Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12]([Cl:19])[C:13](Cl)=[C:14]([Cl:17])[C:15]=1[Cl:16])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1>[CH2:1]([N:5]=[C:6]([OH:20])[C:7]1[C:8](=[C:12]([Cl:19])[C:13]([S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([Cl:17])[C:15]=1[Cl:16])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN=C(O)c1c(Cl)c(Cl)c(Sc2ccccc2)c(Cl)c1C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2 g (5.86 millimols) of tetrachlorophthalic acid N-n-butylimide are initially introduced, together with 2.43 g (17.59 millimols) of potassium carbonate, into 15 ml of tetrahydrofuran at 0° C. A solution of 680 mg (6.16 millimols) of thiophenol in 10 ml of tetrahydrofuran is added dropwise over a period of 2 hours. The mixture is stirred at 0° C. for 3 hours and gradually warmed to 25° C. over a period of 6 hours, and then acidified with 2N HCl solution and extracted with tetrahydrofuran/toluene. After drying over sodium sulfate, the organic phase is evaporated and the residue is recrystallised several times. This yields 0.17 g (7% of theory) of 4-phenylthio-3,5,6-trichlorophthalic acid N-n-butylimide; melting point 159°-63° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2([C:24]([OH:26])=O)[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.S(Cl)([Cl:31])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2([C:24]([Cl:31])=[O:26])[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cl)cc1C1(C(=O)O)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Solvent: c1ccccc1
Product: COc1ccc(Cl)cc1C1(C(=O)Cl)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Yield: 100 %

Procedure:
To a stirred and refluxing mixture of 21 parts of 4-(5-chloro-2-methoxyphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarboxylic acid and 270 parts of benzene are added dropwise 36 parts of thionyl chloride. Upon completion, the whole is stirred and refluxed for 4 hours. The reaction mixture is evaporated and the residue is washed twice with methylbenzene, yielding 22 parts (100%) of 4-(5-chloro-2-methoxyphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonyl chloride.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:10][CH2:11][CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH3:9].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O>[CH2:8]([O:10][CH2:11][CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[N:22]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH3:9]
Reactant: CCOCCn1c(NC2CCN(C(=O)OCC)CC2)nc2cccnc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(N(Cc2ccccc2)C2CCN(C(=O)OCC)CC2)nc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
A mixture of 2.7 parts of a sodium hydride dispersion 50% and 282 parts of N,N-dimethylformamide was stirred at room temperature under nitrogen atmosphere. 18.8 Parts of ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate were added portionwise to the previous mixture. Upon complete addition, stirring for continued for 1 hour at room temperature. 10 Parts of (bromomethyl)benzene were added dropwise and upon completion, stirring was continued for 1 hour. The reaction mixture was decomposed with water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and ethanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 parts (13.6%) of ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b] pyridin-2-yl](phenylmethyl)amino]-1-piperidinecarboxylate; mp. 115.0° C. (compound 177).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:21])[C:8]([F:20])([F:19])[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[H-].[Na+].[CH3:24]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:24])[C:7](=[O:21])[C:8]([F:19])([F:20])[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCCC2)CC1(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of compound 2-Chloro-9-cyclohexyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (6.0 g, 18.98 mmol) in 30 mL of DMA was added sodium hydride (60% dispersion in mineral oil, 1.138 g, 28.47 mmol) at 0° C., followed by the dropwise addition of methyl iodide (1.42 mL, 22.78 mmol). The reaction mixture was warmed up to rt and stirred for 1 h. The whole was poured into ice-water, extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated in vacuo followed by precipitation from ether/EtOA to afford the desired compound (3.0 g, 47.9% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.85 (m, 10H) 3.33 (s, 3H) 4.15 (t, J=12.88 Hz, 2H) 4.44 (m, 1H) 8.31 (s, 1H). [M+H] calc'd for C14H17ClF2N4O, 331. found 331.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)(=O)=O.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>C1COCC1>[CH2:36]([N:38]([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)[CH2:39][CH3:40])[CH3:37]
Reactant: CCNCC
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: C1CCOC1
Product: CCN(CC)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-(Methylsulfonyl)-4-(3,4-difluorobenzyloxy)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 6, 55 mg, 0.10 mmol) was treated with excess diethylamine in THF according to the same general procedure described in Example 31, Step A. Workup (solvent removal under reduced pressure) and flash column chromatography on silica gel (eluted with 87/13 hexanes/ethyl acetate) afforded the title compound. HPLC/MS: m/e=550 (M++1); Rt=4.48 min. 1H-NMR 500 MHz (CDCl3): δ 1.23 (t, J=7 Hz, 3H), 3.65 (q, J=7 Hz, 2H), 5.39 (s, 2H), 7.04 (d, J=8 Hz, 2H), 7.08 (d, J=8 Hz, 2H), 7.13-7.22 (m, 5H), 7.34 (d, J=2 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:16]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:19]2[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=2[N:17]=1>CN(C)C=O>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)N1CCC(O)CC1
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Oc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To a stirred mixture of 3.5 parts of ethyl 4-hydroxy-1-piperidinecarboxylate and 135 parts of N,N-dimethylformamide was added 1 part of a sodium hydride dispersion 50% and stirring was continued for 2 hours at room temperature. After the addition of 5.2 parts of 2-chloro-1-[(4-fluorophenyl)methyl]-1H-benzimidazole, the whole was further stirred overnight at room temperature. The reaction mixture was poured into ice water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 2.5 parts (31.5%) of ethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]oxy]-1-piperidinecarboxylate; mp. 94.0° C. (26).
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:28][O:27][C@H:26]([CH2:29][F:30])[C@H:25]1[CH2:24][S:23][C:22]([NH:31]C(=O)C1C=CC=CC=1)=[N:21]2>CO>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:28][O:27][C@H:26]([CH2:29][F:30])[C@H:25]1[CH2:24][S:23][C:22]([NH2:31])=[N:21]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CF)[C@H]2CS1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 65 °C
Yield: 104.2 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.99 mL, 6.6 mmol) was added to a stirred suspension of N-((4aS,5S,7aS)-7a-(2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (1.34 g, 3.30 mmol) in dry MeOH (10 mL) at RT under nitrogen. The reaction was stirred and heated at 65° C. overnight, under nitrogen. The reaction was allowed to cool to RT and the volatiles were removed in vacuo. The residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 20% to 100% EtOAc in n-hexane) to give the title compound (1.04 g). 1H NMR (400 MHz, CDCl3) δ ppm: 2.78 (dd, J=13.33, 4.03 Hz, 1 H) 2.93-3.01 (m, 1 H) 3.09 (dd, J=13.39, 3.61 Hz, 1 H) 3.83 (dd, J=8.44, 2.45 Hz, 1 H) 4.44-4.56 (m, 3 H) 4.62 (d, J=4.40 Hz, 1 H) 6.75-6.92 (m, 2 H) 7.36-7.47 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:9]([O:23][CH3:24])=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:28]([OH:30])=[O:29])=[CH:6][N:7]2[CH:25]1[CH2:27][CH2:26]1.OS(O)(=O)=O.C([O-])(O)=O.[Na+].[CH3:42][CH2:43]O>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:9]([O:23][CH3:24])=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:28]([O:30][CH2:42][CH3:43])=[O:29])=[CH:6][N:7]2[CH:25]1[CH2:27][CH2:26]1
Reactant: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(NCCNc3ccccn3)c(F)c(N)c2c1=O
Temperature: 0 °C
Yield: 44 %

