Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][N:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(COC)OC>[Cl:11][CH2:12][C:13]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][N:3]2[CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: CCOc1ccc(N)nc1
Solvent: COCCOC
Product: CCOc1ccc2nc(CCl)cn2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-5-ethoxypyridine (1.53 g; prepared by the method of Lombardino, J. Med. Chem. 1981, 24, 39-42), 1,3-dichloroacetone (Aldrich; 1.115 g), and dimethoxyethane (7 mL) is stirred overnight at room temperature. The mixture is concentrated under reduced pressure and ethanol (22.5 mL) is added. After the mixture is stirred for 30 min at 80° C., it is cooled and then concentrated under reduced pressure. The residue is partitioned between dichloromethane and saturated aq. sodium bicarbonate. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and crystallized from ether/dichlormethane/hexane to give 0.94 g of 2-(chloromethyl)-6-ethoxyimidazo[1,2-α]pyridine in three crops; mp 95-96° C.; MS m/z 210, 212; IR (mineral oil) 1192, 1263, 810, 1537, 1511 cm-1 ; 1H NMR (CDCl3) δ1.45, 3.97, 4.75, 6.98, 7.46, 7.55, 7.58.
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH:23]([CH3:27])[C:24](Cl)=[O:25]>C(OCC)C>[Br:22][CH:23]([CH3:27])[C:24]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:25]
Reactant: CC(Br)C(=O)Cl
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Solvent: CCOCC
Product: CC(Br)C(=O)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (2 g, 0.0071 mol) was dissolved in 2-bromopropionyl chloride (8.5 g, 5 mL, 0.05 mol) by heating for 30 minutes on a 100°-110° C. oil bath. The reaction mixture was cooled, 20 mL of ethyl ether were added, and the resultant solution was extracted with aqueous potassium carbonate, dried and then crystallized. The product was obtained as a solid white substance (1 g, 34%), m.p. 112°-115° C. Anal. calc. for C19H17N2O4Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 54.77; H, 4.15; N, 6.69; Br, 19.25. The product had the formula: ##STR77##
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH-].[Na+].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:23]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCCNc1ccccc1C(=O)O
Temperature: 120 °C
Reaction time: 6 h
Yield: 43.1 %

Procedure:
To a solution of anthranilic acid in toluene, n-octyl p-toluenesulfonate prepared according to the conventional method was added and the mixture was refluxed at 120° C. After 6 hours, an aqueous solution of sodium hydroxide was added and the toluene layer was concentrated. N-n-octylanthranilic acid was obtained from the remaining reactant after the purification by column chromatography with the yield of 43.1%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCON=C(C(=O)O)c1csc(N)n1
Reaction time: 0.33 h
Yield: 78.7 %

Procedure:
A solution of ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetate (syn isomer, 36 g.), methanol (133 ml.), tetrahydrofuran (133 ml.) and 2 N aqueous solution of sodium hydroxide (133 ml.) was stirred at 30° C. for 5 hours. After the resultant solution was concentrated in vacuo, the residue was dissolved in water. The solution was adjusted to pH 7 with 10% hydrochloric acid and treated with activated charcoal. The solution was adjusted to pH 2.0 with 10% hydrochloric acid and stirred for 20 minutes under ice cooling. The precipitates were collected by filtration, washed with water and acetone in turn, and dried to give 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetic acid (syn isomer, 25.4 g.).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:41])[C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:38]=[CH:39][CH:40]=1)[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[C:26]([CH3:36])=[C:25]1[CH3:37])[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:33]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([CH2:23][C:22]2[CH:21]=[C:20]([CH:40]=[CH:39][CH:38]=2)[O:19][C@@H:17]([CH3:18])[C:16]([O:15][CH3:14])=[O:41])[C:25]([CH3:37])=[C:26]3[CH3:36])=[O:34])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH2:18][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(O)c1
Reactant: Clc1ccc(Br)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(OCc2cc(Cl)ccc2Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a solution of 3-methoxyphenol (0.84 mL, 7.3 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (2 g, 7 mmol) in DMF (70 mL) was added potassium carbonate (1.94 g, 14 mmol). The reaction mixture was stirred at room temperature for 16 hours, then poured into water (500 mL) extracted into ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield 1-bromo-4-chloro-2-((3-methoxyphenoxy)methyl)benzene (2 g, 87%)
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=O)=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4].[CH3:16][NH:17][CH3:18].CO>>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:17]([CH3:18])[CH3:16])=[O:14])=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(O)C(C)O)cn1
Reactant: CNC
Solvent: CO
Product: CC(O)C(O)c1ccc(C(=O)N(C)C)nc1
Temperature: 100 °C
Yield: 80.6 %

