Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CC#N>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: COC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CN[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
Prepared using General Procedure 9. To a suspension of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (150 mg, 0.36 mmol) in CH3CN (5 mL) was added K2CO3 (150.9 mg, 1.09 mmol) and methyl 2-bromoacetate (67 mg, 0.43 mmol). The suspension was stirred at 80° C. After 6 h more methyl 2-bromoacetate (6.7 mg, 0.043 mmol) was added and heating continued for 12 h. The reaction mixture was filtered and concentrated. The residue was re-suspended in EA (15 mL), washed with water and brine, dried and concentrated. The product was purified by a silica gel column chromatography (MeOH/DCM) to afford 146 mg (90%) of (S)-methyl 2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate as white solid. LCMS-ESI (m/z) calculated for C24H24N4O3S: 448.2; found 449.1 [M+H]+, tR=2.48 min.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.[CH2:18]([O:25][C:26](=[O:41])[C@@H:27]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:29][C:30](O)=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:37]([O:36][C:34]([NH:33][C@@H:27]([CH2:28][CH2:29][C:30]([S:17][C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1)=[O:31])[C:26]([O:25][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:41])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: Fc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)Sc1ccc(F)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
N,N′-Diisopropylcarbodiimide (0.510 ml, 3.26 mmol), N,N-dimethylaminopyridine (45.2 mg, 0.370 mmol), 4-fluorobenzenethiol (0.164 ml, 1.55 mmol) were added to a solution of (S)-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid (Compound 5a-2) (500 mg, 1.48 mmol) in dichloromethane (5 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was then purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→20/80) to afford (S)-benzyl 2-((tert-butoxycarbonyl)amino)-5-((4-fluorophenyl)thio)-5-oxopentanoate (Compound 5e-2) (540 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[C:69]([O:71][CH2:72][CH3:73])=[O:70]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[C:69]([O:71][CH2:72][CH3:73])=[O:70])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)C1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and ethyl piperidine-2-carboxylate in DMSO at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CN(C=O)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH2:1])(=[O:19])=[O:18]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)n1c(N)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 28.7 %

Procedure:
2-amino-benzimidazole (1.0 g, 7.5 mmol) was dissolved in 15 mL of anhydrous CH2Cl2 and 3 mL anhydrous DMF and cooled to ˜0° C. Trethylamine(1.6 mL, 1.5 eq.) was added followed by an addition of methanesulfonylchloride (580 μL, 7.5 mmol) over 1 minute. After 1 minute at ˜0° C., the reaction was warmed to RT. After 1 hour the reaction was quenched with water, and partitioned between a saturated sodium bicarbonate solution and CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with water (2 times), brine then dried over NaSO4, filtered and the solvent was removed in vacuo to give 455 mg of N-methanesulfonyl-2-aminobenzimidazole. HPLC shows the material to be 91% pure, (ret. time=3.70). LCMS: obs. M+H@212.1 amu. The material was carried on without purification.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([C:19]3[S:20][C:21]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:14]([CH3:32])[CH2:13]2)[CH:6]=1.[OH-].[Na+].Cl>CO>[CH3:18][CH:16]1[N:15]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH:14]([CH3:32])[CH2:13][N:12]([CH2:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH2:17]1
Reactant: COC(=O)Cc1cccc(CN2CC(C)N(c3nc4ccc(C(F)(F)F)cc4s3)C(C)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CN(Cc2cccc(CC(=O)O)c2)CC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A mixture of [3-[3,5-dimethyl-4-(6-trifluoromethyl benzothiazole-2-yl)piperazine-1-ylmethyl]phenyl]acetic acid methyl ester (171 mg), 2N sodium hydroxide (1 mL) and methanol (2 mL) was stirred at room temperature for 1 hour. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (82 mg). Yield: 52%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][CH2:19][CH2:20][CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Cl-].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Si:11]([O:18][CH2:19][CH2:20][CH:21]=[O:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC=O

Procedure:
To a solution of anhydrous dimethylsulfoxide (0.05 mole) in anhydrous methylene chloride (100 ml) cooled to 0° C. under nitrogen with stirring is added a solution of oxalyl chloride (0.05 mole) in anhydrous methylene chloride (100 ml). After stirring for 15 minutes, a solution of 1-tert-Butyldimethylsilyloxy-3-hydroxypropane (0.04 mole) inmethylene chloride (150 ml) is added over a period of 30 minutes. Then the reaction is quenched by adding triethyl amine (1 mole) slowly. The reaction mixture is diluted with ethyl acetate (200 ml), washed with water (75 ml), brine (75 ml), dried and concentrated. The product is used as such in the subsequent condensation step.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[CH3:28]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[C:20]([CH3:28])[CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1cc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)ccc1F

