Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:8]1[C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:18]=[CH:19][CH3:20]
Reactant: C=CC(C)O
Reactant: CCC1(CC)CC(=O)c2cc(OC)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1C(=O)c2cc(OC)ccc2C1(CC)CC
Yield: 15 %

Procedure:
A solution of 22.0 g of 6-methoxy-3,3-diethyl-1-indanone, 20.8 ml of 3-buten-2-ol and 220 mg of p-toluenesulfonic acid in 220 ml of 2,2-dimethoxypropane was boiled under reflux for 87 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 6:1). In addition to 15.7 g of educt, there were obtained 4.1 g (15%) of (RS)-2-(2-buten-1-yl)-6-methoxy-3,3-diethyl-1-indanone as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[CH:14]1([O:19][C:20]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:21]=2[CH:22]=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:22]/[C:21]1[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH3:29])[C:20]=1[O:19][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1nc2ccccn2c(=O)c1Br
Reactant: COc1cccc(C=O)c1OC1CCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3ccccn3c(=O)c2Br)c1OC1CCCC1

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (700 mg, 2.921 mmol) and 2-(cyclopentyloxy)-3-methoxybenzaldehyde (998 mg, 4.391 mmol) in the presence of sodium ethoxide (398 mg, 5.842 mmol) in absolute ethanol (30 ml) as described in Intermediate 1 to give 358 mg of the product as a light yellow solid; IR (KBr) 2958, 1679, 1620, 1528, 1436, 1264, 1065, 971 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.60-1.75 (m, 4H), 1.95-2.10 (m, 4H), 3.87 (s, 3H), 4.94 (br s, 1H), 6.90 (d, J=7.8 Hz, 1H), 7.02-7.10 (m, 1H), 7.35 (d, J=7.5 Hz, 2H), 7.56-7.72 (m, 3H), 8.44 (d, J=16.2 Hz, 1H), 8.94 (d, J=7.2 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=3)[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccc(F)cc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
125 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 23 mg (0.17 mmol, 1.1 eq.) of 4-fluorobenzoic acid were reacted according to General Method 1. Yield: 53 mg (83% of theory)
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:1]([N:5]([CH3:6])[S:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][Cl:7])(=[O:15])=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)CCCCCCl
Reactant: CCCCNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(C)S(=O)(=O)CCCCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.47 ml of N-butylmethylamine were added under an inert gas atmosphere to a solution of 410 mg of 5-chloropentane sulfonyl chloride in 10 ml of methylene chloride. The temperature rose from 13° C. to 26° C., and then after cooling to 0° to 5° C., 0.55 ml of triethylamine were added. The mixture was stirred at ambient temperature for 2 hours and the reaction medium was poured into an aqueous solution of 1M hydrochloric acid, extracted with methylene chloride, washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 486 mg of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1.[H-].[Na+].[CH3:19]OS(OC)(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:19])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: COS(=O)(=O)OC
Reactant: Brc1ccccc1-c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2Br)nc2ccccc21
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
To a flask were added 3.3 g 2-(2-bromophenyl)-1H-benzimidazole and 100 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 0.63 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 2.0 g Dimethylsulfate were added and the mixture was heated to 22 C for 30 minutes. The mixture was quenched slowly with 100 ml water, extracted with ethyl acetate and then extracted into a 1M hydrochloric acid solution. The solution was washed with ethyl acetate and then basified with 3M sodium hydroxide. Following extraction with ethyl acetate and solvent removal, the solid was dissolved in a hot mixture of 20 ml hexane with 4 ml 2-propanol. After cooling to 5 C, the product was filtered, washed with hexane and dried giving 2.9 g of a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[C:27]1([C:33]2[CH:34]=[C:35]([C:39]([C:41]3[N:42]=[CH:43][N:44]4[CH:48]=[C:47]([Sn](CCCC)(CCCC)CCCC)[S:46][C:45]=34)=[O:40])[CH:36]=[N:37][CH:38]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:47]3[S:46][C:45]4=[C:41]([C:39]([C:35]5[CH:36]=[N:37][CH:38]=[C:33]([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:34]=5)=[O:40])[N:42]=[CH:43][N:44]4[CH:48]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncc(-c4ccccc4)c3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(-c6ccccc6)c5)c4s3)[C@H](C)[C@H]12
Yield: 14.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-phenylpyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (47 mg) was prepared in substantially the same manner as in step a) of Example 1, except that 270 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 293 mg of 7-(5-phenylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=1.O[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].OC1C=C(C=CC=1)C(C1C=CC=CC=1)=O>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][O:14][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]
Reactant: O=Cc1cccc(O)c1
Reactant: OCc1cccc(CC2OCCO2)c1
Agent: O=C(c1ccccc1)c1cccc(O)c1
Product: O=Cc1cccc(OCc2cccc(CC3OCCO3)c2)c1

