Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[N:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:33][C:34]=1[CH3:35])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[N:31]=[C:32]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:33][C:34]=1[CH3:35])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:50]/[C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccc(C(F)(F)F)cc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(-c2ccc(C(F)(F)F)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carbaldehyde (3.30 g), ethyl diethylphosphonoacetate (1.32 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.236 g) at room temperature, and the mixture was stirred for 30 min at the same temperature. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, and recrystallized from tetrahydrofuran to give ethyl (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propenoate as a colorless powder (2.59 g, yield 69%). melting point: 205-206° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=O>Cl.O=[Pt]=O>[CH:8]1([N:7]2[C:2]([NH2:1])=[C:3]([NH2:15])[C:4](=[O:14])[NH:5][C:6]2=[O:13])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1c(N=O)c(=O)[nH]c(=O)n1C1CCCC1
Agent: O=[Pt]=O
Agent: Cl
Product: Nc1c(N)n(C2CCCC2)c(=O)[nH]c1=O

Procedure:
12.9 g of 6-amino-1-cyclopentyl-5-nitroso-2,4-(1H,3H)-pyrimidinedione (XV) was catalytically hydrogenated in 30 ml of 2N HCl and in the presence of 0.1 g PtO2 for 3 hours and at room temperature and at a pressure of 200 kPa. The catalyst was filtered off and the filtrate was neutralized with 5N NaOH. The crystals were filtered off.
Reaction SMILES: [CH2:1]([Cl:3])Cl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=C[N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1>CO>[Cl:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][N:21]=[C:1]([Cl:3])[CH:23]=3)[CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(N4CCNCC4)c3)n2)c1
Reactant: ClCCl
Solvent: CO
Product: C1CNCCN1
Product: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1

Procedure:
Analogously to Example 1, there is obtained from 100 mg (0.31 mmol) of N-[3-chloro-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine and 500 mg (5.63 mmol) of piperazine, from the melt after chromatography (methylene chloride:methanol=95:5), N-[3-chloro-phenyl]-4-[2-(1-piperazinyl)-4-pyridyl]-2-pyrimidineamine;
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][CH2:57][N:58]([CH3:88])[CH2:59][CH2:60][C@@H:61]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([S:77]([NH2:80])(=[O:79])=[O:78])=[CH:73][C:72]=1[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:80][S:77]([C:74]3[CH:75]=[CH:76][C:71]([NH:70][C@H:61]([CH2:60][CH2:59][N:58]([CH2:57][CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:54])[CH3:53])([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH3:88])[CH2:62][S:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[C:72]([S:81]([C:84]([F:86])([F:87])[F:85])(=[O:82])=[O:83])[CH:73]=3)(=[O:78])=[O:79])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 84.7 %

Procedure:
The title product (110 mg, yield: 88%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 32 utilizing 4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 56.7 mg, 0.11 mmol) and (R)-4-(4-((2-(tert-butyldiphenylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 28, 75 mg, 0.10 mmol) as starting materials. The title product was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→30% EtOAc/hexanes).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([O:26]CCC#N)=[O:25])=[C:5]([O:31][CH3:32])[CH:4]=1)#[N:2].[OH-].[Na+].C(OCC)C.Cl>COCCOC.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([OH:26])=[O:25])=[C:5]([O:31][CH3:32])[CH:4]=1)#[N:2]
Reactant: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: COCCOC
Product: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.75 g (4.05 mmol) of the compound from Example 29A are dissolved in 60 ml of 1,2-dimethoxyethane/water (2:1 v/v), 8.09 ml (8.09 mmol) of 1 N sodium hydroxide solution are added, and the mixture is stirred at room temperature for one hour. 30 ml of diethyl ether are then added to the mixture, and the aqueous phase is acidified with 6 N hydrochloric acid. The resulting precipitate is filtered off and washed with water and a little diethyl ether. Drying in a vacuum drying oven at 40° C. results in 1.47 g (96% of theory) of the title compound.
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][C:41]=1B(O)O>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:41]2[CH:42]=[CH:43][C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:40]=2[Cl:39])[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)cc2Cl)c1

