Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[CH3:37][C@H:38]1[CH2:40][O:39]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:37][C@@H:38]([OH:39])[CH3:40])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: C[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC[C@H](C)O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C

Procedure:
The title compound was prepared according to the procedure described in Example 2 by using N-(3-fluoro-4-((7-hydroxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.00 g, 2.07 mmol), (S)-2-methyloxirane (1.44 mL, 20.70 mmol) and Cs2CO3 (1.35 g, 4.14 mmol) in 10 mL DMF. The title compound was obtained as a white solid (663 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][N:33]1[CH:37]=[C:36]([S:38]([NH2:41])(=[O:40])=[O:39])[N:35]=[C:34]1[CH3:42]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:41][S:38]([C:36]3[N:35]=[C:34]([CH3:42])[N:33]([CH3:32])[CH:37]=3)(=[O:40])=[O:39])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: Cc1nc(S(N)(=O)=O)cn1C
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cn(C)c(C)n3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 1,2-dimethyl-1H-imidazole-4-sulfonamide: 1H-NMR (CDCl3) δ 7.50-7.27 (10H, m), 3.62 (3H, s), 3.46-3.41 (2H, m), 2.87-2.82 (2H, m), 2.37 (3H, s), 2.32 (3H, s), 2.27 (3H, s).
Reaction SMILES: Cl.[CH2:2]([NH2:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>C(O)CCC>[C:10]([NH:9][C:12](=[NH:13])[NH:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])#[N:11]
Reactant: N#C[N-]C#N
Reactant: CCCCCCN
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCCCCNC(=N)NC#N
Yield: 51.5 %

Procedure:
A mixture of hexylamine hydrochloride (63.5 g.), sodium dicyanamide (44.5 g.) and butanol (200 ml.) was heated at reflux for 18 hours and then cooled. The mixture was filtered and the filtrate was evaporated to dryness. The residue was stirred with water and the insoluble solid was collected and crystallised from aqueous ethanol to give 3-cyano-1-hexylguanidine (40 g.) m.p. 103°-105°.
Reaction SMILES: [CH:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20].O>C1COCC1>[CH3:20][O:19][CH:18]([O:21][CH3:22])[CH2:17][C:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CBr)OC
Reactant: N#CC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CC1(C#N)CCCC1)OC
Reaction time: 0.08 h

Procedure:
0.1 mol of cyclopentanecarbonitrile in 50 ml of THF is added in a rapid dropwise manner to a solution, stirred at 78° C. under an argon atmosphere, of 0.1 mol of lithium diisopropylamide (prepared from 0.1 mol of diisopropylamine and 63 ml of 1.6M butyllithium in hexane) in 250 ml of anhydrous THF. The mixture is stirred for 5 minutes at this temperature before adding 0.11 mol of 1-bromo-2,2dimethoxyethane. The mixture is allowed to return to room temperature and is hydrolyzed using 150 ml of water. The medium is allowed to settle, and the aqueous phase is separated and extracted twice with 150 ml of ether. The combined organic phases are washed with 100 ml of aqueous saline solution and 100 ml of water and then dried over magnesium sulfate. The solvents are evaporated off under vacuum and the residual oil is distilled.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1(Cc2cccc(CN)c2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(Cc2cccc(CNC(=O)OCc3ccccc3)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of methyl N-tert-butoxycarbonyl-4-(3-aminomethylbenzyl)piperidine-4-carboxylate (1.67 mmol), benzyl chloroformate (0.48 mL, 3.36 mmol), and diisopropylethylamine (1 mL, 5.74 mmol) in dichloromethane was stirred at room temp. The resultant solution was diluted with dichloromethane, washed with aqueous sodium bicarbonate, and then brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound as clear colorless gum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]([CH3:32])([CH3:31])[C:29]#[CH:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:30]#[C:29][C:28]([CH3:32])([CH3:31])[CH3:27])=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: C#CC(C)(C)C
Product: CC(C)(C)C#Cc1cccc2c1CCN(C(=O)OC(C)(C)C)CC2
Yield: 71.4 %

