Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C=O)C.[OH-].[K+]>O>[Cl:1][C:2]1[C:3]([N:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:15])[CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(Nc1ccccc1)c1c(Cl)cccc1C(=O)O
Yield: 66.7 %

Procedure:
A solution of 3-chloro-2-(bromoacetamido) benzoic acid from Example 39 (4.6 g, 15.7 mmol), aniline (3.58 mL, 39.3 mmol) and DMF (45 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (400 mL) and 5% KOH (125 mL) and washed with CH2Cl2 (3×125 mL). The aqueous layer was acidified to pH 2 with 2 N HCl, cooled below room temperature and filtered. The filter cake was rinsed with cold water (50 mL) and dried under high vacuum at 45° C. to yield 3.19 g (67%) of the title compound as a tan solid; 1H NMR (DMSO-d6) δ 13.1 (broad s, 1H), 9.85 (s, 1H), 7.74 (d, J=7.6, 1H), 7.71 (d, J=8.0, 1H), 7.35 (t, J=7.6, 1H), 7.10 (t, J=7.6, 2H), 6.65-6.58 (m, 3H), 6.1 (broad s, 1H), 3.82 (s, 2H); 13C NMR (DMSO-d6) δ 169.62, 166.77, 148.33, 133.87, 132.70, 131.53, 130.93, 128.90, 128.82, 127.21, 116.59, 112.57, 47.16; MS (LSIMS, m/z) 305 (M+H+)
Reaction SMILES: Cl.[NH2:2][C:3]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:4]=1[OH:5].C(O[C:14](OCC)(OCC)[CH2:15][CH3:16])C.O>C(O)C>[CH2:15]([C:16]1[O:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:3]=2[N:2]=1)[CH3:14]
Reactant: Nc1c(O)cccc1O
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1nc2c(O)cccc2o1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-aminoresorcinol hydrochloride (5.0 g) and triethylorthopropionate (13.7 ml) was heated to 150° C. for 2 h before being poured into a mixture of water (140 ml) and ethanol (35 ml). The mixture was stirred vigorously for 30 minutes at room temperature. The resulting precipitate was removed by filtration and dried to give the title compound as a beige solid (4.11 g).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]3=[C:9]([C:17]([OH:19])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C@@H:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([NH:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH3:27][C:26]([CH3:29])([CH3:28])[C@H:21]([NH:20][C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]=12)=[O:19])[C:22]([NH:24][CH3:25])=[O:23]
Reactant: O=C(O)c1nc(-c2ccccc2)n2c1CCCCC2
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CCCCC2)C(C)(C)C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine-1-carboxylic acid (Intermediate B1) (100 mg, 0.390 mmol) was dissolved in DCM (10 mL) in a 40 mL screw-cap vial. (S)-2-amino-N,3,3-trimethylbutanamide (59.1 mg, 0.410 mmol) and DIEA (204 μl, 1.171 mmol) were added, followed by TBTU (132 mg, 0.410 mmol), and the reaction was stirred for 3 hours. LCMS showed complete consumption of starting material. The solution was extracted with saturated aqueous sodium bicarbonate (10 mL) and the organic layer was removed. The aqueous layer was extracted with DCM (10 ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure to a brown oil which was purified by flash chromatography (silica gel, 25% Hex/EtOAc to 100% EtOAc). Fractions were combined to yield the desired (S)—N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine-1-carboxamide as a white solid (133 mg, 89%). LCMS (+ESI) m/z 383.2 [MH]+. 