Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([S:8](/[N:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][C:25]3[C:24]4=[N:34][N:35]=[CH:36][N:23]4[CH:22]=[CH:21][C:20]=3[N:19]=2)=[CH:14][CH:13]=1)=[O:9])([CH3:7])[CH3:6]>C(Cl)Cl>[CH3:7][C:5]([S:8]([NH:10][CH:11]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][C:25]3[C:24]4=[N:34][N:35]=[CH:36][N:23]4[CH:22]=[CH:21][C:20]=3[N:19]=2)=[CH:16][CH:17]=1)[CH3:1])=[O:9])([CH3:4])[CH3:6]
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)c1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methylmagnesium bromide solution (13.5 mL of 1.4 M solution in 3:1 toluene/THF, 19 mmol) was added to a stirred solution of 2-methyl-N-{(1E)-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]methylidene}propane-2-sulfinamide (7-2, 298 mg, 0.66 mmol) in methylene chloride (5 mL) at −78° C. and the solution was warmed to rt. After 18 h, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give an amber foam, which was purified via silica gel chromatography (0-10% MeOH/CH2Cl2 over 30 min) to give the title compound as a yellow foam.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.Cl.[NH2:41][C@@H:42]([CH2:48][CH3:49])[C:43]([N:45]([CH3:47])[CH3:46])=[O:44].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:39]=[CH:38][C:34]([C:35]([NH:41][C@H:42]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:48][CH3:49])=[O:37])=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:20][CH2:21]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Reactant: CC[C@H](N)C(=O)N(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (14 μL, 0.080 mmol) was added to a mixture of 4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoic acid (11 mg, 0.026 mmol), (2S)-2-amino-N,N-dimethylbutanamide hydrochloride (5.8 mg, 0.034 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14 mg, 0.032 mmol) in DMF (0.4 mL). The mixture was stirred at RT overnight. The residue was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=527.0
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([NH2:25])=[N:22][C:21]=1[CH3:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:22][C:21]=1[CH3:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Benzoyl chloride (0.04 mL, 0.36 mmol) was added to a mixture of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.083 g, 0.033 mmol), 4-dimethylamino-pyridine (10 mg) and triethylamine (0.06 mL, 0.43 mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 8 h, then concentrated. The residue was purified by column chromatography to afford the title compound in 75% yield (87 mg); 1H NMR (CDCl3, 300 MHz) δ 7.90-7.24 (m, 11H), 5.97 (s, br, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.45 (s, 3H); MS (ES+) m/z 352.0 (M+1).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH3:14][O:15][C:16]1[C:36]([O:37][CH3:38])=[CH:35][C:19]([CH2:20][O:21][C:22]([N:24]([CH3:34])[C@@H:25]([CH2:29][S:30][S:31][CH2:32][CH3:33])[C:26]([OH:28])=[O:27])=[O:23])=[C:18]([N+:39]([O-:41])=[O:40])[CH:17]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:14][O:15][C:16]1[C:36]([O:37][CH3:38])=[CH:35][C:19]([CH2:20][O:21][C:22]([N:24]([CH3:34])[C@@H:25]([CH2:29][S:30][S:31][CH2:32][CH3:33])[C:26]([O:28][CH2:2][C:3]#[N:4])=[O:27])=[O:23])=[C:18]([N+:39]([O-:41])=[O:40])[CH:17]=1
Reactant: CCSSC[C@@H](C(=O)O)N(C)C(=O)OCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCSSC[C@@H](C(=O)OCC#N)N(C)C(=O)OCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
2-Bromoacetonitrile (0.115 ml, 1.65 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.105 ml, 0.604 mmol) were added to a solution of (R)-2-((((4,5-dimethoxy-2-nitrobenzyl)oxy)carbonyl)(methyl)amino)-3-(ethyldisulfanyl)propanoic acid (Compound 2k-F) (238 mg, 0.549 mmol) in DMF (2.5 ml), and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100) to afford (R)-cyanomethyl 2-((((4,5-dimethoxy-2-nitrobenzyl)oxy) carbonyl)(methyl)amino)-3-(ethyldisulfanyl)propanoate (Compound 21-F) (221 mg, 85%).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH3:28][C:29]([CH3:34])([CH3:33])[CH2:30][CH2:31][NH2:32]>>[CH3:28][C:29]([CH3:34])([CH3:33])[CH2:30][CH2:31][NH:32][C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27]
Reactant: CC(C)(C)CCN
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NCCC(C)(C)C)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and 3,3-dimethylbutylamine. The crude product was used without further purification (88%, oil). HPLC-MS: m/z=355.1 (M+1); Rt: 3.10 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][C:11](=O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]([NH:22][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:13]=2[CH2:12]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COc1cccc2c1CC(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC(NCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (500 mg) and benzylamine (0.29 ml) in the presence of catalytic amounts of p-toluenesulfonic acid monohydrate in toluene (5 ml) was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the solution of the residue in methanol (5 ml) was added sodium borohydride (99 mg) under nitrogen at 5° C., and the mixture was stirred at room temperature for 12 hours. After the resulting mixture was evaporated in vacuo, the residue was dissolved into ice-cold water and ethyl acetate. After separation, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 1:1) to give N-benzyl-(4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (660 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:16][C:15]([C:27](O)=[O:28])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:33])[CH3:32].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[CH:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:27]([C:15]2[CH:16]=[C:17]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[N:14]=2)=[O:28])[CH2:36][CH2:35]1)([CH3:33])[CH3:32]
Reactant: COCCOCCOCc1cc(C(=O)O)nn1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCCOCc1cc(C(=O)NC2CCN(C(C)C)CC2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Reaction time: 16 h

