Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6]2[C@H:4]1[CH2:5]2.C(N(CC)CC)C.Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>CN(C)C=O.CCOC(C)=O>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[NH:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6]2[C@H:4]1[CH2:5]2
Reactant: Clc1nc2ccccc2o1
Reactant: NC[C@@H]1[C@@H]2C[C@@H]2CN1C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2[C@H]1CNc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of racemic 7-3 (6.3 g, 25.6 mmol) in dimethylformamide (100 mL) at 25° C. was added triethylamine (3.88 g, 38.4 mmol) followed by 2-chlorobenzoxazole (5.11 g, 33.3 mmol) and the reaction mixture was stirred at ambient temperature for 24 h. The mixture was diluted with EtOAc (400 mL) and washed with water (4×100 mL). The combined organic layers were dried over MgSO4 and concentrated to an oil. The oil was purified by normal phase silica gel chromatography (0 to 100% EtOAc in hexanes) to afford the racemic product as an oil. ESI+ MS: [M+H]+ 364.3. This material was then separated into its respective enantiomers by the following method: ChiralPak AD 2×25 cm, 10 uM (40:60 hexane:EtOH, 0.1% diethylamine; flow rate=8 mL/min). Enantiomer A Rt=7.3 min; Enantiomer B Rt=8.7 min. 1H NMR (500 MHz, CDCl3) δ 7.43-7.42 (m, 2H), 7.36-7.33 (m, 4H), 7.08-7.02 (m, 3H), 4.64 (m, 1H), 4.52 (m, 1H), 4.43 (m, 2H), 3.42 (m, 1H), 3.29 (m, 1H), 3.14 (m, 1H), 2.71 (s, 3H), 1.84 (m, 1H), 1.60 (m, 1H), 1.43 (m, 1H), 0.560 (m, 1H). HRMS [M+H] C24H23F1N2O2S1 calc'd 423.1537, found 423.1542.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=C)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].I([O-])(=O)(=O)=[O:39].[Na+]>C1COCC1.O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=[O:39])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C=O)c2)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.7 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (1.12 g, 1.995 mmol) and sodium periodate (1.280 g, 5.98 mmol) in THF (20 ml) and Water (10 ml) was added osmium tetroxide (2.5 wt % 2-butanol) (0.501 ml, 0.040 mmol) and the reaction mixture was stirred at rt for 5 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (930 mg, 1.650 mmol, 83% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.94 (s, 1H), 8.71 (d, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.61 (d, 1H), 7.34-7.47 (m, 2H), 5.59 (s, 2H), 4.47-4.70 (m, 2H), 3.50 (t, 2H), 0.83 (t, 2H), −0.05 (s, 9H).
Reaction SMILES: [C:1](O)(=O)[CH3:2].[C:5]([OH:10])(=O)[CH2:6][CH2:7][CH3:8].[CH2:11]([C:13]([CH3:15])=O)[CH3:12]>[O-2].[O-2].[Mn+4]>[CH2:12]([C:5]([CH2:6][CH2:7][CH3:8])=[O:10])[CH2:11][CH2:13][CH3:15].[CH2:6]([C:5]([CH2:1][CH3:2])=[O:10])[CH2:7][CH3:8]
Reactant: CCC(C)=O
Reactant: CCCC(=O)O
Reactant: CC(=O)O
Agent: [Mn+4]
Agent: [O-2]
Product: CCCC(=O)CC
Product: CCCCC(=O)CCC
Yield: 24 %
Yield: 60 %

Procedure:
Kirk-Othmer i.b.i.d. discloses that unsymmetrical dialkyl ketones are prepared by passing vapors of two different fatty acids over an alkaline earth oxide at elevated temperatures. It is stated that the product necessarily contains the three possible ketones and in the example given a mixture of acetic acid and butyric acid are reacted in the vapor phase at 300° C. on a manganese dioxide catalyst to produce 16% methyl ethyl ketone, 24% propyl butyl ketone and 60% ethyl propyl ketone.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:9]([O:12][CH2:13][C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])([CH3:11])[CH3:10])([OH:8])=O.C([N:35](CC)CC)C.N>O1CCCC1.C(O)C.C(OCC)(=O)C>[C:6]([C:9]([O:12][CH2:13][C@@H:14]1[CH2:18][C@@H:17]([O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:16][N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])([CH3:11])[CH3:10])(=[O:8])[NH2:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CCN(CC)CC
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(OC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(N)=O
Reaction time: 0.5 h

