Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([F:14])=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.[N:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=O)=[CH:17][CH:16]=1.[BH4-].[Na+].Cl>CO.C(Cl)Cl.O>[F:1][C:2]1[C:3]([F:14])=[C:4]2[C:11]([C:7]([CH2:8][CH2:9][NH:10][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([O:21][C:18]4[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=4)[CH:23]=3)=[CH:6][NH:5]2)=[CH:12][CH:13]=1
Reactant: NCCc1c[nH]c2c(F)c(F)ccc12
Reactant: O=Cc1cccc(Oc2ccncc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Fc1ccc2c(CCNCc3cccc(Oc4ccncc4)c3)c[nH]c2c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 6,7-difluoro tryptamine (0.285 g, 1.450 mmol), 3-pyridin-4-yloxybenzaldehyde (0.303 g, 1.52 mmol, 1.05 eq.) and molecular sieves 4 A (0.30 g) and stir in methanol (12 mL). After 4 h. filter the molecular sieves and wash several times with MeOH. To this MeOH solution, add portionwise NaBH4 (55.0 mg, 1.45 mmol), and stir at room temperature for 1 h. Remove MeOH in vacuo, dilute the residue with CH2Cl2/water, extract with CH2Cl2, combine organic layers, dry over Na2SO4 and concentrate in vacuo. Purification by flash chromatography on silica gel (CH2Cl2/MeOH) to give the free base which is converted to the hydrochloride salt: 1H NMR (300 MHz, DMSO-d6) 3.13 (s, 4H), 4.20 (s, 2H), 6.85–7.55 (m, 10H), 8.47–8.50 (m, 1H), 9.58 (br, 1H), 11.57 (br, 1H): MS (electrospray) m/e: 380.2 (M+1-HCl), 378.3 (M−1-HCl).
Reaction SMILES: OC1C=C(C=C(C#N)C=1O)C(O)=O.[CH2:14]([O:17][C:18]1[CH:19]=[C:20]([CH:27]=[C:28]([C:34]#[N:35])[C:29]=1[O:30][CH2:31][CH:32]=[CH2:33])[C:21]([O:23]CC=C)=[O:22])[CH:15]=[CH2:16]>>[CH2:14]([O:17][C:18]1[CH:19]=[C:20]([CH:27]=[C:28]([C:34]#[N:35])[C:29]=1[O:30][CH2:31][CH:32]=[CH2:33])[C:21]([OH:23])=[O:22])[CH:15]=[CH2:16]
Reactant: C=CCOC(=O)c1cc(C#N)c(OCC=C)c(OCC=C)c1
Agent: N#Cc1cc(C(=O)O)cc(O)c1O
Product: C=CCOc1cc(C(=O)O)cc(C#N)c1OCC=C

Procedure:
3,4-Dihydroxy-5-cyanobenzoic acid, (see GB 2 200 109) was converted, essentially as above, to allyl 3,4-diallyloxy-5-cyanobenzoate: NMR (CDCl3) 4.63 (m, 2H); 4.77-4.87 (m, 4H); 5.23-5.51 (m, 6H); 5.92-6.18 (m, 3H); 7.76 (d, 1H); 7.86 (d, 1H). This ester was hydrolysed as above to give 3,4-diallyloxy-5-cyanobenzoic acid: (DMSO-d6) 4.72-4.84 (m, 4H); 5.23-5.51 (m, 4H); 5.93-6.18 (m, 2H); 7.79 (s, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([C:20]([OH:22])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.C(N(CC)CC)C>[CH:23]1([NH:26][C:20]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[CH2:17][CH2:18][CH3:19])=[O:22])[CH2:25][CH2:24]1
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCC)cc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (0.40 g) obtained in Example 43b) in acetonitrile-DMF (7:2, 9 ml) were successively added cyclopropylamine (0.11 ml), triethylamine (0.22 ml), HOBt (0.24 g) and WSC (0.30 g), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a white powder (0.20 g, 44%).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1[C:16]2[C:15](=[O:17])[NH:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.Cl>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]([N:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:16]=2[C:15](=[O:17])[NH:14][C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]1=2)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2N(C(=O)CBr)c2ccccc21

