Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[CH2:7][CH2:6][N:5]([C:8]([C@@:10]2([CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.Cl>CCOCC>[NH2:15][C@@H:12]1[CH2:13][CH2:14][C@@:10]([C:8]([N:5]2[CH2:6][CH2:7][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])([OH:1])[CH2:3][CH2:4]2)=[O:9])([CH:23]([CH3:25])[CH3:24])[CH2:11]1
Reactant: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3C(F)(F)F)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3C(F)(F)F)CC2)CC[C@@H](N)C1
Reaction time: 3.5 h

Procedure:
To a flask containing tert-butyl [(1R,3S)-3-({4-hydroxy-4-[2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-3-isopropylcyclopentyl]carbamate (0.27 g, 0.54 mmol) was added a 2.00 M solution of HCl in ether (5 mL) and the resulting mixture stirred for 3.5 h. The solution was concentrated to give an oil which was used in the next reaction without purification. MS calculated for C21H29F3N2O2: (M+H) 399; found 399.2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12](Cl)=[O:13].Cl.[C:16](=[NH:26])([O:23][CH2:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([N:26]=[C:16]([O:23][CH2:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]
Reactant: O=C(Cl)c1cccc2c(Br)cccc12
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=NC(=O)c1cccc2c(Br)cccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
According to the procedure of Soto et al, Synthesis, 483 (1983), a solution of 5-bromo-1-naphthoyl chloride (10.7 g, 39.8 mmol) in dry toluene (30 mL) was added dropwise to a mixture of ethyl benzimidate hydrochloride (7.4 g, 39.8 mmol) and triethylamine (8.9 g, 12.2 mL, 87.6 mmol) in dry toluene (100 mL). The mixture was stirred for 18 hours at room temperature, then heated to 70° C. for 60 hours. The mixture was cooled to room temperature and the preciptated salt removed by filtration and washed with toluene. The filtrate was concentrated in vacuo to give a red oil which crystallized upon drying in vacuo (15.2 g, guant.). This material was of sufficient purity to be used in the subsequent reaction.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].Cl.Cl.[CH2:26]([N:33]1[CH2:37][CH2:36][C:35]([CH3:39])([NH2:38])[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]1[CH2:37][CH2:36][C:35]([NH:38][C:21](=[O:22])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]2=[O:1])([CH3:39])[CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: CC1(N)CCN(Cc2ccccc2)C1
Agent: Cl
Product: CC1(NC(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CCN(Cc2ccccc2)C1

Procedure:
The title compound was prepared as described in Example 28B reacting 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E) with 1-benzyl-3-methylpyrrolidin-3-amine dihydrochloride. (CAS 181114-76-1). 1H NMR (300 MHz, CDCl3) δ ppm 7.33 (m, 15H), 4.08 (d, J=14.67 Hz, 2H), 4.00 (m, 2H), 3.81 (m, 2H), 3.51 (m, 2H), 3.25 (m, J=2.38 Hz, 1H), 3.05 (d, J=13.88 Hz, 1H), 2.67 (m, 2H), 2.26 (m, 2H), 1.85 (m, 2H), 1.49 (s, 3H); MS (ESI+) m/z 482 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([C:15]3[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:20])=[CH:17][CH:16]=3)[CH2:14][CH:13]=[CH:12][CH2:11]2)[CH:5]=[C:4]([CH3:29])[C:3]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2([C:15]3[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:20])=[CH:17][CH:16]=3)[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:29])[C:3]=1[C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=1
Reactant: Cc1cc(OCC2(c3ccc(C(=O)NCCC(=O)O)cc3)CC=CC2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(OCC2(c3ccc(C(=O)NCCC(=O)O)cc3)CCCC2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 25.9 %

