Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23].C(=O)(O)[O-].[Na+]>COCCOC.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>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
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: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester (2.0 g, 5.6 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (1.78 g, 5.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.56 mmol), and sodium bicarbonate (1.4 g, 16.8 mmol) were combined in DME (30 mL) and H2O (10 mL), and the mixture was purged with N2 (g). The reaction was stirred at 80° C. overnight, and after aqueous workup, the crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:10]([Br:11])=[C:9]([Br:12])[NH:8][N:7]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([N:7]1[C:6]([Br:5])=[C:10]([Br:11])[C:9]([Br:12])=[N:8]1)([O-:4])=[O:2]
Reactant: Brc1n[nH]c(Br)c1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])n1nc(Br)c(Br)c1Br
Temperature: 15 °C
Reaction time: 2 h

Procedure:
HNO3 (d=1.50 g/ml; 18 ml, 0.429 mol) was added dropwise over 10 minutes to a solution of 3,4,5-tribromopyrazole (50 g, 0.164 mol) in glacial acetic acid (750 ml) while maintaining the temperature at 15° C. Acetic anhydride (250 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. Once the reaction was complete, the reaction mixture was poured onto crushed ice (1 kg). After stirring for 1 hour, the crude product was filtered off and then washed with demineralized water (2×60 ml) to give crude 1-nitro-3,4,5-tribromopyrazole. The water (24.6 ml) contained in the wet product was removed by heating a solution of the product in toluene (750 ml) at reflux in Dean-Stark apparatus. The toluene solution was maintained at reflux for a further 30 minutes until a TLC (eluent:toluene) showed that the rearrangement of the 1-nitro-3,4,5-tribromopyrazole (Rf=0.77), the intermediate formed, into 3,4,5-dibromo-4-nitropyrazole 2 (Rf=0.05) was complete. The solution was concentrated to a residual volume of 150 ml and then allowed to cool to 60° C., followed by addition of hexane (275 ml). The solution was cooled to 0-5° C. for 1 hour and the 3,5-dibromo-4-nitropyrazole 2 (29.1 g, 65%) was recovered by filtration and drying under vacuum in the form of a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=3)=[C:10]([CH3:23])[CH:9]=2)[N:4]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2([C:43]3[C:34](=[CH:35][C:36]4[CH2:37][CH2:38][CH2:39][NH:40][C:41]=4[CH:42]=3)[O:33][CH2:32]2)[CH2:28][CH2:27]1>>[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2([C:43]3[C:34](=[CH:35][C:36]4[CH2:37][CH2:38][CH2:39][N:40]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:11]6[CH:12]=[CH:13][C:8]([C:5]7[N:4]=[C:3]([N:2]([CH3:24])[CH3:1])[O:7][N:6]=7)=[CH:9][C:10]=6[CH3:23])=[CH:19][CH:18]=5)=[O:22])[C:41]=4[CH:42]=3)[O:33][CH2:32]2)[CH2:28][CH2:27]1
Reactant: Cc1cc(-c2noc(N(C)C)n2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCCC3
Product: Cc1cc(-c2noc(N(C)C)n2)ccc1-c1ccc(C(=O)N2CCCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1

Procedure:
The title compound was prepared from 4'-(5-dimethylamino-1,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carboxylic acid D(14) and 2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) using a procedure similar to that of Example 1 (26%). This was converted to hydrochloride salt. M.p. 118-120° C.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([CH:7]([O:11][CH3:12])[C:8]([OH:10])=O)=[CH:3][CH:2]=1.[NH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][C:4]([CH:7]([O:11][CH3:12])[C:8]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([C:20]#[N:19])=[CH:22][CH:23]=2)=[O:10])=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc(-c2ccccc2)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
(RS)-Biphenyl-4-yl-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-biphenyl-4-yl-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow solid.
Reaction SMILES: O.NN.[Cl:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][N:12]2C(=O)C3=CC=CC=C3C2=O)=[CH:7][CH:6]=1.Cl>C(O)C>[Cl:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(Cl)nc1
Temperature: 20 °C
Yield: 91.2 %

