Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:26]1([C@@H:32]2[CH2:34][C@H:33]2[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:26]1([C@@H:32]2[CH2:34][C@H:33]2[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C=Cc1cccnc1)NCCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
2.4 g (16.1 mmol) 3-(3-pyridyl)-acrylic acid and 5.3 ml (38.0 mmol) TEA are suspended in 80 ml abs. dichloromethane and cooled to ca. 0° C. under moisture exclusion. 2.9 g (18.9 mmol) 88% HOBT and 3.6 g (18.8 mmol) EDC are added and the mixture is stirred for 30 min under ice cooling. 5.3 g (17.0 mmol) 4-(trans-2-phenyl-cyclopropyl-carbonylamino)-butylamine are dissolved in 30 ml abs. dichloromethane and added drop-wise under ice cooling. The mixture is stirred overnight at RT without further cooling. The formed precipitate is filtered off and crystallized from 120 ml isopropanol. Colorless crystals with MP. 194-196° C. Yield 4.2 g (71%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Yield: 93.2 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (994 mg, 2.73 mmol) and phenyl boronic acid (576 mg, 3.00 mmol) according to the general procedure B. Obtained as a bright yellow solid (800 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:26]CCC(CCO)CCCCCCC/C=C\CCCCCCCCN.B(O)(O)O>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:7][OH:26])[CH2:5][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: NCCCCCCCC/C=C\CCCCCCCC(CCO)CCO
Agent: CCCCCCCCCCCCCCCC=CC1=NCCN1CCO
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCN(CCO)CCO

Procedure:
Approximately 170 g of 1-(2-hydroxyethyl)-2-heptadecenyl imidazoline, 170 g bis(2-hydroxyethyl) oleylamine, 150 g toluene solvent and 62 g boric acid were heated to reflux in a reactor equipped as described in Example 2. Approximately 47 ml water was removed by azeotropic distillation at temperatures up to 175° C. over a period of about 5 hours. The solvent was removed by azeotropic distillation and the borated product was filtered hot through diatomaceous earth to yield a clean, brown, liquid product. Certain of the mixed borated material was then subjected to testing in a low velocity friction apparatus test described below. Test results are reported in Table 1 below.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Pd](Cl)Cl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc([Mg]Br)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 92 %

Procedure:
4-octyloxyphenylmagnesium bromide (124 g, 25% solution in tetrahydrofuran) is added dropwise over ten hours to a refluxing solution of 4-bromobenzonitrile (17 g), palladium (II) chloride (0.68 g) and triphenylphosphine (2.0 g) in tetrahydrofuran (100 ml). [HPLC: yield 92-94%]. After cooling to room temperature tetrahydrofuran is removed under vacuum. Water (20 ml) and toluene (150 ml) are added and the mixture filtered hot (80-85 C.). The aqueous phase is separated off, and the solvent removed by distillation. The crude product is recrystallised from ethanol/n-hexane to give 4'-octyloxybiphenyl-4-carbonitrile as a solid. 1H NMR (CDCl3): 0.89(t,3H), 1.29-1.50(m,10H), 1.81(quint.2H), 4.00(t,2H), 6.99(d,2H), 7.52(d,2H), 7.63(d,2H), 7.68(d,2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[NH3:20].CO>>[NH2:20][CH2:14][C:12]([OH:13])([CH3:15])[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:11]
Reactant: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Reactant: N
Solvent: CO
Product: CC(O)(CN)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
2-Methyl-oxirane-2-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (1.0 g, 3.48 mmoL) was dissolved in 7N NH3/MeOH solution (10 mL) at room temperature. The reaction mixture was stirred overnight and the solvent was removed to yield the title compound as pale yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:32])=[C:11]([C:14]4[CH:19]=[C:18]([CH:20]5OCC(C)(C)C[O:21]5)[CH:17]=[C:16]([O:28][CH3:29])[C:15]=4[O:30][CH3:31])[CH:12]=3)[C:7](=[O:33])[C:6]([C:34]([O:36]CC)=[O:35])=[CH:5]2)[CH2:3][CH2:2]1.Cl>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:32])=[C:11]([C:14]4[CH:19]=[C:18]([CH:20]=[O:21])[CH:17]=[C:16]([O:28][CH3:29])[C:15]=4[O:30][CH3:31])[CH:12]=3)[C:7](=[O:33])[C:6]([C:34]([OH:36])=[O:35])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C4OCC(C)(C)CO4)cc(OC)c3OC)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: COc1cc(C=O)cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)c1OC
Yield: 73.3 %

