Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(N(CC)C(C)C)(C)C.O1CCCC1.[C:42](O)(=[O:46])[C@H:43]([CH3:45])[OH:44]>>[OH:44][C@@H:43]([CH3:45])[C:42]([N:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1)=[O:46]
Reactant: C[C@H](O)C(=O)O
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(C(=O)[C@H](C)O)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of 8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.811 g, 0.000786 mol) and N,N-diisopropylethylamine (0.274 mL, 0.00157 mol) in tetrahydrofuran (5.0 mL, 0.062 mol) was added simultaneously L-lactic acid (0.0708 g, 0.000786 mol) and N,N,N′,N′-tetramethyl-β-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.329 g, 0.000865 mol). The reaction was stirred at room temperature overnight. The mixture was partitioned between saturated sodium bicarbonate and methylene chloride and extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 490 (191.2 mg) as a colorless solid. MS(ESI+) 454.2. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2, 1H), 7.22 (m, 1H), 7.06 (s, 1H), 5.84-5.66 (m, 1H), 5.09 (dd, J=11.1, 5.8, 1H), 4.65 (m, 1H), 4.37 (t, J=5.0, 2H), 4.28 (m, 2H), 4.16 (quin, J=6.5, 1H), 3.94-3.78 (m, 2H), 3.43 (t, J=5.0, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6, 6H), 1.21 (d, J=6.7, 3H)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:34])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([I:33])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:33][C:29]1[CH:28]=[C:27]([C:25]2[CH2:24][C:23](=[O:34])[NH:22][C:9]3[CH:10]=[C:11]([C:14]#[C:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(I)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(I)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1
Yield: 78.2 %

Procedure:
Prepared from {2-[3-(3-iodo-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example K7) (871 mg, 1.5 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (542 mg).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].O.[F:6][CH:7]([F:34])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[C:12]([C:30]([O:32][CH3:33])=[O:31])[CH:11]=1>CC(O)=O>[C:2]([N:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([F:34])[F:6])=[CH:11][C:12]=1[C:30]([O:32][CH3:33])=[O:31])[CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:21][CH2:22]1)(=[O:3])[NH2:1]
Reactant: COC(=O)c1cc(OCC(F)F)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(OCC(F)F)ccc1N(C(N)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 12 h
Yield: 95 %

Procedure:
1.95 g of potassium isocyanate in solution of 4 ml of water are added to a solution of 6.63 g of 1,1-dimethylethyl 4-{[4-(2,2-difluoroethoxy)-2-(methoxycarbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 3.3 in 40 ml of AcOH. The mixture is stirred at AT for 12 h 00. It is extracted with AcOEt and the extract is washed with a saturated K2CO3 solution and then with water. It is dried over MgSO4, filtered and evaporated under reduced pressure to give 6.95 g of the expected product.
Reaction SMILES: [CH2:1]([Li])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][N-:8][CH3:9].[CH3:10][N-:11][CH3:12].C[N-]C.C[N-]C.[Ti+4:19]>CCCCC>[CH3:7][N-:8][CH3:9].[CH3:10][N-:11][CH3:12].[CH2:1]([Ti+2:19][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [Li]CC(C)(C)C
Reactant: [Ti+4]
Agent: C[N-]C
Solvent: CCCCC
Product: CC(C)(C)C[Ti+2]CC(C)(C)C
Yield: 86.4 %

Procedure:
A solution of 4.87 g of neopentyllithium in pentane was added to a solution of 7.0 g of titanium tetrakis(dimethylamide) in pentane with stirring. Lithium dimethylamide precipitated rapidly. The total amount of pentane in the reaction mixture was about 50-100 ml. After being stirred for one hour the mixture was filtered, and pentane was evaporated from the filtrate to give 7.5 g (86%) of dineopentyltitanium bis(dimethylamide) as an air-sensitive yellow oil. Nmr C6D6 : δ (NMe) 3.23, δ (CMe3) 1.05 ppm downfield from tetramethylsilane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[N:4][C:5]([Cl:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:27][NH2:28]>C(O)(=O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:28][NH:27][C:13](=[O:14])[C:6]=2[C:5]([Cl:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1
Reactant: NN
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccc(N)cc2)c(N)c1C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(-c2nc(Cl)c3c(=O)[nH][nH]c(=O)c3c2N)cc1
Temperature: 90 °C