Procedure:
A solution of 3-{4-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-cyclopent-3-enyl]-benzoylamino}-propionic acid (0.134 g, 0.250 mmol) in EtOH (3.0 mL) is treated with 10% palladium on carbon (26.7 mg), flushed with hydrogen, and stirred under 1 atm pressure overnight. The mixture is then filtered through Celite® and concentrated to provide 0.0350 g (26%) of the title compound as a clear syrup. MS (ES): 540.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:10]#[N:11])[CH2:7][CH2:6][N:5]([O:8][CH3:9])[CH2:4][CH2:3]1.CN(C)C1C=CN=CC=1.CN(C1C=CN=CC=1)C.[CH3:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[CH2:39][C:40](Cl)=[O:41].O>ClCCl>[C:10]([C:2]1([O:1][C:40](=[O:41])[CH2:39][C:32]2[C:31]([CH3:30])=[CH:36][C:35]([CH3:37])=[CH:34][C:33]=2[CH3:38])[CH2:3][CH2:4][N:5]([O:8][CH3:9])[CH2:6][CH2:7]1)#[N:11]
Reactant: CON1CCC(O)(C#N)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CON1CCC(C#N)(OC(=O)Cc2c(C)cc(C)cc2C)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−20° C.) solution of 4-hydroxy-1-methoxy-piperidine-4-carbonitrile (0.32 g, 2.05 mmol) in 2 ml dichloromethane was added 4-dimethylaminopyridine DMAP (13 mg, 0.05 mmol) under argon. Then (2,4,6-trimethyl-phenyl)-acetyl chloride (0.52 g, 2.64 mmol) dissolved in dichloromethane (3 ml) was added dropwise. The reaction mixture was stirred at −20° C. for 30 minutes, then 30 minutes at 0° C. and finally left stirring overnight at room temperature. The reaction mixture was poured into water and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel to give pure (2,4,6-trimethyl-phenyl)-acetic acid 4-cyano-1-methoxy-piperidin-4-yl ester (compound P3.5) as white solid, mp 75-78° C. Yield: 480 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Mg].[C:10]([C:12](=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2([CH:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1cccc(I)c1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C1(c2cccc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-chloro-3-iodobenzene (14.1 g, 59.28 mmol) in diethyl ether (12 ml) was added dropwise to a mixture of magnesium turnings (1.59 g, 65.4 mmol) in diethyl ether (50 ml) at room temperature. When the Grignard reaction was complete, the resulting organomagnesium reagent was added dropwise to a stirred mixture of compound 16a (5.0 g, 17 mmol) and cuprous iodide (800 mg, 4.2 mmol) in tetrahydrofuran (30 mL) cooled to 0° C. The reaction mixture was stirred 1 hour at 0° C. and then quenched with saturated ammonium chloride solution. Ethyl acetate (500 ml) was added and the mixture was washed successively with saturated ammonium chloride, water and brine. The organic layer was dried and concentrated and the resulting crude material was purified by column chromatography on silica gel eluting with 4:1 hexane:ethyl acetate. This afforded tert-butyl 4-(3-chlorophenyl)-4-(1-cyano-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (16b) as an oil (5.2 g, 75%). 1H NMR (400 MHz, CDCl3): δ 7.37-7.26 (m, 4H), 3.99 (br.q, 2H, J=6 Hz), 3.91 (br m, 2H), 3.58 (s, 1H), 2.88 (br.m, 2H), 2.52 (ddd, 2H, J=6, 4, 3 Hz), 2.04 (m, 2H), 1.43 (s, 9H), and 1.06 (t, 3H, J=6 Hz). ES-LCMS m/z 429 (M+Na+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[S:31]1(=[O:37])(=[O:36])[CH2:35][CH2:34][CH2:33][NH:32]1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:5]3[CH:4]=[CH:3][C:2]([N:32]4[CH2:33][CH2:34][CH2:35][S:31]4(=[O:37])=[O:36])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][N:10]([CH3:13])[C:9]3=[O:14])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCN(C)C3=O)CC2)c(C)c1
Yield: 44.2 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (85 mg) described in Preparation Example 241 and isothiazolidine 1,1-dioxide (36 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (45 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:10]2[CH:11]=[CH:12][C:13]3[C:18]([C:9]2=[N:8][C:7]=1[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19].C(N(CC)CC)C.Cl[C:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[S:31](=[O:39])(=[O:38])[N:30]=1>C(O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]1[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[S:31](=[O:38])(=[O:39])[N:30]=3)=[C:7]([CH3:20])[N:8]=[C:9]12
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1CSCCN
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2c3cccc(Cl)c3ccn2c1CSCCNC1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a mixture of 3-(2-aminoethyl)thiomethyl-7-chloro-2-methylimidazo[2,1-a]isoquinoline (1.5 g) and triethylamine (0.5 g) in ethyl alcohol (35 ml) was added portionwise 3-chloro-1,2-benzisothiazole-1,1dioxide (1.0 g). After being stirred at ambient temperature for 1 hour, the resulting precipitate was collected by filtration and washed several times with ethyl alcohol to give 3-[2-[(7-chloro-2-methylimidazo[2,1-a]isoquinolin-3-yl)methylthio]ethylamino]-1,2-benzisothiazole-1,1-dioxide (2.2 g).
Reaction SMILES: O1CCCC1.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=O.[CH2:16]([NH2:19])[CH2:17][CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[NH:19][CH2:16][CH2:17][CH3:18]
Reactant: O=C1Cc2ccccc2C1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCNC1Cc2ccccc2C1
Yield: 67.6 %

