Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:23]=[C:22]([NH:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[CH:32]=3)[CH:28]=[CH:29][CH:30]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C>[CH2:4]1[C:9]2[C:10](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][CH2:2][N:3]1[CH2:37][C:33]1[CH:32]=[C:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([CH3:13])[CH:23]=3)[CH:26]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(Nc2cccc(-c3cccc(C=O)c3)c2)c2ccccc2n1
Reactant: Cc1cc(N)c2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(Nc2cccc(-c3cccc(CN4CCc5ccccc5C4)c3)c2)c2ccccc2n1
Reaction time: 19 h
Yield: 55 %

Procedure:
(3-Bromophenyl)-(2-methylquinolin-4-yl)amine (71). 71 is prepared from 70 by the procedure of Example 1 Step 3. Step 2. 3′-(2-Methylquinolin-4-ylamino)biphenyl-3-carbaldehyde (73). To a suspension of 71 (294 mg, 0.94 mmol) in toluene (9.6 mL) under N2 were sequentially added saturated NaHCO3 (aq. 3.8 mL), a solution of 72 (199 mg, 1.33 mmol) in EtOH (6.7 mL), and PdCl2(Ph3P)3 (32 mg, 0.046 mmol). The reaction was heated at 80° C. for 21 hours before it was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate (40 mL) and washed with water (15 mL), brine (15 mL). The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (dichloromethane to 20:1 dichloromethane/methanol) to give 73 as a yellow solid (219 mg, 68.9%). Step 3.3′-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-3-yl]-(2-methylquinolin-4-yl)amine. To a solution of 73 (102 mg, 0.301 mmol) in dichloroethane (3.0 mL) under N2 was added 40 (0.04 mL, 0.315 mmol). The reaction was stirred for 24 minutes before the sequential addition of NaBH(OAc)3 (94 mg, 0.444 mmol) and AcOH (0.02 mL, 0.349 mmol). The reaction was stirred for 19 hours and then extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were washed with 2 N NaOH (aq. 15 mL), brine (15 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane to 30:1 to 20:1dichloromethane/methanol) to give the desired product as a yellow solid (75 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:20])=[C:16]4[CH2:27][CH2:28][CH2:29][CH2:30][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[Li].O>CO.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:31]([F:32])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[C:16]4[CH2:27][CH2:28][CH2:29][CH2:30][C:15]=34)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Yield: 81.9 %

Procedure:
Stir a mixture of methyl 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)acetate (534 mg, 1.0 mmol) and LiOH—H2O (168 mg, 4.0 mmol) in MeOH (20 mL) and water (5 mL) at room temperature for overnight. After removal of organic solvent under vacuum, dilute the residue with ice water (10 mL). Acidify the aqueous mixture with conc. HCl to pH=1, and extract the resultant mixture with EtOAc (15 mL×3). The combined organic layers are washed brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 1:1) to afford 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)acetic acid as a pale yellow solid (427 mg, 82.0%). MS (m/z): 521 (M+1).
Reaction SMILES: BrC1C=C(N(C)C(N2C3N=C(N4CCOCC4)N=C(C4C=NC(N(CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)=NC=4)C=3CC2)=O)C=CC=1.C(N1CCNCC1)(OC(C)(C)C)=O.C(OC([N:72]1[CH2:77][CH2:76][N:75]([C:78]2[CH:83]=[CH:82][CH:81]=[C:80]([N:84]([C:86]([N:88]3[C:92]4[N:93]=[C:94]([N:122]5[CH2:127][CH2:126][O:125][CH2:124][CH2:123]5)[N:95]=[C:96]([C:97]5[CH:98]=[N:99][C:100]([N:103](CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=[N:101][CH:102]=5)[C:91]=4[CH2:90][CH2:89]3)=[O:87])[CH3:85])[CH:79]=2)[CH2:74][CH2:73]1)=O)(C)(C)C>>[CH3:85][N:84]([C:80]1[CH:81]=[CH:82][CH:83]=[C:78]([N:75]2[CH2:74][CH2:73][NH:72][CH2:77][CH2:76]2)[CH:79]=1)[C:86]([N:88]1[C:92]2[N:93]=[C:94]([N:122]3[CH2:127][CH2:126][O:125][CH2:124][CH2:123]3)[N:95]=[C:96]([C:97]3[CH:98]=[N:99][C:100]([NH2:103])=[N:101][CH:102]=3)[C:91]=2[CH2:90][CH2:89]1)=[O:87]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cn2)cc1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)N(C)c3cccc(Br)c3)cn2)cc1
Product: CN(C(=O)N1CCc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21)c1cccc(N2CCNCC2)c1
Yield: 78 %

