Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[C:25]([F:43])=[CH:24][N:23]=1.CC(O)=O.CCCCCC.C(OCC)(=O)C>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH:32]=[CH:33][CH:34]=3)[C:25]([F:43])=[CH:24][N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1ccc(N)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)OC(C)(C)C)c3)n2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 37 %

Procedure:
To a solution of 3-(benzyloxy)-4-(2-methoxyethoxy)aniline (0.500 g) and tert-butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)carbamate (0.556 g) in ethanol (10 mL), was added CH3COOH (54 mg). The reaction mixture was heated to reflux for 24 hr. Completion of reaction was monitored by TLC using hexane:ethyl acetate (5:5) as mobile phase. After completion, reaction mixture was allowed to cool at room temperature and poured into cold water. Product was extracted with ethyl acetate (50 mL×3). Ethyl acetate layer washed with 50 mL brine solution. Ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by using Combiflash chromatography. Desired spot eluted with 18% ethyl acetate in hexane to give 0.35 g of tert-butyl (3-((2-((3-(benzyloxy)-4-(2-methoxyethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)carbamate. 1H NMR: DMSO-d6 (400 MHz): 1.467 (s, 9H), 3.357 (s, 3H), 3.614-3.636 (t, 2H, J=4.4), 4.024-4.046 (t, 2H, J=4.0), 4.921 (s, 2H), 6.811-6.833 (d, 1H, J=8.8), 7.120-7.197 (m, 3H), 7.311-7.448 (m, 7H), 7.827 (s, 1H), 8.05-8.068 (d, 1H, J=3.6), 8.935 (s, 1H), 9.306 (s, 1H), 9.353 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)S([O-])(=O)=O.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]([I+]C1C=CC=CC=1)=[C:21]2[OH:36]>>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[C:21]2[OH:36]
Reactant: CNc1ccccc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(c1ccccc1)c1c(O)c2cc(Br)ccc2[nH]c1=O

Procedure:
The title compound was prepared using N-methylaniline in place of aniline according to the procedure of Intermediate 11, step c except the crude solid was purified by flash column chromatography (silica gel, 50% EtOAc-Heptane), affording the title compound.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:11]=1)(=O)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[OH2:36]>>[OH:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=[CH:14][C:15]=1[C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:10][CH:11]=1)=[O:36]
Reactant: O
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(=O)c2ccccc2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCCCCCCCCc1ccc(C(=O)c2ccccc2)c(O)c1

Procedure:
3-Pentadecylphenyl benzoate (1.366 g) is finely powered, mixed with pulverised anhydrous aluminium chloride (0.616 g) and the intimate miture is heated to 165° during fifteen minutes. After hydrogen chloride evolution has ceased, the cooled mixture is treated with water, concentrated hydrochloric acid added, and the whole thoroughly stirred to decompose the aluminium complex. The product is ethereally extracted and the dried ethereal layer is concentrated to give the crude product (1.348 g) which possesses a greenish ferric chloride reaction. Chromatographic purification and crystallisation from light petroleum (40°-60°) afford 2-hydroxy-4-pentadecylbenzophenone, m.p. 46°-47°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[CH2:10][CH2:11]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Clc1cccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c1

Procedure:
31.7 mg of the target compound (0.09 mmol, 10.6%) was obtained using 1-(3-chlorophenyl)piperazine hydrochloride (382 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]=[C:18]=S)=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[CH:29]([NH2:31])[CH2:28][CH2:27]2>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:18]([NH:31][CH:29]3[C:30]4[C:26](=[CH:25][CH:24]=[CH:23][C:22]=4[O:21][CH3:20])[CH2:27][CH2:28]3)[O:8][CH2:7][C:6]=2[CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1N=C=S
Reactant: COc1cccc2c1C(N)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CC2
Yield: 66.7 %