Procedure:
Use a method similar to the General Procedure 3 to couple 3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.5 g, 1.3 mmol) with 3,3-dimethyl-1-butyne (0.311 mL, 2.5 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to give 3-tert-butoxycarbonyl-6-(3,3-dimethyl-but-1-ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (304 mg, 74%).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.C([Li])CCC.[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17](N(C)OC)=[O:18])=[CH:13][CH:12]=1>C1COCC1>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([CH:1]2[CH2:3][CH2:2]2)=[O:18])=[CH:13][CH:12]=1
Reactant: BrC1CC1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)C1CC1
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution of cyclopropylbromide (1.24 g, 10.24 mmol) in THF (10 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (4.0 mL, 10.00 mmol) at −78° C. and the reaction mixture was stirred for 1 h at this temperature. Then a solution of 6-chloro-N-methyl-N-(methyloxy)pyridine-3-carboxamide (1.00 g, 4.98 mmol) in THF (5 mL) was added quickly at −78° C., and the cooling bath was removed. Stirring was continued for 1 h, then the solution was poured into saturated ammonium chloride (100 mL), extracted with ethyl acetate (3×50 mL) and the organic layers were washed with brine (50 mL), dried over sodium sulfate then filtered and concentrated. Column chromatography on silica (hexanes:ethyl acetate 9:1 to 8:2) afforded (6-chloropyridin-3-yl)(cyclopropyl)-methanone (0.62 g, 68% yield). 1H NMR (400 MHz, CDCl3): 9.04 (d, 1H), 8.22 (dd, 1H), 7.46 (d, 1H), 2.61 (m, 1H), 1.32 (m, 2H), 1.15 (m, 2H).
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([CH3:14])=[C:12](I)[C:11]([F:16])=[C:10]([O:17][CH3:18])[C:9]=1[NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])#[N:7].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=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.C(OCC)(=O)C>[C:6]([C:8]1[C:9]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:10]([O:17][CH3:18])[C:11]([F:16])=[C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]=1[CH3:14])#[N:7]
Reactant: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(F)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Temperature: 95 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (1.45 g, 1.26 mmol) was added to an N,N-dimethylformamide (50 ml) suspension of N-(2-cyano-5-fluoro-4-iodo-6-methoxy-3-methylphenyl)-2,2-dimethylpropionamide (I-69) (2.45 g, 6.28 mmol), phenylboronic acid (1.15 g, 9.42 mmol), potassium phosphate n-hydrate (74-78%, 3.60 g, 12.6 mmol), followed by stirring at 95° C. for 2 hours. The reaction liquid was cooled, then ethyl acetate (200 ml) was added, followed by washing with saturated brine (50 ml×3), drying over anhydrous magnesium sulfate, concentration under reduced pressure. The residue was purified twice by silica gel column chromatography (chloroform), (n-hexane:ethyl acetate=4:1) to obtain the entitled compound (2.06 g, 96%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[Sn](CCCC)(CCCC)CCCC>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Product: Clc1ncc(-c2ccco2)cn1

Procedure:
2-Chloro-5-bromopyrimidine and 2-furyltributyltin are treated in the same manner as in Example 190 to give 2-chloro-5-(2-furyl)pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C@H:20]([NH:27][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=3)[CH:5]=2)[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cncc(-c2cc(C=O)ccc2OC)c1
Reactant: C[C@@H](N)c1ccccc1
Product: COc1cncc(-c2cc(CN[C@H](C)c3ccccc3)ccc2OC)c1

Procedure:
The title compound (0.8 g, white solid as HCl salt) was prepared from 4-methoxy-3-(5-methoxy(3-pyridyl))benzaldehyde (0.71 g) and (R)-α-methylbenzylamine (0.371 mL) analogously to Example 66, step 3.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]([F:44])([F:43])[C:21]1[CH:22]=[C:23]([C:31](=[O:42])[C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[C:34]([CH3:41])[CH:33]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.[F:45][C:46]([Si](C)(C)C)([F:48])[F:47]>O1CCCC1.C(OCC)(=O)C>[F:19][C:20]([F:43])([F:44])[C:21]1[CH:22]=[C:23]([C:31]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[C:34]([CH3:41])[CH:33]=2)([OH:42])[C:46]([F:48])([F:47])[F:45])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (0.2 ml) was added to a solution of 3′,5′-bis-trifluoromethyl-3-methyl-4-nitrobenzophenone (1.4 g) and trifluoromethyltrimethyl-silane (1.0 g) in tetrahydrofuran (20 ml) in an ice bath and stirred at room temperature for 8 hours. The reaction solution was diluted with ethyl acetate and washed with water and a saturated salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was dissolved in tetrahydrofuran (20 ml) and, by adding 2N hydrochloric acid (2 ml), stirred at room temperature for 30 minutes. After diluting with ethyl acetate and washing with water and a saturated salt solution and after drying over anhydrous magnesium sulfate, the solvent was distilled off. Then the residue was purified by silica gel column chromatography to obtain 1-(3,5-bis-trifluoromethylphenyl)-2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethanol (0.8 g).
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1.[F:14][C:15]([F:25])([F:24])[C:16]([C:20]([F:23])([F:22])[F:21])([OH:19])[C:17]#[CH:18].C(N(CC)CC)C>C1COCC1>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:18]=[C:17]([C:16]([OH:19])([C:15]([F:24])([F:14])[F:25])[C:20]([F:21])([F:23])[F:22])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: C#CC(O)(C(F)(F)F)C(F)(F)F
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1cc(C(O)(C(F)(F)F)C(F)(F)F)on1
Yield: 46.7 %