1H-NMR (CDCl3) δ 7.90 (d, 1H), 7.45-7.55 (m, 5H), 5.90 (m, 1H), 4.30 (d, 1H), 4.05 (m, 2H), 3.40 (m, 2H), 2.80 (d, 3H), 1.90 (m, 2H), 1.80 (m, 2H), 1.65 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][O:8][C:9](=[O:29])[C@@H:10]2[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:29])[C@@H:10]2[CH2:14][C@@H:13]([O:15][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12][N:11]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(COC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@@H]2C[C@@H](OC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
Trans-1-(p-Nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester (49 g) was dissolved in 300 ml of dry tetrahydrofuran, and 33 ml of triethylamine, 9.59 g of 4-dimethylaminopyridine and 33.2 g of benzoyl chloride were added thereto, followed by stirring under reflux for 5 hours. The reaction mixture was cooled down to room temperature and distilled to remove the solvent. The residue was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. Recrystallization of the residue from diethyl ether gave trans-1-(p-nitrobenzyloxycarbonyl)-4-benzoyloxy-L-proline p-methoxybenzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)c3)cc2s1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
2-chloro-4-iodopyridine (0.500 g, 2 mmol) was dissolved in 1,4-dioxane (15 ml), then N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.800 g, 3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.300 g, 0.3 mmol) and 2M sodium carbonate (2 ml, 4 mmol) was added to the mixture. The round-bottom flask was fitted with a reflux condenser and placed into a pre-heated (90° C.) bath. The mixture was allowed to stir under inert atmosphere for 3 hours. The progress of the reaction was monitored by LC/MS, which showed desired product in the mixture. The material was allowed to cool to ambient temperature and diluted with DCM and saturated sodium bicarbonate solution. The organic layer was collected by extracting with DCM (3×20 ml). Combined organics, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with ethyl ether (50 ml) and allowed to stir 10 minutes. The precipitate was collected by filtration and washed with ethyl ether. This gave N-(6-(2-chloropyridin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.200 g, 32% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 304 (MH+). Calc'd exact mass for C14H10ClN3OS: 303. 1H NMR (400 MHz, DMSO-d6): 2.23 (s, 3H), 7.80-7.86 (m, 2H), 7.90-7.95 (m, 2H), 8.47 (d, J=5.09 Hz, 1H), 8.54 (s, 1H), 12.49 (s, 1H).
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[CH:28]1([NH:34][CH:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([N:34]([C@H:35]2[CH2:36][CH2:37][C@H:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:39][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: c1ccc(C2CCC(NC3CCCCC3)CC2)cc1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](c3ccccc3)CC2)s1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Example 38) via cyclohexyl-(4-phenyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[F:7][B-:8]([F:11])([F:10])[F:9].[CH3:12][O+](C)C>C(Cl)Cl>[F:7][B-:8]([F:11])([F:10])[F:9].[Br:1][C:2]1[S:3][CH:4]=[CH:5][N+:6]=1[CH3:12]
Reactant: Brc1nccs1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[n+]1ccsc1Br

