Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:28])[NH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)=O)(C)(C)C.Cl.[CH3:30][O:31][C:32]([NH:34][CH:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C.C(OCC)(=O)C>[CH3:30][O:31][C:32](=[O:33])[NH:34][CH:35]([C:36]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:28])[NH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)=[O:37])[CH:39]([CH3:41])[CH3:40]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1cccc(-c2ccc(Cl)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1cccc(-c2ccc(Cl)cc2)c1)C(C)C
Temperature: 50 °C
Reaction time: 1.33 h
Yield: 96.5 %

Procedure:
2-(4′-Chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.66 g, 4.14 mmol) was dissolved in methanol (20 mL) and concentrated HCl (4 mL) was added. The mixture was stirred at 50° C. for 80 min then cooled and concentrated. The residue was treated with 2-methoxycarbonylamino-3-methyl-butyric acid (870 mg, 4.97 mmol) and HATU (2.05 g, 5.38 mmol) and brought up in DMF (20 mL) The mixture was cooled to 0° C. and DIPEA (3.60 mL, 20.7 mmol). After 100 min, the reaction mixture was diluted with ethyl acetate (250 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The resulting residue was purified by silica column chromatography (50% to 80% EtOAc/hexanes) to afford {1-[2-(4′-Chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (1.83 g, 96% over 2 steps).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[CH2:11]([N:18]=[N+:19]=[N-:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[CH2:11]([N:18]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#CCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3ccccc3)nn2)c[nH]1
Yield: 86.1 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.095 g, 0.603 mmol) was reacted with benzyl azide (0.096 g, 0.723 mmol) following the general procedure for click reactions outlined above to produce 4-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol 2-ylamine hydrochloride (0.151 g, 86%) of a pale yellow solid. 1H NMR (300 MHz, D2O) δ 7.79 (s, 1H), δ 7.42-7.35 (m, 5H), δ 6.43 (s, 1H), δ 5.58 (s, 2H), δ 3.86 (s, 2H) ppm; 13C δ 145.4, 136.6, 136.4, 128.8, 128.7, 126.9, 126.8, 126.3, 124.1, 121.8, 109.6, 53.3, 24.1 ppm; HRMS (ESI) calcd for C13H16N6O (M+) 254.1352. Found 254.1352.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([C:32]([O:34]CC)=[O:33])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:18]([Cl:37])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl.C(OCC)(=O)C>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:31])[C:32]([OH:34])=[O:33])=[C:18]([Cl:37])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
The compound of Example 194 (2.74 g) was dissolved in ethanol (10 mL). To this solution, potassium hydroxide (330 mg) was added and the mixture was stirred overnight at 50° C. Subsequently, the reaction mixture was diluted with water, followed by addition of 2 mol/L hydrochloric acid and extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, was dried over anhydrous magnesium sulfate, and was then concentrated. The resulting residue was purified on a silica gel chlomatography (hexane:ethyl acetate=10:1 to 2:1) to give the desired product as a yellow oil (2.38 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:21]3[N:22]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[CH:23]=[N:24][C:20]=3[CH:19]=[C:18]([C:33]#[N:34])[N:17]=2)[CH:13]=[N:14][CH:15]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:23]1[N:22]([CH2:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)[C:21]2[C:16]([C:12]3[CH:13]=[N:14][CH:15]=[C:10]([Cl:9])[CH:11]=3)=[N:17][C:18]([C:33]#[N:34])=[CH:19][C:20]=2[N:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (5.84 g, 32.8 mmol) was added to a room temperature solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (4 g, 10.9 mmol) stirring in degassed chloroform (54.7 mL). The reaction was heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated aqueous sodium thiosulfate (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C20H19BrClN5 [M+H]+ 444. found 444. 1H NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 8.40 (s, 1H), 3.86 (d, J=6.1, 2H), 1.44 (d, J=12.1, 2H), 1.15-1.05 (broad, 1H), 1.00-0.85 (broad, 1H), 0.85-0.73 (m, 4H), 0.72 (d, J=6.1, 3H), 0.56-0.43 (m 2H).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20](O)=[O:21])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:27])=O.CN(C)C=O.Cl>ClCCl>[C:1]1([N:7]([C:14]2[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([Cl:27])=[O:21])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
