Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:28][CH2:29][N:30]3[C@H:35]4[CH2:36][CH2:37][C@@H:31]3[CH2:32][CH:33]([N:38]3[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[N:40]=[C:39]3[CH3:47])[CH2:34]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH:20]C(=O)OC(C)(C)C)[CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:28][CH2:29][N:30]3[C@H:31]4[CH2:37][CH2:36][C@@H:35]3[CH2:34][CH:33]([N:38]3[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[N:40]=[C:39]3[CH3:47])[CH2:32]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH2:20])[CH:17]([CH3:18])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)CC1
Agent: Cl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](N)C(C)C)CC1
Yield: 98.8 %

Procedure:
2,2-dichloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}carbamate (0.614 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S) 3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.512 g, 99%). {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-N-(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide (0.031 g, 53%) as an oil. ES-LCMS m/z 656 (M+1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:15])=[C:12]([OH:14])[CH:13]=1.Cl>CCO>[Cl:15][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:13][C:12]=1[OH:14]
Reactant: Brc1nccs1
Reactant: Nc1ccc(Cl)c(O)c1
Agent: Cl
Solvent: CCO
Product: Oc1cc(Nc2nccs2)ccc1Cl
Temperature: 90 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.25 mL, 2.78 mmol), 5-amino-2-chlorophenol (200 mg, 1.39 mmol) and 37% HCl solution (0.24 mL, 2.78 mmol) in 10% aqueous EtOH solution (5 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 69% yield (217 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[C:16]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:11][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:30][CH:29]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1ccc(C(N)=O)cc1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(C(=O)NC(=O)c2ccc(C(=O)C(C)(C)C)cc2)cc1
Temperature: 5 °C

Procedure:
A solution of 12.3 grams (60 mmol) of 4-(2,2-dimethyl-1-oxo-propyl)-benzamide dissolved in 450 ml of THF is chilled to 5° C.; and 20.6 grams of 35% potassium hydride in oil washed twice with hexane is added as a suspension in hexane. The resulting mixture is stirred for hours at 5° C. A solution of 13.8 grams (61.4 mmol) of p-pivaloyl-benzoyl chloride dissolved in 100 ml of THF is added with stirring over a period of 21/2 hours at 5° C. Sitrring is continued for an additional hour at this temperature, following which the mixture is stirred into 500 ml of an ice-cold saturated NH4Cl solution. The liquid phases are separated, and the aqueous phase is extracted with t-butyl methyl ether. The combined organic layers are washed with saturated sodium chloride solution, separated, and dried over magnesium sulfate. After filtering off the magnesium sulfate, the filtrate is evaporated to a solid, and the crude product is partially purified by chromatography on silica with CHCl3 eluant. The resulting product is twice crystallized from isopropyl alcohol and then from methylene chloride/t-butyl methyl ether, yielding the title product (mp 132°-134° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54](B3OC(C)(C)C(C)(C)O3)=[CH:53][CH:52]=2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:33]3[CH:34]=[C:35]4[C:30](=[CH:31][CH:32]=3)[CH2:29][N:28]([C:26](=[O:27])[C:10]3[CH:11]=[C:12]([C:23]([CH3:25])=[CH2:24])[C:13]([O:15][CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:36]4)=[CH:53][CH:52]=2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(Br)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 135 °C
Yield: 26.9 %

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1,3-dihydro-isoindol-2-yl)-methanone (240 mg, 0.43 mmol), t-butyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine carboxylate (210 mg, 1.25 equiv.), bis(tri-t-butylphosphine)palladium(0) (12.5 mg, 2.5 mol %) and potassium carbonate (350 mg, 6 equiv.) in toluene/water/ethanol (1 ml: 1 ml: 4 ml) was heated at 135° C. for 30 minutes in a CEM explorer microwave synthesiser. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, dried (MgSO4) and evaporated. Purification by flash column chromatography (Biotage SP4-25 S, 25 ml/min) eluting with 1:3 then 1:1 EtOAc/P.E. Evaporation of product containing fractions gave 85 mg of 4-{4-[2-(2,4-bis-benzyloxy-5-isopropenyl-benzoyl)-2,3-dihydro-1H-isoindol-5-yl]-phenyl}piperazine-1-carboxylic acid tert-butyl ester. MS: [M+H]+ 736.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[S:8]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CCC>O>[S:8]1[CH:12]=[CH:11][C:10]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:9]1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccsc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: c1cncc(-c2ccsc2)c1
Temperature: 100 °C
Yield: 92 %