Procedure:
A mixture of methyl 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylate (52.0 mg, 0.25 mmol) and a 2.0 M solution of dimethylamine in methanol (Aldrich, 15.0 ml, 30.0 mmol) was stirred and heated at a bath temperature of 100° C. in a microreactor for four nights. After cooling, the reaction mixture was concentrated in vacuo. The residue (60.3 mg) was purified by preparative TLC [Merck Kieselgel 60, Art 1.05744, 0.5 mm thick, ×2; development: CH2Cl2—MeOH (8:1); elution: CH2Cl2—MOH (3:1), 240 ml]. The recovered white solid residue was suspended in THF, and the mixture was filtered through a short pad of Celite. The filter cake was washed with THF. The combined filtrate and washings were concentrated in vacuo to give 5-(1,2-dihydroxypropyl)-N,N-di-methyl-2-pyridinecarboxamide as a white solid (45.2 mg, 80.6%): 1H-NMR (270 MHz) δ(CDCl3): 8.41 (d, J=1.8 Hz, 1H), 7.76 (dd, J=7.9, 1.8 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 4.86 (d, J=3.7 Hz, 1H), 4.11˜3.97 (m, 1H), 3.80 (br.s, 1H), 3.13 (s, 3H), 3.04 (s, 3H), 2.68 (br.s, 1H), 1.15 (d, J=6.6 Hz, 3H) ppm; MS m/z: 225 (7.9%, M++1), 224 (50.9%, M+), 153 (100%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C@:14]3([CH3:24])[CH2:19][CH2:18][S:17][C:16]([NH:20]C(=O)C)=[N:15]3)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.CO.O>[F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C@:14]3([CH3:24])[CH2:19][CH2:18][S:17][C:16]([NH2:20])=[N:15]3)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)NC1=N[C@](C)(c2cccc(-c3cccnc3F)c2)CCS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@@]1(c2cccc(-c3cccnc3F)c2)CCSC(N)=N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
To a solution of (S)-N-(4-(3-(2-fluoropyridin-3-yl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-yl)acetamide (450 mg, 1.3 mmoles) in methanol (40 mL) is added a solution of K2CO3 (210 mg, 1.5 mmoles) in methanol:water (2:1, 15 mL). The reaction is stirred at room temperature for 6 h. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue is purified by using SCX column chromatography to give the title compound (65% yield): MS (m/z): 302 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].Cl.C(N(CC)CC)C>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Cl)ccc1O