Procedure:
575 mg of ethyl 1-cyclopropyl-7-[5-(5,5-dimethyl-1,3-dioxan-2-yl)-2,3-dimethoxy-phenyl]-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate (Example 7a)) are heated to boiling under reflux in a mixture of 8 ml of a 2N aqueous hydrochloric acid solution and 5 ml of ethanol for 6 hrs. The reaction mixture is cooled in an ice bath and the separated precipitate is filtered off under suction and washed with 20 ml of water and with 50 ml of ether. 330 mg (73%) of 1-cyclopropyl-6-fluoro-7-(5-formyl-2,3-dimethoxy-phenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained as a colourless solid. M.p.>230°. Mass spectrum: peaks: inter alia at 411 (M+, 6%), 367 (100%), 338 (6%), 202 (8%), 184 (10%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[C:29]([CH3:36])[C:3]=1[O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9]COCC[Si](C)(C)C)=[C:7]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:6]=1.C1COCC1.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[C:29]([CH3:36])[C:3]=1[O:4][C:5]1[CH:19]=[CH:18][C:8]([OH:9])=[C:7]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1Oc1ccc(OCOCC[Si](C)(C)C)c(COc2ccc(F)cc2)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])cc(Cl)c1Oc1ccc(O)c(COc2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a stirred solution of {2-[4-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(4-fluoro-phenoxymethyl)-phenoxymethoxy]-ethyl}-trimethylsilane (280 mg) in MeOH (2.5 mL)/THF (0.2 mL) was added 6% sulfuric acid in MeOH (2.5 mL) and the resulting solution was stirred for 1 h. The reaction was quenched with 1 N aqueous sodium bicarbonate, extracted with ethyl acetate, the organic layer dried over sodium sulfate and concentrated in vacuo. Flash chromatography (15% ethyl acetate/hexanes) afforded 4-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(4-fluorophen-oxymethyl)-phenol (170 mg) as a yellow semi-solid.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[C@@H:13]([Cl:28])[CH2:12]3)[CH2:9][C@H:8]1[CH3:29])(=O)C.Cl(O)(=O)(=O)=O>CO>[Cl:28][C@@H:13]1[C:14]2[C@:19]([CH3:20])([CH:18]=[CH:17][C:16](=[O:27])[CH:15]=2)[C@@H:21]2[C@H:11]([C@H:10]3[C@:24]([CH3:25])([CH2:23][C@@H:22]2[OH:26])[C@@H:7]([C:6](=[O:30])[CH2:5][OH:4])[C@H:8]([CH3:29])[CH2:9]3)[CH2:12]1
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)CO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.3 %

