Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17]3)=[O:11])=[CH:5][CH:4]=1.[CH3:31][CH:32]([CH3:41])[CH2:33][C:34]1[O:35][CH2:36][C:37](=[O:40])[NH:38][N:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:26]1([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:38]3[C:37](=[O:40])[CH2:36][O:35][C:34]([CH2:33][CH:32]([CH3:41])[CH3:31])=[N:39]3)=[CH:4][CH:5]=2)[C:10]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17]3)=[O:11])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CBr)cc3)C3CCCC3)c2C1
Reactant: CC(C)CC1=NNC(=O)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CN4N=C(CC(C)C)OCC4=O)cc3)C3CCCC3)c2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
100 mg (0.213 mmol) of methyl 4-({[4-(bromomethyl)phenyl](cyclopentyl)acetyl}amino)-2,3-dihydro-1H-indene-2-carboxylate were dissolved in 3.5 ml of DMF, and 55 mg (0.213 mmol) of 2-(2-methylpropyl)-4H-1,3,4-oxadiazin-5(6H)-one (Example 22A) and 76 mg (0.234 mmol) of cesium carbonate were added. The reaction mixture was stirred at room temperature for 3 d. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC. This gave 8 mg (8% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: NCC[C@@H]1C[C@H](CC(=O)OC2CCCCC2)OC2(CCCCC2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC2CCCCC2)OC2(CCCCC2)O1

Procedure:
According the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and cyclohexyl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:16])=[C:6]([C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[CH:7]=O)(=[O:3])[CH3:2].[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:4]1[C:5]([OH:16])=[C:6]([C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[CH2:7][N:27]1[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]1)(=[O:3])[CH3:2]
Reactant: COc1cc(C(C)=O)c(O)c(C=O)c1OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C(C)=O)c(O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
A solution of 3-acetyl-2-hydroxy-5,6-dimethoxybenzaldehyde (0.14 g, 0.63 mmol) in methylene chloride (5.0 mL) was added with N-Boc-piperazine (0.13 g, 0.70 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C., and then added portionwise with sodium triacetoxyborohydride (0.16 g, 0.76 mmol). After completion of the addition, the reaction mixture was warmed to room temperature, and stirred for 10 hours. The reaction mixture was added with methylene chloride, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (2:1→3:7)) to obtain tert-butyl 4-(3-acetyl-2-hydroxy-5,6-dimethoxybenzyl)piperazine-1-carboxylate (0.20 g, 80%).
Reaction SMILES: [CH2:1]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][C@H:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[N+:45]([O-])=O)[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][CH:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[N+:23]([O-])=O.C(Cl)(Cl)Cl.CO>CO>[CH2:3]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][C@H:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[NH2:23])[CH2:2][CH2:1][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][CH:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[NH2:45]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3[N+](=O)[O-])cc2OC)C1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=C1CC(CO)N(C(=O)c2cc(N)c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4CO)cc3N)cc2OC)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