Procedure:
Using 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-bromo-phenyl)-methyl-amide (70.5 mg) and N-Boc-piperazine (34.9 mg) instead of 2-piperazin-1-yl-ethanol, in the same manner as Step C in Example 1-D-153, 4-{3-[(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbonyl)-methyl-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was obtained as a crude product. Further, PMB group and BOC group were removed according to Deprotection method 3, to obtain the desired compound (D-154) as a yellow solid (37.9 mg, 78%).
Reaction SMILES: [F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:6]=1.[C:30]([N:33]=[C:34]=[O:35])(=[O:32])[CH3:31].FC1N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=C(CCCOC(=O)NC2C=CC=CC=2)N=1>N1C=CC=CC=1>[C:30]([NH:33][C:34]([O:10][CH2:9][CH2:8][CH2:7][C:5]1[N:6]=[C:2]([F:1])[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:4]=1)=[O:35])(=[O:32])[CH3:31]
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CC(=O)N=C=O
Agent: O=C(Nc1ccccc1)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: c1ccncc1
Product: CC(=O)NC(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of 2-fluoro-4-(3-hydroxypropyl)-1-triphenylmethylimidazole in pyridine was treated with acetyl isocyanate at 85°. Work up as for the starting material of Example 11 gave 4-(3-acetylcarbamoyloxypropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in d6DMSO: 1.82 (m, 2H); 2.12 (s, 3H); 2.45 (t, 2H) 4.05 (t, 2H); 6.28 (s, 1H); 7.0-7.5 (m, 15H); 10.12 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[C:16]3([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:35][C:36]([NH2:38])=[NH:37])=[N:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[C:16]3([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:13])=[O:14])=[CH:9][CH:10]=2)[C:5]([NH:35][C:36]([NH2:38])=[NH:37])=[N:4][CH:3]=1
Reactant: CCOC(=O)C1(N(CCOC2CCCCO2)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CCOC3CCCCO3)C3(C(=O)O)CCCC3)cc12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl][2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino}cyclopentanecarboxylate in MeOH (5 ml), was heated to 75° C., NaOH solution (1 ml, 2N, 2 mmol) added, and the reaction stirred at 50° C. for 48 h. The cooled reaction mixture was concentrated in vacuo , to remove the MeOH, and the remaining aqueous solution acidifed to pH 6 using 1N HCl. The resulting precipitate was filtered, washed with water, and the filtrate extracted with EtOAc. The combined organic extracts were dried (MgSO4), and evaporated in vacuo to give 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl][2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino}cyclopentanecarboxylic acid (9 mg, 0.017 mmol) as a pale yellow solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[NH:21]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:21]2[C:22](=[O:29])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:20]2)=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: O=c1[nH][nH]c2ccccc12
Agent: Cl
Product: O=c1c2ccccc2[nH]n1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 1H-indazol-3(2H)-one. M/e+ 375 for C21H16ClN4O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 11.11 (bs, 1H), 8.16 (d, J=6.9 Hz, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.64 (m, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.30 (t, J=7.3 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.75 (t, J=7.7 Hz, 1H), 6.60 (t, J=7.7 Hz, 1H), 6.27 (d, J=8.4 Hz, 1H), 5.34 (s, 2H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]([NH2:28])([CH2:26][CH3:27])[CH3:25]>>[CH:24]([NH:28][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)N
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: CCC(C)Nc1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12

Procedure:
The title compound was prepared following procedure and work up described for example 85 but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and sec-butylamine (53.50 mg; 0.73 mmol; 5.0 eq.) as a white solid (4 mg, 7%). HPLC, Rt: 3.44 min. (purity 89.4%). LC/MS, M+(ESI): 379.1, M−(ESI): 377.0.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=O)=[O:4].O.[NH2:24][NH2:25]>C(O)C>[CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[N:24][NH2:25])=[O:4]
Reactant: NN
Reactant: CC(C)(C)C(=O)Nc1ccncc1C(=O)c1ccccc1F
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)Nc1ccncc1C(=NN)c1ccccc1F
Temperature: 0 °C
Yield: 68.2 %

