Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:13])[C:9]([O:11]C)=O.[Cl:14][CH2:15]C([O-])=O.[Na+].C(N(CC)CC)C.C([Mg]Cl)(C)(C)C.Cl>C(OCC)(=O)C.O.C1COCC1>[Cl:14][CH2:15][C:9](=[O:11])[C@H:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:13]
Reactant: COC(=O)[C@@H](C)OC1CCCCO1
Reactant: O=C([O-])CCl
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](OC1CCCCO1)C(=O)CCl
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A mixture of 9.41 g (50 mmol) of methyl (R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionate, 8.74 g (75 mmol) of sodium chloroacetate, 7.53 g (75 mmol) of triethylamine, and 200 mL of THF was cooled in ice, and 199 g (300 mmol) of a 1.6 M solution of tert-butylmagnesium chloride was added dropwise thereto over a period of 2 hours. After the completion of the dropwise addition, the reaction was performed at room temperature for another 2 hours, and the reaction solution was cooled in ice again. Then, 50 mL of water was added thereto, and subsequently 100 mL of ethyl acetate was added. Furthermore, 10% hydrochloric acid was added in such a manner that the pH was 6.0. After stirring was performed at room temperature for 1 hour, the resulting organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 9.81 g of a crude product. The resulting product was purified by column on silica gel to obtain 6.79 g of the title compound (yield: 73%). 1H-NMR (400 MHz, CDCl3) δ: 1.35 (d, 3H, J=6.6 Hz), 1.50-1.55 (m, 4H), 1.80-1.84 (m, 3H), 3.42-3.53 (m, 1H), 3.83-3.96 (m, 1H), 4.24 (q, 1H, J=6.8 Hz), 5.58 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-].[K+].C(OP([C:23](Br)([F:25])[F:24])(=O)OCC)C>CC#N.O>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH:23]([F:25])[F:24])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: COc1cc(Br)cc(OC)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1cc(Br)cc(OC)c1OC(F)F
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 62 %

Procedure:
5-Bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene was synthesized from 4-bromo-2,6-dimethoxyphenol according to the procedure of Zafrani, Y. Tetrahedron 2009, 65, 5278 as follows. To a solution of 4-bromo-2,6-dimethoxyphenol (1.08 g, 4.6 mmol) in MeCN (27 mL) was added a solution of KOH (5.0 g, 89 mmol) in H2O (27 mL). The mixture was immediately cooled over a −78° C. bath and diethyl(bromodifluoromethyl)phosphonate (1.6 mL, 8.9 mmol) was added. The flask was sealed with a septum and the cold bath was removed. The mixture was stirred for a total of 3.5 hrs during which time the septum was ejected from the flask. The reaction was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were washed with 1 M NaOH, H2O and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-30% EtOAc-hexanes) provided 5-bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene as a white solid (0.808 g, 62% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=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.[CH3:60][O:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][NH2:69])=[CH:64][CH:63]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:69][CH2:68][C:65]3[CH:66]=[CH:67][C:62]([O:61][CH3:60])=[CH:63][CH:64]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.5 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 1-[4-(methyloxy)phenyl]methanamine (65.6 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water and dried to give the title compound (203 mg) as a yellow solid. LC-MS (ES) m/z=475 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:15]([CH2:16][C:17]([NH:19][CH2:20][CH2:21]O)=[O:18])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=12.C(N(CC)CC)C.S(Cl)([Cl:36])=O>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:15]([CH2:16][C:17]([NH:19][CH2:20][CH2:21][Cl:36])=[O:18])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=12
Reactant: O=S(Cl)Cl
Reactant: O=C(Cc1c(O)c2ccccc2c2nc3ccccc3nc12)NCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1c(O)c2ccccc2c2nc3ccccc3nc12)NCCCl
Yield: 81.3 %

