Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[CH2:17][CH2:18][O:19][C:23]2[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: NS(=O)(=O)c1ccc(O)cc1
Product: CC(C)(C)CN(CCOc1ccc(S(N)(=O)=O)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-hydroxybenzenesulfonamide: MS (APCI) m/z 454 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:9]([C:10](=[O:12])[CH3:11])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: CC(=O)CC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 10 g (51 mmol) of 1-(4-chlorophenyl)butane-1,3-dione (commercially available) dissolved in dimethyl sulfoxide was slowly added dropwise to 2.237 g (56 mmol) of sodium hydride in 200 ml of dimethyl sulfoxide such that the temperature did not exceed 30° C. The mixture was stirred at 20° C. for another 30 minutes. 8.558 g (56 mmol) of methyl bromoacetate in a little dimethyl sulfoxide were then slowly added dropwise at 0° C. The mixture was stirred at 20° C. for 4 hours. The reaction mixture was poured into ice-water and extracted with dichloromethane. The organic phase was repeatedly washed with water. Drying of the combined organic phases, removal of the solvent under reduced pressure and chromatography of the residue gave 7.750 g of product (56.7% of theory); NMR (CDCl3, 400 MHz): 2.19 (s, 3H); 2.99 (d, 1H); 3.03 (d, 1H); 3.69 (s, 3H); 4.95 (dd, 1H); 7.49 (d, 2H); 7.98 (d, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:46]=[CH:45][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[NH:35][N:34]=[N:33][N:32]=5)=[CH:27][CH:26]=4)=[CH:20][C:19]=3[N:36](C)[C:37](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:47].O1CCOCC1>>[ClH:47].[NH:32]1[C:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C:21]3[CH:22]=[CH:23][C:18]4[N:17]=[C:15]([CH2:14][O:13][C:12]5[CH:11]=[CH:10][C:9]([CH2:8][CH:4]6[S:3][C:2](=[O:1])[NH:6][C:5]6=[O:7])=[CH:46][CH:45]=5)[N:36]([CH3:37])[C:19]=4[CH:20]=3)=[CH:30][CH:29]=2)=[N:35][N:34]=[N:33]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn[nH]3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(-c4nnn[nH]4)cc3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetylamino]-5-[4-(tetrazol-5-yl)phenoxy]phenyl}-N-methylcarbamate (0.76 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 24 hours. The solvent of the reaction mixture was evaporated. To the residue was added ethyl acetate and insoluble product was isolated by filtration and washed with ethyl acetate to give the title compound (0.44 g).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[CH2:15][N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[CH3:3].CN1CCOCC1.I[Si](C)(C)C>ClCCl>[CH3:3][CH:2]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[CH2:15][N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)[CH3:1]
Reactant: CC(C)c1cc(N2CCCC2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)c1cc(N2CCCC2)ccc1CN1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-(propan-2-yl)-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate (200 mg, 0.52 mmol, 1.00 equiv), dichloromethane (10 mL) with an inert atmosphere of nitrogen. 4-Methylmorpholine (265 mg, 2.62 mmol, 5.00 equiv) and iodotrimethylsilane (412 mg, 2.08 mmol, 4.00 equiv) were added at 0° C. The resulting solution was stirred for 1 h at 0° C. The resulting mixture was concentrated under reduced pressure to provide 150 mg (crude) of 1-[[2-(propan-2-yl)-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine as light yellow oil. LCMS (ESI, m/z): 238 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1>C1(C)C=CC=CC=1.O1CCCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:2]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)=[CH:6][CH:5]=2)=[O:3])[CH:20]=1
Reactant: Nc1cccnc1
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cccnc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(Pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was prepared by treatment of 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50, 2.50 g, 10.20 mmoles) in toluene/tetrahydrofuran (3:1) with pyridine-3-amine (51, 0.960 g, 10.20 mmoles). The reaction mixture was stirred at room temperature for 16 hours, then concentrated. Yield: 3.21 g (93%). LCMS (HP walk-on); 2.89 min., 340.6, M+H.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][C:43]([CH3:48])([CH3:47])[CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[N:54]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1>>[N:54]1([S:58]([NH:61][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([CH:26]3[CH2:28][CH2:27]3)[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][C:43]([CH3:48])([CH3:47])[CH2:42]3)=[CH:31][C:32]=2[F:38])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1
