Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([Sn](CCCC)(CCCC)CCCC)=[CH:54][N:53]=1>CN(C=O)C.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:55]2[CH:54]=[N:53][C:52]([CH3:51])=[CH:57][CH:56]=2)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)nc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)cn1
Yield: 83.9 %

Procedure:
A solution containing the product from Example 23I (0.25 g, 0.354 mmol) in DMF (3.5 mL) was treated with LiCl (0.15 g, 3.54 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.107 mmol), and the product from Example 87A (0.40 mL, 1.67 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% ethyl acetate in dichloromethane to give the title compound (0.193 g, 84% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][NH:10][CH:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2=CC(c3cccs3)NN2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cc(-c3cccs3)[nH]n2)cc1
Yield: 56.2 %

Procedure:
Active manganese dioxide (4.35 g, 50 mM was added to a solution of 3-(4-chlorophenyl)-5-(2-thienyl)-pyrazoline (2.62 g, 10 mM) in toluene (100 ml). This mixture was heated under reflux for 3 hours, and then filtered while hot. After the filtrate was allowed to cool, the precipitated crystals were collected by filtration, washed with a small volume of cold toluene, and then air-dried to obtain 1.46 g of the desired 3-(4-chlorophenyl)-5-(2-thienyl)-1H-pyrazole, m.p. 217° C., in a 56% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17]C3C=NC=CC=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1.Br[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1
Product: Cc1ccc(Nc2cc(F)cc(F)c2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (example 8) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white crystalline solid, MS (ISP): m/e=358.9 (M+H+).
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[N:10]=1)C1C=CC=CC=1.[F:30][C:31]1([F:45])[CH2:33][CH:32]1[CH2:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1>>[F:30][C:31]1([F:45])[CH2:33][CH:32]1[CH2:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([NH:15][C:14]2[C:9]([OH:8])=[N:10][C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[N:12][CH:13]=2)=[O:41])=[CH:38][CH:37]=1
Reactant: O=C(O)c1ccc(OCC2CC2(F)F)cc1
Reactant: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1ncc(NC(=O)c2ccc(OCC3CC3(F)F)cc2)c(O)n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((4-(benzyloxy)-5-nitropyrimidin-2-yl)oxy)propan-2-yl)carbamate and 4-((2,2-difluorocyclopropyl)methoxy)benzoic acid, and in the same manner as in Step A of Example 4 and Step D of Example 83, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)=[CH:4][CH:3]=1.[CH2:23](Br)[CH:24]=[CH:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:23]([NH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)=[CH:4][CH:3]=1)[CH:24]=[CH:25][CH3:26]
Reactant: CC=CCBr
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC=CCNc1ccc(Oc2nc(OC)cc(OC)n2)c(C(=O)OC)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
3.0 g (9.8 mmol) of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate, 1.5 g (10.8 mmol) of 2-butenyl bromide and 1.6 g (11.8 mmol) of potassium carbonate were added to 10 ml of DMF, and the mixture was stirred at 100° C. for one hour. After completion of the reaction, the reaction mixture was poured into water, then extracted with ethyl acetate, dried and concentrated. Then, the obtained residue was purified by column chromatography and crystallized to obtain a solid, which was washed with diisopropyl ether to obtain the desired product as colorless prism crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18](=O)[CH2:19]Br)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2].[C:24]([NH:27][CH:28]([CH3:32])[C:29]([NH2:31])=[S:30])(=[O:26])[CH3:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]3[N:31]=[C:29]([CH:28]([NH:27][C:24](=[O:26])[CH3:25])[CH3:32])[S:30][CH:19]=3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:22][CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)NC(C)C(N)=S
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(C(C)NC(C)=O)n3)c(F)cc2c1=O