Procedure:
The starting material may be prepared by reaction of 2-bromothiazole and trimethyloxonium tetrafluoroborate in CH2Cl2 for 18 hours at ambient temperature to give 2-bromo-3-methylthiazolium tetrafluoroborate.
Reaction SMILES: [Cl:1][C:2]([Cl:12])([F:11])[S:3][C:4]1[CH:5]=[N:6][N:7]([CH2:9]O)[CH:8]=1.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Cl:15][CH2:9][N:7]1[CH:8]=[C:4]([S:3][C:2]([Cl:12])([Cl:1])[F:11])[CH:5]=[N:6]1
Reactant: OCn1cc(SC(F)(Cl)Cl)cn1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: FC(Cl)(Cl)Sc1cnn(CCl)c1

Procedure:
0.22 g of 4-{[dichlorofluoromethyl]thio}-1H-pyrazole-1-ylmethanol was dissolved to 10 ml of chloroform. 0.3 ml of thionyl chloride was added to the solution, and refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.21 g of 1-(chloromethyl)-4-{[dichloro(fluoro)methyl]thio}-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.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>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)=[CH:24][N:23]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: Nc1ccc(-c2cccc(F)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)nc1)Nc1ccc(-c2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(6-chloropyridin-3-yl)acetic acid (521 mg, 3.03 mmol), 5-(3-fluorophenyl)pyridin-2-amine (570 mg, 3.03 mmol), HATU (1250 mg, 3.29 mmol) and DIEA (784 μl, 4.50 mmol) in DMF (10 ml) was stirred at room temperature overnight. DMF was mostly removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (50 ml), washed with 3% Na2CO3 solution (30 ml) and water (50 mL), and dried over Na2SO4. After concentration by evaporation, the residue was subjected to silica gel column chromatography to give 2-(6-chloropyridin-3-yl)-N-(5-(3-fluorophenyl)pyridin-2-yl)acetamide 140-1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1>>[Br:12][C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:23][CH2:24]2)=[N:17][CH:18]=1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: Cc1cc(Br)cnc1N1CCNCC1
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Yield: 43.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 69 and using 6-fluoro-4-methylnicotinic acid (931 mg) and 1-(5-bromo-3-methylpyridin-2-yl)piperazine (1.5 g), the title compound (1 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.Br[CH2:11][C:12]#[N:13].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([CH2:11][C:12]#[N:13])[N:3]=1
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(CC#N)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A mixture of 3-methyl-4-nitro-1H-pyrazole (7 g, 0.055 mol), bromoacetonitrile (13.2 g, 0.11 mol) and K2CO3 (23 g, 0.165 mol) in DMF (120 mL) was stirred at 80° C. for 2 hrs. TLC (petroleum ether:EtOAc=2:1) showed the reaction was complete. The mixture was filtered, concentrated and the residue purified by flash chromatography (petroleum ether:EtOAc=4:1) to give the title compound (3.5 g, 38% yield) as light yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:30](=[O:31])([O:32][CH2:33][CH3:34])[O:21][C@H:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[C@H:12]([NH:15][C:16](=[O:17])[CH:18]([Cl:20])[Cl:19])[CH2:13][F:14]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)O[C@H](c1ccc(S(C)(=O)=O)cc1)[C@@H](CF)NC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of florfenicol (250 g, 0.7 mol), 4-dimethylaminopyridine (42 g, 0.35 mol,), triethylamine (130 mL, 0.91 mol) in 1.2 L of tetrahydrofuran was stirred at 0-5° C. while neat ethyl chloroformate (80 mL, 0.83 mol) was added drop-wise with an addition funnel. The reaction proceeded as indicated by the precipitation of triethylamine hydrochloride salt. The mixture was allowed to stir at room temperature for 30 minutes and the salt was removed from the mixture by filtration. The filtrate was concentrated and 600 mL of ethyl acetate was added and the solution was washed with 1 M HCl (2×200 mL) followed by saturated NaCl (200 mL) and filtered through a layer of Na2SO4/silica gel. The filtrate was concentrated and the crude oil was crystallized from 450 mL of isopropanol to give the pure title product (286 g). m.p. 110-112° C.; H1-NMR (DMSO-d6), δ=1.2 ppm (t, 3 H), 3.2 ppm (s, 3H), 4.1 ppm (q, 2H), 4.3-4.7 ppm (m, 3H), 5.9 ppm (d, 1H), 6.4 ppm (s, 1H), 7.6 ppm (d, 2H), 7.9 ppm (d, 2H), 9.2 ppm (d, 1H); mass spectrum 452.0 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cn1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 12 h
Yield: 80.5 %

Procedure:
To a stirred solution of 5-Bromo-pyridin-2-ylamine (100 mg, 0.578 mmol) in dry THF was added acetic anhydride (70.25 mg, 0.693 mmol). The reaction mixture was stirred at 20° C. for 12 hrs. THF was distilled out and to it was added ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and dried over anhy sodium sulphate. Removal of the solvent afforded N-(5-Bromo-pyridin-2-yl)-acetamide (100 mg, 80%). This was carried to next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC(C)([O-])C.[Na+].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]I)=[C:29]([Cl:36])[CH:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN(C)C=O>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:5]([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])([C:4]([O:3][CH2:1][CH3:2])=[O:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:29]([Cl:36])[CH:28]=1
Reactant: Clc1cc(Br)ccc1CCI
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccc(Br)cc1Cl)(NC(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 15 h
Yield: 64.7 %

Procedure:
Diethyl(tert-butoxycarbonyl)aminomalonate (202 g) was dissolved in a mixed solution of tetrahydrofuran (6000 mL) and N,N-dimethylformamide (714 mL), and sodium tert-butoxide (70.5 g) was added. After heating the mixture to the refluxing temperature, a solution of 2-(4-bromo-2-chlorophenyl)ethyl iodide (246 g) of Reference Example 18 in tetrahydrofuran (940 mL) was added to the reaction mixture, and the mixture was refluxed with stirring for 15 hr. After cooling, the reaction mixture was poured into 25% aqueous citric acid solution. After partitioning and extraction with ethyl acetate, the organic layer was washed with water and 25% brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (227 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([CH3:23])[CH:21]=O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>[Pd].CO>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21][N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)=[CH:17][CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1C[C@@H](C)O[C@@H](C)C1
Yield: 94 %