Procedure:
To a solution of commercially available 4-chlorophenyl glyoxylohydroxamyl chloride (109 mg, 0.5 mmol) in 1,1,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol from step 1 (about 1 mmol) was added a solution of triethylamine (60 mg, 0.6 mmol) in THF (10 ml) dropwise by syringe pump at r.t. over 30 h. The mixture was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl, H2O and dried over MgSO4. Solvent was evaporated under reduced pressure and the residue was purified by preparative TLC (Hexanes:EtOAc, 5:1) to afford the title compound as a white solid (87.2 mg). 1H NMR (DMSO-d6) δ 7.37 (s, 1H), 7.60 (d, 2 H), 8.14 (d, 2H), 9.92 (s, 1H); ESIMS: m/z 372 (M−H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:7][CH:6]=1)=O.[Br:33][C:34]1[C:35]([NH2:40])=[N:36][CH:37]=[CH:38][CH:39]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Br:33][C:34]1[C:35]2[N:36]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:13][N:14]4[C:15](=[O:24])[C:16]5[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:22]4=[O:23])=[CH:9][CH:10]=3)[N:40]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Nc1ncccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cn3cccc(Br)c3n2)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 1,1-dimethylethyl {(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (6.9 mmol), 3-bromo-2-pyridinamine (8.4 mmol), and sodium bicarbonate (10.4 mmol) in isopropanol (70 mL) were stirred at 80° C. for 18 h. The reaction was then cooled to RT and a precipitate formed which was filtered, washed with cold hexanes (3×100 mL), and dried to afford the title compound as light gray solid (72%). ESMS [M+H]+: 576.2.
Reaction SMILES: [Si]([O:18][C:19]1[CH:62]=[CH:61][C:22]([O:23][CH2:24][C@@H:25]([OH:60])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:59]=[CH:58][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]4[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH3:57][O:56][C:50]1[CH:49]=[C:48]([CH2:47][CH2:46][CH2:45][CH2:44][NH:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:58]=[CH:59][C:30]([CH2:29][CH2:28][NH:27][CH2:26][CH:25]([OH:60])[CH2:24][O:23][C:22]4[CH:61]=[CH:62][C:19]([OH:18])=[CH:20][CH:21]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])[CH:53]=[CH:52][C:51]=1[O:54][CH3:55]
Reactant: COc1ccc(CCCCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(CCCCNC(=O)N2CCC(Nc3ccc(CCNCC(O)COc4ccc(O)cc4)cc3)CC2)cc1OC
Yield: 89.4 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-[4-(3,4-dimethoxyphenyl)butyl]-1-piperidinecarboxamide (0.40 g, 0.47 mmol) was reacted according to Procedure H (eluant: 10:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.26 g, 0.42 mmol).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH:36]=[CH:35][N:34]=[CH:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:42][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)=[CH:44][CH:43]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(Cn3ccnc3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-(1H-imidazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C(O)(=[O:25])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:25]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(F)(F)F)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
2-Chloro-6-(trifluoromethyl)nicotinonitrile (1.0 g, 4.84 mmol) was diluted with toluene (5.0 mL), placed under nitrogen and cooled to −78° C. DIBAL-H (9.68 mL, 9.68 mmol) was added dropwise and the reaction was stirred for 1 hour. The reaction was warmed to 0° C. and acetic acid (2 mL in 8 mL of water) was added dropwise. After stirring for 2 hours, the reaction was extracted twice with ethyl acetate, washed with Rochelle's salt, dried over MgSO4, filtered and concentrated. The material was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 30% ethyl acetate/hexanes to yield 2-chloro-6-(trifluoromethyl)nicotinaldehyde (337 mg, 1.61 mmol, 33.2% yield) as a clear oil.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[C:14]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([S:27][CH2:28][C:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH:34]=3)=[C:23](I)[CH:24]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15].CC(N=NC(C#N)(C)C)(C#N)C.C(OCC)(=O)C>C1C=CC=CC=1>[C:14]([N:17]1[C:25]2[CH:24]=[C:23]3[C:29]4([CH2:28][S:27][C:22]3=[CH:21][C:20]=2[CH2:19][CH2:18]1)[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCc2cc(SCC3=CCN(C)CC3)c(I)cc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2cc3c(cc21)C1(CCN(C)CC1)CS3
Reaction time: 0.75 h
Yield: 33.3 %

