Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][C:5]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:12]2[C:7](=[CH:8][C:9]([O:32][CH3:33])=[C:10]([O:30][CH3:31])[CH:11]=2)[N:6]=1>C(C(C)=O)C>[CH3:29][O:28][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][C:23]=1[O:26][CH3:27])[N:6]=[C:5]([CH2:4][I:1])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]2[C:12]1[CH:7]=[CH:8][C:9]([O:32][CH3:33])=[C:10]([O:30][CH3:31])[CH:11]=1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1c(CI)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
A mixture of sodium iodide (1.68 g) and methyl ethyl ketone (15 ml) was stirred at 80° C. for 1 hour, and then ethyl 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (2.0 g) was added thereto, and the resulting mixture was stirred at the same temperature for 12 hours. The insoluble solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (1/1,v/v) gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-iodomethylquinoline-3-carboxylate (1.4 g, 58%) which was then recrystallized from ethyl acetate-hexane.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]3[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=3)[CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[S-:23][C:24]#[N:25].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[C:4](=[O:5])[O:3][CH:2]3[S:23][C:24]#[N:25])[N:14]=1
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3Cl)n1
Reactant: N#C[S-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3SC#N)n1

Procedure:
A mixture of 1.4 g of 3-chloro-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide (see Example 85) and 0.46 g of potassium thiocyanate is heated in the presence of a spatula tip of 18-crown-6 in 15 ml of acetonitrile for 4 hours. The mixture is then filtered through Celite®, concentrated by evaporation and chromatographed with 30% ethyl acetate/n-hexane to yield 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-thiocyano-phthalide in the form of light-yellow crystals, m.p. 161°-163° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C@H:18]4[O:23][CH2:22][CH2:21][N:20]([C:24]5[N:29]=[CH:28][C:27]([C:30]6[CH:31]=[N:32][N:33]([CH:35]7[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]7)[CH:34]=6)=[CH:26][N:25]=5)[CH2:19]4)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1.Br[CH2:42][CH2:43][OH:44].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C@@H:18]4[CH2:19][N:20]([C:24]5[N:29]=[CH:28][C:27]([C:30]6[CH:31]=[N:32][N:33]([CH:35]7[CH2:40][CH2:39][N:38]([CH2:42][CH2:43][OH:44])[CH2:37][CH2:36]7)[CH:34]=6)=[CH:26][N:25]=5)[CH2:21][CH2:22][O:23]4)[N:15]=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1
Reactant: OCCBr
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(C7CCNCC7)c6)cn5)CCO4)c3n2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(C7CCN(CCO)CC7)c6)cn5)CCO4)c3n2)cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 144.3 %

Procedure:
(S)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)morpholine HCl salt 20 mg (0.04 mmol) was dissolved in dimethylformamide 1 ml, and 2-bromoethanol 6.6 mg (0.05 mmol) and K2CO3 15 mg (0.11 mmol) were added and then charged with nitrogen, followed by stirring at 60° C. for 4 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to remove dimethylformamide, followed by extraction with EA and brine, and the organic layer was dried over MgSO4. Separation by column chromatography (methylene chloride:methanol=10:1) gave a product 33 mg (65%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[CH2:15][CH2:16][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>>[CH2:26]([NH:30][C:2]1[N:3]=[C:4]([N:17]2[CH2:23][CH:22]3[CH2:21][CH2:20][CH:19]([CH2:25][CH2:24]3)[CH2:18]2)[N:5]=[C:6]([N:8]2[CH2:14][CH:13]3[CH2:12][CH2:11][CH:10]([CH2:16][CH2:15]3)[CH2:9]2)[N:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: Clc1nc(N2CC3CCC(CC3)C2)nc(N2CC3CCC(CC3)C2)n1
Product: CCCCNc1nc(N2CC3CCC(CC3)C2)nc(N2CC3CCC(CC3)C2)n1

