Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17].CCN(C(C)C)C(C)C>ClCCl>[CH2:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:20][CH2:19]1)[CH3:17]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
1-(Bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (34 g, 120 mmol) obtained in Step (1) above was stirred in a solvent of dichloromethane (300 mL). The reaction solution was added with 1-ethylpiperazine (15.97 mL, 126 mmol) and DIPEA (27.2 mL, 156 mmol), followed by stirring for about 3 hours at room temperature. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (21.7 g, 57%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH3:12]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:12]
Reactant: Oc1ccc2ccccc2c1
Reactant: N
Product: Nc1ccc2ccccc2c1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
In a sealed reactor, 4.32 g (30 mmol, 1 eq) of 2-naphthol, 2.85 g (30 mmol, 1 eq) of (NH4)2SO3 and 50 mL of aqueous ammonia were mixed. The mixture was heated to 150° C., the pressure was raised to 10 bars and the mixture was stirred overnight. The mixture was then cooled down to room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1.C[N:19]1CCOCC1.C(Cl)(=O)OCC(C)C.N[CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([CH2:40][CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:35]1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([NH:19][CH:39]2[CH2:38][CH2:37][N:36]([CH2:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:35][CH2:34]2)=[O:17])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: CC1Oc2c(C(=O)O)cc(Cl)cc2N(C)C1=O
Reactant: NC1CCCN(CCCc2ccccc2)C1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1Oc2c(C(=O)NC3CCN(CCCc4ccccc4)CC3)cc(Cl)cc2N(C)C1=O
Product: Cl

Procedure:
A solution of 4.0 g of 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 80 ml of tetrahydrofuran is cooled to below 0° C. and 3.17 g of N-methylmorpholine is added under stirring thereto. Further, 2.35 g of isobutyl chlorocarbonate is added and the mixture is stirred at the same temperature for 45 minutes. To the resultant mixture is added 3.77 g of 3-amino-1-(3-phenylpropyl)piperidine and the mixture stirred for 3 hours. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off and the residue is recrystallized from ethanol followed by treating with ethnnolic hydrochloric acid to give 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-N-[1-(3-phenylpropyl)-4-piperidyl]-2H-1,4-benzoxazine-8carboxamide hydrochloride, melting at 174°-176° C. with decomposition.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:12][NH2:13])=[S:11])[CH3:2].C(O)(=O)C.[N:18]([O-])=O.[Na+]>O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[S:11][N:18]=[N:13][N:12]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCc1ccccc1NC(=S)NN
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccccc1Nc1nnns1

Procedure:
To a stirred and cooled mixture of N-(2-ethylphenyl)hydrazinecarbothioamide (0.500 g, 2.56 mmol) and acetic acid (2.00 mL, 17.5 mmol) was added sodium nitrite (0.177 g, 2.56 mmol) in water (1 mL). The mixture turned yellow upon addition and the reaction was stirred for 1 hour. The solid was filtered and the title compound was obtained as an orange solid (0.389 g, 73%): 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 7.42-7.28 (m, 4H), 2.76 (q, J=7.5 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 138.69, 137.90, 130.38, 128.28, 128.14, 121.60, 24.73, 14.79; ESIMS m/z 179 ([M+H]-N2+).
