Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4][C:5]1[N:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[CH2:13]([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22](O)=[C:21]([F:27])[CH:20]=1)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:13]([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([O:12][CH2:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH:1]([CH3:3])[CH3:2])[N:10]=2)=[C:21]([F:27])[CH:20]=1)[CH3:14]
Reactant: CC(C)Sc1nccc(CO)n1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(F)c(OCc2ccnc(SC(C)C)n2)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
(2-Isopropylsulfanyl-pyrimidin-4-yl)-methanol (0.08 g, 0.43 mmol) obtained in Step C of Preparation Example 24, 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.1 g, 0.43 mmol) obtained in Step D of Preparation Example 2 and triphenyl phosphine (0.114 g, 0.43 mmol) were dissolved in anhydrous THF (3 mL), and the mixture was stirred at room temperature for 10 minutes. Diisopropyl azodicarboxylate (0.085 mL, 0.43 mmol) was added slowly thereto. The mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure, and separated by column chromatography (eluent: 100% DCM) to obtain the title compound (0.14 g, 81%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].[N:24]([CH2:27][CH2:28][OH:29])=[N+:25]=[N-:26]>CN(C)C=O.CO.[Cu]I>[C:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:26]=[N:25][N:24]([CH2:27][CH2:28][OH:29])[CH:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:23])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:22])(=[O:21])[CH3:20]
Reactant: [N-]=[N+]=NCCO
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (100 mg, 0.318 mmol) in a mixture of N,N-dimethylformamide (DMF) (1.8 mL) and methanol (0.200 mL) were successively added 2-azidoethanol (55.4 mg, 0.636 mmol) and copper(I) iodide (3.03 mg, 0.016 mmol). The resulting mixture was stirred at 100° C. under microwave irradiation for 2 h then cooled to room temperature. The reaction mixture was partitioned between EtOAc and brine and the layers were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient: 2 to 10% MeOH in DCM) gave 1-methylethyl {(2S,4R)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (83 mg, 0.198 mmol, 62%) as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][N:23]=4)[N:18]=[CH:17][C:16]=3[NH2:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:26](OC)(OC)(OC)[CH2:27][CH2:28][CH3:29]>Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:15]4[C:24]5[N:23]=[CH:22][CH:21]=[CH:20][C:19]=5[N:18]=[CH:17][C:16]=4[N:25]=[C:26]3[CH2:27][CH2:28][CH3:29])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Yield: 35.7 %

Procedure:
The methods described in Part A of Example 13 were used to treat N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}[1,5]naphthyridine-3,4-diamine (2.6 g, 7.8 mmol) with trimethyl orthobutyrate (1.9 mL, 12 mmol) in the presence of pyridine hydrochloride (0.018 g, 0.16 mmol) and isolated and purify the final product with the modification that the silica column was eluting with 60-90% ethyl acetate in dichloromethane. 1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridine (1.08 g) was obtained as a white solid.
