Following the same procedure as described for compound 11 (step 1, scheme 2, example 1c) except using 5-formyl-2-thiopheneboronic acid (1.80 g, 11.5 mmol) instead of 5-formylthiophen-3-ylboronic acid to afford 19 (935 mg, 47%) as an orange solid. LRMS (ESI): calc. 342.1; found 343.2 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:18])([CH2:16][CH3:17])[C:11]2=[O:19])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:18])([CH2:16][CH3:17])[C:11]2=[O:19])[CH:7]=[CH:8][CH:9]=1
Reactant: CCC1(C)CC(=O)N(c2cccc([N+](=O)[O-])c2)C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCC1(C)CC(=O)N(c2cccc(N)c2)C1=O

Procedure:
Seventy-four g. of N-m-nitrophenyl-2-methyl-2-ethylsuccinimide, as prepared in Example VI, was added portion wise to 60 g. of iron powder, 4 ml. of concentrated HCl, 200 ml. of ethanol and 160 ml. of water at reflux. When addition was complete and the temperature had fallen to 70° C., the mixture was treated with 4 g. of 50% NaOH and filtered immediately. The filtercake was washed with hot ethyl alcohol and the filtrate stripped under vacuum. The product which crystallized on removal of the ethyl alcohol weighed 49 g. when dry and had a m.p. of 100°-102° C. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[NH:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[OH:28]O>CO>[CH3:27][N:2]([CH3:1])[NH:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[NH+:9]([O-:28])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CN(C)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: OO
Solvent: CO
Product: CN(C)NCCCC[C@@H](C(=O)OC(C)(C)C)[NH+]([O-])C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A solution of 25.3 g of dimethylamine 2, 7.9 mL of 30% hydrogen peroxide and 150 mL of methanol was stirred for 5 h after which an additional 7.9 g of 30% hydrogen peroxide was added. The reaction was allowed to stir for 48 h and monitored by silica gel TLC, eluting with solvent A. A 1 mL aqueous slurry of approximately 5 mg of platinum black was added whereupon the reaction was stirred for 7 h and another slurry of 5-10 mg platinum black added. The mixture was stirred overnight and monitored for peroxides using peroxide test paper with warming to 60° C. to remove peroxides when necessary. Once the reaction tested negative for peroxides, the mixture was filtered and concentrated. The residue was dissolved into 300 mL of EtOAc, dried over Na2SO4, filtered, concentrated and chromatographed on 400 g of silica gel, eluting with Solvent A to produce 13 g of product as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.CC1(C)C(C)(C)OB([C:19]2[CH:31]=[CH:30][C:22]3[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=3[CH:20]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:6]1[C:7]2[C:3](=[C:2]([C:19]3[CH:31]=[CH:30][C:22]4[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=4[CH:20]=3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: Brc1cccc2[nH]ncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cccc4[nH]ncc34)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
4-Bromo-1H-indazole (96.8 mg, 0.491 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (193.2 mg, 6.072 mmol), and tetrakis(triphenylphosphine)palladium(0) (51.5 mg, 44.6 μmol) were suspended in 1,4-dioxane (2.0 mL) and sodium carbonate (0.50 mL, 2M in water, 1.0 mmol) was added. The flask was fit with a reflux condensor and placed in a preheated oil bath (95° C.) and stirred under nitrogen overnight. The mixture was then cooled to RT and filtered through a pad of Celite® (diatomaceous earth). The filtrate was concentrated and purified on HPLC (10-95% MeCN/water with 0.1% TFA over 40 minutes) to give N-(6-(1H-indazol-4-yl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 309 (MH+). Calculated exact mass for C16H12N4OS: 308.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[CH2:9]([NH:16][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[CH2:9]([N:16]1[C:17]2[N:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](=[O:21])[O:20][C:2]1=[O:3])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1cccnc1NCc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1oc(=O)n(Cc2ccccc2)c2ncccc12
Yield: 67.9 %

Procedure:
Trichloromethyl chloroformate (2.5 mL, 21 mmol) was added slowly to a suspension of (1) (4 g, 17.5 mmol) in dioxane and refluxed for 8 h under nitrogen atmosphere. The solution was cooled and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and washed by saturated NaHCO3 solution. The organic phase was dried over Na2SO4 and evaporated to yield a residue. The residue was recrystallized by ether to yields 3.02 g (68%) of 1-benzyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (2) as white solids. MP: 168° C.; 1H-NMR (DMSO-d6): δ 5.35 (s, 2H), 7.26 (m, 1H), 7.30 (m, 2H), 7.39 (m, 3H), 8.41 (dd, J=1.5, 7.5 Hz, 1H), 8.72 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 277 (M+23).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:4].[OH-].[Na+]>CO>[Cl:14][C:10]1[CH:9]=[C:8]([CH:6]2[CH2:7][CH:5]2[C:3]([OH:4])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H]1C[C@H]1c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
The crude cyclopropanated ester from above (1.09 g, 5.17 mmol) was dissolved in 30 mL MeOH and treated with 15 mL of 2 M aqueous NaOH solution. The mixture was stirred at room temperature for 2 h. It was then placed on a rotary evaporator to remove the MeOH. The remaining solution was diluted with water (30 mL), washed with ether (15 mL), then acidified with 5 M aqueous HCl solution. The product was extracted with ether (3×40 mL) and the combined organics were washed with brine and dried (MgSO4). After filtration, the solvents were removed in vacuo to afford 792 mg of 2-(3-chlorophenyl)-cyclopropanecarboxylic acid as a white solid (4.03 mmol, 78% yield).
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]([F:56])([F:55])[C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:44]=[CH:43][C:42]([C:41]([F:40])([F:55])[F:56])=[CH:47][CH:46]=2)[CH2:53][CH2:52]1
Reactant: O=C1CCC(c2ccc(C(F)(F)F)cc2)CC1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: FC(F)(F)c1ccc(C2CCC(=CCC3OCCCO3)CC2)cc1
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.2 g, 27 mmols), followed by adding tetrahydrofuran (100 ml), suspending, and stirring under ice cooling till the liquid temperature reached 10° C. The resulting reaction mixture was added potassium t-butoxide (3.0 g, 27 mmols), followed by elevating the temperature up to room temperature under ice cooling, stirring for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(4-trifluoromethylphenyl) cyclohexanone (6.0 g, 25 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)-ethylidene)-4-(4-trifluoromethylphenyl)cyclohexane.