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:29]3[C:28]4[C@@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25][C:24]=4[S:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[C-:33]#[N:34].[Na+].[NH4+].[Cl-]>CO>[NH2:1][CH:31]([C:33]#[N:34])[CH2:30][C@H:27]1[CH2:26][CH2:25][C:24]2[S:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([O:17][CH:14]4[CH2:15][CH2:16][CH:11]([N:3]([CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8])[CH2:12][CH2:13]4)[C:29]=3[C:28]1=2
Reactant: [C-]#N
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)C#N)CC4)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
Ammonia gas was introduced in 50 mL of CH3OH at 5° C. for 15 min. To the above solution was added tert-butyl N-methyl-N-(4-[[(3R)-3-(2-oxoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (700 mg, 1.57 mmol, 1.00 equiv), NaCN (93.1 mg, 1.90 mmol, 1.20 equiv) and NH4Cl (92.5 mg, 1.73 mmol, 1.10 equiv) successively. The resulting mixture was stirred for 16 h at room temperature and concentrated under reduced pressure. The residue was applied onto a silica gel column with dichloromethane/methanol (1:30) to afford tert-butyl N-(4-[[(3R)-3-(2-amino-2-cyanoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (600 mg, 81%) as a yellow oil.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[C@H:8]([OH:9])[C@@H:7]([O:10][CH3:11])[C:6]([CH3:13])([CH3:12])[O:5][C@H:4]1[O:14][C:15]1[C:24]([CH3:25])=[C:23]2[C:18]([CH:19]=[C:20]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4C)[C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:29])[C:21](=[O:26])[O:22]2)=[CH:17][CH:16]=1.[H-].[Na+].[CH:47]1C=CC(CBr)=CC=1>CO>[OH:2][C@@H:3]1[C@H:8]([OH:9])[C@@H:7]([O:10][CH3:11])[C:6]([CH3:13])([CH3:12])[O:5][C@H:4]1[O:14][C:15]1[C:24]([CH3:25])=[C:23]2[C:18]([CH:19]=[C:20]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([C:38]4[CH:39]=[CH:40][CH:41]=[C:42]([CH3:47])[CH:43]=4)[C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:29])[C:21](=[O:26])[O:22]2)=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C(=O)Nc2cc3ccc(O[C@@H]4OC(C)(C)[C@H](OC)[C@@H](O)[C@H]4O)c(C)c3oc2=O)cc1-c1ccccc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)Nc2cc3ccc(O[C@@H]4OC(C)(C)[C@H](OC)[C@@H](O)[C@H]4O)c(C)c3oc2=O)cc1-c1cccc(C)c1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
Hydrogen chloride was bubbled through 29 (2.00 g, 6.16 mmol) in anhydrous MeOH (44.0 mL) for three minutes at room temperature, then the solution was stirred at 50° C. for 5 minutes. The solvent was concentrated and the residue placed under high vacuum for six hours to ensure complete removal of MeOH. The yellow residue was dissolved in anhydrous dimethylformamide (44.0 mL) and cooled to 0° C., then NaH (997 mg, 24.93 mmol) was added. After 15 minutes, BnBr (1.20 mL, 1.73 g, 10.09 mmol) was added and the reaction was warmed to room temperature over 18 hours. Reaction contents were partitioned between saturated aqueous NaHCO3 (500 mL) and EtOAc (500 mL), then extracted with EtOAc (3×500 mL). The combined organic layers were washed with water (3×1 L), saturated aqueous NaCl solution (1 L), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 9:1 Hexanes:EtOAc) to give 30 as a light orange solid containing greater than 80% 3-bromo isomer (1.70 g, 88%), which was used without further purification.
Reaction SMILES: CN1CCOCC1.[NH:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:9]([C:11]([N:13]([CH3:22])[C@H:14]([C:19]([OH:21])=O)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH3:10].C(Cl)(=O)C(C)(C)C.[NH:37]([CH3:52])[C@H:38]([C:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41]>C(Cl)(Cl)Cl.O>[NH:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:9]([C:11]([N:13]([CH3:22])[C@H:14]([C:19]([N:37]([CH3:52])[C@H:38]([C:43]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:44])[CH2:39][CH:40]([CH3:41])[CH3:42])=[O:21])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:12])[CH3:10]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Reactant: CN[C@@H](CC(C)C)C(=O)Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)N(C)[C@@H](CC(C)C)C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
17.9 ml (16.4 g=162.4 m mol) N-methylmorpholine are added to a solution of 24.5 g (77.3 m mol) BOC-(D)-Ala-MeLeu-OH dissolved in 200 ml chloroform and the whole is cooled to -20° C. 9.5 ml (9.27 g=77.3 m mol) pivaloyl chloride are then added over 5 minutes and the reaction mixture stirred for 90 minutes, still at -20° C. Anhyride formation is followed by means of IR control and when complete a solution of 18.2 g (77.3 m mol) H-MeLeu-Bzl in 50 ml chloroform is added dropwise at -20° within 5 minutes. A reaction period of 18 hours at -20° C. is required until no more anhydride is present. The obtained solution is poured onto 300 ml water and is extracted in a separating funnel after first diluting with a further 300 ml chloroform. The aqueous phase is extracted with 300 ml chloroform, the combined organic phases dried over sodium sulphate, filtered and evaporated. The residue is chromatographed on 1 kg silica gel (0.063-0.24 mm) using 2% methanol in methylene chloride as eluant to yield the title compound: rotation, [α]D25 =-101.3° (c=0.9 in chloroform).