Procedure:
A solution of methanesulfonyl chloride (0.4 ml) in tetrahydrofuran (2 ml) was dropwise added to a solution of (2S,4R)-2-(1-carboxy-1-methylethyl)oxymethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.84 g) and triethylamine (1 ml) in tetrahydrofuran (8 ml) at -10°~-5° C. and the mixture was stirred at the same condition for 30 minutes. The mixture was dropwise added to a 10% solution (20 ml) of ammonia in ethanol and the mixture was stirred at the same temperature for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (50 ml), washed with water (50 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-2-(1-carbamoyl-1-methylethyl)oxymethyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.01 g).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N:10]1([C:16]2[N:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:24]([O-])(=O)C.[Na+].C=O>>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:24][N:13]2[CH2:12][CH2:11][N:10]([C:16]3[N:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])[CH2:15][CH2:14]2)=[CH:2]1
Reactant: CC(=O)[O-]
Reactant: c1cnc2[nH]ccc2c1
Reactant: N#Cc1cccnc1N1CCNCC1
Agent: C=O
Agent: [Na+]
Product: N#Cc1cccnc1N1CCN(Cc2c[nH]c3ncccc23)CC1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 2-(1-piperazinyl)nicotinonitrile (75 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were processed as described in Example 18 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.57 (m, 4H) 3.50 (m, 4H) 3.84 (s, 2H) 6.63 (m, 2H) 6.81 (m, 1H) 7.32 (m, 1H) 7.52 (m, 1H) 7.77 (m, 1H) 7.90 (m, 1H). (ESI) m/z 319 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:28]1[CH:29]=[CH:30][C:31]([C:34]([NH2:36])=[O:35])=[N:32][CH:33]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:28]2[CH:33]=[N:32][C:31]([C:34](=[O:35])[NH2:36])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(O)cc1
Reactant: NC(=O)c1ccc(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(Oc2ccc(C(N)=O)nc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Dissolve (4-hydroxybenzyl)phenethylcarbamic acid tert-butyl ester (0.0915 g, 0.279 mol) in DMF (0.090 mL). Add NaH (80% in mineral oil) (0.0092 g, 0.307 mmol). Stir for 30 minutes before adding 5-fluoropyridine-2-carboxamide (0.0391 g, 0.279 mmol). Heat at 80° C. for 3 days. Load the reaction mixture directly onto a flash 40 column and elute with 35% ethyl acetate, 3% 2.0 M NH3 in methanol and 62% hexanes to give the title compound (0.103 g, 82.4%): MS ES+ 448.5 (M+H)+, base peak ES+ 392.3 (M+2H—C(CH3)3); HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min, 95% over 19.01-25 min], tR=19.5 min, 100% purity.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:26]=2[F:33])[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:35]([CH3:49])[CH2:36][CH2:37][N:38]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:38][CH2:37][CH2:36][CH:35]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:24][C:25]2[CH:30]=[C:29]([CH:28]=[CH:27][C:26]=2[F:33])[C:31]#[N:32])[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)[CH2:12][CH2:13]1)[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc3[nH]ccc3c2)CC1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc3[nH]ccc3c2)CC1

Procedure:
Using general procedure C with the above carbamate (400 mg, 0.891 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (386 mg, 1.78 mmol) followed by general procedure D afforded 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(1H-indol-5-yl)-amino]-methyl}-4-fluoro-benzonitrile as a white solid (92 mg, 26% over 3 steps).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:30]C)=[C:13]([NH:15][S:16]([C:19]3[S:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:3]1.B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>ClCCl.CO>[CH3:8][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:10]=[CH:11][C:12]([OH:30])=[C:13]([NH:15][S:16]([C:19]3[S:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=2)[CH2:5]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccccn2)s1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CN(c2ccc(O)c(NS(=O)(=O)c3ccc(-c4ccccn4)s3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[5-(cis-3,5-Dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-5-(2-pyridinyl)-2-thiophenesulfonamide (E13) (277 mg, 0.66 mmol) was dissolved in dichloromethane (5 ml) and treated with 1M boron tribromide in dichloromethane (1.8 ml, 1.8 mol) for 4.5 hours. Further 1M boron tribromide in dichloromethane (3 ml, 3 mmol) was added and the mixture stirred at room temperature overnight. Water and methanol were cautiously added and the solution basified to pH9 with saturated aqueous sodium bicarbonate solution. The precipitated solids were filtered, washed with ether and purified by mass directed autoprep HPLC to afford the title compound (E120). MS (ES+) m/e 445 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[N:15](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:16]=[CH:17][N:18]=3)[OH:13])[C:6]3[CH2:38][CH2:39][N:40]4[CH:44]([C:5]=3[C:4]=2[CH:3]=1)[CH2:43][CH2:42][CH2:41]4>CO.Cl>[NH:15]1[CH:16]=[CH:17][N:18]=[C:14]1[CH:12]([OH:13])[CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH:44]3[N:40]([CH2:39][CH2:38][C:6]1=2)[CH2:41][CH2:42][CH2:43]3
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN2CCCC12
Agent: Cl
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ncc[nH]2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.9 %