Procedure:
Into a glass reaction vessel equipped with a cooling apparatus were added 0.015 mmol of bis(dicyclopentyl(2-methoxyphenyl)phosphine)dichloropalladium(II), 1.5 mmol of 3-bromopyridine, 2.25 mmol of 3-thiopheneboronic acid, 3.0 mmol of potassium phosphate and 4 mL of n-butanol. The resultant mixture was stirred with heating at 100° C. for 4 hours. The resultant reaction mixture was cooled down to room temperature, 20 mL of water was added, and the mixture was extracted with 20 mL of diethyl ether twice. The resultant organic layers were mixed, and dried over anhydrous magnesium sulfate, then, filtrated, to obtain a solution. This solution was concentrated, and purified by silica gel column chromatography, to obtain 3-(3-thienyl)-pyridine with a yield of 92%.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:11][C:12]([F:26])([F:25])[S:13]([O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=1[Cl:24])(=[O:15])=[O:14].N1C=CC=CC=1.C(N(CC)CC)C>ClCCl.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:12]([F:11])([F:25])[S:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:3]#[C:2][CH2:1][N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH:19][C:18]=1[Cl:24])(=[O:15])=[O:14]
Reactant: C#CCN1CCCCCC1
Reactant: O=S(=O)(Oc1ccc(Br)cc1Cl)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(C#CCN2CCCCCC2)cc1Cl)C(F)(F)F

Procedure:
1.96 g of 1-prop-2-ynylazepane (compound 4.1) are added, under inert atmosphere, to 4 g of 4-bromo-2-chlorophenyl trifluoromethanesulphonate (compound IIIa.1), 0.062 g of copper iodide, 10 ml of pyridine and 20 ml of triethylamine, followed by 0.457 g of the catalyst dichlorobis(triphenylphosphine)palladium. The reaction mixture is heated at the reflux point for 2 hours, the solvents are evaporated off under reduced pressure, and the residue obtained is taken up in dichloromethane, washed in water and dried over magnesium sulphate. After evaporating off the solvents under reduced pressure, the residue obtained is purified by chromatography on a column of silica gel, eluting with an 80/20 cyclohexane/ethyl acetate mixture; m.p.=192° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27]C1C=CC(C2C=C3N=C(CCC4NC(=S)CCCC4)NC3=NC=2)=CC=1.N>CO>[CH3:26][O:27][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)=[CH:6][CH:5]=1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Reactant: COc1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Agent: N
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]c(CCC4CCCCC(N)=N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 98 mg of 7-{2-[6-(4-methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-azepane-2-thione (compound A3) and 6.0 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 5 days. Purification by flash chromatography on LiChroprep-NH2® (eluent: ethanol) affords 23 mg of the title compound as an amorphous, colorless solid of m.p. 306° C. ESI-MS: 364.2 (MH+). TLC: Rf=0.50 (LiChroprep-NH2® HPTLC, methanol/water 10:1 parts by volume).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](SC)[N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CSc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: CCO
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-Amino-4-benzo [1,3] dioxol-5-yl-6-methylsulfanyl-pyrimidine-5-carbonitrile and benzylamine in ethanol. ES-MS m/e (%): 346 (M+H+, 100).
Reaction SMILES: C1([C@H]([NH:9][C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])C)C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:9][C@@H:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][C@H:11]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of 252D (1.18 g, 3.13 mmol) in MeOH (31 mL) was treated with ammonium formate (1.58 g, 25.1 mmol) and 10% Pd/C. The reaction mixture was heated to reflux for 14 hours then cooled to room temperature. The resulting solid was removed by filtration and washed with MeOH. The filtrate was dried (Na2SO4) and concentrated under reduced pressure to give 0.82 g (yield: 96%) of Compound 252E as an oil.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:27])[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2.[Cl-].[NH4+]>CCOCC.C1COCC1>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]1)[C@@H:11]([O:17][C:18](=[O:27])[C:19]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)([OH:26])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccccc1
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclohexylmagnesium cloride, 0.127 mol (63.6 ml of a solution 2M in ether), was added to a solution of 28.7 g (0.111 mol) of 2-oxo-2-phenylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester dissolved in 350 ml of THF, at −70° C. under a N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1 h, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and dried over MgSO4. After removal of the solvent, the oil obtained (27.0 g) was purified by chromatography on silica gel eluting with chloroform/methanol 10:1. The yield was 18.7 g (49.2%) of a pure product, mixture of diastereomers: I-16a and I-16b.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:12]C(OC)=O)[CH2:6]2.[BrH:17]>>[BrH:17].[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6]2
Reactant: COC(=O)NC1Cc2ccc(OC)cc2C1
Agent: Br
Product: NC1Cc2ccc(O)cc2C1