Reaction SMILES: [C:1](=O)([O-:58])[O:2][CH:3]([C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1C=CC=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC1C=CC=CC=1)NC(=O)CN1CCOCC1)[C:4]#[CH:5].C(O)C#C.[CH3:64][S:65]([O:68][CH2:69][C@:70]([OH:120])([CH3:119])[C:71](=[O:118])[C@H:72]([CH2:114][CH:115]([CH3:117])[CH3:116])[NH:73][C:74](=[O:113])[C@H:75]([CH2:106][C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1)[NH:76][C:77](=[O:105])[C@H:78]([CH2:101][CH:102]([CH3:104])[CH3:103])[NH:79][C:80](=[O:100])[C@H:81]([CH2:92][CH2:93][C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1)[NH:82][C:83](=[O:91])[CH2:84][N:85]1[CH2:90][CH2:89][O:88][CH2:87][CH2:86]1)(=[O:67])=[O:66]>>[CH3:64][S:65]([O:68][CH2:69][C:70]([CH3:119])([O:120][C:1]([O:2][CH2:3][C:4]#[CH:5])=[O:58])[C:71](=[O:118])[C@H:72]([CH2:114][CH:115]([CH3:116])[CH3:117])[NH:73][C:74](=[O:113])[C@H:75]([CH2:106][C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1)[NH:76][C:77](=[O:105])[C@H:78]([CH2:101][CH:102]([CH3:104])[CH3:103])[NH:79][C:80](=[O:100])[C@H:81]([CH2:92][CH2:93][C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1)[NH:82][C:83](=[O:91])[CH2:84][N:85]1[CH2:86][CH2:87][O:88][CH2:89][CH2:90]1)(=[O:66])=[O:67]
Reactant: C#CC(OC(=O)[O-])[C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)COS(C)(=O)=O
Agent: C#CCO
Product: C#CCOC(=O)OC(C)(COS(C)(=O)=O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1

Procedure:
Prepared according to the procedure for (4S,7S,10S,13S,15S)-10-benzyl-16-iodo-7,13-diisobutyl-15-methyl-1-morpholino-2,5,8,11,14-pentaoxo-4-phenethyl-3,6,9,12-tetraazahexadecan-15-ylprop-2-yn-1-yl carbonate, except using propargyl alcohol and (4S,7S,10S,13S,15R)-10-benzyl-15-hydroxy-7,13-diisobutyl-15-methyl-1-morpholino-2,5,8,11,14-pentaoxo-4-phenethyl-3,6,9,12-tetraazahexadecan-16-yl methanesulfonate.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]Cl>ClC1C=CC=CC=1>[Cl:18][C:9]12[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15](=[O:17])[O:16][C:1]2([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: O=C(O)C1CCCCC1C(=O)c1ccccc1
Solvent: Clc1ccccc1
Product: O=C1OC(O)(c2ccccc2)C2(Cl)CCCCC12
Temperature: 59 °C
Yield: 35 %

Procedure:
23.2 g (0.1 mol) of 2-benzoyl-cyclohexanecarboxylic acid and 100 ml of chorobenzene are heated to 55° C. while stirring. Chlorine gas is then slowly introduced into the suspension over two hours while maintaining the temperature at 58-60° C. When no more starting material is detected by thin layer chromatography (TLC) analysis, the slightly yellowish solution is purged with nitrogen during one hour and subsequently cooled to room temperature. The solvent is then distilled off in vacuum to give a yellowish oil which according to TLC analysis consists of two main products. These products are isolated via preparative column chromatography on silica gel, using white spirit/ethyl acetate 1:4 as the eluant. The first fraction isolated is obtained as white solid with a melting point of 89-92° C. and is identified by 1H-NMR and elemental analysis as 3a-chloro-3-hydroxy-3-phenyl-hexahydro-isobenzofuran-1-one 9.3 g (35% yield). The second fraction is obtained as viscous yellowish oil, which is identified by 1H-NMR and elemental analysis as 3,3a-dichloro-3-phenyl-hexahydro-isobenzofuran-1-one (6.7 g, 25% yield)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[C:12]([C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1.CO.CCOC(C)=O>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][S:24]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:26])=[O:25])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CC(C)(C)c1ccc(/C=C/S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1ccc(CCS(=O)(=O)Nc2ccccc2S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
