Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=[C:4]([NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(C)(C)CNc1cc(Cl)nc(NCC(C)(C)C)n1
Reactant: C1CNCCN1
Product: CC(C)(C)CNc1cc(N2CCNCC2)nc(NCC(C)(C)C)n1
Yield: 51.5 %

Procedure:
The reaction of 4-chloro-2,6-bis(2,2-dimethylpropylamino)pyrimidine with piperazine as described in Example 4 gives the title product in a yield of 51.5%, m.p.: 138°-140° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl[CH2:16][C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1.O>CN(C)C(=O)C>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:16][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: COc1cc(C=O)c(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2n1C
Temperature: 80 °C
Yield: 267.3 %

Procedure:
To a solution of 2-fluoro-4-hydroxy-5-methoxy-benzaldehyde (39, 3.0 g, 5 mmol) in N,N-dimethylacetamide (120 mL) was added sodium hydride (60% dispersion in mineral oil, 0.8 g, 19 mmol) portion wise. After the addition was complete, the reaction was stirred for 30 minutes after which 2-chloromethyl-1-methyl-1H-benzoimidazole (212, 2.9 g, 16 mmol) was added and then heated at 80° C. overnight. The reaction mixture was then poured into water (1 L) with stirring and the precipitated solid was filtered, washed with water and dried to give the desired compound (213, 4.2 g, 84% yield).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C:26]1[N:31]=[C:30]([C:32]([OH:34])=O)[C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:28][CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:32]([C:30]1[C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=1)=[O:34]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)O)n1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 6′-methyl-[2,3′-bipyridine]-2′-carboxylic acid. MS (ESI) 325 (M+H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:24]1)(=O)=O>CCCCCC.CS(C)=O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][C@@H:23]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:24]2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CCCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1ccc(CCCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (32 mg, 0.81 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (6 ml). After stirring at room temperature for 30 minutes, 5,11-dihydrodibenzo[b,e][1,4]oxazepine (142 g, 0.74 mmol) was added to the obtained suspension. They were stirred at room temperature for 40 minutes and then at 50° C. for 40 minutes. A solution of (S)-3-methanesulfonyloxy-1-[3-(4-methoxyphenyl)propyl]pyrrolidine (254 mg, 1.81 mmol) in dimethyl sulfoxide (3 ml) was added dropwise in the obtained solution, and they were stirred at 50° C. for 5 hours. The reaction liquid was poured into ice/water. After the extraction with a solvent mixture of hexane and ethyl acetate (1:1), the organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a mixture of dichloromethane and methanol (50:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-[3-(4-methoxyphenyl)propyl]pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (78 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1>[Pd].C(OCC)(=O)C.C(O)C>[CH3:18][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[NH2:15]
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reaction time: 5 h
Yield: 97 %

Procedure:
A mixture of 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine (141 g, 0.58 mol) and 10% palladium on charcoal (13 g) in ethyl acetate (200 ml) and ethanol (700 ml) was stirred under an atmosphere of hydrogen (1.2 bar) for 5 hours. After reaction completion, the mixture was purged with nitrogen and the catalyst was filtered off. The filtrate was evaporated to dryness to give 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (120.6 g, 98%) as a white solid; Mass spectrum MH+ 215.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6]O)([O-:3])=[O:2].C(Cl)(Cl)Cl.P(Br)(Br)[Br:18]>O>[N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH2:6][Br:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1CBr
Yield: 80 %

Procedure:
To a solution of 16.5 g. of 2-nitro-4-chlorobenzyl alcohol in 200 ml. of chloroform was added dropwise 13 g. of phosphorus tribromide, and the mixture was heated to reflux for 1 hour on a water bath. The reaction mixture was then poured into water, and the chloroform layer was separated and washed with water. After the solvent was removed, the residue was extracted with ligroin while warming and allowed to stand to form colorless acicular crystals of 2-nitro-4-chlorobenzyl bromide (80% yield) melting at 42° to 43° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[C@H:3]1[C:16]([OH:18])=[O:17].[C:20]([C@@H:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=1)#[N:21]>>[CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])[C@H:3]1[C:16]([O:18][C@H:22]([C:20]#[N:21])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:24]=1)=[O:17]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OC1CCCCC1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CCCCC1
Yield: 42.4 %

