Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:42]=[CH:41][C:17]3[S:18][C:19]([S:22]([N:25]4[CH2:30][CH2:29][N:28]([C:31]5[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=5)[CH2:27][CH2:26]4)(=[O:24])=[O:23])=[C:20]([CH3:21])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][C:20]1[C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:42]=[CH:41][C:17]=2[S:18][C:19]=1[S:22]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([C:37]([F:39])([F:38])[F:40])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:26]1)(=[O:24])=[O:23]
Reactant: Cc1c(S(=O)(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)sc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)sc2ccc(N3CCNCC3)cc12
Yield: 53.9 %

Procedure:
To a solution of 4-{3-methyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-5-yl}-piperazine-1-carboxylic acid tert-butyl ester (95 mg, 0.18 mmol) in DCM (4 mL) was added TFA (1 mL). The resultant mixture was stirred at ambient temperature for 3 hours. The solvent was removed under vacuum. The crude product was triturated with ether then water to give 1-(3-Methyl-5-piperazin-1-yl-benzo[b]thiophene-2-sulfonyl)-4-(3-trifluoromethyl-pyridin-2-yl)-piperazine as a light yellow solid (51 mg, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:21][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NCCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCCc1cccc(F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoronitrobenzene (500 mg, 2.27 mmol), 2-(3-fluorophenyl)ethylamine (411 mg, 2.95 mmol), and potassium carbonate (1.0 g, 7.24 mmol) in 7 mL N,N-dimethylformamide was heated at 80° C. for 1 hour. The mixture was diluted with ethyl acetate, rinsed with brine (three times), dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[N:23]=[C:22]([O:34][CH3:35])[N:21]=1>CN1CCCC1.O>[CH3:35][O:34][C:22]1[N:21]=[C:20]([NH:11][CH2:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([CH3:13])[CH3:12])[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[N:23]=1
Reactant: COc1ccc(C(C)(C)CN)cc1
Reactant: COc1cccc(-c2cc(Cl)nc(OC)n2)c1
Agent: CN1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(C)(C)CNc2cc(-c3cccc(OC)c3)nc(OC)n2)cc1
Temperature: 175 °C
Yield: 69.4 %

Procedure:
A mixture of 2-(4-methoxy-phenyl)-2-methyl-propylamine [172 mg, 0.96 mmol, Intermediate (35)], sodium bicarbonate (0.12 g), and 4-chloro-2-methoxy-6-(3-methoxy-phenyl)-pyrimidine [120 mg, 0.48 mmol, Intermediate (53)] in N-methylpyrrolidine (3 mL), is heated to 175° C. for 3 hours. The mixture is diluted with water, and extracted with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 30% EtOAc in heptane to afford [2-methoxy-6-(3-methoxy-phenyl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-2-methyl-propyl]-amine [131 mg, 69%, Example 29]. LCMS: RT=2.73 minutes, MS: 394 (M+H). 1H NMR (300 MHz, CDCl3): □7.59 (1H, s), 7.51 (1H, d, J=7.8 Hz), 7.35-7.27 (3H, m), 6.96 (1H, dd, J=8.1, 2.4 Hz), 6.88 (2H, d, J=9 Hz), 6.31 (1H, s), 4.02 (3H, s), 3.86 (3H, s), 3.79 (3H, s), 3.62 (2H, brs), 1.4 (6H, s). IC50=792 nM
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:30])[C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1>ClCCl>[C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][C:2]([O:1][S:44]([C:40]5[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=5)(=[O:46])=[O:45])=[CH:3][CH:4]=4)[CH2:9]3)=[O:30])=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=C(NCCCCN1CCc2ccc(O)cc2C1)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCN1CCc2ccc(OS(=O)(=O)c3cccnc3)cc2C1)c1ccc(-c2ccccc2)cc1
Reaction time: 18 h
Yield: 8.5 %