Procedure:
To 0.30 g of 3-amino-6-chloro-4,5-diethoxycarbonyl-2-(4-aminophenyl)pyridine was added 6 ml of hydrazine monohydrate, and the mixture was heated at 90° C. for 30 minutes. The reaction mixture was poured into 150 ml of ice-water and the mixture was adjusted to pH 6 with acetic acid. The resultant precipitate was collected by filtration, and washed with water, followed by reprecipitation from DMSO/H2O, whereby 0.21 g of the title compound was obtained as orange powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[CH3:32][O:33][C:34](=[O:44])[CH:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)O>>[CH3:32][O:33][C:34](=[O:44])[CH:35]([O:8][C:7]1[C:6]([Br:9])=[CH:5][C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:14][CH:15]=2)=[CH:3][C:2]=1[Br:1])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COC(=O)C(O)Cc1ccccc1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2cc(Br)c(O)c(Br)c2)cc1
Product: COC(=O)C(Cc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3nc(-c4ccc(C(F)(F)F)cc4)oc3C)cc2)cc1Br

Procedure:
The title compound was prepared from 3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol, and 3-phenyllactic acid methyl ester in substantially the same manner, as described in Example 7, and was obtained as a white solid, mp 70–72° C.; MS m/e 713 (M+);
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[N:39](S(C2C=CC(C)=CC=2)(=O)=O)[C:20]2=[N:21][CH:22]=[CH:23][C:24]([CH2:25][NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([S:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)=[C:19]2[CH:18]=1>CO.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[NH:39][C:20]2=[N:21][CH:22]=[CH:23][C:24]([CH2:25][NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([S:34][C:35]([F:37])([F:38])[F:36])=[CH:30][CH:29]=3)=[C:19]2[CH:18]=1
Reactant: COc1cc2c(-c3cc4c(CNCc5ccc(SC(F)(F)F)cc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(-c3cc4c(CNCc5ccc(SC(F)(F)F)cc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 97 %

Procedure:
0.265 cm3 of 5N potassium hydroxide is added to a solution of 0.04 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine in 2 cm3 of methanol, at a temperature in the region of 20° C. The reaction medium is refluxed for 6 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 4 cm3 of water. The solid formed is filtered off on a sinter funnel, washed twice with 3 cm3 of water and then dried under vacuum to give 0.030 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine, the characteristics of which are as follows:
Reaction SMILES: COC1C=CC(N(OC(C)C(O)C)OC(C)C(O)C)=C(CCC)C=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.C1(P(Cl)Cl)C=CC=CC=1.[CH2:49]([O:53][CH2:54][CH:55]1[CH2:62][N:61]([C:63]2[CH:68]=[CH:67][C:66]([O:69][CH2:70]CCCCCCCCCCC)=[CH:65][CH:64]=2)[CH2:60][CH:59]([CH2:82][O:83][CH2:84][CH2:85][CH2:86][CH3:87])[O:58][P:57](=[O:94])([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[O:56]1)[CH2:50][CH2:51][CH3:52]>ClCCl>[CH2:84]([O:83][CH2:82][CH:59]1[CH2:60][N:61]([C:63]2[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=2)[CH2:62][CH:55]([CH2:54][O:53][CH2:49][CH2:50][CH2:51][CH3:52])[O:56][P:57](=[O:94])([C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)[O:58]1)[CH2:85][CH2:86][CH3:87]
Reactant: CCCCCCCCCCCCOc1ccc(N2CC(COCCCC)OP(=O)(c3ccccc3)OC(COCCCC)C2)cc1
Agent: CCCc1cc(OC)ccc1N(OC(C)C(C)O)OC(C)C(C)O
Agent: CN(C)c1ccccn1
Agent: ClP(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOCC1CN(c2ccc(OC)cc2)CC(COCCCC)OP(=O)(c2ccccc2)O1
Yield: 24 %

Procedure:
It is prepared from 4-methoxy-N,N-di(2-hydroxy-3-butoxy)-propyl aniline (1.91 g, 5 mmol), pyridine (1.2 g, 15 mmol), dimethylaminopyridine (0.2 g) and phenylphosphonous dichloride (1 g, 5.1 mmol) in dichloromethane as described for compound 200 to obtain a colourless liquid 0.6 g (24%) and its isomer 0.6 g (24% a colourless liquid).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>>[O:21]1[CH2:20][CH:19]1[CH2:17][O:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5]
Reactant: BrCC1CO1
Reactant: COC(=O)CCC(=O)c1ccc(C)cc1O
Product: COC(=O)CCC(=O)c1ccc(C)cc1OCC1CO1

