Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:26][C@@H:25]([N:27]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=3)[C:28]3[N:33]=[CH:32][C:31]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)=[CH:30][N:29]=3)[CH2:24][C@H:23]2[CH2:55][CH3:56])=O)=CC=1)([O-])=O>C1COCC1>[CH3:1][C:2]1([CH2:6][O:7][C:20]([N:22]2[CH2:26][C@@H:25]([N:27]([CH2:40][C:41]3[CH:42]=[C:43]([C:51]([F:52])([F:53])[F:54])[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=3)[C:28]3[N:29]=[CH:30][C:31]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)=[CH:32][N:33]=3)[CH2:24][C@H:23]2[CH2:55][CH3:56])=[O:19])[CH2:5][O:4][CH2:3]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(CO)COC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OCC1(C)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a mixture of 3-methyl-3-oxetanemethanol (0.202 mmol; 20.6 mg) and sodium hydride (60% oil dispersion in mineral oil, 0.202 mmol; 8.1 mg) in THF (0.5 mL) is added a solution of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 4-nitro-phenyl ester (0.101 mmol; 67 mg) in THF (0.5 mL). The reaction mixture is stirred for 1 hour at room temperature, then quenched with saturated aqueous ammonium chloride. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc), followed by another silica gel column chromatography (eluent: dichloromethane/methanol) to give (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 3-methyl-oxetan-3-ylmethyl ester (40.7 mg, 64%); ESI-MS m/z: 626 [M+1]+, Retention time 2.19 min (condition A).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1cccc2[nH]ncc12
Product: C[Si](C)(C)C#Cc1cccc2[nH]ncc12
Yield: 56.7 %

Procedure:
In an adaption of GP 8a, 4-Iodo-1H-indazole (1.00 g, 4.10 mmol) was reacted with trimethylsilyl acetylene (0.61 mL, 4.30 mmol) at 90° C. for 5 h to give 498 mg (57%) of pure 4-(trimethylsilyl)ethynyl-1H-indazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[N:12]3[C:13](=[O:25])[C:14]4[NH:15][CH:16]=[N:17][C:18]=4[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]3=[N:10][N:9]=2)=[CH:5][CH:4]=1.[Br:28]N1C(=O)CCC1=O>C1COCC1>[Br:28][C:16]1[NH:15][C:14]2[C:13](=[O:25])[N:12]3[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=4)=[N:9][N:10]=[C:11]3[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]=2[N:17]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(Cc3ccc(OC)cc3)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(Cc3ccc(OC)cc3)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To the solution of 3-(4-methoxybenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.40 g, 1.1 mmol) in THF was added N-Bromosuccinimide (0.29 g, 1.6 mmol). The mixture was stirred at 70° C. for 1 hour. The mixture was concentrated and purified by preparative LCMS to yield the desired product (290 mg, 60%). 1HNMR (300 MHz, d6-DMSO): δ 7.16 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.46 (s, 3H), 4.20 (t, J=7.2 Hz, 2H), 3.67 (s, 2H), 1.79 (m, 2H), 1.28 (m, 4H), 0.83 (m, 3H). LCMS calculated for C19H21BrN6O2(M+H): 445.1; found: 445,0, 447.0.
Reaction SMILES: O=[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]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([NH:19][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCN
Product: CCCCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and n-hexylamine comparable as in Example A.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([N:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: OCCNCCO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)N(CCO)CCO)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), diethanolamine (29 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (4.9 mg, 9% of theory).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3]1.[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[NH:15][CH3:16]>>[CH3:16][N:15]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:8]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][OH:3]
Reactant: OC1CCCCO1
Reactant: CNc1ccncc1N
Product: Cn1c(CCCCO)nc2cnccc21