Procedure:
To a solution of 100 grams of 2 amino-4-chlorophenol (0.70 mole) in 1 liter of tetrahydrofuran is added 71 grams of triethylamine (0.70 mole). The resulting solution is cooled with an ice bath. To the solution is then slowly added 55 grams of acetyl chloride (0.70 mole) in 200 ml. of tetrahydrofuran. A precipitate forms (triethylamine hydrochloride). The solution is then filtered and the filtrate evaporated under reduced pressure, yielding a dark solid residue. Recrystallization of the residue from methylene chloride and petroleum ether (1:1) yields 4-chloro-2-acetamidophenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[CH2:43][NH2:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:44][CH2:43][CH:39]3[CH2:40][CH2:41][CH2:42][O:38]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NCC1CCCO1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3CCCO3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and C-(tetrahydro-furan-2-yl)-methylamine according to conditions described in general procedure C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[CH3:10][N:11]([CH3:16])[C:12](=[O:15])[CH:13]=[CH2:14].CC(O)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:14][CH2:13][C:12]([N:11]([CH3:16])[CH3:10])=[O:15]
Reactant: C=CC(=O)N(C)C
Reactant: Nc1cc(Cl)ccc1S
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)C(=O)CCSc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
A mixture of 2-amino-4-chlorobenzenethiol (327 mg, 2.05 mmol), N,N-dimethylacrylamide (203 mg, 2.05 mmol) and HOAc (0.5 ml) in CH2Cl2 (5 ml) was stirred at room temperature for 3 days. The reaction was quenched with NaHCO3 (aq.) and then extracted with CH2Cl2 (2×10 ml). The organic layer was washed with water and brine and concentrated in vacuo. The crude product was purified by chromatography on silica gel (50% ethyl acetate in hexane) to yield the title compound (284 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[S:15]2)[CH:6]=[C:7]([NH2:13])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[S:15]2)[CH:6]=[C:7]([NH:13][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCOc1c(N)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(NCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
trans-2-(3-Methoxy-4-propoxy-5-aminophenyl)-5-(3,4,5-trimethoxyphenyl)-tetrahydrothiophene (10 mg, 0.023 mmole) and potassium carbonate (0.2 g) were suspended in 1 mL DMF. To this mixture was added benzyl bromide (39.50 mg, 0.23 mmole). The mixture was stirred at room temperature for 20 hours, quenched with water, and then extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to an oil that was purified by column chromatography using hexane/ethyl acetate (3:1) as solvent.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1.C[Si]([C:17]#[CH:18])(C)C>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.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:17]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1)#[CH:18]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(Br)c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
6 g of 1-bromo-4-methylnaphthalene, 0.11 g of dichlorobis(triphenylphosphine)palladium, 0.17 g of triphenylphosphine, 0.19 g of copper iodide, and 3.1 g of trimethylsilylacetylene were added to 60 ml of triethylamine, and the mixture was allowed to react at 90° C. for 16 hours. After evaporation of the solvent by an evaporator, the compounds obtained were extracted with added ethyl ether. The ethyl ether layer was washed thrice with 300 ml of distilled water, dried over anhydrous magnesium sulfate for 24 hours, and filtered, and after removal of the solvent in the filtrate by vaporization, the residue was purified by column chromatography, by using hexane as the developing solvent. 30 ml of diethylene glycol and 4.4 g of potassium hydroxide were added to the compound obtained, and the mixture was stirred at room temperature for 3 hours. The compounds generated were extracted with added ethyl ether. The ethyl ether layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate for 24 hours and filtered, and the solvent in the filtrate was evaporated. The residue was purified by column chromatography by using methylene chloride/hexane (1/4) as the developing solvent, to give 1.6 g of 1-ethynyl-4-methylnaphthalene.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([F:33])[F:32])[CH:25]=O>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([F:32])[F:33])[CH2:25][N:1]1[CH:2]([C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(OC(F)F)c(Cl)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-chloro-4-(difluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 425.86 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.Cl>[Cl-].[Zn+2].[Cl-]>[NH2:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[CH:13][C:14]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])=[O:5]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1Br
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Nc1ccc(F)cc1C(=O)c1ccccc1Br
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 20 g (0.15 mol) of zinc chloride and 50 g (0.23 mol) of 2-bromobenzoyl chloride was heated to 110° C. 4-Fluoroaniline, 13 g (0.12 mol) Was added over a period of 2 minutes, raising the temperature of the mixture to 160° C. This mixture was then heated and stirred for 3 hours at 210°-220° C. After cooling to 140° C., 200 mL of hot 3N hydrochloric acid was added cautiously. The mixture was stirred and heated to reflux for 5 minutes and the aqueous phase was decanted from the residue. This procedure was repeated twice. The residue was dissolved in 200 mL acetic acid and treated with 100 mL of 3N hydrochloric acid and 10 mL of concentrated sulfuric acid to form a mixture.
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3].[Br:9]C(C1C=CC=CN=1)CC>>[Br:9][CH:1]([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CCC(Br)c1ccccn1
Reactant: CCCc1nccs1
Product: CCC(Br)c1nccs1

Procedure:
The title compound was prepared from 2-propylthiazole (purchased from Waterstone Technologies, Inc., Carmel, Ind.) following a procedure similar to the one described above for the synthesis of 2-(1-bromopropyl)pyridine (Example 230). Mass Spectrum (ESI) m/z=205.8 and 207.8 (M+1).
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2I)[CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccc2cccc(I)c12
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc3cccc(-c4ccc(OC)cc4C)c23)c(C)c1
Yield: 99 %