Procedure:
Methyl 3-(2-hydroxy-4-methylbenzoyl)propionate was reacted wtih epibromohydrin in a similar manner to the procedure described in Example 1 (ii) to give methyl 3-[2-(2,3-epoxypropoxy)-4-methylbenzoyl]propionate, m.p. 61.5°-63°.
Reaction SMILES: C([O-])(=O)C.[Na+].S(O)(O)(=O)=O.[CH3:11][S:12][C:13](=[NH:15])[NH2:14].[CH2:16]([O:18][C:19](=[O:34])[C:20]([C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Br:32])=[CH:21]N(C)C)[CH3:17]>CN(C)C=O>[CH2:16]([O:18][C:19]([C:20]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Br:32])=[N:15][C:13]([S:12][CH3:11])=[N:14][CH:21]=1)=[O:34])[CH3:17]
Reactant: CSC(=N)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Br
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1-c1ccccc1Br
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a suspension of 3.81 g (46.54 mmol) sodiumacetate and 6.47 g (23.27 mmol) S-methylisothiourea sulfate in 100 ml N,N-dimethylformamide a solution of 6.90 g (21.15 mmol) 2-(2-bromo-benzoyl)-3-dimethylamino-acrylic acid ethyl ester in 20 ml N,N-dimethylformamide was added at once and the resulting reaction mixture was stirred for 16 hrs. at 90°. The solvent was evaporated and the residue distributed between 100 ml CH2Cl2 and 100 ml H2O. The aqueous phase was extracted twice with 100 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2) to give 5.20 g (69%) 4-(2-bromo-phenyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester as a pale green oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:39]([C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][C:35]=1[C:43]([F:46])([F:44])[F:45])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(F)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 4-fluoro-2-(trifluoromethyl)benzenesulfonyl chloride (18 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 27 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-fluoro-2-(trifluoromethyl)benzenesulfonamide (percentage yield: 89%), was obtained.
Reaction SMILES: CO.[OH-].[Na+:4].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:24][C:25]([C:27]3[CH:28]=[N:29][CH:30]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:32]=3)=[O:26])[CH:16]=2)=[CH:7][N:6]=1>O1CCOCC1>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O-:21])=[O:20])=[C:17]([NH:24][C:25]([C:27]3[CH:28]=[N:29][CH:30]=[C:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:32]=3)=[O:26])[CH:16]=2)=[CH:7][N:6]=1.[Na+:4]
Reactant: O=C(Nc1cc(-c2cncc3ccccc23)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2cncc3ccccc23)ccc1C(=O)[O-])c1cncc(-c2ccccc2)c1

Procedure:
Methanol (5 mL), dioxane (5 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.091 mL) were added to the obtained 4-(isoquinolin-4-yl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid (81 mg), and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 83 mg of sodium 4-(isoquinolin-4-yl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([F:23])[CH:25]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Reactant: O=C(O)c1cccc(F)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2cccc(F)c2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 3-fluorobenzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-fluorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 452.1 (M)+
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH3:51])[CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:50][CH2:49][CH:48]([CH3:51])[CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 37.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (9.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.9 mg) was obtained.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:8]([C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)[CH3:9])[C:5]([OH:7])=[O:6].[CH3:15]O>>[NH2:3][CH:4]([CH:8]([C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)[CH3:9])[C:5]([O:7][CH3:15])=[O:6]
Reactant: CO
Reactant: CC(c1c[nH]cn1)C(N)C(=O)O
Agent: Cl
Product: COC(=O)C(N)C(C)c1c[nH]cn1

Procedure:
9.40 g (38.9 mmol) of 2-amino-3-(1H-imidazol-4-yl)butyric acid dihydrochloride are solved in 100 ml methanol. Dry HCl-gas is bubbled through the solution while heating under reflux for 4 hours. After cooling the excess hydrochloric acid is removed by evaporation in vacuo. Yield: 9.8 g (98%) methyl 2-amino-3-(1H-imidazol-4-yl)butyrate hydrochloride as an amorphous solid.
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[S:11]([NH:14][CH2:15][C:16]([OH:18])=O)(=[O:13])=[O:12].[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:18])(=[O:12])=[O:13]
Reactant: O=C(O)CNS(=O)(=O)c1ccc2ccccc2c1
Reactant: COC(=O)CCCN
Product: COC(=O)CCCNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Yield: 56 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 30 which is concerned with the preparation of starting materials, N-(2-naphthylsulphonyl)glycine was reacted with methyl 4-aminobutyrate to give methyl 4-[2-(2-naphthalenesulphonamido )acetamido]butyrate in 56% yield.
Reaction SMILES: Br[CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:26][N:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=3)[CH2:36]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(CCCCC(C)Br)Sc2ccc(C)cc2)cc1OC
Agent: Cl
Product: COc1ccc(C(CCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 38 %