Procedure:
Using the procedure of Step D in Example 7, 2.5 g of the product of Step C and 2.2 g of (S)α-cyano-3-phenoxybenzyl alcohol were reacted and the product was chromatographed over silica gel. Elution with a 9-1 hexane-ether mixture yielded 1.883 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[Z-2-(cyclohexyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+41°±2.5° (c=0.5% in chloroform).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][C:17]([CH3:18])([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:25])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CC(C)(C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CC(C)(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,3-dimethyl-3-phenyl-butyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:29]5[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=5)=[C:18]4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(OC)(O[CH3:43])(=O)=O>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:29]5[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=5)=[C:18]4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH3:43])=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1ccc(-c2ccc3ccc(C45CC6CC(CC(C6)C4)C5)cc3c2OCCCCCCO)cc1
Product: COCCCCCCOc1c(-c2ccc(C(=O)O)cc2)ccc2ccc(C34CC5CC(CC(C5)C3)C4)cc12
Yield: 11.5 %

Procedure:
Following the procedure of Example 12(a), but reacting 870 mg (1.7 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxyhexyloxy-2-naphthyl]benzoate with 160 μl (1.7 mmol) of dimethyl sulphate, 100 mg (14%) of the expected compound were obtained, which compound had a melting point of 141°-3° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cccc(I)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(I)c1)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
1.53 g of 3-iodoaniline and 2.78 ml of triethylamine are dissolved in 25 ml of methylene chloride and treated dropwise at room temperature with a solution of 1.6 ml of cyclopropane carbonyl chloride in 10 ml of methylene chloride. The mixture is stirred at room temperature for a further 5 hrs., evaporated and poured into 50 ml of water. The mixture is made slightly acid with dil. hydrochloric acid and extracted three times with ethyl acetate. The residue is recrystallized from toluene. 1.47 g of cyclopropanecarboxylic acid (3-iodo-phenyl)-amide are isolated as a colourless solid. Yield: 74%. M.p.=133°.
Reaction SMILES: F[C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[CH:14]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][O-:28].[K+].O1CCOCCOCCOCCOCCOCC1>CN(C)C=O>[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:21])[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ncccc3F)no2)c1
Reactant: CN(C)CCCC[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCCOc1cccnc1-c1noc(-c2cc(F)cc(C#N)c2)n1

Procedure:
Alternatively, treatment of 3-(3-fluoropyrid-2-yl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole with potassium 4-dimethylaminobutoxide in N,N-dimethylformamide with a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) and heating at 110° C. affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recystallization, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(4-dimethylaminobutoxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH:21]1[CH:26]=[N:25][CH:24]=[C:23]([N:27]=[C:28]=[O:29])[CH:22]=1>ClCCl>[N:25]1[CH:26]=[CH:21][CH:22]=[C:23]([NH:27][C:28]([N:2]2[CH2:3][CH:4]([O:6][C:7]3[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=3)[CH2:5]2)=[O:29])[CH:24]=1
Reactant: Ic1ccc(OC2CNC2)nc1
Reactant: O=C=Nc1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CC(Oc2ccc(I)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
2-(Azetidin-3-yloxy)-5-iodo-pyridine hydrochloride (4.2 g, 13 mmol) was suspended in anhydrous dichloromethane (50 mL) and triethylamine (5.5 mL) was added. Pyridine-3-isocyanate (1.45 g, 11.7 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 hr. The suspension solvents were removed in vacuo and the residue partitioned between ethyl acetate (400 mL) and sat. aqueous sodium bicarbonate solution (400 mL). The mixture was filtered through a pad of celite and the filtrate phases were separated. The organic phase was washed with sat. aqueous sodium bicarbonate solution (250 mL), then sat aqueous sodium chloride solution (250 mL) and dried over sodium sulphate and filtered. The filtrate solvents were removed in vacuo to afford a yellow solid which was purified by flash chromatography on silica gel (100 g), eluting with a 1:19 mix of 7N ammonia in methanol solution: dichloromethane. This affords the title compound (2.0 g, 42%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][OH:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(O)(=O)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.C(O)(=O)C>[C:12]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:14])[CH3:13]
Reactant: CCCCCCC(C)=CCO
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCC(C)=CCOC(C)=O