A 50 mL round bottom flask equipped with a magnetic stirrer and a nitrogen inlet-outlet was charged with 4-(N,N-diphenylamino)cinnamic acid (1.0 g, 3.2 mmol) in 15 mL dichloromethane. Thionyl chloride (0.35 mL, 4.8 mmol) was added followed by 12.4 □L N,N-dimethylformamide. Hydrogen chloride gas evolution began immediately and then ceased within one hour of stirring. The solution was stirred for 3 h and then concentrated on a rotary evaporator. The product was transferred to a high vacuum line and residual solvent was removed under vacuum. The product was obtained as a brown solid and stored under nitrogen without any further purification.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5]I.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:31][CH2:30][CH2:29][C@@:16]3([C:20](=[O:21])[N:19]([C@H:22]4[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[CH2:15]2)=[C:10]([F:32])[CH:9]=1.O[C@H]1CC[C@H](N2CC[C@]3(CCCNC3)C2=O)CC1.[I-].[K+].C(O)(C(F)(F)F)=O>CN(C)C1C=CN=CC=1.CN(C=O)C.CO>[F:32][C:10]1[CH:9]=[C:8]([N:7]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][C:11]=1[N:14]1[CH2:31][CH2:30][CH2:29][C@@:16]2([C:20](=[O:21])[N:19]([C@H:22]3[CH2:23][CH2:24][C@H:25]([OH:28])[CH2:26][CH2:27]3)[CH2:18][CH2:17]2)[CH2:15]1
Reactant: ICCCCI
Reactant: Nc1ccc(N2CCC[C@]3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)c(F)c1
Agent: CN(C)c1ccncc1
Agent: O=C1N([C@H]2CC[C@H](O)CC2)CC[C@]12CCCNC2
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C1N([C@H]2CC[C@H](O)CC2)CC[C@]12CCCN(c1ccc(N3CCCC3)cc1F)C2
Temperature: 110 °C

Procedure:
A mixture of 1,4-diiodobutane (13.5 μL, 0.000100 mol), (5S)-7-(4-amino-2-fluorophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (28.9 mg, 0.0000800 mol, this compound was prepared by using procedures analogous to that described for the synthesis of example 105, step 1 starting from (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one) and 4-dimethylaminopyridine (14.7 mg, 0.000120 mol) in DMF (1.00 mL), and potassium iodide (1.5 mg, 0.0000090 mol) was heated at 110° C. by microwave for 15 min. The mixture was diluted with methanol (0.8 mL) and was adjusted to be acidic with TFA (the pH was about 2.0). The resulting solution was purified by prep-HPLC to give the desired product. LC-MS: 416.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[S:8].[CH:13](Br)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]([O:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[S:8])([CH3:15])[CH3:14]
Reactant: COC(=S)c1cnc(C)c(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=S)c1cnc(C)c(OC(C)C)c1
Temperature: 60 °C

Procedure:
A mixture of methyl 5-hydroxy-6-methylthionicotinoate (3 g), isopropyl bromide (2.1 mL) and anhydrous potassium carbonate (3 g) in dry dimethylformamide (35 mL) is stirred and heated at 60±5° C. for 18 hours. After cooling the solvent is removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase is washed with brine and dried (MgSO4). Evaporation gives a brown oil which is purified by flash chromatography (pentane/ethyl acetate 4:1 v/v as eluent on silica) to give methyl 5-isopropyloxy-6-methylthionicotinoate (2.36 g) as a pale yellow oil. [Elemental analysis: —C, 54.40; H, 6.24; N, 5.88%. calculated: —C, 54.75; H, 6.27; N, 5.81%.].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N+:40]([O-])=[C:39]([CH3:45])[CH:38]=1.C(BC(C(C)C)C)(C(C)C)C>>[CH3:43][C:41]1[CH:42]=[C:37]([C:20]2[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C@@:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12]3=[O:14])[CH3:16])=[CH:22][CH:21]=2)[CH:38]=[C:39]([CH3:45])[N:40]=1
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: CC(C)C(C)BC(C)C(C)C
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine-N-oxide using a procedure analogous to that described in Example 14, followed by treatment with disiamyl borane. LC-MS Method 1 tR=1.1 min, m/z=463 (M+1); 1H NMR (CDCl3) 7.50 (s, 2H), 7.45 (d, 1H), 7.25 (m, 3H), 7.17-6.99 (m, 4H), 5.73 (q, 1H), 4.28 (t, 1H), 3.04 (m, 1H), 2.82 (s, 6H), 2.31 (m, 3H), 1.91 (m, 3H), 1.58 (d, 3H).
