Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[NH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C[O:13][C:14]([C:16]1[O:20][N:19]=[C:18]([O:21][CH2:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])[CH:17]=1)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCOCC1>[N:6]1([NH:5][C:14]([C:16]2[O:20][N:19]=[C:18]([O:21][CH2:22][C:23]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:25][O:26][C:27]=3[CH3:28])[CH:17]=2)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)no1
Reactant: NN1CCCCC1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NN2CCCCC2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 0.6 mL, 1.3 mmol) was added dropwise (exothermic) to a solution of 1-aminopiperidine (127 mg, 1.3 mmol) in dioxane (3 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol) in dioxane (2 mL) was added. The resulting mixture was then heated at 85-90° C. for 4 h and then cooled to room temperature, stirred overnight, and then poured into Seignette's salt and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, dichloromethane:methanol=9:1 to 4:1) afforded the title compound (100 mg, 82%) which was obtained as a white solid. MS: m/e=383.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:28])[C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]2[C:20]([CH2:21]O)=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12.N(C(OCC)=O)=NC(OCC)=O>>[Cl:15][C:14]1[C:9]([C:8](=[O:28])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:10]([N:16]2[C:20]([CH2:21][N:52]3[C:51](=[O:53])[C:50]4=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]4[C:48]3=[O:58])=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:27])[CH3:26])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(CN(C)C)n(-c2cccc(Cl)c2C(=O)c2ccc(F)cc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2cccc(Cl)c2C(=O)c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 4'-fluoro-6-chloro-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[3-chloro-2-(4-fluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(OC([NH:33][C@H:34]([C:37](O)=[O:38])[CH2:35][OH:36])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:51].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:51].[ClH:51].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:35](=[O:36])[C@@H:34]([NH2:33])[CH2:37][OH:38])[CH2:20][CH2:19]3)=[O:17])=[CH:24][CH:25]=2)=[N:2]1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: O
Product: N[C@@H](CO)C(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 60 °C
Yield: 111.1 %

Procedure:
The product obtained using Compound 18 (300 mg, 0.90 mmol), N-(tert-butoxycarbonyl)-L-serine (155 mg, 0.76 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 0.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg, 1.06 mmol) and N-methylmorpholine (0.17 mL, 1.52 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 mol/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 123 (290 mg, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[S:29][CH:30]=[CH:31][N:32]=1)CCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2nccs2)c2nc(-c3ccccc3)sc2c1O
Temperature: 130 °C
Reaction time: 1 h
Yield: 11.6 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (246 mg, 0.65 mmole), 2-(tributylstannyl)thiazole (410 μl, 1.30 mmole) and bis(triphenylphosphine)-palladium(II) dichloride (46 mg, 0.06 mmole) in dimethylformamide (3 ml) was stirred at 130° C. for one hour before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes. Fractions containing the title compound was concentrated and repurified by preparative TLC with a gradient of methanol, dichloromethane and acetic acid to give the title compound as a yellow solid (29 mg). MS: (+) m/z 383.87 (M+1), m/z 406.00 (M+Na+).
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][CH2:11][CH2:12][NH:13][C@:14]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:46])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=O)(C)(C)C>O1CCOCC1>[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][C@:14]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:46])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCNC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.6 %

Procedure:
4.0M HCl in dioxane (32.8 μl, 0.131 mmol) was added to a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(tert-butoxycarbonylamino)propylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (23 mg, 0.033 mmol) in dioxane (1 mL) and the mixture was stirred for 6 h at room temperature. The reaction mixture was concentrated under reduced pressure to provide the title compound as a brown oil (15 mg, 76%). LCMS: m/e 601.48 (M+H)+, 2.88 min (method 10).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=1.[Li]CCCC.[C:19](=[O:21])=[O:20]>C1COCC1>[CH3:13][S:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([C:19]([OH:21])=[O:20])=[CH:3]2)=[CH:8][CH:7]=1
Reactant: O=C=O
Reactant: CSc1ccc2ccc(Br)cc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2ccc(C(=O)O)cc2c1
Temperature: -78 °C
Yield: 79 %

Procedure:
A stirred solution of 199 (850 mg, 3.36 mmol) in THF (10 mL) was treated at −78° C. with n-BuLi (2.5 M in hexanes, 1.48 mL, 3.70 mmol) under N2. The mixture was stirred at −78° C. for 15 nm in, then treated with excess CO2(g) and allowed to warm to room temperature. The solvent was removed under reduced pressure, and the residue was partitioned between water and EtOAc. The aqueous layer was acidified, and the resulting solid was crystallised from MeOH to give 7-(methylsulfanyl)-2-naphthoic acid (200) (577 mg, 79%): mp 217° C.; 1H NMR [(CD3)2SO] δ 13.0 (v br, 1H), 8.53 (d, J=0.7 Hz, 1H), 7.98-7.87 (m, 4H), 7.53 (dd, J=8.7, 1.9 Hz, 1H), 2.60 (s, 3H). Anal. (C12H10O2S) C, H.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([NH:19][CH:20]=[CH:21][CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:1]([NH:11][C@H:12]([C:17]([NH:19][CH:20]1[O:31][CH:21]1[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC=CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC1OC1C
Reaction time: 8 h