Procedure:
156 G. (1 mole) of 3-methyl-2-nonen-1-ol, 122 g. (1.2 moles) of acetic anhydride and 264 ml. of toluene were combined in a reaction flask and heated. The formed acetic acid-toluene azeotropic mixture consisting of 34 parts of acetic acid and 66 parts of toluene and boiling at 105° C. was removed by distillation through a 11/2 ft. Vigreux column. After termination of the reaction, the reaction mass was washed with 100 ml. of aqueous sodium carbonate solution, 100 ml. of aqueous sodium bicarbonate solution, and finally twice with 100 ml. of water. The desired ester, 3-methyl-2-nonen-1-yl-acetate, having a b.p. of 119°-121° C. at 10 mm. and an R.I. at 20°:1.445, was recovered by fractional distillation.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH2:7][CH2:8][CH:9]=[C:10]([F:12])[F:11]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:4][CH2:7][CH2:8][CH:9]=[C:10]([F:12])[F:11])(=[S:3])[CH3:2]
Reactant: FC(F)=CCCBr
Reactant: CC([O-])=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: CC(=S)OCCC=C(F)F
Reaction time: 18 h
Yield: 38.9 %

Procedure:
Potassium thioacetate (1.98 g), 4-bromo-1,1-difluorobut-1-ene (3.0 g) and tetra-n-butylammonium bromide (0.3 g, catalyst) were stirred at the ambient temperature under nitrogen for 5 hours and stored for 18 hours. The mixture was distilled using a Kugelrohr apparatus to give 4,4-difluorobut-3-enyl thioacetate as a colourless liquid (1.12 g); 1H NMR δ 2.25(2H,m); 2.30(3H,s); 2.90(2H,t); 4.20(1H,m); (bp 115° C. at 120 mmHg).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:53](O)=[O:54])[C:48]1=[O:60])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:58])([CH3:57])[CH3:59])[C:53]([NH:1][C@@H:2]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)=[O:54])[C:48]1=[O:60])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
A solution containing the product from Example 23S (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 70A (0.013 g, 0.045 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.039 mL, 0.224 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 5% methanol in ethyl acetate to give the title compound (0.009 g, 30% yield). 1H NMR (300 MHz, CDCl3), δ ppm 0.96 (s, 9 H), 1.00 (s, 9 H), 1.27 (m, 1 H), 2.62 (dd, J=13.79, 8.64 Hz, 1 H), 2.85 (m, 5 H), 3.03 (q, J=8.58 Hz, 1 H), 3.39 (m, 1 H), 3.64 (m, 4 H), 3.82 (d, J=9.19 Hz, 1 H), 3.94 (m, 1 H), 4.00 (s, 1 H), 4.11 (m, 2 H), 4.35 (m, 2 H), 5.31 (m, 1 H), 6.13 (m, 2 H), 7.10 (m, 5 H), 7.21 (m, 2 H), 7.33 (m, 7 H), 7.74 (m, 2 H), 7.89 (d, J=8.46 Hz, 2 H), 8.68 (d, J=4.78 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([C:14]1([CH3:17])[CH2:16][CH2:15]1)#[CH:13]>C(N(CC)CC)C.[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>[CH3:17][C:14]1([C:12]#[C:13][C:2]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH2:16][CH2:15]1
Reactant: C#CC1(C)CC1
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C#Cc2cc([N+](=O)[O-])ccc2N)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (430 mg, 2.0 mmol) and 1-ethynyl-1-methyl-cyclopropane (630 mg, 8.0 mmol) in triethylamine (20 mL) was added CuI (76 mg, 0.40 mmol) and Pd(PPh3)2Cl2 (140 mg, 0.20 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 h. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2-((1-methylcyclopropyl)ethynyl)-4-nitroaniline (340 mg, 79%). NMR (300 MHz, CDCl3) δ 8.15-8.14 (m, 1H), 7.98-7.95 (m, 1H), 6.63 (d, J=6.9 Hz, 1H), 4.80 (brs, 2H), 1.38 (s, 3H), 1.04-1.01 (m, 2H), 0.76-0.73 (m, 2H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5](O)=[O:6])=[CH2:3].[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN1CCN(C)C1=O>[C:10]1([C@@H:16]([N:18]2[C:5](=[O:6])[CH2:4][CH:2]([C:1]([OH:9])=[O:8])[CH2:3]2)[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: C[C@@H](c1ccccc1)N1CC(C(=O)O)CC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Itaconic acid (650 g) and (S)-1-phenylethylamine (605 g) were suspended in 1,3-dimethylimidazolidinone (650 ml), and the suspension was stirred at 80° C. for 1 hr with heating, and further at 120° C. for 3 hr with heating. The mixture was cooled to room temperature, and water (4 l) was added. The precipitated crystals were collected by filtration and dried to give 950 g of 1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid. The crystals were recrystallized 3 times with isopropyl alcohol to give 156 g of (3S)-1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][C:7]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:6]1=O)=O.[NH2:23][NH2:24]>C1(C)C=CC=CC=1>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:7]2([C:6]3[NH:24][NH:23][C:3](=[O:2])[C:5]=3[CH2:9][CH2:8]2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Reactant: NN
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCc3c2[nH][nH]c3=O)CC1
Yield: 61.4 %