Procedure:
The title compound was prepared as described in Example 22 with (3-((1,3-dioxolan-2-yl)methyl)phenyl)methanol and 3-hydroxybenzaldehyde replacing (4-((1,3-dioxolan-2-yl)methyl)phenyl)methanol and 3-hydroxybenzophenone, respectively, in Step 2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][N:14]=2)[CH:3]=1.[N:25]1([CH2:31][CH2:32][OH:33])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CCCCO>[OH:33][CH2:32][CH2:31][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[S:11][C:12]([S:15][C:16]4[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=4)=[CH:13][N:14]=3)[CH:3]=2)[CH2:27][CH2:26]1
Reactant: Cc1nc(Cl)cc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)n1
Reactant: OCCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)cc(N2CCN(CCO)CC2)n1
Temperature: 115 °C
Yield: 69 %

Procedure:
To a stirring solution of 4-(2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazol-5-ylthio)picolinic acid (104 mg, 0.274 mmol) and 2-(piperazin-1-yl)ethanol (195 mg, 1.50 mmol) in n-BuOH (2 mL) was added i-Pr2NEt (0.20 mL, 1.15 mmol). The reaction was then heated to 115° C. in a sealed reaction vessel overnight. The reaction was cooled to room temperature and the solid collected by filtration, the filter cake was washed with n-BuOH then air dried to give the title material (89.5 mg, 69%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.59 (1H, s), 8.27 (1H, d, J=5.05 Hz), 7.71 (1H, s), 7.53 (1H, d, J=2.02 Hz), 7.07 (1H, dd, J=5.05, 2.02 Hz), 6.03 (1H, s), 4.45 (1H, t, J=4.67 Hz), 3.49 (6H, s), 2.41 (2H, t, J=6.32 Hz), 2.33 (3H, s). LC/MS (M+H)+: 474. HPLC ret. time (Condition I): 1.097 min.
Reaction SMILES: [I:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17](O)[CH3:18].[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][C:26]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH:17]([C:3]2[S:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[CH:6][C:2]=2[I:1])[CH3:18])=[CH:27][C:26]=1[CH3:32]
Reactant: COC(=O)CCc1ccc(S)cc1C
Reactant: CC(O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1I
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(SC(C)c2sc(-c3ccc(C(F)(F)F)cc3)cc2I)cc1C
Reaction time: 8 h

Procedure:
To a solution of 1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol (1.52 g, 3.96 mmole) and 3-(4-Mercapto-2-methyl-phenyl)-propionic acid methyl ester (0.769 g, 3.96 mmole) in toluene (20 mL) at room temperature, is added tributylphosphine (1.98 mL, 7.92 mmole) followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (1.99 g, 7.92 mmole) in toluene (20 mL). The reaction is stirred overnight, and then diluted with hexane (100 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[C:23]([S:34](Cl)(=[O:36])=[O:35])[CH:22]=1>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[C:23]([S:34]([N:18]2[CH2:17][CH2:16][N:15]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:8][CH2:9]3)=[O:14])[CH2:20][CH2:19]2)(=[O:35])=[O:36])[CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)oc1ccccc12
Reactant: O=C(C1CCN(c2ccncc2)CC1)N1CCNCC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3c(c2)oc2ccccc23)CC1
Yield: 75 %

