Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][C:15]3=[O:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO[CH:29]1[CH2:33][CH2:32][CH:31](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]3[CH2:9][CH2:10][CH:11]([N:14]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:15]4=[O:16])[CH2:12][CH2:13]3)=[O:7])=[CH:25][CH:26]=2)[CH:29]=[CH:33][CH:32]=[CH:31]1
Reactant: Nc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=C(c1ccc(-n2cccc2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1

Procedure:
1-[1-(4-Aminobenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (500 mg) and 2,5-dimethoxytetrahydrofuran (0.19 ml) are refluxed with heating for 2 hours in acetic acid. The solvent is concentrated and the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) and recrystallized from n-hexane to give 1-{1-[4-(1-pyrrolyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (228 mg) as light gray powder, m.p.: 153°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34](O)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[C:80]([C:84]1[CH:85]=[C:86]([NH2:91])[C:87]([NH2:90])=[CH:88][CH:89]=1)([CH3:83])([CH3:82])[CH3:81]>C(Cl)Cl>[NH2:91][C:86]1[CH:85]=[C:84]([C:80]([CH3:83])([CH3:81])[CH3:82])[CH:89]=[CH:88][C:87]=1[NH:90][C:34](=[O:35])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[O:17]2)[CH:37]([CH3:38])[CH3:39])[CH2:29]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of 3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoic acid (1.1 g, 1.76 mmol), HATU (1 g, 2.64 mmol), HOAT (359 mg, 2.64 mmol) in DCM (30 mL) was added a solution of 4-tert-butylbenzene-1,2-diamine (433 mg, 2.64 mmol) and TEA (533 mg, 5.28 mmol) in DCM (10 mL) dropwise, then the resultant reaction mixture was stirred at rt overnight. After diluted with DCM (50 mL), the mixture was washed water (30 mL×3), dried and concentrated. The crude was purified by SGC (DCM:MeOH=100:1 to 40:1) to afford the desired compound (680 mg, yield: 50%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.16 (s, 1H), 7.19 (d, J=3.5 Hz, 1H), 7.14-7.10 (m, 1.7H),6.99-6.97 (m, 0.6H), 6.92 (s, 0.6H), 6.77 (dd, J=8.0, 2.0 Hz, 1H), 6.66-6.65 (m, 1H), 6.54-6.53 (m, 1H), 6.42 (d, J=8.0 Hz, 1H), 6.20 (d, J=2.0 Hz, 1H), 5.36-5.35 (m, 1H), 4.96-4.95 (m, 1H), 4.65 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H), 3.17-2.73 (m, 4H), 2.33-1.71 (m, 8H), 1.58 (s, 3H), 1.53-1.50 (m, 1H), 1.38 (s, 3H), 1.28 (s, 9H), 1.0 (d, J=5.5 Hz, 3H), 0.84 (d, J=5.0 Hz, 3H) ppm; LC-MS (m/z): 770.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])[CH2:17][CH2:18]2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(COc1ccc(F)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 93.4 %

Procedure:
4-fluoro phenol (95.32 mg, 0.85 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.293 g, 2.125 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was poured into a large volume of water and the solution extracted with ether. Un-reacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (340 mg, 94.44% yield) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (4.78 g) and m-anisidine (2.96 g) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=2)=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>[Pt].C(OCC)(=O)C.C(O)C>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)nc1C
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)nc1C

Procedure:
A mixture of 4-amino-N-(5,6-dimethylpyridin-2-yl)-3-nitrobenzamide (470 mg, 1.64 mmol) and of 5% platinum on carbon (60 mg) in 50 mL of ethyl acetate/ethanol (1:1) was stirred in under a hydrogen balloon. When the reaction was complete by LC/MS, the mixture was filtered through Celite to remove catalyst, and the filtrate was removed under reduced pressure to afford 3,4-diamino-N-(5,6-dimethylpyridin-2-yl)-benzamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[N:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](B2OC(C)(C)C(C)(C)O2)=[N:18]1>>[NH:17]1[C:25]2[C:20](=[C:21]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[N:3]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: COCCNc1nc(Cl)nc2c1cnn2C
Product: COCCNc1nc(-c2cccc3[nH]ncc23)nc2c1cnn2C