Procedure:
A tetrahydrofuran (150 mL) solution of 2-indanone (11.0 g, 92 mmol), propyl amine (12 mL, 146 mmol), sodium triacetoxy borohydride (35.0 g, 165 mmol), and acetic acid (5 mL) was stirred at ambient temperature for 1 hour. The solution was then heated at reflux temperature for 2 hours. After cooling, the solvent was evaporated and the residue taken up in concentrated hydrochloric acid (40 mL). The acidic solution was washed with diethyl ether and then basified (10M sodium hydroxide). Extraction of the aqueous layer with ether, drying over anhydrous sodium carbonate and removal of the solvent yielded 10.9 g of the title compound as a yellow oil (75%).:
Reaction SMILES: [OH:1][NH:2][C:3]1([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:12][C:11]([C:3]1([NH:2][OH:1])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1)=[O:13]
Reactant: CO
Reactant: CON1CCC(NO)(C(=O)O)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(NO)CCN(OC)CC1

Procedure:
To a suspension of 4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid (1.0 g, 5.26 mmol) in methanol (25 ml) at 0-10° C. was added thionyl chloride (1.14 ml, 1.88 g, 15.77 mmol) and the reaction mixture was heated at reflux for 48 hours. After cooling, the mixture was concentrated, the residue diluted with ice water (20 ml) and neutralised with aqueous sodium bicarbonate. The aqueous phase was extracted with diethyl ether (3×25 ml), the combined organic layers washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated. Yield: 0.53 g of 4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid methyl ester (title compound P4ii.2) as a viscous, yellowish oil. This material was identical to the compound described above under preparation ‘EXAMPLE 11, Step 3’.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][C:3]=1[C:19]1[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=1.C[Si]([N:30]=[C:31]=[N:32][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:32][C:31]#[N:30])[CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][C:3]=1[C:19]1[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CC(c2ccccc2)Oc2cc(F)c(-c3cccnc3F)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(c2ccccc2)Oc2cc(F)c(-c3cccnc3F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 120.3 %

Procedure:
To a solution of 7-fluoro-6-(2-fluoropyridin-3-yl)-2-phenylchroman-4-one (78 mg, 0.23 mmol) in CH2Cl2 (5 mL) under N2 was added TiCl4 (1 M solution in DCM, 1.15 mL, 1.15 mmol) dropwise within 15 minutes at room temperature under dark. After addition, the reaction mixture was stirred for 1 h. To this mixture was added bis-trimethylsilylcarbodiimide (94.3 mg, 0.506 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give 7-fluoro-6-(2-fluoro-pyridin-3-yl)-2-phenylchroman-4-ylidene-cyanamide (100 mg, 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:41])C(=O)C1.[NH4+].[Cl-].CCOCC>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:27]([CH2:30][CH3:31])([CH2:32][CH3:33])[CH2:28][CH3:29])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:14][CH:15]=2)[C:10]([I:41])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)c(I)cn2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A solution of 1 g (2.1 mmol) of 1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole in 7 mL DMF was treated portionwise at 0° C. with 1.94 g (8.6 mmol) of NIS and stirred for 2 hrs at 65° C. The mixture was poured into a mixture of a saturated aqueous solution of NH4Cl containing NaS2O3 and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 1.1 g (72%) of 1-benzyl-3-iodo-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole, of which 50 mg were dissolved in 1 mL of MeOH and treated with 0.2 mL of 2M NaOMe in MeOH. After stirring for 30 min at RT, the crude mixture was distributed between aqueous HCl and Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 yielded 30 mg of 2-(1-benzyl-3-iodo-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light brown solid, MS 498 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2C(OC(C)(C)C)=O)=[O:26])[C:10](=[O:23])[N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][NH:28]2)=[O:26])[C:10](=[O:23])[N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccn2)CC1)[C@@H]1Cc2ccccc2CN1

