Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:33]([S:30]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:8][CH2:9][CH2:10]3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)(=[O:32])=[O:31])[CH3:34]
Reactant: CCS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
0.98 g of 4-[5-(4-(ethanesulphonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is placed in 3 ml of a 4N solution of hydrochloric acid in dioxane. The reaction mixture is stirred at ambient temperature for 3 h. It is subsequently evaporated under reduced pressure and then a saturated aqueous sodium hydrogencarbonate solution is added. The aqueous phase is extracted three times with dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated under vacuum. 0.7 g of 1-[5-(4-(ethane-sulphonyl)piperazin-1-yl)pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11](=[NH:13])[NH2:12].[Na].[C:15](OCC)(=[O:22])[CH2:16][C:17](OCC)=[O:18]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11]1[N:12]=[C:17]([OH:18])[CH:16]=[C:15]([OH:22])[N:13]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)Cc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Oc1cc(O)nc(Cc2c(Cl)cccc2Cl)n1
Yield: 76.4 %

Procedure:
To the stirred solution of 2,6-dichlorobenzeneethanimidamide HCl (1:1), (0.0042 mol) in ethanol (20 ml), a solution of sodium (0.013 mol) in ethanol (10 ml) was added dropwise first and then propanedioic acid, diethyl ester (0.0109 mol) was added. The reaction mixture was stirred and refluxed for 4 hours and then stirred at room temperature overnight After adding another equivalent of propanedioic acid, diethyl ester (stirring and refluxing it overnight), the solvent was evaporated and the residue was dissolved in water and acidified with 1 N HCl. The solid was filtered off, washed with water and dried, yielding 0.87 g (76.4%) of 2-[(2,6-dichloro-phenyl)methyl]-4,6-pyrimidinediol (interm. 8).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[S:19])[NH:16][C:15]1=[S:20]>C(O)C>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:19][C:17]2[N:16]=[C:15]([S:20][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N:3]([CH3:12])[CH3:2])=[CH:5][CH:6]=3)[C:14]([CH3:21])([CH3:13])[N:18]=2)=[CH:6][CH:5]=1
Reactant: CC1(C)NC(=S)NC1=S
Reactant: CN(C)c1ccc(CCl)cc1
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc(CSC2=NC(C)(C)C(SCc3ccc(N(C)C)cc3)=N2)cc1

Procedure:
Initially, 3.2 g of 4-dimethylaminobenzylchloride hydrochloride was added to a solution of 1 g of 5,5-dimethyl-2,4-dithiohydantoin in 50 mL of ethanol (EtOH). The reaction mixture was treated following the procedure used in Example 62, and purified by column chromatography (CHCl3). Recrystallization form diethyl ether-n-hexane gave the desired compound in the form of a needle-like crystal. The yield of this compound was 1.9 g with a yield ratio of 71.2%, and the melting point was 91°-92° C.
Reaction SMILES: [CH2:1]([C@@:4]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:15][C:14]=1[Cl:30])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[C:35]([O:34][C:32]([NH:31][C@:4]([CH2:1][CH2:2][CH3:3])([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[CH:15][C:14]=1[Cl:30])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: C=CC[C@](CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@](CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)(NC(=O)OC(C)(C)C)C(=O)OCC
Yield: 73 %

Procedure:
To a solution of the compound of Example 13 (400 mg) in ethyl acetate (20 mL) was added palladium, on activated carbon/ethylene diamine complex (100 mg), and the resultant solution was stirred at room temperature for 24 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was evaporated. The resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain the target product (293 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH2:9].[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:9][N:10]=[CH:8]2
Reactant: O=N[O-]
Reactant: Cc1cccc(Cl)c1N
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1cccc2cn[nH]c12
Temperature: 7.5 °C
Yield: 40.8 %