Reactant: CC1(C)CCCC(COc2cc(F)c(C(=O)O)cc2C2CC2)C1
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(C)CCCC(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 158 step 5 and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid with 5-cyclopropyl-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained (0.12 g, 41%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.72-8.59 (m, 1H), 7.63-7.55 (m, 1H), 6.61-6.51 (m, 1H), 4.34-4.16 (m, 4H), 3.86-3.70 (m, 2H), 2.34-2.20 (m, 2H), 2.13-2.00 (m, 2H), 1.97-1.86 (m, 1H), 1.70-1.38 (m, 4H), 1.20-0.90 (m, 11H), 0.72-0.63 (m, 2H); MS (ES+) m/z 439.2 (M+1).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[CH3:11].Cl>O1CCCC1CCCO.O1CCOCC1>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]([C:12]2[N:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[CH:6][C:5]=1[OH:4]
Reactant: COCOc1cc(-c2cn(C)nn2)ccc1C
Agent: Cl
Agent: OCCCC1CCCO1
Solvent: C1COCCO1
Product: Cc1ccc(-c2cn(C)nn2)cc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(3-methoxymethoxy-4-methyl-phenyl)-1-methyl-1H-[1,2,3]triazol (0.57 g, 2.44 mmol) (from Example 20 supra) in tetrahydrofuran-2-propanol (1:1, 20 mL) was added HCl in dioxane (4 M, 8 mL) (Aldrich). The reaction mixture was stirred at room temperature for 2 days. The solution was concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexanes and dried to give 2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenol. (Yield 0.24 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[CH2:22]([SH:25])[CH2:23][SH:24]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[S:25][CH2:22][CH2:23][S:24]3)=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(F)cc21
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Product: Fc1ccc2c(c1)C1(CCC2)SCCS1
Temperature: 25 °C
Yield: 100 %

Procedure:
Dissolved 7-fluorotetralone, 51 (10.0 g, 60.9 mmol) in 1,2-ethanedithiol (10 mL) and cooled reaction to 0° C. Boron trifluoride diethyl etherate (7.5 mL) was added dropwise. The white suspension became yellow and homogenous. The wet ice bath was removed and the reaction was warmed to ambient temperature. The reaction was then diluted with heptanes (25 mL) and poured into an ice cold solution of saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated to give colorless oil (14.69 g, 60.9 mmol, 100% yield). 1H NMR (400 MHz, CDCl3) δ: 7.60 (d, J=12 Hz, 1H), 6.94 (t, J=4 Hz, 1H), 6.84 (t, J=8 Hz, 1H), 3.56 (m, 2H), 3.46 (m, 2H), 2.75 (m, 2H), 2.37 (m, 2H), 1.99 (m, 2H).
Reaction SMILES: [NH3:1].[CH3:2][C:3]([CH3:12])([CH3:11])[CH2:4][CH2:5][CH2:6][S:7](Cl)(=[O:9])=[O:8]>O1CCCC1>[CH3:2][C:3]([CH3:12])([CH3:11])[CH2:4][CH2:5][CH2:6][S:7]([NH2:1])(=[O:9])=[O:8]
Reactant: N
Reactant: CC(C)(C)CCCS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)CCCS(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Anhydrous ammonia gas was passed into a solution of 4,4-dimethylpentane sulphonyl chloride (1.85 g) in dry tetrahydrofuran (5 ml) at 5-10° C. until saturation. The resulting suspension was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (20 ml) and 2N aqueous hydrochloric acid (20 ml). The organic phase was separated, washed (brine 20 ml), dried (Na2SO4) and evaporated. Column chromatography on silica eluting with dichloromethane:methanol 98:2 gave 4,4-dimethylpentane sulphonic acid amide as an off-white solid (0.72 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([CH3:30])[CH:9]=1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:9][C:10]=3[CH3:30])=[O:15])[CH2:21][CH2:20]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C)CC2)c(C)c1
Yield: 44.9 %

Procedure:
Using pyrrolidin-2-one (47 mg) and (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (194 mg) described in Preparation Example 118 and by the reaction and treatment in the same manner as in Example 1, the title compound (88 mg) was obtained.
