Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1>CO.[Pd]>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1
Reactant: CN(C)CCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN1CCN(c2ccc(N)cc2)CC1

Procedure:
A solution of 4-(4-(3-dimethylaminopropyl)piperazino)nitrobenzene (1.5 g) in methanol (50 mL) was hydrogenated at atmospheric pressure over Pd (5% on carbon) (0.3 g; 50% water content) for 4 h. The catalyst was filtered off and the solvent removed under reduced pressure to give the title compound as a brown solid
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][CH:17]=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([CH3:28])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:28][C:22]1[CH:21]=[C:20]([C:17]2[S:16][C:14]3[C:13]([N:18]=2)=[CH:12][CH:11]=[C:10]([C:7]2([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]2)[N:15]=3)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: c1ccc(C2(c3ccc4ncsc4n3)CC2)cc1
Reactant: Cc1cc(Br)ccc1C#N
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C#N
Temperature: 190 °C

Procedure:
A mixture of 5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (50.6 mg, 201 μmol), 4-bromo-2-methylbenzonitrile (47 mg, 241 μmol), PdCl2(AmPhos)2 (7.1 mg, 10 μmol), and cesium carbonate (196 mg, 602 μmol) in DMF (1.6 mL) was heated (microwave) under argon at 190° C. for 30 min. The reaction mixture was then partitioned between EtOAc (40 mL) and water (15 mL). The organic layer was separated, washed with water and brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 10% EtOAc/hexanes) provided 2-methyl-4-(5-(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzonitrile as a light-yellow solid. MS (ESI) m/z: Calculated: 367.1; Observed: 368.1 (M++1).
Reaction SMILES: [CH2:1]([N:5]([CH2:29][CH2:30][CH2:31][CH3:32])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=O)[C:15]=2[O:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:33]([C:35]1[C:36](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[O:37][C:38]([CH3:45])([C:41]([F:44])([F:43])[F:42])[C:39]=1[CH3:40])#[N:34]>C(O)C>[CH2:29]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=[CH:40][C:39]3[C:38]([CH3:45])([C:41]([F:44])([F:42])[F:43])[O:37][C:36](=[C:46]([C:47]#[N:48])[C:49]#[N:50])[C:35]=3[C:33]#[N:34])[C:15]=2[O:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=CC=O)CC(C)(C)C2)c(OC)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=CC=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)CC(C)(C)C2)c(OC)c1
Temperature: 60 °C
Yield: 72.8 %

Procedure:
In 5 ml of ethanol were dissolved 200 mg (0.46 mmol) of [3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-2-methoxy-5,5-dimethyl-2-cyclohexenylidene]acetaldehyde and 127 mg (0.50 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 60° C. for 2 hours, the solvent was evaporated off. The residue was purified by silica gel column chromatography to give 226 mg of a brown crystal (yield: 73.6%; mp: 141-151° C.)
Reaction SMILES: [C:1]([CH:4]=[C:5]1[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)([OH:3])=O.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>CCOC(C)=O.CN(C)C=O>[CH2:14]([NH:18][C:1]([CH:4]=[C:5]1[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=[O:3])[CH2:15][CH2:16][CH3:17]
Reactant: O=C(O)C=C1CCCc2sccc21
Reactant: CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCNC(=O)C=C1CCCc2sccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 4-carboxymethylidene-4,5,6,7-tetrahydrobenzo[b]thiophene (0.50 g), n-butylamine (0.28 ml), 1-hydroxybenzotriazole (0.43 g) and dimethylformamide (DMF) (5 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 g). The reaction mixture was stirred at r.t. for 5 hours and poured into a mixture of AcOEt and a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3). The separated organic layer was washed with water and brine, and dried over MgSO4, and evaporated to give 4-(N-butylcarbamoyl)methylidene-4,5,6,7-tetrahydrobenzo[b]thiophene (0.60 g).
Reaction SMILES: C(OC(N1[CH2:11][CH:10]([N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:13][CH3:14])C1)=O)(C)(C)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][CH2:35][NH2:36]>>[CH2:13]([N:12]([CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:36][CH2:35][CH2:34][C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1)[CH2:10][C@H:11]1[CH2:17][CH2:16][CH2:15][NH:12][CH2:10]1)[CH3:14]
Reactant: NCCc1cccs1
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CN(C(=O)OC(C)(C)C)C1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3cccs3)n2)c1)C[C@H]1CCCNC1