Procedure:
To a solution of 1000 mg of 5-hydroxy-N-β-hydroxyethylbenzo[a]phenazine-6-carboxyamide in 30 ml of dry chloroform was added 300 mg of triethylamine, followed by 660 mg of thionyl chloride. The mixture was heated at reflux for 30 minutes and evaporated to dryness under reduced pressure. The residue was dissolved in chloroform, washed with water, dried and the solvent was evaporated. The resulting residue was recrystallized from dimethylformamide to obtain 856 mg (91.8% yield) of 5-hydroxy-N-β-chloroethylbenzo[a]-phenazine-6-carboxyamide as yellow needles, m.p. 183°-186° C., Anal. Calcd. (%) for C19H14N3O2Cl: C, 64.87; H, 4.01; N, 11.94; Found: C, 64.60; H, 4.03; N, 11.66
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:23]=[C:24]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[O:29])[CH:25]=[CH:26][CH:27]=1.[OH-].[Na+]>>[F:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: O=C(c1ccc(O)cc1)c1cccc(F)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3cccc(F)c3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with (3-Fluoro-phenyl)-(4-hydroxy-phenyl)-methanone from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H25FO6 [M+H]+: 453.5.
Reaction SMILES: [OH:1][N:2]=[CH:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:19])=[CH:13][CH:12]=1.C[O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][C:34]#[CH:35].C(N(CC)CC)C.Cl[O-].[Na+]>ClCCl>[C:40]([O:39][C:37]([NH:36][CH:32]([CH2:33][C:34]1[O:1][N:2]=[C:3]([CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[C:9](=[O:28])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[O:19])=[CH:15][CH:16]=2)[CH:35]=1)[C:31]([OH:44])=[O:30])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCCC2C=NO)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCCC2c2cc(CC(NC(=O)OC(C)(C)C)C(=O)O)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
A solution of 1-(4-{2-[2-(hydroxyimino-methyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-phenyl)-3-o-tolyl-urea (300 mg, 0.789 mmol), 2-tert-butoxycarbonylamino-pent-4-ynoic acid methyl ester (359 mg, 1.182 mmol, crude mixture) and triethyl amine (12.9 μL) in dichloromethane (2 mL) was stirred 5 minutes. A sodium hypochlorite solution (5.25%, 2 mL) was added. The reaction was stirred at room temperature overnight. The aqueous portion was extracted 4 times with dichloromethane. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated. Chromatography of the crude mixture on a Biotage Flash 40S column eluting with ethyl acetate/hexane 1:5 gave the title compound (66 mg, 14%). MS (Cl) m/z 604.5 (M−1), 505.9 (M−99) C. 2-tert-Butoxycarbonylamino-pent-4-ynoic acid methyl ester
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH:18]([OH:29])[C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[C:18]([C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=1)=[O:29]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(O)c3nc4ccccc4n3C)sc21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(=O)c3nc4ccccc4n3C)sc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.8 %

Procedure:
Prepared according to the method described in Example 37 step c from 5-bromo-6-[hydroxy(1-methyl-1H-benzimidazol-2-yl)methyl]-3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (5.0 g), 4-methylmorpholine-N-oxide (1.84 g), powdered 4 Å sieves (5.0 g) and tetra-n-propyl-ammonium perruthenate (0.18 g) in dry dichloromethane (170 ml) with stirring at room temperature for 24 hours. After work up, the residue was purified by column chromatography over silica eluting with a gradient of 0-2% ethanol in dichloromethane to give the subtitle compound as a yellow powder (2.93 g).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][CH2:62][NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](=[O:20])[NH:63][CH2:62][CH2:61][S:60][C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
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: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
351 mg (0.63 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 200 mg (0.63 mmol) 2-(Tritylsulfanyl)ethanamine, 0.11 ml (0.63 mmol) N,N-diisopropylethyl-amine and 238 mg (0.63 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 98 mg (0.110 mmol, 16% of theory) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[C:14](I)[CH:15]=[CH:16][C:7]=3[C:6]=2[N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>CN1CCCC1=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[C:14]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([O:28][CH3:27])[CH:30]=4)[CH:15]=[CH:16][C:7]=3[C:6]=2[N:18]=1
Reactant: COc1cccc(N)c1
Reactant: Nc1ncc2c(n1)-c1ccc(I)cc1NC(=O)C2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cccc(Nc2ccc3c(c2)NC(=O)Cc2cnc(N)nc2-3)c1
Temperature: 90 °C
Yield: 60.8 %

Procedure:
2-Amino-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (200 mg, 0.568 mmol, 1.0 equiv), anhydrous K3PO4 powder (241 mg, 1.14 mmol, 2.0 equiv) and palladium bis-tri-t-butyl phosphine (58 mg, 0.1136 mmol, 20 mol %) were combined in a sealable vial with a magnetic stir bar under a nitrogen atmosphere (glove box). 3-Methoxyaniline (209 mg, 1.70 mmol, 3.0 equiv) was added, followed by 6 mL of anhydrous N-methylpyrrolidinone. The vial was sealed with a silicone lined crimp cap and removed from the glove box. The vial was sonicated for 2 minutes and then heated to 90° C. (oil bath temperature) for 18 hours. The dark brown solution was diluted with 50 mL of water and the brown solids were collected by filtration and washed with water and then diethyl ether. Purification by silica gel chromatography (10% methanol, 85% dichloromethane, 5% formic acid) afforded an orange powder, which was recrystallized from methanol and diethyl ether to yield 120 mg (61%) of 2-amino-9-(3-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-225) as a yellow-orange powder.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7]1.C(N(CC)CC)C.O.C(OCC)(=O)C>CS(C)=O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7]1
Reactant: OCC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
To a solution of {1-[2,4-bis(trifluoromethyl)benzyl]pyrrolidin-3-yl}methanol (4.69 g) and triethylamine (5.99 mL) in dimethyl sulfoxide (50 mL) was added sulfur trioxide pyridine complex (6.84 g), and the mixture was stirred at room temperature for 4 hr. Water/ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.50 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:9]Cl>>[C:4](=[O:8])([O:5][CH:6]([Cl:9])[CH3:7])[O:3][CH2:1][CH3:2]
Reactant: CCOC(=O)OCC
Reactant: ClCl
Product: CCOC(=O)OC(C)Cl
Yield: 42.9 %

