Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:23]=1[S:32]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: Nc1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3,5-dichloro-4-quinolin-3-ylmethyl-phenyl)-4-trifluoromethyl-benzenesulfonamide was synthesized (80%) from 3,5-dichloro-4-quinolin-3-ylmethyl-phenylamine (230), 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.49 (br s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.19 (s, 1H), 7.98 (d, J=7.0 Hz, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 781 (s, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 7.24 (s, 2H), 4.34 (s, 2H). MS (EI): m/z 543 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[N:17]=[C:16]([C@:18]3([CH3:36])[CH2:23][C@@H:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20]([NH:28]C(=O)OC(C)(C)C)=[N:19]3)[C:15]([F:37])=[CH:14][CH:13]=2)=[O:10])=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:20]1[O:21][C@H:22]([C:24]([F:25])([F:27])[F:26])[CH2:23][C@:18]([C:16]2[N:17]=[C:12]([NH:11][C:9](=[O:10])[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:13]=[CH:14][C:15]=2[F:37])([CH3:36])[N:19]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(NC(=O)c3ccc(C#N)cn3)ccc2F)C[C@@H](C(F)(F)F)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(c2nc(NC(=O)c3ccc(C#N)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of tert-butyl ((4S,6S)-4-(6-(5-cyanopicolinamido)-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7l, 0.096 g, 0.18 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h and the solvent was removed under reduced pressure. The residue was treated with 1 N NaOH (5 mL) and extracted with DCM (3×5 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude material was triturated with ether and the solid was filtered off to give the title compound as a white solid (0.065 g, 84% yield, 0.15 mmol) after drying under vacuum. MS m/z=423.0 [M+H]+. Calculated for C18H14F4N6O2: 422
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[S:9][CH:8]=[C:7]([CH:10]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][C:12]#[N:13])[CH:6]=1)C.C1COCC1.Cl>O>[CH:4]([C:5]1[S:9][CH:8]=[C:7]([CH:10]([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][C:12]#[N:13])[CH:6]=1)=[O:3]
Reactant: CCOC(OCC)c1cc(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4csc(C=O)c4)c3)ncnc21
Temperature: 25 °C

Procedure:
A solution of 3-[5-(diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (70 mg, 0.0001 mol) in THF (1 mL, 0.01 mol) was treated with 1 M HCl in water (400 μL). The reaction was stirred at room temperature. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-formyl-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile as a semisolid residue (60 mg, 98%). 1H NMR (400 MHz, CDCl3): 9.96 (s, 1H), 8.89 (s, 1H), 8.44 (m, 2H), 7.46 (1H), 5.73 (s, 2H), 4.15 (m, 1H), 3.73-3.43 (m, 3H), 1.35 (m, 1H), 1.01 (m, 2H), 0.03 (s, 9H); MS(ES): 479 (M+1).
Reaction SMILES: C[N:2]1[CH:9]=[CH:8][C:6](=[O:7])[N:5](C)[C:3]1=O.[O-]CC.[Na+].[NH:15]1[C:19](N)=[CH:18]C=N1>C(O)C>[N:15]1[N:2]2[CH:9]=[CH:8][C:6](=[O:7])[NH:5][C:3]2=[CH:18][CH:19]=1
Reactant: Nc1ccn[nH]1
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1ccn2nccc2[nH]1
Temperature: 60 °C
Yield: 58 %