Procedure:
A solution of [4-(2,2-dimethylpropionamido)-3-pyridinyl]-2-fluorophenylmethanone (9.8 g) and hydrazine monohydrate (3.3 g) in 100 mL ethanol was stirred at reflux for five hours, cooled, stirred with ice-water and extracted with ethyl acetate-ether. The dried organic layer was filtered and evaporated. The residue was eluted through silica with dichloromethane then 15% ethyl acetate in dichloromethane via flash column chromatography and then was triturated with hexane-ether to yield 7 g of [4-(2,2-dimethylpropionamido)-3-pyridinyl]-2-fluorophenylmethanone-hydrazone, as a solid, m.p. 78°-82° C. Four grams were converted to the maleate salt in methanol-ether and thereafter recrystallized from methanol-ether to yield 2.3 g of crystals, d 161°-162° C.
Reaction SMILES: NCC(O)=O.[OH-].[Na+].P([O-])([O-])([O-])=O.[O:13]=[CH:14][C@H:15]([C@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])[OH:16]>C(O)(=O)C>[OH:13][CH2:14][C:15]([C@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])=[O:16]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: NCC(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
50 mm each of acetic acid buffer (pH 4.5 to 6.0), tris-HCl buffer (pH 7 to 8.6), glycine-NaOH buffer (pH 8.0 to 10.5) and phosphate buffer (Na2HPO4—NaOH, pH 8 to 11), 0.1M of mannose and 0.15 units of mannose isomerase were added to form a mixture with a total volume of 0.4 ml, and reacted at 40° C. for 30 minutes. The amount of fructose produced was determined by the cysteine-carbazole process. The relative activities at each pHs are shown in Table 3 and FIG. 1, with the activity at pH 8.2, which was the maximum activity, defined as 100.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([O:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:10]=[C:11]([O:15][CH2:16][C:17]([OH:19])([CH3:18])[CH3:20])[N:12]=[CH:13][N:14]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC(C)(O)COc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OCC(C)(C)O)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.9 %