Procedure:
The title compound, off-white solid (73 mg, 85%), MS (ISP) m/z=343.5 [(M+H)+], mp 235.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
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]=1[CH:11]=[CH:12][C:13]([NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[O:14].C1COCC1>CO.Cl[Ni]Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)=[O:14]
Reactant: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc3ccccc3c2)cc1
Agent: Cl[Ni]Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)CCc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Ref. J. of Org. Chem., 2000, 65, 8001. To a stirred solution of amide 42 (0.086 g, 0.249 mmol) and NiCl2 6H2O (0.118 g, 0.498 mmol, 2 eq) in methanol (8 ml) and THF (4 ml) NaBH4 (0.028 g, 0.749 mmol, 4 eq) was added portionwise over 20 min at 0° C. After stirring for 1 h at room temperature, the solvent was distilled off under reduced pressure. Water (10 ml) and ethyl acetate (10 ml) was added. The resulting mixture was filtered through a celite bed which was washed with ethyl acetate (20 ml). After collecting the filtrate, the organic phase was separated, dried over Na2SO4 and the solvent was distilled off under reduced pressure to give the pure product 69 as a white solid (0.066 g, 0.190 mmol, 79%), mp 119-121° C. 1H NMR (400 MHz, CDCl3) δ 1.38 (3H, t, J 7.2 Hz, CH2CH3) 2.75 (2H, t, J 7.2 Hz, CH2CO), 3.23 (2H, t, J 7.2 Hz, CH2—Ar), 4.35 (2H, q, J 7.2 Hz, CH2CH3), 7.12 (1H, bs, N—H), 7.37 (1H, dd, J 1.6, 8.4 Hz, CH, Ar), 7.42-7.50 (4H, m, 4×CH, Ar), 7.69 (1H, bs, CH, Ar), 7.76-7.82 (3H, m, 3×CH, Ar), 7.97 (2H, d, J 9.2 Hz, 2×CH, Ar). MS (API-ES): m/z 348 [M+H]+ (100%), HRMS (API-ES) m/z found 348.1602 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O.C(OC(=O)C)(=O)C>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1
Reactant: O=C(O)CC(CSc1nc2ccccc2s1)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(CSc2nc3ccccc3s2)C(=O)O1
Temperature: 0 °C

Procedure:
A suspension of 20 parts 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylic acid and 200 parts acetic anhydride is heated at 55° during 1.5 hours. The resulting yellow solution is cooled, poured onto 1000 parts ice-water, stirred until solid to give 3-(benzothiazol-2-ylthio)propane-1,2-dicarboxylic anhydride m.p. 87°-88°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[N:32]1([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:35]4[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)[CH2:33][CH2:34]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1ccc(CCN2CCNCC2)nc1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(CCc2ccccn2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-piperazinyl-2-(2-pyridinyl)ethane as in General Procedure 10 to give the title compound. LCMS: m/z=620.99 (M+H+); retention time=0.55 minutes.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[CH2:54]([C@H:61]([NH-:64])[CH2:62][OH:63])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:54]([C@H:61]([NH-:64])[CH2:62][OH:63])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-][C@H](CO)Cc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 110 mg of Z-Phe-His-OH, 84 mg of H-Leu-Val-Ala-1(S)-benzyl-2-hydroxyethyl amide, 38 mg of HOBt and 60 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.27.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:19][C:20]4[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:14][CH:13]=2)[CH:8]=1)=O.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:19][C:20]4[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:14][CH:13]=2)[CH:8]=1
Reactant: NC(=O)c1cccc2nc(-c3ccc(-n4ccc(CNC(=O)C(F)(F)F)c4)cc3)[nH]c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccn(-c2ccc(-c3nc4cccc(C(N)=O)c4[nH]3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.7 g (4 mmol) of the compound from Example 24 were dissolved in 70 ml of tetrahydrofuran and admixed with a solution of 0.38 g (15.9 mmol) of lithium hydroxide in 25 ml of water. The entire mixture was stirred at room temperature for 2 hours. The reaction mixture was then neutralized using dilute hydrochloric acid and the organic solvent was removed under reduced pressure. The resulting precipitate was filtered off with suction and dried. This gives 0.87 g of the product.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:15][C@H:9]12)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:19]([O:18][C:16]([N:14]1[CH2:13][C@@H:10]2[C@@H:9]([NH:8][CH2:12][CH2:11]2)[CH2:15]1)=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@H]2CCN[C@H]2C1

Procedure:
The product of Example 1A ((3aR,6aR)-hexahydro-pyrrolo[3,4-b]pyrrole-1,5-dicarboxylic acid 5-benzyl ester 1-tert-butyl ester) (4.5 g, 12.5 mmole), was stirred with a mixture of dichloromethane and trifluoroacetic acid (15 ml/15 ml) for 2 hours. The solvent was removed under reduced pressure, and the residue was basified with saturated sodium bicarbonate, then extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0.6% ammonium hydroxide and 6% methanol in dichloromethane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.28-7.40 (m, 5H) 5.12 (s, 2H) 3.74-3.87 (m, 1H) 3.53-3.71 (m, 2H) 3.36-3.48 (m, 1H) 3.18-3.32 (m, 1H) 3.01-3.13 (m, 1H) 2.88-3.01 (m, 1H) 2.70-2.83 (m, 1H) 1.87-2.03 (m, 1H) 1.58-1.76 (m, 1H). MS: (M+H)+=247.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH:18]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)=[CH:4][CH:3]=1.Br.C([O-])([O-])=O.[K+].[K+].[CH3:34][O:35][CH2:36][CH2:37]Cl>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH:36]([O:35][CH3:34])[CH3:37])[CH2:20][CH2:19]3)[N:8]=2)=[CH:25][CH:26]=1
Reactant: COCCCl
Reactant: O=c1c2ccccc2c(Cc2ccc(Cl)cc2)nn1C1CCCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(C)N1CCCC(n2nc(Cc3ccc(Cl)cc3)c3ccccc3c2=O)CC1
Temperature: 25 °C