Procedure:
A solution of tributyltin hydride (0.251 ml, 0.934 mmol) in benzene (10 ml) was added dropwise over 30 minutes to a stirred solution of 1-acetyl-2,3-dihydro-6-iodo-5-[(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)methylthio]-1H-indole (D51) (0.200 g, 0.467 mmol) and AIBN (5 mg) in benzene (20 ml) under argon at reflux. Reflux was continued for a further 0.75 h. The reaction mixture was then allowed to cool. Ethyl acetate (10 ml) was then added and the mixture washed with 2.5M HCl (3×10 ml). The combined aqueous washings were then basified with solid potassium carbonate and the resultant suspension was extracted with dichloromethane (3×15 ml). The combined organic extracts were then dried (Na2SO4) and evaporated under reduced pressure to give a pale yellow solid which was dried in vacuo (0.127 g). The solid was purified by prep. TLC (15% MeOH/CH2Cl2 as eluant) to give the title compound as a cream solid (0.047 g, 33%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:23]([C:22]2[CH:21]=[N:20][N:17]3[CH:18]=[CH:19][C:14]([N:9]4[CH2:10][C@H:11]([OH:13])[CH2:12][C@@H:8]4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:15][C:16]=23)=[O:24])[CH2:28][CH2:27]1
Reactant: O=C(O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Reactant: NC1CC1
Product: O=C(NC1CC1)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Yield: 66 %

Procedure:
Prepared by the method described in Example 1 using 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and substituting tert-butyl amine with cyclopropylamine to provide the final product as a white solid (15 mg, 66% yield). MS (apci) m/z=382.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=O)[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:19]=1.N>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C@H:11]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:22]=2)[C@@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[CH2:12]1
Reactant: COc1ccc(OC)c(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)c1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(OC)c([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 78 %

Procedure:
1-(2,5-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.27 g (78%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C28H38N2O4, 466.3; m/z found, 467.5 [M+H]+. 1H NMR (MeOH-d4): 7.14 (m, 1H), 7.09 (d, J=3.2, 1H), 6.97 (dd, J=3.2, 9.0, 1H), 6.93 (d, J=1.6, 1H), 6.88 (m, 1H), 6.75 (m, 1H), 4.03 (d, J=18.4, 1H), 3.91 (m, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 3.43 (m, 3H), 2.40 (m, 6H), 2.30 (m, 1H), 2.15 (m, 1H), 1.90 (m, 3H), 1.80 (m, 1H), 1.75 (m, 3H), 1.55 (m, 4H), 1.41 (m, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][N:17]2[C@@H:11]([CH2:12][NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]1([C:30]2[CH:47]=[CH:46][CH:45]=[CH:44][C:31]=2[C:32]([NH:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][N:17]2[C@@H:11]([CH2:12][N:13]([C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32](=[O:33])[C:31]4[CH:44]=[CH:45][CH:46]=[CH:47][C:30]=4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:43][CH:42]=3)[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H]2CNc3ccccc3C(=O)N2C1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3C(=O)N2C1
Yield: 95.2 %

Procedure:
The same procedures used in Example 25 were repeated using (2R, 11aR)-2-(tert-butyldimethylsilyloxy)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo [2,1-c][1,4]benzodiazepin-5-one prepared in Reference Example 27 and 4-[(2-phenylbenzoyl)amino]benzoic acid to thus give the title compound.