Procedure:
1,3-Dimethyl uracil (3.15 g, 22.5 mmol) and sodium ethoxide (23 mL of a 21% solution in ethanol) were added to a solution of 1H-pyrazol-5-amine (1.7 g, 20.4 mmol) in ethanol (50 mL). The resulting mixture was heated to 60° C. for 2 h and was then cooled to room temperature. The pale brown solid was isolated by filtration to give pyrazolo[1,5-a]pyrimidin-5(4H)-one (1.6 g, 58%). Retention time (min)=0.820, method [3], MS (ESI) 136.1 (M+H).
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.C[O:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([Cl:17])=[CH:13][N:12]=1)=O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:17][C:14]1[N:15]=[CH:16][C:11]([C:9]([NH2:2])=[O:8])=[N:12][CH:13]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cnc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
Suspend ammonium chloride (0.465 g, 8.69 mmol) in toluene (14 mL). Cool to 0° C. and slowly add 2.0 M Al(CH3)3 in toluene (4.3 mL, 8.69 mmol). After the gas stops evolving, add 5-chloropyrazine-2-carboxylic acid methyl ester (0.500 g, 2.89 mmol). Heat at 50° C. overnight. Cool the reaction mixture to room temperature, then slowly pour into a slurry of silica gel (10 g) in CHCl3 (50 mL). Stir for 10 minutes before filtering. Wash the silica plug with methanol (2× 100 mL) before concentrating. Take the resulting solid up in dichloromethane and wash with water (30 mL) and brine (40 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 50% ethyl acetate in hexanes to give the title compound (0.155 g, 34.0%): TOF MS EI+ 157.0 (M+), HRMS calcd for C5H4N3OCl 157.0043 (M+H)+, found 157.0047, time 4.19 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min. 5-95% over 19 min], tR=7.1 min, 100% purity.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH2:23][CH2:24]Br>CC(N(C)C)=O.C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][N:14]([CH2:24][CH2:23][CH:22]([O:26][CH3:27])[O:21][CH3:20])[C:13]1=[O:17])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(CCBr)OC
Reactant: CC(C)(C)[Si](C)(C)OCCCN1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COC(CCN1CCN(CCCO[Si](C)(C)C(C)(C)C)C1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
1-[3-(tert-Butyldimethylsilanyloxy)propyl]imidazolidin-2-one (17.65 g, 68.30 mmol; prepared as described in Preparation 1) was slowly added to a suspension of NaH (8.20 g, 204.9 mmol, 3.0 eq, 40% mineral oil) in DMA (400 mL). Deprotonation was monitored with a bubbler, and bubbling was ceased after one hour of stirring at room temperature. A solution of 3-bromopropionaldehyde dimethyl acetal (25.0 g, 136.6 mmol, 2.0 eq) in DMA (100 mL) was slowly added to the reaction mixture over a period of 2 hours via an addition funnel. Following an additional hour of stirring at room temperature, the solution was concentrated in vacuo and the crude reaction mixture was taken up in DCM (200 mL) and washed with water (2×200 mL) and brine (2×200 mL). The organic phase was dried over Na2SO4, filtered and concentrated to afford the title compound (24.53 g, 68.8 mmol) as light yellow oil. The material was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][NH2:35])[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].O.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:35][CH2:34][CH2:33][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][O:24][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:36])[CH:32]=[CH:31][CH:30]=1)(=[O:40])[CH3:39]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCN)c3)c2)Cc2ccccc2C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(CCNC(C)=O)c1

Procedure:
The compound of Step 2 of example 246 (85 mg, 0.174 mmol) was dissolved in acetic anhydride and stirred under reflux for 30 min. Water was added in excess and the mixture was refluxed for 10 min. After cooling, the mixture was extracted with EA, the combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the methyl ester of the title compound. Hydrolysis of this ester in analogy to example 2 yielded 17 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=2)=[CH:4][C:3]=1[F:9]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Yield: 93.6 %

Procedure:
By analogy to Example A2, 4-amino-3-fluorophenol (0.12 g, 0.53 mmol), potassium tert-butoxide (0.080 g, 0.71 mmol) and tert-butyl 4-chloropicolinate (159 mg, 0.53 mmol) were combined to provide tert-butyl 4-(4-amino-3-fluorophenoxy)picolinate (151 mg, 67% yield). MS (ESI) m/z: 305.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)cc2)cc1
Reaction time: 16 h
Yield: 134.9 %

Procedure:
To a solution of 4-methoxybenzenesulfonyl chloride (5.0 g, 24 mmol) and 4-methoxyaniline (3.0 g, 24 mmol) in dichloromethane (24 mL) at 0° C. was added triethylamine (3.4 mL, 24 mmol) over 10 minutes. The ice bath was removed, and the mixture was stirred for 16 hr. The mixture was diluted with dichloromethane (100 mL) and the combined solution was washed with water (50 mL) and brine (50 mL). The organic solution was dried over MgSO4, filtered, and evaporated, and the crude product was purified by silica gel chromatography (15-60% EtOAc/Hex). Product-containing fractions were pooled, evaporated, and dried under high vacuum to yield 9.5 g (79%) of the product as a tan-colored oil: 1H-NMR (DMSO-d6) δ 9.29 (s, 1H), 7.63 (d, 2H), 7.23-7.19 (m, 1H), 7.11-7.01 (m, 3H), 6.91-6.83 (m, 2H), 3.79 (s, 3H), 3.52 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][CH2:41]O.[C:43]([OH:51])(=[S:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.C(OCC)(=O)C>[C:43]([S:50][CH2:41][CH2:40][C:36]1[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=1)(=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: OC(=S)c1ccccc1
Reactant: Cn1ccnc1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ccnc1CCSC(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (10.48 g) was dissolved in tetrahydrofuran (120 ml). To the solution were added diisopropyl azodicarboxylate (8.07 g) at 0° C. The mixture was stirred for 15 minutes at the same temperature. To the mixture were added a solution of 2-(1-methyl-2-imidazolyl)ethanol (2.52 g) in tetrahydrofuran (10 ml) and thiobenzoic acid (4.7 ml) in the order mentioned. The mixture was stirred for 2.5 hours at 0° C. and then for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, then washed with saturated solution of sodium hydrogencarbonate in water and saturated solution of sodium chloride in water in the order mentioned. The residue was dried over anhydrous sodium sulfate and concentrated under reduced pressure, which was then subjected to column chloromatography on silica gel (developing solvent: ethyl acetate-methanol: 100:0→93:7) to give the title compound (3.52 g).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:4][CH:3]=1.[CH:21]12[CH2:29][CH:25]([CH2:26][CH2:27][CH2:28]1)[CH2:24][NH:23][CH2:22]2.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:21]12[CH2:29][CH:25]([CH2:26][CH2:27][CH2:28]1)[CH2:24][N:23]([C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:7])=[CH:4][CH:3]=1)[CH2:22]2
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc(F)cc1
Reactant: C1CC2CNCC(C1)C2
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(N2CC3CCCC(C3)C2)cc1

