Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([NH2:28])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:29])[CH2:10][CH2:9]1)[CH3:7].C(N(CC)CC)C.[C:38](Cl)(=[O:58])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([NH:28][C:38](=[O:58])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:29])[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCC(=O)N[C@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]12
Reaction time: 8 h
Yield: 35.3 %

Procedure:
1.0 g of 3β-amino-7α,12α-dihydroxy-5β-cholan-24-oic methylester (FIGS. 1A-1) [see Example I] were dissolved in 30 ml dry dimethylformamide and treated with 15 ml triethyl amine under stirring. 1.0 g of arachidoyl chloride in 10 ml dimethylformamide were added dropwise to the resulting solution, and the stirring was continued overnight. The reaction mixture was poured into water, extracted with methylene chloride, the organic fraction was then dried over sodium sulfate, evaporated to dryness and chromatographed over silica gel with a mixture of ethyl acetate and hexane (6:4 and 8:2), to give 0.6 g 3β-arachidylamido-7α,12α-dihydroxy-5β-cholan-24-oic methylester (FIGS. 1A-4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:28]([NH2:30])=[O:29])[C:12]3[NH:13][C:14]4[CH:15]=[C:16]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[CH:17]=[CH:18][C:19]=4[C:20]=3[N:21]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:32][CH2:33][Cl:34].C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O.N>CN(C=O)C.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:28]([NH2:30])=[O:29])[C:12]3[NH:13][C:14]4[CH:15]=[C:16]([N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH:17]=[CH:18][C:19]=4[C:20]=3[N:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:32][CH2:33][Cl:34]
Reactant: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: ClCCBr
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(OCCCl)c(Cl)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 40 °C
Yield: 66.9 %

Procedure:
A mixture of 2-(3-chloro-4-hydroxyphenyl)-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (120 mg, 0.284 mmol), 1-bromo-2-chloroethane (67 μL, 1.42 mmol) and K2CO3 (196 mg, 1.42 mmol) in DMF (4.8 mL) in a vial was heated at 40° C. for 3 h. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA; gradient of 0 to 100% B over 10 min at 42 mL/min) followed by SCX capture and release with 2 N NH3 in MeOH left 2-(3-chloro-4-(2-chloroethoxy)phenyl)-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (94 mg, 0.19 mmol, 68% yield) as a yellow solid. MS (ESI) m/z 485.22 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.25 (1H, s), 8.53 (1H, s), 8.36 (1H, d, J=2.44 Hz), 8.28 (1H, s), 8.23 (1H, dd, J=8.70, 2.29 Hz), 8.08 (1H, d, J=8.55 Hz), 7.83 (1H, s), 7.34 (1H, d, J=8.85 Hz), 7.22 (1H, d, J=2.14 Hz), 7.01 (1H, dd, J=8.85, 2.14 Hz), 4.43-4.48 (2H, m), 4.01-4.05 (2H, m), 3.78-3.84 (4H, m), 3.21-3.27 (4H, m).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[N:37]=[C:38]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[C:39]2[N:44]=[C:43]([CH2:45][N:46]3[CH2:51][CH2:50][CH:49]([C:52]([OH:55])([CH3:54])[CH3:53])[CH2:48][CH2:47]3)[S:42][C:40]=2[N:41]=1.[CH3:62][C:63]1[NH:67][C:66]2[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=2[N:64]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[CH3:62][C:63]1[N:67]([C:36]2[N:37]=[C:38]([N:56]3[CH2:57][CH2:58][O:59][CH2:60][CH2:61]3)[C:39]3[N:44]=[C:43]([CH2:45][N:46]4[CH2:51][CH2:50][CH:49]([C:52]([OH:55])([CH3:54])[CH3:53])[CH2:48][CH2:47]4)[S:42][C:40]=3[N:41]=2)[C:66]2[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=2[N:64]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)sc2n1
Yield: 47.2 %

