Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]Br>C1(C)C(C)=CC=CC=1>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]2[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:27][CH2:28][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][CH2:11][O:12][C:13]=2[CH:18]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccc(Oc2ccccc2CCBr)c(OCCBr)c1
Solvent: Cc1ccccc1C
Product: Clc1ccc2c(c1)OCCN(Cc1ccccc1)CCc1ccccc1O2
Yield: 64 %

Procedure:
9.1 ml of benzylamine were added to a solution of 7.26 g of 2-(2-bromoethoxy)-1-[2-(2-bromoethyl)phenoxy]-4-chlorobenzene in 714 ml of xylene and the mixture was heated to reflux for 24 h. After cooling the precipitate was removed with suction, washed with toluene and the filtrate was evaporated to dryness. The residue was chromatographed over silica with toluene-ethanol (9:1) to yield 4,17 g (64%) of 3-chloro-7,8,9,10-tetrahydro-8-phenylmethyl-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine. Rf 0.7 (silica; toluene-ethanol 8:2).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=4)[N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[OH-].[Na+].Cl>C1COCC1.O>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=4)[N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CNc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CNc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2)cc1
Temperature: 40 °C

Procedure:
To a solution of 20 (1.9 g, 4.2 mmol) in a mixture of THF (8 mL), MeOH (8 mL) and water (4 mL) was added NaOH (373 mg, 9.3 mmol). The mixture was heated at 40° C. for 16 h, then acidified to pH 6 by adding 1N HCl, concentrated, and dried under high vacuum to afford the title compound 21, which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[O:20])[C:15]([NH2:17])=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C=O.[BH3-][C:40]#N.[Na+]>CO>[CH3:40][N:1]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[O:20])[C:15]([NH2:17])=[O:16])[CH2:12][CH2:13]2)[CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: COc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)(C(N)=O)N1CCN(C2CCCNCC2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)(C(N)=O)N1CCN(C2CCCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a solution of 4-(homopiperidin-4-yl)piperazin-1-yl-2-(2-methoxyphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetamide (150 mg, 0.30 mmol) and HCHO (37% aq., 0.067 mL, 0.90 mmol) in MeOH (5.0 mL), NaBH3CN (57 mg, 0.90 mmol) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to give the titled compound (40 mg). MS 514.5 qnd 516.5 (M+H, Cl pattern).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].CC1C=CC(S(O[CH2:29][CH:30]2[CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH:30]1[CH2:29][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COCCOCCOCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCC1COCCOCCOCCO1)NC(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (242 mg, 0.955 mmol) in N,N-dimethylformamide (1 ml) was added (1,4,7,10-tetraoxacyclododecan-2-yl)methyl 4-methylbenzenesulfonate (218.4 mg, 0.6060 mmol) and cesium carbonate (253 mg, 0.776 mmol). The solution was heated to 60° C. for 15 hours, cooled to room temperature, concentrated in vacuo, and the residue purified by flash chromatography (30%-100% ethylacetate in hexanes) to afford the title compound as a clear oil (quantitative); LRMS (ESI/APCI) m/z 442 [M]+.
Reaction SMILES: [N+](C(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(F)(F)F)CC3)C=2)C=1)(C)CCC(O)=O)([O-])=O.C[O:33][C:34](=[O:67])[CH2:35][CH2:36][C:37]([N+:64]([O-:66])=[O:65])([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:53][C@H:54]3[CH2:59][CH2:58][C@@H:57]([C:60]([F:63])([F:62])[F:61])[CH2:56][CH2:55]3)[C:45]=2[C:49]([F:52])([F:51])[F:50])[CH:40]=1)[CH3:38]>>[N+:64]([C:37]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:53][C@H:54]3[CH2:55][CH2:56][C@@H:57]([C:60]([F:61])([F:62])[F:63])[CH2:58][CH2:59]3)[C:45]=2[C:49]([F:50])([F:51])[F:52])[CH:40]=1)([CH3:38])[CH2:36][CH2:35][C:34]([OH:67])=[O:33])([O-:66])=[O:65]
Reactant: COC(=O)CCC(C)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Product: CC(CCC(=O)O)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Yield: 93 %

Procedure:
4-Nitro-4-[5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid was synthesized as per 4-nitro-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid (Example 280) in 93% yield, using 4-nitro-4-[5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid methyl ester as the starting material.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[C:20]([C:21]([OH:23])=O)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:21]([C:20]3[C:11](=[O:10])[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:23])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: O=C(O)c1cc2ccccc2[nH]c1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2ccccc2[nH]c1=O
Temperature: 25 °C