Procedure:
According to example 30, reacting 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester with 2-(acetylamino)thiopropionamide in ethanol gave 7-[2-[1-(N-acetylamino)ethyl]-4-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 236°-238° C., which was hydrolyzed with refluxing 6N hydrochloric acid to afford the title compound, mp 246°-250° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[K+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCCCCCCCBr
Reactant: N#Cc1ccc(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(C#N)c(F)c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
60 g of 3-fluoro-4-cyanophenol and 16 g of potassium hydroxide were dissolved in a solvent mixture of 600 ml of ethanol and 60 ml of water. To the resulting solution, was added dropwise 55.8 g of octyl bromide. After the completion of the addition, the obtained mixture was refluxed for six hours and then allowed to cool to room temperature. The solvent was distilled off and 300 ml of ethyl acetate was added to the residue. The organic layer was washed with water until the aqueous layer became neutral. The organic layer was dehydrated over anhydrous sodium sulfate and the solvent was distilled off. After purifying by distillation (main fraction: 0.5 mmHg, 157° to 160° C.), 63 g of 2-fluoro-4-octyloxybenzonitrile was obtained. Yield: 58%. 63 g of the 2-fluoro-4-octyloxybenzonitrile thus obtained was dissolved in 70 ml of absolute ether and 12.7 g of absolute ethanol was added thereto. The obtained mixture was cooled to -10° C. Then hydrogen chloride gas was bubbled therein for 30 minutes under stirring. After confirming that no hydrogen chloride was absorbed any more, the mixture was stirred at room temperature for 72 hours. 400 ml of absolute ether was added to the mixture. The crystals thus precipitated were filtered and vacuum-dried to thereby give 42 g of imino ester hydrochloride. Yield: 52%.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:32][CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])=[O:19])[CH:8]=1)=[O:5]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a solution of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111, 150 mg, 0.33 mmol) and 1-amino-2-methylpropan-2-ol (50 mg, 0.66 mmol) in DMF (2 mL) was added DIPEA (0.11 mL, 0.66 mmol, 2 eq) and HATU (188 mg, 0.50 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium carbonate solution (50 mL) and EtOAc (50 mL). The organic layer was collected, washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with acetonitrile to afford the title compound (63 mg, 36%).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:45])[C:29]=1[N:30]1[CH2:35][C@@H:34]([F:36])[CH2:33][C@@H:32]([NH:37]C(=O)OC(C)(C)C)[CH2:31]1)=[O:23])=O)(C)(C)C.N>Cl.CO.CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:45])[C:29]=1[N:30]1[CH2:35][C@@H:34]([F:36])[CH2:33][C@@H:32]([NH2:37])[CH2:31]1)=[O:23]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1C[C@@H](F)C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: N
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1C[C@H](N)C[C@H](F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
A mixture of tert-butyl (3R,5S)-1-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-5-fluoropiperidin-3-ylcarbamate (200 mg, 0.31 mmol) in HCl/MeOH (10 mL) was stirred at ambient temperature for 20 hours and concentrated under reduced pressure to give a residue. The residue was diluted with MeOH (10 mL), neutralized with 28% ammonia solution, and concentrated to give a crude product. The crude product was purified by preparative HPLC to afford 184 as pale solid (138 mg, 99%). 1H NMR (500 MHz, CD3OD) δ (ppm): 7.60 (s, 1H), 7.50-7.45 (m, 1H), 7.14-7.11 (m, 2H), 5.36-5.23 (m, 1H), 3.84-3.74 (m, 4H), 3.63-3.49 (m, 2H), 2.72-2.62 (m, 2H), 2.54-5.41 (m, 1H), 2.16-2.05 (m, 1H); MS (ESI) m/z: 452 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S([O-])([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH:10](=[N:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CN=Cc1ccccc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
To a solution of 33.61 gms of glycine t-butyl ester and 27.19 gms of benzaldehyde in 215 ml benzene was added 21.5 gms of magnesium sulfate in one portion with stirring at room temperature. The reaction was stirred 18 hours at room temperature, filtered, diluted with ether and washed with saturated sodium bicarbonate and brine. The ether solution was then dried over magnesium sulfate, concentrated and distilled to yield 48.41 gms (86%) of t-butyl N-benzylideneglycinate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:22]=[N:23]O)=[N:11][CH:12]=[C:13]([N:15]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[N:16]3)[N:14]=2)=[CH:4][CH:3]=1.CO>[Ni].C(O)C>[NH2:23][CH2:22][C:10]1[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:14][C:13]([N:15]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[N:16]2)=[CH:12][N:11]=1
Reactant: Cc1cc(C)n(-c2cnc(C=NO)c(Nc3ccc(Cl)cc3)n2)n1
Agent: [Ni]
Solvent: CO
Solvent: CCO
Product: Cc1cc(C)n(-c2cnc(CN)c(Nc3ccc(Cl)cc3)n2)n1
Reaction time: 1 h
Yield: 28.6 %