Procedure:
93 g (0.55 mol) of bromoacetyl chloride were added dropwise, with stirring, to a suspension of 105 g (0.5 mol) of 5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepin-11-one in 1 liter of toluene, at 90° C. The mixture was then refluxed for a further 30 minutes, during which there was a strong development of hydrogen chloride. After cooling, the dark blue crystal slurry obtained was suction filtered;
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C@H:8]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O)([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[Cl:52][CH2:53][CH2:54][NH:55][CH2:56][CH2:57][Cl:58].C(N(CC)CC)C>C(#N)C>[Cl:52][CH2:53][CH2:54][N:55]([CH2:56][CH2:57][Cl:58])[C:12]([C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[CH2:9][C@@H:8]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:27])=[O:14]
Reactant: ClCCNCCCl
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1C(=O)O)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1C(=O)N(CCCl)CCCl)NC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
Adapting a literature known protocol (Levi and Weed, U.S. Pat. No. 3,235,594), to a reaction mixture of 2-[(2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butyl]benzoic acid (23b) (759 mg, 2.0 mmol), N-hydroxysuccinimide (NHS, HOSu) (235 mg, 2.2 mmol) in anhydrous acetonitrile (MeCN) (10 mL) is added solid dicyclohexylcarbodiimide (DCC) (433 mg, 2.1 mmol) in small portions at about room temperature. The reaction mixture is stirred for about 12 hours and the precipitated dicyclohexylurea side product is filtered off using a Büchner funnel. The filtrate is treated with commercial di-(2-chloroethyl)amine hydrochloride (2-chloro-N-(2-chloroethyl)ethanamine hydrochloride; HN(CH2—CH2—Cl)2.HCl) (393 mg, 2.2 mmol) followed by neat triethylamine (Et3N, TEA) (321 μL, 233 mg, 2.3 mmol). The reaction mixture is stirred for about 12 hours at room temperature. The reaction is followed by TLC and/or LC/MS to completion. Acidic aqueous work-up and purification by silica gel column chromatography furnish the title compound tert-butyl(3R)-4-[2-[bis(2-chloroethyl)carbamoyl]phenyl]-3-(tert-butoxycarbonylamino)butanoate (23c).
Reaction SMILES: Cl[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][O-].[K+].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[Cl:12][C:13]1[CH:18]=[CH:17][N:16]2[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:19]=[C:15]2[CH:14]=1
Reactant: CCOC(=O)C(Cl)=C[O-]
Reactant: Nc1cc(Cl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc2cc(Cl)ccn12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To a flask equipped with a reflux condenser, mechanical stirring, and internal temperature probe was added potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (58.70 g, 311.1 mmol) followed by 200 mL of EtOH. Aqueous hydrogen chloride (4.862 ml, 15.56 mmol) in EtOH was added to the slurry. The slurry was stirred for about 15 minutes, and then 4-chloropyridin-2-amine (20.00 g, 155.6 mmol) was added, and the mixture was warmed to 70° C. After about one hour, an additional 2 equivalents of 3.2 M aqueous HCl were added and the mixture stirred at 70° C. for 16 hours. An additional 30 g of potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate were added and the mixture was stirred at 70° C. for 2 hours. The mixture was cooled to ambient temperature and 500 mL of water added, followed by pH adjustment to 11 with 10% aqueous sodium carbonate. After stirring for several hours, the precipitated solids were collected by filtration and dried under vacuum to give 31 g (88%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:67]=[CH:68][C:69](=[O:72])[NH:70][CH:71]=1>C(Cl)Cl>[O:72]=[C:69]1[NH:70][CH:71]=[C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:30])[CH:67]=[CH:68]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(=O)[nH]c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(=O)[nH]c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.44 mmol) in methylene chloride (8 mL), HATU (Aldrich, 166 mg, 0.50 mmol) was added followed by the addition of DIPEA (200 uL) and 5-amino-2-pyridinone (Alfa, 97 mg, 0.88 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 40-80% EtOAc/hexanes) to give a solid. 168 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH:17]=[C:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:24])=[CH:15][CH:14]=1)=[O:8]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:24])=[CH:15][CH:14]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCOc1ccc(C=C2SC(=O)NC2=O)cc1
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=O)NCCOc1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
5-(4-[2-(N-(5-Chloro-2-methoxybenzoyl)amino)ethoxy]-benzylidene)-2,4-thiazolidinedione (1.7 g) was dissolved in dioxan (80 ml) and hydrogenated for a total of 22 hours in a manner similar to that described in Example 2. The title compound was obtained as a foam, mp 66-67° C.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:23]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([O:8][CH:9]([C:18]([F:19])([F:21])[F:20])[CH2:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1ccccn1)C(F)(F)F
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccn1
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 88.5 %

