Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C=O)[CH2:6][CH2:5]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25](N)([CH3:27])[CH3:26].[O-]CC.[Na+]>C(O)C>[CH3:26][C:25]1([CH3:27])[NH:2][C:1]([CH2:3][CH:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]2)=[N:23][CH2:24]1
Reactant: CC(C)(N)CN
Reactant: N#CCC1CCN(C=O)CC1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CN=C(CC2CCNCC2)N1
Temperature: 185 °C
Yield: 69 %

Procedure:
A mixture containing 4(cyanomethyl)-1-piperidinecarboxaldehyde (3.5 g, 0.023M) and 1,2-diamino-2-methylpropane mono-p-toluenesulfonate (12.4 g, 0.047M) was heated at 185° C. under nitrogen for 5 hrs. The reaction mixture was dissolved in ethanol (20 ml), basified with sodium ethoxide (0.052M), filtered and stripped to dryness. The residue was distilled at 150° C. to about 185° C., 0.02 mmHg, to give (3.1 g, 63%) 4-[(4,5-dihydro-5,5-dimethyl-1H-imidazol-2-yl)methyl]-piperidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[NH:15][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1-c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: Fc1ccc2c(c1)[nH]c1cc(F)ccc12
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A solution of 4,4′-difluoro-2-nitro-1,1′-biphenyl (0.580 g, 2.5 mmol) and triphenylphosphine (1.617 g, 6.2 mmol) in anhydrous 1,2-dichlorobenzene (5 mL) was heated to 175° C. in a microwave reactor for 4 hrs. The mixture was cooled to room temperature and concentrated to a black residue under high vacuum. The crude product was purified by silica gel chromatography (5-50% methylene chloride/hexanes) to afford the product as a light brown powder (0.41 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 8.10 (br s, 1H), 7.93 (dd, 2H, J=8.7, 5.4 Hz), 7.11 (dd, 2H, J=9.3, 2.4 Hz), 6.99 (ddd, 2H, J=9.6, 9.0, 2.4 Hz).
Reaction SMILES: Cl[P:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH:6]([CH3:22])[C:5]2[CH:23]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:4]=2[O:3]1.[OH2:35].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:35]=[PH:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH:6]([CH3:22])[C:5]2[CH:23]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:4]=2[O:3]1
Reactant: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2OP(Cl)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Reactant: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2O[PH](=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a solution of 5.5 g (11 mmol) of the compound of Example 7 in 100 mL of toluene at ambient temperature is added dropwise a solution of 0.20 mL (11 mmol) of distilled water in 3.0 mL (22 mmol) of triethylamine. After the addition is complete, the reaction mixture is stirred at room temperature for 15 minutes. The toluene is removed under vacuum and the residue is recrystallized twice from 50 mL of diethyl ether. The ether is removed in vacuo and the residue is dried under vacuum to give 3.95 g (74% yield) of the title compound as an off-white solid melting at 209° C.
Reaction SMILES: O[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(C(F)(F)F)c(C#N)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Reaction time: 2 h
Yield: 90 %

Procedure:
To 2-hydroxy-6-methyl-4-(trifluoromethyl)nicotinonitrile (1 g, 5 mmol) was added phosphoryl trichloride (15 mL). Then the mixture was heated to reflux and maintained at the same temperature with stirring for 2 hours. The resultant mixture was concentrated to give a residue and the residue was purified by chromatography (petroleum ether/ethyl acetate=1:1) to give 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (1 g, 90%). 1H NMR (300 MHz, CD3OD): δ 7.81 (s, 1H), 2.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32](NC)[CH:31]=1.[CH3:42][N:43](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]([CH2:42][NH:43][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:10]2)=[O:28])[CH:31]=1
Reactant: CNc1cnc2ccccc2c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCc2cnc3ccccc3c2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 47.6 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example 1d was reacted with quinolin-3-yl-methylamine (47.5 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight. to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (quinolin-3-ylmethyl)-amide (54.4 mg, 47.5%) as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][CH2:7][N:8]([CH3:32])[C:9](=[O:31])[C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29].C(N(CC)CC)C>C1COCC1>[C:1]([O:5][CH2:6][CH2:7][N:8]([CH3:32])[C:9](=[O:31])[C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])(=[O:3])[CH3:2]
Reactant: CN(CCO)C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCN(C)C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 44.2 %

