Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:18])([CH2:12][O:13][C:14](=[O:17])[CH2:15][CH3:16])[CH2:10][OH:11].[CH3:19][S:20](Cl)(=[O:22])=[O:21].N1C=CC=CC=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:18])([CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:12][O:13][C:14](=[O:17])[CH2:15][CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
Into a solution wherein 0.5 g (R)-2-(2,4-difluorophenyl)-3-propionyloxy-1,2-propanediol obtained in Example 37 was dissolved in 5 ml of ethyl acetate was added dropwise 0.66 g of methanesulfonyl chloride at a temperature of 0° to 5° C., and thereto was added dropwise 0.46 g of pyridine at a temperature of 0° to 5° C. After dropping, the resulting liquid was stirred at room temperature for 16 hours. To the reaction mixture was added 20 ml of 1N hydrochloric acid and an organic layer separated. The organic layer was washed with saturated aqueous solution with sodium hydrogencarbonate and with saturated aqueous solution with sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 0.53 g of oily (S)-2-(2,4-difluorophenyl)-1-propionyloxy-3-methanesulfonyloxy-2-propanol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 24.3 minutes ((R)-form) and 26.9 minutes ((S)-form)).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.Cl[C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([O:22][C:25]5[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: Cc1ccc(Cl)nn1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(O)cc43)sc2C(=O)N1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)nn1
Yield: 83.4 %

Procedure:
A stirred solution of Example 57 (0.05 g, 0.15 mmol) and 3-chloro-6-methylpyridazine (0.019 g, 0.15 mmol) in DIPEA (0.1 mL, 0.3 mmol) was heated to 180° C. under microwave irradiation in a sealed tube for 4 h, then concentrated in vacuo. Purification by preparative HPLC (Method 7) gave the title compound (0.053 g, 19%) as an off-white solid. δH (CDCl3) 7.98 (1H, d, J 2.4 Hz), 7.34 (1H, d, J 9.0 Hz), 7.08 (1H, d, J 9.0 Hz), 7.00-6.80 (2H, m), 5.45 (1H, s), 4.40-4.30 (2H, m), 4.20-4.10 (2H, m), 2.86 (2H, s), 2.64 (3H, s), 1.38 (6H, s). LCMS (ES+) 424.0 (M+H)+, RT 2.92 minutes (Method 2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Yield: 565.7 %

Procedure:
Beginning with 0.10 gm (0.39 mMol) 5-amino-3-(1-propylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.055 mL (0.046 mMol) 4-fluorobenzoyl chloride, 0.099 gm (67%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+]>>[C:15]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)=[CH:21][CH:22]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Clc1cncc(OCc2ccc(-c3ccccc3)cc2)n1
Yield: 61.8 %

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol),p-phenylbenzyl alcohol (607 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). Recrystallization from hexane gave 0.55 g (88%) of the title compound: mp 86-87° C. MS m/z: 297 (M+H)+. Anal. (C17H13ClN2O) C, H, N.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:8]([CH3:22])=[CH:9][C:10]2[O:15][C:14]([C:16]([NH2:18])=O)=[CH:13][C:12](=[O:19])[C:11]=2[C:20]=1[CH3:21]>CN(C)C=O>[Cl:6][C:7]1[C:8]([CH3:22])=[CH:9][C:10]2[O:15][C:14]([C:16]#[N:18])=[CH:13][C:12](=[O:19])[C:11]=2[C:20]=1[CH3:21]
Reactant: Cc1cc2oc(C(N)=O)cc(=O)c2c(C)c1Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2oc(C#N)cc(=O)c2c(C)c1Cl
Temperature: 0 °C

