Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:19].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=3)=[CH:4][C:3]=2[OH:19])=[O:29])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1O
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Br)cc1)Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1O
Reaction time: 8 h

Procedure:
To 3.0 g (2.5 mmol) of above resin-bound 2-amino-5-(4-trifluoromethyl-phenoxy)-phenol were added 1.62 g (7.5 mmol) of 4-bromophenylacetic acid, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalytic amount of DMAP. The resulting mixture was left on a shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each to give resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(4-trifluoromethyl-phenoxy)-phenyl]-acetamide.
Reaction SMILES: [Cl:1][C:2]([Cl:37])([Cl:36])[CH2:3][O:4][C:5](=[O:35])[O:6][CH:7]([CH:24]([CH3:34])[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:8]([CH3:23])[C:9](=[O:22])[C:10]([CH3:21])([CH3:20])[CH:11](OC(C)C)[O:12]C(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[Cl:1][C:2]([Cl:36])([Cl:37])[CH2:3][O:4][C:5](=[O:35])[O:6][CH:7]([CH:24]([CH3:34])[CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:8]([CH3:23])[C:9](=[O:22])[C:10]([CH3:21])([CH3:20])[CH:11]=[O:12]
Reactant: CC(C)OC(OC(C)C)C(C)(C)C(=O)C(C)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(COCc1ccccc1)C(OC(=O)OCC(Cl)(Cl)Cl)C(C)C(=O)C(C)(C)C=O
Temperature: 70 °C
Yield: 73.2 %

Procedure:
To solution of 32a (1.28 g, 2.25 mmol) in 4:1 THF/H2O (25 mL) was added p-TsOH (111.0 mg, 0.6 mmol). After heating at 70° C. 5 h, the reaction mixture was poured into a cold (0° C.) sat. NaHCO3 aq solution (12 mL) and then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 84:16) to give 67 (793.2 mg, 76%) as a clear oil: 1H NMR (400 MHz, CDCl3) □ 0.90 (d, J=5.8 Hz, 3H), 1.0 (d, J=6.9 Hz, 3H), 1.24 (s, 6H), 1.97-2.04 (m, 1H), 3.24 (dd, J=4.8 and 9.2 Hz, 1H), 3.34 (m, 1H), 3.42 (dd, J=5.8 and 9.2 Hz, 1H), 4.35 (d, J=11.9 Hz, 1H), 4.39 (d, J=11.9 Hz, 1H), 4.64 (d, J=11.9 Hz, 1H), 4.69 (d, J=11.9 Hz, 1H), 4.96 (t, J=6.0 Hz, 1H), 7.19-7.28 (m, 5H), 9.49 (s, 1H); 13C NMR (100 MHz, CDCl3) −12.0, 14.8, 19.5, 19.6, 35.4, 43.3, 60.9, 71.1, 73.3, 80.37, 94.5, 127.7, 127.8, 128.3, 137.9, 154.1, 201.0, 210.1; IR (film, NaCl, cm−1) 2973, 2880, 1758, 1701, 1453, 1380, 1248; LRMS (ESI) calcd for C21H27O6Cl3Na [M+Na+] 503.0, found 503.0; [α]23D=−18.5 (c=0.8, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1C
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
Ortho toluidine (0.75 moles, 80 g.) was taken in a one liter round bottom flask equipped with a liquid addition funnel and a guard tube. Triethylamine (1.13 moles, 113.77 g.) was added to it in one lot. Above mixture was cooled to 0-5° C. and acetyl chloride was added drop-wise maintaining the temperature below 10° C. After addition of acetyl chloride the cooling was removed and reaction was stirred at 25-28° C. for 3 hours. After the completion of reaction (TLC), the reaction mixture was poured on 500 g. of ice-water, and aqueous layer was extracted with dichloromethane (2×300 mL). The combined dichloromethane extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 113.6 grams solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.Br[CH:21]([CH2:25]Br)[C:22]([NH2:24])=[O:23].C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:21]([C:22]([NH2:24])=[O:23])[CH2:25]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)C(Br)CBr
Reactant: COc1cccc(NCCNCc2ccccc2)c1
Solvent: CCN(CC)CC
Product: COc1cccc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1

