Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[OH-].[Na+].[C:12]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]=[C:22](SC)[S:23][CH3:24])(=[O:20])=[O:19].O>CN(C)C=O>[C:12]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:22](=[N:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[S:23][CH3:24])(=[O:19])=[O:20]
Reactant: Cc1cc(C)nc(N)n1
Reactant: CSC(=NS(=O)(=O)c1ccccc1-c1ccccc1)SC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CSC(=Nc1nc(C)cc(C)n1)NS(=O)(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
12.3 g of 2-amino-4,6-dimethylpyrimidine was suspended in 300 ml of dimethylformamide, and 4 g of sodium hydroxide (oily 60%) was added. The mixture was stirred at room temperature for 1 hour. Furthermore, 33.7 g of dimethyl N-(2-biphenylylsulfonyl)carbonimidodithioate was added, and the mixture was stirred at room temperature for a day and night. The reaction mixture was poured into 2 liters of water, and filtered. When the filtrate was made weakly acidic, white crystals precipitated. The crystals were collected by filtration, and recrystallized from ethanol to give 29.2 g of the desired 1-(2-biphenylylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)2-methylisothiourea of the following formula, mp. 154°-157° C.: ##STR18##
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1.Cl[C:27]1N=C2C(N=CN2CC)=C(N2CCOC[C@@H]2C)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]2[CH2:11][CH3:27])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CCOCC1)n2C
Reactant: CCn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Product: CCn1c(C2(O)CCOCC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
This compound (g-1) was prepared in an analogous fashion to (S)-4-(2-chloro-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol, using (S)-4-(2-chloro-9-ethyl-9H-purin-6-yl)-3-methylmorpholine as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 5.65 to 4.75 (broad d, 2H), 4.46 (q, 2H), 4.05 to 3.85 (m, 5H), 3.83 to 3.73 (m, 2H), 3.62 (dt, J=11.6 Hz, 2.6 Hz, 1H), 3.55 to 3.39 (broad s, 1H), 2.59 (s, 1H), 2.46 to 2.34 (m, 2H), 1.87 (d, J=12.8 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H); LC-MS m/z (method B2)=382/384 [M+H]+, RT=1.79 min.
Reaction SMILES: COC(=O)CC[S:6][C:7]1[CH:8]=[C:9]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:15]=2)=[N:11][CH:12]=1.Cl[C:41]1[CH:46]=[CH:45][N:44]=[C:43]2[CH:47]=[CH:48][S:49][C:42]=12.CC([O-])(C)C.[K+].[NH4+].[Cl-]>CS(C)=O>[O:32]([C:9]1[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)[N:15]=2)=[N:11][CH:12]=[C:7]([S:6][C:41]2[CH:46]=[CH:45][N:44]=[C:43]3[CH:47]=[CH:48][S:49][C:42]=23)[CH:8]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ns2)c(Oc2ccccc2)c1
Reactant: Clc1ccnc2ccsc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
A 250 mL flask was charged with tert-butyl 4-(5-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (10 g, 17 mmol), 7-chlorothieno[3,2-b]pyridine (3.6 g, 21 mmol), and DMSO (125 mL). Nitrogen was bubbled vigorously through the solution for 10 minutes. Potassium 2-methylpropan-2-olate (5.9 g, 52 mmol) was added and the reaction was stirred at ambient temperature under nitrogen for 5 hours. The reaction was poured into saturated aqueous NH4Cl and extracted with EtOAc (1×500 mL). The organic layer was washed with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica (50 to 75% EtOAc in hexanes) to afford tert-butyl 4-(5-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (10 g, 92% yield) as a white foam.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:5][C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC(O)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of diethyl 3-hydroxycyclobutane-1,1-dicarboxylate (159) (649 mg, 3 mmol) in DCM (7 mL) was added PCC (1.37 g, 6.3 mmol) and the mixture was stirred for 4 hours at room temperature. The product was filtered through a silica gel plug and the residue was purified using column chromatography with hexanes/ethyl acetate as eluent to yield diethyl 3-oxocyclobutane-1,1-dicarboxylate (160). 1H NMR (400 MHz, CD2Cl2) δ 4.28 (q, J=7.2 Hz, 4H), 3.63 (s, 4H), 1.31 (t, J=7.2 Hz, 6H). MS m/z 215.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:13]1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].O>O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26]2=[O:27])[CH2:16][CH2:17]1
Reactant: Cc1cccc2c1CCC[C@H]2N1CCC(Nc2ccccc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c1CCC[C@H]2N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 60.9 %

