Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([NH2:20])[C:14](=[CH:18][CH:19]=1)[C:15]([OH:17])=[O:16])([O-:10])=[O:9].[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(Cl)(=O)OCC>C(Cl)Cl>[CH2:37]([C:38]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][C:13]=2[N:20]=1)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCc1nc2cc([N+](=O)[O-])ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 51 %

Procedure:
Triethylamine (4.85 ml) was added to a suspension of 4-nitroanthranilic acid (3.00 g) in methylene chloride (30 ml) and then the mixture was cooled with ice. The reaction mixture, with stearoyl chloride (4.99 g) dropwise added thereto, was stirred for 3.25 hours at room temperature and then was cooled with ice. Then, triethylamine (2.55 ml) and ethyl chlorocarbonate (1.74 ml) were added to the reaction mixture successively. The reaction mixture was stirred for 1 hour at 0° C. and for 3 hours at room temperature successively, and then concentrated. The residue, with chloroform added thereto, was washed with water and saturated brine successively. The organic layer was dried over sodium sulfate anhydride, and then concentrated. The residue was purified by silica gel column chromatography (silica gel 200 g, chloroform-hexane), thereby yielding 3.62 g of the aimed compound as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: Cc1ccc2c(c1)CCCC2
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1S(=O)(=O)Cl)CCCC2
Yield: 95.4 %

Procedure:
A solution of 20 g (0.137 mol) 2-methyl-5,6,7,8-tetrahydro-naphthalene in 200 mL CHCl3 was added to 48 g (0.412 mol) chlorosulfonic acid at 0° C. After 2 hrs at room temperature the solution was slowly poured onto ice. The organic phase was washed, dried and concentrated to give 32 g 2-methyl-5,6,7,8-tetrahydro-naphthalene-sulfonic acid chloride used directly for the subsequent reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:6][CH:7]=1.[C:19]([NH:29][CH2:30][C:31]#[CH:32])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(NC(C)C)(C)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:14]([O:13][C:12]([NH:11][CH2:10][C:9]#[C:8][C:5]1[N:6]=[CH:7][C:2]([C:32]#[C:31][CH2:30][NH:29][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:3][CH:4]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(C#CCNC(=O)OCc2ccccc2)cn1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of tert-butyl 3-(5-bromopyridin-2-yl)prop-2-ynylcarbamate (3-1) (1.44 g), N-Cbz propargylamine (1.09 g), Pd(PPh3)2Cl2 (73 mg), and CuI (10 mg) in diisopropylamine (25 mL) was heated under reflux under a nitrogen atmosphere for 3 hours. The mixture was cooled to ambient temperature and diluted with ethyl acetate (70 mL). The precipitates were filtered and rinsed with ethyl acetate (30 mL). The filtrate and washings were combined, concentrated under reduced pressure, and purified by silica gel column chromatography using a mixture of MTBE and hexanes (2:3 to 4:1). The fractions containing the product were combined and concentrated under reduced pressure. The residue was crystallized from MTBE. Crystals were filtered, washed with MTBE, and dried to give 6-1 (1.07 g). An additional 120 mg of 6-1 was isolated from the mother liquors and washings.
Reaction SMILES: [F:1][C:2](=[C:13]([F:15])[F:14])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1COCC1>[F:1][C:2](=[C:13]([F:15])[F:14])[CH2:3][C:4](=[S:17])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CC(F)=C(F)F)Nc1ccccc1
Solvent: C1CCOC1
Product: FC(F)=C(F)CC(=S)Nc1ccccc1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A mixture of 3,4,4-trifluoro-N-phenyl-3-butenamide (1.0 g, 4.65 mmol) and phosphorus pentasulfide (2.07 g, 4.65 mmol) in anhyd. THF (100 mL) was heated at reflux under nitrogen for 1 hour. The reaction mixture was cooled to r.t. and filtered. The filtrate was concentrated and the residue was chromatographed over silica gel (dichloromethane/hexanes, 80/20) to give 0.65 g (60%) of the desired compound as a pale yellow solid. m.p. 65°-67° C.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[C:11](#[N:13])[CH3:12]>>[CH3:12][C:11]1[N:13]=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: CC#N
Reactant: N[n+]1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2ccccn2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 1-aminopyridinium iodide (139 g, 626 mmol) in acetonitrile (1.25 L) was added 10% aqueous sodium hydroxide solution (751 mL, 1.88 mmol), and the mixture was stirred at room temperature for 12 hr. Half of the reaction mixture was evaporated under reduced pressure, and the residue was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (47.0 g, yield 56%)
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[NH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1O)[C:17]([CH3:19])=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:16][C:17]([CH3:19])=[O:18])=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: CC(=O)Nc1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1OC(=O)CCC1CCN(C(=N)N)CC1
Reaction time: 44 h
Yield: 92.7 %

