Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOCC>[Br:27][CH2:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C(=C\c1ccc(C)cc1)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)/C(=C\c1ccc(CBr)cc1)c1ccccc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of the product of Step B (31 mg, 0.123 mmol) in dry CCl4 (1 mL) under N2 were added NBS (20 mg, 0.9 eq) and a catalytic amount of AIBN. The mixture was stirred at reflux under N2 for 1.5 hours. The mixture was cooled to room temperature, diluted with Et2O and filtered to remove the precipitated succinimide. The filtrate was concentrated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 15:1 hexane/EtOAc to afford 27.4 mg (67%) of the title compound.
Reaction SMILES: [C-]#[N:2].[Na+].S(=O)(=O)(O)O.[C-]#N.[CH2:11]([C:13]([CH2:24][CH3:25])(O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12].[OH-].[Na+]>C(O)(=O)C>[CH2:11]([C:13]([NH2:2])([CH2:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12]
Reactant: [C-]#N
Reactant: CCC(O)(CC)Cc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC(N)(CC)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Powdered sodium cyanide (1.18 g, 24 mmol) was placed in a flask and covered with 5.5 mL of acetic acid. A mixture of sulfuric acid (3 mL) and acetic acid (2.75 mL) was cooled to 0° C. and then added to the cyanide suspension over a period of 3 minutes. The mixture was stirred for 30 minutes at room temperature, followed by the addition of 1,1-diethyl-2-(4-methoxyphenyl)ethanol (4.6 g, 22 mmol). The mixture was stirred overnight then poured into ice and sodium hydroxide. The product was extracted with ether, and the ether layer dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in 20% sodium hydroxide and refluxed overnight under nitrogen. The reaction was cooled, diluted with water, and extracted with ether. The ether layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC (C-18 using 0.1% HCl acetonitrile as the elutant) to give 1.91 g of 1,1-diethyl-2-(4-methoxyphenyl)ethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:34]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[C:31]([C:44](=O)[CH3:45])[CH:30]=1)[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].Cl.[OH:53][NH2:54]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][N:7]([CH2:15][C@@H:16]([OH:48])[C@@H:17]([NH:27][C:28](=[O:47])[C:29]1[CH:30]=[C:31](/[C:44](=[N:54]/[OH:53])/[CH3:45])[CH:32]=[C:33]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=1)[CH2:18][C:19]1[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=1)[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13]
Reactant: NO
Reactant: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(C(C)=O)c2)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(NC(=O)c3ccccc3)cc(/C(C)=N/O)c2)C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
A mixture of tert-butyl 3-methoxybenzyl((2R,3S)-3-(3-acetyl-5-(benzamido)benzamido)-4-(3,5-difluorophenyl)-2-hydroxybutyl)carbamate (20 mg, 0.0282 mmol) and hydroxyamine hydrochloride (0.0564 mmol) in ethanol (0.14 mL) was heated at 80° C. for 2 h. The reaction mixture was purified by reverse phase prep HPLC to give the title compound (10 mg): HPLC retention time: 2.255 min (method A). MS (ESI) (M+H)+ 725.53.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22](N)=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2].[I:30]CI.CCCCCON=O>C(#N)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([I:30])=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: ICI
Agent: CCCCCON=O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
To a solution of (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-(2-amino-6-chloropurin-9-yl)oxolan-3-yl acetate (3.8 g, 8.88 mmoles) in acetonitrile (40 ml) was added diiodomethane (3.4 ml) and n-amyl nitrite (8.2 ml). The resulting mixture was refluxed overnight, then the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with a mixture of 40% ethanol/60% hexane, to provide (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-(6-chloro-2-iodopurin-9-yl)oxolan-3-yl acetate (2.7 g) as a light yellow solid.
Reaction SMILES: [C:1]([CH:5]([CH:8]=O)[CH:6]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:10][NH:11][C:12](=[O:17])[CH2:13][N+:14]([O-:16])=[O:15].N1CCCC1>C(O)C>[C:1]([C:5]1[CH:6]=[C:13]([N+:14]([O-:16])=[O:15])[C:12](=[O:17])[N:11]([CH3:10])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C(C=O)C=O
Reactant: CNC(=O)C[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CCO
Product: Cn1cc(C(C)(C)C)cc([N+](=O)[O-])c1=O
Yield: 29.5 %