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1)=[O:14]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[O:10][CH2:9][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][O:8]2)[CH2:17][CH2:16]1)=[O:14]
Reactant: CCCCCC(CO)CO
Reactant: COC(=O)C1CCC(C=O)CC1
Solvent: Cc1ccccc1
Product: CCCCCC1COC(C2CCC(C(=O)OC)CC2)OC1
Yield: 85.1 %

Procedure:
2-Pentyl-1,3-propanediol 17.0 g (116 mol) and 4-formylcyclohexane carboxylic acid methyl ester 18.8 g (111 mmol) were dissolved in toluene 120 ml, and PTS 1.0 g was added, and the mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with a saturated sodium bicarbonate aqueous solution, and then with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=4/1) to obtain 4-(5-pentyl-1,3-dioxane-2-yl)cyclohexanecarboxylic acid methylester 28.2 g (94.5 mmol). The yield was 85.1% from 4-formylcyclohexanecarboxylic acid methylester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:26][CH2:27][OH:28].Cl>CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[OH:28][CH2:27][CH2:26][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: OCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C

Procedure:
10 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and, while stirring, sodium hydride (1.45 g of a 50% strength suspension in mineral oil, de-oiled with hexane) is added. The mixture is then stirred for 30 minutes at room temperature, 5.22 g of 2-iodoethanol are added dropwise thereto, and the mixture is then stirred for 15 minutes at room temperature and poured into a mixture of 30 ml of 2 N hydrochloric acid and 400 ml of ice-water. After being left to stand for some time the oil which separates crystallises and is taken up in 200 ml of methylene chloride. The solution is dried over magnesium sulphate and concentrated to dryness by evaporation. To crystallise, the residue is triturated with diethyl ether. 2-(2-hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 83°-84° is obtained.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[N:22]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([N:35]([CH3:37])[CH3:36])=[CH:27][CH:26]=1)=[C:23]=[S:24]>ClC(Cl)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:5]2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:23]([NH:22][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([N:35]([CH3:37])[CH3:36])=[CH:27][CH:26]=3)=[S:24])[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:15]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CN(C)c1ccc(N=C=S)c2ccccc12
Solvent: CC(Cl)Cl
Product: CN(C)c1ccc(NC(=S)NC2N=C(c3ccccc3)c3cc(Cl)ccc3N(C)C2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-amino-7-chloro-5-phenyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (INTERMEDIATE 1) (0.299 g, 1 mmol) in dichloroethane (15 mi) was added 4-isothiocyanato-N,N-dimethyl-1-naphthalenamine (0.230 g, 1 mmol). The reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0.345 g, 65%). 1H-NMR (CD3OD): δ 8.25 (d, 8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.85-7.81 (m, 2H), 7.77-7.72 (m, 2H), 7.65 (d, J=8.8 Hz, 1H), 7.61-7.58 (m, 4H), 7.51-7.47 (m, 2H), 7.29 (d, J=2.4 Hz, 1H), 6.01 (s, 1H) and 3.49 (s, 9H). MS (ESI) (M+H)+=528.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@H:20]2[C@H:24]([O:25][Si](C(C)(C)C)(C)C)[C@H:23]([O:33][Si](C(C)(C)C)(C)C)[C@@H:22]([CH2:41][O:42][CH3:43])[O:21]2)=[C:13]([NH:44][CH2:45][CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@H:20]2[C@H:24]([OH:25])[C@H:23]([OH:33])[C@@H:22]([CH2:41][O:42][CH3:43])[O:21]2)=[C:13]([NH:44][CH2:45][CH:46]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNCc4ccccc4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNCc4ccccc4)nc32)[C@H](O)[C@@H]1O
Yield: 61.9 %

Procedure:
The title compound was prepared by a similar method to example 38 using N-benzyl-N-(2-{9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}ethyl)amine (360 mg, 0.44 mmol) (preparation 39) and a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran (0.92 ml, 0.92 mmol). The product was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (93:7) increasing in polarity to dichloromethane:methanol:ammonia (90:10:1) to give the title compound (162 mg) as a foam. MS: 596 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH2:12][CH2:13][OH:14])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CNCCO
Product: Cc1cc(N(C)CCO)nc(Cl)n1