Procedure:
A mixture of 5-methoxy-N-methoxycarbonylindan-2-amine (0.25 g) and 47% hydrobromic acid (20 ml) was refluxed for 4 hours. After cooling, the mixture was concentrated in vacuo. Toluene was added to the residue and the whole was concentrated in vacuo to dryness to give 5-hydroxyindan-2-amine hydrobromide (0.26 g).
Reaction SMILES: I[C:2]1[CH:19]=[N:18][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[C:4]=2[CH:3]=1.[CH3:20][N:21]([CH3:43])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:42])[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1>>[C:10]([N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:18]=[CH:19][C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([CH3:20])[CH3:43])=[O:42])=[CH:28][CH:29]=3)=[CH:3][C:4]1=2)(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Reactant: CN(C)CCCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C)CCCNC(=O)c1ccc(-c2cnc3c(c2)N(C(=O)c2ccccc2)CCN3)cc1
Yield: 44 %

Procedure:
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenyl-methanone (50 mg) was reacted with N-(3-dimethylamino-propyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide as in General Procedure 4A to give the title compound as a light yellow solid (44% yield). M.p. 94° C., LCMS: m/z=444.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.72-1.80 (m, 2H), 2.27 (s, 6H), 2.48-2.53 (t, J=5.8 Hz, 2H), 3.48-3.54 (m, 2H), 3.67-3.73 (m, 2h), 3.98-4.04 (m, 2H), 5.44 (bs, 1H), 7.10-7.18 (m, 2H), 7.36-7.48 (m, 6H), 7.69 (d, J=8.1 Hz, 2H), 8.07 (s, 1H), 8.42 (bs, 1H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C@H:27]([C:73]1[CH:82]=[CH:81][C:80]([OH:83])=[C:79]2[C:74]=1[CH:75]=[CH:76][C:77](=[O:84])[NH:78]2)[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([C:41]1[CH:42]=[C:43]([S:47]([C:50]2[CH:51]=[C:52]3[C:57](=[C:58]([CH3:60])[CH:59]=2)[N:56]=[CH:55][C:54]([C:61]([NH2:63])=[O:62])=[C:53]3[NH:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([O:71][CH3:72])[CH:66]=2)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=1)=[O:40])(C(C)(C)C)(C)C.C(O)(=O)C>C1COCC1>[OH:26][C@H:27]([C:73]1[CH:82]=[CH:81][C:80]([OH:83])=[C:79]2[C:74]=1[CH:75]=[CH:76][C:77](=[O:84])[NH:78]2)[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([C:41]1[CH:42]=[C:43]([S:47]([C:50]2[CH:51]=[C:52]3[C:57](=[C:58]([CH3:60])[CH:59]=2)[N:56]=[CH:55][C:54]([C:61]([NH2:63])=[O:62])=[C:53]3[NH:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([O:71][CH3:72])[CH:66]=2)(=[O:48])=[O:49])[CH:44]=[CH:45][CH:46]=1)=[O:40]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Yield: 28.5 %