Procedure:
To 400 parts of N,N-dimethylformamide was slowly added 21 parts of phosphorus oxychloride with stirring and ice cooling. Then in small quantities 33.9 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxamide was added to the solution. After the addition was completed the reaction mixture was stirred at room temperature for 18 hours. The dark solution which resulted was poured into 1500 parts of ice/water. The precipitated solid was filtered off and crystallised from ethanol to give 30.5 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carbonitrile, melting point 142°-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:27]C(=O)C)=[C:17]([CH:26]=2)[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:27])=[C:17]([CH:26]=2)[C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 49.3 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]morpholine (0.045 g, 0.101 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.020 g, 0.0498 mmol, 49%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.O1CCNC1=O.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29]>O1CCCC1.Cl.C(OCC)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: C=CCCC(=O)Cl
Agent: Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Flush with nitrogen a 12 L 3-neck round bottom flask equipped with a mechanical stirrer, internal temperature probe/N2 inlet, and 1 L addition funnel for 20 min and then add (R)-4-benzyl-2-oxazolidinone (250 g, 1.41 mol). Dilute with tetrahydrofuran (THF) (1.8 L) and cool in a dry ice/acetone bath until the internal temperature is −74° C. Transfer a 1.6M hexanes solution of n-butyllithium (970 mL, 1.552 mol) to the addition funnel via cannula, and add to the oxazolidinone solution at a rate such that the internal temperature does not reach above −65° C. After the addition is complete, allow the reaction to stir in the cooling bath 30 min. Transfer 4-pentenoyl chloride (175 mL, 1.585 mol) to the addition funnel and add dropwise to the anion solution over a 25 min period. Stir the reaction for 45 min in the cooling bath. Remove the cooling bath and stir the reaction 18 hr as it slowly reaches room temperature. Dilute the mixture with 1N aqueous hydrochloric acid (1.5 L) and diethyl ether (1 L). Separate the layers and wash the organic phase with water (2×1 L) then brine (1 L). Extract the combined aqueous washes with ether (1 L). Dry the combined organic phases over anhydrous magnesium sulfate, filter, and concentrate to 390 g of a light tan oil. Purify this material by silica gel chromatography using hexanes:ethyl acetate to obtain 345 g (94.5%) of a clear, yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:20](=[O:22])[NH2:21])[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[CH:23]([O-])([O-])OCC.CN(C)C=O>C(OCC)(=O)C>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:20]([OH:22])=[N:21][CH:23]=[N:1][C:2]=23)=[CH:12][CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC([O-])[O-]
Reactant: NC(=O)n1ncc(-c2ccc(Cc3ccccc3)cc2)c1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1ncnc2c(-c3ccc(Cc4ccccc4)cc3)cnn12
Reaction time: 0.75 h

Procedure:
A mixture of 3-amino-4-(4-benzylphenyl)-2-carbamoylpyrazole (1.00 g), ethyl orthoformate (0.61 ml) and N, N-dimethylformamide (0.86 ml) was stirred at 100° C. to 110° C. for 45 minutes. To the reaction mixture was added ethyl acetate (20 ml). After stirring at room temperature for 30 minutes, the precipitate was separated by filtration, washed with ethyl acetate, and dried to give the title compound (0.72 g).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[NH:11][N:12]=[C:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH:14]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[OH-:27].[Na+]>C(O)C.O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:13]2[CH:14]=[C:10]([NH:9][C:7]([C:6]3[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:27])=[CH:26][CH:25]=3)=[O:8])[NH:11][N:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(C#N)cc3)[nH]n2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(C(N)=O)cc3)[nH]n2)c1
Temperature: 80 °C
Yield: 9.5 %

