Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:21]OC(OC)OC>C(O)(=O)C>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][CH:21]=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Reactant: COC(OC)OC
Solvent: CC(=O)O
Product: c1ccc(C(c2ccc3[nH]cnc3c2)n2ccnc2)cc1
Yield: 65 %

Procedure:
A mixture of 2.64 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine, 50 parts of trimethoxymethane and 1.2 parts of acetic acid was stirred and refluxed for 8 hours. The reaction mixture was evaporated in vacuo. The residue was dissolved in dilute hydrochloric acid. The solution was treated with ammonia and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The solid residue was washed with 2-propanone, yielding 1.8 parts (65%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzimidazole; mp. 186.2° C. (compound 111).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:23]=[CH:22][C:9]2[S:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[CH3:21])=[CH:12][C:8]=2[CH:7]=1)=[O:5])C.COC(C1C2SC=CC=2C=CC=1)=O>>[CH3:1][O:3][C:4]([C:6]1[C:7]2[S:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[CH3:21])=[CH:12][C:8]=2[CH:9]=[CH:22][CH:23]=1)=[O:5]
Reactant: CCOC(=O)c1ccc2sc(-c3ccc(OC)cc3C)cc2c1
Agent: COC(=O)c1cccc2ccsc12
Product: COC(=O)c1cccc2cc(-c3ccc(OC)cc3C)sc12
Yield: 12 %