Procedure:
A solution of TBAF (1.0 M in THF, 0.244 mL, 0.244 mmol) was added to a stirring solution of Intermediate 148 (76 mg, 0.0813 mmol) in THF (2 mL) at rt. After stirring over night, glacial acetic acid (0.023 mL, 0.407 mmol) was added and stirred for an additional 16 h. The reaction mixture was concentrated and purified by PREP-HPLC to give the title compound (19 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([O:11]C)=[N:10][C:5]2=[CH:4][CH:3]=1.O1CCOCC1.Cl>O>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: COc1nc2ccc(Cl)nc2s1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(Cl)nc2s1
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
To round bottom flask was added give 5-chloro-2-methoxy[1,3]thiazolo[5,4-b]pyridine (1-3) (5.76 g, 28.7 mmol), 1,4-dioxane (90 mL), and a 6N solution of HCl in water (23.9 mL, 144 mmol). The reaction mixture was then heated to 95° C. while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 20 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted methanol and concentrated to give 5-chloro[1,3]thiazolo[5,4-b]pyridin-2(1H)-one (1-4) as a tan solid. HRMS (M+H)+: observed=186.9731, calculated=186.9727.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)=[C:10]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]=[CH:7][CH:8]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1cccc(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(c2cccc(OC)c2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of ethyl(RS)-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in EtOH (3 ml) was added 10% palladium on activated carbon (45 mg). The resulting suspension was shaken on a Parr hydrogenator at 50 psi H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (43 mg, 94%), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH2:12][CH2:11][N:10]2C(OCC2C=CC=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13]([C:15]([F:17])([F:18])[F:16])([OH:19])[CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(OCc1ccccc1)N1CCC(O)(C(F)(F)F)CC1c1ccc(F)c(F)c1
Agent: [Pd]
Solvent: CO
Product: OC1(C(F)(F)F)CCNC(c2ccc(F)c(F)c2)C1
Yield: 77 %

Procedure:
A solution of benzyl 2-(3,4-difluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (0.24 g, 0.60 mmol) in methanol (100 mL) was hydrogenated in the presence of catalytic 10% palladium on carbon at atmospheric pressure for 12 h. The catalyst was filtered off and the filtrate was concentrated and dried to give 2-(3,4-difluorophenyl)-4-(trifluoromethyl)piperidin-4-ol (0.13 g, 78%). MS (EI) for C12H12F5NO: 282 (MI-1′).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][CH2:30][C:31]#[N:32])[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:29][CH2:30][C:31]#[N:32])[CH2:26][CH3:27])=[O:25])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCCC#N
Product: CCN(CCC#N)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-ethylamino-propionitrile
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COC(COc1ccc(O)cc1)OC
Agent: [N-]=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Oc2ccc(OCC(OC)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 4-Methoxyphenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-4-methoxyphenylcarbamate as the residue.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]([NH2:12])[CH:6]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[N:14]([C:6]1[C:7]([NH2:12])=[N:8][C:9]([NH2:11])=[N:10][C:5]=1[O:4][CH2:3][CH:2]([CH3:13])[CH3:1])=[O:15]
Reactant: CC(C)COc1cc(N)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)COc1nc(N)nc(N)c1N=O
Temperature: 32 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a stirred solution of 18.2 g (0.100 mol) 6-(2-methylpropoxy)-2,4-diaminopyrimidine in 100 ml acetic acid (10% conc. in water) at 6° C. was added dropwise over 1 h a solution of 9.11 g (0.132 mol) sodium nitrite in 40 ml water, whereupon the temperature was allowed to increase to 32° C. Stirring was then continued for a further 2 h at room temperature. The resulting precipitate was filtered off with suction, washed with water and dried. 5-Nitroso-2,4-diamino-6-(2-methylpropoxy)-pyrimidine (18.3 g, 81%) was obtained as a violet solid.