Procedure:
A mixture of 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (428 mg, 1.00 mmol) and concentrated H2SO4 (1.0 mL) in EtOH (15 mL) was refluxed for 8 h. After cooling, the mixture was poured into ice water (100 mL). Saturated aq. NaHCO3 (50 mL) was added and the crude product was extracted with CH2Cl2 (2×50 mL). The extraction mixture washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.), EtOAc) to give ethyl 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylate (311 mg, 44%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1.[F:36][C:37]([F:56])([F:55])[C@H:38]([O:45][C:46](=[O:54])[C:47]1[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].CN(C1C=CC=CN=1)C>C1COCC1.C(N=C=NC(C)C)(C)C>[F:36][C:37]([F:55])([F:56])[C@H:38]([O:45][C:46]([C:47]1[CH:48]=[CH:49][C:50]([O:34][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:3]3[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])=[C:7]([F:8])[C:2]=3[F:1])=[CH:28][CH:29]=2)=[O:35])=[CH:51][CH:52]=1)=[O:54])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(O)cc1)C(F)(F)F
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCC[C@@H](OC(=O)c1ccc(OC(=O)c2ccc(-c3ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c3F)cc2)cc1)C(F)(F)F
Reaction time: 24 h
Yield: 65 %

Procedure:
To a solution of 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid (14 A) (1 equi.), (4-hydroxy benzoic acid (R)-1-trifluoromethyl-heptyl ester (7) (1 equi.), and DMAP (dimethylaminopyridine) (0.1 equi.) in THF (25 mL/mmole), DIC (diisopropyl carbodiimide) (1.2 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) gave 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid 4-[(R)-1-trifluoromethyl-heptyloxycarbonyl]-phenyl ester (15A) as a white solid (65%).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[C:19]([CH3:22])[N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:17][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:18])[N:7]3[C:19]([CH3:22])=[CH:20][S:21][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][NH:28]3)[CH3:3])[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 110 °C
Yield: 50.8 %