Procedure:
A solution of 1,8-diiodonaphthalene, (1.70 g, 4.5 mmol), 2-methyl-4-methoxyphenylboronic acid, 2, (2.20 g, 13.4 mmol), Pd(PPh3)4 (0.78 g, 0.67 mmol) and K3PO4, (4.30 g, 20.1 mmol) in 50 mL toluene was stirred at 100° C. for 18 hours. The resulting mixture was allowed to come to room temperature, quenched with water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (CH2Cl2:hexanes 2:3) afforded 1.65 g (4.5 mmol, >99%) of off-white crystals containing syn- and anti-isomers of 7 in a ratio of 1:3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[NH:21]1[C:25]([CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[N:24][N:23]=[N:22]1.C([O-])([O-])=O.[K+].[K+].Cl>CN1CCCC1=O.O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[CH:3]=[C:2]([N:28]2[CH2:29][CH2:30][CH2:31][CH:26]([C:25]3[N:21]=[N:22][NH:23][N:24]=3)[CH2:27]2)[N:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: C1CNCC(c2nnn[nH]2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(N2CCCC(c3nn[nH]n3)C2)n1
Temperature: 140 °C
Yield: 74.9 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine [300 mg, 0.9 mmol], 3-(1H-tetrazol-5-yl)-piperidine [383 mg, 2.25 mmol] and K2CO3 (373 mg, 2.7 mmol) in N-methylpyrollidinone (5 mL) is heated at 140° C. for 16 hours. The mixture is diluted with water (50 mL), acidified to pH 3 with 10% HCl and extracted three times with EtOAc (40 mL). The organic extracts from the acidic layer are combined and dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 15% ethyl methanol:DCM to afford an oil which is diluted with water (20 mL). A solid is formed and collected by filtration to afford [2-(2,4-dichloro-phenyl)-ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine [303 mg, 75%, Example 96] as a solid. LCMS: RT=1.95 minutes, MS: 449 (M+H). IC50=5 nM
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([CH:20]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:24][O:23][C:21](=[O:22])[CH:20]([CH:18]1[CH2:17][N:16]([CH:2]([C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:19]1)[C:25]1[CH:26]=[C:27]([F:32])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: Clc1ccc(C(Br)c2ccccc2)cc1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1

Procedure:
A solution of 0.042 g (0.15 mmol) of 1-[bromo(phenyl)methyl]-4-chlorobenzene, 0.028 g (0.1 mmol) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate (Example 25, Step 1) and 0.298 g (0.3 mmol) of Cs2CO3 in 5 mL of acetonitrile was heated at 45° C. for 18 h. The solution was concentrated and the residue was dissolved in 5 mL of ethyl acetate. This solution was washed with 1 mL water and the aqueous layer was washed with a second aliquot of 3 mL ethyl acetate. The organic extracts were washed with brine, combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography on a Waters RCM column (5 micron silica gel, 20 mm×10 cm) using a 2:1 mixture of hexane and 5:4:1 hexane-methyl tert-butyl ether-acetonitrile. Homogenous fractions were pooled and concentrated to afford the title compound. 1NMR(CDCl3) δ 2.65-2.69 (m, 1H), 2.88-2.93 (m, 1H), 3.05-3.16 (m, 2h). 3.41-3.46 (m, 1H), 3.67 (s, 3H), 3.81-3.86 (m, 1H), 4.30 (s, 1H), 6.69-6.74 m, 1H), 6.80-6.85 (m, 2H), 7.19-7.37 (m, 9H). Mass Spectrum: m/e=442 (M+1 35Cl) and 444 (M+1 37Cl).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(4-hydroxyphenyl)propanoate (275 mg, 1.42 mmol) in acetic acid (2 mL) was added nitric acid (60-62%, 300 mg, 2.86 mmol) at room temperature. The mixture was stirred for 1 hour at 50° C. and cooled to room temperature. The reaction mixture was poured into ice water (20 mL) and extracted with EtOAc. The organic layer was dried with MgSO4 and filtered. EtOAc was removed by evaporation. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=6/1.