Procedure:
To 60 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-[2-(2-methoxy-ethoxy)-ethoxymethyl]-1H-pyrazole-3-carboxylic acid in 2 ml DCM and 0.1 ml NEt3, 30 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 34 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 19 mg MS (ES+): m/e=566, chloro pattern.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](B(O)O)[S:4][C:3]=1[CH3:10].Br[C:12]1[S:16][C:15](O)=[CH:14][CH:13]=1.C([O-])([O-])=[O:19].[Na+].[Na+]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:6]=[C:5]([C:12]2[S:16][CH:15]=[C:14]([OH:19])[CH:13]=2)[S:4][C:3]=1[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)s1
Reactant: Cc1sc(B(O)O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1sc(-c2cc(O)cs2)cc1Br

Procedure:
Compound 3 is mixed with 5-bromothiophen-2-ol in the presence of tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] and Na2CO3 in tetrahydrofuran (THF) for 24 h at 80° C. The crude product is distillated in vacuo and purified by silica-gel column chromatography (eluent:hexane). Compound 5 (5.01 g) is obtained as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].ClC1C(CC)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:20][CH2:21][C:22](=[O:23])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NCC(=O)c1ccccc1
Agent: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: Cl
Product: Cc1c(N[C@@H](C(=O)NCC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Yield: 91.7 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (6.0 g, 22.33 mmol) and 2-amino-1-phenylethanone hydrochloride (3.83 g, 22.33 mmol) were reacted using the techniques described in for the preparation of intermediate 11c to furnish the title compound (7.9 g, 92%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.03 (d, J=8 Hz, 2H), 7.92 (br s, 1H), 7.68 (t, J=8 Hz, 1H), 7.54-7.58 (m, 3H), 6.70 (d, J=8 Hz, 1H), 5.63 (d, J=6 Hz, 1H), 4.79-4.81 (m, 2H), 4.70 (d, J=4 Hz, 1H), 4.38-4.42 (m, 1H), 4.08-4.12 (m, 1H), 2.38 (s, 3H), 1.33 (d, J=6 Hz, 3H).
Reaction SMILES: C(OP(CC1C=CC=C(O[C:17]2[CH:22]=[CH:21][C:20](C(F)(F)F)=[CH:19][N:18]=2)C=1)(=O)OCC)C.[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([CH:47]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][N:52]=2)[CH:49]=1)[CH:33]=[C:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42]C(C)(C)C)=O)[CH2:36][CH2:35]1)[CH3:28].[H-].[Na+].C(OC([N:70]1CCC(=O)CC1)=O)(C)(C)C.O>C1COCC1.O1CCOCCOCCOCCOCC1>[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([CH:47]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:59])([F:58])[F:60])=[CH:53][N:52]=2)[CH:49]=1)[CH:33]=[C:34]1[CH2:35][CH2:36][N:37]([C:40]([NH:70][C:20]2[CH:19]=[N:18][CH:17]=[CH:22][CH:21]=2)=[O:42])[CH2:38][CH2:39]1)[CH3:28]
Reactant: CCOc1cc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cn2)c1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C=C2CCN(C(=O)Nc3cccnc3)CC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
tert-Butyl 4-(3-ethoxy-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate [3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (395 mg, 0.911 mmol) from Step 4 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.003 mL, 0.0182 mmol) were combined in THF (3 mL). Sodium hydride (40 mg, 60% dispersion in mineral oil, 1.0 mmol) was added and the mixture was stirred for 30 min. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 1.0 mmol) in THF (2 mL) was added and the reaction was stirred at room temperature. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a thick oil (436 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.CN(C=O)C.C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1>C(Cl)Cl.O>[OH:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH2:25])=[S:27])=[N:7][CH:6]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccc(CCCO)cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=S)Nc1ccc(CCCO)cn1
Temperature: 25 °C