Procedure:
The title compound was prepared by the method of Preparation 18 using 2-hydroxytetrahydropyran and 3-amino-4-(methylamino)pyridine as the starting materials
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:68]=[CH:67][C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([C:45]4[CH:50]=[CH:49][C:48]([O:51][C:52]5[CH:57]=[CH:56][C:55]([N:58]=[N:59][C:60]6[CH:65]=[CH:64][C:63]([NH2:66])=[CH:62][CH:61]=6)=[CH:54][CH:53]=5)=[CH:47][CH:46]=4)([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:35]=[CH:34][C:33]([N:36]=[N:37][C:38]6[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=6)=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[CH3:22])=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:69]1(=[O:79])O[C:72](=[O:73])[C:71]2=[CH:75][CH:76]=[CH:77][CH:78]=[C:70]12>C(O)(=O)C>[C:69]1(=[O:79])[N:66]([C:63]2[CH:64]=[CH:65][C:60]([N:59]=[N:58][C:55]3[CH:56]=[CH:57][C:52]([O:51][C:48]4[CH:49]=[CH:50][C:45]([C:21]([C:23]5[CH:24]=[CH:25][C:26]([O:29][C:30]6[CH:35]=[CH:34][C:33]([N:36]=[N:37][C:38]7[CH:43]=[CH:42][C:41]([N:44]8[C:69](=[O:79])[C:70]9=[CH:78][CH:77]=[CH:76][CH:75]=[C:71]9[C:72]8=[O:73])=[CH:40][CH:39]=7)=[CH:32][CH:31]=6)=[CH:27][CH:28]=5)([C:18]5[CH:19]=[CH:20][C:15]([O:14][C:13]6[CH:67]=[CH:68][C:10]([N:9]=[N:8][C:5]7[CH:4]=[CH:3][C:2]([N:1]8[C:72](=[O:73])[C:71]9=[CH:75][CH:76]=[CH:77][CH:78]=[C:70]9[C:69]8=[O:79])=[CH:7][CH:6]=7)=[CH:11][CH:12]=6)=[CH:16][CH:17]=5)[CH3:22])=[CH:46][CH:47]=4)=[CH:53][CH:54]=3)=[CH:61][CH:62]=2)[C:72](=[O:73])[C:71]2=[CH:75][CH:76]=[CH:77][CH:78]=[C:70]12
Reactant: CC(c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1)(c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1)c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CC(c1ccc(Oc2ccc(N=Nc3ccc(N4C(=O)c5ccccc5C4=O)cc3)cc2)cc1)(c1ccc(Oc2ccc(N=Nc3ccc(N4C(=O)c5ccccc5C4=O)cc3)cc2)cc1)c1ccc(Oc2ccc(N=Nc3ccc(N4C(=O)c5ccccc5C4=O)cc3)cc2)cc1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Into a 250 mL three-necked flask equipped with a magnetic stir bar and nitrogen inlet and outlet were placed 1,1,1-tris{4-[4-(4-aminophenyldiazenyl)phenoxy]phenyl}ethane (Example 5; 0.892 g, 1.00 mmol), phthalic anhydride (0,444 g, 3.00 mmol) and acetic acid (20 mL). The mixture was stirred under refluxing for 14 hours and allowed to cool to room temperature. The precipitate was collected by filtration and dried in an oven to afford 0.96 g (75%) of orange powder, mp >300° C. MS (m/e): 1282 (M+). Anal. Calcd. for C80H51N9O9: C, 74.93%; H, 4.01%; N, 9.83%. Found: C, 75.00%; H, 4.11%; N, 9.44%. 1H-NMR (d6-DMSO, δ in ppm): 2.21 (s, 3H, CCH3), 7.08-7.13 (d, 6H, Ar—H), 7.19-7.21 (dd, 12H, Ar—H), 7.67-7.71 (d, 6H, Ar—H), 7.87-8.03 (m, 24H, Ar—H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:16][CH:17]1[NH:22][CH2:21][CH2:20][N:19]([S:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(=[O:25])=[O:24])[CH2:18]1>>[CH3:16][CH:17]1[N:22]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:21][CH2:20][N:19]([S:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(=[O:25])=[O:24])[CH2:18]1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Product: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 3-methyl-1-(2-naphthylsulphonyl)piperazine to give 3-methyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 32% yield;
Reaction SMILES: N[C:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].Cl.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22].[OH-].[Na+]>Cl>[F:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]2[CH:3]=[C:4]([NH2:5])[N:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:14])[N:22]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccccc1NN
Reactant: N#CC=C(N)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1-n1nc(-c2ccc(F)cc2)cc1N
Temperature: 25 °C
Yield: 85.3 %

