Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:36]=[CH:35][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:25][C:26]=3[CH3:27])=[C:18]([O:37][CH3:38])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[Cl-].[CH2:40]([C:42]1[S:43][CH:44]=[C:45]([CH2:47][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:46]=1)[CH3:41].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:40]([C:42]1[S:43][CH:44]=[C:45](/[CH:47]=[CH:1]\[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:36]=[CH:35][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:25][C:26]=4[CH3:27])=[C:18]([O:37][CH3:38])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:7]=2)[N:46]=1)[CH3:41]
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3C=O)cc2OC)c(C)o1
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3/C=C\c3csc(CC)n3)cc2OC)c(C)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.3 %

Procedure:
A mixture of ethyl (2E)-3-{4-[(4-([(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (0.87 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.06 g), anhydrous potassium carbonate (0.36 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give ethyl (2E)-3-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-propenoate as colorless crystals (0.14 g, yield 17%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 119-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][NH:10]2)=[CH:5][CH:4]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=O.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(c1)NCCC2
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)N(Cc1ncc[nH]1)CCC2

Procedure:
Prepared analogously to Example 1, from 7-methoxy-1,2,3,4-tetrahydro-quinoline, imidazole-2-carboxaldehyde, zinc chloride and sodium cyanoborohydride in methanol. MS (ISP): 244.4 ([M+H]+).
Reaction SMILES: [C@@H:1]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][C:20]3[S:21][C:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)=[CH:23][CH:24]=3)[CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].CI.[C:32](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C@@H:1]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][C:20]3[S:21][C:22]([C:25]4[N:29]=[N:28][N:27]([CH3:32])[N:26]=4)=[CH:23][CH:24]=3)[CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4nnn[nH]4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1nnc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(β-D-glucopyranosyl)-4-chloro-3-(5-(1H-tetrazol-5-yl)-2-thienylmethyl)benzene (140 mg) obtained in Example 181 was dissolved in dimethylformamide (5 ml) and added thereto were methyl iodide (100 μl) and potassium carbonate (220 mg). The mixture was stirred at room temperature overnight. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methyl-2H-tetrazol-5-yl)-2-thienylmethyl)benzene as colorless powder. APCI-Mass m/Z 470/472 (M+NH4).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([S:16][CH3:17])[CH:9]=2)=[CH:6][C:5](=O)[N:4]([CH3:19])[C:3]1=[O:20].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].O>N1C=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([S:16][CH3:17])[CH:9]=2)=[CH:6][C:5](=[S:22])[N:4]([CH3:19])[C:3]1=[O:20]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1SC
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=S)n(C)c(=O)n2C)cc1SC
Yield: 159.3 %

Procedure:
To a suspension of 1,3-dimethyl-6-(4-methoxy-3-methylthiophenyl)-1,2,3,4-tetrahydropyrimidine-2,4dione (6.5 g) in pyridine (60 ml) was added phosphorus pentasulfide (4.95 g), and refluxed for 8 hours. After cooled, the mixture was poured into water (600 ml). The precipitates were collected, dried in the air, and refluxed with ethanol (150 ml) for 2 hours. After cooled, resulting precipitates were filtered, and washed with ethanol and diisopropyl ether, to give 1,3-dimethyl-6-(4-methoxy-3-methylthiophenyl)-1,2,3,4-tetrahydro-4-thioxopyrimidin-2-one (5.47 g). mp 174°-176° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: O=C(CCN1CCCC1)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc2nnc(CCN3CCCC3)n2c1
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Intermediate 1a (400 mg) was dissolved in THF (20 mL) and cooled in an ice/water bath. Triphenylphosphine (643 mg, 2.45 mmol) was added followed by triethylamine (682 μL, 4.90 mmol) and hexachloroethane (581 mg, 2.45 mmol). The reaction mixture was stirred for 18 h and then loaded onto an SCX-2 cartridge, which was washed with MeOH then eluted with 2M NH3 in MeOH. The resulting residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (292 mg, 1.16 mmol, 52%). 1H NMR (400 MHz, CDCl3): 1.80-1.87 (4H, m), 2.60-2.68 (4H, m), 3.00-3.10 (2H, t, J 7.3), 3.24-3.34 (2H, t, J 7.3), 7.13-7.21 (1H, ddd, J 9.9, 7.6, 2.3), 7.70-7.77 (1H, dd, J 9.8, 4.5), 8.00-8.04 (1H, m).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:13]([CH2:20][CH2:21][OH:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[O:13]([CH2:20][CH2:21][O:22][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:22][CH2:21][CH2:20][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:7])=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: OCCOc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCCOc1ccccc1)c1ccc(C(=O)OCCOc2ccccc2)cc1