Procedure:
5-(tert-Butyl)-2′-chloro-2-hydroxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 2-chloro-4-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]([C:27]([NH2:29])=[O:28])[NH2:26]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18](/[C:21](=[N:26]/[NH:25][C:27]([NH2:29])=[O:28])/[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 84.5 %

Procedure:
A solution of 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (35 mg, 0.115 mmol) and hydrazinecarboxamide hydrochloride (17.32 mg, 0.231 mmol) in MeOH was stirred at room temperature for overnight. Solid was filtered and dried to provide the title compound as a light yellow solid (35 mg, 84%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.90 (s, 1H), 9.10 (d, 1H), 8.79 (d, 1H), 8.37 (d, 1H), 8.17 (m, 3H), 8.03 (d, 1H), 7.83 (m, 1H), 6.85 (broad, 2H), 4.84 (s, 2H), 2.24 (s, 3H). LCMS (method A): [MH]+=361.1, tR=3.58 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15]>CCOCC>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:17])[C:14]([Cl:16])=[O:15])=[CH:5]1
Reactant: COCn1ccc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: COCn1cc(C(=O)C(=O)Cl)c2ccccc21
Yield: 48.3 %

Procedure:
Using the procedure of Example 1, step B, the reaction of 0.23 g (1.43 mmol) of 1-methoxymethyl-1H-indole (9) from Step A above with 0.25 ml (2.86 mmol) of oxalyl chloride in 3.5 ml of ether produced 0.174 g (48.5%) of (1-methoxymethyl-1H-indol-3-yl)-oxo-acetyl chloride (10) as a yellow solid. This material was used without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[C:12]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]2[CH3:29])=[N:13][C:14]([Cl:18])=[N:15][C:16]=1[CH3:17]>CN(C)C=O>[ClH:18].[CH3:10][C:11]1[C:12]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]2[CH3:29])=[N:13][C:14]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1cc(F)ccc1N
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(C)c(C)c(N2CCc3ccccc3C2C)n1
Product: Cl
Yield: 68.1 %

Procedure:
After 2-methyl-4-fluoroaniline(1.1 ml, 9.9 mmol) was added to a mixture solution of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.4 g, 4.8 mmol) prepared in the above Step 2 and dimethylformamide (10 ml), 1.35 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: CCOCC.[Li].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>C(Cl)Cl.O>[CH3:14][N:15]1[CH2:20][CH2:19][C:18]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:21])[CH2:17][CH2:16]1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1ccccc1
Agent: [Li]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CN1CCC(O)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Anhydrous ether (1900 ml) is placed, under nitrogen, in a previously dried 5 liter 3-necked flask fitted with dropping funnel, reflux condenser and magnetic stirrer. Lithium (28.4 g, 4.1 g. at.) is added together with 20 ml bromobenzene (20 ml). The mixture is heated at reflux temperature until a reaction commences. Heating is discontinued and a total of 312 g. (2.0 moles) bromobenzene is added dropwise during 0.5 hour. The mixture is stirred for a further 3 hours and the remaining traces of lithium are removed. The solution is cooled to 0° C. and 1-methyl-4-piperidone (161 g, 1.42 moles) is added over a 0.5 hour period. The mixture is stirred for a further 2 hours at room temperature, cooled to 0° C. and water (500 ml) is added. The mixture is transferred to a separating funnel. Methylene chloride is added to redissolve the precipitate which formed and the aqueous layer is extracted with ether. The combined ether extracts are dried over Na2SO4, evaporated and crystallized from methylene chloride-pentane to give the title compound, mp 110°-112° C. (S. M. Elreain and J. C. Safranski, Jr., supra, reported bp 128°-130° C./0.9mm).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][S:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]([OH:6])=[O:5].O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([OH:23])(=[O:22])=[O:21].[CH2:25]([O:5][C:4](=[O:6])[CH:3]([NH2:2])[CH2:7][S:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)SCC(N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Product: CC(C)(C)SCC(N)C(=O)OCc1ccccc1
Yield: 78.9 %