Procedure:
The title compound (130 mg, 12%) is prepared essentially as described in the synthesis of 2-(4-methoxy-2-methyl-phenyl)-benzo[b]thiophene-5-carboxylic acid ethyl ester, utilizing benzo[b]thiophene-7-carboxylic acid methyl ester. 1H NMR (CDCl3): δ 8.08 (dd, 1H, J=7.55 Hz, 1.1 Hz), 7.97 (dd, 1H, J=7.8 Hz, 1.1 Hz), 7.48-7.42 (m, 2H), 6.87-6.79 (m, 2H), 4.03 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH2:6][C@@H:5]1[CH2:22][CH2:23][CH2:24][CH3:25].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[CH:45]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:31]([O:30][C:28]([NH:27][CH2:26][CH:2]([NH:1][CH2:45][C:36]1[CH:37]=[CH:38][C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH2:6][C@@H:5]1[CH2:22][CH2:23][CH2:24][CH3:25])=[O:29])([CH3:33])([CH3:32])[CH3:34]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1CC(N)CNC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1CC(CNC(=O)OC(C)(C)C)NCc1ccc2ccccc2c1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step D except using 1-[(2-amino-3-tert-butoxycarbonylaminoprop-1-yl]-2(S)-butyl-4-(1-naphthoyl)piperazine (0.287 g, 0.613 mmol), naphthalene-2-carboxaldehyde (0.95 g, 0.613 mmol), sodium triacetoxyborohydride (0.194 g, 0.919 mmol), in dichloroethane (15 mL) at pH 6. The crude product was chromatographed on silica gel with 5% methanol in chloroform (Rf 0.30), and the title compound isolated as a foam. FAB ms (m+1) 609.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1.[H-].[Na+].I[CH3:27]>CN(C)C=O>[NH2:1][C:2]1[N:7]([CH3:27])[C:6](=[O:8])[C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1
Reactant: CI
Reactant: COc1ccc(-c2c(-c3cccc(F)c3)nc(N)[nH]c2=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3cccc(F)c3)nc(N)n(C)c2=O)cn1
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of 2-amino-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3,4-dihydro-4-pyrimidinone (1.0 g, 3.2 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (77 mg, 3.2 mmol). After stirring for 10 minutes, iodomethane (454 mg, 0.2 mL, 3.2 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After removing the solvent from the reaction mixture, the residue was washed with water, to give the title compound (600 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12](O)=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:17])=O.CN(C)C1C=CC=CC=1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([Cl:17])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(O)n(-c2ccc(Cl)nn2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Cl)n(-c2ccc(Cl)nn2)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To the mixture of 12.6 /0.04 moles/ of 3-chloro-6-(3-methyl-5-hydroxy-1-pyrazolyl)-pyridazine and 48 ml of phosphorus oxychloride, 7.28 g /0.04 moles/ of dimethyl aniline are dropped under stirring at 0° C. during half an hour, then the reaction mixture is stirred at room temperature for one hour and at boiling temperature for 2 hours. Excess of the phosphorus oxychloride is evaporated under reduced pressure, then the residue is poured into water and set aside overnight. The separated precipitate is filtered, washed with water and dried. Yield: 10.5 g (93%); m.p.: 123°-126° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>CN(C=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:39][CH:36]4[CH2:38][CH2:37]4)[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: N#Cc1c(NC2CC2)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At RT, 50 mg (0.09 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.013 ml (0.19 mmol) of cyclopropanamine were stirred in 1.3 ml of DMF overnight. The crude product was purified directly by preparative HPLC (acetonitrile/water). The collected product fractions were once more dissolved in 2 ml of DMF, 0.013 ml (0.19 mmol) of cyclopropanamine was added and the mixture was stirred at RT overnight. The crude product was then once more purified by preparative HPLC (acetonitrile/water). This gave 20 mg (39% of theory) of the desired target compound.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[C:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>O>[Cl:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:13][CH:14]=1
Reactant: ClCCCBr
Reactant: COC(=O)C(C)=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)=Cc1ccc(OCCCCl)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Methyl 4-hydroxy-α-methylcinnamate (16.3 g), DMF (50 ml) and anhydrous potassium carbonate (11.7 g) were mixed, and stirred at 90° C. for 1 hour. The reaction solution was allowed to cool to 50° C., added 1-bromo-3-chloropropane (8.4 ml) thereto, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water (200 ml), and the mixture was extracted with ether (150 ml), washed with water (150 ml) 2 times, and then, dried over anhydrous magnesium sulfate. The ether layer was concentrated urder reduced pressure to give methyl 4-(3-chloropropoxy)-α-methylcinnamate (20 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1F)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Mg].C([Si]1(C2C=CC=CC=2)CCC(=O)CC1)CCCC.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1F
Agent: CCCCC[Si]1(c2ccccc2)CCC(=O)CC1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A Grignard reagent was prepared from 30.5 g of 4-bromo-2-fluorophenol t-butyldimethylsilyl ether and 2.43 g of magnesium in 100 ml of tetrahydrofuran. 20.0 g of 4-n-pentyl-4-phenyl-4-silacyclohexanone was dropped in the resultant solution at 25° C. The reaction mixture was agitated at 25° C. for 5 hours and poured into an ammonium chloride aqueous solution, followed by extraction with ethyl acetate. The ethyl acetate solution was washed with brine, dried and concentrated. 400 ml of benzene and 800 mg of p-toluenesulfonic acid monohydrate were added to the resultant residue, followed by removal of generated water under reflux. When distilling of water was stopped, the benzene solution was concentrated, followed by purification of the resultant residue to obtain 31.6 g (yield: 88%) of 2-fluoro-4-(4-n-pentyl-4-phenyl)-4-sila-1-cyclohexnyl)phenol t-butyldimethylsilyl ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)=[O:33]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([CH:32]=[O:33])[CH:39]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:31]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cc(-c2cccc(C=O)c2)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 99.9 %

Procedure:
In the same manner as described in Example 241, 505.4 mg (1.0 mmol) of the product of Example 89 and 165 mg (1.1 mmol) of 3-formylbenzeneboronic acid provided 530 mg (100%) of the desired product as a pale yellow crystal. Electrospray Mass Spec 531 (M+H).
Reaction SMILES: [CH2:1]([C:13]1[NH:17][N:16]=[N:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1NN=NN=1)CCCCCCCCC.[CH2:33]([O:35][C:36](=[O:44])[CH:37](Br)[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH3:34].BrC1C=CC=CC=1CC(OCC)=O>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:36]([O:35][CH2:33][CH3:34])=[O:44])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(Br)C(=O)OCC
Reactant: CCCCCCCCCCCCc1nnn[nH]1
Agent: CCCCCCCCCCc1nnn[nH]1
Agent: CCOC(=O)Cc1ccccc1Br
Product: CCCCCCCCCCCCc1nnn(C(CCCCC)C(=O)OCC)n1