Procedure:
Nine grams (0.025 mole) of 3,3'-(6-chloro-s-triazine-2,4-diyl)bis-3-azabicyclo[3.2.2]nonane and 9.7 g. (0.13 mole) n-butylamine is placed in a glass liner in a bomb and then heated in an oil bath maintained at 160°-180° C. for 16 hours. After cooling, the contents of the bomb are rinsed with chloroform and water into a flask and 50 ml. of 10 N NaOH is added. The solution is then evaporated in vacuo and the aqueous solution remaining is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered through Magnesol® and the Magnesol® washed with chloroform. Removal of solvent in vacuo, column chromatography on silica gel and recrystallization of the pure fractions containing the major component from n-heptane gives 4.9 g. of colorless prisms, m.p. 101°-103° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ncc(Br)cn1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1

Procedure:
A mixture of 5-bromo-2-chloro-pyrimidine (1.67 g, 8.63 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.08 g, 10.36 mmol, 1.2 equiv; commercially available) in acetonitrile (10 mL) was heated by microwave irradiation to 120° C. for 40 min. The organic phase was concentrated under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.48 g (48%) of the title compound. MS (ISP): 357.3 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH2:14][Cl:15])=[O:12].[CH3:16][C:17]1[C@@H:34]([O:35][C:36]([C@H:38]([OH:55])[C@@H:39]([NH:46][C:47]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:48])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH2:33][C@:29]2([OH:56])[C:30]([CH3:32])([CH3:31])[C:18]=1[C@@H:19]([O:74][C:75]([CH3:77])=[O:76])[C:20]([C@@:22]1([CH3:73])[C@H:27]([C@@H:28]2[O:57][C:58]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)=[O:59])[C@:26]2([O:68][C:69]([CH3:71])=[O:70])[CH2:66][O:67][C@@H:25]2[CH2:24][C@@H:23]1[OH:72])=[O:21]>ClCCl>[C:75]([O:74][C@@H:19]1[C:18]2[C:30]([CH3:31])([CH3:32])[C@@:29]([OH:56])([CH2:33][C@H:34]([O:35][C:36](=[O:37])[C@H:38]([O:55][C:11]([O:13][CH2:14][Cl:15])=[O:12])[C@@H:39]([NH:46][C:47](=[O:48])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:17]=2[CH3:16])[C@@H:28]([O:57][C:58](=[O:59])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:27]2[C@:26]3([O:68][C:69](=[O:70])[CH3:71])[CH2:66][O:67][C@@H:25]3[CH2:24][C@H:23]([OH:72])[C@@:22]2([CH3:73])[C:20]1=[O:21])(=[O:76])[CH3:77]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)OCCl)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.7 %

Procedure:
DIPEA (0.026 g, 46.0 mmol, 4.0 eq) was added to a solution of chloromethyl chloroformate (CMCF) [8] (0.04 g, 23.0 mmol, 4.0 eq) in dry dichloromethane under an argon atmosphere at 0° C. To the above reaction mixture at 0° C., a solution of paclitaxel 14114 (0.10 g, 11.7 mmol, 1.0 eq) in dry dichloromethane (y ml) was added. The reaction mixture was stirred at room temperature for 16 h. reaction progress was monitored by TLC. After 16 h the reaction mixture was diluted with dichloromethane (25 ml), washed with a 10% solution of NaHCO3 (15 ml), brine (10 ml), and then dried over anhydrous Na2SO4. Evaporation of the solvents under vacuum gave a white solid, (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(((chloromethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b-diyl diacetate [315], (0.08 g, 70%)
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[S:39][C:38]([CH2:40][C:41]([O:43]CC)=[O:42])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>>[C:12]([O:11][C:9]([C:8]1[C:7]([OH:16])=[C:6]([C:24]([F:27])([F:25])[F:26])[CH:5]=[CH:4][C:3]=1[CH2:2][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[S:39][C:38]([CH2:40][C:41]([OH:43])=[O:42])=[CH:37][CH:36]=2)=[CH:33][CH:34]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(O)cc2)s1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)s3)cc2)ccc(C(F)(F)F)c1O
Yield: 14 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (366 mg, 0.8 mmol) obtained in Example (28-5) and ethyl [5-(4-hydroxyphenyl)-2-thienyl]acetate (211 mg, 0.8 mmol) obtained in Example (28-6), the title compound was obtained as a colorless powder (56 mg, three-step total yield: 14%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]([F:35])([F:34])[C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[ClH:36].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:36].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:31](=[O:32])[C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:23]=[N:24][C:19]([C:18]([F:35])([F:17])[F:34])=[CH:20][CH:21]=5)=[CH:30][CH:29]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)nc2)cc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)nc4)cc3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-[6-(trifluoromethyl)-3-pyridyl]benzenecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O>CN(C=O)C>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15]([Cl:35])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCCC=C(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCC=C(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1.7 g (5 mmol) of 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenoic acid, 20 ml of toluene and 73 μl of DMF were introduced into a round-bottomed flask. The mixture was heated to 50° C. and 714 μl (6 mmol) of thionyl chloride were added and the mixture was stirred at this temperature for one hour. The mixture was evaporated to dryness and the crude acid chloride was employed as is in the synthesis to follow.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH2:20][CH2:21]O.O.C([O-])(=O)C.[K+]>Br>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[O:1][CH2:21][CH2:20][CH2:19][C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c(CCCO)c(O)c2cccnc2n1-c1ccccc1
Agent: Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=c1c2c(c3cccnc3n1-c1ccccc1)OCCC2
Temperature: 90 °C