Procedure:
A solution of 2-chloro-6-methyl-phenylamine (500 mg, 3.53 mmol) in H2SO4 (1.37 mL) was diluted by adding over 15 min. 2 mL of water in order to maintain a temperature below 90° C. Then the reaction mixture was cooled to 5-10° C. and a solution of sodium nitrite (246 mg, 3.57 mmol) in water (1 mL) was added over 2 hours. The resulting diazonium solution was then added to a solution of sodium acetate (5.21 g, 63.6 mmol) in water (20 mL) at a temperature maintained between 65 to 75° C. The resulting precipitate was filtered and treated with a solution of NaOH (6.00 g) in water (100 mL) at 95-100° C. The aqueous phase was separated while hot from the small amount of black tarry by-products, cooled to 50-60° C. and acidified with HCl (37%, 12.5 mL). The reaction mixture was cooled down to room temperature, the resulting precipitate was filtered, was washed thrice with cold water and was dried under vacuum to yield 7-chloro-1H-indazole (220 mg, 1.44 mmol, 41%) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.44 mmol) and triethylamine (91 μL, 0.66 mmol) in methylene chloride (20 mL) was 4-(trifluoromethyl)benzoyl chloride (96 mg, 0.46 mmol) in methylene chloride (5 mL) added dropwise. After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent. Yield: 150 mg (81%) of the title compound as white crystals: mp 203-204° C.; [α]21D -20° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 417 (10, M+).
Reaction SMILES: C(N(CC[OH:13])C1C=CC=C(C)C=1)C.[S:14]([OH:18])([OH:17])(=[O:16])=[O:15].[NH2:19][C:20]1[CH:31]=[CH:30][C:23]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][OH:27])=[CH:22][C:21]=1[CH3:32].S(=O)(=O)(O)O>>[S:14]([OH:18])([OH:17])(=[O:16])=[O:15].[CH2:28]([N:24]([CH2:25][CH2:26][OH:27])[C:23]1[CH:30]=[CH:31][C:20]([N:19]=[O:13])=[C:21]([CH3:32])[CH:22]=1)[CH3:29]
Reactant: CCN(CCO)c1cccc(C)c1
Reactant: CCN(CCO)c1ccc(N)c(C)c1
Agent: O=S(=O)(O)O
Product: CCN(CCO)c1ccc(N=O)c(C)c1

Procedure:
A process for producing 4-amino-3-methyl-N-ethyl-N-(β-hydroxyethyl)aniline sulfate which comprises nitrosating N-ethyl-N-(β-hydroxyethyl)-m-toluidine with an alkyl nitrite in an aqueous alcohol solution containing 30-90% by volume of the alcohol and about 0.5 to about 1 mole of sulfuric acid per mole of the N-ethyl-N-(β-hydroxyethyl)-m-toluidine to form N-ethyl-N-(β-hydroxyethyl)-3-methyl-4-nitrosoaniline sulfate, and catalytically hydrogenating the N-ethyl-N-(β-hydroxyethyl)-3-methyl-4-nitrosoaniline sulfate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:22]([NH:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:58][C@H:56]([OH:57])[CH2:55][O:54][C:51]3[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=3)=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCN)cc2)CC1
Product: CCCCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 17.6 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfonyl}-N-octyl-1-piperidinecarboxamide (1.53 g, 3.612 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (1.39 g, 3.431 mmol) according to Procedure G to give the title compound (eluant: 20: chloroform-ethanol) (0.500 g, 0.604 mmol).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.P(CCCC)(CCCC)CCCC.O[C:37]1[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:39]([CH3:50])[CH:38]=1>C1COCC1>[CH3:50][C:39]1[CH:38]=[C:37]([O:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:22])[F:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:49]=[CH:48][C:40]=1[O:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: CCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a solution of 1-[4′-(trifluoromethyl)-4-biphenylyl]-1-pentanol (250 mg, 0.81 mmol) in dry THF (20 mL) under nitrogen at 0° C. (ice/water bath) was added nBu3P (0.41 mL, 1.64 mmol), followed by ethyl (4-hydroxy-2-methylphenoxy)acetate (170 mg, 0.81 mmol) and ADDM (420 mg, 1.64 mmol) portion-wise. After stirring the mixture for 18 hours at rt under nitrogen the solvent was removed under vacuum. The residue was partitioned between water and EtOAc and the aqueous re-extracted with EtOAc (3×30 mL). The organic combined extract was dried (MgSO4) and then reduced under vacuum. Purification by flash chromatography (silica), eluting with cyclohexane:EtOAc (9:1) afforded the title compound as a colourless gum (310 mg).
Reaction SMILES: [N+:1](=[CH:3][CH3:4])=[N-:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>CCOCC>[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[C:3](=[N+:1]=[N-:2])[CH3:4])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1cccc(Oc2ccccn2)c1
Reactant: CC=[N+]=[N-]
Solvent: CCOCC
Product: CC(=[N+]=[N-])C(=O)c1cccc(Oc2ccccn2)c1

Procedure:
To a solution of diazoethane (2.5 mol equivalent) in ether (150 ml), a solution of 3-(2-pyridyloxy)benzoyl chloride in anhydrous ether (90 ml) is added dropwise at -20°C for 40 minutes. The resultant mixture is stirred at -20°C for 20 minutes. The diazoethane is evaporated at -20°C under reduced pressure, and the ether is evaporated at -10°C to 0°C under reduced pressure. The residue is chromatographed on a column of silica gel, which is eluted with 20% ether/benzene and 30% ether/benzene to give 3-(2-pyridyloxy)-1-(2-diazopropionyl)benzene (2.87 g) as an oily substance. IR (CCl4): 2060, 1630 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:54]=[CH:53][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][CH:44]3[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][F:52])[CH2:46][CH2:45]3)=[N:26]2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH:41][C:15]([C:12]5[C:13](=[O:14])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]=[CH:10][CH:11]=5)=[O:17])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][CH:44]3[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][F:52])[CH2:48][CH2:49]3)=[N:26]2)=[CH:53][CH:54]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(NC3CCN(CCF)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: COc1ccc(Cn2nc(NC3CCN(CCF)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Yield: 80 %