Procedure:
(R)-N-[1-(5-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (1.83 g) was dissolved in tetrahydrofuran (100 ml), 1,1′-carbonyldiimidazole (973 mg) was added, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) and crystallized with hexane/ethyl acetate to give the title compound (1.2 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.Cl[CH2:31][CH2:32][C:33]1[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:31][CH2:32][C:33]4[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=4)[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: CC(C)c1noc(CCCl)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCc5nc(C(C)C)no5)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (14 mg, 0.033 mmol), 5-(2-chloroethyl)-3-isopropyl-1,2,4-oxadiazole (9 mg, 0.053 mmol) and DIEA (29 uL, 0.17 mmol) in NMP (1 mL) was stirred at 50° C. for 3 days. The crude reaction mixture was purified by RP-HPLC to give 5-Chloro-N2-(4-(1-(2-(3-isopropyl-1,2,4-oxadiazol-5-yl)ethyl)piperidin-4-yl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; ESMS m/z 550.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=O)[C:4]([O:6]CC)=O.[C:12]1([C@H:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:11][C:2]([CH3:1])([CH3:10])[C:3](=[N:20][C@@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])[C:4]([NH:20][C@@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])=[O:6]
Reactant: CCOC(=O)C(=O)C(C)(C)C
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@@H](N=C(C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)c1ccccc1
Yield: 46.7 %

Procedure:
The procedure described under h) was carried out using 15 g of ethyl trimethyl-pyruvate and 50 g of (R)-1-phenylethylamine. There were isolated 14.9 g of (47%) of (R)-3,3-dimethyl-N-[(R)-1-phenylethyl]-2-(1-phenylethylimino)-butyramide of melting point 95°-96° C. [α]=+59.6 (c=1.0, CHCl3).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[C:26]([O:32][CH3:33])=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=1>>[Br:31][C:29]1[CH:30]=[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)[C:26]([O:32][CH3:33])=[N:27][CH:28]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ncc(Br)cc1Br
Product: COc1ncc(Br)cc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 63 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3,5-dibromo-2-methoxypyridine (literature preparation: J. M. Barger, J. K. Dulworth, M. T. Kenny, R. Massao, J. K. Daniel, T. Wilson, R. T. Sargent J. Med. Chem. 1986, 29, 1590), the title compound was formed in 63% yield as an off-white solid, mp 250°-251° C. (dec). free base: 1H NMR (CDCl3, 300 MHz) 8.08 (d, J=2.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.21 (m, 4H), 6.90 (m, 4H), 4.26 (s, 1H), 3.97 (s, 3 H), 3.56 (s, 1H), 3.47 (s, 2H), 2.86 (m, 2H), 2.77 (dt, J=2.6, 11.4 Hz, 2H), 2.60 (d, J=1.4 Hz, 2H), 1.96 (m, 4H) MS (CI, CH4) m/z 491 (M+1,100), 483 (89), 492 (37), 494 (26), 521 (M+29, 13), 473 (28) hydrochloride salt:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][C:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:14]5[CH:13]=[CH:12][C:11]4=[C:10]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Br:38]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:38][C:17]1[C:18]2[C:23]3=[C:22]4[C:21](=[CH:20][CH:19]=2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:9][C:10]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[C:11]4[CH:12]=[CH:13][C:14]3=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH:16]=1
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)cc(-c5ccc(C)cc5)c5ccc2c3c45)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Br)c3ccc4c(-c5ccc(C)cc5)cc(-c5ccc(C)cc5)c5ccc2c3c45)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A mixed solution of 1.5 g of the above-mentioned 1,3,6-tri(4-methylphenyl)pyrene, 0.68 g of N-bromosuccinimide and 30 ml of dimethylformamide was stirred under nitrogen gas stream at a temperature of 60° C. for 6 hours. After cooling the mixed solution to room temperature, 50 ml of water was injected thereinto to extract therefrom with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography and thereafter vacuum dried under a temperature of 70° C. to obtain 1.5 g of 1-bromo-3,6,8-tri(4-methylphenyl)pyrene as pale-yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[C:8]([CH:11]=1)[CH2:9]O)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[C:8]([CH:11]=1)[CH2:9][Br:37])([O-:3])=[O:2]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc(-n2cccc2)c(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(CBr)c1