Procedure:
In a manner similar to Preparation 1, react N-(3-methoxyphenyl)-N'-(phenylmethyl)-1,2-ethanediamine (16 g, 63 mmol) with 2,3-dibromopropanamide (29 g, 126 mmol) and triethylamine (25 g, 0.25mol) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11].[CH3:18][C:19]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH3:20]>>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([NH:1][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:19]([CH3:20])([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[CH3:18])=[CH:31][CH:30]=2)(=[O:33])=[O:34])=[C:3]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:4]=1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1ncco1
Reactant: Nc1cc(F)c(F)cc1C(=O)c1cccnc1
Product: CC(C)(c1ccc(S(=O)(=O)Nc2cc(F)c(F)cc2C(=O)c2cccnc2)cc1)c1ncco1

Procedure:
The title compound was prepared from (2-Amino-4,5-difluoro-phenyl)-pyridin-3-yl-methanone and 4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following the general procedure described for the preparation of N-aryl-benzenesulfonamides. MS: m/z 484 (M++1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:30]=[CH:29][C:11]2[C:12]([CH2:15][O:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[C:20]([C:26](O)=[O:27])[NH:21]4)=[CH:13][O:14][C:10]=2[CH:9]=1)[CH3:2].[NH2:31][CH:32]1[CH2:37][CH2:36][C:35]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][C@H:44]([OH:47])[C@@H:43]([CH3:48])[CH2:42]2)([OH:38])[CH2:34][CH2:33]1>>[OH:38][C:35]1([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][C@H:44]([OH:47])[C@@H:43]([CH3:48])[CH2:42]2)[CH2:34][CH2:33][CH:32]([NH:31][C:26]([C:20]2[NH:21][C:22]3[C:18]([CH:19]=2)=[C:17]([O:16][CH2:15][C:12]2[C:11]4[CH:29]=[CH:30][C:8]([O:7][CH2:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:9][C:10]=4[O:14][CH:13]=2)[CH:25]=[CH:24][CH:23]=3)=[O:27])[CH2:37][CH2:36]1
Reactant: CCOCCCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: CCOCCCOc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[6-(3-ethoxy-propoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid 30g and amine 14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][C@@H:18]([C@H:20]3[CH2:24][NH:23][C:22](=[O:25])[CH2:21]3)[CH3:19])[C:14]3[N:26](COCC[Si](C)(C)C)[CH:27]=[N:28][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][C@@H:18]([C@H:20]3[CH2:24][NH:23][C:22](=[O:25])[CH2:21]3)[CH3:19])[C:14]3[NH:26][CH:27]=[N:28][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc3ncn(COCC[Si](C)(C)C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3nc[nH]c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC

Procedure:
Into the solution of (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.08 (200 mg, 0.39 mmol) in THF (5 mL), was added 1 M solution of TBAF in THF (3.9 mL, 3.9 mmol). After reflux for 12 h, the reaction mixture was taken up with ethyl acetate (150 mL) and washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to yield residues which were purified by silica gel column chromatography to isolate (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.09.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].CO[Na].[C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br)#[N:27]>CS(C)=O>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[C:26]#[N:27])=[CH:18][CH:17]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(O)cc1
Reactant: N#Cc1ccccc1CBr
Agent: CO[Na]
Solvent: CS(C)=O
Product: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(OCc2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 2.97 g of 2-butyl-3-p-hydroxybenzyl--4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine (obtainable from IIIa and p-hydroxybenzyl bromide), 0.5 g of CH3ONa and 40 ml of DMSO is stirred for 0.5 hour. A solution of 2.2 g of o-cyanobenzyl bromide in 15 ml of DMSO is added dropwise and the mixture is stirred at 20° for 16 hours and evaporated to give 2-butyl-3-(4-o-cyanobenzyloxybenzyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine after conventional working-up.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:30])[CH2:11][CH2:12][N:13]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:14][C:15](OCC)=[O:16])[CH3:8].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([CH:11]1[C:15](=[O:16])[CH2:14][N:13]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:12]1)=[O:30])[CH3:8]
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of potassium t-butoxide (2.52 g, 22.4 mmol, 1.4 equiv.) in toluene (50 mL) at 0° C. under nitrogen, was added diester 70 (5.41 g, 16 mmol) in toluene (10 mL) over a 10 min period. The solution was stirred for 30 min at 0° C. and 2 mL of glacial acetic acid was added, immediately followed by 10 g of NaH2PO4.H2O in 100 mL of ice-cold water. The resultant mixture was extracted with chloroform (3×150 mL), and the combined organic extracts were washed twice with phosphate buffer (2×25 mL, pH=7.0), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in toluene (200 mL), cooled to 0° C., and extracted with cold pH 9.5 carbonate buffer (3×150 mL). The aqueous extracts were converted to pH 3 with phosphoric acid, and extracted with chloroform (5×125 mL) which were combined, dried, and evaporated to a afford keto ester 71 (2.2 g, 42%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[CH3:13]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH3:13][O:12][C:6]1[CH:5]=[CH:4][C:3]2[C:2](=[O:1])[CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1
Reactant: CI
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(n1)CCCC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.3 %