Procedure:
Intermediate 105 was coupled with 2-thiophen-2-yl-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 437. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.71 (s, 1H), 8.40 (d, 2H), 7.98 (d, 1H), 7.75 (s, 2H), 7.21 (d, 1H), 6.93 (d, 2H), 4.61 (s, 2H), 4.03 (s, 2H), 3.13 (m, 6H), 2.85 (t, 2H), 2.67 (t, 1H), 2.39 (m, 2H), 1.81 (m, 4H), 1.29 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[O:15])[CH:8]=2)=[C:4]([F:26])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:42]1([CH2:48][C:49]([N:51]=[C:52]=[S:53])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:26][C:4]1[CH:3]=[C:2]([NH:1][C:52]([NH:51][C:49](=[O:50])[CH2:48][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[S:53])[CH:25]=[CH:24][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN1CCC(NC(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCC(NC(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncn2)CC1
Reaction time: 0.08 h
Yield: 18.1 %

Procedure:
1-[6-(4-Amino-2-fluorophenoxy)pyrimidin-4-yl]-3-(1-methylpiperidin-4-yl)urea (50 mg) was dissolved in ethanol, and then D-10-camphorsulfonic acid (64.6 mg) was added thereto, followed by stirring for 5 min. A solution of phenylacetyl isothiocyanate in toluene (1.5 ml) was added thereto, followed by stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (0.5 ml)-hexane (2.0 ml) was then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (13.5 mg, 18.1%) as white powder.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:19][OH:20])=[C:4]([CH2:9][NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:5]=[N:6][C:7]=1[CH3:8].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:1][C:2]2[C:3]([CH2:19][OH:20])=[C:4]([CH2:9][NH:10][C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[CH:5]=[N:6][C:7]=2[CH3:8])=[CH:24][CH:25]=1)#[N:30]
Reactant: Cc1ncc(CNc2ccc(C#N)cc2)c(CO)c1O
Reactant: N#Cc1ccc(CBr)cc1
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Yield: 2 %

Procedure:
The coupling of 4-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-benzonitrile (805 mg, 3.0 mmol) (7) and α-bromo-p-tolunitrile (588 mg, 3.0 mmol), as described in Example 3, gave 4-{[5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-benzonitrile (8) (23 mg, 9% yield) as a colorless solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27](O)(=[O:31])[C:28]#[C:29][CH3:30]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:31])[C:28]#[C:29][CH3:30])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC#CC(=O)O
Agent: Cl
Product: CC#CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, light brown solid (71 mg, 72%), MS (ISP) m/z=393.3 [(M+H)+], mp 161° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and but-2-ynoic acid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:16]([N:17]=[CH:18]N(C)C)=[CH:15][C:14](=[O:22])[N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:12]1=[O:32].O.[Cl-].[NH4+]>C(O)(C)(C)C.C(O)C>[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:16]([NH:17][CH3:18])=[CH:15][C:14](=[O:22])[N:13]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:12]1=[O:32]
Reactant: COc1ccc(Cn2c(=O)cc(N=CN(C)C)n(-c3ccc(I)cc3F)c2=O)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CC(C)(C)O
Product: CNc1cc(=O)n(Cc2ccc(OC)cc2)c(=O)n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a suspension of sodium borohydride (326 mg) in t-butanol/ethanol [2:1 (volume ratio), 18.0 ml] was added N′-[3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine 83 (3.00 g) with stirring at room temperature. The mixture was stirred at room temperature for 1 hr, and at 65° C. for 2 hrs. With stirring at the same temperature, water (30.0 ml) and ammonium chloride (461 mg) were successively added, and the mixture was stirred to allow to cool to room temperature. The reaction solution was extracted twice with ethyl acetate. The organic layers were combined, washed successively with saturated aqueous hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to give 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-methylamino-1H-pyrimidine-2,4-dione 84 (2.57 g, yield 93.1%) as a pale-yellow solid.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2.[F:17][C:18]([F:37])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:33][N:32]=[C:31]([CH2:34]Cl)[N:30]=2)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:37][C:18]([F:17])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:33][N:32]=[C:31]([CH2:34][N:4]3[C:5]4[C:10](=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=4)[CH:11]=[C:3]3[CH:2]([F:1])[F:16])[N:30]=2)[CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1C#N
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1C#N