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-methoxy-ethyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica yielded 130. NMR: (CDCl3): 3.48 (s, 3H, CH3), 3.77 (t, H, ArH, J=5.13 Hz), 4.04 (m, 2H, CH2), 4.18 (s, 3H, CH3), 5.80 (sbr, H, NH), 7.53 (t, H, ArH, J=7.29 Hz), 7.63 (d, H, ArH, J=8.29 HZ), 7.95 (s, H, ArH), 8.43 (d, H, ArH, J=7.24 Hz), 9.17 (s, H, ArH), 10.2 (sbr, H, NH). MS: (ESI+) MH+=324.14
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:41]=[CH:40][C:15]([CH2:16][C@H:17]2[C:21](=[O:22])[NH:20][C@H:19]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[O:24])[CH2:18]2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:20]2[C:21](=[O:22])[C@H:17]([CH2:16][C:15]3[CH:40]=[CH:41][C:12]([F:11])=[CH:13][CH:14]=3)[CH2:18][C@H:19]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C1N[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C[C@H]1Cc1ccc(F)cc1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)C(=O)N1C(=O)Cn1cncn1
Yield: 4 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, gave Compound 71, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (18.2 mg, 4%). 1H-NMR (400 MHz, CDCl3): σ 8.17 (s, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.39 (d, 2H), 7.19-7.15 (m, 1H), 7.04-6.99 (m, 4H), 9.95-6.91 (m, 4H), 5.67 (d, 1H), 5.59 (d, 1H), 4.67 (d, 1H), 3.48-3.40 (m, 1H), 3.25 (dd, 1H), 2.78 (dd, 1H), 2.46 (dd, 1H), 2.06-1.97 (m, 1H). MS (EI) for C28H23F2N5O4. found 532.2 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.C[N:9]([CH:11]=[C:12]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)[C:13]([O:15]CC)=O)C.[CH:23]1([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[C:37]([NH:39]N)[N:36]=[CH:35][N:34]=3)[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[CH:23]1([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:34]=[CH:35][N:36]=[C:37]([N:39]4[C:13](=[O:15])[C:12]([N:18]5[CH:22]=[CH:21][N:20]=[CH:19]5)=[CH:11][NH:9]4)[CH:38]=3)[CH2:29][CH2:28]2)[CH2:24][CH2:25][CH2:26]1
Reactant: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid are added to a mixture of 211 mg (1.0 mmol) of the compound from Example 5A and 250 mg (1.0 mmol) of the compound from Example 9A in 4 ml of ethyl acetate, and the mixture is stirred at 100° C. for 20 h. The reaction mixture is concentrated under reduced pressure, more ethyl acetate and trifluoroacetic acid (the same amounts as above) are added and the mixture is stirred at 100° C. for 20 h. The reaction mixture is cooled to RT, and the precipitated solid is filtered off and washed with diethyl ether. The residue is pre-purified by column chromatography on silica gel (mobile phase dichloromethane/methanol/ammonia 10/2/0.2) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 137 mg (36% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:13][CH2:12][CH:9]1[CH2:11][CH2:10]1
Reactant: OCC1CC1
Reactant: Clc1ccncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnccc1OCC1CC1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a solution of 3-bromo-4-chloropyridine (CAN 36953-42-1, 8 g, 41.6 mmol) in dry DMF (100 ml) under argon atmosphere at room temperature were added cyclopropylmethanol (CAN 2516-33-8, 3.15 g, 3.45 ml, 43.6 mmol) and by portions sodium hydride 60% (1.75 g, 43.6 mmol). The resulting reaction was stirred at room temperature until gas evolution stopped. The reaction mixture was then stirred at 100° C. for 3 hours, cooled down to room temperature and quenched by addition of water. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an aqueous solution 1.0M sodium bicarbonate. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (8.25 g, 87%) as a light yellow oil. MS (ESI, m/z): 228.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:21][C:22]3[CH:27]=[N:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:20]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1cccc(CNc2cccn3nc(Cl)nc23)c1
Product: COc1cccc(CNc2cccn3nc(Nc4ccc(OC)nc4)nc23)c1