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C@H:14]([N:25]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][C@@H:12]1[CH3:38])=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:29]([O:28][C:26](=[O:27])[N:25]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C@H:14]1[C:15]2[C:20](=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[NH:11][C@@H:12]([CH3:38])[CH2:13]1)[CH3:30]
Reactant: [H][H]
Reactant: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OCc2ccccc2)c2cc(OC)c(OC)cc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)Nc2cc(OC)c(OC)cc21
Yield: 90.4 %

Procedure:
A solution of cis-4-(benzyl-ethoxycarbonyl-amino)-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (Example 4) (1.0 g, 1.9 mmol) in ethanol (20 mL) was placed in a Parr bottle, charged with 10% palladium on carbon (100 mg), and agitated under 50 psi of hydrogen gas on a Parr shaker for 2 h. The mixture was then filtered through a bed of Celite®, eluting with ethyl acetate, and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography using 30% ethyl acetate/hexanes as eluent to afford 660 mg of the desired final product (89%): MS m/z 204 (M+−PhCH2NHCO2Et−H2+1); 1H NMR (CDCl3) δ1.12 (d, 3H), 1.17 (t, 3H), 3.65 (s, 3H), 3.8 (s, 3H), 6.10 (C5, s, 1H), 6.44 (C8, s, 1H), 7.1-7.3 (m, 5H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:13])[CH3:2].N1C=CC=CC=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:22](=[O:23])[CH2:21][Cl:20])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:13])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCN1C(=O)Cc2cc(O)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1C(=O)Cc2cc(OC(=O)CCl)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a slurry of 100 g. (0.565 mole) of 1-ethyl-5-hydroxyoxindole in 91.3 ml. (1.13 moles) of pyridine and 565 ml. of dichloromethane at 0° C. was added dropwise a solution of 89.3 ml. (1.13 moles) of chloroacetyl chloride in 100 ml. of dichloromethane. The reaction mixture was allowed to stir for 15 minutes, and was then added to 1 l. of ice cold 2N hydrochloric acid and 500 ml. of dichloromethane. The aqueous layer was extracted once again with 300 ml. of dichloromethane and the combined organic extracts washed once with 500 ml. of a saturated brine solution, dried over magnesium sulfate and concentrated to give the desired product in quantitative yield. A small sample was crystallized from hexane, m.p. 53°-57° C.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:47])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:46])[CH2:12][CH2:13][C@@:14]3([C:30]([N:32]4[CH2:37][CH2:36][C:35]([C:44]#[N:45])([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:49])[CH3:48])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:47])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:46])[CH2:12][CH2:13][C@@:14]3([C:30]([N:32]4[CH2:37][CH2:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:44]#[N:45])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:49])[CH3:48]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-cyano-4-phenylpiperidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 75, 2.0 g) was taken in MeOH: THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (1.5 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure and the residue was taken in water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.15-4.18 (m, 2H); 4.56 (s, 1H); 4.71 (s, 1H); MASS: 624 (100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=[S:21].[NH4+].[OH-]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]([NH2:22])=[S:21])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COCCOc1cc(Oc2cccnc2)cnc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOc1cc(Oc2cccnc2)cnc1NC(N)=S
Reaction time: 48 h
Yield: 69 %

Procedure:
3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-ylamine (0.48 mmol) is dissolved in THF (7 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 2 days. 32% NH4OH (20 eq.) is added and stirred 4 hours at room temperature. The solved is removed in vacuo and water (150 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-yl]-thiourea is obtained as yellow solid in a yield of 69%. HPLC (method C): 1.15 min; LC-MS (method A): 0.9 min, 321.15 (MH+).