Procedure:
To a solution of 2-tert-butyl-malonaldehyde (385 mg, 3.00 mmol) and the above amide (355 mg, 3.00 mmol) dissolved in ethanol (6.0 mL) was added pyrrolidine (63 microL, 0.750 mmol). The mixture was heated at reflux for 18 h and concentrated in vacuo. Purification by silica-gel chromatography (75% ethyl acetate in hexanes) provided 5-tert-butyl-1-methyl-3-nitro-1H-pyridin-2-one (186 mg, 30%) as an orange solid.
Reaction SMILES: [C:1]1([CH2:11][CH:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][C:13]2=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1.CO>[C:1]1([CH2:11][CH:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][C:13]2=[S:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: S=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Temperature: 160 °C

Procedure:
A suspension of 200 mg (0.73 mmol) of 3-naphthalen-1-ylmethyl-imidazo[1,2-a]pyridin-2-one and 250 mg (0.62 mmol) of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) in 20 mL of toluene is heated at 160° C. for 1 h under microwave condition. The resulting mixture is dissolved in methanol and absorbed on silica gel. The slurry is dried under reduced pressure and is purified by flash chromatography on silica gel. The compound is eluted 5˜10% methanol in dichloromethane solution to give the desired compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.O>[CH2:13]([O:12][CH2:11][CH2:10][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCOCc1ccccc1
Reactant: O=C1NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCN1CCOCc1ccccc1

Procedure:
To a solution of imidazolidin-2-one (500 mg) in DMF (5.0 mL) was added a sodium hydride 60% dispersion in mineral oil (232 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. ((2-Bromoethoxy)methyl)benzene (0.83 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (388 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2].[CH3:14][Si](C)(C)Cl>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2]
Reactant: C[Si](C)(C)Cl
Reactant: COc1nc(C(=O)O)ccc1C#N
Solvent: CO
Product: COC(=O)c1ccc(C#N)c(OC)n1

Procedure:
5-Cyano-6-methoxypyridine-2-carboxylic acid (see above) is reacted in methanol with the help of trimethylchlorosilane to give methyl 5-cyano-6-methoxypyridine-2-carboxylate (m.p. 125°-125° C.). Subsequent hydrogenation in methanol on palladium/charcoal in the presence of hydrochloride acid gives the desired aminomethyl compound (m.p. of the hydrochloride: 224°-226° C.). By the addition of a few drops of triethanolamine, the hydrogenation solution is brought to a pH of 7 and used directly for the following reaction.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:14]C1C=CC(C#N)=C(C(F)(F)F)C=1.C(N(CC)CC)C>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:14])=[O:8])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1C(N)=O

Procedure:
2-Isopropoxy-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-4-Cyano-3-trifluoromethyl-phenyl)-2-Isopropoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Yield: 94 %

Procedure:
A solution of 1-bromomethyl-3-nitrobenzene (2.16 g, 10 mmol), morpholine (1.76 g, 20.2 mmol) and triethylamine (1.0 mL) in THF (60 mL) was heated for two hours at 60° C. The solvent was evaporated, water was added and the product was isolated by extraction with ether. The ether extract was dried over Mg2SO4 and the solvent was evaporated. The crystalline residue was used in the next step without further purification. The product, 4-(3-nitrobenzyl)morpholine, was obtained in 94% yield (2.09 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:12])[CH2:9]C=C)[C:5]([CH:19]=[CH2:20])=[C:4]([NH:21][CH3:22])[N:3]=1>C1C=CC=CC=1.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:22])[C:5]2[CH:19]=[CH:20][CH2:9][C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([OH:12])[C:6]=2[N:7]=1
Reactant: C=CCC(O)(c1ccccc1)c1nc(Cl)nc(NC)c1C=C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: c1ccccc1
Product: CNc1nc(Cl)nc2c1C=CCC2(O)c1ccccc1
Temperature: 85 °C
Yield: 91.5 %