Procedure:
1.5 g of 21-acetoxy-6α-chloro-11β-hydroxy-16α-methyl-1,4-pregnadiene-3,20-dione is dissolved in 42 ml of methanol; 1.3 ml of 70% perchloric acid is added thereto and the mixture allowed to stand at room temperature for 20 minutes. The reaction mixture is stirred into ice water, the thus-obtained precipitate is filtered off, washed with water, and dried in the open air. After recrystallization from acetone-diisopropyl ether, 1.02 g of 6α-chloro-11β,21-dihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione is obtained, m.p. 128° C. [α]D25 =+55° (chloroform).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[N:8]O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8]
Reactant: CC1(C)CCCCC1=NO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCCCC1N
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
In a dry 50 mL 3-neck round-bottomed flask, 2,2-dimethylcyclohexanone oxime (0.235 g, 1.66 mmol) was dissolved in THF (10 mL). Lithium aluminum hydride (1.0 M solution in THF, 4.0 mL, 4.0 mmol) was added dropwise over 15 min at room temperature. The reaction mixture was stirred at 60° C. overnight then cooled to room temperature and carefully quenched with 10 mL of saturated aqueous Rochelle-salt solution. The biphasic mixture was stirred at room temperature overnight then extracted with 2×50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide 151 mg (71%) of 2,2-dimethylcyclohexylamine as a yellow oil which was used without further purification.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13](O)[CH3:14]>>[O:1]([CH2:13][CH3:14])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Glucose (500 g, 2.78 mol) and a strong acid cation exchange resin (100 g Amberlyst™ 15, BDH Chemicals) was suspended in ethanol (2000 ml, 34.3 mol) The mixture was stirred at 80° C. for 16 hours. The progress of the reaction was followed by HPLC. The ion exchange resin was removed by filtration and the solution was treated with activated carbon (10 g). After filtration the ethanol was removed in vacuo giving ethyl D-glucopyranoside (a 1:1 mixture of α and β anomers) as a syrup (578 g, quantitative yield).
Reaction SMILES: Cl.[OH:2][CH2:3][C@@H:4]1[NH:8][CH2:7][C@@H:6]([OH:9])[CH2:5]1.[C:10](#[N:13])[CH:11]=[CH2:12]>C(=O)([O-])[O-].[K+].[K+].C(#N)C>[OH:9][C@@H:6]1[CH2:7][N:8]([CH2:12][CH2:11][C:10]#[N:13])[C@@H:4]([CH2:3][OH:2])[CH2:5]1
Reactant: C=CC#N
Reactant: OC[C@H]1C[C@H](O)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCN1C[C@@H](O)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(3S,5R)-5-Hydroxymethylpyrrolidin-3-ol hydrochloride (0.4 g) described in Biochemistry, Vol. 5, pp. 1154-1155 (1966) was dissolved in aqueous potassium carbonate solution (2 mL) and acetonitrile (2 mL). Acrylonitrile (0.5 mL) was added and the mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the reaction mixture was concentrated and the obtained residue was suspended in chloroform-methanol and dried by adding magnesium sulfate. Magnesium sulfate was filtered off and the solvent was concentrated to give 3-[(2R,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile (0.47 g).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:22][CH:23]=2)[C:14]([NH2:17])=[N:15][CH:16]=1>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:22][CH:23]=2)[C:14]2[N:15]([CH:16]=1)[CH2:4][CH2:5][S:6](=[O:8])(=[O:7])[N:17]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(OC2CCCCC2)nc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(OC4CCCCC4)nc3)C2=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 553 mg) in THF (dry) (30 mL) was added 2-chloroethanesulfonyl chloride (0.582 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 5-chloro-6′-(cyclohexyloxy)-3,3′-bipyridin-2-amine (840 mg) in THF (dry) (30 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. carefully. EtOAc and THF were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane). The residue was crystallized from THF/IPE to give the title compound (336 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23]C(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.NC1[NH:52][N:51]=[N:50][N:49]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20]([NH:22][C:23]2[NH:52][N:51]=[N:50][N:49]=2)=[O:21])[CH2:31][CH3:32])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: Nc1nnn[nH]1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1nnn[nH]1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, 5-amino-1H-tetrazole was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [O-]S([O-])=O.[Na+:5].[Na+].C([O-])(O)=O.[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25]>O.CC(C)=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25].[Na+:5]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(S(=O)[O-])cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
A solution of Na2SO3 (400 mg, 3.2 mmol) and NaHCO3 (270 mg, 3.2 mmol) in H2O (10 mL) was treated slowly with a solution of 4-methoxy-3-nitrobenzenesulfonyl chloride (400 mg, 1.6 mmol) in acetone (3 mL), heated to 50° C. for 2 hours, cooled to room temperature, and washed with dichloromethane. The aqueous wash was filtered through cotton, lyophilized, suspended in methanol, filtered, concentrated, and dried under vacuum to provide the desired product.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[N:15]1([CH2:14][CH2:13][NH:12][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCCN1CCCC1
Reactant: Fc1ncccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cccnc1NCCN1CCCC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
To the solution of 2-fluoro-3-(trifluoromethyl)pyridine (990 mg, 6 mmole) in 5 ml of NMP, 2-aminoethylpyrrolidine (1.13 ml, 9 mmole) and triethylamine (1 ml, 7.2 mmole) were added. The reaction solution was stirred at 85° C. for overnight. The reaction mixture was poured into 40 ml of saturated NaHCO3 and extracted with ethyl acetate (2×80 ml). The combined organic layers were washed with water (2×30 ml) and brine (30 ml), then dried over Na2SO4 and evaporated in vacuo to give a brown oily N-(2-(pyrrolidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2-amine (1.61 g). ES/MS m/z 260.1 (MH+).
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:6]1[CH:7]=[CH:8][C:3]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C1(c2ccc(Br)cc2)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
At 5° C. bromine (1.5 mL, 30 mmol) is added dropwise to a solution of 1-phenyl-1-cyclopropylcarboxylic acid (5 g, 30 mmol) and sodiumacetate (2.7 g, 33 mmol) in 30 mL glacial acetic acid. Then the mixture is heated to 50° C. and stirred for 2 days. The reaction mixture is diluted with 100 mL water, and the precipitate formed is filtered off and washed with 50% acetic acid. Yield: 5.7 g.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)CCCCCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 2 g of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 131), 1.4 g of potassium carbonate, 4 ml of ethyl 6-bromohexanoate, and 50 ml of methylisobutylketone, a reaction similar to that conducted in Example 171 was carried out. As a result, 2.89 g of N-(trans-4-methylcyclohexyl)-4-[5-(ethyoxycarbonyl)pentyloxy]-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [O:1]=[C:2]1[CH2:15][CH:14]2[C:9]([C:16]([O:18]C)=[O:17])([CH2:10][CH2:11][CH2:12][CH2:13]2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C[Si](C)(C)[O-].[K+]>C1COCC1>[O:1]=[C:2]1[CH2:15][CH:14]2[C:9]([C:16]([OH:18])=[O:17])([CH2:10][CH2:11][CH2:12][CH2:13]2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: COC(=O)C12CCCCC1CC(=O)c1ccccc12
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CC2CCCCC2(C(=O)O)c2ccccc21
Yield: 77.6 %