Procedure:
Using an analogous procedure to that described in Example 2, 1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reacted with dibenzofuran-3-sulphonyl chloride to give 1-(dibenzofuran-3-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine as a glassy solid in 75% yield;
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[NH:37][CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1.[C:48]([O:52][C:53]([N:55]1[CH2:58][CH2:57][C@H:56]1[C:59](O)=[O:60])=[O:54])([CH3:51])([CH3:50])[CH3:49].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[N:37]([C:59]([C@@H:56]4[CH2:57][CH2:58][N:55]4[C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])=[O:60])[CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
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: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)N1CCC2CN(Cc3ccc(F)cc3)CCN2c2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (177 mg, 0.465 mmol) was added to a mixture of the product of Example 64C (97 mg, 0.31 mmol) and (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (94 mg, 0.465 mmol, prepared as described in J. Med. Chem. 2005, 48, 7637-7647) in CH2Cl2 (2.0 mL). Diisopropylethylamine (0.108 mL, 0.620 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was applied directly to a column of silica gel and eluted with 5% methanol-CH2Cl2 to provide the title compound: MS (DCI) m/z 496 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH:30]1[CH2:32][CH2:31]1)([CH3:29])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[CH:30]1([C:20]([NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([CH3:29])[CH2:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:32][CH2:31]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)CC(C)(N)C1CC1
Product: CC(C)(C)OC(=O)CC(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and tert-butyl 3-amino-3-cyclopropyl-butanoate (example 229b) as starting materials and isolated (890 mg, 88%); MS (ESI, m/z): 443.6 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]#[C:13][CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[CH:11][C:6]=2[C:5](=[O:22])[CH2:4][S:3]1(=[O:24])=[O:23].C(N(CC)CC)C.[Cl:32][C:33]1[CH:42]=[CH:41][C:36]([CH2:37][N:38]=[C:39]=[O:40])=[CH:35][CH:34]=1.Cl>CS(C)=O>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][NH:38][C:39]([C:4]2[S:3](=[O:23])(=[O:24])[N:2]([CH3:1])[C:7]3[CH:8]=[CH:9][C:10]([C:12]#[C:13][CH2:14][O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)=[CH:11][C:6]=3[C:5]=2[OH:22])=[O:40])=[CH:41][CH:42]=1
Reactant: O=C=NCc1ccc(Cl)cc1
Reactant: CN1c2ccc(C#CCOC3CCCCO3)cc2C(=O)CS1(=O)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1c2ccc(C#CCOC3CCCCO3)cc2C(O)=C(C(=O)NCc2ccc(Cl)cc2)S1(=O)=O
Reaction time: 4 h
Yield: 28.4 %

Procedure:
To a solution of 1-methyl-6-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl)-1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide (Preparation 52, 1.00 g) and triethylamine (0.60 mL) in DMSO (25 mL) is added a solution of 4-chlorobenzylisocyanate (0.72 g) in DMSO (5 mL) at ambient temperature. After 4 h, 10% HCl (100 mL) is added to the reaction vessel and the aqueous layer is extracted with EtOAc (3×100 mL). The organic layers are combined, dried over MgSO4, filtered, and concentrated in vacuo to afford 0.42 g (28%) of the title compound as a lime green solid. Physical characteristics: m.p. 148-149° C.; 1H NMR (300 MHz, CDCl3) δ15.81, 8.22, 7.93, 7.71, 7.33, 7.16, 4.91, 4.60, 4.52, 3.91, 3.60, 3.48, 1.86, 1.62; IR (diffuse reflectance) 3373, 2940, 1616, 1574, 1543, 1493, 1390, 1327, 1297, 1279, 1253, 1116, 1097, 1077, 1037 cm−1; MS (FAB) m/z 517 (MH+); HRMS (EI) m/z 516.1140 (C25H25ClN2O6S). Anal. Found: C, 57.55; H, 4.95; N, 5.63.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[C@@H:15]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:32][C:24]1[CH:23]=[C:22]([C@@H:15]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:14]([NH:13][C:10]2[CH:11]=[CH:12][NH:8][N:9]=2)=[O:33])[CH:27]=[CH:26][C:25]=1[S:28]([CH3:31])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cc[nH]n2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
3-[2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazole-1-carboxylic acid tert-butyl ester (1.72 g, 3.47 mmol) was dissolved in methylene chloride (12 mL) and trifluoroacetic acid (4 mL) was added. The solution was stirred at 25° C. for 4 h. The mixture was concentrated in vacuo and the resulting oil was dissolved in ethyl acetate (25 mL), washed with saturated aqueous sodium bicarbonate solution (2×15 mL), saturated aqueous brine solution (2×15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to produce a yellow oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-pyrazol-3-yl)-propionamide as a white foam (802 mg, 58%) ESI-LRMS m/e calcd for C18H22ClN3O3S [M+] 395.1, found 396.0 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.00-1.19 (m, 2H, CH2), 1.34-1.91 (m, 8H, 4×CH2), 2.08-2.29 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.65 (t, J=7.6 Hz, 1 H, CH), 6.54 (d, 1H, J=1.7, Ar), 7.39 (m, 2H, Ar), 7.54 (d, Jm=1.3 Hz, 1H, Ar), 7.94 (d, Jo=8.2 Hz, 1H, Ar), 9.26 (s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH:21]([CH3:23])[CH3:22].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(N(CC(C)C)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1 g, 3.04 mmol) and isobutyraldehyde (1.09 g, 15.24 mmol) in methanol (15 mL), acetic acid (0.456 g, 7.6 mmol) was added. The reaction mixture was stirred at room temperature for 8 h. Sodium cyanoborohydride (0.522 g, 7.56 mmol) was then added at 0° C. and the reaction mixture stirred overnight at room temperature. The solvent was then removed under reduced pressure and crude product purified by column chromatography to afford methyl 5-bromo-3-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (0.52 g, 54.33%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=[C:14]([Br:24])[CH:13]=1)=[O:11].C(Cl)Cl.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1>[Br:24][C:14]1[CH:13]=[C:12]([C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:29](=[O:30])[O:31][CH3:32])=[O:11])[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=1
Reactant: Cc1cccc(N)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cccc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 0 °C
Yield: 31.6 %