Procedure:
Hydrazine hydrate (2.00 ml, 0.04 mol) was added at ambient temperature (20° C.) to a solution of N-(6-chloro-3-pyridylmethyl) phthalimide (10.70 g, 0.039 mol) in ethanol (150 ml), and the resulting solution was heated under reflux for 4 hours before being cooled to ambient temperature (20° C.). 25% w/v aqueous hydrochloric acid (60 ml) was added directly and the resulting mixture was heated under reflux for 1 hour. The reaction mixture was then cooled to ambient temperature (20° C.), filtered and evaporated under reduced pressure. The resulting concentrated mixture was filtered and the filtrate was cooled, with ice/salt bath cooling, and solid potassium hydroxide was added with stirring until the mixture became basic. The reaction mixture was then extracted with diethylether (5×150 ml). The combined ether extracts were dried using magnesium sulphate and evaporated under reduced pressure to give the product, 6-chloro-3-pyridylmethylamine as a brown oil (5.07 g, 90.6%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>C(O)CCC.[OH-].[Na+]>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:14](=[O:16])[C:3]3=[CH:4][NH:5][C:6]4[CH2:7][CH2:8][CH:9]([CH2:12][CH3:13])[CH2:10][C:11]=4[C:2]3=[N:27]2)=[CH:22][CH:21]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CC(CC)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCC1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.6 g of ethyl 4-chloro-6-ethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate in 30 ml n-butanol is treated with 1.38 g of 4-chlorophenylhydrazine at room temperature under nitrogen. After stirring at room temperature overnight, the reaction mixture is heated at reflux for 41/2 hours. The reaction mixture is cooled to room temperature, the precipitate is filtered off, washed with hexane and air-dried to yield a yellow solid. The crude product is dissolved in 30 ml 1N NaOH and extracted with ether. The aqueous layer is then treated with 1.6 g of NH4Cl. The precipitate which forms is filtered off, washed with water, and dried in a vacuum oven at 120° overnight to yield 2,3,6,7,8,9-hexahydro-2-p-chlorophenyl-8-ethylpyrazolo[4,3-c]quinolin-3-(5H)-one, m.p. 318°-320°.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:17][C:14]1[N:13]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:12]2[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][N:41]3[CH2:40][CH2:39][N:38]([C:36](=[O:37])[CH2:35][C:29]4[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=4[F:27])[CH2:43][CH2:42]3)[C:16]=2[N:15]=1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: O=C(Cc1ccc(F)cc1F)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCN(C(=O)Cc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, (2,4-difluorophenyl)piperazin-1-yl-ethanone hydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 1-(4-(2-(5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)ethyl)piperazin-1-yl)-2-(2,4-difluorophenyl)ethanone: LC/MS (M+1=507.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.45 (m, 4H), 2.72 (t, 2H, J=6.4 Hz), 3.43 (m, 2H), 3.48 (m, 2H), 3.69 (s, 2H), 4.26 (t, 2H, J=6.4 Hz), 6.59 (d, 1H, J=32 Hz), 6.71 (m, 1H), 7.01 (dt, 1H, J=8.4 Hz and 1.6 Hz), 7.17 (m, 3H), 7.28 (m, 1H), 7.49 (br s, 2H, NH2), 7.91 (s, 1H). Anal. calculated for (C25H24F2N8O2+⅓H2O): C, 58.59; H, 4.85; F, 7.41; N, 21.86; 0, 7.28. Found C, 58.73; H, 5.06; N, 21.22.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][C:24]#[N:25].[NH2:26][OH:27]>CS(C)=O>[OH:27][NH:26][C:24](=[NH:25])[CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1]
Reactant: N#CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: NO
Solvent: CS(C)=O
Product: N=C(CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
To a stirred solution of 3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)propanenitrile (2.00 g, 6.0 mmol) in dimethyl sulfoxide (15.0 mL) was added hydroxylamine (50% wt solution in water, 1.6 mL, 24 mmol). The reaction was stirred at ambient temperature for 16 h, then the product was precipitated upon addition of water/ethanol (3:1, 100 mL). The solvent was decanted and the remaining solid was triturated in distilled water (75 mL). The solid was filtered and air-dried to afford N-hydroxy-3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)propanimidamide as a colorless solid (2.00 g, 91%): MS (ES+) m/z 368.2 (M+1).
Reaction SMILES: CSC.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13]1([CH:19]=[N+]=[N-])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]2[CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10]2)=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: [N-]=[N+]=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CSC
Solvent: ClCCl
Product: Clc1ccc(C2OC2c2ccccc2)cc1
Yield: 76 %