Procedure:
A solution of 4-fluoro-N-quinolin-3-yl-benzamide (0.080 g, 0.299 mmol), 3-aza-bicyclo[3.3.1]nonane (0.200 g, 1.60 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in dimethyl sulfoxide (2 mL) was heated to 100° C. for 11 days. The DMSO solution was applied to a preparative reverse phase C18 column, and the product was eluted with a gradient of acetonitrile in water with 0.1% trifluoroacetic acid, to give the product as a trifluoroacetate salt, a yellow solid, 0.065 g (36%). MS: m/z 372 (MH+). 1H NMR (DMSO-d6): 1.40-1.50 (m, 1 H), 1.58-1.93 (m, 7 H), 2.05 (br s, 2 H), 3.04-3.08 (m, 2 H), 3.85 (d, 2 H), 7.00 (d, 2 H), 7.62-7.76 (m, 2 H), 7.96 (d, 2 H), 8.02 (d, 2 H), 8.95 (d, 1 H), 9.28 (d, 1 H) and 10.45 (s, 1 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][C:8]([C:31]3[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=3)=[CH:9][C:10]=2[C:11]([NH:13][CH:14]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:15][NH:16]C(=O)OC(C)(C)C)=[O:12])=[CH:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:16][CH2:15][CH:14]([NH:13][C:11]([C:10]1[CH:9]=[C:8]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)[S:7][C:6]=1[C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:12])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)Cc2ccccc2)c(-c2ccoc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)NC(CN)Cc2ccccc2)c(-c2ccoc2)s1
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl [2-({[2-(3-furanyl)-5-(1-methyl-1H-pyrazol-5-yl)-3-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part e) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue passed through a silica plug (3% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C@@:25]2([CH3:26])[C@H:23]([O:24]2)[CH2:22][C@@H:21]([OH:27])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36]>CN(C)C=O.O>[C:14]([Si:1]([O:18][C@@H:19]1[CH2:20][C@H:21]([O:27][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:22][C@@H:23]2[C@@:25]1([CH3:26])[O:24]2)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@H](O)C[C@H]2O[C@]21C)(c1ccccc1)c1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H]1C[C@H]2O[C@@]2(C)[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Yield: 90 %

Procedure:
The compound of Example 13B (16.0 g, 42 mmol) was dissolved in 20 mL of dimethylformamide; 7.1 g of imidazole (100 mmol, 2.5 equivalents) was added, followed by 10.5 mL of chlorotriethylsilane. The resultant mixture was stirred overnight at ambient temperature, then was diluted with water and extracted with ethyl acetate. The organic phase was concentrated washed with brine and dried over Na2SO4. After concentrating in vacuo, the residue was purified by flash chromatography, eluting with a gradient from 50% to 100% dichloromethane in hexanes to provide the titled compound (14.0 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=[O:21])[N:11]([CH3:20])[C:12]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:13]=2[CH3:14])=[CH:5][CH:4]=1.[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][CH2:14][C:13]1[C:12]2([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[N:11]([CH3:20])[C:10](=[O:21])[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C2=C(C)C3(CCCCC3)N(C)C2=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2=C(CBr)C3(CCCCC3)N(C)C2=O)cc1
Temperature: 25 °C