Procedure:
A mixture of 2,500 parts by volume of methanol, 366 parts of cis-2,6-dimethylmorpholine, 606 parts of 3-p-tertiary butylphenyl-2-methyl-prop-2-enal and 35 parts of catalyst, comprising 0.5% by weight of Pd, 5% by weight of Pr2O3, 1% by weight of Mn, remainder Al2O3, is hydrogenated stepwise, in a stirred autoclave of 5,000 parts by volume capacity, first at 50° C. under 50 bar hydrogen pressure, then at 90° C. under the same pressure and finally at 120° C. under the same pressure, until no further hydrogen is absorbed. The autoclave is then allowed to cool, the catalyst is filtered off and the filtrate is purified by distillation. 856 parts of N-(3'-p-tertiary butylphenyl-2'-methyl-propyl)-cis-2,6-dimethylmorpholine, boiling point 206° C./24 mbar, are obtained. This corresponds to a yield of 94% of theory (based on 3-p-tertiary butylphenyl-2-methyl-prop-2-enal).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:15][CH:14]=1)(C)(C)C>ClCCl>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(-c2ccc(OC(C)(C)C)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2ccc(O)cc2)c1
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A solution of 4-tert-butoxybenzeneboronic acid (0.50 g), 3-bromoanisole (0.44 g), and tetrakis(triphenylphosphine)palladium(0) (0.09 g) in toluene (5 ml), ethanol(1.2 ml) and aqueous sodium carbonate (2 M, 2.4 ml) was heated at 100° C. for 19 hours. After cooling the reaction mixture was added to brine (50 ml) and ethyl acetate (50 ml). The organic layer was separated and dried over anhydrous magnesium sulfate. The solution was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with hexane:toluene 9:1 to give 4-tert-butoxy-3'-methoxybiphenyl (0.61 g). (MS (EI) 256 (M)+). Trifluoroacetic acid (5 ml) was added to a solution of 4-tert-butoxy-3'-methoxybiphenyl (0.60 g) in dichloromethane (20 ml) and the resulting solution stirred for 1 hour. The solution was then concentrated under reduced pressure. The residue was partitioned between a solution of saturated aqueous sodium hydrogen carbonate (25 ml) and ether (3×25 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane to give the sub-title compound as a solid (0.25 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Li]CCCC.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1
Reactant: CCCCCCCCCBr
Reactant: Cc1cc(C)c2c(n1)N(C)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cc(C)c2c(n1)N(C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 181 mg (1.12 mmol) of 1,4,6-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 3 mL of THF was added 1.19 mL (1.90 mmol, 1.6 M in hexanes) of n-BuLi followed by 255 μL (1.34 mmol) of 1-bromononane at −78° C. The reaction mixture was slowly warmed to room temperature and stirred for another 16 h. The reaction mixture was quenched by the addition of 10 mL of sat aq NH4Cl at 0° C. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (25 3.2 cm). Elution with 10:1 hexanes/ethyl acetate gave the product as a yellow oil: yield 210 mg (66%); silica gel TLC Rf 0.18 (8:1:1 hexanes/ethyl acetate/MeOH); 1H NMR (CDCl3) δ 0.86 (t, 3H, J=6.8 Hz), 1.24-1.30 (m, 16H), 1.65 (quint, 2H, J=7.6 Hz), 2.08 (s, 3H), 2.54 (t, 2H, J=8.0 Hz), 2.81 (t, 2H, J=8.0 Hz), 2.90 (s, 3H), 3.38 (t, 2H, J=8.0 Hz) and 6.13 (s, 1H); 13C NMR (CDCl3) δ 14.2, 18.1, 22.8, 24.5, 29.5, 29.68, 29.73, 29.75, 29.77, 30.1, 32.1, 33.4, 38.2, 52.6, 112.6, 118.4, 141.3, 159.3 and 163.9; mass spectrum, m/z 288.3 (M+) (theoretical 288.3); mass spectrum (APCI), m/z 289.2653 (M+H)+ (C19H33N2 requires 289.2644).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxyphenethyl alcohol (33 g, 0.24 mol) in dry dimethylformamide (200 ml), cooled to 0° C., was added potassium tert-butoxide (29 g, 0.26 mol) by portions. After 10 minutes, benzyl bromide (41 g, 0.28 mol) was added slowly. The reaction mixture was stirred for 15 minutes at 0° C., then for 3 hours at room temperature and was quenched with water (200 ml). The precipitate was collected, dried and recrystallized from isopropyl ether/hexanes (34 g).
Reaction SMILES: [OH:1][CH2:2][NH:3][C:4](=[O:6])[CH3:5].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13](O)=[O:14]>>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([O:1][CH2:2][NH:3][C:4](=[O:6])[CH3:5])=[O:14]
Reactant: O=C(O)Cc1cccs1
Reactant: CC(=O)NCO
Product: CC(=O)NCOC(=O)Cc1cccs1
Yield: 44.4 %

Procedure:
N-(Hydroxymethyl)-acetamide (13.4 g, 0.15 mol) and thiolacetic acid (14.3 g, 0.188 mol) were heated for 3 days at 40° C. The resulting mixture was chromatographed on silica gel (63-200 um, 700 g) with toluene-ethyl acetate 4:1 and 1:1 to give pure crystalline acetamidomethyl thiolacetate (14.2 g, 64%), m.p. 93-94° C.