Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)C.[C:12]1([C:23]2[C:24]([C:29](OCC)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:13]([C:18](OCC)=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1>O>[C:23]1([C:12]2[C:13]([CH2:18][OH:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:24]([CH2:29][OH:30])=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1ccccc1-c1ccccc1CO
Yield: 75 %

Procedure:
To 3 g LiAlH4 was added 100 ml anhydrous ethyl ether. While cooling with ice-bath and stirring intensely, 0.05 mol diethyl 2,2′-biphenyldicarboxylate was slowly added dropwise. The reaction mixture was heated refluxing for 5 hours, then cooled. Excess LiAlH4 was decomposed with water. The mixture was filtered, and the filtrate was extracted with ethyl ether. The extract was dried over anhydrous sodium sulfate. The solvent was removed. Column chromatography gave 2,2′-biphenyldimethanol as a white solid, the yield was 75%, and m.p. was 98-103° C. IR spectrum had a strong absorption peak at 3400 cm−1, and had no absorption peak at about 1700 cm−1. This demonstrated that the reduction reaction was carried out completely.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].CCCCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]([C:19](=[O:20])[CH2:18][Cl:17])[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1
Temperature: -15 °C

Procedure:
A mixture of 25 g (0.11 mol) N-(2′-chloro-6′-fluorophenyl)-4-methylaniline and 40 ml (0.5 mol) of chloroacetylchloride is heated under a nitrogen atmosphere for 15 minutes at 60°. The solvent is evaporated under reduced pressure to give an oil which is dissolved in 25 ml of ethyl acetate. Pentane (250 ml) is added dropwise over 15 minutes to precipitate the product. The mixture is cooled to −15° C. and the solid is filtered and washed with pentane to give N-(2′-chloro-6′-fluorophenyl)-N-chloroacetyl-4-methylaniline, m.p. 80-83°.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)P(=O)(N(C)C)N(C)C>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Na]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(OCc1ccccc1)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
10.4 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt are dissolved in 75 parts of hexamethylphosphoric triamide while heating to 110° C. After cooling to 20° C, 3.4 parts of (chloromethyl)benzene are added dropwise. Upon completion, stirring is continued for 18 hours at room temperature. The reaction mixture is poured onto 300 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding phenylmethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 76.7° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([NH2:11])=[O:10])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH2:28]([O:27][C:25]([N:5]1[CH2:6][CH2:7][CH2:8][C:3]([C:9](=[O:10])[NH2:11])([CH3:2])[CH2:4]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C(N)=O)CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C(N)=O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 409.7 %

Procedure:
To a solution of 3-Methyl-piperidine-3-carboxylic acid amide hydrochloride (740 mg, 4.1 mmol) in a cosolvent of 1,4-dioxane and water (12 mL, v:v=5:1) was added sodium carbonate (1.6 g, 15 mmol). The mixture was cooled to 0° C., benzyl chloroformate (900 mg, 0.53 mmol) was added, and the mixture was allowed to stir at room temperature for 3 h. LCMS showed starting material was consumed. The volatile components were removed, and the residue was extracted with ethyl acetate, purified by column chromatography (eluting with 10% methanol in dichloromethane) to give 600 mg (53%) of 3-Carbamoyl-3-methyl-piperidine-1-carboxylic acid benzyl ester. LCMS (Method K, ESI): RT=1.18 min, m+Na=298.8; 1H NMR (400 MHz, CDCl3) δ: 7.32-7.23 (m, 5H), 5.07-5.03 (m, 2H), 4.30-4.10 (m, 1H), 4.10-3.90 (m, 1H), 3.10-2.40 (m, 2H), 1.65-1.75 (m, 2H), 1.60-1.30 (m, 2H), 1.25-1.15 (m, 1H), 1.09 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([NH:36][CH2:35][CH2:34][N:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(NCCN1CCOCC1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2-morpholinoethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 22 mg of 255. MS (Q1) 493.8 (M)+.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:28].C([O-])([O-])=O.[Na+].[Na+]>>[I:28][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])[C:7]2=[O:12]
Reactant: I
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)OC[C@@H](C)n1ccc2c(I)cccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic acid (R)-2-(5-amino-1-oxo-1H-isoquinolin-2-yl)-propyl ester (790 mg, 0.0030 mol) was added to a solution of sodium nitrite (800 mg, 0.01 mol) in dimethyl sulfoxide (10 mL, 0.1 mol) at room temperature. Aqueous hydrogen iodide (4 mL, 0.03 mol) in dimethyl sulfoxide (10 mL, 0.1 mol) was added. The reaction mixture was stirred at room temperature for 1 hour. The cooled reaction mixture was neutralized with saturated aq. Na2CO3 and extracted with methylene chloride (3×100 mL). The combined methylene chloride extracts were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on 40 of silica gel column (0-50% EtOAc/Hexane) to give the desired product as a brown oil. MS m/z (M+H) 371.9
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Br:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Br:30])[CH:19]=1>CN(C=O)C>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Br:30])[CH:19]=1
Reactant: C=C(c1cc(Br)cc(Br)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Br)cc(Br)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.7 %