Procedure:
3-(6-Amino-pyridin-3-yl)-propan-1-ol (7-3), 2.83 g (19.5 mmol) was stirred in 15 mL of anhydrous CH2Cl2 under Ar. Anhydrous DMF, 5 mL was added and the solution became homogeneous. Benzoylisothiocyanate (2.62 mL, 19.5 mmol) was added and after 2 h the reaction was concentrated in vacuo. To the residue was added 60 mL 1 M NaOH, and 120 mL THF and the resulting mixture was heated to reflux. After 2 h reaction was cooled to RT, and diluted with water (pH 9). The aqueous phase was extracted three times with EtOAc. The combined organic phases was dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (gradient: CH2Cl2 to 95:5 CH2Cl2/MeOH) to afford the pure titled compound. 1H NMR (DMSO-d6) δ 10.57 (bs, 1H), 10.43 (bs, 1H), 8.80 (bs, 1H), 8.05 (d, 1H, J=2.3 Hz), 7.62 (dd, 1H, J=2.4, 8.6 Hz), 7.10 (d, 1H, J=8.7 Hz), 4.48 (t, 1H, J=3.0 Hz), 3.41 (m, 2H), 2.59 (t, 2H, J=6.9 Hz), 1.68 (m, 2H).
Reaction SMILES: FC(F)(F)C1C=CC(C2C=CC=C(CO)C=2)=CC=1.C[O:20][C:21](=[O:51])[CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33][CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)[CH:38]=[CH:39][CH:40]=2)=[C:29]2[C:25]=1[CH2:26][CH2:27][CH2:28]2>>[F:50][C:47]([F:48])([F:49])[C:44]1[CH:45]=[CH:46][C:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([CH2:34][S:33][C:30]3[CH:31]=[CH:32][C:24]([O:23][CH2:22][C:21]([OH:51])=[O:20])=[C:25]4[C:29]=3[CH2:28][CH2:27][CH2:26]4)[CH:36]=2)=[CH:42][CH:43]=1
Reactant: COC(=O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)c2c1CCC2
Agent: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Product: O=C(O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)c2c1CCC2

Procedure:
Preparation of (4′-Trifluoromethyl-biphenyl-3-yl)-methanol (compound 48A) The title compound was prepared in the manner analogous to Example 3A with 1-bromo-4-trifluoromethyl-benzene and 3-(hydroxymethyl)phenyl boronic acid. MS m/z 251 (M−1). Step 2. Preparation of 3-Chloromethyl-4′-trifluoromethyl-biphenyl (compound 48B) The title compound was prepared in the manner analogous to Example 3B using 48A. MS m/z 236 (M+1-Cl). Step 3. Preparation of [7-(4′-Trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-indan-4-yloxy]-acetic acid methyl ester (compound 48C) The title compound was prepared in the manner analogous to Example 1F using 12C and 48B. MS m/z 473 (M+1). Step 4. Preparation of [7-(4′-Trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-indan-4-yloxy]-acetic acid (compound 48) The title compound was prepared in the manner analogous to Example 1 using 48C. 400 MHz 1H NMR (DMSO-d6) δ 12.96 (br(s), 1H), 7.75 (d, 2H, J=8.3 Hz), 7.67 (d, 2H, J=8.1 Hz), 7.52 (m, 1H), 7.37 (t, 1H, J=7.6 Hz), 7.29 (m, 2H), 7.13 (d, 1H, J=8.5 Hz), 6.61 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.05 (s, 2H), 2.71 (t, 2H), 2.58 (t, 2H), 1.81 (m, 2H). MS m/z 459 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][C:26]3[O:27][C:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=4[N:30]=3)[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: NCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1ccc(C(OC2CCN(CCNc3nc4ccccc4o3)CC2)c2ccccn2)cc1
Yield: 48 %

Procedure:
To a mixture of 1.12 g (3.24 mmol) of 2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethylamine obtained in Example 12 and 0.60 g (3.91 mmol) of 2-chlorobenzoxazole were added 0.57 g (4.12 mmol) of potassium carbonate and 5 ml of dioxane, and the mixture was stirred under heating at an oil-bath temperature of 80° to 85° C. for 3 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using chloroform as an eluent, and the desired fraction was concentrated under reduced pressure to give 0.72 g (48%) of 2-[2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethylamino]benzoxazole as an oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[NH:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH3:2].C(OCC1NC(C(OCC)=O)=C(C(OCC)=O)N=1)(=[O:21])C.C[Mg]I>C(OCC)(=O)C>[C:1]([O:3][CH2:4][C:5]1[NH:6][C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=1)(=[O:21])[CH3:2]
Reactant: CCOC(=O)c1nc(COC(C)=O)[nH]c1C(=O)OCC
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: C[Mg]I
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c(COC(C)=O)nc1C(C)(C)O
Reaction time: 8 h