Procedure:
In 6 ml of tetrahydrofuran was suspended 0.29 g of sodium hydride (60% in oil), to which 0.4 ml of a solution containing 0.25 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.4 ml of a solution containing 0.66 g of 1-(6-chloropyrimidin-4-yloxy)-2-methyl-2-propanol in tetrahydrofuran at 0° C., followed by increasing the temperature up to room temperature and stirring for 5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.33 g of 4-(2-butynyloxy)-6-(2-hydroxy-2-methylpropyloxy)pyrimidine.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:11][C:12]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:15]([NH2:16])=[C:14]([Cl:23])[CH:13]=1.O>C(#N)C>[Br:11][C:12]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:15]([NH:16][C:8](=[O:9])[CH2:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([Cl:23])[CH:13]=1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Nc1c(Cl)cc(Br)cc1C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(CCC1CCCC1)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyclopentyl propionyl chloride (1.28 g, 8.0 mmol) was added to a solution of 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (100% DCM) afforded the title compound as a powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1C=CC=CC=1.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)CBr
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)CN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
4-Benzylpiperazine(3.3 ml, 18.9 mmol) was added to a solution of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene(9 ml), which was then stirred for 2 hours at a room temperature, diluted with ethyl ether, and washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.38 g of the titled compound. (Yield 100%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]2[N:10]=[C:9](Cl)[N:8]=[C:7]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:20]=1.[CH2:29]([CH2:31][NH2:32])[OH:30]>O>[OH:30][CH2:29][CH2:31][NH:32][C:2]1[N:3]=[C:4]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]2[N:10]=[C:9]([NH:32][CH2:31][CH2:29][OH:30])[N:8]=[C:7]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:20]=1
Reactant: NCCO
Reactant: Clc1nc(NCc2ccccc2)c2nc(Cl)nc(NCc3ccccc3)c2n1
Solvent: O
Product: OCCNc1nc(NCc2ccccc2)c2nc(NCCO)nc(NCc3ccccc3)c2n1
Temperature: 150 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
A mixture of 2,6-dichloro-4,8-di-(benzylamino)pyrimidopyrimidine (0.32 g, 0.78 mmol) and ethanolamine (2 ml) was stirred at 150° C. for 12 h. The reaction mixture was cooled to room temperature and water (15 ml) was added, after which the mixture was stirred for a further 20 min, filtered, washed with water, and the collected solid dried in vacuo. Purification by silica column chromatography (dichloromethane: methanol, 9:1) yielded the title compound (0.11 g, 31%) as a fluorescent yellow solid (Found: C, 61.0; H, 6.0; N, 23.7. C24H28N8O2.0.14CH2Cl2 requires C, 61.4; H, 5.6; N, 23.2); NMR data was as follows:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:32]=1[C:33](Cl)=[O:34]>O1CCCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:33](=[O:34])[C:32]2[CH:36]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:38]=[CH:39][C:31]=2[F:30])/[N:7]([CH2:11][CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Cn2cc(C(C)(C)C)sc2=N)C1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(Cn2cc(C(C)(C)C)s/c2=N\C(=O)c2cc(C(F)(F)F)ccc2F)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To a solution of the product of Example 42A (4.1 g, 12.5 mmol) in tetrahydrofuran (40 mL) was added triethylamine (5.2 mL, 37.6 mmol) followed by 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.0 mL, 13.2 mmol). This mixture was warmed to 50° C. and was allowed to stir for 90 min then the mixture was cooled to ambient temperature and was stirred for 16 h. The mixture was quenched with saturated, aqueous NH4Cl (20 mL) and diluted with ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 60% hexanes in ethyl acetate) to give the title compound (5.2 g, 10.0 mmol, 80% yield). MS (DCI/NH3) m/z 516 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[N:26][CH:27]=1)=[O:6]
Reactant: NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=442.1, tR (minutes, Method F)=3.24. [α]D20=12.8 (c=6.8 mg/mL,CHCl3)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][S:9]1.[CH3:20][Si:21]([CH3:42])([CH3:41])[CH2:22][CH2:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[NH:35][CH2:36][C:37](O)=[O:38])[CH:30]=[CH:31][CH:32]=1)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>>[C:16]([O:15][C:13]([C@@H:11]1[CH2:10][S:9][C@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]1[C:37](=[O:38])[CH2:36][NH:35][C:34](=[O:40])[NH:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:25]([O:24][CH2:23][CH2:22][Si:21]([CH3:42])([CH3:41])[CH3:20])=[O:26])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(c2ccccc2F)N1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(NC(=O)NCC(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCC[Si](C)(C)C)c1
Yield: 33.6 %

Procedure:
2-Trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tertbutoxycarbonyl]-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoate may be prepared in a fashion similar to that described in Example 41 §A, but starting from 3.35 g of tert-butyl (2RS,4R)-2-(2-fluorophenyl)-4-thiazolidinecarboxylate, 4.0 g of 2-{3-[3-(2-trimethylsilylethoxycarbonyl)phenyl]ureido}acetic acid and 2.45 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 2.4 g of 2-trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoate are thus obtained in the form of an amorphous beige solid, used as it is in subsequent syntheses ([α]D20 =±50.2°+1.6° (C=0.38%; CHCl3))
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]([CH3:36])=[C:13]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:22][CH:23]=4)[CH2:18][CH:17]3[CH3:35])[N:14]=2)[CH:5]=1.[Li+].[OH-].Cl>CCOCC>[CH3:36][C:12]1[O:11][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:37])=[O:2])=[N:14][C:13]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:27])([F:28])[F:29])=[CH:22][CH:23]=2)[CH2:18][CH:17]1[CH3:35]
Reactant: COC(=O)c1cccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1oc(-c2cccc(C(=O)O)c2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A solution of 50 mg (0.095 mmol) of 3-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-benzoic acid methyl ester (example 90) was added 1 mL of a 1M aqueous LiOH-solution and the mixture stirred at RT for 1 h. After acidification with aqueous HCl to pH of ca 3–4, Et2O was added, the phases were separated and the aqueous one extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 49 mg (quantitative) of 3-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-benzoic acid, off-white solid, MS: 513, (M−H)−.