Procedure:
To a solution of (Z)-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (850 mg, 3.55 mmol) and 1,3-dibromo-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.75 g, 5.32 mmol) in DMF (10 mL) at rt was added TEA (0.5 mL, 3.55 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the desired title compound 5-(5-(3,5-dibromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (600 mg; 32% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.79 (m, 4H), 7.73 (dd, J=8.0 Hz, 0.8 Hz, 1H), 4.45 (d, J=18.8 Hz, 1H), 4.33 (d, J=18 Hz, 1H), 1.50 (d, J=2.8 Hz, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=534.0 (M+1, ESI+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27]>>[CH:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:36])[CH:30]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)on4)c3)c2cc1OC
Yield: 47 %

Procedure:
The title compound was prepared as described in Example 113C by using 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (102 mg, 0.3 mmol) and phenyl 5-isopropylisoxazol-3-ylcarbamate described in Example 133A (110 mg, 0.45 mmol) to give 1-(5-isopropylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (69.5 mg, 47%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.05 (s, 1H), 8.55 (s, 1H), 7.52 (s, 2H), 7.45-7.36 (m, 2H), 7.25 (d, 1H), 6.99 (d, 1H), 6.5 (s, 1H), 4.35 (bs, 2H), 4.00 (s, 3H), 3.89 (bs, 2H), 3.36 (s, 3H), 3.01-2.99 (m, 1H), 1.22 (d, 6H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[C:8]([OH:12])=[CH:7][C:5]=2[N:6]=1.[N+:13]([O-])([OH:15])=[O:14]>C(OCC)(=O)C.ClCCl>[CH3:1][C:2]1[S:3][C:4]2[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([OH:11])[C:8]([OH:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(O)c(O)cc2s1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc2cc(O)c(O)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methyl-benzothiazole-5,6-diol was dissolved in ethyl acetate and a solution of nitric acid in dichloromethane (2M, 0.38 ml) was gradually added at 20° C. into. The solution was stirred 10 min at room temperature and then it was poured into ice water and extracted into ethyl acetate and evaporated. The product was purified by column chromatography using toluene-ethyl acetate-acetic acid 8:1:1 as the eluent.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C.C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCCBr
Reactant: Oc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: OCCCCCCOc1ccccc1-c1ccccc1
Yield: 165.7 %

Procedure:
40.0 g (235 mmol) of 2-phenylphenol from Tokyo Chemical Industry Co., Ltd. and 51.06 g (282 mmol) of 6-bromo-1-hexanol from Tokyo Chemical Industry Co., Ltd. were dissolved in 600 mL of methyl ethyl ketone from Kanto Chemical Co., Inc. to prepare a solution. 97.4 g of sodium carbonate were added to the solution, and refluxed for 8 hrs. After the solution was cooled to have room temperature, it was filtered and condensed. The resultant light brown liquid was dissolved in methylene chloride and washed with water. The isolated organic layer was dried with magnesium sulfide and a solvent was removed therefrom. The residue was refined by silica gel column chromatography using methylene chloride as an eluent to obtain 105.3 g of 6-(2-phenyl-phenoxy)hexane-1-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C:5](=O)[CH:6]([CH3:34])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:22]([N:23]3[C:27](=[O:28])[N:26]([CH3:29])[N:25]=[N:24]3)=[CH:21][CH:20]=[CH:19][C:18]=2[CH:30]2[CH2:32][CH2:31]2)=[C:11]([CH3:33])[CH:10]=1)=O)[CH3:2].[NH2:37][NH2:38]>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[NH:37][N:38]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[C:22]([N:23]4[C:27](=[O:28])[N:26]([CH3:29])[N:25]=[N:24]4)=[CH:21][CH:20]=[CH:19][C:18]=3[CH:30]3[CH2:31][CH2:32]3)=[C:11]([CH3:33])[CH:10]=2)[C:6]=1[CH3:34])=[O:36])[CH3:2]
Reactant: CCOC(=O)C(=O)C(C)C(=O)c1ccc(OCc2c(C3CC3)cccc2-n2nnn(C)c2=O)c(C)c1
Reactant: NN
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]nc(-c2ccc(OCc3c(C4CC4)cccc3-n3nnn(C)c3=O)c(C)c2)c1C