Procedure:
3-(4-Methoxyphenyl)-1,4-dimethyl-1-azaspiro[4.5]dec-3-ene-2-one (881 mg, 3.09 mmol) and N-bromosuccinimide (1.2 eq.) were stirred in 40 mL CCl4 with a catalytic amount of benzoyl peroxide for 3 h at 85° C. After cooling to room temperature the mixture was diluted with CH2Cl2, washed with water, dried (Na2SO4) and evaporated. The 4-bromomethyl-3-(4-methoxyphenyl)-1-methyl-1-azaspiro[4.5]dec-3-ene-2-one thus obtained was dissolved in ethanol (100 mL), CH2Cl2 (20 mL), and ethylamine (70% solution in water, 2 mL), the mixture was stirred overnight at room temperature and concentrated. The residue was dissolved in CH2Cl2, washed with water and extracted with 0.5 M HCl.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Cl:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:25])[CH:15]=[CH:16][C:17]1[N:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[S:20][CH:21]=1.O>CC(O)=O.OP(O)(O)=O>[Cl:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[N:18]=[C:19]([CH:22]([CH3:23])[CH3:24])[S:20][CH:21]=4)[CH2:15][C:14](=[O:25])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)C=Cc3csc(C(C)C)n3)c(N)c2c1Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2oc3c(c2c1Cl)NC(c1csc(C(C)C)n1)CC3=O
Temperature: 25 °C
Yield: 108.4 %

Procedure:
10A (9.96 g, 26.43 mmol) was dissolved in AcOH (50 mL) and H3PO4 (50 mL). The solution was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (200 mL) The brown precipitates were collected by filtration and dried to give product 10B (10.8 g), which was used for the next step directly.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(C(C)C)C(C)C)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:8]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[NH:25][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of C-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (231.4 mg, 0.6672 mmol), DMAP (4 mg, 0.033 mmol), and (iPr)2EtN (174 μL, 129 mg, 1 mmol) in dry CH2Cl2 (5 mL), cooled to 0° C., pivaloyl chloride (90 μL, 89 mg, 0.734 mmol) was added under N2 atmosphere, the cooling bath was removed, and the reaction mixture was allowed to stir at ambient temperature for 16 h. The reaction was quenched with H2O and extracted with CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with (1×30 mL each) 0.25M citric acid (pH 2-3), H2O, NaHCO3 sat. aq. sol., and brine, dried over anhydrous MgSO4, and filtered. Sample was purified by filtration through a plug of silica gel, eluting with EtOAc:CH2Cl2 10:1→5:1 (300 mL). Filtrate was concentrated in vacuo, yielding the title compound, as a yellow solid, containing approximately 10% of bis-acetylated material; 1H NMR (CDCl3, 400 MHz) δ 1.23 (s, 9H), 6.75 (d, J=7.6 Hz, 1H), 7.43-7.48 (m, 1H), 7.49-7.55 (m, 2H), 7.60 (d, br, J=7.6 Hz, —NH), 7.72-7.77 (m, 1H), 7.81-7.89 (m, 2H), 7.90 (s, 1H), 8.07-8.14 (m, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.38 (d, J=2.8 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H); MS (ES+): m/z 430.9/432.9 (100/37) [MH+]; HPLC: tR=3.5 min (OpenLynx, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:49])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41]S(C)(=O)=O)[C:24]=1[CH2:46][CH2:47][CH3:48])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:49])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:46][CH2:47][CH3:48])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 69.1 %

Procedure:
A mixture of 1.100 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.939 g of 4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.56 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a dark oil which was purified by high pressure liquid chromatography using 40% ethyl acetatehexane to give 2.413 g (69% yield) of 4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH:9]([N:11]3[CH2:16][CH2:15][C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:17](O)=[O:18])[CH2:13][CH2:12]3)[NH:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[C:26]([C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])([CH3:29])([CH3:28])[CH3:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[C:26]([C:30]1[CH:31]=[C:32]([NH:33][C:17]([C:14]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:13][CH2:12][N:11]([C:9]3[C:10]4[C:2]([CH3:1])=[CH:3][NH:4][C:5]=4[N:6]=[CH:7][N:8]=3)[CH2:16][CH2:15]2)=[O:18])[CH:34]=[CH:35][CH:36]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: Cc1c[nH]c2c1C(N1CCC(C(=O)O)(c3ccccc3)CC1)NC=N2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ncnc(N3CCC(C(=O)Nc4cccc(C(C)(C)C)c4)(c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-phenylpiperidine-4-carboxylic acid from step B (33 mg, 0.1 mmol) in DMF (2 mL) was added 3-tert-butylaniline (15 mg, 1.0 mmol), BOP (50 mg, 0.11 mmol) and triethylamine (0.04 mL, 0.3 mmol). The reaction mixture was stirred at room temperature for 20 hours, and the amide product was isolated by prep HPLC to give the title compound.