Procedure:
When in the general procedure of Example 71 an appropriate amount of 5-dodecyl-1H-tetrazole was substituted for 5-decyl-1H-tetrazole and an appropriate amount of ethyl-2-bromoheptanoate was substituted for ethyl 2-bromophenylacetate, the title compound was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2=[N:8][NH:9][C:10]([CH:11]3[CH2:14][CH:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#N)[CH2:12]3)=[C:5]2[CH:4]([C:23]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=2[F:31])[CH2:3]1.CC(C)=[O:34].C(=O)=O.CC(C[AlH]CC(C)C)C>C(Cl)(Cl)Cl>[O:1]=[C:2]1[NH:7][C:6]2=[N:8][NH:9][C:10]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=[O:34])[CH2:14]3)=[C:5]2[CH:4]([C:23]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=2[F:31])[CH2:3]1
Reactant: N#Cc1cccc(C2CC(c3[nH]nc4c3C(c3cc(F)c(F)cc3F)CC(=O)N4)C2)c1
Reactant: CC(C)=O
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc(C2CC(c3[nH]nc4c3C(c3cc(F)c(F)cc3F)CC(=O)N4)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-{3-[6-oxo-4-(2,4,5-trifluoro-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-cyclobutyl}-benzonitrile (0.16 g, 0.34 mmol) in CHCl3 (5 mL) at −78° C. (acetone/CO2 bath) was added a solution of DIBAL-H (1.8 mL, 1M in CH2Cl2). After 30 min, the reaction was quenched cold with MeOH (1 mL), followed by a saturated aqueous solution of sodium and potassium tartrates. The reaction mixture was allowed to warm to room temperature and stirred for one hr. The reaction mixture was extracted with CHCl3, and the combined organic layers were dried over MgSO4. The organic layer was filtered, and concentrated under reduced pressure. Purification of this material was accomplished by MPLC using a 10 g ISCO column, eluting with 4% MeOH/CHCl3. The product-containing fractions were collected and concentrated to give the title compound. LRMS m/z (APCI+) 426 (M+1)
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:8]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:7]2[C:6]=1[OH:24])=[O:4].[NH2:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27].C[O-].[Na+]>>[Cl:23][C:21]1[CH:22]=[C:7]2[C:6]([OH:24])=[C:5]([C:3]([NH:25][C@@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:8]2[CH:20]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(F)cc2)c1=O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(F)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-(4-fluoro-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 408 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH:10]([CH3:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.[OH-:15].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[OH:15][C:10]([CH3:13])([CH2:11][CH3:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: CCC(C)C(=O)c1ccc(SC)cc1
Reactant: [OH-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)(O)C(=O)c1ccc(SC)cc1

Procedure:
To a mixture of the ketone from Step 1 (10 g, 48 mmol) and Aliquat® 336 (20 mL) in CCl4 (40 mL) and toluene (80 mL) at r.t. was added NaOH pellets (3.8 g, 96 mmol). While stirring vigourously, the mixture was heated briefly to reflux and was then stirred overnight at r.t. After partitioning between CH2Cl2 and H2O, the whole was filtered through celite. The organic layer was dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography (1:10 EtOAc: hexane) to give the title compound as a syrup (5.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C[Al](C)C.C([O:22][C:23]([C:25]1[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=1)=O)C.Cl.N>ClCCl>[CH3:30][N:29]1[C:25]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[CH2:15][N:14]4[C:10]([S:11][CH2:12][CH2:13]4)=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[O:22])=[CH:26][C:27]([CH3:31])=[N:28]1
Reactant: Nc1cccc(C2CN3CCSC3=N2)c1
Reactant: CCOC(=O)c1cc(C)nn1C
Agent: C[Al](C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cccc(C3CN4CCSC4=N3)c2)n(C)n1
Yield: 34.1 %