Procedure:
DIEA (50.7 μL, 0.29 mmol) was added to 2-Oxo-1,2-dihydro-quinoline-3-carboxylic acid (50.0 mg, 0.26 mmol) and HATU (110.6 mg, 0.29 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (55.3 mg, 0.26 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give the final product: LCMS (ESI) m/z 381 (MH+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[CH:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[CH:18]([NH:25][CH3:28])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: NC(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2.50 g of 1-benzhydryl-2-(α-aminobenzyl)azetidine in 25 ml. of N,N-dimethylformamide, add 365 mg. of a 55% dispension of sodium hydride. Stir the mixture under a nitrogen atmosphere and when frothing subsides, warm and maintain the stirred mixtuure at 40° for twenty mintues. Cool the mixture to -25° C. and add 1.20 g. of methyl iodide. Remove the reaction mixture from the cooling bath and allow it to warm to room temperature. After ca. 15 minutes at room temperature, pour the contents of the reaction flask into a stirred mixture of 100 ml. of water and 25 ml. of ether. Separate the layers and re-extract the aqueous phase with ether. Combine all ether extracts, wash successively with water and brine, dry over anhydrous sodium sulfate, and strip off solvent in vacuo. Crystallize the residual solid from ether to obtain the analytically pure title compound containing 1/4 mole of water-of-crystallization and having m.p. 111°-113°.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=CC(C2N(C([N:71]3[CH2:76][CH2:75][CH:74]([CH2:77][CH2:78][S:79]([CH3:82])(=[O:81])=[O:80])[CH2:73][CH2:72]3)=O)[C@@](C3C=CC(Cl)=CC=3)(C)[C@@](C3C=CC(Cl)=CC=3)(C)N=2)=C(OCC)C=1)(C)(C)C>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:71]3[CH2:76][CH2:75][CH:74]([CH2:77][CH2:78][S:79]([CH3:82])(=[O:81])=[O:80])[CH2:73][CH2:72]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCS(C)(=O)=O)CC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 2) was reacted with 4-(2-methanesulfonyl-ethyl)-piperidine hydrochloride (example 53) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O4S [(M+H)+] 714.2642, observed 714.2644.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:17]([C:26]5[CH:31]=[CH:30][C:29]([C:32]6([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]6)=[CH:28][CH:27]=5)=[N:16][C:13]=4[O:14][CH2:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([C:7]2[N:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:17]([C:26]5[CH:27]=[CH:28][C:29]([C:32]6([NH2:36])[CH2:35][CH2:34][CH2:33]6)=[CH:30][CH:31]=5)=[N:16][C:13]=4[O:14][CH2:15][C:10]3=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccccc3)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccccc3)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 40.8 %

Procedure:
Tert-butyl (1-(4-(1,8-diphenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.026 mmol) was dissolved in dichloromethane (1 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexanes (2 ml) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (5 mg, 40% yield). LCMS (Method D) RT=0.846 min, M+1=472. 1H NMR (500 MHz, CDCl3): 7.91-7.86 (2H, dd), 7.83-7.76 (3H, m), 7.59-7.54 (2H, d), 7.53-7.48 (2H, d), 7.42 (1H, s), 7.37-7.28 (3H, m), 7.09-7.03 (2H, dd), 5.86 (2H, s), 2.91-2.81 (2H, m), 2.74-2.63 (2H, m), 2.40-2.29 (1H, m), 2.13-2.02 (1H, m).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH:35]=[N:34][CH:33]=[N:32]5)[CH:26]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cncn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3cncn3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K39) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (115 mg).
Reaction SMILES: FC1C=C(C(C)(C)CC(O)(C(F)(F)F)C=O)C2OCCC=2C=1.NC1C(Cl)=CC=C2C=1C=CC(C)=N2.[F:36][C:37]1[CH:38]=[C:39]([C:46]([CH3:69])([CH3:68])[CH2:47][C:48]([OH:67])([C:63]([F:66])([F:65])[F:64])[CH:49]=[N:50][C:51]2[C:60]([Cl:61])=[CH:59][CH:58]=[C:57]3[C:52]=2[CH:53]=[CH:54][C:55]([CH3:62])=[N:56]3)[C:40]2[O:44][CH2:43][CH2:42][C:41]=2[CH:45]=1.C([BH3-])#N.[Na+]>>[F:36][C:37]1[CH:38]=[C:39]([C:46]([CH3:69])([CH3:68])[CH2:47][C:48]([OH:67])([C:63]([F:66])([F:64])[F:65])[CH2:49][NH:50][C:51]2[C:60]([Cl:61])=[CH:59][CH:58]=[C:57]3[C:52]=2[CH:53]=[CH:54][C:55]([CH3:62])=[N:56]3)[C:40]2[O:44][CH2:43][CH2:42][C:41]=2[CH:45]=1
Reactant: Cc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)c(Cl)ccc2n1
Agent: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: Cc1ccc2c(N)c(Cl)ccc2n1
Agent: [BH3-]C#N
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)c(Cl)ccc2n1