Procedure:
To a solution of 3-amino-3-(4-fluorophenyl)acrylonitrile (600 mg, 3.70 mmol) in 1 N HCl (6 mL) was added (2-methylphenyl)hydrazine hydrochloride (558 mg, 3.51 mmol). The reaction was allowed to reflux for 16 h, and then cooled to rt. The resulting mixture was basified to pH 12 by slow addition of 1 N aqueous sodium hydroxide. The precipitate was collected by filtration, and then recrystallized from EtOH/Et2O to afford the intermediate (800 mg, 81%) as a light orange solid. 1H NMR (400 MHz, CD2Cl2) δ 2.20 (s, 3H), 2.14 (br s, 2H), 5.91 (s, 1H), 7.06 (t, 2H), 7.36 (d, 4H), 7.75 (m, 2H). This material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CCNC1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-methoxycarbonyl-ethylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.73 g, 2.68 mmol) in dichloroethane (10.0 mL) was added 4-chlorobenzaldehyde (0.42 g, 2.95 mmol), sodium triacetoxy borohydride (1.71 g, 8.04 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (15%) to hexane/ethyl acetate (50%). 1H-NMR (CDCl3) δ: 1.35 (9H, s), 1.80 (1H, m), 1.90 (1H, m), 2.40 (2H, t), 2.85 (2H, t), 3.00-3.80 (7H, m), 4.70 (1H, d), 7.20 (4H, m). ESI-MS m/z: 397 (M+1), UV retention time: 1.99 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:20][N:21](C)C=O>[C-]#N.[Zn+2].[C-]#N>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:20]#[N:21])[C:9](=[O:11])[CH3:10])=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)c1cccc(Br)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Temperature: 56 °C
Reaction time: 4.5 h

Procedure:
A 4-neck 12 L flask equipped with a mechanical stirrer, thermocouple, nitrogen inlet, and gas adapter connected to a bubbler was charged with 3-(3-bromophenyl)-4-(4-chlorophenyl)butan-2-one, zinc cyanide (201 g), and dimethylformamide 4.0 L. Nitrogen gas was bubbled through the suspension for 30 min at room temperature and for 1 h at 56° C. using a heating mantle. The bromoketone/Zn(CN)2 slurry (at 56° C.) was added to the catalyst solution (at 56° C.). After the transfer was complete, the reaction mixture was stirred at 56° C. for 4.5 h under N2. The resulting suspension was cooled in an ice bath, and 30% aqueous ammonium hydroxide (971 mL) was added over 5 min, keeping the temperature below 30° C. The suspension was warmed to room temperature, stirred for 60 min, and then filtered through a pad of SOLKA FLOC eluting with toluene (5 L). The filtrate was added into an extractor containing 20% aqueous ammonium hydroxide (6.9 L) and 5 L of toluene. The biphasic mixture was stirred at room temperature for 15 min and then separated. The organic layer was washed with 7 L of brine (1:1 saturated NaCl:Water), then 7 L of water. The organic phase was transferred to a 12 L 4 neck flask equipped with an overhead stirrer, thermocouple, mechanical stirrer, and connected to a batch concentrator. The batch was concentrated under vacuum at 15-38° C. to a volume of 1.5 L, and then heptane (850 mL) was added.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([CH2:15][O:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](O)=[O:20])[C@H:12]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:33][C:28]1[CH:27]=[C:26]([C@@H:12]2[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][C@H:13]2[CH2:15][O:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](=[O:20])[NH:38][S:35]([CH3:34])(=[O:37])=[O:36])[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COc2ccccc2C(=O)O)C1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COc2ccccc2C(=O)NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
To a solution of 2-{[(6S,7R)-4-(tert-butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methoxy}benzoic acid (100 mg) in DMF (1 ml) were added methanesulfonamide (38.3 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (62.5 mg) and N,N-dimethyl-4-aminopyridine (49.2 mg) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (40 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12].O>C1COCC1>[CH2:11]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: CCN
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (51 g, 325 mmol) in THF (650 mL) was added a 2 M solution of ethylamine in THF (365 mL, 731 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was poured into water (˜1.5 L) and the resulting solid was filtered and dried under reduced pressure to give the title compound (52 g).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][CH:8]=[CH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: BrCCC=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CCC=Cc1ccccc1)CC2
Yield: 39 %

Procedure:
Prepared analogously to Example 8 from 4-phenyl-3-buten-1-yl-bromide [boiling point 93° C./1,5 torr; prepared from 1-cyclopropyl-1-phenyl-carbinol with phosphorous tribromide] with 4 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in pure chloroform during 8 hours at 60° C. Yield: 39% of theory, Melting point: 157°-158° C. (chloroform/toluene)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=O)[C:3]=1[S:21]([CH3:23])=[O:22].Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:25][OH:26])[C:3]=1[S:21]([CH3:23])=[O:22]
Reactant: CS(=O)c1c(C=O)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Yield: 61.1 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde (2.74 g), hydroxylamine hydrochloride (0.99 g) and pyridine (1.68 g) was stirred in methanol at 46° C. for 2.8 hours, evaporated, washed (water) and crystallized from ethanol to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.74 g) as a white solid m.p.219-221° C. (decomposition). Compound 1
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([CH2:20][CH:21]=O)[C:16]2=O)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][CH2:14][C:15]3[CH:20]=[CH:21][N:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:16]=3[C:17]=2[CH:18]=1
Reactant: O=CCC1CCc2ccc(Cl)cc2C1=O
Reactant: CC(=O)NCCN
Solvent: ClCCl
Product: CC(=O)NCCn1ccc2c1-c1cc(Cl)ccc1CC2
Yield: 54.1 %