Procedure:
To a solution of 1-(2-chloro-6-(methylamino)-5-vinylpyrimidin-4-yl)-1-phenylbut-3-en-1-ol (60 mg) in benzene (5 mL) was added Grubbs I (16 mg), and the reaction mixture was heated at 85° C. for 1 h. The solvent was removed, and the residue was purified by preparative TLC eluting with 40% EtOAc/Hexanes to give the title compound as a colorless oil (50 mg). 1H NMR (500 MHz, CDCl3) δ ppm 7.4 (5H, m), 6.25 (1H, m), 6.07 (1H, m), 5.14 (1H, br. S), 4.52 (1H, s), 3.10 (3H, d<J=5.0 Hz), 2.99 (2H, m). 13C NMR (125 MHz, CDCl3) 164.32, 159.38, 158.85, 144.15, 128.24, 128.02, 127.83, 125.51, 117.54, 108.14, 60.51, 38.50, and 28.57. HRMS calcd. for C15H15ClN3O (M+H) 288.0904. found: 288.0899.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[C:49]([O:53][C:54]([NH:56][C:57]1([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:59][CH:58]1[CH:60]=[CH2:61])=[O:55])([CH3:52])([CH3:51])[CH3:50].C1(N(C)C2CCCCC2)CCCCC1>O1CCOCC1.C(OCC)C.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:49]([O:53][C:54]([NH:56][C:57]1([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH2:59][CH:58]1/[CH:60]=[CH:61]/[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:36][CH2:37][S:38](=[O:42])(=[O:41])[CH2:39][CH2:40]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: C=CC1CC1(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(/C=C/C6CC6(NC(=O)OC(C)(C)C)C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 110 °C

Procedure:
The mixture of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (50 mg, 0.070 mmol), ethyl 1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate (17.76 mg, 0.070 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.018 mL, 0.083 mmol) in dioxane (1 mL) was placed in a sealable pressure tube and N2 was bubbled through the solution for 10 min. Bis(tri-tertbutylphosphine) Palladium(0) (0.355 mg, 0.695 μmol) was added to the reaction mixture and the tube was sealed, and heated to 110° C. for 4 h. After cooling to rt, the crude reaction mixture was diluted with diethyl ether and filtered. The filtrate was concentrated and purified using a flash silica gel column (4 g; eluted with ethyl acetate in hexane from 0 to 45%) to give the title compound as a yellow film (13 mg, 22.7%). MS: m/e 824.55 (M+H)+, 2.625 min (method 4). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.23-5.36 (m, 2H), 5.27-5.12 (m, 1H), 4.72 (br. s., 1H), 4.61 (br. s., 1H), 4.26 (m, 2H), 3.24-2.92 (m, 8H), 2.72-2.45 (m, 5H), 2.32-1.76 (m, 11H), 1.68 (br. s., 3H), 1.53-0.74 (m, 42H).
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][O:12][CH3:13])[O:10][C:6]=2[C:5]([NH2:14])=[CH:4][C:3]=1[CH3:15].[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.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>[CH3:13][O:12][CH2:11][CH:9]1[CH2:8][C:7]2[C:2]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)=[C:3]([CH3:15])[CH:4]=[C:5]([NH2:14])[C:6]=2[O:10]1
Reactant: COCC1Cc2c(Br)c(C)cc(N)c2O1
Reactant: OB(O)c1ccncc1
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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1Cc2c(c(N)cc(C)c2-c2ccncc2)O1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-2-(methoxymethyl)-5-methyl-2,3-dihydrobenzofuran-7-amine (8c) (0.85 g, 3.1 mmol), pyridin-4-ylboronic acid (0.76 g, 6.2 mmol), Cs2CO3 (2.5 g, 7.8 mmol), Pd(PPh3)4 (0.18 g, 0.16 mmol) and water (6 mL) in DMF (20 mL) was stirred at 135° C. under N2 for 1 h. It was cooled to ambient temperature, poured into water (50 mL), extracted with EtOAc (60 mL), washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1 to 5:1 to 1:1) to give the title compound (8d) as a yellow oil. MS-ESI (m/z): 271 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:14][C:15]1([CH3:26])[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18](=[O:24])[CH2:17][C:16]1=[O:25].C(N(CC)CC)C.CC(C)(O)C#N>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([CH:17]1[C:16](=[O:25])[C:15]([CH3:26])([CH3:14])[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18]1=[O:24])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Agent: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
2-Nitro-4-chlorobenzoyl chloride (2.2 g, 10 mmol) and 4,4,6,6-tetramethyl-1,3,5-cyclohexanetrione (1.8 g, 10 mmol) were dissolved in methylene chloride. Triethylamine was added and the resulting solution stirred at room temperature for 30 minutes. The solution was washed with 1 normal hydrochloric acid (1N HCl), and saturated sodium chloride (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 20 ml acetonitrile. Triethylamine (5 ml, 3.5 equivalents) and acetone cyanohydrin (0.5 g, 0.6 equivalent) were added and the mixture stirred at room temperature for 4 hours. After dilution with ether, the solution was washed with 1N HCl and extracted with 5% K2CO3. The basic extract was acidified with HCl and extracted with ether. The ether extract was washed with brine, dried over MgSO4 and concentrated under vacuum, yielding 2.2 g of crude product. This was recrystallized from benzene to remove syncarpic acid still present. Concentration of the mother liquor under vacuum gave 1.7 g of the desired product as an oil, which solidified on standing (m.p. 76°-82° C.). It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[OH-].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>CN(C=O)C.O>[CH:23]1([N:13]2[C:14]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15][S:16][C:12]2=[N:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrC1CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Temperature: 30 °C
Reaction time: 18 h
Yield: 26.6 %

