Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH2:17])[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>C1COCC1>[F:31][C:2]([F:30])([F:1])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH:17][C:42]([O:44][CH3:45])=[O:43])[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of the compound from Example 63 (0.075 g) in THF (4 mL) was added DIEA (0.10 mL) and methyl chloroformate (0.020 mL). After 3 hours, the reaction was concentrated and purified by chromatography (silica gel; 98:2 CH2Cl2/methanol, Chromatotron) to afford the titled compound (0.0715 g): MS (m/z) 533 [MH+]. mp 119.8° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]2[N:21]=[C:20]([CH3:22])[C:19]([C:23]([NH2:25])=[O:24])=[CH:18][N:17]=2)=[N:8]1.[CH3:30]N(C)C=O>C(#N)C>[F:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]2[N:17]=[CH:18][C:19]3[C:23](=[O:24])[NH:25][CH:30]=[CH:22][C:20]=3[N:21]=2)=[N:8]1
Reactant: CN(C)C=O
Reactant: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1[nH]ccc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc12
Temperature: 150 °C
Reaction time: 48 h

Procedure:
Under argon, 21 mg (0.522 mmol) of sodium hydride (60% suspension in mineral oil) were initially charged and washed repeatedly with hexane. Subsequently, dimethylformamide (0.18 ml) was added, and a solution of 158 mg (0.435 mmol) of the compound from example 46A in dimethylformamide (6.0 ml) was added to the suspension. The reaction mixture was stirred at 150° C. for two days, then diluted with acetonitrile at RT, then filtered, and the filtrate was concentrated. The residue was separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 31 mg (18% of theory) of the title compound in solid form.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:23]([O:30][C:31](=[O:39])[CH2:32][C@@H:33]([NH2:38])[CH2:34][N:35]([CH3:37])[CH3:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31](=[O:39])[CH2:32][C@@H:33]([NH:38][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:34][N:35]([CH3:36])[CH3:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)CCCCCCCCCCCc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=403.6 ([M−H]−), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 12-phenyldodecanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(12-phenyl-dodecanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Clc1ncccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3Nc1ncccn1
Temperature: 150 °C

Procedure:
A solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (43 mg, 0.16 mmol) and 2-chloropyrimidine (56 mg, 0.49 mmol) in N,N-dimethylformamide (1.0 mL) was sealed in a microwave vial and heated by a Smith Synthesizer microwave at 150° C. for 15 minutes. The mixture was diluted with ethyl acetate (10 mL) and washed with water (2×10 mL). The organic phase was concentrated and purified by flash column chromatography on silica (20% to 50% gradient of ethyl acetate/hexanes) to provide 6-bromo-N-pyrimidin-2-yl-2,3,4,9-tetrahydro-1H-carbazol-1-amine. The amine was diluted with diethyl ether (3 mL) and hydrogen chloride (1.0 M in diethyl ether) was added. The suspension was concentrated, diluted with acetonitrile and water, frozen and lyophilized to provide 6-bromo-N-pyrimidin-2-yl-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (16 mg, 26%) as a yellow solid. 1H-NMR (DMSO-d6): δ 10.94 (s, 1H), 8.44-8.39 (m, 2H), 8.03-7.96 (m, 1H), 7.55 (s, 1H), 7.23 (d, 1H), 7.12 (d, 1H), 6.72 (t, 1H), 5.37-5.32 (m, 1H), 2.63-2.59 (m, 2H), 2.09-1.95 (m, 2H), 1.87-1.75 (m, 2H); MS m/z (M−1) 341, 343.
Reaction SMILES: [C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45].O>C(Cl)(Cl)Cl>[C:44]([N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C@@H:15]2[N:19]([C:20]([C@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[NH:28][C:29](=[O:36])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:21])[CH2:18][CH2:17][C@H:16]2[C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:46])[CH3:45]
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21)c1ccccc1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1c2ccccc2[C@H]2[C@@H](CCN2C(=O)[C@H]2CCCC[C@H]2NC(=O)c2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
The compound (130 mg, 0.27 mmol) of Example 1 and triethylamine (69 mg, 0.30 mmol) were dissolved in chloroform (2 ml), acetyl chloride (99 mg, 0.33 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. and at 60° C. for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated. The residue was subjected to column chromatography using silica gel (150 g), and eluted with hexane-ethyl acetate (3:1-0:1, v/v) to give the title compound (65 mg, 46%) as an amorphous form.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)(=O)C.[OH-].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C1COCC1.O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:11]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)OCCCCCC1CCCNC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(CCCCCO)C1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 5-(3-piperidinyl)-1-pentanol acetate (7.37 g, 31.9 mmol) in THF (50 ml) was added a solution of potassium hydroxide (5.36 g, 96 mmol) in water (30 ml) and the mixture was stirred in an ice-water bath. To this was added a solution of benzyl chloroformate (5.00 ml, 35.0 mmol) in THF (25 mL) dropwise over a period of 40 mins. After stirring in the cold bath for 30 mins., the mixture was allowed to warm to rt and stirred for 5 hours. The organic solvent was removed by evaporation in vacuo and the aqueous phase was diluted further with water (75 ml) and extracted with EtOAc (3×100 ml). The combined organic extracts was washed with saturated NaCl solution (100 ml), separated, dried (Na2SO4), filtered the solvent evaporated in vacuo and the residue was purified by column chromatography. The sample was loaded in dichloromethane and purified on silica (Si) 2×100 g cartridges using a gradient of 0-100% ethyl acetate in cyclohexane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (6.50 g).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:18][CH2:17][CH2:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[CH:23]=1>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]([CH:1]=[O:3])[CH2:17][CH2:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[CH:23]=1
Reactant: CC(=O)O
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.84 ml) was added dropwise formic acid (0.4 ml), under ice-cooling, and the mixture was stirred, under nitrogen atmosphere, at 50° C. for 2 hours. To the mixture was added THF (5 ml), and to the mixture was added dropwise, under ice-cooling, a solution of methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g) in THF (15 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.07 g) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[O:11])[CH:9]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]=1[C:10]([C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][CH:7]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)c2c(-c3ccccc3)noc2C)c[nH]1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1C(=O)c1c[nH]c(C(=O)O)c1
Yield: 92.8 %