Procedure:
Prepared from (5-bromo-2-isothiocyanato-benzyloxy)-tert-butyl-dimethyl-silane (Example 32, step B) (4.0 g, 11.2 mmol) and the rac-7-methoxy-indan-1-ylamine (Example 10, step A) (1.82 g, 11.2 mmol) according to the procedure described for Example 1. Obtained the title compound as a white solid (2.79 g, 67%), m.p. 151° C.; MS (ISP) m/e=375.1 [(M+H)+].
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Reactant: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2CCCCC2)C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (Reference Example 5a, 12.15 g, 45.8 mmol) and piperidine (100 mL, 1.01568 mole) was stirred at 70° C. overnight. The residue was purified by silica gel chromatography (100% ethyl acetate to 97:3 ethyl acetate/methanol). Fractions containing product were combined and concentrated under reduced pressure to give (R)-tert-butyl 3-(piperidin-1-yl)pyrrolidine-1-carboxylate. 1H NMR (300 MHz, CD3OD) δ ppm 1.45 (s, 9H), 1.45-1.53 (m, 2H), 1.56-1.66 (m, 1H), 1.66-1.84 (m, 1H), 2.09-2.20 (m, 1H), 2.35-2.60 (m, 4H), 2.73-2.89 (m, 1H), 3.06 (t, J=10 Hz, 1H), 3.17-3.29 (m, 1H), 3.51 (t, J=10 Hz, 1H), 3.58-3.66 (m, 1H); MS (DCI/NH3) m/z 255 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[H-].[Na+].S(O[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)(=O)(=O)C.C1OCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][CH2:17][O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1OC
Reactant: OCCCN1CCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(CCCOCCCN2CCCC2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.1 %

Procedure:
A To a solution of 1-(3-hydroxypropyl)pyrrolidine (631 mg) in toluene (10 mL) stirred at a temperature close to 0° C. is added sodium hydride (208 mg, 60% wt in paraffin). The mixture is stirred for three hours at room temperature, cooled to a temperature close to 0° C. and 3-(3,4-dimethoxyphenyl)propan-1-ol mesylate (750 mg), 15-crown-5 (30 μL), tetrabutylammonium iodide (8 mg) are added. The mixture is heated at reflux for 30 min, stirred overnight at room temperature and diluted with diethyl oxide. The organic layer is washed twice with water, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with dichloromethane/methanol 94/6 as eluent. Fractions containing the expected product are pooled, concentrated under reduced pressure, dissolved in diethyl oxide and salted with a solution of 68.8 mg of oxalic acid in 1 mL of acetone. The precipitate is filtered, rinsed with diethyl oxide and dried to give 110 mg of 1-{3-[3-(3,4-dimethoxyphenyl)propoxy]propyl}-pyrrolidine, oxalate as a solid melting at 78-79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11].CC(O)C.[CH3:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22].N1CCCCC1>C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:20]([C:19](=[O:24])[CH3:18])[C:21](=[O:23])[CH3:22])=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1cc(C=O)ccc1Cl
Solvent: O=CO
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(Cl)c(S(C)(=O)=O)c1)C(C)=O
Temperature: 23.5 °C
Reaction time: 20 h

Procedure:
4-Chloro-3-(methylsulfonyl)benzaldehyde (760 mg), 2-propanol (10 mL), 2,4-pentanedione (0.8 mL), formic acid (22 mL) and piperidine (57 mL) were mixed and stirred at 22-25° C. for 20 h. The product was filtered, washed with 2-propanol and dried. The compound was purified by crystallization from toluene (15 mL, yield 790 mg, melting point 170-172° C.). 1H-NMR (400 MHz, DMSO-d6) d=2.27 (s, 3H), 2.47 (s, 3H), 3.40 (s, 3H), 7.72 (dd, J=8.3 Hz, 2.2 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.84 (s, 1H), 8.19 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3=[N:28][N:29]=[C:30]([C:31]4[CH:35]=[C:34]([CH3:36])[O:33][N:32]=4)[N:20]3[N:19]=2)=[N:14][CH:15]=1)(C(C)(C)C)(C)C>CC(O)=O.C1COCC1.O>[CH3:36][C:34]1[O:33][N:32]=[C:31]([C:30]2[N:20]3[N:19]=[C:18]([O:17][CH2:16][C:13]4[N:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=4)[C:27]4[C:22]([C:21]3=[N:28][N:29]=2)=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:35]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO[Si](C)(C)C(C)(C)C)cn4)nn23)no1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO)cn4)nn23)no1