Procedure:
A solution of 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (Method C2a; 33.2 g, 114 mmol) in DMF (1 L) was treated with NaOH (690 g, 17.3 mol) and cyclopentyl bromide (865 mL, 6.3 mol) and the resulting mixture was stirred at 20-40° C. for 18 h, then cooled to 4° C., and treated with water (1.5 L). A conc. HCl solution was added to adjust the pH to 0, and the mixture was extracted with EtOAc (80 mL). The organic phase was washed with a 1N HCl solution (1 L), dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (500 mL) and filtered through a pad of silica gel (9×4 cm). Hexane was added to the resulting solution and volatiles were slowly removed by partial vacuum until crystals formed. The solids were collected to yield 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane as yellow crystals (10.9 g, 26%): mp 118-9° C.; TLC (5% EtOAc/hex) Rf0.34.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH2:11][C:12](OC)=[O:13])=O)=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]2[NH:3][N:2]=[C:12]([OH:13])[CH:11]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Oc1cc(-c2ccc(Cl)cc2)[nH]n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.2 %

Procedure:
Hydrazine monohydrate (0.80 g, 20 mmol) was added to a solution of methyl 4-chlorobenzoylacetate (3.19 g, 15.0 mmol) in ethanol (40 ml) at 0° C., and the mixture was stirred at room temperature for 2 days. After completion of the reaction, a precipitated solid was filtered and washed with diethyl ether, to give a white solid of 5-(4-chlorophenyl)-3-hydroxypyrazole (2.02 g, yield: 55.1%). mp: 240-241° C.; 1H-NMR (DMSO-d6, DMSO, ppm): δ 5.92 (s, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 9.30-10.60 (br s, 1H), 11.60-12.70 (br s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:16]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCC1CCC(O)CC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: OC1CCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-(Hydroxymethyl)cyclohexanol (2.0 g, 0.015 mol) was dissolved in pyridine (15.0 mL) and the mixture was cooled to 0° C. To the reaction was added triphenylmethyl chloride (4.7 g, 0.017 mol) and the resulting mixture was stirred at 0° C. for 2 hours and at 25° C. for 16 hours. The reaction was then concentrated using a rotory evaporator, and the concentrate was extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated in vacuo. The reaction was chromatographed on silica gel using 30% EtOAc/hexanes to give the cis isomer (0.74 g) 1H NMR(CDCl3): δ 7.52 (m, 6H), 7.27 (m, 9H), 3.98 (m, 1H), 2.93 (m, 2H), 1.21-1.68 (m, 9H); and the trans isomer (2.72 g) 1H NMR(CDCl3): δ 7.44 (m, 6H), 7.20-7.31 (m, 9H), 3.54 (m, 1H), 2.88 (m, 2H), 1.98 (m, 2H), 1.88 (m, 2H), 1.60 (m, 1H), 0.99-1.37 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.[CH:11]12[O:18][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][C@@H:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[OH:18]
Reactant: C1CCC2OC2CC1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O[C@@H]1CCCCC[C@H]1Nc1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,4-dichloroaniline (200 g., 1.23 mole), cycloheptene oxide (400 ml.), and concentrated HCl (2 ml.) is heated at reflux temperature for seven (7) days. The unreacted epoxide is evaporated at 60° C. and the residue is treated with excess ethereal HCl, and a syrup results. This is washed with 1000 ml. ether. The residue is crystallized and recrystallized from methanol/ether (1/5,5, v/v ) to give trans-3,4-dichloro-N-(2-hydroxycycloheptyl)aniline, hydrochloride salt.