Procedure:
In a typical laboratory setting, bis(aryloxyalkyl)terephthalates are made by reacting terephthaloyl chloride with the corresponding aryloxyalkanol. For example, the reaction of terephthaloyl chloride with 2-phenoxyethanol in the presence of excess triethylamine and a solvent, followed by an organic workup to remove the ammonium salt, concentration, and recrystallization provides bis(2-phenoxyethyl)-terephthalate (see Scheme 1, compound 2 and Synthetic Examples 1 and 2 in U.S. Pat. Appl. Publ. No. 2009/0087764). Unfortunately, the lab procedure is impractical on a commercial scale because of the cost of terephthaloyl chloride and, among other issues, the need to recover a solvent and dispose of the ammonium salt.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17]C[C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].O(C[C@@H]1CCN1S(C1C=C2C(=CC=1)NC(=O)C2=O)(=O)=O)C1C=CC=CC=1.BrC[C:57]1[CH:58]=[CH:59][C:60]([F:63])=[N:61][CH:62]=1>>[F:63][C:60]1[N:61]=[CH:62][C:57]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]4[CH2:18][CH2:17][C@H:15]4[CH2:19][O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)(=[O:13])=[O:12])=[CH:8][CH:9]=3)[C:4](=[O:27])[C:3]2=[O:28])=[CH:58][CH:59]=1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reactant: Fc1ccc(CBr)cn1
Agent: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Product: O=C1C(=O)N(Cc2ccc(F)nc2)c2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc21
Yield: 62 %

Procedure:
(S)-1-(6-Fluoropyridin-3-ylmethyl)-5-(2-phenoxymethylazetidine-1-sulfonyl)-1H-indole-2,3-dione (18g) was prepared according to the same procedure for compound 11a, except using compound 17 and 5-(bromomethyl)-2-fluoropyridine, and purified with ether to afford 74 mg (62%) of 18g as an orange solid, mp 176.8-178.3° C. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=2.4 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.79 (td, J=8.1 Hz, J=2.4 Hz, 1H), 7.22 (m, 2H), 7.00-6.77 (m, 5H), 4.92 (s, 2H), 4.49 (m, 1H), 4.09 (m, 2H), 3.85 (m, 2H), 2.35-2.23 (m, 2H). Anal. Calcd for C24H20FN3O5S: C, 59.87, H, 4.19; N, 8.73. Found: C, 59.81, H, 4.16; N, 8.62.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]5[O:26][CH2:25][CH2:24][C:23]=5[CH:27]=4)[CH:18]=[C:13]3[C:12]([C:28]3[CH:29]=[N:30][N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:32]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](C(C)C)C(C)C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]5[O:26][CH2:25][CH2:24][C:23]=5[CH:27]=4)[CH:18]=[C:13]3[C:12]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(-c3ccc4c(c3)CCO4)cnc21
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2cc(-c3ccc4c(c3)CCO4)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a solution of 48 (187 mg, 0.270 mmol) in CH2Cl2 (2 mL) was added triisopropylsilane (0.14 mL), TFA (0.73 mL) and distilled water (6 drops). The mixture was stirred at room temperature for 1 h 30 min. The reaction was quenched and made neutral by addition of aqueous saturated NaHCO3 and diluted with EtOAc (200 mL) and water (100 mL). The aqueous layer was extracted further with CH2Cl2 (150 mL), the organic solutions were combined, dried (MgSO4) and concentrated to afford a light brown oily solid. Purification by preparative TLC (EtOAc) afforded 49 (45 mg, 38%) as an off white solid; 1H NMR (400 MHz, CDCl3+1 drop CD3OD) δ 2.62 (t, J=17.7, 8.6 Hz, 2H), 3.96 (t, J=17.3, 8.6 Hz, 2H), 6.22 (d, J=8.2 Hz, 1H), 6.65 (t, J=8.0, 2.4 Hz, 2H), 6.76 (s, 1H), 6.84-6.88 (m, 2H), 6.93-6.96 (m, 1H), 7.19 (s, 1H), 7.27 (s, 1H), 7.41 (s, 1H), 7.56 (d, J=7.9 Hz, 2H), 7.97 (s, 1H).
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[CH:25]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13].Br[CH2:30][C:31]([O:33]CC)=[O:32]>C(OCC)C.C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4cc[nH]c34)no2)cc1Cl
Reactant: CCOC(=O)CBr
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To methylmagnesium bromide solution (3 mol/L in diethyl ether, 0.4 mL) stirred under nitrogen at 0° C. was added a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D51) (354 mg) in diethyl ether (5 mL) dropwise. The reaction mixture was stirred at 0° C. for 30 mins. Ethyl bromoacetate (0.13 mL) in toluene (15 mL) was added dropwise. The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with saturated ammonium chloride solution; the organic layer was separated and the solvent was evaporated off. The residue was dissolved in tetrahydrofuran (5 mL) and sodium hydroxide (40 mg) in water (5 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. Evaporated off the organic solvent, extracted with ether (100 mL), the water layer was separated and acidified with HCl (1 M) to pH around 1. The solid was filtered and purified by Mass Directed Auto Prep to afford [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]acetic acid (E31) (86 mg) as a yellow solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 3.74 (2H, s), 4.87-4.93 (1H, m), 7.22 (1H, t), 7.40 (1H, d), 7.45 (1H, d), 7.78 (1H, d), 7.95 (1H, d), 8.21 (1H, dd), 8.37 (1H, d), 10.91 (1H, s), 12.19 (1H, br s). MS (ES): C21H18ClN3O4 requires 411; found 412.1 (M+H+).
Reaction SMILES: O[C:2]1([C:20]([F:23])([F:22])[F:21])[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:5]=2[O:4][CH2:3]1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.O>[N+:17]([C:15]1[CH:14]=[CH:13][C:6]2[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:2]([C:20]([F:21])([F:22])[F:23])[CH2:3][O:4][C:5]=2[CH:16]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCC(O)(C(F)(F)F)N2CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)OCC(C(F)(F)F)N2CC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.3 %