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.105 g, 0.327 mmol) (1st peak from Example 23, step 1 chiral separation), 6-bromo-9H-purine (0.117 g, 0.588 mmol), and N,N-diisopropylethylamine (0.114 mL, 0.654 mmol) in ethanol (1.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (0.073 g, 51%). LCMS calculated for C20H16F2N7OS (M+H)+: m/z=440.1. Found: 440.0. 1H NMR (DMSO-d6, 500 MHz) δ 8.05 (2H, s), 7.34 (1H, br s), 7.18 (1H, m), 7.12 (2H, m), 6.84 (1H, s), 7.01 (1H, s), 5.07 (1H, m), 2.43 (3H, s), 1.31 (3H, d, J=7.0 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −111 ppm.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:1]([O:21][S:36]([C:33]1[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=1)(=[O:38])=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCCCO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of eicosanol (5.0 g, 16.70 mmol) and triethylamine (4 ml) in methylene chloride (80 ml) was added dropwise a solution of 4-chlorobenzene-sulphonyl chloride (3.90 g, 18.50 mmol) in methylene chloride (20 ml) and this solution was stirred for 24 h. The reaction mixture was then diluted with more methylene chloride (100 ml) and washed with water (2×75 ml). The organic layer was dried over MgSO4, filtered and concentrated to give a crude product which was recrystallized from methanol to give n-eicosanyl-4-chlorobenzenesulphonate the product (5.10 g, 65%) m.p. 69°-70° C. max; 3000-2800, 1367, 1184, 1176, 963 cm-1. m/z, 472 (M+). Found C, 66.16%; H 9.75%; S, 6.74% Cl, 7.40% C26H45O3SCl requires C, 66.00%; H, 9.59%; S, 6.78%; Cl, 7.49%. 1Hnmr, 0.855 (t, J-6.6 Hz, 3H); 1.10-1.65 (m); 4.030 (t, J=6.4 Hz, 2H); 7.48-7.53 (m, 2H); 7.80-7.84 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]([O:15]C)[CH:4]=1.Cl>CN1CCCC1=O>[N+:9]([C:8]1[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([OH:15])=[CH:4][C:3]=1[OH:2])([O-:11])=[O:10]
Reactant: COc1cc(OC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)cc1O
Temperature: 130 °C
Yield: 47.5 %

Procedure:
A 100 mL, 3-necked, round-bottom flask is charged with 30 mL of N-methylpyrrolidinone, 2.6 g (0.02 mole) of 1,3-dimethoxy-4,6-dinitrobenzene. The resulting solution is heated to 130° C. for two to three hours. The reaction mixture is then cooled and poured into an excess of dilute hydrochloric acid. The resulting solid is isolated by filtration to yield 1.9 g (95% yield) of 4,6-dinitroresorcinol.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][N:13]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[CH3:12][N:13]([CH:21]1[CH2:22][CH2:23][N:24]([C:2]2[C:3]3[C:10]([CH3:11])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:25][CH2:26]1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(N(C)C(=O)OC(C)(C)C)CC3)c12
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine D4 (1 g), 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (1.918 g, 8.95 mmol, commercially available from e.g. Fluorochem, Apollo or Butt Park) and N,N-diisopropylethylamine (2.61 mL, 14.92 mmol) was heated at 150° C. for 20 minutes. LC/MS showed incomplete reaction. Further NMP (2 mL) and DIPEA (1.3 mL) was added. The mixture was heated at 150° C. for 20 minutes. The mixture was partitioned between ethyl acetate (70 mL) and water (60 mL) and the organic phase washed with water (2×60 mL) and brine (50 mL). It was dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by silica chromatography, eluting 50-100% EtOAc in isohexane. The desired fractions collected and the solvent has been evaporated to give the desired product D22 in 0.793 g as a white solid. LCMS [M+H]+345.87@0.88 min (2 min run)
Reaction SMILES: [NH2:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[CH2:9]([CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13])[CH3:10]>C(O)C>[CH2:17]([C:11]1[C:12](=[O:13])[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[N:1][C:9]=1[CH3:10])[CH3:19]
Reactant: NC1=NCCCCC1
Reactant: CCOC(=O)C(CC)C(C)=O
Solvent: CCO
Product: CCc1c(C)nc2n(c1=O)CCCCC2
Yield: 61 %