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution in dichloromethane (10 ml) of the compound (239 mg) obtained in Example 1b, triphenyl phosphine (345 mg) and carbon tetrabromide (436 mg) were sequentially added dropwise under cooling with ice. The reaction mixture was stirred for 2 hours under cooling with ice and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:9) to give the titled compound (yield,47%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C:10](=[O:11])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.[F:18][C:19]1([F:23])[CH2:22][NH:21][CH2:20]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:2]([O:5][C:6]([N:8]1[CH2:9][C:10](=[O:11])[CH2:12][C@H:13]1[C:14]([N:21]1[CH2:22][C:19]([F:23])([F:18])[CH2:20]1)=[O:16])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: FC1(F)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
N-tert-BOC-4-oxo-L-proline (458 mg, 2 mmol), 3,3-difluoroazetidine hydrochloride (258 mg, 2 mmol) (prepared as described in WO 2000/47582), and DIPEA (0.35 mL, 2 mmol) were mixed in anhydrous methylene chloride (10 mL) and cooled to 0° C. HOBT (405 mg, 3 mmol) was then added in one portion followed by EDC hydrochloride (422 mg, 2.2 mmol). The resulting mixture was allowed to warm to RT and stirred overnight. Saturated sodium bicarbonate was added, the organic layer was separated, and the aqueous phase extracted with methylene chloride. The combined organic extracts were washed twice with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product (570 mg) was triturated with hexanes:methylene chloride (10:1), filtered, and dried in a vacuum oven to afford 510 mg (84% yield) of the title product as a light orange powder. MS (m/z): 305.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([Cl:19])[C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)CCc1ccc(O)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Product: CC(=O)C(Cl)Cc1ccc(O)c([N+](=O)[O-])c1

Procedure:
To a solution of 4-(4-hydroxy-3-nitrophenyl)-2-butanone (17.5 g) in chloroform (150 ml) was dropwise added a sulfuryl chloride (11.2 g) at 20° to 27° C. under stirring and the mixture was stirred at ambient temperature for 7 hours. The reaction mixture was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oily residue of 4-(4-hydroxy-3-nitrophenyl)-3-chloro-2-butanone. To this oily residue was added a mixture of 2-amino-4-methylpyridine (22.6 g) in acetonitrile (150 ml) and the resultant mixture was refluxed for 8 hours under stirring. The precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and 5% hydrochloric acid and separated aqueous layer was adjusted to pH 7.5 with aqueous 20% potassium carbonate. The resultant mixture was extracted with chloroform and the extract was washed with brine and dried over magnesium sulfate. The solvent was concentrated in vacuo and the crystalline residue was collected by filtration to give 3-(4-hydroxy-3-nitrobenzyl)-2,7-dimethylimidazo[1,2-a]pyridine (2.2 g).
Reaction SMILES: S1C=CC=[C:2]1S(O)(=O)=O.[C:10]([OH:27])(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CO>[CH3:2][O:26][C:10](=[O:27])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: O=S(=O)(O)c1cccs1
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)OC

Procedure:
The thienylsulfonic acid-functionalized SBA-15 (15ThioSO3H-SBA-15-p) was used as the solid acid catalyst in the liquid phase esterification of palmitic acid (PA) with methanol (MeOH) to form methylpalmitate. The reaction was carried out at the reflux temperature of MeOH.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:15]=2[C:16]([F:19])([F:18])[F:17])[NH:12][C:11](=[O:20])[C:10](=[O:21])[NH:9]3)[CH:5]=[CH:4][CH:3]=[CH:2]1.Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl.C(OCC)(=O)C>[CH3:27][O:26][C:24]([CH2:23][N:9]1[C:8]2[C:13](=[CH:14][C:15]([C:16]([F:17])([F:18])[F:19])=[C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[CH:7]=2)[NH:12][C:11](=[O:20])[C:10]1=[O:21])=[O:25]
Reactant: COC(=O)CBr
Reactant: O=c1[nH]c2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc21
Yield: 39.7 %

Procedure:
35 g (118.6 mmol) of 6-(1-pyrrolyl)-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione (Example 2) were reacted with 23.8 g (155.5 mmol) of methyl bromoacetate as in Example 23. The mobile phase used for the chromatography was methylene chloride/ethyl acetate=3/2. 17.3 g (40%) of the product were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1>C(Cl)Cl.O=[Mn]=O>[CH3:19][C:16]1[S:17][CH:18]=[C:14]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=3)[O:10][C:9](=[O:13])[CH:8]=2)[N:15]=1
Reactant: Cc1nc(-c2cc(=O)oc3cc(CO)ccc23)cs1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nc(-c2cc(=O)oc3cc(C=O)ccc23)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7-(hydroxymethyl)-4-(2-methyl-1,3-thiazol-4-yl)-2H-chromen-2-one (0.387 g, 1.42 mmol) in CH2Cl2 (7 ml) was added MnO2 (1.85 g, 21.2 mmol) and stirred at rt for 4 h. A second portion of MnO2 (1.85 g, 21.2 mmol) was added and 3 h later the reaction mixture was filtered on celite, evaporated to dryness and purified by trituration in CH2Cl2-MeOH (9:1) to give the title compound. 1H NMR (400 MHz, acetone-d6): δ 10.12 (s, 1H), 8.45 (m, 1H), 8.31 (s, 1H), 7.95 (s, 1H), 7.85 (m, 1H), 6.9 (s, 1H), 2.80 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)(Cl)=O.[NH2:16][C:17]1[N:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)[C:20]([C:35]#[N:36])=[CH:19][N:18]=1.N1C=CC=CC=1>ClCCl>[C:35]([C:20]1[C:21]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)=[N:22][C:17]([NH:16][C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])=[N:18][CH:19]=1)#[N:36]
Reactant: COc1cc(-c2nc(N)ncc2C#N)cc(OC)c1OC
Reactant: O=C(O)Cc1ccccc1I
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nc(NC(=O)Cc3ccccc3I)ncc2C#N)cc(OC)c1OC

Procedure:
From 2-iodophenylacetic acid, thionyl chloride and N,N-in dichloromethane. Then treatment with 2-amino-5-cyano-4-(3,4,5-trimethoxyphenyl)pyrimidine and pyridine in dichloromethane. ES-MS m/e (%): 553 (M+Na+, 15), 531 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].C([O:19][C:20](=O)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:20](=[O:19])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(=O)N(C)C
Reactant: Fc1ccc(Br)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C(=O)C(=O)c1cc(Br)cnc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
5-Bromo-2-fluoro-pyridine (1 g, 5.68 mmol) in THF (1 mL) was added dropwise to a freshly prepared solution of lithium N,N-diisopropylamide (6.81 mmol) in THF at −78° C. The mixture was stirred 2 h at −78° C. The orange suspension was quickly added via cannula to a cold (−78° C.) solution of N,N-dimethyl-oxalamic acid ethyl ester (925.6 uL 6.81 mmol). After 1.5 h at −78° C., the reaction was quenched by addition of saturated NH4Cl solution and was allowed to warm to room temperature. The mixture was extracted with diethyl ether and the product was purified by silica gel chromatography using hexanes and ethyl acetate (0-100% gradient) to afford 2-(5-bromo-2-fluoro-pyridin-3-yl)-N,N-dimethyl-2-oxo-acetamide (1.01 g, 65.1%). 1H NMR (500 MHz, DMSO-d6) δ 3.0 (d, 6H), 8.6 (dd, 1H), 8.78 (dd, 1H) MS: m/z 275 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[C:10]3[C:11]([O:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:12]2[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[OH-].[K+].[I:27]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:24])[C:10]3[C:11]([O:19][C:20]=2[CH:21]([CH3:22])[CH3:23])=[C:12]2[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]2[I:27])=[CH:6][CH:7]=1
Reactant: CC(C)c1oc2c(ccc3[nH]ncc32)c(=O)c1-c1ccc(Cl)cc1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1oc2c(ccc3[nH]nc(I)c32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-(4-chlorophenyl)-2-isopropyl-7H-pyrano[2,3-e]indazol-4-one (20 mg, 0.059 mmol) in dry N,N-dimethylformamide (2 ml) at room temperature are added potassium hydroxide (6.3 mg, 0.112 mmol) and iodine (55 mg, in three portions over 3 h, 0.217 mmol). The reaction mixture is stirred at room temperature for 20 h, then diluted with ethyl acetate and washed successively with 10% aqueous sodium thiosulfate solution (40 ml) and saturated brine (40 ml). The organic phase is dried (MgSO4), filtered and evaporated under reduced pressure. The resulting solid is triturated with n-hexane/dichloromethane to give a colourless solid that is recovered by filtration and dried.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: Nc1ccccc1
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Product: N#Cc1ccc(N(CC(=O)Nc2ccccc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine and aniline: MS (APCI) m/z 374 (M+1).