Procedure:
A mixture of compound 5 (8.2 g, 50 mmol) prepared as described in Example 1, methyl iodide (15.7 mL, 250 mmol), and silver carbonate (8.3 g, 30 mmol) in 150 mL of chloroform was stirred in a flask at room temperature for 48 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo, and purified by column chromatography (elution with hexanes-ethyl acetate 3:1) to give compound 8 (7.2 g, 81%) as a light yellow solid, mp 101-102° C. 1H NMR (CDCl3): δ 2.15 (quin, J=6.4 Hz, 2H), 2.62 (t, J=6.6 Hz, 2H), 3.01 (t, J=6.2 Hz, 2H), 3.99 (s, 3H), 6.65 (d, J=8.7 Hz, 1H), 8.15 (d, J=8.7 Hz, 1H); 13C NMR (CDCl3): δ 22.01, 32.49, 38.20, 53.89, 109.83, 122.73, 137.62, 163.89, 166.11, 197.08. FABMS: m/e 178 (M+1, 100), 154 (16), 137 (16). Analysis: Calcd. for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.94; H, 6.36; N, 7.91.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@H:15]1[C@:19]2([CH3:33])[CH2:20][C@H:21]3[C@H:30]([CH2:31][C@H:18]2[CH2:17][CH2:16]1)[C@@H:29]1[C@H:24]([CH2:25][C:26](=[O:32])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3.CC(O)C>CC(C)=O>[CH3:33][C@:19]12[C:15](=[O:14])[CH2:16][CH2:17][C@@H:18]1[CH2:31][C@H:30]1[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:29]1[CH2:28][CH2:27][C:26](=[O:32])[CH2:25]3)[CH2:20]2
Reactant: C[C@@]12C[C@@H]3CC[C@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CC[C@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: C[C@@]12C[C@@H]3CC[C@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CCC2=O
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
Jones reagent was added to a solution of compound 37 (605 mg, 2.2 mmol) in acetone (40 mL) at 0° C. until a brown-yellowish color persisted. After 10 min, 2-propanol (1.0 mL) was added to consume excess oxidant. Brine (50 mL) was added and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to give compound 38 (580 mg, 96%) as a white solid: [α]D25 −13.1 (c 0.145, CHCl3); 1H NMR (CDCl3) δ 0.81 (s, 3H); 13C NMR (CDCl3) δ 220.1, 211.0, 48.2, 47.8, 47.6, 45.6, 45.4, 43.5, 40.9, 38.9, 37.6, 3.54, 34.0, 33.4, 29.9, 28.7, 23.8, 13.4; IR νmax 1716, 1715 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[CH:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1C(=O)N([Br:34])C(=O)C1>C1COCC1>[Br:34][C:22]1[C:21]2[C:25](=[C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=4)[O:16][N:15]=3)[CH:18]=[CH:19][CH:20]=2)[N:24]([CH3:26])[CH:23]=1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4ccn(C)c34)no2)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Br)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole (D58) (300 mg) in THF (10 mL) was added NBS (160 mg). The reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was concentrated and the residue was purified by column chromatography (15% ethyl acetate in hexane) to afford 3-bromo-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole (D59) (330 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 3.70 (3H, s), 4.88 (1H, m), 7.32 (1H, dd), 7.45 (1H, d), 7.56 (1H, dd), 7.68 (2H, m), 8.12 (1H, dd), 8.20 (1H, d). MS (ES): C20H17BrClN3O2 requires 445; found 446.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=1.C(O)C>[Pt](=O)=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Reaction time: 20 h
Yield: 97.7 %

Procedure:
Platinum(IV) oxide (0.107 g) was added to the suspension of tert-butyl 4-(5-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.05 g; 3.15 mmol) in the mixture of ethanol (20 mL) and acetic acid (10 mL). After degassing, the mixture was subjected to hydrogenation for 20 hours and was filtered through celite. The filtrate was concentrated under reduced pressure to give 1.03 g (98%) of tert-butyl 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylate as a solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18]>CCCCCC>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=3[NH2:18])=[N:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: Cc1cccc(CCl)c1N
Agent: Cl
Solvent: CCCCCC
Product: COc1ccc2[nH]c(SCc3cccc(C)c3N)nc2c1
Yield: 48.5 %