Reaction SMILES: [CH3:1][CH:2]([OH:21])[CH2:3][C:4]1[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:24][O:21][CH:2]([CH3:1])[CH2:3][C:4]1[N:5]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1
Reactant: CC(C)Cn1c(CC(C)O)nc2cnc3ccccc3c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)Cc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
α-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-ethanol (6.5 g, 23 mmol, Example 74) was dissolved in N,N-dimethylformamide (50 mL) then cooled to 0° C. Sodium hydride (0.8 g, 25 mmol), 80% dispersion in mineral oil) was added and the resulting mixture was stirred at 0° C. for about 1 hour. Methyl iodide (2.2 mL, 34 mmol) was added and the resulting mixture was stirred at 0° C. for about 1 hour and then allowed to warm to room temperature. The reaction was quenched with water and then diluted with ethyl acetate. The organic layer was separated, washed several times with water, dried over magnesium sulfate then concentrated under vacuum. The resulting residue was purified by silica gel chromatography using 2-5% methanol in methylene chloride to give about 3 g of the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12](I)=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C=O)C.[CH:48]([C:50]1[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=1)=[CH2:49]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:1]1([C:4]2[C:5]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:6]3[C:12](/[CH:49]=[CH:48]/[C:50]4[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=4)=[N:11][N:10]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C=Cc1cccnc1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(/C=C/c3cccnc3)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
A 50 mL round bottom flask charged with tert-butyl 4-(5-cyclopropyl-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (500 mg, 0.85 mmol), triethylamine (355 μL, 2.54 mmol), Pd2dba3 (19.4 mg, 0.021 mmol), tri-o-tolylphosphine (19.4 mg, 0.064 mmol), and DMF (7 mL) was purged under N2 (3 cycles). 3-vinylpyridine (270.24 mg, 1.7 mmol) was added, and the mixture was stirred at 100° C. under a N2 atmosphere for 6 hours. The reaction mixture was cooled to room temperature, diluted with warm EtOAc (100 mL) and washed with water (2×30 mL). The phases were separated, and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Biotage Flash 40S+) eluting with 25% EtOAc/hexane followed by 50% EtOAc/hexane to provide (E)-tert-butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-3-(2-(pyridin-3-yl)vinyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (390 mg, 81% yield) as a solid. LCMS (APCI+) m/z 567.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([C:20](OC)=[O:21])[CH:11]=1)#[N:2].[BH4-].[Na+].O>CO>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]([CH2:20][OH:21])[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=1)#[N:2]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(CO)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of dimethyl 2′-cyano-4′-methylbiphenyl-3,5-dicarboxylate (343 mg, 1.05 mmol) in methanol (20 mL) was cooled at 0° C. and sodium tetrahydroborate (0.60 g, 16 mmol) was added slowly. The mixture was stirred at rt for 6 h, and then treated with water (20 mL). The volatiles were removed in vacuo and the acqueous phase was extracted with CH2Cl2 (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13][C:14]([F:35])([F:34])[C:15]1[CH:16]=[C:17]([S:21]([CH2:24][CH2:25][S:26][C:27]2[C:32]([NH2:33])=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>S(Cl)(Cl)=O.O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:33][C:32]2[C:27]([S:26][CH2:25][CH2:24][S:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:34])([F:35])[F:13])[CH:16]=3)(=[O:23])=[O:22])=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(F)ccc1C(=O)O