Procedure:
A solution of 6-[5(tert-butyldimethylsilyloxymethyl)pyridin-2-ylmethyloxy]-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (1.4 g, 2.78 mmol) in AcOH/THF/H2O [3:1:1, 50 ml] was stirred at room temperature for 36 h. The mixture was concentrated under reduced pressure and then azeotroped with toluene (2×50 ml). The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([NH:32][CH3:33])[CH2:28][CH2:27]1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[C:11]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:12]=[C:13]([N:32]([CH3:33])[CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[N:14]=2)[CH:5]=[CH:4][C:3]=1[OH:24]
Reactant: CNC1CCN(C)CC1
Reactant: Oc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(N(C)c2nc(Nc3ccc(O)c(Cl)c3)nc(NC3CCCCCC3)n2)CC1
Yield: 14.3 %

Procedure:
To E7 (1.00 g, 2.7 mmol) dissolved in THF (25 mL) was added a solution of N-methyl-4-(methylamino)-piperidine (0.45 mL, 3.1 mmol) in THF (5 mL) followed by addition of 2.5 N NaOH (1.1 mL, 2.7 mmol) and 2.5 mL of water. The reaction mixture was stirred and heated at reflux overnight. The reaction mixture was extracted three times using dichloromethane, the combined organic layers were washed with a brine and dried over sodium sulfate. The sample was concentrated and the resulting solid was dried overnight under vacuum. Column chromatography (silica gel, 100% methanol) yielded an off-white solid (138) (177 mg, 14%); mp 68° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 v:v:v [KH2PO4 (0.01 M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 4.7 min, 99.6% purity; MS (TOF ES+) m/z 460 (M+H, 55.3), 251 (100), 224 (51.1).
Reaction SMILES: [CH2:1]([C:6]1([C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=C.CSC.C[OH:27]>>[O:27]=[CH:4][CH2:3][CH2:2][CH2:1][C:6]1([C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: CO
Reactant: C=CCCCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CSC
Product: COC(=O)C1(CCCC=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of methyl 4-(pent-4-en-1-yl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylate (29.4 g, 0.0945 mol) from Step B in methanol (1000 mL) was cooled to −78° C. in a dry ice/methanol bath and ozone was bubbled into the solution until a blue color persisted. The excess ozone was removed with a stream of nitrogen and then methyl sulfide (69 mL, 0.95 mol) was added, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature over 1.5 h. The reaction mixture was then concentrated. The residue was then purified by flash chromatography eluting with 2:1 heptane/ethyl acetate to afford the title compound (23.0 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22](I)[CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)CCC.[Cu]I.O>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[C:24]([N:15]2[CH2:16][CH2:17][C:10]3([C:9](=[O:18])[N:8]([C@H:5]4[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:7][CH2:6]4)[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)[CH:25]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCNCC2
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCCCO
Solvent: O
Product: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCN(c1cc(Br)ccc1F)CC2
Temperature: 100 °C

Procedure:
A mixture of 2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (0.50 g, 2.0 mmol), 4-bromo-1-fluoro-2-iodobenzene (0.894 g, 2.97 mmol), copper(I) iodide (0.0586 g, 0.308 mmol), potassium phosphate (1.26 g, 0.596 mmol) and 1,2-ethanediol (0.23 mL, 4.1 mmol) in 1-butanol (2.5 mL) was heated at 100° C. overnight. The reaction mixture was treated with water, extracted with ether. The combined organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column with ethyl acetate in hexane (gradient: 0 to 50%) to give the desired product (0.59 g, 70%). LCMS: (M+H)+=425.0/427.0.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].C1COCC1.O.[OH-].[Na+:40]>CCO>[CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([O-:18])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[Na+:40]
Reactant: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)[O-])cc2)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 4-{(1S)-1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]ethyl}benzoic acid from Example 12 (1.70 g, 3.68 mmol) in a mixture of EtOH (50 mL), THF (15 mL) and water (15 mL) was added NaOH (1N in water, 3.68 mL, 3.68 mmol). After 10 min. the solution was concentrated to dryness and the residue was dried under high vacuum to afford the desired product as an off-white solid. MS (−APCI): m/z 460 (M−23)−.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1.[CH2:15](I)[CH3:16]>>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:15][CH3:16])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1
Reactant: CC(=O)Nc1ccc(CCCl)cc1C
Reactant: CCI
Product: CCN(C(C)=O)c1ccc(CCCl)cc1C
Yield: 88 %