Procedure:
To a stirred solution of dimethyl sulphide (0.20 mmol), rhodium (II) acetate (0.01 mmol) and p-chlorobenzaldehyde (1 mmol) in dichloromethane (4 ml) was added a solution of phenyldiazomethane (1 mmol in 6 ml of tert-butylmethyl ether) at room temperature over a period of 24 hours. After addition was completed the solvent was removed in vacuo and the residue was chromatographed over silica to provide the title oxirane in 76% yield.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1cc2cc(N)ccc2o1
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1

Procedure:
Patent application WO0248132 describes a method for the synthesis of dronedarone using 2-n-butyl-5-nitro-benzofuran which is reduced, under pressure, with hydrogen in the presence of platinum oxide as catalyst in order to form 2-n-butyl-5-amino-benzofuran. This benzofuran derivative is then subjected to the action of methanesulfonyl chloride, which gives 2-n-butyl-5-methanesulfonamido-benzofuran which is treated with 4-[3-(di-n-butylamino)-propoxy]-benzoyl chloride to give dronedarone.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[C:28]([F:31])([F:30])[F:29].[H-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:16]2[C:17]([C:28]([F:30])([F:31])[F:29])=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[CH:20][C:21]=2[N+:22]([O-:24])=[O:23])[C:8](=[O:12])[O:9][CH2:10][CH3:11])=[CH:13][CH:14]=1
Reactant: CCOC(=O)NCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccc(Cl)cc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Yield: 17.9 %

Procedure:
Ethyl 4-chlorobenzylcarbamate (865.9 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (996.7 mg) were dissolved in tetrahydrofuran (15 ml), and to the solution was added sodium hydride (162.1 mg). The reaction mixture was heated at reflux for 3 hours. After allowing to cool, to the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer-was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (75 g, hexane:ethyl acetate=10:1) to give the title compound (294.7 mg, 18%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][C:27]#[N:28]>C1COCC1>[C:27]([CH2:26][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([NH:16][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=2)[NH:22][CH:21]=1)#[N:28]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#CCc1c[nH]c2ccc(NC(=O)c3ccccc3)cc12
Reaction time: 18 h