Reactant: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(F)ccc1C(=O)Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A solution of 510 mg (3.0 mmol) 4-fluoro-2-methoxybenzoic acid in thionyl chloride (3 ml) was stirred for 2 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with dioxane (15 ml). Then a solution of 1.09 g (3.0 mmol) [2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine (VPF-001) in dioxane (15 ml) and 1.06 g (10.0 mmol) Na2CO3 were added and the mixture was stirred for 16 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with water and extracted with EE. The organic phase was washed with a saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Crystallisation (DCM/hexane) of the residue yielded 895 mg (1.7 mmol, 58%) 4-fluoro-2-methoxy-N-[2-[2-[[3-(trifluoromethyl)-phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]-benzamide. MS: m/z 514.1 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17](=[N:19]O)[CH3:18])[CH:9]=1.[H][H]>[Pd].CCO.CC(O)=O>[NH2:19][CH:17]([C:10]1[CH:9]=[C:8]([N:7]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:1])[CH3:30])[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=1)[CH3:18]
Reactant: [H][H]
Reactant: CC(=NO)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(N)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Yield: 104.7 %

Procedure:
A solution of 1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)pyrazolo[1,5-a]pyrimidin-5-yl]ethanone oxime (4.50 g, 8.77 mmol) in 4:1 EtOH/AcOH (90 mL) under nitrogen in a Parr bottle was treated with 10% Pd on carbon (933 mg, 0.877 mmol), and the mixture was shaken on the Parr apparatus under 45 psi hydrogen for 23 h. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure, azeotroping with toluene at 40-45° C. to remove most AcOH. The oily residue was taken up in EtOAc (˜100 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give the title compound, 5-(1-aminoethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (4.02 g, 91% purity, 95% yield) as an oil: MS (ESI+) for C20H39N5O2Si2 m/z 438 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)=[O:27]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[O:27])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc2ccccc2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc5ccccc5c4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 5.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and 4-hydroxyphenyl 2-naphthyl ketone (124 mg) obtained in Example 36 were mixed and stirred at 180° C. for 30 minutes. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and then the chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, a portion (50 mg) of the resulting residue (227 mg) was purified by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1) to obtain 11 mg of the title compound (yield: 23%).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:122])[C:82]2[CH:81]=[C:80]([C:83]3[NH:87][C:86]([C@@H:88]4[CH2:96][C:91]5([O:95][CH2:94][CH2:93][O:92]5)[CH2:90][N:89]4[C:97](=[O:107])[C@@H:98]([NH:102][C:103](=[O:106])[O:104][CH3:105])[CH:99]([CH3:101])[CH3:100])=[N:85][CH:84]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:108]1[CH:109]=[CH:110][C:111]3[N:115]=[C:114]([C@@H:116]4[CH2:120][CH2:119][CH2:118][NH:117]4)[NH:113][C:112]=3[CH:121]=1)=[CH:74][CH:75]=2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:117]1[CH2:118][CH2:119][CH2:120][C@H:116]1[C:114]1[NH:113][C:112]2[CH:121]=[C:108]([C:73]3[CH:74]=[CH:75][C:76]4[C:77]5[C:82](=[CH:81][C:80]([C:83]6[NH:87][C:86]([C@@H:88]7[CH2:96][C:91]8([O:95][CH2:94][CH2:93][O:92]8)[CH2:90][N:89]7[C:97](=[O:107])[C@@H:98]([NH:102][C:103]([O:104][CH3:105])=[O:106])[CH:99]([CH3:100])[CH3:101])=[N:85][CH:84]=6)=[CH:79][CH:78]=5)[C:70]([F:69])([F:122])[C:71]=4[CH:72]=3)[CH:109]=[CH:110][C:111]=2[N:115]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc4c(c3)C(F)(F)c3cc(-c5ccc6nc([C@@H]7CCCN7)[nH]c6c5)ccc3-4)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc4c(c3)C(F)(F)c3cc(-c5ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c6c5)ccc3-4)[nH]1)OCCO2)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-1-((S)-8-(5-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 929.83 [M+H]+. (90 mg, 63%).