Procedure:
Following a procedure similar to that described in Preparation 44(iii), 1.54 g of diethyl 2-acetoxymethyl-imidazole-4,5-dicarboxylate were reacted with 6.5 equivalents of methylmagnesium iodide. Ethyl acetate was then added to the reaction solution, whilst ice-cooling, and the reaction solution was concentrated by evaporation under reduced pressure. The resulting residue was mixed with 50 ml of pyridine and 25 ml of acetic anhydride, and left at room temperature overnight. At the end of this time, 10 ml of methanol were added to the reaction solution, which was then stirred for 30 minutes. The solution was then concentrated by evaporation under reduced pressure. The residue was mixed with water and ethyl acetate, and the ethyl acetate layer was separated, washed twice with a saturated aqueous solution of sodium hydrogencarbonate and then once with an aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:4 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.46 g of the title compound as a syrup.
Reaction SMILES: [CH:1]1([C@@H:7]2[NH:32][C:31](=[O:33])[O:30][CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][CH2:26][CH2:25][C:24]3[CH:36]=[C:37]4[C:21](=[CH:22][C:23]=3[O:38][CH3:39])[N:20]3[C:16](=[N:17][CH:18]=[CH:19]3)[CH:15]=[C:14]4[O:13][C@H:12]3[CH2:40][N:9]([C@H:10]([C:41]([O:43]C)=[O:42])[CH2:11]3)[C:8]2=[O:45])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH:1]1([C@@H:7]2[NH:32][C:31](=[O:33])[O:30][CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][CH2:26][CH2:25][C:24]3[CH:36]=[C:37]4[C:21](=[CH:22][C:23]=3[O:38][CH3:39])[N:20]3[C:16](=[N:17][CH:18]=[CH:19]3)[CH:15]=[C:14]4[O:13][C@H:12]3[CH2:40][N:9]([C@H:10]([C:41]([OH:43])=[O:42])[CH2:11]3)[C:8]2=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)OCC(C)(C)CCCc1cc3c(cc4nccn4c3cc1OC)O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c3cc1CCCC(C)(C)COC(=O)N[C@@H](C1CCCCC1)C(=O)N1C[C@@H](C[C@H]1C(=O)O)Oc3cc1nccn12
Temperature: 50 °C

Procedure:
To a solution of the product from Step 9, methyl (3R,5S,8S)-8-cyclohexyl-18-methoxy-13,13-dimethyl-7,10-dioxo-2,11-dioxa-6,9,21,24-tetraazapentacyclo[15.9.2.13,6.020,27.021,25]nonacosa-1(26),17,19,22,24,27-hexaene-5-carboxylate (100 mg, 0.161 mmol) in THF (4 mL), MeOH (1 mL) and water (1 mL) was added LiOH (39 mg, 1.61 mmol). The mixture was then heated to 50° C. for 1 h and 1N HCl was then added to neutralize the base. The mixture was then extracted with EtOAc, the organic layer was dried over MgSO4, and the solvent was removed in vacuo to yield the title compound. LRMS (M+H)+=607.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:35][CH3:36])[CH:10]=1.ClC1C(C2C3C(=CC=CC=3)N(C)C=2)=NC(NC2C=C([N+]([O-])=O)C(F)=CC=2OC)=NC=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[CH3:36][O:35][C:11]1[CH:10]=[C:9]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]=1[NH:18][C:19]1[N:24]=[C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)[CH:22]=[CH:21][N:20]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 80 %

Procedure:
1-Methylpiperazine (89 mg, 0.89 mmol), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129 (which may be prepared by the method described for Intermediate 87), 350 mg, 0.89 mmol) and DIPEA (0.186 mL, 1.07 mmol) were suspended in DMA (6 mL) and sealed into a microwave tube. The reaction was heated to 140° C. for 1 h in a microwave and then cooled to r.t. CH3OH was added and an orange solid precipitated from solution. The solid was collected by filtration and was washed with CH3OH and then diethyl ether. The solid was then dried to give the title compound (339 mg, 80%) as an orange solid; 1H NMR: 2.26 (3H, s), 3.06-3.11 (4H, m), 3.88 (3H, s), 3.99 (3H, s), 6.86 (1H, s), 7.13 (1H, t), 7.23-7.29 (2H, m), 7.53 (1H, d), 8.10 (1H, s), 8.32-8.38 (3H, m), 8.81 (1H, s); (signals for 4 protons were not observed and are likely to be obscured under the DMSO peak); m/z: ES+ MH+ 474.56.