Procedure:
N-(Cbz-leucinyl)-amino-propene (2.95 g, 9.7 mmol) was dissolved in methylene chloride (100 ml), then mCPBA (5.0 g, 29.1 mmol) was added and the reaction was stirred overnight. The reaction was diluted with saturated aqueous sodium bicarbonate, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 50% EtOAc:hexanes).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)=[C:25](O)[CH:26]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH:1]([N:14]1[CH2:17][C:16]([O:18][C:23]2[CH:22]=[C:21]([Br:20])[CH:26]=[CH:25][C:24]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)([CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1cc(Br)ccc1OCc1cccc(Cl)c1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(Oc2cc(Br)ccc2OCc2cccc(Cl)c2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 150 °C
Yield: 43.7 %

Procedure:
The mixture of the title compound from Step A (0.5 mmol), 5-bromo-2-(3-chloro-benzyloxy)-phenol (0.5 mmol), and cyanomethylenetri-n-butylphosphorane (0.5 mmol) in toluene (3 mL) was heated at 150° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (120 mg). MS (ESI): mass calcd. for C30H27BrClNO2, 547.1; m/z found, 548.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:9][C:10]=2[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:29][CH:30]=1
Reactant: O=C(O)c1nc(-c2ccccc2Cl)oc1C(F)(F)F
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3Cl)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H18ClF3N4O3 (m/e) 454, obsd 455 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:28][CH:27]=[N:26][CH:25]=1)CCC>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[S:28][CH:27]=[N:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(cc(-c3cncs3)n2Cc2ccccc2)n1
Temperature: 110 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.15 g, 0.47 mmol, from Example 62, Step 2) and 5-(tributylstannyl)-1,3-thiazole (0.17 g, 0.47 mmol, Synthonix) in toluene (9.0 mL) was degassed using a stream of nitrogen through the solution. Tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.047 mmol) was added and the mixture was heated to 110° C. for 5 hours. Solvent was removed in vacuo and the residue was dissolved in MeCN, filtered, and purified by flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes. Yield: (67 mg, 44%). LCMS (M+H)+: 325.9.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[CH3:16])=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:15]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:7]1[S:6][C:5]2=[N:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=3)[N:9]2[N:8]=1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: Cc1ccncc1-c1nn2c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccncc1-c1nn2c(-c3cnc(N)c(C(F)(F)F)c3)cnc2s1
Temperature: 120 °C
Yield: 40.1 %