Procedure:
To 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (2.4 g, 11 mmol) in dry dichloromethane (30 ml) under nitrogen was added trimethylaluminium (4.8 ml; 25% in hexane). After 20 mins at room temperature 1,3-dimethylpyrazole-5-carboxylic acid ethyl ester (1.8 g, 11 mmol) in dry dichloromethane (1 ml) was added and the mixture heated under reflux for 24 hours. Hydrochloric acid (20 ml; 2 N aqueous) was added slowly, the resulting mixture basified with aqueous ammonia solution (5 N; 100 ml) and extracted with chloroform (3×200 ml) which after drying (MgSO4) and concentrating in vacuo afforded an oil. Separation of the oil on alumina eluting with chloroform gave the amide (1.28 g; 34%).
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1.C([N:21](CC)CC)C>ClCCl>[NH2:21][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (5. 26 mL, 68 mmol) was added dropwise over 5 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-hydroxypyrrolidine-1-carboxylate (10.6 g, 56.7 mmol) and triethylamine (11.8 mL, 85 mmol) in dichloromethane (250 mL) at −10° C. After stirring for 1 hour at 0° C., the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (25:75 to 50:50), to give the title compound as an oil.
Reaction SMILES: C(NC1C=CC=CC=1)=O.[K].C(NC1C=CC=CC=1)=O.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])=O.[K+].[N+:31]([C:34]1[CH:39]=[CH:38][C:37](Cl)=[CH:36][CH:35]=1)([O-:33])=[O:32].[C]=O>C1(C)C(C)=CC=CC=1>[CH:24]1[CH:25]=[CH:26][C:21]([NH:20][C:37]2[CH:38]=[CH:39][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=2)=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: O=CNc1ccccc1
Agent: O=C[O-]
Agent: [C]=O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Reaction time: 3 h
Yield: 94 %

Procedure:
To the aforedescribed slurry of 103.0 parts by weight of potassium formanilide 30.2 parts by weight of formanilide, 2.1 parts by weight of aniline and 0.3 parts by weight potassium formate in 272.0 parts by weight of xylene is added 78.5 parts by weight of p-nitrochlorobenzene at 75°±5° C. The solution is heated to reflux under a 5-plate column with a take-off allowing sampling of the overhead between the reactor and column. The pot temperature is 145°±5° C. at reflux. The reaction begins at a batch temperature of 120°±10° C., as indicated by the evolution of carbon monoxide accompanied by a color change of the batch from yellow to deep red. As soon as heatup is complete and the reflux is established, forward flow of the overhead is begun at a rate sufficient to remove 200 parts by weight of xylene. When this is accomplished, the batch temperature is 162°±3° C. and p-nitrochlorobenzene conversion is over 90%. The endpoint of the reaction is indicated when the para-nitrochlorobenzene content is less than about 0.01%. If necessary, a hold period at the upper batch temperature is used to reach the endpoint. The time required is about 3±0.5 hours. After completion of the reaction, the reaction mass is transferred to a washing vessel and washed twice with 270 parts by weight of hot water. The washed oil layer contains 100.0 parts by weight (about 94% yield) of 4-nitrodiphenylamine, no p-nitrochlorobenzene, 10.4 parts by weight of by-products, 16.3 parts by weight of aniline, 25.3 parts by weight of formanilide and 72.0 parts by weight of xylene. From 225.0 parts by weight of the washed oil, there is recovered approximately 90 wt. % of the 4-nitrodiphenylamine by crystallization, the difference being eventually recovered after xylene, aniline and formanilide have been separated and recycled to the system.
Reaction SMILES: [CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]([O:24]CC)=[O:23])/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1.[ClH:27]>C(O)(=O)C>[ClH:27].[CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]([OH:24])=[O:23])/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Reaction time: 288 h
Yield: 27 %