Procedure:
A suspension of 4-hydroxy-3-(3-hydroxypropyl)-1-phenyl-1,8-naphthyridin-2(1H)-one (5.67 g.) in 47% HBr (50 ml.) was stirred in an atmosphere of nitrogen and was heated to 90° C. for 5 hrs. After cooling, the product was poured into water, and the pH was adjusted to 4.5 with potassium acetate. Chromatographic purification of the product on silica gel eluting with CH2Cl2 : 5% ether and subsequent recrystallization of the product from the relevant fractions yielded the product, m.p. 253°-255° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:42])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:12]=[CH:11][N:10]=[C:9]2[NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[C:29]([Cl:41])[CH:28]=1)=[O:4].[C:43](Cl)(=[O:46])[CH:44]=[CH2:45].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:41][C:29]1[CH:28]=[C:27]([NH:26][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:6]([NH:5][C:3]([C@@H:2]([NH:1][C:43](=[O:46])[CH:44]=[CH2:45])[CH3:42])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1
Reactant: C[C@H](N)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N[C@@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Yield: 33 %

Procedure:
500 mg of (2S)-2-amino-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-yl}-propionamide as a starting material was dissolved in 12 ml of THF and 4 ml of water, and reacted with 0.08 ml of acryloylchloride at room temperature for 1.5 hours after adding 213 mg of sodium bicarbonate. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=15:1) to obtain the title compound (180 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([O:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[O:2][CH3:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(C)ccc1O
Solvent: CCN(CC)CC
Product: COc1cc(C)ccc1OC(=O)c1ccccc1

Procedure:
The synthesis of this compound proceeded in the same fashion as in Example 1 using 27.63 g (0.20 mol) of 2-methoxy-4-methyl phenol, 22.26 g (0.22 mol) of triethylamine and 28.11 g (0.20 mol) of benzoyl chloride. The product amounted to 46.78 g, m.p. 73°-75° C.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)C.C(O)C.[N:27]1C=CC=CC=1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[NH:27][O:3][C:4](=[O:23])[C:5]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=2)=[CH:9][CH:10]=1
Reactant: c1ccncc1
Reactant: CCOC(=O)C(C(=O)c1ccc(F)cc1)c1ccnc(SC)n1
Solvent: CCO
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)[nH]oc2=O)n1