Procedure:
Acetyl chloride (2.7 g, 0.0344 mole) was added dropwise in 5 mins. to a solution of N-(2-hydroxyethyl)-N-methyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzamide (7.2 g, 0.0172 mole), triethylamine (25 ml) and THF (25 ml). The resulting mixture was heated up to and held at reflux for 2.5 hrs., cooled and concentrated. The residue was taken into 500 ml of ether, washed two times with water, dried over MgSO4 and concentrated to 8.6 g of crude product. The crude product was purified on a column of silica gel using ethyl acetate cyclohexane (1:3) as eluent to yield 3.5 g of pure N-[2-(acetoxy)ethyl]-N-methyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzamide as a gum; nmr (CDCl3) δ 2.04 (s, 3H), 2.92 (s)-3.15 (s) (3H), 3.40 (t)-3.79 (t) (2H); 4.12 (t)-4.40 (t) (2H), 6.80-8.42 (m, 6H); ir (CHCl3) 1750, 1655 Cm-1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)#[CH:13].C(N(C(C)C)CC)(C)C>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.[Cu]I>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[C:14]([C:12]#[C:13][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=1
Reactant: C#Cc1cnc2ccccc2c1
Reactant: COC(=O)c1cccc(Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C#Cc2cnc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 6-bromo-2-pyridinecarboxylate (0.3 g, 1.3 mmol), 3-ethynylquinoline (0.3 g, 1.3 mmol), Pd(PPh3)4 (0.11 g, 0.01 mmol), CuI (0.179 g, 0.1 mmol) and diisopropylethylamine (0.5 ml, 3 mmol) in DMF (15 ml) was stirred at ambient temperature for 12 hrs under an atmosphere of nitrogen. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 10% ethyl acetate in n-hexane) to provide methyl 6-[(quinolin-3-yl)ethynyl]pyridine-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:15][CH2:16][N:17]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[CH2:18][CH2:19]1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3ncccn3)CC2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCN(c4ncccn4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 87.5 %

Procedure:
With 300 mg of the compound obtained in Step 45-1 and 201 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 402 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:15]([NH:27][NH2:28])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1>C1COCC1>[Cl:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:28][N:27]=2)[CH:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2ccnc(NN)c2Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccn3c(=O)[nH]nc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
To a stirred solution of triphosgene (2.64 g, 8.9 mmol) in THF (25 mL) at room temperature under argon was added 1-(3-chloro-4-p-tolylpyridin-2-yl)hydrazine (0.692 g, 3.0 mmol). The reaction mixture was stirred at room temperature for 16 h. Analysis by HPLC/MS indicated that starting material had been consumed. Water (25 mL) was added while stirring. The resulting suspension was heated at 100° C. for 40 h. Upon cooling to room temperature, the desired product was filtered and further washed with water (15 mL×2). After drying in a vacuum oven under reduced pressure overnight, 562 mg of the title compound was obtained as a white solid. HPLC/MS: retention time=2.98 min, [M+H]+=260.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([CH3:25])([O-:24])=[O:23]>C(O)C>[CH2:1]([N:8]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[S:9]([CH2:12][CH2:13][CH2:25][N+:22]([O-:24])=[O:23])(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: CCOC(CN(Cc1ccccc1)S(=O)(=O)CC)OCC
Solvent: CCO
Product: CCOC(CN(Cc1ccccc1)S(=O)(=O)CCC[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of crude ethanesulfonic acid benzyl-(2,2-diethoxy-ethyl)-amide (10 g, 32 mmol) in ethanol (150 ml) under argon was added nitromethane (100 ml) followed by Na-tert-pentoxide (1.8 g, 16 mmol) at rt. After stirring for overnight at ambient temperature, the mixture was concentrated in vacuo, diluted with chloroform (300 ml), washed with cold 1N HCl (200 ml), dried over MgSO4, filtered, and purified on silica gel column (dichloromethane) to give the title compound (5 g, 42% for 2 steps); 1H NMR (CDCl3): 1.25 (t, 6H), 2.55 (m, 2H), 3.20 (m, 2H), 3.55 (m, 2H), 3.75 (m, 21), 4.60 (m, 5H), 7.40 (m, 5H); LCMS: 393 (MH+).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:20][CH:21]([OH:37])[CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[O:12][C:11](=[O:38])[CH:10]=1)C1C=CC=CC=1.[H][H]>CN(C=O)C.[Pd]>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH:21]([OH:37])[CH2:20][O:19][C:15]3[CH:14]=[C:13]4[C:18]([C:9]([OH:8])=[CH:10][C:11](=[O:38])[O:12]4)=[CH:17][CH:16]=3)[CH2:24][CH2:25]2)=[CH:35][CH:34]=1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(OCC(O)CN3CCN(Cc4ccc(Cl)cc4)CC3)cc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1cc(O)c2ccc(OCC(O)CN3CCN(Cc4ccc(Cl)cc4)CC3)cc2o1
Yield: 61.8 %