Procedure:
A solution of the compound from Example 51 (1.5 g, 5.8 mmol) and potassium trimethylsilanolate (1.5 g, 11.6 mmol) in 25 ml THF was refluxed 60 hours. Workup as before and chromatography on silica gel gave the title compound (1.1 g, 78%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:47])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][C:26]=1[O:34][CH2:35][CH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2)(=[O:24])=[O:23])[C:15](N(OC)C)=[O:16])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:47])[CH2:13][C@H:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][C:26]=1[O:34][CH2:35][CH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2)(=[O:24])=[O:23])[CH:15]=[O:16])([CH3:10])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C[C@@H](C=O)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Temperature: -65 °C
Reaction time: 2 h

Procedure:
To a −65° C. solution of lithium aluminum hydride (0.51 mL, 1M in diethyl ether) in diethyl ether (5 mL) was added a solution of 3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester (0.10 g, 0.17 mmol) in diethyl ether (5 mL). The reaction was stirred at −65° C. for 2 h. The reaction was then diluted with ethyl acetate (100 mL) and washed with 10% potassium hydrogen sulfate and then saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield (S)-3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester as a clear oil. MS(APCI) m/z 528.1 (M−H).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:39])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([S:27]([CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=2[Cl:38])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[NH:13][C:12]=1[CH3:40])=[O:10].[N:41]1([CH2:46][C@@H:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)[CH2:45][CH2:44][CH2:43][CH2:42]1>>[Cl:38][C:32]1[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=1[CH2:30][S:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:39])/[C:18]/2=[CH:17]\[C:14]1[NH:13][C:12]([CH3:40])=[C:11]([C:9]([N:48]2[CH2:49][CH2:50][CH2:51][C@H:47]2[CH2:46][N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:10])[C:15]=1[CH3:16])(=[O:28])=[O:29]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)ON1C(=O)CCC1=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CN1CCCC1

Procedure:
5-[5-(2,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (120 mg, 0.2 mmol) was coupled with (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (31 mg, 0.2 mmol) to give the titled compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:14][C:5]2[NH:6][C:7]([C:9]([O:11]CC)=[O:10])=[CH:8][C:4]=2[CH2:3]1.O.[OH-].[Li+]>>[CH3:1][CH:2]1[CH2:14][C:5]2[NH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH2:3]1
Reactant: CCOC(=O)c1cc2c([nH]1)CC(C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC1Cc2cc(C(=O)O)[nH]c2C1
Yield: 14.1 %

Procedure:
The title compound was synthesized from ethyl 5-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.017 g, 0.09 mmol) and lithium hydroxide monohydrate (0.019 g, 0.45 mmol) according to General Procedure 7. The crude was purified by reverse phase HPLC (50-100% MeOH: water, 0.1% formic acid) to give 5-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (22) as a light brown solid (2.1 mg, 14%). Rf (1:1 EtOAc:heptane)=0.12; 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.19 (d, J=6.6, 3H), 2.17-2.20 (m, 1H), 2.26-2.32 (m, 1H), 2.75-2.80 (m, 1H), 2.84-2.90 (m, 2H), 6.56 (s, 1H); LCMS-MS (ESI+) 166.0 (M+H); HPLC (UV=100%), (ELSD=100%).