Procedure:
4-Cyano-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide (Example 23) (0.2 g, 0.58 mmol) and NaOH (69 mg, 1.73 mmol) were added to a solution of ethanol/water (20 ml, 3:1) and heated at 80° C. until complete consumption of starting material was observed. Care was required as the amide further hydrolysed to the carboxylic acid. The reaction was extracted with DCM (3×50 ml), dried and the solvent was removed in vacuo to yield a white solid. This was triturated with DCM to afford a white solid (20 mg, 10%); 1H NMR (400.132 MHz, DMSO) δ 2.90 (s, 4H), 3.75 (s, 3H), 6.42 (s, 1H), 6.82-6.75 (m, 3H), 7.20 (t, 1H), 7.46 (s, 1H), 7.95 (d, 2H), 8.16-8.03 (m, 3H), 10.82 (s, 1H), 12.18 (s, 1H); MH+366.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:33]1([N:30]2[CH2:29][CH2:28][CH:27]([S:24]([CH2:23][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)=[O:12])=[CH:21][CH:22]=4)[O:6][C:2]=3[CH3:1])(=[O:25])=[O:26])[CH2:32][CH2:31]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide (300 mg, 0.66 mmol, 1.00 equiv), cyclohexanone (98 mg, 1.00 mmol, 1.51 equiv) and acetic acid (120 mg, 2.00 mmol, 3.03 equiv) in 1,2-dichloroethane (10 mL) was stirred for 4 h at room temperature. To this was added sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified on a silica gel column with water/acetonitrile (95/5-20/80) to give 350 mg (99%) of 4-[4-[(1-cyclohexylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS (ES, m/z): 537 [M+H]+; 1HNMR (300 MHz, CD3OD, ppm) δ 8.60 (s, 1H), 8.47 (d, 1H), 8.11 (d, 2H), 8.00 (d, 2H), 7.89 (d, 1H), 7.47-7.43 (m, 1H), 4.65 (s, 2H), 4.40 (s, 2H), 3.14 (d, 3H), 2.50 (d, 3H), 2.41-2.33 (m, 3H), 2.25 (d, 2H), 1.92-1.83 (m, 6H), 1.67 (d, 1H), 1.29-1.09 (m, 5H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[CH2:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21]>>[CH2:23]([N:22]([CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)[CH2:20][CH3:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNCc1ccccc1
Reactant: ICCCC1c2ccccc2C=Cc2ccccc21
Product: CCN(CCCC1c2ccccc2C=Cc2ccccc21)Cc1ccccc1

Procedure:
5-(3-Iodopropyl)-5H-dibenzo[a,d]cycloheptene is added gradually to an excess of N-ethyl benzylamine in absolute alcohol with stirring and cooling. The reaction mixture then is heated to refluxing for 30 minutes and the alcohol distilled under reduced pressure. The residue is warmed with dilute acid and the acid-insoluble material separated. The aqueous layer then is rendered alkaline with sodium hydroxide and the liberated bases extracted into ether. The ether is evaporated and the product isolated by vacuum distillation.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:7][CH2:6]1.[CH2:25]([N:32]1[CH:37]=[C:36]([CH3:38])[C:35](=[O:39])[NH:34][C:33]1=[O:40])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[CH:37]=[C:36]([CH3:38])[C:35](=[O:39])[N:34]([CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:7][CH2:6]2)[C:33]1=[O:40])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cn(Cc2ccccc2)c(=O)[nH]c1=O
Reactant: CC(C)(CCl)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Product: Cc1cn(Cc2ccccc2)c(=O)n(CC(C)(C)CN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O

Procedure:
substituting 1-chloro-2,2-dimethyl-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propane and 1-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione gave 1-benzyl-3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}-2,2-dimethylpropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][NH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][NH:15][CH2:29][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCc1ccccc1
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CCNCCCOc2ccc3ccccc3c2)cc1
Temperature: 145 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 2-phenylethylamine (0.51 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 145° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-phenylethyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 270° C., (yield 0.65 gm, 93.7%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].B(Br)(Br)Br.CCOCC>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ccccc1Nc1ccccc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1ccccc1Nc1ccccc1O
Temperature: -78 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
A solution of 9.74 g (0.0359 mole) of ethyl 2-(2-methoxyphenylamino)benzoate in 50 ml of methylene dichloride was cooled to -78° C. and 114 ml of boron tribromide (1M in methylene dichloride) was added dropwise over a period of 20 minutes. The reaction mixture was stirred at -78° C. for three hours, then at -40° C. for one hour and finally kept in a refrigerator at -4° C. overnight. Ether (50 ml) was added and the mixture poured into ice-water and ether. The ether solution was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile to give 5.3 g of ethyl 2-(2-hydroxyphenylamino)benzoate, m.p. 105°-106° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][OH:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: NCCO
Product: OCCNc1nc(Cl)ncc1I
Yield: 83 %