Procedure:
A 5-20 mL microwave vial equipped with a magnetic follower was charged with Pd2(dba)3 (28 mg, 0.03 mmol), Xphos (58 mg, 0.12 mmol), 2-[1-(5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol (500 mg, 1.21 mmol), 2-methyl-1H-benzoimidazole (176 mg, 1.33 mmol), cesium carbonate (593 mg, 1.82 mmol) and dioxane (5 mL). The reaction mixture was degassed for 5 min and irradiated at 150° C. for 30 min. The reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed and the residue was subjected to flash chromatography (Si—PCC, 0-10% (2M NH3 in MeOH) in EtOAc) to give 223 as a red oil (290 mg, 47%). LCMS: (Method G): RT 6.76 min; [M+H]+ 508.4. 1H NMR (400 MHz, CHCl3-d): δ 8.10-8.05 (m, 1 H); 7.73-7.69 (m, 1 H); 7.32-7.26 (m, 2 H); 4.42 (m 4 H); 3.88 (t, J=4.6 Hz, 7 H); 3.11 (d, J=10.7 Hz, 2 H); 2.95 (s, 3 H); 2.31-2.19 (m, 2 H); 1.79 (d, J=12.7 Hz, 2 H); 1.50 (m, 2 H); 1.34 (m, 1 H); 1.22 (s, 6 H)
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([NH:27][C:28]([NH:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)=[O:29])[CH:4]=[N:3]1.[ClH:41]>CO.O1CCOCC1>[ClH:41].[ClH:41].[ClH:41].[NH2:33][CH2:32][CH2:31][NH:30][C:28]([NH:27][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH2:7])=[O:29]
Reactant: Cn1ncc(NC(=O)NCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc(NC(=O)NCCN)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl {2-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]ethyl}carbamate (10.8 g) in methanol (50 ml) was added 4M hydrogen chloride solution in dioxane (50 ml). The mixture was stirred at room temperature for 3 hours. The solvent was concentrated in vacuo, and the residue was triturated with ethyl acetate and dried in vacuo to give N-(2-aminoethyl)-N′-(5-amino-1-methyl-1H-pyrazol-4-yl)urea trihydrochloride (5.6 g) as a solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C@@:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C4CCCCO4)=[O:21])[C:13](=[O:35])[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.O>ClCCl.O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C@@:19]([CH3:34])([S:30]([CH3:33])(=[O:31])=[O:32])[C:20]([NH:22][OH:23])=[O:21])[C:13](=[O:35])[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C[C@@](CCn1ccc(-c2ccc3c(c2)OCCO3)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C[C@@](CCn1ccc(-c2ccc3c(c2)OCCO3)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 8 h

Procedure:
(2R)-4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (581 mg, 1 mmol) was dissolved in 3 mL of dichloromethane. To this solution was added 1 mL of 4M HCl in dioxane 1 mL of water. The reaction was monitored for completion by LCMS. After standing overnight, a solid precipitated. The solid was collected by filteration and dried in vacuo yielding 25 mg (68%) of light yellow solid. LCMS m/z 423.5 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 2.09-2.22 (m, 1H) 2.36-2.46 (m, 1H) 3.10 (s, 3H) 3.65-3.79 (m, 1H) 4.03-4.15 (m, 1H) 4.28 (s, 4H) 6.59-6.66 (m, 2H) 6.94 (d, J=8.20 Hz, 1H) 7.19-7.26 (m, 2H) 7.67-7.73 (m, 1H)
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:22][C@H:23]([C:25]([OH:27])=[O:26])[CH3:24]>>[OH:21][C:7]1[C:6]([C:4]([NH:22][C@@H:23]([CH3:24])[C:25]([OH:27])=[O:26])=[O:5])=[N:11][CH:10]=[C:9]2[O:12][N:13]=[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=12
Reactant: CCOC(=O)c1ncc2onc(-c3ccccc3)c2c1O
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](NC(=O)c1ncc2onc(-c3ccccc3)c2c1O)C(=O)O