Procedure:
A mixture of 5-Iodo-2-(4-methyl-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole (18 mg, 0.053 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (20 mg, 0.068 mmol, 1.3 eq), Pd(PPh3)2Cl2 (9 mg, 0.011 mmol, 0.2 eq) and sat aq K2CO3 (0.22 mL) in DME (0.5 mL) was heated under microwave irradiation at 120° C. for 30 min. On cooling, DCM was added and the mixture was washed with water. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM/MeOH 95:5) to afford the desired product (8 mg, 40%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.32 min, [M+H]+ m/z 377.1; 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 8.70 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.31 (s, 1H), 7.56 (s, 1H), 7.28 (d, J=5.0 Hz, 1H), 5.39 (s, 2H), 2.63 (s, 3H).
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[CH:18]1([CH2:23][CH2:24][C:25](Cl)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19]1>ClC(Cl)C>[CH:18]1([CH2:23][CH2:24][C:25]([NH:10][C:9]2[CH:1]=[C:2]3[C:6]4=[C:7]([CH2:11][CH2:12][N:5]4[C:4]4[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:3]3=4)[CH:8]=2)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Solvent: CC(Cl)Cl
Product: O=C(CCC1CCCC1)Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 6.5 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine (0.10 g, 0.44 mmol), 3-cyclopentylpropionyl chloride (0.068 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided 3-cyclopentyl-N-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indol-2-ylpropanamide (10 mg). MS (ESI) m/z 351; HPLC purity 100% at 210-370 nm, 11.4 min.; 100% at 250 nm, 11.4 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C23H30N2O+H+, 351.24309; found (ESI, [M+H]+), 351.2423.
Reaction SMILES: [CH:1](/[C@@H:5]1[CH2:10][C@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])[CH3:12])[CH2:8][CH2:7][C@@H:6]1[NH:16]C(=O)OCC1C=CC=CC=1)=[CH:2]/[CH2:3][CH3:4]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([C@H:5]1[C@@H:6]([NH2:16])[CH2:7][CH2:8][C@@H:9]([N:11]([CH:13]([CH3:14])[CH3:15])[CH3:12])[CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC/C=C\[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
A sample of benzyl (1S,2S,4R)-2-((Z)-but-1-enyl)-4-(isopropyl(methyl)amino)cyclohexylcarbamate (2.0 g, 5.6 mmol) was dissolved in MeOH (30 mL). The resulting solution was charged with Pearlman's catalyst (600 mg) and degassed under vacuum before being hydrogenated (50 psi H2) for 12 h. The mixture was filtered and concentrated in vacuo. The residue was dissolved in 30% HBr/AcOH (15 mL) and stirred for 30 min before being partitioned between Et2O and water. The aqueous phase was basified (NaOH) and extracted twice with EtOAc. The organic extracts were combined, dried (sodium sulfate), filtered, and concentrated to afford (1R,3R,4S)-3-butyl-N1-isopropyl-N1-methylcyclohexane-1,4-diamine (396 mg). MS found: (M+H)+=227.3.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([N:29]1[CH2:30][CH2:31][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=2)[CH2:28]1)(=[O:34])[CH3:33]
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Yield: 40.7 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.098 mmol) was reacted with acetic anhydride (13 mg, 0.127 mmol) following the procedure of Example 107. The product was chromatographed on an ISCO® instrument (4 g column). The eluent was 0-6% (2N NH3 in methanol)/dichloromethane to yield 18 mg (41%) of desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1 H), 8.00-7.75 (m, 4 H), 7.60-7.40 (m, 4H), 7.23 (d, 1 H), 6.77 (d, 1 H), 5.72 (s, 2 H), 4.10-3.20 (m, 5H), 2.52-2.15 (m, 2H), 2.05 (s, 3 H); ES-MS m/z 452.4 [M+H]+, HPLC RT (min) 2.36.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([OH:16])[CH:10]=[CH:9]2)=[O:5].[C:17]1([CH2:25]Cl)[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Cl)[CH:18]=1>CN(C)C=O>[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:16][CH2:25][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:16][C:11]3[CH:10]=[CH:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=4)[CH:12]=3)[CH:18]=1)[CH:10]=[CH:9]2)([O:3][CH3:2])=[O:5]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: ClCc1cccc(CCl)c1
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OCc3cccc(COc4ccc5cc(C(=O)OC)ccc5c4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
To sodium salt of 2-hydroxynaphthalene-6-carboxylic acid methyl ester (44.8g) N,N-dimethylformamide (200 ml) was added with stirring at room temperature. Then a solution of m-xylylenedichloride (17.5 g, 0.1 mol) in N,N-dimethylformamide was added in drops thereto in 10 minutes. The reaction mixture was stirred at 105° C. for 4 hours and then cooled to give a precipitate. The precipitate was rinsed with N,N-dimethylformamide, treated with hot water at 80° C. for 30 minutes with stirring, and then with methanol at 60° C. for 30 minutes with stirring; cooled, filtered and dried to give a white crystals of 1,3-bis(6-carbomethoxy-2-naphthoxymethyl)benzene (39.7 g, yield 77.8%): m.p. 177.3°-178.0° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[C:4]([OH:6])=O.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([N:27]2[CH2:34][CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[CH2:28]2)[N:20]=1>>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([N:27]2[CH2:34][CH:33]3[CH:29]([CH2:30][N:31]([C:4]([C:3]4[C:7]([C:11]5[N:16]=[CH:15][CH:14]=[CH:13][N:12]=5)=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])=[O:6])[CH2:32]3)[CH2:28]2)[N:20]=1
Reactant: O=C(O)c1c(F)cccc1-c1ncccn1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4c(F)cccc4-c4ncccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 14 and Intermediate 39. MS (ESI) mass calcd. for C23H23FN6O3, 450.47; m/z found, 451.1 [M+H]+. 1H NMR (CDCl3): rotamers observed, 8.75-8.65 (m, 2H), 8.12-8.01 (m, 1H), 7.45-7.38 (m, 1H), 7.20-7.12 (m, 1H), 7.05 (t, J=4.9 Hz, 1H), 5.32 (s, 1H), 3.96-3.41 (m, 12.4H), 3.32-2.27 (m, 0.7H), 3.22-3.15 (m, 0.5H), 3.06-2.86 (m, 2.4H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:8][CH2:9][CH2:10][NH:11][C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCO[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(NCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 52.8 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butyldimethylsilyloxy)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.211 g, 0.301 mmol) in THF (2 mL) was added TBAF (1M in THF) (0.601 mL, 0.601 mmol). The mixture was stirred at rt for 2.75 h then was diluted with water (10 mL) and was extracted with dichloromethane (3×10 mL). The combined organic layers were dried with Na2SO4, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was adsorbed to silica gel and was purified by flash chromatography using a 0-25% EtOAc in hexanes gradient. The title compound (93.4 mg, 0.159 mmol, 52.9% yield), was isolated as a colorless film. LCMS: m/e 588.6 (M+H)+, 1.98 min (method 2). 1H NMR (500 MHz, CHLOROFORM-d) d ppm 7.91 (d, J=8.24 Hz, 2H), 7.18 (d, J=8.24 Hz, 2H), 5.27 (d, J=4.58 Hz, 1H), 4.70 (d, J=1.83 Hz, 1H), 4.59 (s, 1H), 3.89 (s, 3H), 3.54-3.64 (m, 2H), 2.52-2.69 (m, 3H), 2.09 (dd, J=17.09, 6.41 Hz, 1H), 1.68 (s, 3H), 1.07 (s, 3H), 0.98 (s, 3H), 0.97 (s, 3H), 0.93-2.05 (m, 21H), 0.91 (s, 3H), 0.91 (s, 3H).