A mixture of the diol 76 (0.98 g, 1.49 mmol) and SnCl20.2H2O (3.36 g, 14.9 mmol) in MeOH (35 mL) was heated at reflux and the progress of the reaction monitored by TLC (90% CHCl3/MeOH). After 45 minutes, the MeOH was evaporated in vacuo and the resulting residue was cooled (ice), and treated carefully with saturated NaHCO3 (120 mL). The mixture was diluted with EtOAc (120 mL), and after 16 hours stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give a brown solid. Flash chromatography (95% CHCl3/MeOH) afforded the pure bis-amine 77 as an orange solid (0.54 g, 61%): [α]19D=−31.8° (c=0.30, CHCl3); 1H NMR (270 MHz, CDCl3) δ6.74 (s, 2Harom), 6.32 (s, 2Harom), 5.00 (br s, 2H, NCH2C═CH2), 4.93 (br s, 2H, NCH2C═CH2), 4.54 (br s, 2H, NCHCH2OH), 4.24-4.14 (m, 4H, OCH2CH2CH2O), 3.98-3.50 (m, 14H, NCHCH2OH, NCH2C═CH2 and OCH3), 2.76 (dd, 2H, J=8.61, 15.91 Hz, NCH2C═CH2CH2), 2.46-2.41 (m, 2H, NCH2C═CH2CH2), 2.33-2.28 (m, 2H, OCH2CH2CH2O); 13C NMR (67.8 MHz, CDCl3) δ171.0 (NC═O), 151.0 (Cquat), 143.5 (Cquat), 141.3 (Cquat), 140.6 (Cquat), 112.4 (C—Harom), 111.9 (Cquat), 107.8 (NCH2C═CH2), 102.4 (C—Harom), 65.2 (OCH2CH2CH2O), 65.0 (NCHCH2OH), 59.8 (NCHCH2OH), 57.1 (OCH3), 53.3 (NCH2C═CH2), 34.4 (NCH2C═CH2CH2), 29.0 (OCH2CH2CH2O); MS (FAB) (Relative Intensity) 596 (M+., 13), 484 (M—NCH2CCH2CH2CHCH2OH, 14), 389 (10), 371 (29), 345 (5), 224 (8), 206 (44), 166 (100), 149 (24), 112 (39), 96 (34), 81 (28); IR (NUJOL™) 3600-3000 (br, OH), 3349 (NH2), 2922, 2852, 2363, 1615, 1591 (NH2), 1514, 1464, 1401, 1359, 1263, 1216, 1187, 1169, 1114, 1043, 891, 832, 761 cm−1. (2S,4R)&(2S,4S)-1,1′-[[(Propane-1,3-diyl)dioxy]bis[(2-amino-5-methoxy-1,4-phenylene)carbonyl]]bis[2-(hydroxymethyl)-4-methylpyrrolidine] (77).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][C:8]=1[CH3:9].I[CH2:18][CH3:19]>>[CH2:18]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[N:7][C:8]=1[CH3:9])[CH3:19]
Reactant: CCI
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1CO
Product: CCOCc1ccc(NC(=O)C(C)(C)C)nc1C

Procedure:
This material was prepared in analogy to example 86 step A] from N-(5-hydroxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.445 g, product of example 112 step B]) and iodoethane (0.34 g) as a light yellow oil (0.32 g). MS (ESI): 251.2 (MH+).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[N:6]=[C:7]2[S:22][CH:21]=[C:20]([CH3:23])[N:8]2[C:9](=[O:19])[C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH3:4].Cl[C:25]1[N:30]=[CH:29][NH:28][C:27]2=[N:31][CH:32]=[CH:33][C:26]=12.C(N(CC)C(C)C)(C)C>C(O)(C)C>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9](=[O:19])[N:8]3[C:20]([CH3:23])=[CH:21][S:22][C:7]3=[N:6][C:5]=2[CH:3]([NH:2][C:25]2[C:26]3[CH:33]=[CH:32][NH:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH3:4])[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]ccc34)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 100 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one hydrochloride (0.030 g, 0.084 mmol), 4-chloropyrrolo[2,3-d]pyrimidine (0.013 g, 0.084 mmol), and N,N-diisopropylethylamine (0.044 mL, 0.25 mmol) in isopropyl alcohol (0.2 mL) was heated at 100° C., in a sealed tube, for three days. The resultant mixture was applied on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C21H17F2N6OS (M+H)+: m/z=439.1. Found: 439.1.