Yield: 61 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-6-methylpyrimidine and 2-(methylamino)ethanol. The title compound was isolated as a yellowish oil in a yield of 61%. MS ISP (m/e): 202.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=6.22 (s, 1H), 3.86 (t, 2H), 3.70-3.60 (m, 2H), 3.11 (s, 3H), 2.70 (s very broad, 1H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:8][C:9]3[N:10]([N:11]=[CH:12][C:13]=3[C:14]3[CH:15]=[N:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:18][CH:19]=3)[C:5]=2[NH:4][N:3]=1.[C:32](O)(=[O:36])[C@@H:33]([CH3:35])[OH:34].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[OH:34][C@H:33]([CH3:35])[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([C:7]2[C:6]3[C:2]([CH3:1])=[N:3][NH:4][C:5]=3[N:10]3[N:11]=[CH:12][C:13]([C:14]4[CH:15]=[N:16][C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:18][CH:19]=4)=[C:9]3[N:8]=2)[CH2:27][CH2:28]1)=[O:36]
Reactant: Cc1n[nH]c2c1c(C1CCNCC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: C[C@@H](O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]c2c1c(C1CCN(C(=O)[C@@H](C)O)CC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-methyl-6-(6-phenylpyridin-3-yl)-4-(piperidin-4-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidine (Int-9l, 42 mg, (\10 mmoL), D-(−)-lactic acid (9.3 mg, 0.10 mmoL), EDC (39.4 mg, 0.20 mmoL), HOBt (13.9 mg, 0.10 mmoL) and DIEA (89 μL, 0.51 mmoL) in DMF (4 mL) was stirred at room temperature for 2 hr. Purification with prep-LC provided (R)-2-hydroxy-1-(4-(3-methyl-6-(6-phenylpyridin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)piperidin-1-yl)propan-1-one (30): LCMS tR=3.07 min (10 min run, UV254nm) Mass calculated for, M+481.2, observed LC/MS m/z 482.6 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([F:8])[CH2:5][N:4]1[C:9]([NH:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([NH2:23])=[O:22])[CH:13]=1)=[O:10].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C(N(CC)CC)C.O>C(Cl)Cl>[C:28]1([O:27][C:25](=[O:26])[NH:1][CH2:2][C@@H:3]2[CH2:7][C@@H:6]([F:8])[CH2:5][N:4]2[C:9](=[O:10])[NH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21](=[O:22])[NH2:23])[CH:13]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC[C@@H]1C[C@@H](F)CN1C(=O)Nc1cn(C(N)=O)c2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2CNC(=O)Oc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-[((2S,4R)-2-aminomethyl-4-fluoro-pyrrolidine-1-carbonyl)-amino]-indole-1-carboxylic acid amide (50 mg, 0.157 mmol, prepared as described in Scheme B11) and phenyl chloroformate (22 μL, 0.17 mmol) in CH2Cl2 (0.5 mL), was added triethylamine (24 μL, 0.17 mmol) and the resulting suspension was stirred at RT under nitrogen overnight. The mixture was poured into water and extracted with CH2Cl2 (×2). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, eluent: 20% to 100% CH3CN in H2O in 15 min, CH3CN and H2O containing 0.1% HCOOH, flow: 20 mL/min) to give after lyophilization of the purified fractions the desired material. Rf, TLC (EtOAc)=0.45; MS (LC-MS): 440 [M+H]+, 901.3 [2M+Na]+; tR (HPLC conditions f): 1.77 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>>[C:13]1([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=2[C:10]([OH:12])=[O:11])[CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1[nH]c2ccccc2c1C1=CCCC1

Procedure:
Condensation of the indole carboxylic acid with cyclopentanone in the presence of aqueous sodium hydroxide gave the 3-cyclopentenyl indole carboxylic acid, which was subjected to hydrogenation in the presence of catalytic amount of palladium on carbon to afford the corresponding cyclopentyl carboxylic acid in 80% overall yield. Double methylation of the carboxylic acid and the nitrogen with methyl carbonate in NMP at 130° C. provided the N-methyl indole carboxylate methyl ester in 90% yield. Bromination of the indole carboxylate with bromine in acetonitrile furnished the 2-bromo-3-cyclopentyl indole carboxylate in 90% yield.
Reaction SMILES: C([CH:4]([CH2:10][CH2:11][C:12](=[O:23])[CH:13]([C:17]1[O:21][N:20]=[C:19]([CH3:22])[CH:18]=1)[C:14](=O)[CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.C(N(CC)CC)C.O>CO>[CH2:8]([O:7][C:5]([CH:4]1[CH2:10][CH2:11][C:12](=[O:23])[C:13]([C:17]2[O:21][N:20]=[C:19]([CH3:22])[CH:18]=2)=[C:14]1[CH3:15])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(CCC(=O)C(C(C)=O)c1cc(C)no1)C(C)=O
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(=O)C(c2cc(C)no2)=C1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
0.85 g of the obtained ethyl 2-acetyl-5,7-dioxo-6-(3-methylisooxazol-5-yl)octanoate was dissolved in 5 ml of methanol and 0.32 g of triethylamine was added. The resulting solution was stirred at room temperature for 2 hours and then heated at reflux for 3 hours. After cooling, water was added to the reaction solution to extract with ethyl acetate. The organic layer was washed with saturated salt water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The obtained residue was purified on silica gel column chromatography to give 0.27 g of the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[CH:28][C:27]=1[F:26]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless solid. MS (m/e)=528.2 [M+H+].