Procedure:
A mixture of 1.2 g (4 mmol) 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid methyl ester and 1.3 g (31 mmol) LiOH.H2O in 40 mL THF, 5 mL methanol and 10 mL water was heated to reflux for 3 h. The mixture was concentrated, acidified and extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and evaporated to yield 1.1 g (96%) of the title compound as light yellow solid. (m/e): 295.1 (M−; 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.O[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: OCc1cccc(Br)c1
Product: OB(O)c1ccc(COCc2cccc(Br)c2)cc1

Procedure:
According to the method of (Example 129) <Step 1>, from (3-bromophenyl)methanol (0.50 g) and (4-(hydroxymethyl)phenyl)boronic acid (0.69), the subject compound (0.25 g) was obtained as a colorless solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(N(CC)CC)C.CO>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:32]3[CH:31]=[CH:30][C:29]([C:27]([O:26][CH3:25])=[O:28])=[N:34][CH:33]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2cnc(C#N)cn2)C[C@@H]1C
Reactant: COC(=O)c1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2cnc(C#N)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 120 °C
Yield: 87 %

Procedure:
5-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrazine-2-carbonitrile (for a preparation, see Intermediate 51) (390 mg, 1.010 mmol), (6-(methoxycarbonyl)pyridin-3-yl)boronic acid (219 mg, 1.21 mmol), PdCl2(dppf) (111 mg, 0.151 mmol) and triethylamine (0.281 ml, 2.02 mmol) were combined in a mixture of dry MeOH (6 mL) and DME (1 mL). The mixture was heated under microwave irradiation to 120° C. for 45 mins. The mixture was then concentrated in vacuo and the residue purified by chromatography (100 g column, EtOAc/cyclohexane gradient) to give methyl 5-((2S,4R)-1-acetyl-4-((5-cyanopyrazin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (389 mg, 0.879 mmol, 87% yield) as a pink solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]#[CH:11].[OH:12]S([O-])(=O)=O.[K+]>C1COCC1>[O:12]=[C:2]1[N:3]([CH2:9][C:10]#[CH:11])[CH:4]=[CH:5][O:1]1
Reactant: C#CCBr
Reactant: C1=NCCO1
Reactant: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCn1ccoc1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a suspension of 2-oxazoline (1.0 g, 11.5 mmol) in THF (40 mL) was added 60% NaH (460 mg, 11.5 mmol) and 3-bromopropyne (1. 0 mL, 11.2 mmol). The mixture was stirred for 1 h at 50° C. then for 3 h at 60° C., poured into aqueous 5% KHSO4, and extracted with ethyl acetate. The Organic layers were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 1:1 hexane/ethyl acetate to give the title compound (1.02 g, 71%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:25]1([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CCN(CC)CC>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:28]4[CH2:29][CH2:30][N:25]([C:31]([NH2:33])=[O:32])[CH2:26][CH2:27]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(=O)N1CCNCC1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (317 mg, 1 mmol), piperazine-1-carboxylic acid amide hydrochloride (273 mg, 1.65 mmol), absolute ethanol (12.7 ml), activated 3 Å molecular sieves (320 mg), Et3N (0.278 ml), titanium (IV) isopropoxide (1.46 ml, 5.20 mmol) and STAB (1.8 g, 8.5 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a off white solid (70 mg, 16%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H), 6.86 (d, 2H), 4.30 (br s, 2H), 4.02 (t, 2H), 3.80-3.71 (m, 2H), 3.58-3.48 (m, 2H), 3.23-3.15 (m, 4H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.40 (s, 2H), 2.19-1.73 (m, 14H).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28]
Reactant: CN(C)CCN
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(NCCN(C)C)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 85 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using N,N-dimethylethylenediamine instead of thiomorpholine to the title compound (202 mg, 85%) which was obtained as an off-white solid. MS: m/e=438.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH:12]1(Br)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O.O>[CH:12]1([O:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrC1CCCC1
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(OC3CCCC3)cc21
Yield: 81 %