Procedure:
Raney nickel (50% slurry in water, 1 mL) was added to a solution of 3-(4-chloro-phenylamino)-5-(3,5-dimethyl-pyrazol-1-yl)-pyrazine-2-carbaldehyde oxime (60 mg, 0.17 mmol) in ethanol (99%, 6 mL). The reaction mixture was stirred under a hydrogen atmosphere for one hour. Methanol was added followed by filtration and evaporation. The crude product was purified by flash chromatography (dichloromethane/methanol as eluent) to give [3-aminomethyl-6-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-(4-chloro-phenyl)-amine (16 mg, 28%) as a white solid. Mp.=156-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Br)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: OCC(F)(F)F
Product: COC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 48a, using 5-bromo-6-(4-chlorophenyl)-2-pyrazinecarboxylic acid methyl ester (CAN 960247-79-4) and 2,2,2-trifluoroethanol as starting materials; MS (EI) 347.1 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=1[F:22])([CH3:14])[CH3:13])[CH2:2]2.[CH:24]1(B(O)O)[CH2:26][CH2:25]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[C:19]([CH:24]3[CH2:26][CH2:25]3)[CH:18]=[CH:17][C:16]=1[F:22])([CH3:14])[CH3:13])[CH2:2]2
Reactant: OB(O)C1CC1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cc(Br)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cc(C2CC2)ccc1F
Yield: 323.3 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(5-bromo-2-fluorophenyl)propan-2-yl]carbamate (750 mg, 0.649 mmol), cyclopropylboronic acid (139 mg, 1.62 mmol) and palladium (II) acetate gave the title compound as a white solid (727 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J=6.4 Hz, 1H), 6.97-6.78 (m, 2H), 5.19 (s, 1H), 4.65-4.57 (m, 1H), 2.66 (s, 6H), 1.85 (tt, J=5.1, 8.4 Hz, 1H), 2.00-1.17 (m, 5H), 1.71 (d, J=8.7 Hz, 6H), 0.92 (ddd, J=4.6, 6.3, 8.4 Hz, 2H), 0.62 (dt, J=4.7, 6.4 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.2, 157.8, 139.2, 139.2, 125.6, 125.5, 125.4, 116.5, 116.3, 71.3, 55.8, 54.2, 47.6, 46.7, 29.9, 29.6, 28.6, 25.6, 24.8, 19.6, 15.2, 9.1 ppm. Purity: 100% UPLCMS (210 nm); retention time 0.87 min; (M+1) 347.2. Anal. Calcd. for C20H27FN2O20.0.07 (CHCl3): C, 68.00; H, 7.70; N, 7.90. Found: C, 67.99; H, 7.86; N, 7.81.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:33])[S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([S:21]([N:20]([CH3:19])[CH3:33])(=[O:23])=[O:22])=[CH:25][CH:26]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Yield: 34.8 %

Procedure:
Using the procedure described in Example 55, Part B, N1-(4-methoxybenzoyl)-1,2-benzenediamine (534 mg, 2.21 mmol) was reacted with 4-(dimethylaminosulfonyl)benzoic acid (534 mg, 2.33 mmol) to yield 349 mg (35%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO.[Cu]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:10][CH3:9])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Nc1ccc(Br)cn1
Agent: [Cu]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N)nc1
Temperature: 160 °C
Reaction time: 72 h
Yield: 41.7 %

Procedure:
Add 2-amino-5-bromopyridine (5.0 g, 29 mmol) to a freshly prepared solution of sodium methoxide (1.3 g, 58 mmol) in methanol (50 mL) and then add copper powder (1.8 g, 2.9 mmol). Heat and stir the mixture in a sealed tube at 160° C. for 3 days. Cool, filter through celite and concentrate under reduced pressure. Dissolve the residue in dichloromethane, then wash with water and saturated aqueous sodium chloride. Dry over magnesium sulfate, concentrate under reduced pressure, and subject the residue to silica gel chromatography, eluting with hexane/ethyl acetate; 3:1 to 0:1 to provide the title compound (1.5 g).
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([O:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])(=[O:6])[CH3:5].O>CS(C)=O>[C:4]([O:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:1]#[N:2])(=[O:6])[CH3:5]
Reactant: [C-]#N
Reactant: CC(=O)Oc1c(CBr)cccc1Oc1ccccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Oc1c(CC#N)cccc1Oc1ccccc1Cl
Temperature: 25 °C
Yield: 101.8 %