Procedure:
N-[4-(2-Chloro-ethyl)-2-methyl-phenyl]-N-ethyl-acetamide was prepared according to the general method as outlined in Preparation 43 starting from N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-acetamide (0.40 g, 1.89 mmol) and ethyliodide (0.189 mL, 2.36 mmol). After chromatographic purification, the product was isolated as a viscous oil (0.399 g, 1.66 mmol).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[C:9]1[CH3:29])(C)(C)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:20]1[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]=2[CH3:29])=[N:19]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(-c2nn(Cc3ccccc3)c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The sub-title compound was prepared from the product of step c) and benzyl bromide using the procedure described in example 14. 1H NMR (DMSO-d6) δ 13.20 (bs, 1H), 8.37-8.34 (m, 1H), 7.88-7.80 (m, 2H), 7.52 (d, J=9.3 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.36-7.09 (m, 7H), 5.39 (d, J=15 Hz, 1H), 5.35 (d, J=15 Hz, 1H), 5.08 (s, 2H), 2.18 (s, 3H); MS: ESI (negative): 456,458 (M−H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>CC(C)=O>[Cl:15][CH2:16][C:17]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:18]
Reactant: NCc1ccccn1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCl)NCc1ccccn1
Temperature: 0 °C

Procedure:
To a solution of 0.5 g (4.6 mmol) 2-(aminomethyl)pyridine in 10 ml acetone at 0° C. were added 1.27 g (9.2 mmol) potassium carbonate and 0.57 g (5.1 mmol) 2-chloro acetylchloride. The reaction was stirred at 0° C. until no starting material remained and then poured onto ice water. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with aqueous NaHCO3 (sat.) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was used directly for the next step. MS(ISP): 185.21 ([MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[N:8]=[C:9](O)[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH3:24])=[C:18]([CH3:25])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:9]1[C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=3)[O:13][C:11]=2[N:12]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1c(C)cc(-c2nc3c(O)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C
Product: COc1c(C)cc(-c2nc3c(Cl)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C

Procedure:
10 g of 5-(4-chlorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidin-7-ol and 50 ml of phosphorus oxychloride were heated at 90° C. for 5 h. The mixture was then allowed to cool. The solid formed was filtered off with suction, washed with diethyl ether and dried. This gave 10.4 g (99%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:18])[CH2:14][O:15][C:39](=[O:41])[CH3:40])[CH2:10]2)=[CH:30][CH:31]=1
Reactant: COc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)cc(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)N[C@@H](CCN2CC(Oc3ccc(Cl)cc3)C2)COC(C)=O)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3,5-dimethoxy-phenyl)-urea (0.05 g, 0.111 mmol) and triethylamine (0.031 ml, 0.222 mmol) in DCM (3 ml) is treated with acetic anhydride and left to stir at room temperature for 3 hours. The reaction mixture is partitioned between DCM and water. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulphate and evaporated to afford acetic acid (S)-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-2-[3-(3,5-dimethoxy-phenyl)-ureido]-butyl ester. [M+H] 492.08
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:14]=[O:15])=[CH:5][N:6]2[CH:11]([CH3:13])[CH3:12].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[CH:16]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([CH:14]=[O:15])=[CH:5][N:6]3[CH:11]([CH3:13])[CH3:12])[CH2:18][CH2:17]1
Reactant: CC(C)n1cc(C=O)c2c(Br)cccc21
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(C=O)c2c(C3CC3)cccc21
Temperature: 140 °C
Yield: 18.5 %

Procedure:
To a solution of 4-romo-1-(propan-2-yl)-1H-indole-3-carboxaldehyde (120 mg, 0.451 mmol) (from Example 9-1, Step 1) and cyclopropylboronic acid (77 mg, 0.902 mmol) in dioxane (2 mL) and water (0.5 mL) in a 5 mL microwave reaction vial was added potassium carbonate (187 mg, 1.35 mmol) and dichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium (II) (29 mg, 0.045 mmol). The reaction was placed under nitrogen, sealed and heated in a microwave reactor at 140° C. for 25 minutes. The solvent was removed in vacuo and the residue was partitioned with ethyl acetate and aqueous sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (COMBI FLASH 24 gm column, gradient of 0-100% ethyl acetate/hexanes) to give the title intermediate (19 mg).