Procedure:
A suspension of 2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(1-trityl-1H-imidazol-2-yl)ethanol (0.4 g, 0.69 mmol) in MeOH (10 mL), 1N HCl (1 mL) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture concentrated under vacuum to obtain the crude product that was basified with satd. sodium bicarbonate solution and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product, which was purified by reverse HPLC to obtain 11.30 mg 1-(1H-imidazol-2-yl)-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethanol. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.44 (s, 2H), 7.27 (s, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 5.37 (t, 1H), 5.1 (m, 1H),4.56 (dd, 1H), 4.46 (dd, 1H), 3.67 (m, 3H), 3.42 (m, 1H), 3.24 (m, 2H), 2.7 (m, 1H), 2.4 (s, 3H), 2.2 (m, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:10]([OH:12])=[O:11])[C:7]([OH:9])=[O:8])=[CH:2]1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CS(O)(=O)=O.C(Cl)Cl>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]([O:9][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])=[O:8])[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:11])=[CH:2]1
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)C(C(=O)O)c1ccsc1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCCCOC(=O)C(C(=O)OCCCCCCCCCCCC)c1ccsc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.1 %

Procedure:
In a one-necked flask, 3-thienylmalonic acid (10.0 g, 53.7 mmol) and 1-dodecanol (4 eq., 40.0 g, 215 mmol) were dissolved in THF (80 mL) at room temperature. To this solution was added methanesulphonic acid (1.99 g, 20.7 mmol). The reaction mixture was stirred at room temperature for 3 days. The solvent was then evaporated at 40° C. The residue was re-dissolved in CH2Cl2 to form a solution, which was loaded onto a column (eluent: CH2Cl2) to give didodecyl 2-(thiophen-3-yl)malonate (yield: 18.0 g, 69%). 1H NMR (CDCl3): 0.9 (6H, t), 1.3 (36H, m), 1.7 (4H, m), 4.2 (4H, t), 4.8 (1H, s), 7.2 (1H, d), 7.3 (1H, d), 7.4 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:49])([F:48])[CH2:26][C@@H:27]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:48])([F:49])[CH2:26][C@@H:27]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH2:28])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H](N)CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a stirred solution of the material from Step 7 (290 mg, 0.419 mmol) in dichloromethane (1.8 mL) at 0° C. were added anisole (0.137 mL, 1.258 mmol) and TFA (0.388 mL, 5.03 mmol). The reaction mixture was stirred at room temperature for 2 hours, poured into saturated aqueous NaHCO3, and extracted with dichloromethane (2×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford 210 mg of the title compound as a colorless foam. LCMS (M+1)=492.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:40][C:41]1[C:42]([O:59][C@H:60]([CH2:62][CH:63]=[CH2:64])[CH3:61])=[C:43](B2OC(=O)CN(C)CC(=O)O2)[CH:44]=[C:45]([F:47])[CH:46]=1.C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(F)C(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C(C)=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:43]5[CH:44]=[C:45]([F:47])[CH:46]=[C:41]([F:40])[C:42]=5[O:59][C@H:60]([CH2:62][CH:63]=[CH2:64])[CH3:61])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: C=CC[C@H](C)Oc1c(F)cc(F)cc1B1OC(=O)CN(C)CC(=O)O1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)cc(F)c5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 99 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate and (S)-2-(3,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione in 99% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 716.9.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:17]=[CH:16][C:9]([CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:8][CH:7]=1.[CH3:18]O>>[ClH:3].[CH3:18][O:14][C:13](=[O:15])[C@H:11]([CH2:10][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:17][CH:16]=1)[NH2:12]
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Product: Cl