Procedure:
Prepared in analogy to Example 11 from 4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and L-alanine; ESI MS (m/z): 328.20 (M+H+); 326.16 (M−H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)c2ccc(OCCCl)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.1 %

Procedure:
To a stirred solution of (4-(2-chloroethoxy)phenyl)(4-methoxyphenyl)methanone (20 g, 1.0 eq) in 150 mL CH2Cl2 was added BBr3 (52 g, 3.0 eq) dropwise at 0° C. The reaction was stirred for 4 h at rt, then quenched with 500 mL ice water. The suspension was filtered and washed with water to give the product (16 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.69 (dd, J=6.8 Hz, 2.0 Hz, 2H), 7.64 (dd, J=6.8 Hz, 2.0 Hz, 2H), 7.11 (dd, J=7.2 Hz, 2.0 Hz, 2H), 6.90 (dd, J=6.8 Hz, 2.0 Hz, 2H), 4.38 (t, J=5.2 Hz, 2H), 4.01 (t, J=5.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1c(-c2cccc(F)c2)ccnc1Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: OCc1c(-c2cccc(F)c2)ccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.8 %

Procedure:
To a solution of 2-chloro-4-(3-fluorophenyl)nicotinic acid (8.37 g) in tetrahydrofuran (70 ml) was added thionyl chloride (11.9 g), and the mixture was heated under reflux for 2.5 hrs. The reaction mixture was concentrated and the obtained residue was dissolved in tetrahydrofuran (50 ml). This solution was added dropwise to an ice-cooled aqueous sodium borohydride (4.58 g) solution, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give [2-chloro-4-(3-fluorophenyl)pyridin-3-yl]methanol (3.07 g) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:36][CH3:37])[C@H:3]([NH:24][C:25]([C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=1)=[O:26])[C:4](=[O:23])[NH:5][CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])[CH2:8][CH:7]1[OH:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][CH:2]([CH2:36][CH3:37])[C@H:3]([NH:24][C:25]([C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=1)=[O:26])[C:4](=[O:23])[NH:5][CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:14])=[O:15])[CH2:8][C:7]1=[O:22]
Reactant: CCC(C)[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(S(=O)(=O)c2ccccn2)CC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCC(C)[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(S(=O)(=O)c2ccccn2)CC1=O
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a stirring solution of the compound of example 193 (37 mg, 0.07 mmol) in CH2Cl2 (0.5 ml) was added Dess-Martin reagent (45 mg, 0.105 mmol). After stirring for 30 minutes, solutions of sodium thiosulfate (10% in water, 0.50 ml) and saturated aqueous sodium bicarbonate (0.50 ml) were added simultaneously to the reaction. The mixture was then extracted with dichloromethane (2 times). The organic layer was dried, filtered, and concentrated. The residue was purified by HPLC to yield the two diastereomers of the title compound as solids (first eluting: 7 mg, second eluting: 5.5 mg): MS (ESI) 526.91 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24].CC[O:27]CC>O1CCCC1>[OH2:27].[ClH:24].[ClH:24].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Agent: Cl
Agent: c1ccc(CN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Solvent: C1CCOC1
Product: O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(1-benzyl-4-piperidinyl)-1H-indazol-5-amine (3.06 g, 10.0 mmol) in tetrahydrofuran (31 ml) was added a 1N-hydrochloric acid/ether solution (25 ml) at room temperature, and stirred at room temperature for 30 minutes. The solid precipitated was collected by filtration and recrystallized from methanol to obtain N-(1-benzyl-4-piperidinyl)-1H-indazol-5-amine dihydrochloride monohydrate (2.86 g, 72%).
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[N:2]1.C(O)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH2:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C.C([O-])C.[Na+]>[C:3]([CH:4]=[CH:5][NH:16][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:2]
Reactant: c1cnoc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: CC(=O)[O-]
Agent: CC[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(NC=CC#N)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
Into a 500-mL round-bottom flask was placed isoxazole (25 g, 354.76 mmol, 1.00 equiv, 98%) in ethanol (100 mL) and sodium ethanolate (124 mL, 21%). The resulting solution was stirred at 0° C. for 30 min. Then acetic acid (6.9 mL, 98%), sodium acetate (20.5 g, 244.91 mmol, 0.69 equiv, 98%) and diethyl 2-aminomalonate hydrochloride (48 g, 222.26 mmol, 0.63 equiv, 98%) were added. The resulting solution was allowed to react, with stirring, for an additional 48 h at room temperature, concentrated under vacuum, dissolved in 200 mL of dichloromethane, washed with 2×100 mL of water, dried over anhydrous sodium sulfate and concentrated to afford 30 g (37%) of diethyl 2-(2-cyanovinylamino)malonate as a yellow oil
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH2:34][CH2:33][C:32]([CH3:40])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH:30]=2)[C:9]=1/[CH:41]=[CH:42]\OCC.C(O)(C(F)(F)F)=O.O>>[CH3:40][C:32]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:34][C:29]([C:10]2[C:9]3[CH:41]=[CH:42][NH:7][C:8]=3[N:13]3[N:14]=[CH:15][C:16]([C:17]4[CH:18]=[N:19][C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:21][CH:22]=4)=[C:12]3[N:11]=2)=[CH:30][CH2:31]1
Reactant: CCO/C=C\c1c(C2=CCC(C)(C(=O)OCC)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)C1(C)CC=C(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]ccc23)CC1