Procedure:
Powdered sodium cyanide (3.65 g) was added to a solution of 2-chlorophenyl 2-acetoxy-3-bromomethylphenyl ether (22 g) in dimethylsulfoxide (80 ml) with stirring at room temperature, and the mixture was stirred at the same temperature for 10 minutes. Water (200 ml) was added to the reaction mixture and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and then evaporated to give oily 2-[2-acetoxy-3-(2-chlorophenoxy)phenyl]acetonitrile (19 g).
Reaction SMILES: [C:1]12([C:14]([O:16]C)=[O:15])[CH2:9][CH2:8][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO.O>[CH3:13][O:12][C:10]([C:5]12[CH2:6][CH2:7][C:1]([C:14]([OH:16])=[O:15])([CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4]2)=[O:11]
Reactant: COC(=O)C12CCCC(C(=O)OC)(CC1)CC2
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C12CCCC(C(=O)O)(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a stirred solution of dimethyl bicyclo[3.2.2]nonane-1,5-dicarboxylate (2.02 g, 8.41 mmol), in methanol (20 mL) and water (4 mL) was added barium hydroxide octahydrate (1.33 g, 4.20 mmol). The reaction mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (20 mL) and washed with isohexane (2×100 mL), then the aqueous phase was acidified with 2M HCl to pH 2 and extracted into EtOAc (2×100 mL). The organic extracts were combined, dried (MgSO4) and concentrated to leave the title compound (931 mg, 4.11 mmol, 49%) as a clear colourless gum which slowly formed a white solid; 1H NMR (CDCl3) δ 1.72-1.75 (m, 2H), 1.87-1.92 (m, 12H), 3.65 (s, 3H); GC-MS EI m/e M+ 226.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[N-:14]=[N+:15]=[N-:16].[Na+].C1(C)C=CC=CC=1.[Cl-]>CN(C=O)C>[N:14]([CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1)=[N+:15]=[N-:16]
Reactant: N#Cc1ccc2c(c1)OCCC2Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)OCCC2N=[N+]=[N-]
Temperature: 80 °C

Procedure:
4-Chloro-7-cyanochroman (Step C) (8.1 g, 42 mmol) was dissolved in dry DMF (90 mL) and NaN3 (4.0 g, 62 mmol) was added and the reaction was heated to 80° C. under N2. After 5 h TLC (SiO2, toluene) showed that no starting chloride was present. The reaction was cooled and partitioned between EtOAc (200 mL) and H2O (150 mL). The organic phase was washed with H2O (2×100 mL) and brine (100 mL). The solution was dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified by column chromatography (SiO2, 15% EtOAc in hexane) to provide the title compound.
Reaction SMILES: O.[S-2:2].[Na+].[Na+].Cl[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1.CC(C)=O.Cl>O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([SH:2])=[CH:7][C:8]=1[C:15]([F:18])([F:17])[F:16])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(S)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
A stirred solution of sodium sulfide monohydrate 65.4 g. (0.276 moles) in 1 liter of water is treated with 50 g. (0.222 moles) of 4-chloro-2-trifluoromethylnitrobenzene in 500 ml. of acetone over 11/2 hour. The reaction mixture is stirred for 141/2 hours and the resultant solution treated with 25 ml. of concentrated hydrochloric acid. An oil separates from the reaction mixture which is dissolved in 200 ml. of ether, washed with water and extracted with 2.5 N sodium hydroxide solution. The aqueous solution is washed with ether and acidified with 25 ml. of hydrochloric acid. The resulting oil is extracted with ether and the ether solution washed with water affording 47 g. of 4-nitro-3-trifluoromethylbenzenethiol which is used in the next step.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][C:6]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH:10]=[CH:11]2)=[O:7]>CCOCC>[CH3:1][N:2]([CH2:5][C:6]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH:10]=[CH:11]2)=[O:7])[CH3:3]
Reactant: O=C(CCl)C1CC2C=CC1C2
Reactant: CNC
Solvent: CCOCC
Product: CN(C)CC(=O)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 3.5 g (5.2 ml; 0.078 mole) of dimethylamine in 40 ml of ether at -15° was added 6.5 g (0.038 mole) of 5-chloroacetyl-2-norbornene. The reaction mixture was stirred for 7 hr. at 0° (ice bath) and then allowed to warm to room temperature overnight. The solid dimethylamine hydrochloride was removed by filtration and the ether was removed at reduced pressure to give 6.1 g (89%) of crude product. Distillation gave product bp 83°-90°/0.8 mm.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH2:15])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:19][CH3:20]>>[N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH:15][S:27]([C:24]4[CH:25]=[CH:26][C:21]([CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=4)(=[O:29])=[O:28])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc2c(s1)CCc1ccc([N+](=O)[O-])cc1-2
Product: CCCc1ccc(S(=O)(=O)Nc2nc3c(s2)CCc2ccc([N+](=O)[O-])cc2-3)cc1

Procedure:
The title compound was prepared from 8-nitro-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (100 mg, synthesized according to METHOD I from 7-nitrotetralone) and 4-n-propylbenzenesulfonyl chloride (106 mg) as described in the synthetic METHOD A to give a yellow powder (3.5 mg) with a purity of 87%: MS-ES (neg) m/z 428.4.