Procedure:
N(8)-(3-Methoxy-benzyl)-N(2)-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) and 5-amino-2-methoxypyridine (48.11 mg, 0.3875 mmol) in a manner analogous to Example 2d. Product was isolated as a red foam (41.48 mg, 32%). 1H NMR (400 MHz, CD3OD, δ, ppm): 8.42 (s, 1H), 8.04 (d, J=9 Hz, 1H), 7.83 (d, J=6.5 Hz, 1H), 7.24 (m, 1H), 6.98 (s, 2H), 6.83-6.71 (m, 3H), 6.40 (d, J=7.4 Hz, 1H), 4.48 (s, 2H), 3.88 (s, 3H), 3.76 (s, 3H). MS=377 (MH)+.
Reaction SMILES: [C:1]1([S:7]([N:10](S(C2C=CC=CC=2)(=O)=O)[C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[I:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>O1CCOCC1>[C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][C:12]=2[I:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a suspension of the compound obtained in Example 8 (4) (4.90 g) in 1,4-dioxane (85 ml), a 1N aqueous potassium hydroxide solution (21.2 ml) was added and the mixture was stirred at 100° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into a saturated aqueous NaCl solution, extracted with tetrahydrofuran, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (chloroform methanol=10:1) to obtain 3.47 g of the desired product in a colorless amorphous form.
Reaction SMILES: C([S:3]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:7]=1)(=O)=O)C.[C:26]([N:34]=[C:35]=S)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O>C1COCC1>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:14]1[C:13]([C:8]2[N:7]=[C:6]3[S:3][C:35]([NH:34][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:12][C:11]3=[CH:10][CH:9]=2)=[CH:17][N:16]([CH3:18])[N:15]=1
Reactant: CCS(=O)(=O)c1nc(-c2cn(C)nc2-c2ccccc2F)ccc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3nc(NC(=O)c4ccccc4)sc3n2)c(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
To a solution of 2-(ethylsulfonyl)-6-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine-3-amine (1.04 g, 2.89 mmol, 1.0 eq.) in THF under nitrogen at 0° C. was added benzoyl isothiocyanate (0.47 mL, 3.50 mmol, 1.2 eq.). The cold bath was removed, and the reaction mixture was stirred to room temperature for 20 min. It was then heated to 70° C. for 6 h. After cooling to room temperature, it was diluted with EtOAc and water. The layers were separated, and the organi layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Trituration with EtOAc afforded N-(5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridine-2-yl)benzamide as a light tan solid (1.05 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>>[CH2:24]([O:23][C:21]([C:3]1[C:4]([CH3:20])=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[C:10]([O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15](=[O:17])[NH:33][CH2:32][C:29]1[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=1)[CH:9]=[CH:8][CH:7]=2)=[O:22])[CH3:25]
Reactant: NCc1ccncc1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCc3ccncc3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and pyridin-4-ylmethanamine as a brown solid (43%). MS 437 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH3:17])=[O:7])[CH3:4].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:18]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])=[C:9]1[CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)n(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
General Procedure 11.-To a mixture of sodium hydride (0.28 g, 60% in mineral oil, 0.17g, 7.0 mmol) in 10 ml of tetrahydrofuran stirring at 0° C. under argon, was added 2-methyl-1H-indole-3-carboxylic acid ethyl ester (1.17 g, 5.8 mmol) and the solution was stirred at 0° C. for 15 min. Benzyl bromide (0.80 ml, 1.15 g, 6.7 mmol) was then added and the reaction allowed to warm to room temperature and stirred for 24 h. The reaction was cooled to 0° C., quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40% EtOAc-hexanes) to yield 1-benzyl-2-methyl-1H-indole-3-carboxylic acid, ethyl ester (Compound 57) as a tan solid (1.13 g, 67%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)=[CH:7][C:6]=2[Cl:20].B(Br)(Br)Br>>[Br:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)=[CH:7][C:6]=2[Cl:20]
Reactant: COc1ccc(-c2cc(Cl)c3cc(O)c(Br)cc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(Cl)c3cc(O)c(Br)cc3c2)cc1