Procedure:
To a solution of tert-butyl 2-(methoxycarbonyl)-1-oxo-8-azaspiro[4.5]decane-8-carboxate from Procedure 1, Step F (0.448 g, 1.46 mmol) in toluene (15 mL) was added hydrazine (0.084 mL, 1.72 mmol). The reaction mixture was refluxed for 12 h, concentrated and the residue was purified by flash chromatography eluting with 5% MeOH/dichloromethane and 0.1% triethylamine to give the title compound (0.263 g). MS/EI (acetonitrile/water): m/z 294.3 retention time=2.0 min.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[N+:11]([C:14]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17])([O-:13])=[O:12]>ClCCl>[N+:11]([C:14]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:15]=1[C:16]([CH:3]1[C:4](=[O:9])[CH:5]2[CH2:8][CH:1]([CH2:7][CH2:6]2)[C:2]1=[O:10])=[O:17])([O-:13])=[O:12]
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)C2C(=O)C3CCC(C3)C2=O)c([N+](=O)[O-])c1

Procedure:
To a solution of 10 g of bicyclo[3.2.1]octane-2,4-dione in 100 ml of dichloromethane was added dropwise 70 ml of a dichloromethane solution having dissolved therein 19.1 g of 2-nitro-4-methylsulfonylbenzoyl chloride while ice cooling.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O1CCOCC1.[S:15](=[O:19])(=[O:18])([OH:17])O>ClC(Cl)=C(Cl)Cl>[OH:1][C:2]1([S:15]([OH:19])(=[O:18])=[O:17])[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]1[S:15]([OH:17])(=[O:19])=[O:18]
Reactant: Oc1ccc(O)cc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: ClC(Cl)=C(Cl)Cl
Product: O=S(=O)(O)C1C=C(O)C=CC1(O)S(=O)(=O)O
Temperature: 140 °C
Reaction time: 4 h
Yield: 139 %

Procedure:
190 g of p-dihydroxy benzene monosulfonic acid, 100 ml of dioxane, and 100 ml of perchloroethylene are mixed in a flask provided with a reflux condenser. The flask is heated in an oil bath to the reflux temperature (in the oil bath at 140°C). It is refluxed for half an hour, and then is left to cool a little to set the coolant for distillation. In the flask, two layers are formed: a colourless lower layer, and a coloured upper layer in which the acid is dissolved. The flask is heated again and 100 ml of the solvent mixture are distilled. In the mixture collected, two layers form, the upper, moderate, is aqueous. To the flask provided with a reflux condenser, 98 g of sulfuric acid containing 20 % of SO3 are added, and it is heated again, to a lower temperature, so that the reflux is barely noticeable (bath temperature: 130°C), for four hours. The liquids accompanying the acid are removed by distilling at reduced pressure, the residue is dissolved in a little water, 2 g of active charcoal are added, and it is filtered. The solution is concentrated, cooled, and is precipitated by adding five volumes of acetone. The precipate is filtered, and 189 g of p-dihydroxy benzene disulfonic acid, with a melting point of 166° - 169°C are obtained.