Procedure:
Using the procedure from Example 1k set forth above, substitute 3-(4-fluorophenyl)-3-oxo-2-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid ethyl ester for 2-(4-fluorophenyl)-3-oxo-3-pyridin4-yl-propiornc acid methyl ester and ethanol for pyridine to produce the title compound.
Reaction SMILES: [S:1]([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)([O:4]CCC)(=[O:3])=[O:2]>CN(C)C=O.CC(OC)(C)C>[CH3:12][C:11]1[CH:13]=[CH:14][C:8]([S:1]([OH:4])(=[O:3])=[O:2])=[CH:9][CH:10]=1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A 72 liter unjacketed reactor was charged with 1.84 kg (10.87 mol) of R(+)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole (R(+) diamine), followed by 14.7 L of dimethyl formamide (DMF). Under continuous stirring, the mixture was heated to a temperature of between 65° C. and 68° C. A solution of 2926 grams propyl tosylate and 1761 grams diisopropylethyleamine in 3.455 L DMF was added slowly over a period of 2 hours. The reaction was continued at 67° C. for an additional 4 hours, after which the solution was gradually cooled to room temperature (18° C. to 22° C.) and stirred for an additional 15 hours. The solution was diluted with 14.72 L of MTBE over a time period of 30 minutes, and stirred for an additional 1 hour. The precipitated material was collected by filtration and washed with 7.32 L, MTBE, followed by 3 washes of 3.68 L each of ethanol, and a wash with 9.2 L heptane. The washed precipitated cake was dried under high vacuum at 30° C. to 35° C. The final weight of the dried product was 2090 grams, representing a 50% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32]C)=[O:31].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:36][CH2:35][CH2:34][C@H:29]4[C:30]([OH:32])=[O:31])[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]acetaldehyde (90 mg, 0.224 mmol) (D15) in Dichloromethane (DCM) (20 mL) stirred at room temperature was added methyl L-prolinate (149 mg, 0.898 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water, and EtOH was evaporated in vacuo. i-PrOH was added, followed by sodium hydroxide (8.98 mg, 0.224 mmol). The reaction mixture was stirred for another 2 hours. i-PrOH was evaporated in vacuo. The aqeuous layer was extracted by EA/THF for 3 times. The combined organic solution was washed by brine. The organic layers were concentrated, and purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]ethyl}-L-proline (E52) (24 mg) as a off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=2[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:10]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
In DMF (3 ml) was dissolved methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g), and the solution was added dropwise to a suspension of 60% sodium hydride (0.05 g) in DMF (1 ml) under ice-cooling. The mixture was stirred under nitrogen atmosphere for 10 minutes. Benzyl bromide (0.15 ml) was added thereto, and the mixture was heated at 45° C. for 4 hours. The mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-benzyl-7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g) as yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20]>>[CH3:28][O:27][C:23]1[CH:22]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:24]=1[O:25][CH3:26])[C:19]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1)=[O:20]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc(C=CC(=O)O)cc2)cc(OC)c1OC

Procedure:
4-(3,4,5-Trimethoxybenzoylamino)-cinnamic acid was prepared as described in Example 3 from 5 g (0.0271 mol) of p-aminocinnamic acid hydrochloride and 3,4,5-trimethoxybenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][CH:4]=1.OOS([O-])=O.[K+].[K+].[Br-:27]>C(#N)C.O>[Br:27][C:8]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)c(C)c1
Reactant: [Br-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)c(Br)c2)c(C)c1
Reaction time: 2.5 h

Procedure:
To a solution of methyl 4′-methoxy-2-methylbiphenyl-4-carboxylate (71.5 g, 0.279 mol) in acetonitrile (1.43 L) and water (572 mL) was added oxone (180.1 g, 0.293 mol). Then a solution of KBr (38.2 g, 0.321 mol) in water (143 mL) was slowly added over 30 minutes. The reaction was stirred for 2.5 hours, then water (715 mL) was added and the mixture was left standing for 1 hour. The solids were filtered and washed as follows: with a solution of MeCN/water (1:1, 350 mL, twice), water (700 mL, twice, then 350 mL) and dried to afford methyl 3′-bromo-4′-methoxy-2-methylbiphenyl-4-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.3-7.2 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[C:15](OC)=O.FC(F)(F)S(OC1C=CC(C(=O)C)=CC=1C#[N:35])(=O)=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[C:15]#[N:35]
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Reactant: COC(=O)c1cc(C(C)=O)ccc1-c1ccco1
Product: CC(=O)c1ccc(-c2ccco2)c(C#N)c1

Procedure:
The title compound was prepared according to the procedure for preparation of 4-(2-furyl)-3-(methoxycarbonyl)phenyl-1-ethanone using 2-Cyano-4-acetylphenyl trifluoromethanesulfonate instead of 2-Methoxycarbonyl-4-acetylphenyl trifluoromethanesulfonate.