Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[NH:36][C:35](=[O:37])[NH:34][C:33]2=[O:38])[CH2:28][CH2:27]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:26]3[CH2:27][CH2:28][CH:29]([CH:32]4[NH:36][C:35](=[O:37])[NH:34][C:33]4=[O:38])[CH2:30][CH2:31]3)=[O:18])[CH2:15][C:4]=2[CH:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=C1NC(=O)C(C2CCNCC2)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(C2CCN(C(=O)C[C@@H]3Cc4cc(Cl)c5[nH]ncc5c4CN(CC(F)(F)F)C3=O)CC2)N1
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a solution of (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) in DMF (2.0 mL) was added 5-(piperidin-4-yl)imidazolidine-2,4-dione (37 mg, 0.2 mmol) followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (47 mg, 0.15 mmol) and triethylamine (1.0 mL). After 2 h, the solvent was removed under reduced pressure and the crude product was purified by Prep HPLC to give 5-(1-(2-((S)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)piperidin-4-yl)imidazolidine-2,4-dione (30 mg) in 42% yield. 1H NMR (500 MHz, CD3OD): in δ 8.27 (s, 1H), 7.21 (s, 1H), 5.54 (d, J=17 Hz, 1H), 4.82 (d, J=17 Hz, 1H), 4.69-4.54 (m, 2H), 4.18-3.95 (m, 4H), 3.30-2.96 (m, 4H), 2.71-2.62 (m, 1H), 2.58-2.48 (m, 1H), 2.21-2.12 (m, 1H), 1.91-1.84 (m, 2H), 1.66-1.31 (m, 2H); MS (ESI) 541 (M+H); Rf=2.05.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([O:18][CH2:19][CH3:20])[CH:10]=1)[C:3](OCC)=[O:4].[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+]>COCCO>[CH2:19]([O:18][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH3:17])[CH2:8][CH:2]1[S:23][C:22](=[NH:21])[NH:24][C:3]1=[O:4])[CH3:20]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC)c(OCC)c1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCOc1ccc(CC2SC(=N)NC2=O)cc1OCC
Temperature: 110 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
In 120 ml of ethylene glycol monomethyl ether is dissolved 11.7 g of ethyl 2-chloro-3-(3,4-diethoxyphenyl)propionate, followed by addition of 4.4 g of thiourea and 3.8 g of sodium acetate. The mixture is stirred at 110° C. for 15 hours. The solvent is distilled off under reduced pressure, water is added to the residue and extraction is carried out with ethyl acetate. The extract is washed with water, dried (over MgSO4) and distilled to remove the ethyl acetate. The above procedure provides 7.5 g (65.2%) of 5-(3,4-diethoxybenzyl)-2-iminothiazolidin-4-one as crystals melting at 171°-172° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:6][N:5]2[C:17](=[O:20])[NH:18][N:19]=[C:4]2[CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:23][N:18]1[C:17](=[O:20])[N:5]2[N:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[C:2]([CH3:1])=[CH:3][C:4]2=[N:19]1
Reactant: CI
Reactant: Cc1cc2n[nH]c(=O)n2nc1-c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nn(C)c(=O)n2nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
A suspension of 3.0 g. of 7-methyl-6-(m-nitropheyl)-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one in 30 ml. of dry dimethylformamide is stirred for 10 minutes. A 0.54 g. portion of a 50% oil suspension of sodium hydride is added and the mixture is stirred for 1/2 hour with cooling. A 0.75 ml. portion of methyl iodide is added, the mixture is stirred for one hour and then filtered. The solid is washed with water and dried, giving 2.12 g. of the desired product as a yellow solid, m.p. 250°-253° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[CH2:9][C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)c(OC)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(CC(=O)O)C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of ethyl 2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)amino)-acetate (0.260 g, 0.736 mmol) in THF (1.5 ml), lithium hydroxide 1N (0.883 ml, 0.883 mmol) was added, and the reaction was stirred at RT for 4 hours. The mixture was diluted with EtOAc (15 ml) and acidified with HCl 1M. The organic phase was washed with brine and dried over Na2SO4; the solvent was evaporated to dryness affording 2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)amino)acetic acid as a yellow oil (0.233 g, 0.716 mmol, 97% yield, MS/ESI+ 348.1 [MNa]+). This product was used without any further purification.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>CCCCCCC>[C:1]([C:6]1[C:7](=[O:17])[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])=[CH:9][C:10](=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCC(C)(C)c1cccc(C(C)(C)CC)c1O
Solvent: C1CCNCC1
Solvent: CCCCCCC
Product: CCC(C)(C)C1=CC(=Cc2ccccc2)C=C(C(C)(C)CC)C1=O
Yield: 41.7 %