Procedure:
A solution of 1-[3-(4-benzyloxycoumarin-7-yloxy)-2-hydroxypropyl]-4-(4-chlorobenzyl)piperazine (7 g) in dry DMF (80 ml) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst till one equivalent of hydrogen was absorbed. Filtration and evaporation of the solvent in vacuo afforded an oily product which crystallized from ethanol/petrol to give 3.60 g (63%) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][OH:15])=[CH:11][CH:12]=2)[N:7]=[C:6]([CH3:16])[CH:5]=1.F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>CN(C)C=O>[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][O:15][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:11][CH:12]=2)[N:7]=[C:6]([CH3:16])[CH:5]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c2ccc(COc3ccc(C#N)cc3)cc2n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
Sodium hydride (55–65% dispersion in mineral oil, 220 mg, 5.50 mmol) was added to a solution of (4-chloro-2-methyl-quinolin-7-yl)-methanol (example 2c, 1.10 g, 5.30 mmol) and 4-fluorobenzonitrile (642 mg, 5.30 mmol) in N,N-dimethylformamide (20 mL), and the resulting mixture was stirred at 50° C. for 3 h. After cooling the mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane, the organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) yielded the title compound (1.28 g, 78%). Yellow solid, ISP-MS: m/e=309.3 ([M+H]+).
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH3+:14])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([OH:4])=[O:3].Cl.[CH3:16]O>>[Cl-:1].[CH3:16][O:3][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([NH3+:14])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4]
Reactant: CO
Reactant: [NH3+]C1(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Agent: [Cl-]
Product: COC(=O)c1ccc(C2([NH3+])CC2)cc1
Temperature: 25 °C

Procedure:
1-(4-Carboxyphenyl)cyclopropanaminium chloride from Example 16, Step 1 (4.17 mmol) in MeOH (10 mL) was heated to the reflux temperature, in the presence of HCl (4M in dioxane, 104 μL, 0.417 mmol), for 16 h and cooled to r.t. The mixture was concentrated to dryness and the residue was partitioned between EtOAc and a phosphate buffer (pH 10). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was dissolved in dioxane (10 mL) and excess HCl (4M in dioxane) was added. The mixture was then concentrated to dryness affording the desired product as a brown solid. The crude was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.B(Br)(Br)Br>>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1
Reactant: COc1ccc(-c2nc3c(C)cc(OC)cc3s2)cc1
Agent: BrB(Br)Br
Product: Cc1cc(O)cc2sc(-c3ccc(O)cc3)nc12
Yield: 66.9 %

Procedure:
4-Methyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (174 mg, 0.61 mmol) was treated with boron tribromide under standard condition to give 4-methyl-6-hydroxy-2-(4-hydroxy-phenyl)-benzothiazole (105 mg, 67% yield) as a yellow solid. Mass spec: MH+=258.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28]O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:28][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][N:22]2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCCCC1CO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Product: CN1CCCCC1COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-Methyl-2-piperidinemethanol.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20][N:21]3[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23][CH2:22]3)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:29])=[C:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(OC(C)(C)C)=O.Cl>C(OCC)C>[Br:29][C:10]1[C:11]2[C:16](=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH2:20][N:21]3[CH2:26][CH2:25][S:24](=[O:27])(=[O:28])[CH2:23][CH2:22]3)[CH:12]=2)[NH:8][C:9]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CN3CCS(=O)(=O)CC3)cc([N+](=O)[O-])c21
Agent: Cl
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(CN2CCS(=O)(=O)CC2)cc2c(Br)c(-c3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-BOC-3-bromo-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-7-nitro-2-phenyl-1H-indole obtained in Step 3 (825 mg, 1.6 mmol) was dissolved in diethylether (5 mL), and then HCl (4M dioxane solution, 5 mL). The reaction solution was stirred for 2 hours at room temperature. At the end of the reaction, removed solvent under reduced pressure and dried to obtain 3-bromo-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-7-nitro-2-phenyl-1H-indole, which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)N[CH:14]([C:20](OCCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:13]3)[CH:10]=[CH:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>>[C:36]([OH:38])([C:35]([F:40])([F:39])[F:34])=[O:37].[CH3:35][CH2:20][CH2:14][CH2:13][CH2:12][CH2:16][CH2:17][CH2:18][CH2:19][CH2:11][CH2:10][CH2:9][NH2:8]
Reactant: CC(C)(C)OC(=O)n1ccc2c3c(ccc21)NC(C(=O)OCCc1ccc([N+](=O)[O-])cc1)C3
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCN

Procedure:
2-(4-Nitrophenyl)ethyl 3-[(tert-butyl)oxycarbonyl]pyrrolo[4,5-e]indoline-7-carboxylate (1.62 g) (Compound 1-1 of Scheme I) was selectively deprotected by treatment with 15 mL of trifluoroacetic acid (i.e., TFA) for 1 h. TFA was evaporated to afford a TFA salt of amine 12. Residual TFA was removed by co-evaporation with ether followed by drying under vacuum. The TEA salt was dissolved in 30 mL of anhydrous DMF in the presence of 0.9 mL of triethylamine. Compound 1-2 of Scheme II (see Example 1) (1.86 g) was added and the reaction was stirred at room temperature overnight. The solvent was evaporated under vacuum and the semi-solid residue was triturated with 10% MeOH/dichloromethane. The resulting yellow solid was collected by filtration and washed with the MeOH/dichloromethane mixture followed by ether. Drying under vacuum afforded 2.2 g of the dimer 13. The product contained about 1 equivalent of DMF according to the NMR analysis. 1H MNR (d6-DMSO) δ: 11.96 (s, 1H, NH), 10.27 (s, 1H, NH), 8.84 (br s, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H), 8.12 (br s, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.08 (s, 1H), 7.07 (s, 1H), 4.64 (t, J=8 Hz, 2H), 4.57 (t, J=6.4 Hz, 2H), 4.03 (t, J=8.5 Hz, 2H), 3.44 (t, J=8 Hz, 2H), 3.27 (t, J=8.5 Hz, 2H), 3.22 (t, J=6.6 Hz, 2H), 3.09 (m, 6H), 1.52 (s, 9H) and 1.16 (t, J=7.4 Hz, 9H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=O.[ClH:7].[N:8]1([CH2:14][CH:15]=[CH:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl.CN(C)C=O>[ClH:4].[ClH:7].[N:8]1([CH2:14][CH:15]=[CH:16][C:17]([O:19][C:1](=[O:5])[CH:2]=[CH:15][CH2:14][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C=CCN1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(C=CCN1CCCCC1)OC(=O)C=CCN1CCCCC1
Reaction time: 1 h

Procedure:
Oxalyl chloride (4.2 ml) was added to a stirred solution of 4-(piperidin-1-yl)-but-2-enoic acid hydrochloride (10 g) in dichloromethane (200 ml). Dimethylformamide (2 drops) was then added. The resultant suspension was stirred for 4 h and then concentrated to ˜25 ml. The slurry obtained was stirred a further 1 h and then filtered. The filter pad was washed with dichloromethan (50 ml) and dired in vacuo to give the title compound as a white solid (4.95 g). M.p. 120-124° C. (decomposition).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[N:23]=[C:22]([CH3:27])[NH:21][C:20]=3[C:19]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[CH3:33].CCN(C(C)C)C(C)C>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:18]2[N:17]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:10]([CH3:33])[CH:11]=3)=[O:16])[CH2:26][CH2:25][C:24]3[N:23]=[C:22]([CH3:27])[NH:21][C:20]=3[C:19]=2[CH:28]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc2c([nH]1)-c1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(C)c1)CC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c([nH]1)-c1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)C(C)C)c(C)c1)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
Isobutyryl chloride (0.07 ml, 0.07 mmol) was added to a solution of (4-aminomethyl-3-methyl-phenyl)-(9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E125.3 (24 mg, 0.07 mmol) in dichloromethane (3 ml) and DIEA (0.10 ml, 0.57 mmol) at 0° C. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane to 10% methanol:90% di-chloromethane) to give a colourless oil identified as the title compound 24 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][S:4][CH2:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[OH:11]O>C(O)(C)C>[NH2:1][C:2]1[CH2:3][S:4](=[O:11])[CH2:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C1=C(N)CSC1
Reactant: OO
Solvent: CC(C)O
Product: COC(=O)C1=C(N)CS(=O)C1
Temperature: 50 °C

Procedure:
3.2 g (0.02 mol) of 3-amino-4-methoxycarbonyl-2,5-dihydrothiophene are suspended in 30 ml of isopropanol. 2.2 ml of 35% strength hydrogen peroxide are added, with cooling. The mixture is then stirred at an internal temperature of 50° C. until starting material can no longer be detected in a thin layer chromatogram (approx. 5 hours). The mixture is then cooled in an ice bath and the precipitated crystals are filtered off with suction and washed with ice-cold isopropanol and with diethyl ether. Yield: 3.5 g (91% of theory). When recrystallized from methanol, the crystals melt at 137°-140° C.