Procedure:
5.6 g. of 7-amino-3,4,5,6-tetrahydro-2H-azepine and 7.5 g. of ethyl 2-ethyl-acetoacetate are boiled in 50 ml. ethanol for 3 hours. The ethanol is then evaporated at reduced pressure. The residual oil is dissolved in 20 ml. of 10% hydrochloric acid and shaken out twice with 10 ml. ethyl acetate. The aqueous layer is neutralized with sodium hydrogen carbonate and shaken out with 3×10 ml. chloroform. The combined chloroform layer is dried over calcinated sodium sulphate and evaporated. The residual colorless oil is fractionated at reduced pressure. 6.3 g. (61%) 3-ethyl-2-methyl-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine are obtained. Boiling point: 156°-160° C./2 mmHg.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][O:10][C:11]([NH:13][C@H:14]([C:18]([OH:20])=O)[CH:15]([CH3:17])[CH3:16])=[O:12])[N:8]=1)([CH3:3])[CH3:2].[NH2:21][C@H:22]([C@@H:30]([OH:49])[CH2:31][C@H:32]([NH:39][C:40]([O:42][CH2:43][C:44]1[S:48][CH:47]=[N:46][CH:45]=1)=[O:41])[CH2:33][C:34]1[S:38][CH:37]=[N:36][CH:35]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CO>C(Cl)(Cl)Cl>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][O:10][C:11]([NH:13][C@H:14]([C:18]([NH:21][C@H:22]([C@@H:30]([OH:49])[CH2:31][C@H:32]([NH:39][C:40]([O:42][CH2:43][C:44]2[S:48][CH:47]=[N:46][CH:45]=2)=[O:41])[CH2:33][C:34]2[S:38][CH:37]=[N:36][CH:35]=2)[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:20])[CH:15]([CH3:16])[CH3:17])=[O:12])[N:8]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nc(COC(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1cncs1)NC(=O)OCc1cncs1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(COC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](Cc2cncs2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)valine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-2-amino-1-phenyl-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane provided, after silica gel chromatography using 1% methanol in chloroform, 54 mg (66%) of the desired compound (Rf 0.6, 10% methanol in CH2Cl2). 1H NMR (DMSO-d6) δ0.69 (d, 3H), 0.74 (d, 3H), 1.31 (d, 6H), 1.47 (m, 2H), 1.85 (m, 1H), 2.75 (m, 4H), 2.95 (m, 1H), 3.57 (m, 1H), 3.80 (m, 2H), 4.08 (m, 1H), 4.95 (d, 1H), 5.03 (s, 2H), 5.19 (s, 2H), 7.12-7.29 (m), 7.45 (s, 1H), 7.47 (s, 1H). Mass spectrum: (M+H)+ =715.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CC1(C)[O:26][C@@H:25]([CH2:27][CH2:28]OS(C)(=O)=O)[CH2:24][O:23]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:28][CH2:27][C@H:25]([OH:26])[CH2:24][OH:23])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: CC1(C)OC[C@H](CCOS(C)(=O)=O)O1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CC[C@H](O)CO)CC1

Procedure:
In analogy to the procedure described for example 167A and 167B, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (prepared from 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol and methanesulfonyl chloride) gave the title compound as an white foam. MS: 401.3 (MH+, 2Cl).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@H:10]([CH:12]([CH3:14])[CH3:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:22][S:19](=[O:21])(=[O:20])[O:18][CH2:17]1>CO>[CH2:1]([O:8][C:9]([C@@H:10]([NH:11][CH2:17][CH2:16][CH2:22][S:19]([OH:21])(=[O:20])=[O:18])[CH:12]([CH3:13])[CH3:14])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: CO
Product: CC(C)[C@H](NCCCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of L-valine benzylester in MeOH (12 mL) was slowly added 1,3-propanesultone (604 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with cold MeOH and acetone (2×25 mL). It was dried in the vacuum oven (50° C.), affording the title compound (649 mg, 39%). 1H NMR (D2O, 500 MHz) δ ppm 7.47 (m, 5H), 5.41 (d, 1H, J=11.7 Hz), 5.31 (d, 3H, J=11.7 Hz), 4.04 (m, 1H), 3.19 (m, 2H), 2.95 (t, 2H, J=6.8 Hz), 2.35 (m, 1H), 2.14 (m, 2H), 1.04 (d, 3H, J=6.3 Hz), 0.95 (d, 3H, J=6.3 Hz). 13C (D2O, 125 MHz) δ ppm 168.75, 134.81, 129.38, 129.31, 129.17, 69.00, 65.96, 48.24, 46.71, 29.67, 21.40, 18.39, 16.65. [α]D=−7.2° (c=0.0015 in water), ES-MS 330 (M+1).