Procedure:
6.0 g (0.026 Mol) of 2,6-di-tert-amylphenol, 2.75 g (0.026 mol) of benzaldehyde and 4.37 g (0.05 1 mol) of piperidine are refluxed under nitrogen in 50 ml of heptane on a Dean-Stark trap for 24 hours. The solution is then evaporated in vacuo and the residue chromatographed twice on silica gel with hexane and then with hexane:ethyl acetate (9:1 ) to give 3.5 g of the title compound as a thick yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(-c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cnn(-c2ccccc2)c1
Reaction time: 8 h
Yield: 73.3 %

Procedure:
10% Pd/C (25 mg) was added to a stirred solution of 4-nitro-1-phenyl-1H-pyrazole (240 mg, 1.2 mmol) in a mixture of MeOH (2.5 mL) and EtOAc (2.5 mL) and stirred under H2 atmosphere overnight. The reaction mixture was filtered through celite and the filtrate so obtained was concentrated under reduced pressure to afford 140 mg (69365% Yield) of 4-amino-1-phenyl-1H-pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:6][C:7]=1[O:8]C.CC(O)=O.O>I>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)cc1F
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc(O)c(F)c2)oc2ccccc12
Temperature: 110 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To a solution of 2′-hydroxyacetophenone (1.36 g, 10 mmol) in 20 mL anhydrous pyridine was added 3-fluoro-4-methoxybenzoyl chloride (1.89 g, 10 mmol) and the reaction mixture was stirred at rt for 15 h under a nitrogen atmosphere. The reaction mixture was poured into 200 mL of 2 N HCl. The formed solid was isolated by filtration, washed with water and dried under vacuum to give a white solid (2.76 g, 95.7%). The compound (2.68 g, 9.3 mmol) was dissolved in 10 mL anhydrous pyridine. Powdered potassium hydroxide (1.57 g, 27.9 mmol) was added and the reaction mixture was stirred at rt overnight under nitrogen. Water (100 mL) was added, the solid was isolated by filtration and washed with water to give a yellow solid (1.83 g, 68%). The compound (1.78 g, 6.17 mmol) was suspended in 15 mL glacial AcOH. Five drops of conc. HCl was added and the reaction mixture was stirred at 110° C. for 2 h, then cooled to rt. Water (100 mL) was added. The formed solid was separated by filtration, washed with water and dried under vacuum to give 2-(3-fluoro-4-methoxyphenyl)chromen-4-one as a white solid (1.62 g, 97%). 2-(3-Fluoro-4-methoxyphenyl)chromen-4-one (1.6 g, 5.92 mmol) was suspended in 40 mL of HI. Glacial AcOH (15 mL) was added and the reaction mixture was stirred at 110° C. for 4 h, then cooled to rt. Water (200 mL) was added, and the solid was isolated by filtration, washed with water and dried under vacuum. The crude compound was washed with 1:1 dichloromethane and methanol (15 mL) to give 1.1 g of 2-(3-fluoro-4-hydroxyphenyl)chromen-4-one (72%) as a pale yellow solid. MS (ES) m/z: 257.91 (M+1), 256.88 (M); Mp. 275-276° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1>>[CH:18]1([N:13]2[C:12]([C:33]3[CH:34]=[CH:35][S:31][CH:32]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: c1cc(-c2c3c(nn2C2CCCC2)CCNCC3)cs1
Yield: 89.9 %

Procedure:
The title compound (114 mg) was prepared as in Example 177, Steps C and D, using 200 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 169 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C16H21N3S, 287.15; found, m/z 288.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.68-7.63 (m, 1H), 7.56-7.51 (m, 1H), 7.17-7.12 (m, 1H), 4.58 (m, 1H), 3.43-3.37 (m, 2H), 3.34-3.28 (m, 2H), 3.19-3.14 (m, 2H), 2.86-2.80 (m, 2H), 2.04-1.85 (m, 6H), 1.67-1.57 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-])=O.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[NH2:1][C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:5]=1[C:6]([N:27]1[CH2:28][CH2:29][N:24]([C:18]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=2[CH3:16])[CH2:25][CH2:26]1)=[O:8]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N)CC2)c(C)c1
Yield: 95 %