Procedure:
A mixture of 14 (23.4 g, 109.5 mmol), p-toluenesulfonic acid monohydrate (62.5 g, 328.5 mmol), and benzyl alcohol (56.7 mL, 547.4 mmol) in CHC13 (320 mL) was refluxed for 4 h by using a Soxhlet apparatus containing dry silica gel. After cooling, CHC13 was evaporated and an equal volume of diethyl ether was added to the residue. The resulting ppt was collected by filtration, washed with ether, and air-dried to provide 15 as a white solid (38.0 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 8.58 (br s, 3H), 7.45 (m, 7H), 7.11 (d, 2H), 5.24 (AB, 2H), 4.38 (t, 1H), 3.00 (d, 2H), 2.29 (s, 3H), 1.26 (s, 9H).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:33][CH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]1.CC(O)=O>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:31][CH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33]1
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (30 mg, 0.066 mmol) and tert-butyl azetidine-3-carboxylate, AcOH (21.52 mg, 0.099 mmol) in DMSO (2 mL) was added TEA (0.028 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 30-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions were obtained with the correct mass were freeze-dried overnight to yield 10 mg of Preparation 1D. MS (m+1)=531. HPLC Peak RT=3.67 minutes (Analytical Method A). Purity=92%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:10][O:11][C:12]1[C:13]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[CH3:9])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1cc(Cl)ccc1Br
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc(Cl)cc1C
Yield: 89.2 %

Procedure:
Treatment of 2-bromo-5-chlorotoluene (5.0 g, 24.33 mmol) with 2-methoxybenzeneboronic acid (4.8 g, 31.63 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.478 g, 0.608 mmol), and potassium carbonate (8.41 g, 60.83 mmol) generally according to the procedure described for Intermediate 37 provided 5.05 g (89%) of 4′-chloro-2′-methyl-1,1′-biphenyl-2-yl methyl ether. Treatment of 4′-chloro-2′-methyl-1,1′-biphenyl-2-yl methyl ether (5.05 g, 21.48 mmol) with boron tribromide (5.37 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided 4.58 g (97%) of 4′-chloro-2′-methyl-1,1′-biphenyl-2-ol as a yellow oil. Anal. calcd. for C13H11ClO: C, 71.4; H, 5.07. Found: C, 71.03; H, 4.84.
Reaction SMILES: [C:1]1([C:7](=O)[C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:27]2)=[CH:22][CH:21]=1
Reactant: O=C(Cc1ccccc1)C(=O)c1ccccc1
Reactant: NNc1ccc(Br)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-n2nc(-c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
In a 500-ml four-necked flask were placed 25.2 g (0.11 mole) of 1,3-diphenylpropanedione, 25.3 g (0.11 mole) of p-bromophenylhydrazine hydrochloride, and 234.7 g of toluene. The mixture was stirred at room temperature and 6.0 g (0.11 mole) of sodium methoxide was added in drops at room temperature. After the addition, the mixture was heated under reflux with stirring for three hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and a solid was recovered by filtration. The filtrate was concentrated under reduced pressure to dryness. To the residue was added 350 ml of methanol and the mixture was heated with stirring for one hour. Thereafter, the mixture was cooled to room temperature and a solid was recovered by filtration. The solid was washed with methanol and dried under reduced pressure to give 28.4 g of 1-(p-bromophenyl)-3,5-diphenylpyrazole.
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])[CH2:34][CH2:33]1.O>CN(C)C=O>[ClH:28].[ClH:28].[CH3:45][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[N:35]1[CH2:34][CH2:33][N:32]([CH2:31][CH2:30][CH2:29][O:2][C:1]([C:4]2[C:13]3[O:12][C:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[C:10]([CH3:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][CH:5]=2)=[O:3])[CH2:37][CH2:36]1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCOC(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Product: Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4.24 g of 8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 6.3 g of anhydrous potassium carbonate in 60 ml of dimethylformamide was stirred at 80° C. for 30 minutes. 5.23 g of 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine was then added and stirring was continued at 80° C. for 3.5 hours. The reaction mixture was cooled to ambient temperature, poured on to iced water and extracted with ethyl acetate. The organic extracts were washed with aqueous sodium chloride solution, dried on anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residue was taken up in ethanol and excess ethanolic hydrogen chloride was added to the solution. Yield: 8.16 g of the title compound, m.p. 198°-203° C.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[S:37][C:36]([C:38](Cl)=[O:39])=[CH:35][CH:34]=1.[N:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH2:75][CH2:74][C:50]3([CH2:55][CH2:54][N:53]([C:56]([C:58]4[N:59]=[C:60]5[CH2:65][N:64](C(OC(C)(C)C)=O)[CH2:63][CH2:62][N:61]5[CH:73]=4)=[O:57])[CH2:52][CH2:51]3)[CH2:49][CH2:48]2)=[CH:43][CH:42]=1>C(Cl)Cl>[Cl:32][C:33]1[S:37][C:36]([C:38]([N:64]2[CH2:63][CH2:62][N:61]3[CH:73]=[C:58]([C:56]([N:53]4[CH2:52][CH2:51][C:50]5([CH2:74][CH2:75][N:47]([C:44]6[CH:43]=[CH:42][N:41]=[CH:46][CH:45]=6)[CH2:48][CH2:49]5)[CH2:55][CH2:54]4)=[O:57])[N:59]=[C:60]3[CH2:65]2)=[O:39])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCn2cc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)nc2C1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cn2c(n1)CN(C(=O)c1ccc(Cl)s1)CC2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Reaction time: 0.5 h
Yield: 11 %