Reaction SMILES: C1(C)C=CC=CC=1.[OH:8][N:9]=[C:10]1[CH2:18][C@@H:17]2[C@@H:12]([CH2:13][CH:14]=[CH:15][CH2:16]2)[CH2:11]1.[H-].[Na+].Cl[CH2:22][CH2:23][CH2:24][C:25]#[N:26]>O>[C:25]([CH2:24][CH2:23][CH2:22][O:8][N:9]=[C:10]1[CH2:11][C@@H:12]2[C@@H:17]([CH2:16][CH:15]=[CH:14][CH2:13]2)[CH2:18]1)#[N:26]
Reactant: N#CCCCCl
Reactant: ON=C1C[C@H]2CC=CC[C@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCCCON=C1C[C@H]2CC=CC[C@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a toluene solution (20 ml) of 8-hydroxyimino-cis-bicyclo[4,3,0]nona-3-ene (1 g), was added sodium hydride (50% mineral oil dispersion, 330 mg), and the mixture was stirred for 0.5 hr at room temperature. After addition of γ-chlorobutyronitrile (5 g) to the mixture, stirring was continued for 2 hr. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over Na2SO4 and concentrated to give an oil. This material was chromatographed on silica gel to give 8-(3'-cyanopropoxy)imino-cis-bicyclo[4,3,0]nona-3-ene as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[C:16]([Cl:19])([Cl:18])=[CH2:17].Cl>C(Cl)Cl>[Cl:18][C:16]([Cl:19])=[CH:17][C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([Cl:11])=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Reactant: C=C(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
A solution of the 2,6-dichloro-nicotinoyl chloride (1.0 g, 4.76 mmol) from the previous reaction in CH2Cl2 (5 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (0.64 g, 4.76 mmol) in CH2Cl2 (20 mL). After 15 min, vinylidene chloride (0.38 mL, 0.46 g, 4.76 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was then poured over ice and was acidified using 1 N HCl (15 mL). Stirring was continued for 20 min and the product was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give 3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (0.88 g, 68% ) as a light yellow oil: 1H-NMR (CDCl3, 300 MHz) δ 8.38, d, J=8.4, 1H). 7.40 (d, J=8.4, 1H), 7.10 (s, 1H); Rf=0.51 (4:1 Hex:EtOAc).
Reaction SMILES: [O:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]12([CH2:26][C:27](Cl)=[O:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[C:16]12([CH2:26][C:27]([N:13]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([C:27](=[O:28])[CH2:26][C:16]45[CH2:25][CH:20]6[CH2:19][CH:18]([CH2:24][CH:22]([CH2:21]6)[CH2:23]4)[CH2:17]5)[CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:15][CH2:14]3)=[O:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: C1COCCNCCOCCOCCN1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCOCCN(C(=O)CC23CC4CC(CC(C4)C2)C3)CCOCC1

Procedure:
Analogously to Example 2 from 1,4,10-trioxa-7,13-diazacyclopentadecane and (1-adamantyl) acetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:6]([N:7]=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=O)=[O:23])=[CH:18][CH:17]=2)[N:3]=1.O=S(Cl)[Cl:28]>CN(C)C=O>[Cl:28][S:22]([C:19]1[CH:20]=[CH:21][C:16]([N:4]2[C:5](=[O:15])[CH:6]([N:7]=[N:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:2]([CH3:1])=[N:3]2)=[CH:17][CH:18]=1)(=[O:25])=[O:23]
Reactant: CC1=NN(c2ccc(S(=O)(=O)O)cc2)C(=O)C1N=Nc1ccccn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1=NN(c2ccc(S(=O)(=O)Cl)cc2)C(=O)C1N=Nc1ccccn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
9.0 g (0.025 mole) of 3-methyl-4-(2-pyridylazo)-1-(p-sulfophenyl)-2-pyrazolin-5-one was added in portions with stirring to 70 ml of SOCl2. To this suspension was added dropwise 3 ml of dimethylformamide. The mixture was stirred overnight. The resulting solution was poured slowly with vigorous stirring into 500 ml of ice water. The solid product was filtered and pressed dry. This product was slurried in 50 percent tetrahydrofuran/ethyl ether, filtered, and dried to obtain 5.3 g (56 percent) of orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[N:5]([C:7]([C:9]1([CH2:14][CH2:15][O:16][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])[CH3:6].[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)[N:5]([CH3:6])[C:7]([C:9]1([CH2:14][CH2:15][O:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13]1)=[O:8]
Reactant: COCCC1(C(=O)N(C)[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COCCC1(C(=O)N(C)[C@@H](Cc2ccc(N)cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a mixture of N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-N-methyl-4-nitro-L-phenylalanine methyl ester (1.35 mmol, 530 mg), zinc dust (˜325 mesh, 13.5 mmol, 0. 88 g, 10 equiv.) and ammonium chloride (20.2 mmol, 1.08 g, 15 equiv.) was added methanol (10 mL) and water (5 mL) at room temperature. After addition of water, the reaction was exothermic. The suspension was stirred for 2 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material, the reaction mixture was filtered through a pad of celite and the filter cake was washed with methanol (50 mL) and water (40 mL). The mixture was concentrated and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine solution (30) mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent afforded 490 mg (100%) of a yellow oil. HR MS (C20H30N2O4): Obs. mass, 362.2202. Calcd. mass, 362.2206 (M+).