Procedure:
A solution of 810 mg (2.54 mmol) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluorobutyl]pyridine in 8 nL of THF was treated with 2.54 mL (3.81 mmol, 1.5 eq.) of LDA (1.5 M solution in cyclohexane) at −75° C. After stirring at −75° C. for 45 minutes, 474 μL (7.61 mmol, 3.0 eq.) of methyl iodide was added at −75° C. The resulting mixture was stirred at this temperature for 10 minutes and quenched with saturated NH4Cl solution. The product was extracted into ether. The ethereal layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 750 mg (89%) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1-methylbutyl]pyridine (a mixture of two diastereomers) as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][C:4]=1[Cl:20])#[N:2].[NH2:21][OH:22]>C(O)C>[Cl:20][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:3]=1[C:1](=[N:21][OH:22])[NH2:2])[CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11]
Reactant: NO
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)c(Cl)c1
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)c(Cl)c1

Procedure:
A solution of tert-butyl 2-((4-cyano-3-chlorobenzyl)(methyl)amino)acetate (1.95 g, 6.60 mmol) and 50% aqueous hydroxylamine (2.02 mL) in ethanol (10 mL) was heated at 80° C. for 5 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was poured through a hydrophobic frit and evaporated in vacuo to afford the title compound (2.16 g, quantitative). 1H NMR (CDCl3, 400 MHz) δ 7.48-7.42 (2H, m), 7.28 (1H, m), 4.97 (2H, s), 3.69 (2H, s), 3.18 (2H, s), 2.37 (3H, s), 1.48 (9H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH3:22])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]Cl)[CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([CH3:22])[CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)c1c(O)cccc1n2Cc1ccccc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cc(C)ccc1n2Cc1ccccc1
Yield: 74.5 %

Procedure:
9-Benzyl-6-methyl-9H-carbazol-4-ol (0.0597 g, 0.21 mmol), 2-diethylaminoethylchloride hydrochloride (0.0565 g, 0.33 mmol), potassium carbonate (0.1007 g, 0.73 mmol), sodium iodide (0.0054 g, 0.036 mmol) and DMF (1 mL) are heated at 85° C. for 4.5 h. After the mixture had cooled, it is partitioned between water and ether. The aqueous layer is also washed twice with ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated to dryness. The residue is chromatographed on silica gel (60 mL) using methanol/dichloromethane (1/99 to 3/97 to 5/95) to give 0.0605 g (75%) of the title compound containing N-{2-[(9-benzyl-3-bromo-6-methyl-9H-carbazol-4-yl)oxy]ethyl}-N,N-diethylamine as an impurity. Attempts at purifying this material through recrystallization are unsuccessfull; MS (ESI+) for C26H30N2O m/z 387.3 (M+H)+. 1H NMR (CDCl3) δ1.17 2.53, 2.78, 3.17, 4.37, 5.47, 6.68, 6.96, 7.11, 7.21-7.34, 8.17.
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:24][C@H:25]([C:36]([N:38]1[CH2:49][CH2:48][CH2:47][C@H:39]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.Cl.[NH:51]([C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[C@@H:52]([C:60](O)=[O:61])[CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:51]([C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[C@@H:52]([C:60]([NH:24][C@H:25]([C:36]([N:38]1[CH2:49][CH2:48][CH2:47][C@H:39]1[C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:61])[CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.28 ml (10 mmoles) of N-ethylmorpholine and 2.26 g (11 mmoles) of DCC are added at 0° C. to a solution of 3.46 g (10 mmoles) of H-Trp-Pro-OBut.HCl. 2.29 g (10 mmoles) of Z-D-Phe-OH and 1.35 g (10 mmoles) of HOBt in 25 ml of dimethylformamide. The mixture is stirred for 2 hours at 0° C. and left to stand overnight at room temperature. The precipitate is filtered and the filtrate is concentrated. The residue is worked up analogously to Example 1 a. The residue crystallizes from ether. Yield 3.91 g (61%), melting point 186°, [α]D23 =-53.6° (c=1, methanol).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[CH2:12][CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>CN(C)C=O>[C:1]([O:9][CH2:12][CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CCCl)OCC
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CCOC(=O)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a stirred solution of 5.0 grams (0.034 mole) of sodium benzoate in 100 ml of dimethylformamide was added 5.2 grams (0.031 mole) of 3-chloro-1,1-diethoxypropane. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for four hours. After this time the reaction mixture was cooled to ambient temperature and was filtered to remove a solid. The filtrate was diluted with water, and the mixture was extracted with diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The nmr spectrum indicated the presence of solvents. The oil was redissolved in diethyl ether and washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was evacuated under high vacuum yielding 6.3 grams of 3-ethoxy-4-oxahexyl benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][N:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH3:32]>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:30][CH2:31][CH3:32])[N:19]=3)=[O:17])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C(NCCN1CCN(Cc2ccc(F)cc2)CC1)c1n[nH]c2ccccc12
Reactant: CCCBr
Product: CCCn1nc(C(=O)NCCN2CCN(Cc3ccc(F)cc3)CC2)c2ccccc21