Procedure:
0.14 mol (10 ml, 16.5 grams) of thionyl chloride were dropped at -5° C. into 100 ml of methanol. After addition of 0.11 mole (22 grams) of 4-chlorophenylalanine the mixture was heated under reflux for 15 hours. After drawing off the solvent the white residue was dried in a high vacuum.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].S(Cl)(Cl)=O.Cl.CN.[CH:19]([N:22](CC)C(C)C)(C)C>ClCCl.C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([C:6]([NH:22][CH3:19])=[O:7])[CH:9]=[CH:10][CH:11]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc(CCl)c1
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cccc(CCl)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
5 g (29.31 mmol) of 3-chloromethylbenzoic acid were suspended in 20 ml of abs. toluene, 5.23 g (43.96 mmol) of thionyl chloride were added dropwise and the mixture was stirred at 90° C. overnight. After cooling to RT, excess thionyl chloride and toluene were evaporated and the residue was dried under high vacuum for 1 h. Under argon, the residue was dissolved in 40 ml of abs. dichloromethane and cooled to 0° C., and 2.18 g (32.24 mmol) of methylamine hydrochloride were added. At 0° C., 7.58 g (58.62 mmol) of N,N-diisopropylethylamine were slowly added dropwise, and the reaction mixture was stirred at 0° C. for 15 min. 100 ml of dichloromethane were added, and the reaction mixture was washed three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated using a rotary evaporator.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CN(CCN(CCN(C)C)C)C.[Li]CCCC.CN([CH:38]=[O:39])C>C1COCC1>[Si:5]([O:8][C:9]1[C:10]([F:17])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:38]=[O:39])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of Intermediate 188.2 (7.50 g, 29.5 mmol) and PMDTA (6.5 mL, 31.1 mmol) in 30 mL THF at −78° C., was added BuLi (1.4 M in hexanes, 23.2 mL, 44.3 mmol). The thick slurry was stirred at −40° C. for 30 min, was recooled to −70° C. DMF (4.57 mL, 59 mmol) was added. The yellow solution was removed from the cooling bath and allowed to warm to rt and stirred 1 h. The reaction was quenched with sat. NH4Cl, then was diluted with hexanes. The organic phase was washed with H2O (3×) and brine, dried (Na2SO4), filtered through 2″ silica gel (eluting with 5% EtOAc/hexanes), then concentrated to afford 8.03 g of Intermediate 188.3 as a pale yellow oil.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([S:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:25]=[C:24]([CH2:26]O)[CH:23]=[C:22]3[C:18]=2[C:19]2[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:20]=2[NH:21]3)[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH3:7].[CH:33]([N:36](C(C)C)[CH2:37]C)(C)C.CNC>C1COCC1>[CH2:6]([S:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:25]=[C:24]([CH2:26][N:36]([CH3:37])[CH3:33])[CH:23]=[C:22]3[C:18]=2[C:19]2[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:20]=2[NH:21]3)[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH3:7]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Methanesulfonyl chloride (18 μL, 0.24 mmol) was added to a solution of Compound 133 (46 mg, 0.12 mmol) and diisopropylethylamine (43 μL, 0.25 mmol) in THF (1 mL) at 0° C. After stirring for 3 h, dimethylamine (2M, 1 mL, 2 mmol) was added, and the reaction stirred for 16 h. The solution was concentrated in vacuo and purified by prep-HPLC to give 32 mg (65%) of the title compound as a pale yellow oil. 1H NMR (400 MHz, CD3OD) δ 8.36 (br s, 1H), 8.22 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.05 (d, 1H, J=7.6 Hz), 7.88-7.94 (m, 2H), 7.85 (s, 1H), 7.44 (s, 1H), 4.57 (s, 2H), 3.33 (q, 2H, J=7.2Hz), 2.94 (s, 6H), 2.39 (s, 3H), 1.30 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C23H25N3O2S, 408; found 408.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([CH2:51]Br)=[N:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]([CH2:51][CH:15]2[C:14]3[N:10]([C:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:13]=3)[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[N:7]([CH2:6][C:5](=[O:28])[N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16]2=[O:17])=[N:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Yield: 63 %

Procedure:
Following the procedure described for Example 3(A), Step A, N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide (Preparation 7(A)) (411.7 mg, 0.9118 mmol) was alkylated with 3-bromomethyl-indazole-1-carboxylic acid tert-butyl ester (309 mg, 0.993 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (EtOAc to 5% MeOH in EtOAc) provided 391.9 mg of 3-{6-[(isopropyl-phenyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester. 1H NMR (CD3OD) δ 7.99 (m, 2H), 7.22-7.66 (m, 15H), 7.01 (dd, 1H), 4.53-4.81 (m, 3H), 3.88-4.21 (m, 3H), 1.65 (m, 9H), 0.94 (m, 6H).