Procedure:
Into the same flask as used in Example 1, 236.6 grams (2 moles) of pure diethylcarbonate were added, and then 2.6 moles of chlorine gas were introduced into the flask over a five hour period at a range of 50° C. to 52° C. under the irradiation of ultraviolet rays. When the reaction was completed, the unreacted diethylcarbonate was removed by subjecting it to fractional distillation to yield 131 grams of ethyl α-chloroethyl carbonate. B.P.: 160°-163° C.; Yield: 59.8% to the consumed diethylcarbonate. The data of the IR and the NMR were identified to be the same as those in Example 1.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N:18]2[CH2:23][CH2:22][C@@H:21]([NH2:24])[C@H:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:19]2)[C:16]=1[Cl:17])[C:12]#[N:13]>ClCCl>[NH2:8][C:9]1[C:16]([Cl:17])=[C:15]([N:18]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:5](=[O:7])[CH3:6])[C@H:20]([O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:27])[CH3:28])[CH2:19]2)[CH:14]=[C:11]([C:12]#[N:13])[CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(N)c2Cl)CC[C@H]1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Acetic anhydride (0.011 mL, 0.119 mmol) was added to a solution of (+/−)-3-amino-5-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-4-chlorobenzonitrile (Example 171D), (41 mg, 0.108 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0.5-5% methanol/dichloromethane). (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)acetamide (44 mg) was obtained as a colorless oil which solidified upon standing.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1ccc(CCBr)cc1
Product: COc1ccc(CCN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1
Yield: 32 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-methoxyphenethyl bromide. Yield: 32%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.78 (t, J=7.4 Hz, 2H), 3.50 (t, J=7.4 Hz, 2H), 3.69 (s, 3H), 4.02 (s, 2H), 5.16 (s, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.73 (s, 1H), 8.12 (s, 1H). MS M+H calculated 410.18; found 410.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.04 μM.
Reaction SMILES: [N:1]([C@@H:4]([CH3:22])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([C:16]([CH3:19])([CH3:18])[CH:15]=[CH:14][C:13]=3[O:20][CH3:21])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:21][O:20][C:13]1[CH:14]=[CH:15][C:16]([CH3:19])([CH3:18])[C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][C@@H:4]([NH2:1])[CH3:22]
Reactant: COC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2C(C)(C)C=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Solvent: CCOCC
Product: COC1=C2C=c3c(cnn3C[C@H](C)N)=C2C(C)(C)C=C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
1.38 g (4.6 mmol) of (S)-1-(2-azido-propyl)-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol were hydrogenated over 140 mg of platinum oxide for 1.5 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 80 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 534 mg (4.6 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 18 hours and the white crystals were subsequently filtered off. 1.23 g (69%) of (S)-2-(7-methoxy-4,4-dimethyl-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 160°-162° were obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([CH3:29])[C:25]([CH3:30])=[N:24]3)=[CH:19][C:18]=2[CH3:31])=[C:4]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[CH3:31][C:18]1[CH:19]=[C:20]([N:23]2[C:27]([CH3:28])=[C:26]([CH3:29])[C:25]([CH3:30])=[N:24]2)[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:3]1[C:2]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(Br)cccc1-n1nnn(C)c1=O
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(C#C[Si](C)(C)C)cccc1-n1nnn(C)c1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 32.2 %

Procedure:
A mixture of 1-{3-bromo-2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 70) 0.3 g, trimethylsilylacetylene 0.2 g, tetrakis triphenylphosphine palladium 0.05 g, tri-tert-butylphosphine 0.07 g, potassium phosphate 0.6 g, 1,4-dioxane 5 ml and water 0.5 ml was stirred at 100° C. for five hours. After cooling, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-3-trimethylsilylethynyl-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one 0.1 g.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>>[CH3:32][N:33]([CH3:37])[C:34]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH:2]([CH3:3])[CH3:4])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:35]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)N(C)C)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and N,N-dimethylcarbamoyl chloride. Off-white solid. MS (m/z): 484.4 (M+H)+.