Procedure:
A solution of 2.0 g (0.014 mole) of benzoyl chloride in THF was treated with 10 ml pyridine followed by 2.43 g (0.014 mole) of 5-aminoindole-3-acetonitrile, Example 1, and stirred 18 hr. The solvent was removed in vacuo and crude product recrystallized from EtOH to give product used directly in next step below.
Reaction SMILES: COC([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]>C(#N)C.O>[CH2:51]([O:50][C:48](=[O:49])[CH2:47][N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)[CH3:52]
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
A solution containing amine 50 (200 mg, 0.41 mmol) in ACN (5 mL) was cooled to 0° C. K2CO3 (63 mg, 0.46 mmol) was added followed by ethyl bromoacetate (75 mg, 0.45 mmol) and the reaction mixture was warmed to ambient temperature. After 16 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 194 mg (82%) of 58 as an off-white-colored foam. 1H NMR (300 MHz, CDCl3), mixture of amide rotamers: δ8.50 (s, 0.8H), 8.29 (s, 0.2H), 7.55 (dd, J=5.4, 8.7 Hz, 1H), 7.11 (s, 1H), 6.99 (d, J=9.0 Hz, 0.2H), 6.82 (d, J=9.6 Hz, 0.8H), 5.30-5.24 (m, 1H), 4.85-4.82 (m, 1H), 4.34 (t, J=6.0 Hz, 1H), 4.23-4.07 (m, 2H), 3.93 (t, J=8.7 Hz, 1H), 3.68-3.64 (m, 2H), 3.59-3.54 (m, 2H), 3.44-3.40 (m, 2H), 2.82 (app t, J=9.0 Hz, 1H), 2.05-2.01 (m, 1H), 1.83-1.65 (m, 6H), 1.38 (s, 9H), 1.28 (t, J=6.9 Hz, 3H), 1.24-1.05 (m, 2H) ppm. Mass spectrum, m/z [571.4] (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[C:43]([CH3:48])[N:44]=[C:45]([CH3:47])[CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J28) (271 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH:6]1[CH3:15]>O1CCCC1>[N:4]([C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][C@H:6]1[CH3:15])=[C:1]=[S:3]
Reactant: S=C=S
Reactant: COC(=O)N1CCC(N)C(C)C1
Solvent: C1CCOC1
Product: COC(=O)N1CC[C@H](N=C=S)[C@H](C)C1
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 138.6 parts of carbon disulfide, 113.8 parts of N,N'-methanetetraylbis[cyclohexanamine] and 450 parts of tetrahydrofuran were added dropwise 106 parts of methyl 4-amino-3-methyl-1-piperidinecarboxylate at this low temperature. The reaction mixture was allowed to attain room temperature. After stirring for 1 hour at room temperature, the mixture was evaporated and the residue was stirred in 2,2'-oxybispropane. The precipitate was filtered off and the filtrate was evaporated, yielding 141.1 parts (100%) of methyl cis-4-isothiocyanato-3-methyl-1-piperidinecarboxylate as a residue (interm. 28).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]=3[C:41]([O:43]C(C)(C)C)=[O:42])[C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:49][C:2]([F:1])([F:48])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]([CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]=3[C:41]([OH:43])=[O:42])[C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1c(CN(C(=O)OCc2ccccc2)S(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1c(CN(C(=O)OCc2ccccc2)S(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A solution of Example 9F (1.19 g, 1.72 mmol) in CH2Cl2 (35 mL) under N2 at −20° C. was treated with trifluoroacetic acid (13.3 mL, 0.172 mol) and allowed to stir at 0° C. 2 for 1 hour and then quenched with 2.6 M Na2CO3 (50 mL). The reaction mixture was reacidified to pH 3 with 1 M aq HCl, extracted with ethyl acetate. The combined ogranic layers were washed with brine, dried (Na2SO4), filtered, and concentrated (chasing with anhydrous toluene) to provide 1.096 g (100%) of the desired compound white powder.
Reaction SMILES: NC1C=CC=CC=1[S:8]([OH:11])(=[O:10])=[O:9].[N+](C1C=CC(N[C:22]2[C:31]3[C:26](=[CH:27][C:28](S(O)(=O)=O)=[CH:29][C:30]=3[OH:32])[CH:25]=[C:24]([S:37]([OH:40])(=[O:39])=[O:38])[CH:23]=2)=CC=1)([O-])=O.[S-2].[Na+].[Na+].[Cl-].[Na+]>>[OH:32][C:30]1[C:31]2[C:26](=[CH:25][C:24]([S:37]([OH:40])(=[O:38])=[O:39])=[CH:23][CH:22]=2)[C:27]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(O)c23)cc1
Reactant: Nc1ccccc1S(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [S-2]
Product: O=S(=O)(O)c1ccc2c(O)ccc(S(=O)(=O)O)c2c1

Procedure:
6.8 parts of 2,4,6-trifluoro-1,3,5-triazine are added dropwise to a solution of 13.4 parts of 1,4-diaminobenzene-2,5-disulphonic acid in 200 parts by volume of water at 0° C. and a pH value of 4 to 5 is maintained by constantly neutralising the hydrogen fluoride liberated. The course of the reaction is followed chromatographically. The resulting solution of the intermediate product is condensed, at a pH value of 7 to 8 and at 10° to 20° C. with 31 parts of the aminoazo dyestuff obtained by coupling diazotised 1-aminobenzene-2-sulphonic acid with 1-(4'-nitrophenylamino)-8-hydroxynaphthalene-3,6-disulphonic acid and subsequently reducing the nitro group with sodium sulphide. The dyestuff is salted out completely with sodium chloride, filtered off, washed and again converted to a neutral solution in 500 parts by volume of water. Further diazotisation of the resulting aminoazo dyestuff and coupling with 15 parts of 1-hydroxynaphthalene-4,6-disulphonic acid gives the dyestuff of the formula ##STR43## which is precipitated with sodium chloride, isolated and then washed and dried. It is a dark red powder which gives a red solution in water.