Procedure:
A solution of 8.0 g of 6-hydroxy-1-indanone, 6.3 ml of cyclopentyl bromide, 16.4 g of potassium carbonate and 10 ml of N,N-dimethylformamide in 100 ml of acetone was heated to 75° for 35 hours. After cooling, the solution was poured into 150 ml of water and extracted twice with 200 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate 3:1). 9.45 g (81%) of 6-cyclopentoxy-1-indanone were obtained as an orange oil which was used directly in the next reaction.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[C:47]([CH3:49])([CH3:48])[S:46][C@H:45]2[CH2:50][CH2:51][CH2:52][CH2:53][N:44]2[C:43]1=[O:54]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[C:47]([CH3:48])([CH3:49])[S:46][C@H:45]2[CH2:50][CH2:51][CH2:52][CH2:53][N:44]2[C:43]1=[O:54])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: CC1(C)S[C@H]2CCCCN2C(=O)[C@H]1N
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@@H]3C(=O)N4CCCC[C@@H]4SC3(C)C)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((3R,9aS)-2,2-dimethyl-4-oxooctahydropyrido[2,1-b][1,3]thiazin-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (15 mg, 0.026 mmol) and Intermediate 30 (8.7 mg, 0.026 mmol) to give a white solid (12 mg, 56% yield). Anal. Calcd. for C41H54N4O6S2 m/z 762.4. found: 763.4 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 8.09 (d, J=7.70 Hz, 1H), 7.94 (d, J=9.35 Hz, 1H), 7.28-7.06 (m, 10H), 5.54 (dd, J=6.32, 3.02 Hz, 1H), 5.13-5.07 (m, 1H), 5.03 (dd, J=10.17, 3.57 Hz, 1H), 4.82-4.78 (m, 1H), 4.76 (d, J=9.35 Hz, 1H), 4.20 (d, J=13.20 Hz, 1H), 3.63 (s, 3H), 3.14-3.04 (m, 1H), 3.00-2.91 (m, 1H), 2.91-2.76 (m, 4H), 2.77-2.66 (m, 3H), 2.41-2.28 (m, 1H), 2.14-2.03 (m, 1H), 2.02-1.87 (m, 2H), 1.84-1.51 (m, 14H), 0.99 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH3:13])[N:3]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH3:13][N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:3]1
Reactant: Cn1nc(I)c2cc(C#N)ccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C#N)cc12
Temperature: -16 °C
Reaction time: 0.5 h

Procedure:
In a round-bottomed flask, 3-iodo-1-methyl-1H-indazole-5-carbonitrile (383 mg, 1.35 mmol) was partially dissolved in THF (10 ml). The light yellow suspension was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.82 ml, 1.64 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 30 min then tributylchlorostannane (0.43 ml, 1.59 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to provide 1-methyl-3-tributylstannanyl-1H-indazole-5-carbonitrile as a brown oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][N:23]=[C:24]2[Cl:27])=[CH:19][CH:18]=1>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][N:23]=[C:24]3[Cl:27])=[CH:19][CH:18]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1=O
Reactant: Clc1nccc2ccc(CBr)cc12
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Yield: 80.1 %

Procedure:
Same procedure as EXAMPLE 101D, but using (2-oxopyrrolidin-3-(R)-yl)carbamic acid tert-butyl ester (312 mg, 1.56 mmol) and 7-bromomethyl-1-chloroisoquinoline (440 mg, 1.72 mmol) as the starting materials. The crude product is purified by column chromatography on silica with 50-100% ethyl acetate/hexanes. The product fractions are combined and concentrated to give the product as a pale yellow powder (471 mg. 1.25 mmol).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([NH2:22])[CH:13]=1>>[F:1][C:2]1[C:7]([C:12]2[N:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[N:15]=[C:14]([NH2:22])[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: Nc1cc(Cl)nc(C(F)(F)F)n1
Product: Nc1cc(-c2cccnc2F)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in an analogous manner to that described above in Example 4 using 2-fluoropyridin-3-ylboronic acid and 6-chloro-2-(trifluoromethyl)pyrimidin-4-amine (SynChem Inc., Elk Grove Village, Ill.), and the desired product 6-(2-fluoropyridin-3-yl)-2-(trifluoromethyl)pyrimidin-4-amine was isolated as a white solid (34%). LCMS (API-ES) m/z 259 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.57 (t, J=8.80 Hz, 1H) 8.38 (d, J=3.91 Hz, 1H) 7.83 (br. s., 2H) 7.46-7.63 (m, 1H) 7.15 (s, 1H).