Procedure:
N-Acetylethylenediamine (2.9 g) was dissolved in 50 ml of methylene chloride under argon, treated in succession with 4.5 g of molecular sieve 4 Å and a solution of 5.7 g of 7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde in 20 ml of methylene chloride and heated to reflux for 16 hours while stirring. The reaction mixture was cooled, filtered over a Celite® pad and the filtrate was freed from solvent. The crude product, 6.6 g of brown solid, was dissolved in a 6-fold amount of hot ethyl acetate and, after the addition of an 8-fold amount of hexane, boiled briefly. There were obtained 4.0 g (55%) of N-[2-(8-chloro-4,5-dihydro-1H-benzo[g]indol-1-yl)ethyl]acetamide; m.pt.: 144°-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].N1C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][S:27]([C:22]1[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=1)(=[O:29])=[O:28]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)c2ccc(F)c(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2,4-dimethoxybenzylamine (3.35 mL, 22.3 mmol) and pyridine (9.02 mL, 111.5 mmol) in dichloromethane (75 mL), 3,4-difluorobenzenesulfonyl chloride (3.04 mL, 22.3 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 16 hours. To the reaction solution, 2 M hydrochloric acid (100 mL) was added, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate and vacuum concentrated to yield the title compound (7.66 g, 99%) as a colorless solid.
Reaction SMILES: [Br:1]Br.[CH:3]1([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(Cl)Cl.C(O)(=O)C>[Br:1][C:11]1([C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: BrBr
Reactant: O=C(c1ccccc1)C1CCCCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(c1ccccc1)C1(Br)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Temperature was kept at 20-25° C. when bromine (2.8 ml) was added slowly to a stirred mixture of cyclohexylphenyl ketone (10 g) in CH2Cl2 (50 ml) and acetic acid (1 ml). The mixture was stirred at the ambient temperature for 1 hour and extracted with 5% NaHCO3 (2×30 ml) and water (30 ml). The organic phase was dried over Na2SO4 and evaporated. Yield was 14.1 g.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Yield: 61 %

Procedure:
2,4-Difluorobenzoic acid (5 g, 0.031 M) was dissolved in concentrated sulfuric acid (30 ml), and cooled to 0°. The mixture was stirred, and fuming nitric acid (d 1.567 g/ml, 1.91 ml, 0.047 M) added dropwise, keeping the temperature below 5°. After stirring for 3 hours, the mix was poured onto ice, and organics extracted into dichloromethane (2×75 ml). The combined organic layers were washed with water, dried (MgSO4), and evaporated to give 2,4-difluoro-5-nitrobenzoic acid (3.9 g, 61%). Nmr (DMSO-d6): δ 7.18 (t, 1H); 8.88 (t, 1H); 9.93 (br, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][NH:4][C:5]([NH:7][C:8]([NH2:10])=[S:9])=[NH:6].Cl[CH2:14][C:15](=O)[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>CCO>[F:12][C:2]([F:1])([F:11])[CH2:3][N:4]=[C:5]([NH2:6])[NH:7][C:8]1[S:9][CH:14]=[C:15]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[N:10]=1
Reactant: N=C(NCC(F)(F)F)NC(N)=S
Reactant: COC(=O)CCCC(=O)CCl
Solvent: CCO
Product: COC(=O)CCCc1csc(NC(N)=NCC(F)(F)F)n1

Procedure:
To 2,2,2-trifluoroethylamidinothiourea (2.1 g.) in hot EtOH (20 ml.) was added a solution of methyl 6-chloro-5-oxohexanoate (2.0 g.) in hot EtOH (20 ml.). The mixture was heated under reflux for 1 hour and then evaporated to dryness. The residue was partitioned between ether (20 ml.) and water (60 ml.). The aqueous layer was separated, basified with sodium bicarbonate and extracted with EtOAc. The organic layer was evaporated to dryness to give a gum which was recrystallised from EtOAc/ether/acetone to give methyl 4-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butyrate which was used without further purification.