Procedure:
(Z)-Ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(2-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-methylcyclohex-3-enecarboxylate (crude Int-18h) was treated with a mixture of 50% TFA/H2O at rt overnight. The reaction mixture was evaporated to dryness and purified by Prep-LC to give ethyl 1-methyl-4-(3-(6-phenylpyridin-3-yl)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-5-yl)cyclohex-3-enecarboxylate (Int-18i). HPLC-MS tR=1.86 min (UV254nm); mass calculated for formula C29H27N5O2 477.2, observed LCMS m/z 478.3 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:8][CH2:9][CH2:10][CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:16]([CH3:30])[C:15]1=[O:31])[CH2:12][OH:13])([CH3:6])([CH3:5])[CH3:4].I[CH3:45]>CN(C)C=O>[C:3]([Si:7]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:8][CH2:9][CH2:10][CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=2)[CH:16]([CH3:30])[C:15]1=[O:31])[CH2:12][O:13][CH3:45])([CH3:4])([CH3:5])[CH3:6]
Reactant: CI
Reactant: CC1C(=O)N(C(CO)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCN1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1CCN(c2cccc(C(F)(F)F)c2)C(C)C1=O
Yield: 61.1 %

Procedure:
NaH (55% dispersion in mineral oil, 20 mg, 0.45 mmol) was added at 0° C. to a solution of 1-[3-(tert-butyl-diphenyl-silanyloxy)-1-hydroxymethyl-propyl]-3-methyl-4-(3-trifluoromethyl-phenyl)-piperazin-2-one (224 mg, 0.38 mmol) in N,N-dimethylformamide (3.5 mL), then after 5 min a solution of iodomethane (54 mg, 0.45 mmol) in N,N-dimethylformamide (1.5 mL) was added, then after 3 h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 19:1) afforded the title compound (139 mg, 61%). Light yellow oil, MS: 599.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCCCCCOc1ccc(O)cc1
Yield: 68.7 %

Procedure:
In a 500 ml flask equipped with a stirrer and a condenser were charged 32.2 g of ethyl 11-(p-hydroxyphenoxy)undecanoate synthesized in Synthetic example 2, 100 g of a 10% aqueous sodium hydroxide solution and 100 ml of ethanol, and the mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was concentrated, poured into 600 ml of a 2% aqueous hydrochloric acid solution and precipitated crystals were collected by filtration. The resulting crystals were washed with distilled water and recrystallized from acetonitrile to obtain 20.2 g of the title compound.
Reaction SMILES: [F:1][C:2]1([F:21])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13]/[C:12]/3=[N:17]\C(=O)C)=[CH:10][C:4]=2[O:3]1.Cl>C(O)C.O>[F:21][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([CH3:16])[S:13][C:12]3=[NH:17])=[CH:10][C:4]=2[O:3]1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(C)=O)S1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)O3)c(=N)s1