2-Aminobenzenesulfonamide (0.057 g, 0.33 mmol) was dissolved in pyridine (2.5 mL) followed by addition of (E)-2-(4-tert-butylphenyl)ethenesulfonyl chloride (0.078 g, 0.30 mmol) and the reaction was stirred at RT overnight. The solvent was then removed under reduced pressure and the pale yellow oily residue was used in the next step without further purification. The crude material (0.118 g, 0.3 mmol) was dissolved in MeOH (5 mL) with a few drops of EtOAc and was subjected to reduction using the H-cube instrument. The reaction mixture was eluted through the Pd/C (10%) cartridge using full hydrogen (1 atm) at 1 ml/min. The mixture was subjected to the H-cube once again using the same conditions for full conversion of the starting material and purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (56 mg, 47%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][O:21][CH3:22])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH:39]1([NH2:43])[CH2:42][CH2:41][CH2:40]1>O1CCCC1.Cl>[CH:39]1([NH:43][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:19][C:18]([CH2:20][O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[CH2:42][CH2:41][CH2:40]1
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)O)c2)c(Cl)c1
Reactant: NC1CCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)NC3CCC3)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of the title compound of Step D (238 mg, 0.67 mmol) in tetrahydrofuran (7 ml) at 0° C. under nitrogen was added isobutylchloroformate (0.13 mL, 1 mmol) and N-methylmorpholine (0.15 ml, 1.3 mmol). After stirring for about 30 minutes at 0° C., cyclobutylamine (0.11 ml, 1.3 mmol) was added. The reaction mixture was warmed to room temperature and stirred for about 19 hours. The reaction solution was diluted with 1N HCl (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl (2×50 ml), brine (50 ml), dried, filtered, and concentrated. The crude product was purified by preparative TLC (50% ethyl acetate in hexanes) to afford the title compound (170 mg) as a viscous oil. MS (APCI+) Calc: 409.1, found: 409.7 (M+1)
Reaction SMILES: [CH2:1]([CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH:9]([OH:21])[CH2:10][CH:11]([C:18](=[NH:20])[NH2:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:20]=[C:18]([NH2:19])[CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([OH:21])[CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=N)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N=C(N)C(CCC(C)(C)F)CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.0 equivalents of quinoxaline-2-carboxylic acid (1-benzyl-4-carbamimidoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide in methylene chloride is added 1.0 equivalents of triethylamine followed by 1.0 equivalents of acetyl chloride. The reaction is stirred at ambient temperature for approximately 5 hours. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:49])[CH2:22][NH:23][C:24](=[O:48])[C:25]2[CH:30]=[CH:29][C:28]([S:31](=[O:47])(=[O:46])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:27][CH:26]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)C.[Cl:55]CCl>C(O)C>[ClH:55].[O:49]=[C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[CH2:22][NH:23][C:24](=[O:48])[C:25]1[CH:26]=[CH:27][C:28]([S:31](=[O:47])(=[O:46])[NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)[C@@H]2CCCN2C(=O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccccc3Oc3ccccc3)cc2)CC1