Procedure:
Synthesized as described in Example 23 from 2-(difluoromethyl)-1H-indole-4,5-dicarbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: MS (ES) m/z 510 (M−1).
Reaction SMILES: [O:1]=[C:2]1[CH:26]=[C:25]2[C@:20]([CH3:38])([CH2:21][CH2:22][C@H:23]([O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:39])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH2:6][CH2:5]1.O[Li].O.N#N>CC(O)(C)C.O>[O:1]=[C:2]1[CH:26]=[C:25]2[C@:20]([CH3:38])([CH2:21][CH2:22][C@H:23]([O:27][Si:28]([CH:29]([CH3:31])[CH3:30])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:33])[CH3:34])[CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:39])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#N
Agent: [Li]O
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)[Si](O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1)(C(C)C)C(C)C
Yield: 94 %

Procedure:
Methyl 7-oxo-3β-triisopropylsilyloxychol-5-en-24-oate (3) (5.85 g, 10.5 mmoles) was dissolved with warming in t-BuOH (100 ml). A solution of LiOH.H2O (1.76 g, 41.9 mmoles) in H2O (33 ml) was added, and the two phase mixture was heated at 80° with magnetic stirring in an N2 atmosphere for 2 hrs. Most of the t-BuOH was evaporated in vacuo, the residue-diluted with H2O (~50 ml), and acidified with 2N HCl (22 ml). The gummy suspension was extracted with CH2Cl2 (4 times). The extracts were washed with H2O and saturated brine and dried (MgSO4). Evaporation in vacuo gave 5.38 g of 4 as a gummy solid. NMR (CDCl3): δ0.68 (s, 3H, 18-Me); 0.95 (d, 3H, 20-Me); 1.05 (s, 18H, TIPS Me); 1.20 (s, 3H, 19-Me); 3.68 (m, 1H, 3-H); 5.67 (s, 1H, 6-H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:7]=1)C.[OH-].[Li+]>CO.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:27])=[O:3])[CH:11]=[CH:10][CH:9]=2)=[C:14]([CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:15]=1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(F)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cccc(Oc2ccc(F)cc2CN2CCOC2=O)c1

Procedure:
Hydrolysis of {3-[4-fluoro-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester with lithium hydroxide in MeOH and H2O provided the desired product.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12](Br)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccsc1
Reactant: OC1(C#Cc2ncc(Br)cc2Cc2ccccc2)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: OC1(C#Cc2ncc(-c3ccsc3)cc2Cc2ccccc2)CN2CCC1CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A mixture of 127 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol (Example 22-a), 61.4 mg of 3-thiopheneboronic acid, 55.4 mg of tetrakis (triphenylphosphine)palladium(0), 2 ml of toluene, 0.5 ml of methanol and 1 ml of aqueous 2 mol sodium carbonate solution was stirred at 80° C. for 2 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 83.9 mg of the target compound.
Reaction SMILES: Br.Br.[C:3]([C:7]1[N:11]=[C:10]([S:12][CH2:13][CH2:14][NH2:15])[NH:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[C:3]([C:7]1[N:11]=[C:10]([S:12][CH2:13][CH2:14][NH:15][C:32](=[O:33])[NH:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:35])[F:34])=[CH:26][CH:27]=2)[NH:9][N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1n[nH]c(SCCN)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1n[nH]c(SCCNC(=O)Nc2ccc(C(F)(F)F)cc2)n1
Temperature: -40 °C
Yield: 86 %

Procedure:
To 10 g (27 mmole) of 3-t-butyl-5-(2-aminoethylthio)-1H-1,2,4-triazole dihydrobromide in 100 ml of methylene chloride was added 5.5 g (54 mmole) of triethylamine. The mixture was cooled to -40° C. and a solution of 5.2 g (27 mmole) of 4-trifluoromethylphenyl isocyanate in methylene chloride was slowly added. The stirred mixture was slowly allowed to warm to room temperature and was stirred at room temperature for eighteen hours. The reaction mixture was washed twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 9 g of 3-t-butyl-5-(2-(4-trifluoromethylphenylcarbamoylamino)-ethylthio)-1H-1,2,4-triazole, m.p. 238°-240° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:39](=[O:40])[C:38]5[CH:37]=[CH:36][C:35]([N:32]6[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]6)=[CH:43][CH:42]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CN1CCN(c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCN(c5nccc6c5OCC6)CC4)CC3)cc2)CC1