Procedure:
Prepared from 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (177 mg, 0.755 mmol, prepared according to the procedure for Example 19, Step C) and 1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (128 mg, 0.252 mmol) according to the procedure for Example 138, Step D. The product was obtained as a waxy solid (145 mg, 80%). LRMS (APCI+): 100% purity, 220 nm, m/z 725 (M+1) detected.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:31][N:30]=1.C([O-])(=O)C.[K+].O>O1CCOCC1.C(=O)(O)[O-].[Na+]>[F:28][C:29]1[C:34]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:33][C:32]([CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:31][N:30]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: OB(O)c1cc(CN2CCOCC2)cnc1F
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4)cnc3F)n2)cc1
Reaction time: 0.5 h
Yield: 23 %

Procedure:
A mixture of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (8.82 g, 22.91 mmol), 2-fluoro-5-(morpholinomethyl)pyridin-3-ylboronic acid (5.000 g, 20.83 mmol), potassium acetate (6.28 g, 63.9 mmol), and Am-Phos (1.036 g, 1.666 mmol) in dioxane (40 mL) and water (3.00 mL, 167 mmol) was heated in a CEM Voyager Microwave (Large-Scale Unit) for 25 min at 120° C. while 100 Watts of energy was supplied via Powermax (Simultaneous heating while cooling technology). The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with CHCl3 (3×100 mL). The organic extracts were combined and dried over Na2SO4. The solution was filtered and concentrated to give crude product as a yellow oil. This was purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (330 gram) using a gradient of 0-100% ethyl acetate/hexanes over 40 min, followed by a gradient of 1-20% methanol/dichloromethane over 30 min to give a tan oil. This was triturated with DCM and diethyl ether and the mixture was filtered. The filtrate was concentrated to give 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.615 g, 4.80 mmol, 23% yield) as a light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=1.56 Hz, 1H); 7.79 (td, J=7.97, 2.05 Hz, 1H); 7.22 (dd, J=8.61, 7.04 Hz, 4H); 6.81-6.92 (m, 4H); 4.82 (d, J=3.33 Hz, 2H); 3.76-3.86 (m, 4H); 3.70 (ddd, J=9.54, 4.99, 4.84 Hz, 4H); 3.45-3.57 (m, 6H); 2.55 (s, 3H); 2.46 (dq, J=12.79, 4.41 Hz, 4H). m/z (ESI, +ve ion) 545.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1)[CH3:2].S(OC)(O[CH3:18])(=O)=O>[OH-].[Na+]>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[N:5]=[C:6]([O:11][CH3:18])[CH:7]=[C:8]([OH:10])[N:9]=1)[CH3:13]
Reactant: CCN(CC)c1nc(O)cc(O)n1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1nc(O)cc(OC)n1