Procedure:
At room temperature, to a mixture of 4-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-3-methyl-2,4-dioxo-butyric acid ethyl ester (described in Reference Preparation example 115) 5.5 g, tetrahydrofuran 100 ml was added hydrazine one hydrate 0.56 g and the resulting mixture was stirred for twelve hours. The reaction mixture was concentrated under reduced pressure to give 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-4-methyl-2H-pyrazole-3-carboxylic acid ethyl ester crude product 5 g. Next, the mixture of the above-mentioned 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-4-methyl-2H-pyrazole-3-carboxylic acid ethyl ester crude product 5 g, toluene 70 ml and dimethyl sulfate 3.8 g was stirred at 100° C. for three hours. To the reaction mixture was added water and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester 1.4 g (hereinafter, referred to as “Present compound 48”).
Reaction SMILES: [S:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1N)([OH:4])(=[O:3])=[O:2].C1C(C(O)=O)=CC2C=CC([OH:27])=CC=2C=1.S(=O)(=O)(O)O.S(=O)(=O)=O.S(=O)(=O)=O>>[S:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:27])([OH:4])(=[O:3])=[O:2]
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1S(=O)(=O)O
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1ccc2c(S(=O)(=O)O)c(O)ccc2c1

Procedure:
The 1-sulfo-6-carboxy-2-aminonaphthalene starting compound has not been disclosed before. It can be prepared according to the present invention by first sulfonating 2-naphthol-6-carboxylic acid in a sulfuric acid/sulfur trioxide mixture (oleum) having a sulfur trioxide content of 0 to 65% by weight at a temperature between 0° C. and 40° C., preferably at 0° to 10° C., to 1-sulfo-6-carboxy-2-naphthol, isolating this compound and then reacting it at a temperature between 100° and 160° C. in an autoclave in aqueous medium with ammonium hydrogen-sulfite. The 1-sulfo-6-carboxy-2-naphthol is isolated from the reaction mixture in a conventional manner by carefully pouring the reaction batch onto ice. The precipitated product is filtered off with suction and suspended in ice-water, and any sulfuric acid still present is neutralized with sodium carbonate by adjusting the suspension to a pH between 4 and 4.5. The compound can then be isolated by filtering off with suction and drying.
Reaction SMILES: [NH2:1][C:2]1[S:11][C:5]2[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=O.O=[C:22]([CH3:33])[CH2:23][CH:24]([CH2:30][CH2:31][CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl[Si](C)(C)C>CN(C=O)C>[CH3:33][C:22]1[C:23]([CH:24]([CH2:30][CH2:31][CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]2[C:4]3[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][C:5]=3[S:11][C:2]=2[N:1]=1
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCN(C)C3)cc1
Reactant: CCCC(CC(C)=O)C(=O)OCC
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(C)C3
Temperature: 100 °C

Procedure:
To a solution of (2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone (0.286 g; 1 mmol) and ethyl 4-oxo-2-propylpentanoate (0.204 g; 1.1 mmol) in dry DMF (8 mL) under nitrogen atmosphere was added chlorotrimethylsilane (0.511 mL; 4 mmol) dropwise. The mixture was stirred in a sealed tube and heated at 100° C. for 24 h. An extra volume of chlorotrimethylsilane was added (0.100 mL) and the reaction mixture was stirred at 100° C. for 48 h. The volatiles were removed under reduced pressure and the residue was purified by flash-chromatography on silica gel using a gradient of methanol (1-20%) in dichloromethane to furnish the title compound as a dark oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@@H:35]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]4)=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl (R)-3-amino-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:12]=[CH:11][C:10]=1[CH:19]=[CH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][C:24]=1[OH:37])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:12]=[CH:11][C:10]=1[CH:19]=[CH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:25][C:24]=1[O:37][C:45](=[O:47])[CH3:46])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1ccc(C=CC(=O)c2ccc(OCc3ccccc3)cc2O)c(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Product: COCOc1ccc(C=CC(=O)c2ccc(OCc3ccccc3)cc2OC(C)=O)c(OCc2ccccc2)c1
Temperature: 60 °C
Yield: 92 %