Reaction SMILES: [Br-].[C:2]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)([O:4][CH3:5])=[O:3].CC(C)([O-])C.[K+].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[C:53]([CH:54]([CH:57]3[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]3)[CH:55]=O)=[C:52]3[C:47]([CH2:48][CH2:49][CH2:50][CH2:51]3)=[N:46]2)=[CH:41][CH:40]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[CH3:5][O:4][C:2](=[O:3])[C:6]1[CH:7]=[CH:8][C:9](/[CH:10]=[CH:55]/[CH:54]([C:53]2[N:45]([C:42]3[CH:43]=[CH:44][C:39]([Cl:38])=[CH:40][CH:41]=3)[N:46]=[C:47]3[C:52]=2[CH2:51][CH2:50][CH2:49][CH2:48]3)[CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)=[CH:30][CH:31]=1
Reactant: O=CC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(/C=C/C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 379 mg (0.772 mmol) 4-carbomethoxybenzyl triphenylphosphonium bromide ([1253-46-9]) in 6 ml THF was added 87 mg (0.772 mmol) potassium tert-butoxide at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. [2-(4-Chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetaldehyde (0.772 mmol; 1 eq.) was added at 0° C. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was poured on 30 ml citric acid 10% in H2O and 30 ml EtOAc. The aqueous layer was extracted a second time with 30 ml EtOAc. The combined organic layers were washed with 30 ml brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (20 g silica gel; gradient: n-heptane:EtOAc) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH2:13])[N:3]=1.[OH-].[Na+].[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH2:13])[N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCn1cnc2c(N)nc(Cl)nc21
Reactant: OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCn1cnc2c(N)nc(OCc3ccccc3)nc21
Temperature: 85 °C

Procedure:
To a mixture of 2-chloro-9-ethyl-9H-purin-6-ylamine (0.2 g, 1.01 mmol), a compound of formula (3), and dry sodium hydroxide (5 mmol) was added benzyl alcohol (9.0 mmol). This mixture was heated at 85° C. for 3 hours. The solvent was then removed under reduced pressure and the residue was neutralized with 2N HCl and extracted with CHCl3. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on a silica gel column eluting with a mixture of ethyl acetate/cyclohexane/methanol (60/33/5) to give 2-benzyloxy-9-ethyl-9H-purin-6-ylamine as a chromatographically pure solid.