Procedure:
Analogously to Example 1, 4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-amino-6-chloro-2-methylquinoline into 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]-6-chloro-2-methylquinoline, which is reduced with sodium cyanoborohydride to the product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])[O:16][C:17]=2[CH2:18][CH2:19][C:20]([NH2:22])=O)=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])[O:16][C:17]=2[CH2:18][CH2:19][C:20]#[N:22])=[CH:11][CH:12]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(N)=O)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC#N)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
Phosphorus oxychloride(585 mg) was added dropwise into a N,N-dimethylformamide solution (20 ml) of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionamide(840 mg) at room temperature. After stirring for 1 hour, the reaction mixture was poured into ice water, and neutralized with saturated sodium bicarbonate. The precipitating crystals are collected by filtration to give 4-(4-chlorophenyl)-5-(2-cyanoethyl)-2-(2-methyl-1-imidazolyl)oxazole(650 mg, 82%). This was recrystallized with acetone-isopropyl ether to give colorless prisms. mp 163-164° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)C.Cl[C:23]1C(C)=NC=C(C2CC2)N=1>>[CH:9]1([C:6]2[N:5]=[C:4]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])[C:3]([CH3:1])=[N:8][CH:7]=2)[CH2:10][CH2:23]1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: Cc1ncc(C2CC2)nc1Cl
Product: Cc1ncc(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-5-cyclopropyl-2-methylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.95, 1.93, 2.38, 2.61, 3.09, 3.22, 4.75, 5.50, 7.30, 7.77; MS (ESI+) for C17H19N3O m/z 282 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:33])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[NH:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:9]=1.[NH3:34]>C(O)C>[NH2:34][C:5]1[C:4](=[O:33])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[NH:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: COc1ccc(C(NCCC2CCCCC2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(C(NCCC2CCCCC2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(2-cyclohexylethylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione (630 mg) [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 2.8 ml) were reacted, to give the title compound (536 mg) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]=1.[OH-].[Na+].Cl.O>CO>[C:10]([O:9][C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[CH:15][C:14]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:3]([OH:39])=[O:2])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)c1ccc(OCCCCCCCCCCCCCCC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
4-(14-tert-Butoxycarbonyl-tetradecyloxy)-isophthalic acid 3-tert-butyl ester 1-methyl ester (381 mg, 0.69 mmol) was dissolved in methanol (10 ml). The solution was cooled to 0° C. and 4 N NaOH (1 ml) was added. The solution was allowed to warm to rt and more methanol (15 ml) was added. The reaction was stirred at rt for 30 min under N2, and at reflux for 2 h. The solution was cooled to 0° C. and 1 N HCl (1 ml) was added slowly. Water (25 ml) was added, and the solution was extracted with AcOEt (2×50 ml). The organic phases were pooled and washed with 1:1 water/sat. NaCl, dried over MgSO4, and concentrated under vacuum to yield an oily solid (326 mg, 89%)
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10]=1[O:23][CH3:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[CH2:27](Cl)[CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[C:1]([C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10]=1[O:23][CH3:24])([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCCCCCl
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Yield: 97.1 %

Procedure:
A solution of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (5 g) in dimethylformamide (10 ml) was added dropwise to a suspension of sodium hydride (65%, 600 mg) in dimethylformamide (30 ml) in 10 minutes at temperature below 10° C. with stirring, and the mixture was stirred at the same temperature for 10 minutes. n-Pentyl chloride (3.3 g) was added to the mixture and stirred at 110° C. for 2 hours. The reaction mixture was treated in a similar manner to that of Example 25-(1) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]-n-heptanoate (5.9 g).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][NH:6][C:7](=[O:37])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])(F)F)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[OH-].[Na+].[CH3:41]O>>[F:36][CH:33]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:38])=[O:37])=[CH:9][CH:10]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)[CH3:41]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CC(Sc1ccc(-c2ccc(OC(C)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 5 h

Procedure:
To a mixture of 3-{4-[3-Methyl-1-(4′-trifluoromethoxy-biphenyl-4-ylsulfanyl)-butyl]-benzoylamino}-propionic acid methyl ester (20 mg) in methanol (2 mL) is added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 h. The reaction mixture is concentrated and acidified by 5 N HCl (0.5 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (18 mg). MS (ES): 531.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[C:29]([O:28][C:26]([CH:25]=[N:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(N=CC(=O)OC(C)(C)C)c3)n2)c1

Procedure:
N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butyl bromoacetate were reacted together to give N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 29.34 min.; purity: 97.2%; MS (m/e): 427.07 (MH+).