Procedure:
To a stored solution of 7-hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline (05 g, 1.3 mmol) and triethylamine (0.21 ml; 1.5 mmol) in dichloromethane (20 ml) was added pyridine-3-sulfonyl chloride (0.25 g, 1.4 mmol). The mixture was stirred for 18 h, then partitioned between dichloromethane (4×30 ml) and saturated aqueous NaHCO3 (100 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica using 0-5% methanolethyl acetate gradient elution gave the title compound (0.06 g, 12%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(N)cc1OC
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: COc1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (d, 1H, J=6.6 Hz), 7.59 (bs, 1H), 7.30 (s, 1H), 7.20-7.10 (m, 2H), 7.00-6.75 (m, 4H), 6.59 (bd, 1H, J=7.8 Hz), 3.87 (s, 3H), 3.84 (s, 3H); 19F NMR (CDCl3): −47229; LCMS: ret. time: 17.77 min.; purity: 78%; MS (m/e): 357 (MH|).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[F:12][CH:13]([F:33])[C:14]1[N:19]=[C:18]([C:20](O)=O)[N:17]=[C:16]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:15]=1>>[F:33][CH:13]([F:12])[C:14]1[CH:15]=[C:16]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)[N:17]=[C:18]([C:20]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=3)[N:7]=2)[N:19]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)F)n1
Product: Nc1ccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)n2)cn1

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.15 g, 1.0 mmol) and 6-difluoromethyl-4-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid (example D.3) (0.16 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.066 g, 30%). MS (ISP) 435.1 [(M+H)+]; mp 219° C.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]1([CH3:17])[CH:13]=[CH:12][C:11]([S@:14]([CH3:16])=[O:15])=[CH:10][CH:9]=1.[CH2:18]([O:25][C:26]([N:28]1[CH2:41][CH2:40][CH2:39][C@H:29]1[C:30]([N:32]1[CH2:38][CH2:37][CH2:36][C@H:33]1[CH:34]=[O:35])=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[CH2:18]([O:25][C:26]([N:28]1[CH2:41][CH2:40][CH2:39][C@H:29]1[C:30]([N:32]1[CH2:38][CH2:37][CH2:36][C@H:33]1[CH:34]([OH:35])[CH2:16][S@@:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:17])=[CH:9][CH:10]=1)=[O:15])=[O:31])=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc([S@](C)=O)cc1
Reactant: O=C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc([S@@](=O)CC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To diisopropylamine (0.26 ml) in THF (6 ml) was dropwise added 1.62M n-butyllithium-hexane solution (1.12 ml) at -78° C., and the mixture was stirred at 0° C. for 0.5 hour. The reaction mixture was cooled to -30° C., dropwise added with (S)-(-)-methyl p-tolyl sulfoxide (255 mg) in THF (6 ml), and stirred at 0° C. for 0.5 hour. The reaction mixture was cooled to -78° C. and dropwise added with known N-benzyloxycarbonyl-L-prolyl-L-prolinal (300 mg) in THF (6 ml). After stirring for 0.5 hour, an aqueous solution of saturated ammonium chloride was added thereto, followed by stirring at room temperature for 10 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine order, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate; chloroform-methanol) to give 388 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:26][C:27]1(OCCCC)[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3([O:26][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCOC1(OCCCC)CCCC1
Product: CCCCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCC1
Yield: 29.2 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-di-n-butoxycyclopentane (2.14 g, 10 mmol) in the same manner as the example 20 to give the compound 35 (142 mg, 29.3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[H-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25](F)[C:24]([CH3:28])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30].O>C1COCC1>[Cl:20][C:21]1[C:22]([N+:29]([O-:31])=[O:30])=[CH:23][C:24]([CH3:28])=[C:25]([CH:26]=1)[O:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C

Procedure:
A flask was charged with tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (905 mg, 3.7 mmol, commercially available from Alrich), sodium hydride, 95% (24 mg, 4.6 mmol) and THF (10 mL), and the mixture was stirred under N2 for 15 minutes, after which time a solution of 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (700 mg, 3.7 mmol, commercially available from Aldrich) in THF (10 mL) was added to the sodium hydride mixture at 0° C. The reaction mixture was heated to 65° C. for 15 hours. Water was added to the cooled reaction mixture and the mixture was extracted with ethyl acetate. The organic solvent was concentrated under reduced pressure and the resulting solid was purified by silica column chromatography eluting with 5% methanol in dichloromethane, to give 1.2 g (78 5 yield) of tert-butyl 4-(3-(5-chloro-2-methyl-4-nitrophenoxy) propyl)piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 6.92 (s, 1H), 3.92 (t, 2H), 3.06 (m, 4H), 2.62 (m, 4H), 2.36 (m, 2H), 2.34 (s, 3H), 1.84 (m, 2H), 1.42 (s, 9H). MS (EI): 414 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[I:30]N1C(=O)CCC1=O>CC#N.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([I:30])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:22])[CH3:23])=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2cc(-c3ccccc3)nc2CO[Si](C)(C)C(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc(Cn2c(CO[Si](C)(C)C(C)(C)C)nc(-c3ccccc3)c2I)cc1
Yield: 85 %