Reaction SMILES: [CH:1](OCC)=[O:2].[NH2:6][CH:7]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[CH2:8][N:9]1[CH2:16][CH:15]2[CH2:17][CH:11]([CH2:12][N:13]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[CH2:10]1>>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([CH:7]([NH:6][CH:1]=[O:2])[CH2:8][N:9]2[CH2:10][CH:11]3[CH2:17][CH:15]([CH2:14][N:13]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:12]3)[CH2:16]2)=[CH:25][CH:26]=1)#[N:31]
Reactant: CCOC=O
Reactant: CC(C)OC(=O)N1CC2CC(CN(CC(N)c3ccc(C#N)cc3)C2)C1
Product: CC(C)OC(=O)N1CC2CC(CN(CC(NC=O)c3ccc(C#N)cc3)C2)C1
Yield: 40 %

Procedure:
Ethyl formate (0.5 mL) was added to a stirred solution of iso-propyl 7-[2-amino-2-(4-cyanophenyl)ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from Example 9(viii) above; 0.71 g; 2.0 mmol), and the reaction mixture was refluxed for 5 h. The solvent was evaporated and the residue partitioned between diethyl ether and NaOH (2 M). The organic layer was separated, washed with water, dried and then concentrated. The resulting residue was then recrystallized from MeOH and di-iso-propyl ether to give the title compound in 40% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[N:17]=[C:16]([C:26]([OH:29])([CH3:28])[CH3:27])[CH:15]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C(#N)C>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]1[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[CH:3]=3)=[CH:9][CH:10]=2)=[CH:15][C:16]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:17]1
Reactant: CC(C)(O)c1cc(-c2ccc(-c3cccc(N)c3)cc2)n(-c2ccccc2Cl)n1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1cccc(-c2ccc(-c3cc(C(C)(C)O)nn3-c3ccccc3Cl)cc2)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a solution of 2-(5-(3′-aminobiphenyl-4-yl)-1-(2-chlorophenyl)-1H-pyrazol-3-yl)propan-2-ol (370 mg, 037 mmol) in acetonitrile (1.6 mL) was added triethylamine (0.12 mL, 0.86 mmol) followed by acetyl chloride (27 μL, 380 μmol). The reaction vial was then shaken at 75° C. overnight. After cooling the reaction solution was concentrated under reduced pressure and the crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexane to afford N-(4′-(1-(2-chlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)biphenyl-3-yl)acetamide (82 mg, 49% yield) as an oil. 1H NMR (400 MHz CDCl3): δ 7.79 (1H, s), 7.49-7.42 (4H, m), 7.41-732 (4H, m), 7.31-7.21 (3H, m), 6.54 (1H, s), 2.68 (1H, s), 2.19 (3H, s), 1.69 (6H, s). MS(ES): 445[M+H]+. The following compounds are prepared essentially according to the previous examples:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:31]=[C:32]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:36]2[N:38]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)C1CC(c2cccc(C(F)(F)F)c2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1cccc(F)c1
Product: O=C(N1CCC(O)CC1)N1CC(c2cccc(C(F)(F)F)c2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
75 mg (0.2 mmol) of the compound from Example 150A and 52 mg (0.3 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 16 mg (18% of theory)
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])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([CH3:31])[N:26]=1>>[CH3:31][N:27]1[C:28]([CH3:30])=[CH:29][C:25]([CH2:24][N:15]2[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:22])[CH:12]=3)[C:14]2=[O:21])=[N:26]1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: Cc1cc(CCl)nn1C
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cc(C)n(C)n3)C(C)(C)C2=O)cn1

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 3-(chloromethyl)-1,5-dimethyl-1H-pyrazole. MS 412 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.16 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1>S(Cl)(Cl)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=1)=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-nitrobenzoic acid (1.99 g, 9.87 mmol) was stirred for 18 hrs at 60° C. in thionyl chloride (10 ml). The excess thionyl chloride was removed by evaporation and the crude oil dissolved in chloroform (20 ml). To this solution was added ethyl (4-aminophenyl)acetate (1.18 g, 6.58 mmol) and the reaction was stirred at 60° C. for 18 hrs. The reaction was diluted with water and the phases separated. The organic layer was dried (Na2SO4), solvent evaporated and the residue purified by flash chromatography (Biotage SP4, 40+M 0→50% ethylacetate/hexane) to afford the title compound as an off white solid (2.28 g, 96%).