Procedure:
In a mixed solvent of 15 ml of acetic acid and 10 ml of concentrated hydrochloric acid, 0.44 g (1.1 mmol) of (E)-1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-3-ethoxycarbonylmethylidene-4-mercaptopiperidine were dissolved and the resulting solution was allowed to stand for 12 days at room temperature in a dark place. The reaction mixture was concentrated to dryness, followed by crystallization from ethyl ether. The crystals collected by filtration were purified by chromatography on a silica gel column (eluting solvent: chloroform/methanol=30/1), whereby 0.12 g (yield 27%) of the title compound were obtained as light yellowish white crystals.
Reaction SMILES: C1(C[N:8]2[CH2:12][C@H:11]([CH3:13])[C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]2)C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:20][C:18]([CH3:21])([O:17][C:15]([NH:14][C@H:10]1[C@@H:11]([CH3:13])[CH2:12][NH:8][CH2:9]1)=[O:16])[CH3:19]
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reaction time: 3.5 h

Procedure:
A solution of 1.5 g(5.2 mmol) of cis-1-phenylmethyl-3-(1,1-dimethylethoxycarbonylamino)-4-methylpyrrolidine (cf. U.S. Pat. No. 4,753,953) in 50 mL methanol was treated with 200 mg of Pd(OH)2 /C followed by hydrogenation under 1 atmosphere of H2 for 3.5 h. The mixture was filtered through celite, washing the filter cake with methanol. The filtrate was concentrated in vacuo to afford a colorless oil, which was used directly in the next step. 1H NMR (CD3OD) δ 4.85, 4.03, 3.14, 3.05, 2.66, 2.45, 2.23, 1.46, 0.95.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:19][C:20]2[CH:21]=[N:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:17][CH:16]([CH3:18])[CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[O:31])=[CH:13][CH:12]=1)[NH:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:30]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cnc3c(C)cccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc2cc(NC(CC(C)C)c3ccc(C(=O)NCCC(=O)O)cc3)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 3-{4-[3-Methyl-1-(8-methyl-quinolin-3-ylamino)-butyl]-benzoylamino}-propionic acid methyl ester (44 mg, 0.1 mM) in 1:1 mixture of THF/MeOH (1 mL) was added 1N NaOH solution (0.25 mL, 0.25 mM). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated to remove organic solvent. The aqueous solution was diluted with DCM (5 mL), acidified by 1N HCl solution to pH=3-4. The organic solution was separated and the aqueous solution was extracted with 10% i-PrOH-DCM (3×5 mL). The combined organic solution were dried (Na2SO4) and concentrated to give a yellow solid product (˜100%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.93 (d, J=6.59 Hz, 3 H) 0.98 (d, J=6.34 Hz, 3 H) 1.56 (dt, J=13.30, 6.77 Hz, 1 H) 1.71 (dt, J=13.36, 6.62 Hz, 1 H) 1.76-1.85 (m, 1 H) 2.46 (t, J=7.07 Hz, 2 H) 2.59 (s, 3 H) 3.36-3.46 (m, 2 H) 4.64 (t, J=7.07 Hz, 1 H) 7.10 (br. s., 1 H) 7.21 (br. s., 1 H) 7.26 (d, J=6.83 Hz, 1 H) 7.32 (t, J=7.56 Hz, 1 H) 7.45 (d, J=8.05 Hz, 1 H) 7.53 (d, J=8.05 Hz, 2 H) 7.76 (d, J=8.29 Hz, 2 H) 8.42 (t, J=5.49 Hz, 1 H) 8.60 (d, J=2.44 Hz, 1 H), one proton was exchanged. LC-MS: 420.2 (M+1).