Procedure:
The title compound was synthesized by using N-[2-(4-p-fluorobenzyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 11 and 1-bromopropane according to the same process as in Example 12.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:6]2=[N:5][C:4]=1[CH3:15])=[O:2]>CO.[Pd]>[NH2:12][C:11]1[C:6]2[N:7]([C:3]([CH:1]=[O:2])=[C:4]([CH3:15])[N:5]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1nc2c([N+](=O)[O-])cccn2c1C=O
Agent: [Pd]
Solvent: CO
Product: Cc1nc2c(N)cccn2c1C=O

Procedure:
0.5 g 3-formyl-2-methyl-8-nitro-imidazo[1,2-a]pyridine, dissolved in 200 ml methanol, is hydrogenated after addition of a catalytic amount& of a commercial Pd/C-catalyst at room temperature at low pressure for 11/2 hours.
Reaction SMILES: [IH:1].[CH3:2][O:3][C:4](=[O:36])[C@H:5]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22](SC)=[NH:23])=[CH:18][CH:17]=2)[CH:9]=1.C([O-])(=O)C.[NH4+:41].CCOCC.C(OC(C)C)(C)C>CO>[IH:1].[CH3:2][O:3][C:4](=[O:36])[C@H:5]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22](=[NH:41])[NH2:23])=[CH:18][CH:17]=2)[CH:9]=1
Reactant: [NH4+]
Reactant: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(NC(=O)c2ccc(C(=N)SC)cc2)c1
Agent: CC(=O)[O-]
Agent: I
Solvent: CC(C)OC(C)C
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c1cccc(NC(=O)c2ccc(C(=N)N)cc2)c1
Yield: 71 %

Procedure:
A solution of 3-(t-butoxycarbonyl)-N-[m-[p-[1-(methylthio)formimidoyl]benzamido]benzoyl]-L-alanine methyl ester hydroiodide in methanol is reacted with ammonium acetate in an analogous manner to that described in Example 33 B) h). There is obtained in 71% yield N-[m-(p-amidinobenzamido)benzoyl]-3-(t-butoxycarbonyl)-L-alanine methyl ester hydroiodide in the form of a colourless solid, m.p. 118°-120° C. (ether/isopropyl ether), MS: 469 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[C:31]#[N:32])[O:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23]S(C)(=O)=O.C[O-].[Na+].[C:36](OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH2:22][O:23][CH3:36])[CH:28]=[CH:29][C:30]=1[C:31]#[N:32]
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
120 mg Methanesulfonic acid 5-(3-chloro-4-cyano-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethyl ester were dissolved in 5 ml methanol. 12.9 mg sodium methoxide were added and the mixture stirred at 50° C. for one hour. The reaction mixture was diluted by addition of 50 ml ethyl acetate, washed with one molar hydrochloric acid then dried over MgSO4. The solvent was removed in vacuo and the residue purified by RP-HPLC to provide 30 mg of 2-chloro-4-[4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as lyophilisate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 60 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 60% of theory; LC (method 1): tR=2.44 min; Mass spectrum (ESI+): m/z=318 [M+H]+; 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ 1.20-1.34 (m, 1H), 1.41-1.56 (m, 1H), 1.56-1.71 (m, 1H), 1.92-2.02 (m, 1H), 2.68-3.11 (m, 3H), 3.11-3.27 (m, 1H), 3.47-5.43 (very broad signals, 2H), 7.07-7.30 (m, 5H), 7.54-7.62 (m, 1H), 7.64-7.72 (m, 1H), 8.29 (s, 1H), 12.51-12.65 (m, 1H).