Procedure:
To a solution of 2-benzyloxy-4-methoxymethyloxy-4′-benzyloxy-2′-hydroxy-chalcone (0.496 g, 1 mmol), in 10 mL of acetic anhydride was added triethylamine (0.25 mL, 2 mmol) and the solution heated at 60° C. for ca. 6 hrs. After disappearance of starting material (TLC), the hot reaction mixture was poured into ice water:methanol (1:1) ca. 50 mL. A solid precipitated upon vigorous stirring. The solid was filtered, dried and recrystallized from methanol (ca. 15 mL) to obtain 0.495 g (92%) of white solid: mp 94-96° C.; TLC Rf0.21 in hexanes:EtOAc (3:1); 1H NMR (400 MHz, DMSO-d6) δ 7.78-7.75 (m, 2H), 7.71-7.69 (d, 1H, J=8.8 Hz, Ar—H6′), 7.49-7.36 (m, 10+1H, 2×C6H6+Ar—H8), 6.99-6.96 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5′), 6.90 (d, 1H, J=2.4 Hz, Ar—H3′), 6.85 (d, 1H, J=2 Hz, Ar—H3), 6.72-6.69 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5), 5.26 (s, 2H, O—CH2), 5.20 (s, 4H, O—CH2), 3.39 (s, 3H, OCH3), 2.18 (s, 3H, CH3CO); 13C NMR (100 MHz, DMSO-d6) δ 189, 169.5, 162.5, 160.9, 159.6, 151.4, 139.5, 137.2, 136.9, 132.3, 131.7, 129.3, 129.2, 128.8, 128.6, 128.6, 125.2, 123.3, 117.6, 113, 110.8, 109.1, 102.2, 94.5, 70.7, 70.5, 56.6, 21.5; analysis calc'd. for C33H30O7: C, 73.60; H, 5.61; O, 20.81. found: C, 73.86; H, 5.62; O, 20.79.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[CH:15]=2)[N:11]=1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: NCCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(Cl)nc1NCCc1cccc(F)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 54.8 %

Procedure:
A mixture of methyl 2,6-dichloronicotinate (53.3 g, 0.26 mol), 3-fluorophenethyl amine (37.3 mL, 0.29 mol), K2CO3 (72 g 0.52 mol) and NMP (150 mL) was stirred at 100° C. for 10 hrs. The mixture was diluted with ethyl acetate (2×300 mL) and washed with brine. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography using hexane-EtOAc (9:1) as eluant to give methyl 6-chloro-2-(3-fluorophenethylamino)nicotinate as an off-white solid (44 g, 54%). LRMS (M+H+) m/z 309.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
A mixture of 4-fluorobenzoic acid (4.9 g, 35.3 mmol), benzyl bromide (3.8 mL, 31.7 mmol), and cesium carbonate (17.2 g, 53 mmol) in DMF (50 mL,) at room temperature was stirred for 24 hours, diluted with water, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI) m/e 248 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[CH3:6])=[O:4].C1N2CN3CN(C2)C[N:23]1C3.[Br-].[NH4+].C(O)(C)C>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:7]2[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][N:23]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:17]=1
Reactant: CN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: [Br-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
Reflux 1.8 g. (0.005 moles) of 2-(2-bromo-N-methylacetamido)-5-chlorobenzophenone, 2.8 g. (0.020 moles) of hexamethylenetetramine and 1.96 g. (0.020 moles) of ammonium bromide together for 2 hours in 14 ml. of 85% (v/v) aqueous isopropyl alcohol. Pour the reaction mixture into water and extract the product with benzene. Wash the benzene solution with water, dry over anhydrous sodium sulfate, filter and evaporate to dryness. After recrystallization, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one is obtained. The material gives a single spot by thin layer chromatography, and after drying under vacuum at 110° C., shows no depression on mixed melting point with an authentic sample (M.P. 129.5°-130.5° C.).