Procedure:
EDCl (1.29 mmol, 1.5 equiv.), HOBt (1.29 mmol, 1.5 equiv.) and DIPEA (3.44 mmol, 4 equiv.) were added at 0° C. to a solution of 5-chlorothiophene-2-carbonyl chloride (0.86 mmol, 1.0 equiv.) in DCM (20 ml), and the mixture was stirred for 30 min. A solution of tert-butyl 2-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (0.86 mmol, 1.0 equiv.) in DCM (5 ml) was then added, the ice bath was removed, and stirring was carried out for 16 h at 25° C. The reaction mixture was diluted with dichloromethane (100 ml) and washed with sat. sodium carbonate solution (65 ml), sat. ammonium chloride solution (65 ml), water (50 ml) and sat. sodium chloride solution (50 ml), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (8% methanol in DCM) and the desired product was thus obtained in the form of a white solid. Yield: 11%. MS, Rt=2.7 min; m/z=525.2 [MH]+
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:24])[CH2:17][C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19].[NH2:25][C:26]([CH3:37])=[CH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:29].C(O)(=O)C>CC(O)C>[CH3:24][C:16]1[NH:25][C:26]([CH3:37])=[C:27]([C:28](=[O:29])[C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19]
Reactant: CCCOC(=O)CC(C)=O
Reactant: CC(N)=CC(=O)c1ccc(C)cc1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(C)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 76 mg (0.53 mmol) of n-propyl 3-oxobutanoate, 93 mg (0.24 mmol) of 3-amino-1-(4-methylphenyl)but-2-en-1-one and 3 μl (0.05 mmol) of acetic acid in 5 ml of 2-propanol and heated under reflux under argon for 30 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 173 mg (69% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([OH:20])=[CH:15][CH:16]=2)[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>CN(C)C=O>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH3:21])=[CH:15][CH:16]=2)[S:9]1(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(O)cc2S(=O)(=O)N1Cc1ccccc1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(Cc1ccccc1)C2=O
Temperature: 0 °C
Yield: 78 %

Procedure:
A mixture of 2-benzyl-6-hydroxysaccharin (0.86 g), 2-bromoethyl 2-methoxyethyl ether (d=1.347, 0.45 mL), potassium carbonate (1.24 g), methyl ethyl ketone (50 mL) and dimethylformamide (2 mL) was heated under reflux for five hours, then poured into ice-water (500 mL). The resulting solid was collected, washed with water and dried affording 2-benzyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin (0.92 g, 78% yield, mp 86°-88° C.).