Reaction SMILES: [CH:1]1([N:5]([CH3:13])[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10])[CH2:4][CH2:3][CH2:2]1.O[Li].O.[ClH:17]>C1COCC1.O>[ClH:17].[CH:1]1([N:5]([CH3:13])[CH2:6]/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)/C=C/CN(C)C1CCC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CN(C/C=C/C(=O)O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of (E)-methyl 4-(cyclobutyl(methyl)amino)but-2-enoate (20) (1.47 g, 8 mmol) in THF/H2O (8 mL/2 mL) was added LiOH.H2O (730 mg, 16 mmol). The reaction mixture was stirred at RT overnight, then acidified with 1N HCl to pH=1 and concentrated in vacuum to afford (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid hydrochloride salt (21) (2.31 g, 97%, mixed with LiCl) as a white solid which was used in the next step without purification. LC-MS (ESI): m/z (M+1) 170.2.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]2[N:24]3[C:19]([C:20]([NH2:25])=[N:21][CH:22]=[N:23]3)=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=4[F:46])=[O:34])=[C:28](F)[CH:27]=3)[CH:17]=2)[CH2:12]1)(=[O:10])[CH3:9]>>[C:8]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]2[N:24]3[C:19]([C:20]([NH2:25])=[N:21][CH:22]=[N:23]3)=[C:18]([C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=4[F:46])=[O:34])=[CH:30][CH:31]=3)[CH:17]=2)[CH2:12]1)(=[O:10])[CH3:9]
Reactant: CC(=O)N1CCC(c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c3c(N)ncnn23)C1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c3c(N)ncnn23)C1
Yield: 25 %

Procedure:
Example 206 (91 mg, 0.182 mmol) is allowed to react with acetic anhydride (20 mg, 0.200 mmol) following the procedure to make N-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea. The product was purified by ether trituration to yield 25 mg (25%) pure desired product. 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1 H), 10.05 (bs, 1 H), 8.54 (d, J=5.1 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.39 to 7.23 (m, 3H), 6.65 (d, J=4.5 Hz, 1H), 3.94 to 3.29 (m, 5H), 2.94 to 2.15 (m, 2H), 1.95 (s, 3H); MS [M+H]+=543.2; HPLC RT=2.66.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:8])[CH2:6][OH:7])[CH2:2][CH3:3].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[Na+].Cl>C1C=CC=CC=1>[CH2:1]([O:4][CH:5]([CH3:8])[CH2:6][O:7][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16])[CH2:2][CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCOC(C)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 41.6 %

Procedure:
4.75 g of 2-propoxypropanol, 5.39 g of p-toluenesulfonyl chloride, 2,24 g and 10 ml of benzene were placed in a 50 ml-reaction vessel and stirred in a nitrogen gas stream for 22 hours at room temperature. Thereafter, 8.6 ml of heated conc. NaOH solution was added to the reaction mixture, followed by stirring for 5 minutes. The reaction liquid was poured into 200 ml of cooled 10%-hydrochloric acid solution and extracted with hexane to obtain 3.2 g of 2-propoxypropyl-p-toluenesulfonate (tosylate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]#[N:12])[CH:5]=1.[H-].[Na+].CI.[CH3:18]COC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:18])=[C:6]([C:11]#[N:12])[CH:5]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(OC)c(C#N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-cyano-4-hydroxybenzoic acid methyl ester from step 1 (1 g, 3.6 mmol) was dissolved in DMF (18 ml) and treated with NaH (290 g, 7.2 mmol) and CH3I (450 μl, 7.2 mmol). The reaction mixture was stirred at room temperature for 24 hours. EtOAc was added to the mixture and extracted with 5% citric acid (2×10 mL), saturated NaHCO3 (2×10 mL) and brine (1×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[Cl:58][C:59]1[CH:60]=[C:61]([N:65]2[C:69]([CH2:70][NH2:71])=[CH:68][C:67]([C:72]([F:75])([F:74])[F:73])=[N:66]2)[CH:62]=[CH:63][CH:64]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([NH:71][CH2:70][C:69]2[N:65]([C:61]3[CH:62]=[CH:63][CH:64]=[C:59]([Cl:58])[CH:60]=3)[N:66]=[C:67]([C:72]([F:73])([F:74])[F:75])[CH:68]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To a solution of 2-(3-chloro-4-(methylsulfonyl)phenyl)propanoic acid (60 mg, 0.229 mmol) in THF (1.9 mL) was added 1-hydroxybenzotriazole (30 mg, 0.229 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (74 mg, 0.229 mmol), N-ethyldiisopropylamine (0.078 mL, 0.458 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (63 mg, 0.229 mmol). The solution was stirred for 48 h at room temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography (eluent: ethyl acetate/cyclohexane (1:2)) to give 2-(3-chloro-4-methylsulfonyl-phenyl)-N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide (example compound D5) (100 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH2:27])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH3:23]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.396 g (10 mmol) of