Procedure:
The procedure of Example 49 is repeated using 5.22 g of 4-[6-bromo-1-[(4-methylphenyl)thio]heptyl]-1,2-dimethoxybenzene, 3.29 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 2.49 g of the desired product as a yellow gum.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:28]=[C:29]([OH:36])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34].O>CN(C)C=O>[CH3:26][C:27]1[CH:28]=[C:29]([O:36][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])c(C)c1
Temperature: 110 °C
Reaction time: 60 h
Yield: 112.9 %

Procedure:
1-Bromooctadecane (43.54 g, 0.131 mol) and potassium carbonate (54.15 g, 0.392 mol) were added to a solution of 3-methyl-4-nitrophenol (20 g, 0.131 mol) in dimethylformamide (120 mL) The reaction mixture was heated to 110° C. and stirred at this temperature for 60 hours. The reaction mixture was cooled and poured into water (2 L), stirred for 0.5 hour and extracted with methylene chloride (1 L). The organic extract was washed with 5% aqueous solution sodium bicarbonate (0.5 L), water (2×0.6 L), dried over sodium sulfate and concentrated to give (60 g) of crude product. This product was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:13]1[CH2:18][CH2:17][CH:16]2[S:19][C:20](=[O:22])[CH:21]=[C:15]2[CH2:14]1)[C:9]([O:11][CH3:12])=[O:10].Cl[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25].C(OC(OC1SC2CCN([C@@H](C3C=CC=CC=3Cl)C(OC)=O)CC=2C=1)=O)C(C)C>CO>[CH:27]([O:26][C:24]([O:22][C:20]1[S:19][C:16]2[CH2:17][CH2:18][N:13]([C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([O:11][CH3:12])=[O:10])[CH2:14][C:15]=2[CH:21]=1)=[O:25])([CH3:29])[CH3:28]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1CCC2SC(=O)C=C2C1
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sc(OC(=O)OCC(C)C)cc2C1
Solvent: CO
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sc(OC(=O)OC(C)C)cc2C1
Yield: 94 %

Procedure:
Following the method described in Example 18, (2S)-methyl 2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate (IV-1) (85 mg) was reacted with isopropyl chloroformate (0.23 ml), to prepare (S)-methyl 2-(2-(isobutoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-15) (100 mg). Yield: 94%, ee=97.5% (chiral HPLC analysis conditions were the same as those in Example 4), [α]D20=+34.00° (c 0.50, MeOH); 1H-NMR (300 MHz, CDCl3) δ 1.36 (d, 6H, J=6.2 Hz), 2.77-2.78 (m, 2H), 2.86-2.89 (m, 2H), 3.52 (d, 1H, J=14.2 Hz), 3.64 (d, 1H, J=14.3 Hz), 3.72 (s, 3H), 4.90 (s, 1H), 4.93-5.01 (m, 1H), 6.30 (s, 1H), 7.24-7.68 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 21.6, 25.4, 48.1, 50.3, 52.1, 67.8, 73.9, 112.2, 125.7, 127.1, 129.4, 129.8, 129.9, 130.3, 133.7, 134.7, 150.5, 152.0, 171.2; ESI-MS m/z 424.1 [M+H]+; HRMS Calcd for C20H23NO5SCl [M+H]+ m/z 424.0989. found 424.0985.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1.C(OC(C)C)(C)C>O1CCCC1>[CH3:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:10][CH2:9]1
Reactant: C=C1CC(=O)O1
Reactant: CC1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CC(=O)CC(=O)NC1CCC(C)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
29 g of diketene were added over 20 minutes to a stirred mixture of 39 g of 4-methylcyclohexylamine in 100 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 3 hours. Isopropyl ether was added thereto and the precipitate formed was recovered by vacuum filtration, was washed and dried to obtain 46 g of N-(4-methylcyclohexyl)-acetylacetamide melting at 111° C. A mixture of 46 g of the latter product, 37 g of methyl orthoformate, 1.5 g of p-toluene sulfonic acid and 100 ml of methanol was stirred for 2 hours at 20° C. and after standing for 16 hours, 3 ml of quinoline were added thereto. The mixture was distilled to dryness under reduced pressure and the residue was added to toluene. The stirred mixture was heated at 145° C. for 3 hours while distilling a toluene-methanol azeotrope and was then cooled and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with an 8-2 methylene chloride-acetone mixture gave 24 g of N-(4'-methylcyclohexyl)-3-methoxy-crotonamide melting at 125° C. The RMN spectra showed the product to be the E isomer.