Procedure:
500 cc of sodium hydroxide solution 1N are added while stirring to 91.5 g (0.5 mol) of 2-diethylamino-4,6-dihydroxy-pyrimidine. The solution is stirred at 50° for a short period and then cooled to 20°. 63 g (0.5 mol) of dimethyl sulphate are added dropwise, over the course of 1 hour, to the clear solution; by further addition of sodium hydroxide solution 1N the pH value is kept between 7.5 and 8. A total of approximately 100 cc of sodium hydroxide solution 1N is further used. The mixture is stirred for a further 5 hours at room temperature and filtered off at 5° from the precipitated crystals; then it is washed with water. The crystalline product is subsequently decomposed with 1500 cc of carbon tetrachloride by means of a vibration mixer. The undissolved parts are suction filtered and the carbon tetrachloride solution is then concentrated by evaporation, whereupon crystallization commences; 200 cc of petroleum ether are then added. The mixture is suction filtered, washed with petroleum ether and dried at 80° in a high vacuum. Optionally it may be recrystallized from benzene. M.P.: 165°-166°.
Reaction SMILES: C(Cl)(=O)OCC.[OH:7][C:8]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28].Cl>C(Cl)Cl.C(N(CC)CC)C>[OH:7][C:8]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([O:20][CH3:21])[CH:14]=[CH:13][C:9]=1[C:10]([NH:28][CH2:27][C:23]1[S:22][CH:26]=[CH:25][CH:24]=1)=[O:12]
Reactant: NCc1cccs1
Reactant: CCCc1c(OC)ccc(C(=O)O)c1O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OC)ccc(C(=O)NCc2cccs2)c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under argon atmosphere, a solution of ethyl chlorocarbonate (7.65 ml) in methylene chloride (90 ml) was cooled to -15° C., and to the solution was added dropwise a solution of 2-hydroxy-3-n-propyl-4-methoxybenzoic acid (8 g) and triethylamine (11.1 ml) in methylene chloride (160 ml) for 30 minutes, and the mixture was agitated for another 15 minutes. 2-thiophenemethylamine (4.7 ml) was added to the mixture and the mixture was agitated for 3 hours while the temperature of the mixture was elevated to 0° C. The reaction mixture was poured into 1N aqueous hydrochloric acid, and extracted with methylene chloride. The organic layer was washed with a mixed solution of saturated aqueous solution of sodium chloride and saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated in evacuated atomosphere. The residue was dissolve in methanol (100 ml), and the solution was cooled to 0° C. The solution was added to 8.5% aqueous solution of sodium hydroxide (50 ml) and the mixture was agitated at room temperature for 4.5 hours. The reaction mixture was acidified by adding 6N aqueous hydrochloric acid thereto, and extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in evacuated atomosphere. The residue was subjected to column chromatography using silica gel, and there was obtained N-(2-hydroxy-3-n-propyl-4-methoxybenzoyl)-2-thiophenemethylamine (5.7 g) from fractions eluted with n-hexane-methylene chloride (2:1).
Reaction SMILES: Br.Br.[N:3]1([CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[OH:19])[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Br.Br.N1(CC2C3C(=CC(O)=CC=3)CCN2)CCCC1.[Cl:39][C:40]1[CH:41]=[C:42]([CH2:47][C:48](O)=[O:49])[CH:43]=[CH:44][C:45]=1[Cl:46].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[N:3]1([CH2:8][C:9]2([C:48](=[O:49])[CH2:47][C:42]3[CH:43]=[CH:44][C:45]([Cl:46])=[C:40]([Cl:39])[CH:41]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[OH:19])[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: Oc1cccc2c1C(CN1CCCC1)NCC2
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1ccc2c(c1)CCNC2CN1CCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCC2)NCCc2cccc(O)c21

Procedure:
Prepared as Ex. No. 5, from 13.2 g (33.50 mmoles) of a mixture containing 1-(pyrrolidin-1-yl)methyl-8-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide and 1-(pyrrolidin-1-yl)methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 9.6 g (46.8 mmoles) of 3,4-dichlorophenylacetic acid, 14 ml (99.6 mmoles) of triethylamine and 17 g (82.52 mmoles) of dicyclohexylcarbodiimide, in 280 ml of dry chloroform.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[NH:12][CH:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.CN[C@H]1[C@H](NC)CCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13](=[O:14])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c[nH]c(=O)c(-c2ccc(F)cc2)c1
Reactant: Brc1ccccn1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(=O)n(-c2ccccn2)c1
Temperature: 120 °C
Yield: 93.5 %

Procedure:
To a solution of methyl 5-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (77.0 mg, 0.31 mmol) in dioxane (2.1 mL) were added 2-bromopyridine (0.15 g, 0.92 mmol), trans-(1R,2R)—N,N′-bismethyl-1,2-cyclohexanediamine (17.7 mg, 0.13 mmol) and potassium carbonate (86.0 mg, 0.62 mmol). The mixture was heated in the microwave reactor at 120° C. for 1 h then heated in an oil bath at 80° C. for 8 h. The mixture was cooled to ambient temperature and dichloromethane was added. The mixture was washed with water, sat. NaHCO3, brine and dried with sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→75% dichloromethane/ethyl acetate) gave the title compound (94 mg). MS 325.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:16]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][C:14]([OH:21])=[O:15])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:18])[CH3:17]
Reactant: CC(C)=O
Reactant: CCCc1c(OCCCO)ccc(C(C)=O)c1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCc1c(OCCC(=O)O)ccc(C(C)=O)c1O
Reaction time: 0.25 h
Yield: 57 %

Procedure:
A solution of 2.00 g of 1-[2-hydroxy-4-(3-hydroxy-propoxy)-3-propylphenyl]ethanone in 30 ml of acetone was added dropwise over 45 minutes to a stirred, ice cooled solution of 4.0 ml of Jones reagent in 10 ml of acetone. After 15 additional minutes, the cooling bath was removed and the reaction mixture was stirred at 23° for 15 minutes. Jones reagent (0.5 ml) was added and stirring was continued for 15 minutes. The reaction mixture was concentrated in vacuo and the residue was treated with water and extracted with ether. The ether extract was washed with three portions of 1N sodium hydroxide and the aqueous layers were combined and acidified. The product was extracted with ether and the dried (over magnesium sulfate) extract was concentrated in vacuo to a solid (1.48 g). Recrystallization from ether-hexane gave 1.21 g, mp 142°-146°, (57% yield) of 3-(4-acetyl-3hydroxy-2-propylphenoxy)propanoic acid, the titled compound.