Procedure:
A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.6 g of o-acetaminophenol was dissolved in 40 ml of dry pyridine. To the solution was added with ice-cooling and stirring 3.5 g of dicyclohexylcarbodiimide, and the resulting mixture was allowed to stand at room temperature for 44 hours. After removal of any insoluble materials, the solvent was removed under reduced pressure. The residue was washed with ethyl acetate, and dry ether was then added to the residue to give crystals. The crystals were washed with ether several times, then with warm dichloromethane and finally with ethyl acetate. Dry ether was added to the crystals, and the mixture was evaporated to dryness to obtain 5.8 g (yield: 92.7%) of o-acetaminophenyl 1-amidino-4-piperidinepropionate hydrochloride as hygroscopic crystals.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[C:13]3([CH2:29][CH2:28][CH2:27][CH2:26]3)[C:12]2=[O:30])[CH2:7][CH2:6]1)=[O:4].[C:31]1(=[O:37])[NH:35][C:34](=[O:36])[CH2:33][CH2:32]1>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([C:14]2[C:13]3([CH2:29][CH2:28][CH2:27][CH2:26]3)[C:12](=[O:30])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:35]4[C:31](=[O:37])[CH2:32][CH2:33][C:34]4=[O:36])[CH2:10][CH2:9]3)[N:15]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C23CCCC3)cc1OC
Reactant: O=C1CCC(=O)N1
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C23CCCC3)cc1OC

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-4-(3,4-dimethoxyphenyl)-2,3-diazaspiro[4.4]non-3-en-1-one (compound A10) and succinimide as starting compounds.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:38]5[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: OC1CCNCC1
Agent: OC1CCNC1
Product: OC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 4-hydroxypiperidine. A yellow solid 119 was obtained (0.031 g, 63%). 1H-NMR (CDCl3, 400 MHz) δ 1.75–1.84 (m, 2H), 2.02–2.10 (m, 2H), 3.67–3.74 (m, 2H), 4.00–4.07 (m, 2H), 4.10–4.16 (m, 1H), 4.28–4.34 (m, 4H), 4.72–4.76 (m, 1H), 6.93–6.97 (m, 3H), 7.05 (dd, J=1.8 Hz, 8.0 Hz, 1H), 7.10 (d, J=1.8 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 8.25 (d, J=6.3 Hz, 1H); MS (APCI) m/z 489 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[O:28][CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[N:17][C:2]([O:27][C:24]2[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[C:22]([O:28][CH3:29])[CH:23]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cc(F)cnc1Cl
Reactant: COc1cc(O)ccc1SC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)ccc1SC
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 4-methylsulfanyl-3-methoxy-phenol (94 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a Chemelute™ cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(4-methylsulfanyl-3-methoxy-phenoxy)-nicotinamide (99 mg) as an off-white foam.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1F.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(C2OCCCO2)c(F)c1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2OCCCO2)c(Sc2ccccc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
The reaction was carried out under argon. 4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (207 mg, 1 mmol) and thiophenol (100 mg, 0.9 mmol; 1.1 eq.) were initially charged in DMF (3 ml). Potassium carbonate (314 mg, 2.27 mmol; 2.5 eq.) was added at RT, and the mixture was stirred at 100° C. for 4 h. LC/MS control then showed complete conversion. The reaction mixture was purified directly by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (238 mg, 80% of theory).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C(O)(=O)C.N1CCCCC1.[Cl:18][CH:19]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1)[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:18][CH:19]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1)[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH:26]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:28][CH:29]=1
Reactant: O=C1CSC(=O)N1
Reactant: CCc1ccc(C(Cl)COc2ccc(C=O)cc2)nc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCc1ccc(C(Cl)COc2ccc(C=C3SC(=O)NC3=O)cc2)nc1