Procedure:
To a solution of (±)-3,4-dihydro-3-hydroxy-7-nitro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine (0.10 g, 0.29 mmol) in 3 mL of trifluoroacetic acid and then sodium cyanoborohydride (3.0 g, 47.4 rmmol) was slowly added via an solid addition funnel under nitrogen at 0° C. over the course of 30 minutes the reaction was allowed to warm to rt and stirred for 12 hours. The reaction mixture was then diluted with water and cooled to 0° C. Solid potassium carbonate was then added slowly to pH 7.The solution was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give an oil. The oil was purified via flash chromatography (7:3 hexanes:EtOAc) to afford 51 mg (52%) of (±)-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine. 1H NMR (400 MHz, CDCl3) d 7.87 (dd, 1H, J=9.1, 2.8), 7.81 (d, 1H, J=2.5), 6.92 (d, 1H, J=9.1), 4.73 (d, 1H, J=12.1), 4.48–4.39 (m, 1H), 4.13–4.06 (m, 2H), 3.99–3.88 (mn, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[CH:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:24][C:22]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:23])=[CH:27][CH:28]=1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 72.3 %

Procedure:
Aspartic acid (100 g, 0.75 mol) was suspended in 400 ml methylene chloride and stirred mechanically. Trimethylsilyl chloride (244 g, 2.25 mol) was added. The mixture was refluxed for 1.5 hours and then cooled in an ice bath. Triethylamine (303 g, 3.0 mol) was slowly added with stirring and cooling. Carbobenzoxy chloride (128 g, 0.75 mol) was slowly added with cooling. The mixture was stirred for 2 hours at 0° C. and then warmed to RT for 2 hours. The reaction mixture was poured into a stirred mixture of 500 ml 2.5% NaHCO3 and 500 ml Et2O. The layers were separated and the aqueous phase was extracted with 3×300 ml Et20. The aqueous layer was acidified to pH 2 with conc. HCl and extracted with 3×200 ml EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to a white solid. Recrystallization from 290 ml H2O yielded 145 g (72.3%) Z-aspartic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:12])[CH3:2].[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19])[CH3:2]
Reactant: CCOC(=O)c1c(C)cccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C)cccc1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
To a solution of 2-hydroxy-6-methyl-benzoic acid ethyl ester (5.00 g, 27.8 mmol) and t-butyl-di-methylsilyl chloride (6.27 g, 41.6 mmol) in dichloromethane (100 ml) was added diisopropyl ethylamine. The solution was stirred at 50° C. for 24 hours, washed with water, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo, which afforded 7.6 g (93%) of 2-(tert-butyl-dimethyl-silanyloxy)-6-methyl-benzoic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]4[CH2:21][CH2:20][CH:17]([C:18]=3[CH3:19])[N:16](C3C=CC(OC)=CC=3)[CH2:15]4)=[CH:10][CH:11]=2)[N:6]([CH3:30])[C:5]1=[O:31].CC#N.OS(O)(=O)=O.I(O)(=O)(=O)=O>O>[CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]4[CH2:21][CH2:20][CH:17]([C:18]=3[CH3:19])[NH:16][CH2:15]4)=[CH:10][CH:11]=2)[N:6]([CH3:30])[C:5]1=[O:31]
Reactant: COc1ccc(N2CC3CCC2C(C)=C3c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: CC1=C(c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)C2CCC1NC2
Temperature: 50 °C