Procedure:
N-(2-amino-6-methylphenyl)-3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide prepared in Step 2 (1.18 g, 2.91 mmol), CH2Cl2 (2 M, 1.46 mL) and pyridine (1 M, 2.91 mL) were introduced to a 50 mL round flask. The mixture thus obtained was cooled down to 0° C., added with methyl chloroformate (2.25 mL, 29.1 mmol, 10.0 eq), and refluxed at 80° C. for 15 hours. Upon completion of the reaction, the solvent was removed under reduced pressure. The residue was extracted with 1 M HCl (20 mL) and ethyl acetate (20 mL x 2), washed with brine (20 mL). The organic layer thus obtained was dried over MgSO4 and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EA:Hex=2:3→EA:Hex=1:1) to obtain the title compound (426.7 mg, yield: 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:5]#[N:6].CCN(CC)CC.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>CN(C=O)C>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:10]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11]2)=[C:2]([NH:1][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:3]=1)#[N:6]
Reactant: CCCC(=O)Cl
Reactant: N#Cc1ccc(C2CCc3cncn32)c(N)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(C#N)ccc1C1CCc2cncn21

Procedure:
A DMF (3 mL) solution of 3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (0.095 g, 0.42 mmol), given as example 6B, is treated with Et3N (0.09 mL, 0.64 mmol) and butyryl chloride (0.05 mL, 0.51 mmol) at room temperature. After 1 h the solution is concentrated. Purification via prep HPLC gives N-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-phenyl]-butyramide. MS (ESI) m/z 295.1 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (t, J=7.3 Hz, 3 H), 1.67-1.80 (m, 2 H), 2.35 (t, J=7.5 Hz, 2 H), 2.49-2.61 (m, 1 H), 2.88-3.01 (m, 2 H), 3.05-3.18 (m, 1 H), 5.56 (dd, J=8.0, 5.9 Hz, 1 H), 6.84 (s, 1 H), 6.97 (d, J=8.1 Hz, 1 H), 7.40 (s, 1 H), 7.45 (dd, J=8.1, 1.5 Hz, 1 H), 7.70 (br s, 1 H), 7.91 (s, 1 H).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:11][C@@H:12]1[CH2:20][C@@H:15]2[O:16][C:17](=[O:19])[CH2:18][C@@H:14]2[C@H:13]1[CH:21]=[O:22])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:3]([O:11][C@@H:12]1[CH2:20][C@@H:15]2[O:16][C:17](=[O:19])[CH2:18][C@@H:14]2[C@@H:13]1[CH2:21][OH:22])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@H](CO)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Reaction time: 0.42 h
Yield: 68.7 %

Procedure:
To a suspension of sodium borohydride (650 mg, 17.1 mmol) in methanol (20 mL) at 0° C. (bath temperature) was added a solution of (3aR,4R,5R,6aS)-5-(benzoyloxy)hexahydro-2H-cyclopenta[b]furan-2-one-4-carboxaldehyde (1) (3.5 g, 12.8 mmol) as a solution in 1:1 methanol:methylene chloride (40 mL). After 25 min, saturated citric acid was added cautiously (60 mL), the mixture was extracted with ethyl acetate (3×40 mL), the combined organic layers were washed with water (2×80 mL) and saturated brine (2×80 mL), dried (magnesium sulfate), filtered, and concentrated to afford 2 (2.43 g, 69%).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:10]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:18]([CH:17]([O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8])[CH2:16][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)CCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCC(Oc1ccccc1C)C(=O)OCC
Temperature: 70 °C

Procedure:
A mixture of o-cresol (0.1 mol) and diethyl 2-bromoglutarate (0.1 mol) and K2CO3 (0.11 mol) in 50 mL of DMF are heated at 70° C. overnight. The reaction is poured into water and extracted with ethyl acetate. The organic solution is washed with water, 0.1N NaOH solution, dried and evaporated to give ethyl 4-carbethoxy-4-(2-methylphenoxy)butyrate which is used directly in the next step.