glycine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:8]([CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:14][CH:13]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([C:38]([O:40]C)=[O:39])[CH:35]=[C:34]([C:42]([O:44]C)=[O:43])[CH:33]=2)=[O:30])[C:12]1=[O:46])=[O:9])([CH3:7])([CH3:6])[CH3:5]>O1CCCC1>[C:4]([C:8]([CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:14][CH:13]([NH:28][C:29](=[O:30])[NH:31][C:32]2[CH:33]=[C:34]([C:42]([OH:44])=[O:43])[CH:35]=[C:36]([CH:37]=2)[C:38]([OH:40])=[O:39])[C:12]1=[O:46])=[O:9])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)c1cc(NC(=O)NC2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)CN1C(=O)C(NC(=O)Nc2cc(C(=O)O)cc(C(=O)O)c2)CN(C2CCCCC2)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
Aqueous lithium hydroxide monohydrate (420 mg) solution (20 ml) was added to a solution of 1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-[3,5-bis(methoxycarbonyl)phenyl]urea (593 mg) in tetrahydrofuran (20 ml), the mixture was stirred at 50° C. for 2 hours. After allowed to cool, the reaction mixture was concentrated under reduced pressure, the residue was acidified with 1N hydrochloric acid, extracted with the mixed solvent of chloroform and methanol (5:1), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, Isopropyl alcohol was added to the residue, crystals so precipitated were collected by filtration, to thereby obtain 420 mg of the title compound (Yield: 74%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15][C:14](=O)[C:9]2[C:10]([CH3:13])=[CH:11][O:12][C:8]=2[CH2:7]1.[C:17]([NH:20][NH2:21])([NH2:19])=[NH:18].[ClH:22].Cl>C(O)C>[ClH:22].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:15]/[C:14](=[N:21]\[NH:20][C:17]([NH2:19])=[NH:18])/[C:9]2[C:10]([CH3:13])=[CH:11][O:12][C:8]=2[CH2:7]1
Reactant: Cc1coc2c1C(=O)CC(c1ccco1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccco1)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of 6-(2-furyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.22 g) and aminoguanidine hydrochloride (113 mg) were ethanol (20 ml) and 6N hydrochloric acid (0.088 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-furyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 47) (0.22 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[N:6][CH:7]=1.N(OCCC(C)C)=O.[CH3:17][CH:18]([OH:20])[CH3:19]>Cl>[Br:8][C:4]1[CH:3]=[C:2]([O:20][CH:18]([CH3:19])[CH3:17])[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)O
Reactant: Nc1cncc(Br)c1
Agent: CC(C)CCON=O
Agent: Cl
Product: CC(C)Oc1cncc(Br)c1

Procedure:
A slurry of 5-amino-3-bromopyridine (1.29 g, 7.46 mmol) in 6M HCl solution (5 mL) was stirred 30 min at ambient temperature. The mixture was concentrated under high vacuum, and the residue was vacuum dried for 15 h at 50° C., affording a tan solid. The solid was slurried in 2-propanol (25 mL), and treated with isoamyl nitrite (1.70 g, 15.00 mmol). The mixture was stirred and heated under reflux for 1.5 h. The solution was concentrated by rotary evaporation, and the residue was partitioned between diethyl ether and 1M NaOH solution. The aqueous layer was separated and extracted with ether. The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing an orange oil (2.03 g). The oil was purified by vacuum distillation, collecting the fraction with bp 105-115° C. at 9 mm Hg. The distilled product was further purified by column chromatography on silica gel, eluting with 10→20% (v/v) diethyl ether in hexane. Selected fractions, based upon TLC analysis (Rf 0.40 in hexane-ether, (4:1, v/v)) were combined and concentrated by rotary evaporation to give 566.0 mg (35.2%) of a clear, colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11](=[O:13])[CH3:12].[Br-:14].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:14][CH2:12][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1)=[O:13]
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
25 g (143 mmol) of 1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone were dissolved in 750 ml of THF, 64.7 g (172 mmol) of phenyltrimethylammonium tribromide were added, and the mixture was stirred at room temperature for 15 h. The resultant precipitate was filtered, and the filtrate was evaporated to dryness. The residue was taken up in ethyl acetate, washed with 2× sat. sodium hydrogencarbonate solution and 1× sat. sodium chloride solution, the organic phase was dried over sodium sulfate and evaporated to dryness.
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: CC#CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
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.