Procedure:
The title compound was prepared by the method of Example 1 using 3.75 g of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 4.00 g of 2-(chloromethyl)-6-methylaniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Trituration with hexane gave 3.02 g of the title compound: m.p. 132-134° C. Analysis. Calc'd. for C16H17N3OS: C, 64.19; H, 5.72; N, 14.04; S, 10.71. Found: C, 64.21; H, 5.77; N, 14.00; S, 10.38.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:46]=[CH:45][C:38]([C:39]([NH:41][CH:42]2[CH2:44][CH2:43]2)=[O:40])=[CH:37][CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:36]=[CH:37][C:38]([C:39](=[O:40])[NH:41][CH:42]3[CH2:44][CH2:43]3)=[CH:45][CH:46]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CC1)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 4-bromo-N-cyclopropyl-benzamide (39.7 mg, 0.17 mmol), and Pd[P(Ph)3]4 (13.7 mg, 7.2 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.3 mg. MS: 484.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.51-0.70 (m, 4H), 1.76-1.98 (m, 3H), 2.08-2.30 (m, 1H), 2.77-2.86 (m, 1H), 3.38-3.52 (m, 2H), 4.27-4.37 (m, 1H), 4.86-5.08 (m, 2H), 6.96-7.65 (m, 7
Reaction SMILES: [CH:1]1([Zr:6](C)C)[CH:5]=[CH:4][CH:3]=[CH:2]1.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1>C1(C)C=CC=CC=1>[CH:1]1([Zr:6]([O:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:9])([F:18])[F:19])[CH:12]=2)[O:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:18])([F:19])[F:9])[CH:12]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: C[Zr](C)C1C=CC=C1
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(O[Zr](Oc2cccc(C(F)(F)F)c2)C2C=CC=C2)c1
Temperature: 25 °C

Procedure:
To a 50 ml Schlenk flask containing 138.7 mg (0.5 mmole) of (1-methylboratabenzene) (cyclopentadienyl) dimethyl zirconium [intermediate product of 1st Step] in 15 ml toluene and at 0° C., 162.1 mg (1 mmole) of Trifluoro-m-Cresol in 10 ml toluene is added slowly under stirring. After warming up to room temperature and stirring one hour at room temperature, toluene of the reaction mixture is moved by vacuum. The desired product (1-methylboratabenzene) (cyclopentadienyl) bis(3-trifluoromethylphenoxy) zirconium can be obtained from the residue of vacuum distillation.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][CH3:30])[C:26]([Cl:31])=[CH:25][N:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:31][C:26]1[C:27]([NH:29][CH3:30])=[N:28][C:23]([NH:1][C:2]2[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[O:11])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=2)=[N:24][CH:25]=1
Reactant: COc1cc(C(=O)N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: CNc1nc(Cl)ncc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(Nc2cc(C(F)(F)F)c(C(=O)N3CCOCC3)cc2OC)ncc1Cl
Temperature: 100 °C
Yield: 8 %

Procedure:
A mixture of (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (94 mg, 0.31 mmol), 2,5-dichloro-N-methylpyrimidin-4-amine (55 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 36 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-10% EtOAc in iso-hexane) gave (4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (11 mg, 8%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=446 at 3.60 min. 1H NMR (400 MHz, CDCl3): δ 8.97 (s, 1H), 8.40 (br s, 1H), 7.90 (s, 1H), 6.76 (s, 1H), 5.59 (q, J=4.9 Hz, 1H), 3.96 (s, 3H), 3.95-3.87 (m, 1H), 3.82-3.69 (m, 3H), 3.62-3.56 (m, 2H), 3.26-3.20 (m, 2H), 3.13 (d, J=4.9 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH3:9])=[O:7].C=O.[C:12]([BH3-])#N.[Na+]>CO>[CH3:12][N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [BH3-]C#N
Reactant: COC(=O)C1CCCN1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCN1C
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Methyl pyrrolidine-2-carboxylate 10b crude product (5 g) was dissolved in 100 mL of methanol. The solution was cooled to 0-5° C. in an ice-water bath, followed by addition of 13 mL of 40% formaldehyde. The reaction mixture was warmed up to room temperature and stirred for 2 hours, then cooled to 0-5° C. in an ice-water bath, and sodium cyanoborohydride (5.45 g, 87.20 mmol) was added in batches. The reaction mixture was warmed up to room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure and added with 5 mL of water, extracted with dichloromethane (5 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain methyl 1-methylpyrrolidine-2-carboxylate 10c (4.7 g, yield 70.1) crude product as a brown oil.