Procedure:
Using 2,4-dinitrobenzoic acid (585 mg) and 1-(2,4-dimethylphenyl)piperazine (523 mg) and by the reaction and treatment in the same manner as in Preparation Example 148, the title compound (847 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([OH:26])[C@H:5]([S:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[NH2:25])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C(O)C.[OH-].[Na+]>O>[NH2:25][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[S:14][C@H:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[C@@H:4]([OH:26])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)[C@H](O)[C@H](Sc1ccc2ccccc2c1N)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc([C@@H](Sc2ccc3ccccc3c2N)[C@@H](O)C(=O)O)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 8.9 g (0.023 mol) of (±)-(S*,R*)-β-[(1-amino-2-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid methyl ester, 50 ml ethanol and 140 ml 1N sodium hydroxide was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and extracted with ether (2×75 ml). The aqueous solution was chilled, then neutralized with acetic acid and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with water (75 ml) and dried (MgSO4). Removal of the solvent gave 8.2 g (96%) of (±)-(S*,R*)-β-[(1-amino-2-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid, mp 167°-168°. The analyzed sample was recrystallized from ethyl acetate, mp 167°-168°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:15](=[O:18])[CH:16]=[CH2:17]
Reactant: C=CC(=O)Cl
Reactant: COCCNc1ccc([N+](=O)[O-])cc1
Product: C=CC(=O)N(CCOC)c1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 3, react N-(2-methoxyethyl)-4-nitrobenzenamine with propenoyl chloride to obtain the title compound.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]([F:41])([F:40])[C:23]1[CH:24]=[C:25]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.[OH-].[Na+]>>[F:21][C:22]([F:40])([F:41])[C:23]1[CH:24]=[C:25]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:37][CH:38]=2)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 3′,5′-Bis-trifluoromethyl-biphenyl-4-ol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C27H24F6O5 [M+Na]+: 565, [M+H]+: 543.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: COc1ccc(S)cc1
Product: COc1ccc(Sc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1

Procedure:
The title compound was prepared from 4-methoxybenzenethiol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 239.4-242.3° C. 1H NMR (acetone-d6/300 MHz) 7.84 (s, 1H), 7.55 (m, 3H), 7.16 (d, 2H, J=8.7 Hz), 6.20 (s, 1H), 5.75 (q, 1H, J=7.0 Hz), 3.90 (s, 3H). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz) ESLRMS m/z 415 (M−H). ESHRMS m/z 415.0005 (M−H, Calc'd 415.0019). Anal. Calc'd for C18H12ClF3O4S: C, 51.87; H, 2.90; Cl, 8.51; S, 7.69. Found: C, 51.76; H, 2.83; Cl 8.55; S, 7.77.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH3:15])=[CH:10][CH:9]=1.S(=O)(=O)(O)[O-:18].[Na+]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]=[O:18])=[CH:10][CH:9]=1
Reactant: O=S(=O)([O-])O
Reactant: CC(O)c1ccc(OC2CCCCO2)cc1
Agent: [Na+]
Solvent: ClCCl
Product: O=CCc1ccc(OC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 740 g. of Celite diatomaceous earth and 396 g. of chromium trioxide-dipyridine complex (Collins' reagent) in 4 l. of anhydrous methylene chloride, cooled to 0°C is added dropwise a solution of 58 g. of 4-(tetrahydropyran-2-yloxy)phenylethanol in 3 l. of anhydrous methylene chloride, maintaining the temperature of the reaction mixture at 0°-5°C. After completion of the addition, the reaction mixture is stirred for 30 minutes further at 0°C, 396 g. of sodium bisulfate are added and the mixture stirred for 15 additional minutes. It is then filtered through anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, to yield 4-(tetrahydropyran-2-yloxy)phenylacetaldehyde.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[CH2:12]([NH:15][CH2:16][CH:17]=[O:18])[C:13]#[CH:14]>C(OCC)(=O)C>[CH2:12]([N:15]([CH2:16][CH:17]=[O:18])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11])[C:13]#[CH:14]
Reactant: C#CCNCC=O
Reactant: O=C=Nc1nnc(C2CC2)s1
Solvent: CCOC(C)=O
Product: C#CCN(CC=O)C(=O)Nc1nnc(C2CC2)s1