Procedure:
The title compound was prepared by reacting 3-bromo-8-chloro-6-(4-methoxyphenyl)-2-naphthol (0.24 g, 0.66 mmol) with boron tribromide (1.6 mL of 1N solution, 1.6 mmol) according to method D to yield 0.1.4 g (61%) of a yellow oil. The product was further purified by reverse phase preparative HPLC to yield the title compound as a white solid: mp 188–190° C.; 1H NMR (DMSO-d6): δ 6.88 (1H, d, J=8.60 Hz), 7.57 (1H, s), 7.71 (2H, d, J=8.61 Hz), 7.89 (1H, d, J=1.60 Hz), 8.02 (1H, s), 8.31 (1H, s), 9.67 (1H, s), 11.01 (1H, s); MS (ESI) m/z 347/349/351 (M−H)−.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCC1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCC1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of cyclopentanone (25.0 mL, 0.28 mol, 1.0 eq.) in toluene (100 mL), was added pyrrolidine (27.5 mL, 1.2 eq.). The reaction was equipped with a Dean-Stark and heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated to give the crude 1-cyclopent-1-enyl-pyrrolidine (45.8 g, >100%).
Reaction SMILES: [C:1](=[O:4])(O)[O-:2].[CH2:5]1[S:9][C@@H:8]([CH2:10][CH2:11][CH2:12][CH2:13]C(NCCCCCC(ON2C(=O)C(S([O-])(=O)=O)CC2=O)=O)=O)[C@H:7]2[NH:36][C:37]([NH:39][C@@H:6]12)=[O:38].[Na+]>O>[OH:2][C:1]([CH2:13][CH2:12][CH2:11][CH2:10][C@H:8]1[C@@H:7]2[C@@H:6]([NH:39][C:37]([NH:36]2)=[O:38])[CH2:5][S:9]1)=[O:4]
Reactant: O=C([O-])O
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)[O-])C1=O
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 0.07 h

Procedure:
About 2.0 mg of DBP is buffer exchanged with 20 mM bicarbonate at pH 9.6 three times to give a final volume of 1.0 mL. Two aliquots of sulfo-NHS-LC-biotin (Pierce) are dissolved in water to give a 1 mg/mL solution just prior to addition. The first aliquot (10 uL) is added and the reaction is maintained at room temperature for 5 minutes. The second aliquot (10 uL) is added and the reaction proceeds for an additional 4 minutes. The unreacted biotin is removed by size exclusion chromatography using SEPHADEX G-25 and 100 mM PBS, pH 7.4 as the mobile phase.
Reaction SMILES: [CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][CH:11]([CH2:18][CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:10][CH:11]([CH:12]([C:2]([OH:9])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][CH3:19]
Reactant: CCOC(=O)CC(C)CC
Reactant: CCCCCCC(C)=O
Product: CCCCCCC(C)(O)C(C(=O)OCC)C(C)CC

Procedure:
A sample of the prepared hydroxy-ester pyrolyzes at 230° C. to a 1:1 mixture of 2-octanone and ethyl 3-methylvalerate.
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[N+:26]([O-])=O)[CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].C1COCC1.NN>C(O)C.[Pd]>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[C:19]([NH2:26])=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Nc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(Nc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
([8-(tert-Butyl-dimethyl-silanyloxy)-quinolin-2-yl]-(4-methoxy-2-nitro-phenyl)-amine C (21.9 g, 51.3 mmol) was dissolved in 200 mL ethanol (EtOH) and 70 mL of THF under an atmosphere of dry N2. To this solution was added 10% palladium on carbon (2.18 g) followed by the dropwise addition of 10 mL of anhydrous hydrazine. The reaction mixture was stirred at ambient temperature for 2 hours after which time it was filtered through Celite™ and the Celite™ washed with DCM. The combined filtrates were concentrated under vacuum and the resulting residue was partitioned between DCM and aqueous saturated NaHCO3. The DCM layer was then washed again with saturated NaHCO3 and then brine, dried over Na2SO4, filtered and concentrated under vacuum to give 18.3 g of a tan solid as the title compound D.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].O.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH2:36][CH2:37][C:38]3=[O:43])O1>CN(C)C=O>[CH:12]1([CH2:11][O:10][C:4]2[C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH2:36][CH2:37][C:38]4=[O:43])[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH2:14][CH2:13]1
Reactant: COCOc1c(Br)ccc(OC)c1OCC1CC1
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OCC1CC1
Temperature: 80 °C
Yield: 51.6 %

Procedure:
A stirring solution of 1-bromo-3-(cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)benzene (3 g, 9.46 mmol) in dimethylformamide (50 mL) was purged with argon for 1 h, to this cesium carbonate (9.23 g, 28.39 mmol), water (3 mL), tetrakis triphenylphosphine palladium (546 mg, 0.472 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (2.93 g, 11.35 mmol) were added and the resultant reaction mixture was heated to 80° C. for 5 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 4-(3-(Cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)phenyl)-2,3-dihydro-1H-inden-1-one as a solid (1.8 g, 51%).