Procedure:
1-(2,2-Dimethylpropyl)-5-[2-(4-methoxyphenyl)-6-methyl-2-azabicyclo-[2.2.2]oct-5-en-5-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (7-3, 40.3 mg, 0.09 mmol, 1.0 equiv) was added to CH3CN (820 μL) and water (820 μL). To this suspension was added aqueous H2SO4 (90 μL, 0.09 mmol, 1.0 equiv, 1.0 M) followed by periodic acid in one portion (21 mg, 0.09 mmol, 1.0 equiv). The reaction contents were heated to 50° C. for 18 h. Following this duration, LCMS showed consumption of starting material. The mixture was subsequently filtered through Celite, rinsed with CH3CN and purified by reverse-phase HPLC (15-90% CH3CN:0.1% TFA in H2O) to give 7-4 as a tan solid.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([C:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]=2)[CH:9]=1.[Br:50]N1C(=O)CCC1=O>C(#N)C>[Br:50][C:9]1[C:10]([C:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=2)=[N:11][C:12]2[N:13]([N:14]=[CH:15][C:16]=2[C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=1[NH2:7]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1c(Br)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.071 mmol, 50 mg) was charged to a 20 mL scintillation vial containing 1 mL acetonitrile. To this solution was added N-bromosuccinimide (0.078 mmol, 14 mg). The reaction mixture was allowed to stir at room temperature for 1 hour. After 1 hour, the reaction was concentrated in vacuo and the crude intermediate was dissolved in 1 mL TFA. The reaction mixture was stirred for 1 hour at room temperature and concentrated in vacuo to yield 6-bromo-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([OH:9])[C:7]=1[Cl:8].[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([Cl:8])[C:6]=1[OH:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Cl)c(Cl)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of 5,6-dichloro-2-nitrophenol (1.8 g, 8.7 mmol) and tin (II) chloride (5.8 g, 26.1 mmol) in ethanol (50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (1.4 mg, 90%). 1H NMR (CD3OD): d 6.71 (d, 1H), 6.45 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nc1
Yield: 65 %

Procedure:
As described for example 10b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (94 mg, 0.29 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (69 mg, 65%) which was obtained as a white solid. MS: m/e=370.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([C:18](OCC)=[O:19])[C:13](OCC)=[O:14])[O:8][CH2:7][CH:6]([CH2:23][CH2:24][CH3:25])[CH2:5]2.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH2:18][OH:19])[CH2:13][OH:14])[O:8][CH2:7][CH:6]([CH2:23][CH2:24][CH3:25])[CH2:5]2
Reactant: CCCC1COc2cc(C(C(=O)OCC)C(=O)OCC)c(F)cc2C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCC1COc2cc(C(CO)CO)c(F)cc2C1

Procedure:
8.7 g (21.1 mmol) of the diethyl 2-(6-fluoro-3-propylchroman-7-yl)malonate obtained under 1.2. are initially introduced in 60 ml of toluene, and 106 ml (106 mmol) of a 1 M solution of diisobutylaluminium hydride in toluene are added dropwise at 5° C. The batch is subsequently added to ice-cold sat. ammonium chloride soln., acidified using dil. hydrochloric acid and extracted with MTB ether. The combined org. phases are dried over sodium sulfate and evaporated. Chromatography of the crude product on silica gel with MTB ether/heptane (4:1) gives 2-(6-fluoro-3-propylchroman-7-yl)propane-1,3-diol as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]([O:17][CH3:18])[C:12]([O:15][CH3:16])=[CH:13][CH:14]=1>O1CCOCC1>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[O:7])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COC(=O)N=C=O
Reactant: COc1ccc(N)cc1OC
Solvent: C1COCCO1
Product: COC(=O)NC(=O)Nc1ccc(OC)c(OC)c1

Procedure:
To a solution of methoxycarbonylisocyanate (3.78 g. 0.0374 mole) in 45 ml. of dioxane is added 4-aminoveratrole (5.73 g., 0.037 mole) while maintaining a temperature of 20°-30°. After completing the addition, another 45 ml. portion of dioxane is added and the mixture then heated at reflux for a period of one hour. Evaporation of the solvent and crystallization of residual material from nitromethane provides analytically pure 1-(3,4-dimethoxyphenyl)-3-methoxycarbonylurea, m.p. 168°-170°.