Procedure:
In analogy to GP 2, reaction of 2,4-dichloro-5-iodopyrimidine (2.0 g, 7.3 mmol) with 2-amino-ethanol (480 mg, 7.9 mmol) provided the desired product in 83% yield (1.8 g) after chromatographic purification (silica gel, dichloromethane/methanol (0% to 20% methanol)).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[N:23]=[C:22]5[CH:24]=[CH:25][O:26][C:21]5=[CH:20][CH:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[N:23]=[C:22]5[CH:24]=[CH:25][O:26][C:21]5=[CH:20][CH:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:35][CH:36]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4occc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Cc1cc2cc(OCc3ccc4occc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of 540 mg(1.1 mmol) of the ester from Step 4 in THF (11 mL) and MeOH (5.5 mL) was added aqueous LiOH 1.0N (3 mL, 3 mmol). The resulting solution was heated at 50° C. for 5 hours. The reaction was diluted with aqueous NH4OAc 25% w/v (50 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by crystallization in EtOAc/hexane (1:4, 30 mL) to give the title compound as a white solid; m.p. 157° C. The sodium salt was prepared by dissolving the acid in ethanol, adding one equivalent of aqueous NaOH, and freeze drying the resulting solution. The sodium salts of the remaining examples were prepared in the same way.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:24]1[C:25]2[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])=[CH:34][S:33][C:26]=2[N:27]=[C:28]([CH:30]2[CH2:32][CH2:31]2)[N:29]=1>C(O)C>[CH:30]1([C:28]2[N:29]=[C:24]([N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:12]3)[C:25]3[C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[CH:34][S:33][C:26]=3[N:27]=2)[CH2:32][CH2:31]1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Reactant: COc1ccccc1-c1csc2nc(C3CC3)nc(Cl)c12
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccccc1-c1csc2nc(C3CC3)nc(N3CCC(COCCN4CCCC4)CC3)c12
Yield: 19 %

Procedure:
4-(2-Pyrrolidin-1-ylethoxymethyl)piperidine (0.10 g, 0.47 mmol), triethylamine (0.089 mL, 0.63 mmol) and 4-chloro-2-cyclopropyl-5-(2-methoxyphenyl)thieno[2,3-d]pyrimidine (0.10 g, 0.32 mmol) were combined and heated to 50° C. in ethanol (10 mL) overnight. The solvent was removed at reduced pressure. The residue was taken up in DCM (20 mL), washed with water (20 mL) and the organic dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of DCM to 90/10/1 DCM/MeOH/NH4OH to afford 2-cyclopropyl-5-(2-methoxyphenyl)-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (0.03 g). LCMS: purity 100%, RT=3.62 min, M+1=493.1
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([O:17][CH3:18])([C:15]#[N:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH3:20].C(O)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH:15]([NH2:16])[CH2:19][CH3:20])([O:17][CH3:18])[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: COC1(C#N)CCC(OCc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(N)C1(OC)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon, 1.2 g of 39 were dissolved in 60 mL of absolute toluene. Then, 2.9 mL of ethylmagnesium bromide (3M in diethylether) were added dropwise. The mixture was allowed to warm to room temperature. After conversion was complete, the reaction mixture was cooled to 5° C. and 2 mL of dry ethanol were added. The mixture was filtered over celite and the filter cake was washed with tetrahydrofuran. Volatiles were removed in vacuo, the residue was dissolved in 20 mL of dry ethanol, 331 mg of sodium borohydride were added and the mixture was stirred for 2 h at 0° C. The mixture was evaporated, 20 mL of methyl tert.butyl ether and 20 mL of water were added and 1N aqueous hydrochloric acid was added dropwise until gas evolution ceased. The organic layer was separated, washed with brine, dried and evaporated to give 1 g of the desired product as a cis/trans mixture. Rt=0.96/0.99 min (Method M). Detected mass: 278.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[O:17][CH:16]([CH3:19])[C:15](=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].Br[CH:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[O:17][CH:16]([CH3:19])[C:15](=[O:20])[N:14]([CH:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCCC(Br)CCC
Reactant: Cc1ccc(-c2cccc3c2OC(C)C(=O)N3)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)N1C(=O)C(C)Oc2c(-c3ccc(C)cc3C)cccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 8-(2,4-dimethylphenyl)-2-methyl-2H-1,4-benzoxazin-3(4H)-one (300 mg, 1.12 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydride (43 mg, 1.68 mmol). After the mixture was stirred at 80° C. for 30 min, 4-bromoheptane (804 mg, 4.49 mmol) was added. The mixture was stirred at 80° C. for 18 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 5% ethyl acetate/n-hexane to afford 186 mg (30%) of the title compound.