Procedure:
N-{(1R)-1-[(4-Chlorophenyl)methyl]-2-oxo-2-(4-(2-pyridyl)piperazinyl)ethyl}((3S)(3-1,2,3,4-tetrahydro-isoquinolyl))carboxamide was prepared according to the procedure used for Preparation XVI using tert-butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-(4-(2-pyridyl)piperazinyl)ethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step 2) (450 mg, 0.745 mmol) and 10 mL HCl satd EtOAc. The resulting solid was purified by preparative HPLC (AcOH buffer) and freeze-dried yielding the acetate salt (410 mg). Mass Spec. m/z: 504 (M+H), (ESI, neg. ion) m/z: 502 (M−H). Calc'd for C28H30ClN5O2: 503.21. Anal. Calcd for C28H30ClN5O2—C2H4O2: C, 63.88; H, 6.08; N, 12.42. Found C, 63.66; H, 6.02; N, 12.64.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:9]([C:16]#[N:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]2=[N:4][CH:3]=1.[F:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(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>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:16]#[N:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([F:26])[CH:32]=3)=[CH:3][N:4]=2)[CH:7]=1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc12
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccnc(F)c3)cnc12
Temperature: 150 °C
Yield: 40 %

Procedure:
In a sealed tube, a mixture of 3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (115 mg, 0.25 mmol, prepared according to Example 35, Step 20.2), 2-fluoro-4-pyridine-boronic acid (45.3 mg, 0.32 mmol), PdCl2(PPh3)2 (9.6 mg, 0.014 mmol) and Na2CO3 (2.0 M solution in water, 0.43 mL) in DME (1 mL) was heated at 150° C. for 25 min in a microwave oven. The reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and washed with water (2×10 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/TBME 95:5→6:4) to yield the title compound (46.6 mg, 0.10 mmol, 41%) as a white solid. MS: 455 [M+1]+; HPLC: AtRet=3.18; TLC: RF 0.25 (hexane/TBME 1:1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][NH2:16]>O1CCOCC1>[NH2:13][C:11]1[N:10]([CH3:14])[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:16][CH3:15])[N:7]=2)[CH:12]=1
Reactant: CN
Reactant: Cn1nc(-c2ccnc(Cl)n2)cc1N
Solvent: C1COCCO1
Product: CNc1nccc(-c2cc(N)n(C)n2)n1
Temperature: 50 °C

Procedure:
The reaction mixture of 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-pyrazol-5-amine, 9.C (74.0 mg, 353.0 μmol) and methanamine (394.7 mg, 1.0 ml, 40% in water, 1.27 mmol) in 1,4-dioxane (1.5 ml) in a seal tube was heated at 50° C. for 7 h. LCMS results showed the reaction was done. The solvent was removed. The crude product was used for next step. MS ESI (pos.) m/e: 205.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCSc1cccc(Br)c1
Temperature: 50 °C
Yield: 81.1 %

Procedure:
A mixture of 3-bromobenzenethiol (1.5 g, 7.93 mmol), 2-bromoethanol (1.19 g, 9.52 mmol) and Cs2CO3 (5.16 g, 15.8 mmol) in DMF (10 ml) was heated to 50° C. overnight. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and dried. The crude product was purified by column chromatography to afford the titled compound (1.5 g, 81%). 1HNMR (400 MHz, CDCl3): δ 3.12 (t, J=6.0 Hz, 2H), 3.77 (t, J=6.4 Hz, 2H), 7.14 (t, J=8.0 Hz, 1H), 7.26-7.34 (m, 2H), 7.51 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH:16]([CH2:25]Cl)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[CH2:18]([O:17][CH:16]1[CH2:25][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:15]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCC(CBr)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(C(=O)OCC)CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 4.67 g, 0.117 mol) in 1,4-dioxane (69 mL) was added diethyl malonate (17.7 mL, 0.117 mol) dropwise. The mixture was stirred for 1.5 hours at ambient temperature after complete addition. To this mixture was added [2-bromo-1-(chloromethyl)ethoxy]methylbenzene (prepared according to the procedure found in Organic Letters (2004), 6(11), pp. 1853-1856; 32.0 g, 0.121 mol) dropwise and the resulting mixture was stirred for 1 hour at ambient temperature, then heated at reflux for 16 hours. The mixture was cooled briefly in an ice bath and sodium hydride (60% dispersion in mineral oil, 4.67 g, 0.117 mol) was added portionwise. The mixture was heated to reflux for a further 24 hours. Upon cooling to room temperature, the mixture was poured into pH 7 buffer and brine, and the product was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated. Flash column chromatography, eluting with a gradient of 5-60% ethyl acetate in hexanes afforded product (26.9 g, 75%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.Cl.[F:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1>>[F:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:11]1
Reactant: O=Cc1ncc[nH]1
Reactant: FC1CCNC1
Agent: Cl
Product: FC1CCN(Cc2ncc[nH]2)C1

Procedure:
The title compound was prepared from 2-imidazolecarboxaldehyde and 3-fluoropyrrolidine hydrochloride using the synthetic procedure described for Intermediate 5.