Procedure:
Treat a solution of 1-(4-methoxybenzyl)-2-tert-butyldimethylsilyloxymethyl-4-phenylimidazole (2.08 g, 5.09 mmol) in MeCN (25 mL) with N-iodosuccinimide (NIS) (1.35 g, 6.00 mmol) at room temperature for 24 hours. Dilute the mixture with Et2O (100 mL), wash with saturated NaHCO3 (25 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, hexane/EtOAc 20:1→9:1) to provide 2.30 g (85% yield). MS (ES+): m/z 535 (M+H)+
Reaction SMILES: [CH:1](=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[C:7]1([S:13]([C:16]#[N:17])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1.B(O)(O)O>C(O)CCC>[C:7]1([S:13]([C:16]2[CH:4]=[C:3]([CH3:5])[CH:2]=[CH:1][N:17]=2)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: CC(C)=CC=O
Agent: OB(O)O
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: Cc1ccnc(S(=O)(=O)c2ccccc2)c1
Temperature: 119 °C
Yield: 72.9 %

Procedure:
First, 9.00 g (107 mmol) of senecialdehyde (3-methyl-2-butenal) and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 0.30 g (4.85 mmol) boric acid were added. Then the mixture was heated under reflux for 3 hours while agitating at an internal temperature of 119° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 8.50 g of 2-benzenesulfonyl-4-methylpyridine with the following properties as colorless crystals (purity of 99%, yield of 72% based on benzenesulfonyl cyanide).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C@@H:12]([CH:36]([CH3:39])[CH2:37][CH3:38])[C:13]([NH:15][C:16]1([C:33]([OH:35])=O)[CH2:28][C:27]2[C:26]3[C:21](=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]=2[CH2:18][CH2:17]1)=[O:14])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:73][O:74][NH:75][C:76](=[O:83])[C@@H:77]([NH2:82])[CH:78]([CH3:81])[CH2:79][CH3:80]>CN(C=O)C>[CH3:73][O:74][NH:75][C:76]([C@@H:77]([NH:82][C:33]([C@:16]1([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:36]([CH3:39])[CH2:37][CH3:38])[CH2:28][C:27]2[C:26]3[C:21](=[C:22]([C:29]([F:32])([F:30])[F:31])[CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]=2[CH2:18][CH2:17]1)=[O:35])[CH:78]([CH3:81])[CH2:79][CH3:80])=[O:83]
Reactant: CCC(C)[C@H](N)C(=O)NOC
Reactant: CCC(C)[C@H](NC(=O)Cc1ccccc1F)C(=O)NC1(C(=O)O)CCc2[nH]c3c(C(F)(F)F)cccc3c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)[C@H](NC(=O)Cc1ccccc1F)C(=O)N[C@]1(C(=O)N[C@H](C(=O)NOC)C(C)CC)CCc2[nH]c3c(C(F)(F)F)cccc3c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.500 g (0.91 mmol) of (R/S)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (synthesized in according to WO 2006/005484), 0.521 g (1.37 mmol) of HATU and 2.0 mL (11.76 mmol) of DIPEA were dissolved in DMF and stirred for 30 min at room temperature. 0.220 g (1.37 mmol) of (S)-2-Amino-3-methyl-pentanoic acid methoxy-amide were added and the reaction mixture and heated at 110° C. for 3 h. The solvent was removed under vacuum and the residue was purified by high performance liquid chromatography.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH:23][S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(CCCC3CCCCC3)CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCC3CCCCC3)CC21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
To a solution of 3-[3-(3-cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]-hex-6-yl]phenylamine (Preparation 10, 25 mg, 0.08 mmol) in dichloromethane (2 ml) at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) then dropwise over 5 minutes methanesulfonylchloride (25 μl, 37 mg, 0.32 mmol). The mixture was allowed to warm to room temperature and was stirred for 90 minutes. Further methanesulfonylchloride (10 μl, 15 mg, 0.13 mmol) was added and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (18 mg, 58%).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)(C(C)(C)C)(C)C.C([SiH](CC)CC)C.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>CC#N.[Bi](Br)(Br)Br>[CH2:19]([CH:11]1[CH2:10][CH:9]([O:8][CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[CH2:13][CH:12]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C1CC(O[Si](C)(C)C(C)(C)C)CC1CC
Agent: Br[Bi](Br)Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CC(OC2CCOCC2)CC1CC
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 281 %