Procedure:
The title compound, white solid (116 mg, 87%), MS (ISP) m/z=533.4 [(M+H)+], mp 235.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-(4-methyl-piperazin-1-yl)-benzoic acid.
Reaction SMILES: N1(CCS(N2CCC(C3C4C(=C(C(N)=O)C=C(C5C=CSC=5)C=4)NC=3)CC2)(=O)=O)CCCC1.Br[C:35]1[CH:36]=[C:37]2[C:41](=[C:42]([C:44]([NH2:46])=[O:45])[CH:43]=1)[NH:40][CH:39]=[C:38]2[CH:47]1[CH2:52][CH2:51][N:50]([S:53]([CH2:56][CH2:57][CH2:58][N:59]2[CH2:63][CH2:62][CH2:61][CH2:60]2)(=[O:55])=[O:54])[CH2:49][CH2:48]1.[OH:64][CH2:65][C:66]1[S:70][C:69](B(O)O)=[CH:68][CH:67]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:64][CH2:65][C:66]1[S:70][C:69]([C:35]2[CH:36]=[C:37]3[C:41](=[C:42]([C:44]([NH2:46])=[O:45])[CH:43]=2)[NH:40][CH:39]=[C:38]3[CH:47]2[CH2:52][CH2:51][N:50]([S:53]([CH2:56][CH2:57][CH2:58][N:59]3[CH2:63][CH2:62][CH2:61][CH2:60]3)(=[O:54])=[O:55])[CH2:49][CH2:48]2)=[CH:68][CH:67]=1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Reactant: OCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCN4CCCC4)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccc(CO)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12

Procedure:
The title compound was prepared following the general procedure described in intermediate 16. Thus, 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (95 mg, 0.19 mmol) in dioxane (3 mL) and water (1 mL), [5-(hydroxymethyl)-2-thienyl]boronic acid (120 mg, 0.76 mmol), Pd(PPh3)4 (22.2 mg, 10%) and potassium carbonate (211 mg, 1.52 mmol) were reacted to form the desired product which was purified by flash column chromatography (ethyl acetate/hexane, 1/1) to yield the desired product (25 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH2:24][CH2:25][NH2:26])(=[O:23])=[O:22])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:26][CH2:25][CH2:24][S:21](=[O:23])(=[O:22])[NH:20][CH:17]1[CH2:18][CH2:19][N:14]([CH:11]([CH3:12])[CH3:13])[CH2:15][CH2:16]1)=[O:7]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Product: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2cccc(Cl)c2)CC1

Procedure:
3-Chloro-N-[2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-benzamide was prepared by an analogous procedure as described in example 9 starting from 104 mg (1.1 equiv.) 3-chloro-benzoic acid and 150 mg (0.60 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 3-chloro-N-[2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-benzamide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][NH:9]1)=O)CCC.[NH3:16]>CO>[CH3:14][N:13]([CH3:15])[C@@H:11]1[CH2:10][NH:9][C@H:8]([C:6]([NH2:16])=[O:5])[CH2:12]1
Reactant: N
Reactant: CCCCOC(=O)[C@@H]1C[C@H](N(C)C)CN1
Solvent: CO
Product: CN(C)[C@@H]1CN[C@H](C(N)=O)C1

Procedure:
A solution of (2S,4S)-4-dimethylamino-pyrrolidine-2-carboxylic acid butyl ester (Stage Q.1, 326 mg) and 7 M ammonia in MeOH (8 ml) was stood for 18 h at it in a sealed vessel. Filtration, evaporation and trituration with Et2O/MeOH gave the title compound as a beige solid.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:13].Cl.[NH:15](C(OCC1C=CC=CC=1)=O)[C@H:16]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH2:69])=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CO.[Pd]>[NH2:15][C@H:16]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH2:69])=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[ClH:13].[ClH:13]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Agent: [Pd]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1ccccc1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
3.14 g of the dihydrochloride of Z-Phe-His-Leu-Val-Ile-His-NH2 from Example 1 are hydrogenated for 4 hours at normal pressure in 100 ml of water/methanol (5:95) in the presence of 350 mg of palladium-on-carbon (5%). After removing the catalyst by filtration, evaporating off the solvent and drying in a high vacuum, H-Phe-His-Leu-Val-Ile-His-NH2.2HCl is obtained in the form of a colourless powder. Rf (B11)=0.26.