Procedure:
A mixture of 2 g (0.017 mol) thiazolidin-2,4-dione, 2 g (0.034 mol) acetic acid and 3 g (0.03 mol) piperidine were added to a solution of 5 g (0.017 mol) 4-[2-chloro-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzaldehyde dissolved in 50 mL toluene. Reaction mixture was heated and water was removed azeotropically. After completion of the reaction an TLC, toluene was distilled out completely under reduced pressure. Product was poured into excess of water and extracted with ethyl acetate. After concentrating ethyl acetate in vacuo and making its HCl salt in usual way 4.3 g (60%) desired product obtained.
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[C:11](Cl)=[O:12].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:36])=[C:19]([NH:21][C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])=[CH:25][CH:24]=2)[CH:20]=1>>[CH3:36][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])=[CH:20][C:19]=1[NH:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])=[CH:25][CH:24]=1
Reactant: CCOCCOc1ccc(C(=O)Nc2cc(N)ccc2C)cc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: CCOCCOc1ccc(C(=O)Nc2cc(NC(=O)c3ccc4ccccc4c3)ccc2C)cc1
Yield: 23 %

Procedure:
Using an analogous procedure to that described in Example 22, 2-naphthoyl chloride was reacted with N-(5-amino-2-methylphenyl)-4-(2-ethoxyethoxy)benzamide to give the title compound in 23% yield; Mass Spectrum: M+H 470.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.N1C2C=CC=C(C(OC)=O)C=2C=C1.[CH3:24][C:25]1[NH:26][C:27]2[C:32]([C:33]=1[CH3:34])=[CH:31][C:30]([C:35]([O-:37])=[O:36])=[CH:29][CH:28]=2>>[CH3:24][C:25]1[N:26]([CH2:2][CH2:3][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)[C:27]2[C:32]([C:33]=1[CH3:34])=[CH:31][C:30]([C:35]([OH:37])=[O:36])=[CH:29][CH:28]=2
Reactant: BrCCOC1CCCCO1
Reactant: Cc1[nH]c2ccc(C(=O)[O-])cc2c1C
Agent: COC(=O)c1cccc2[nH]ccc12
Product: Cc1c(C)n(CCOC2CCCCO2)c2ccc(C(=O)O)cc12

Procedure:
This compound is prepared analogously to Intermediate AO replacing (2-bromoethoxy)benzene with (2-(2-bromoethoxy)tetrahydro-2H-pyran and replacing Methyl indole-4-carboxylate with 2,3-dimethyl-1H-indole-5-carboxylate; [M+H]+ 318
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1([CH2:10][NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(O)CCC>[NH2:3][C:4]1([CH2:10][NH:11][C:12](=[O:20])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8][N:7]([C:22]2[C:23]3[CH:30]=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:6][CH2:5]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC1(CNC(=O)c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NC1(CNC(=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 100 °C
Reaction time: 17 h
Yield: 56.3 %

Procedure:
A degassed mixture of crude N-(4-amino-piperidin-4-ylmethyl)-4-chloro-benzamide dihydrochloride (6.1 mg), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.6 mg, 0.016 mmol), triethylamine (16 μL, 0.09 mmol) and n-butanol (0.3 mL) was stirred at 100° C. for 17 hours. The solvents were concentrated. The crude mixture was first purified on an SCX-II acidic resin, eluting with methanol then 2M ammonia-methanol, and then by preparative TLC, eluting with 15% methanol-dichloromethane, to give N-[4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylmethyl]-4-chloro-benzamide (3.3 mg, 0.009 mmol, 69% over 2 steps).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:33][N:34](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:33]#[N:34])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CCCCCCc1cccc(-c2nc(C#N)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of 0.275 g (0.50 mmol) of [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) in 10 ml of DMF was treated with 0.118 g (1.0 mmol) of zinc cyanide and 0.058 g (0.05 mmol) of tetrakis-(triphenylphosphine)-palladium. This reaction mixture was heated up to 150° C., stirred for 8 hours at this temperature and subsequently cooled down to RT. Then, it was poured into crashed ice and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.18 g (81%) of the title compound as light yellow oil. MS: 448.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(F)cc2o1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2o1
Yield: 85 %