Procedure:
To a solution of ethyl 4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (0.100 g, 0.333 mmol) in MeCN (2.2 mL) was added triethylsilane (0.080 mL, 0.499 mmol) and bismuth(III) bromide (0.010 g, 0.022 mmol). The reaction mixture was stirred at ambient temperature for about 1 min followed by dropwise addition of dihydro-2H-pyran-4(3H)-one (0.050 g, 0.499 mmol). The reaction mixture was stirred at ambient temperature for about 15 min. The reaction was filtered through an Acrodisc® and the solvent was removed under reduced pressure. To a solution of ethyl 4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (0.200 g, 0.666 mmol) in MeCN (4.5 mL) was added triethylsilane (0.160 mL, 1.00 mmol) and bismuth(III) bromide (0.020 g, 0.045 mmol). The reaction mixture was stirred at ambient temperature for about 1 min followed by dropwise addition of dihydro-2H-pyran-4(3H)-one (0.100 g, 0.998 mmol). The reaction mixture was stirred at ambient temperature for about 15 min. The reaction was filtered through an Acrodisc® and the solvent was removed under reduced pressure. The residues were dissolved in DCM (2 mL) each, combined, and the crude material was purified by silica gel chromatography using a gradient of 10-100% EtOAc in heptane to give ethyl 2-ethyl-4-(tetrahydro-2H-pyran-4-yloxy)cyclopentanecarboxylate (0.253 g, 98%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 4.13 (q, J=7.1, 2H), 4.05-3.98 (m, 1H), 3.98-3.88 (m, 2H), 3.58-3.47 (m, 1H), 3.46-3.36 (m, 2H), 2.80 (q, J=8.5, 1H), 2.16 (dt, J=13.3, 7.7, 1H), 2.09-1.93 (m, 3H), 1.90-1.81 (m, 2H), 1.62-1.49 (m, 3H), 1.43 (ddd, J=11.1, 7.4, 5.2, 1H), 1.33-1.22 (m, 4H), 0.92-0.83 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].Cl.C1C(O)=CC=CC=1C.[CH3:19][NH:20][C:21]#[N:22].[OH-].[Na+]>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:21]([NH:20][CH3:19])=[NH:22]
Reactant: CNC#N
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: CNC(=N)Nc1c(Cl)cccc1Cl

Procedure:
To 51 g (0.315 mole) of 2,6-dichloroaniline is added 0.4 moles of ethereal HCl and 200 ml of m-cresol. The mixture is then sitrred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 17.7 g (0.315 mole) of methyl cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2×1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dichlorophenyl)-3-methylguanidine hydrochloride.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:17]([CH:18]=[CH:19][C:20]([O:22]CC)=[O:21])=[CH:16][C:15]=3[C:31]([F:34])([F:33])[F:32])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][C:15]=3[C:31]([F:34])([F:32])[F:33])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(C=CC(=O)O)cc3C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.23 g (0.46 mmol) of ethyl cinnamate derivative from Example 13 are dissolved in 10 ml of dioxane, 4 ml of 1 molar sodium hydroxide solution are added and the mixture is stirred for 5 hours at room temperature. The reaction solution is acidified to pH 4 using 1N hydrochloric acid, treated with ethyl acetate and the aqueous phase is extracted a further two times with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulphate, filtered, concentrated and dried overnight in a high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[N:17]=1>C(O)C>[Cl:25][C:18]1[N:17]=[C:16]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1

Procedure:
A mixture of aniline (7.24 g, 78 mmol), triethylamine (13 mL, 93 mmol), and 2,6-dichloro-3-nitropyridine (15 g, 78 mmol) was stirred overnight in 500 mL ethanol at room temperature under nitrogen. The solid that formed was filtered off, washed with water and ethanol, and dried. The solid was purified by column chromatography eluting with 20% ethyl acetate/hexane (8.62 g, 44%).