Reactant: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: Cl
Product: O=C(NCC(=O)N1CCC[C@H]1C(=O)N1CCNCC1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of 4-((S)-1-{2-[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-pyrrolidine-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (0.115 g, 0.166 mmol) in dichloromethane (2 mL) 9 M hydrogen chloride in ethanol (0.2 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then diethyl ether (20 mL) was added, the precipitated crystals were filtered, washed with diethyl ether and dried to yield 0.089 g (89%) of the title compound. MS (EI) 592.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[N:18][CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:20]([C:16]2[CH:17]=[N:18][CH:19]=[C:14]([C:13]([F:25])([F:12])[F:24])[CH:15]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cncc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cncc(C(F)(F)F)c1
Yield: 17.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (70 mg, 0.48 mmol), 5-trifluoromethyl-pyridine-3-sulfonyl chloride (Intermediate 442) (153 mg, 0.63 mmol), DMAP (cat.), pyridine (1.5 ml) and DCM (2 ml) gave the title compound (30 mg, 11%) after purification by column chromatography with n-hexane/EtOAc (85:15) as the eluent.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:32]([F:31])=[CH:39][CH:38]=[CH:37][C:36]=3[F:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cccc(F)c1CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2c(F)cccc2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,6-difluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.39 (m, 1 H), 7.34-7.28 (m, 1 H), 7.23-7.16 (m, 1 H), 7.11-7.06 (m, 1 H), 6.98-6.87 (m, 3 H), 6.22-6.16 (m, 1 H), 5.62-5.49 (m, 3 H), 4.31-4.24 (m, 2 H), 2.93-2.77 (m, 2 H), 2.73 (s, 3 H), 2.09-2.06 (m, 2 H), 1.00-0.93 (s, 9 H); LC/MS (m/z) ES+=521.36 (M+1).
Reaction SMILES: O1C=CC2C=CC=C(N3CCN(CCCC(=O)C4C=CC(F)=CC=4)CC3)C1=2.[Br:28][C:29]1[CH:30]=[C:31]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][Cl:47])[CH2:41][CH2:40]2)[C:32]2[O:37][CH2:36][CH2:35][O:34][C:33]=2[CH:38]=1.[Cl:48]C1C=C(N2CCN(CCCl)CC2)C2OCCOC=2C=1.[Cl:68][C:69]1[CH:70]=[C:71]2[C:76](=[CH:77][CH:78]=1)[C:75](=[O:79])[NH:74][CH2:73][CH2:72]2>>[ClH:47].[ClH:48].[Br:28][C:29]1[CH:30]=[C:31]([N:39]2[CH2:40][CH2:41][N:42]([CH2:45][CH2:46][N:74]3[CH2:73][CH2:72][C:71]4[C:76](=[CH:77][CH:78]=[C:69]([Cl:68])[CH:70]=4)[C:75]3=[O:79])[CH2:43][CH2:44]2)[C:32]2[O:37][CH2:36][CH2:35][O:34][C:33]=2[CH:38]=1
Reactant: ClCCN1CCN(c2cc(Br)cc3c2OCCO3)CC1
Reactant: O=C1NCCc2cc(Cl)ccc21
Reactant: ClCCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1
Agent: O=C(CCCN1CCN(c2cccc3ccoc23)CC1)c1ccc(F)cc1
Product: Cl
Product: O=C1c2ccc(Cl)cc2CCN1CCN1CCN(c2cc(Br)cc3c2OCCO3)CC1
Yield: 37 %

Procedure:
This compound was obtained analogous to the method described in EP-A-0190472 for 1-(benzo-[b]furan-7-yl)-4-[3-(4-fluorobenzoyl)-propyl)piperazine using 1-(7-bromo-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(2-chloroethyl)piperazine (which was prepared similar to the method described for 1-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(2-chloroethyl)piperazine as described in EP-A-0190472), and 6-chloro-3,4-dihydroisoquinolin-1(2H)-one. Yield 37%, m.p. <240° C. (dec.), 1H-NMR (DMSO:CDCI3 =4:1)δ3.09 (t, 2H, NCH2CH2Ar J=7 Hz), 3.16 (m, 2H, Hax pipCH2), 3.45 (m, 2H, +NCH2CH2), 3.55 (m, 2H, Heq pipCH2), 3.65-3.75 (cluster, 4H), 3.94 (t, 2H, CH2CH2NC=O), 4.26 (m, 4H, OCH2CH2O), 6.62 (d, 1 H, H-6, J=2 Hz), 6.75 (d, 1H, H-8 J=2 Hz), 7.37 (cluster, 2H), 7.88 (d, 1H, J=8 Hz), 11.0 (br, 1H, NH+)