Procedure:
A solution cf 6-fluoro-2(3H)-benzoxazolone (1.0 g) in 80% aqueous sulfuric acid (6.5 g) was cooled to 0° to 5° C., and 60% nitric acid (0.8 g) was gradually added thereto at 0° to 5° C. The resultant mixture was stirred at the same temperature for 30 minutes and poured onto ice water. The precipitated crystals were collected by filtration, washed with water and dried to give 6-fluoro-5-nitro-2(3H)-benzoxazolone (1.1 g). m.p., 175.4° C. 1H-NMR (CDCl3 +DMSO-D6) δ ppm: 4.0 (1H, broad), 6.8-7.9 (3H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([NH2:16])[C:8]1[N:9]=[C:10]([NH:13][CH:14]=[O:15])[S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH:7]([C:8]1[N:9]=[C:10]([NH:13][CH:14]=[O:15])[S:11][CH:12]=1)[NH:16][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)C(N)c1csc(NC=O)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NC(C(=O)OC(C)(C)C)c1csc(NC=O)n1
Temperature: -45 °C
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
In 100 ml of methylene chloride was dissolved 5.5 g (21.4 mmole) of 2-amino-2-(2-formylamino-1,3-thiazol-4-yl)acetic acid tert-butyl ester, and 2.165 g (21.4 mmole) of triethylamine was added thereto. Then, the mixture was cooled to -45° C. and a solution of 2.92 g (21.4 mmole) of ethyl chlorooxalate dissolved in 10 ml of methylene chloride was added dropwise thereto for 10 minutes. Then, a cooling bath was removed, and the mixture was stirred for 30 minutes. After the mixture was washed with water, it was dried over anhydrous magnesium sulfate and the solvent was evaporated to obtain 7.5 g of the oily title compound. (Yield: 98%)
Reaction SMILES: [I:1]Cl.[CH3:3][C:4]1[CH:10]=[C:9]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[NH2:6][C:5]1[C:4]([CH3:3])=[CH:10][C:9]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:8][C:7]=1[I:1]
Reactant: ClI
Reactant: Cc1cc(-n2cnnn2)ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-n2cnnn2)cc(I)c1N

Procedure:
A solution of iodine monochloride (4.46 g) in acetic acid (30 cm3) was added dropwise to a stirred solution of 2-methyl-4-(tetrazol-1-yl)aniline (4 g) in acetic acid (30 cm3). After 2 hours the mixture was brought to pH 6 by addition of aqueous sodium carbonate solution and extracted with dichloromethane (250 cm3). The organic phase was dried (MgSO4), filtered and evaporated to yield a dark brown solid. This solid was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane to afford 1-(4-amino-3-iodo-5-methylphenyl)tetrazole, m.p. 172°-175°, (6.2 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:28])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[H][H]>CO.C1C=CC=CC=1.[Pd]>[C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=1)([CH3:28])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cn1)O2
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cn1)O2

Procedure:
6 g of 6-acetoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman (prepared as described in Preparation 36) were dissolved in a mixture of 80 ml of methanol and 15 ml of benzene, and, in the presence of 1.5 g of 10% w/w palladium-on-carbon, were catalytically reduced at room temperature for about 20 hours under about 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure, to give the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH:8]1[CH2:11][N:10]([C:12]2[N:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=2[C:14](O)=[O:15])[CH2:9]1.Cl.[NH2:31][C:32]1([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)[CH2:34][CH2:33]1>>[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH:8]1[CH2:11][N:10]([C:12]2[N:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:13]=2[C:14]([NH:31][C:32]2([C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)[CH2:34][CH2:33]2)=[O:15])[CH2:9]1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4cccc(OC(F)(F)F)c4)C3)CC2)cc1
Yield: 73 %

Procedure:
The title compound (D177) (113 mg) was prepared according to the experimental procedure described in Description 144 starting from 2-(3-(3-(trifluoromethoxy)phenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D126) (110 mg, 0.26 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (59.31 mg, 0.26 mmol).