Procedure:
A mixture of 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (7 grams), the dimethyl acetal of 2-propargylaminoacetaldehyde (5 grams) and ethyl acetate (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the mixture is stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:25]4[CH2:30][CH2:29][S:28][CH2:27][CH2:26]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C1CSCCN1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 37 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using thiomorpholine instead of 2,2,2-trifluoroethylamine, to the title compound (46 mg, 37%) which was obtained as a light yellow solid. MS: m/e=414.4 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1.Cl.[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1
Reactant: CC1(C)OB(c2ccc(OCCCBr)cc2)OC1(C)C
Reactant: C[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 78 °C
Reaction time: 12 h
Yield: 84.2 %

Procedure:
2-[4-(3-Bromopropoxy)phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (20.47 g, 60 mmol), (R)-2-methylpyrrolidine hydrochloride (7.663 g, 63 mmol) and dry, pulverized K2CO3 (24.96 g, 180 mmol) were mixed in dry CH3CN (650 mL). After stirring for 12 h at 78° C. under a nitrogen atmosphere, the reaction mixture was cooled and further (R)-2-methylpyrrolidine hydrochloride (10.0 g, 82 m mol) was introduced and heating at 78° C. was continued for 24 h. The reaction mixture was cooled, filtered and the filtrate was evaporated. Chromatography on silica gel, eluting initially with CH2Cl2, then with a mixture of CH2Cl2/EtOH/aq. NH3 (290:10:1) and later with a (90:10:1) and (40:10:1) mixture of these solvents provided the title compound (17.44 g, 84%). The material crystallized on seeding. A sample was converted into a hydrochloride salt, m.p. 212-214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=O.[CH2:16]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18].CCN=C=NCCCN(C)C>CN(C)C=O.C(OCC)C>[CH2:16]([N:19]([CH2:20][CH2:21][CH3:22])[C:13]([CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1)=[O:15])[CH2:17][CH3:18]
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Reactant: CCCNCCC
Agent: CCN=C=NCCCN(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)Cc1c[nH]c2ccc(OC)cc12
Reaction time: 12 h
Yield: 51.2 %

Procedure:
A solution of 5-methoxyindole-3-acetic acid (500 mg, 2.44 mmol) in 4.8 mL of N,N-dimethylformamide was added di-n-propylamine (0.60 mL, 7.2 mmol) and EDCI (1.90 g, 9.6 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 12 h, the reaction mixture was diluted with diethyl ether, and washed with water and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (360 mg, 51%).
Reaction SMILES: [CH3:1][CH:2]([CH:13](C([O-])=O)[C:14]([O:16]CC)=[O:15])[CH2:3][CH:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>>[CH3:1][CH:2]([CH2:3][CH:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCCCCCCC(C)CC(C)C(C(=O)[O-])C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCC(C)CC(C)CC(=O)O
Temperature: 170 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, the crude product (41.6 g, 0.0899 mol) of ethyl 2-(1,3-dimethyldecyl)malonate (4Et) obtained in the method of Example 1-1 and a 13% by weight aqueous sodium hydroxide solution (87 g) were placed in a reaction vessel and stirred for one hour under refluxing with heating. Then ethanol thus generated therein was distilled off in one hour. The resulting mixture was subjected to addition of 20% by weight hydrochloric acid (87 g) and extracted with a mixture of toluene and tetrahydrofuran. The resulting organic phase was concentrated under reduced pressure, and then the residue was stirred under heat at 170° C. for 6 hours in a nitrogen atmosphere. This reaction mixture was diluted with tetrahydrofuran, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate thus obtained was distilled under reduced pressure (bp 130 to 140° C./2 mmHg) to obtain 3,5-dimethyldodecanoic acid (5) (18.9 g, 0.0828 mol). A total yield of three steps from the 2-methylnonyl chloride (1Cl) was 67%.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])=[CH:33][CH:32]=1>O1CCCC1.C(N(C(C)C)CC)(C)C>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:34]4[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=4)=[O:42])=[CH:3][C:4]=3[F:29])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (84.3 mg) in tetrahydrofuran (2.5 ml) were added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 5.02 ml) and diisopropylethylamine (0.218 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine 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, then ethyl acetate:methanol=95:5) to provide the titled compound (34.0 mg, 28%) as white powder.