Procedure:
A mixture of Example 5 (1.8 g, 5.76 mmol) and hydrochloric acid (38%, 4.76 mL) in 40 mL of ethanol-water (1:1) was refluxed for 15 hours. Then the solvent was removed under reduced pressure, and the residue was carried on to the next step. 1H NMR (CD3OD) δ ppm 2.28 (3H), 7.15 (1H), 7.40-7.65 (3H); MS (ESI) 271 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:13][NH:12][CH2:11]2)[S:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:45]=[C:46]1[NH:55][C:54]2[N:53]=[CH:52][C:51](/[CH:56]=[CH:57]/[C:58](O)=[O:59])=[CH:50][C:49]=2[CH2:48][CH2:47]1>CN(C)C=O.O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:11][N:12]([C:58](=[O:59])/[CH:57]=[CH:56]/[C:51]3[CH:50]=[C:49]4[C:54](=[N:53][CH:52]=3)[NH:55][C:46](=[O:45])[CH2:47][CH2:48]4)[CH2:13]2)[S:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: Clc1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4cc(Cl)cs4)C3)cnc2N1
Reaction time: 8 h
Yield: 23.5 %

Procedure:
3-((4-Chlorothiophen-2-yl)methoxy)-azetidine hydrochloride (141 mg, 0.59 mmol), EDCI (113 mg, 0.59 mmol), HOBt (82 mg, 0.59 mmol) and diisopropylethylamine (171 μL, 1.00 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (100 mg, 0.39 mmol) in dimethylformamide (6 mL) at room temperature. The reaction mixture was stirred overnight and then diluted by addition of ethyl acetate (40 mL) and water (40 mL). The aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was triturated in diethyl ether to afford the title compound as a pale yellow solid (37 mg, 23%).
Reaction SMILES: N1(C(N2CCC(OC3N=CN=C(N4[C:29]5[C:24](=[CH:25][C:26](S(C)(=O)=O)=[CH:27][CH:28]=5)[CH2:23][CH2:22]4)C=3)CC2)=O)C=CN=C1.CC([OH:38])CC>>[CH3:22][CH:23]([OH:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Reactant: CCC(C)O
Product: CC(O)c1ccccc1

Procedure:
The same reaction as in the method described in Example 9 was performed using the 1-(6-{[1-(1H-imidazol-1-ylcarbonyl)piperidin-4-yl]oxy}pyrimidin-4-yl)-5-(methylsulfonyl)indoline (150 mg, 0.311 mmol) produced in Reference Example 29 and, instead of 2-butanol, DL-1-phenylethanol (113 μL, 0.933 mmol) to obtain the title compound as white powder (60.5 mg, yield: 37%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:29]4[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Solvent: O
Product: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 4-(tert-butyl)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an off-white solid, mp: 167-168° C. Mass spectrum (ESI, [M+H]+) m/z 396. 1HNMR (400 MHz, DMSO-d6): δ 7.77 (d, 1H, J=1.38 Hz), 7.55 (d, 2H, J=8.56 Hz), 7.52-7.51 (m, 2H), 7.43 (d, 1H, J=8.40 Hz), 7.36 (d, 1H, J=8.55 Hz), 7.31 (d, 2H, J=8.40 Hz), 7.14 (d, 2H, J=8.40 Hz), 6.51 (d, 1H, J=3.05 Hz), 5.38 (s, 2H), 1.30 (s, 9H), and 1.21 ppm (s, 9H). Elemental Analysis for C29H33N.0.3 H2O: Calculated: C, 86.87; H, 8.46; N, 3.49. Found: C, 87.08; H, 8.51; N, 3.46.