Procedure:
6 grams (0.013 mole) of 4-(4-chlorobenzyl)-2-(hexahydroazepin-4-yl)-1-(2H)-phthalazinone× HBr were stirred together with 3.6 grams (0.026 mole) of K2CO3, 7.4 grams (0.078 mole=7.1 ml) of 2-chloroethyl methyl ether and 30 ml of dimethylacetamide for 21/2 hours at an oil bath temperature of 120° C. Subsequently the mixture was cooled to room temperature and filtered off with suction from the insolubles. The solution was concentrated in a vacuum and the brownish oil obtained chromatographed by means of a silica gel column (elution agent: CH2Cl2 /CH3OH=90:10). The desired fractions were combined and the solvent distilled off on the rotary evaporator. The oily residue was made acid with isopropanol/HCl. The hydrochloride was precipitated as a viscous mass by addition of ether. After decanting off the supernatant solution the residue was triburated with methyl ethyl ketone at boiling heat, whereby the desired hydrochloride was obtained as a crystalline product. M.P. 194°-197° C. Yield: 1.8 grams (28%).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)(=[NH:3])[CH3:2].C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>ClCCl>[CH3:42][O:41][C:40]([CH2:2][C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)=[NH:3])=[O:43]
Reactant: CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine (300 mg) and triethylamine (199 mg) in dichloromethane (30 ml) was added methyl chlorocarbonate (192 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (171 mg).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15](O)([CH3:17])[CH3:16])=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1>[N+](C)([O-])=O>[Br:5][C:6]1[CH:7]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]2[O:12][CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:10]=2[CH:11]=1
Reactant: CC(C)(O)CCOc1ccc(Br)cc1C(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)c1cc(Br)cc2c1OCCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a cold (0° C.) suspension of AlCl3 (1.67 g, 12.51 mmol, 1 equiv) in nitromethane (20 mL) is added a solution of 4-bromo-2-tert-butyl-1-(3-hydroxy-3-methylbutoxy)benzene (3.94 g, 12.51 mmol) in nitromethane (5 mL). The resulting red solution is stirred at 0° C. After 1 h, the reaction mixture is quenched by slow addition of water, diluted with hexanes, and washed with water and brine. The aqueous layers are extracted with hexanes; the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified by flash column chromatography on silica (hexanes) to give the title compound (2.87 g, 77%) as a solid which is recrystallized using hexanes to give white crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:13])[C:9]=1[CH2:10][C:11]#[N:12].Br[CH2:15][CH2:16]Br>C1COCC1>[F:13][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([F:3])[C:9]=1[C:10]1([C:11]#[N:12])[CH2:16][CH2:15]1
Reactant: N#CCc1c(F)cncc1F
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2c(F)cncc2F)CC1
Yield: 174.1 %

Procedure:
Sodium hydride 60% in mineral oil (3.35 g, 83.7 mmol) was suspended in 10 ml THF. At −10° C. a solution of 2-(3,5-difluoro-4-pyridyl)acetonitrile (4.30 g, 27.9 mmol) in 45 ml THF was added drop wise. The reaction mixture was stirred until no more gas evolution was visible. The reaction mixture was then a yellow suspension. At 0° C. 1,2-dibromoethane (9.71 mL, 112 mmol) was added drop wise. The reaction mixture was stirred 2 h at 0° C. then over night at rt. It was quenched with aq. NH4Cl, diluted with EtOAc. The organic layer was separated and dried with Na2SO4. Filtrated, the filtrate was evaporated. The residue gave a brown oil (8.75 g). The crude product was purified by flash chromatography (Solvent: Cyclohexane/EtOAc 1/1). The desired product was isolated as a colorless oil which crystallised upon standing (3.816 g).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:25]1([C:23]([C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)([OH:24])[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][CH2:1][OH:10])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=CC=Cc1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Product: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCc2ccccc2)cc1

Procedure:
The (RR,SS; RS,SR)-isomer mixture is prepared from 13.2 g of cinnamaldehyde and 28.8 g of 4-benzyloxybenzophenone according to the precedure described in Example 9. Recrystallization is performed from toluene. The yield is 32.5 g (77%) of a product having m.p. 109°-15° C. The product contains both isomer pairs (RR,SS: RS,SR 1:1).