Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=O)[N:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:53]1[CH2:58][CH2:57][CH:56]([CH2:59][NH2:60])[CH2:55][CH2:54]1>CN(C=O)C.O>[Br:1][C:2]1[N:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:60][CH2:59][CH:56]2[CH2:57][CH2:58][O:53][CH2:54][CH2:55]2)=[O:19])[N:15]=1
Reactant: NCC1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Yield: 100 %

Procedure:
A solution of the compound (1.8 g, 5.23 mmol) obtained in step 7, HATU (2.386 g, 6.27 mmol), DIEA (1.093 mL, 6.27 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.723 g, 6.27 mmol) in DMF (1 mL) was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50% ethyl acetate/hexane→5% methanol/ethyl acetate) to give 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (2.31 g, 5.23 mmol, 100%) as a colorless oil
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:25])[CH:4]([N:12]1[C:18](=[O:19])[CH:17]([NH2:20])[CH2:16][C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[CH2:13]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:26][CH:27]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45])[C:28](O)=[O:29]>>[CH3:1][NH:2][C:3](=[O:25])[CH:4]([N:12]1[C:18](=[O:19])[CH:17]([NH:20][C:28](=[O:29])[CH:27]([Br:26])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[C:39](=[O:40])[C:38]3=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]3[C:36]2=[O:45])[CH2:16][C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[CH2:13]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)C(Br)CCCCN1C(=O)c2ccccc2C1=O
Reactant: CNC(=O)C(Cc1ccccc1)N1Cc2ccccc2CC(N)C1=O
Product: CNC(=O)C(Cc1ccccc1)N1Cc2ccccc2CC(NC(=O)C(Br)CCCCN2C(=O)c3ccccc3C2=O)C1=O

Procedure:
Prepare by the method of Example 3.1 using 2-(4-amino-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionic acid, N-methyl amide and 2-bromo-6-phthalimidohexanoic acid to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.[CH3:12][O-:13].[Na+]>C1(C)C(C)=CC=CC=1.CO>[CH3:12][O:13][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1
Reactant: Nc1nc(Cl)c2c(n1)CCC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1nc(N)nc2c1CCC2
Yield: 98 %

Procedure:
(S M:Ross, L. O.; Goodman, L.; Baker, B. R. J. Am. Chem. Soc. 1959, 81, 3108) 5.3 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml xylene and 30 ml absolute methanol. Then 5.4 gram for sodium methoxide was added and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. Filter and wash the cake with water (50 ml). The solid was further vacuumed to dry for several hours. The desired product weighed 4.8 gram (98% yield). Mp: 133.8˜134.9° C.; MS: 166.2.0 (M+H)
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)Cl>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:3]1[N:2]([CH3:1])[C:6]([S:7]([CH3:8])=[O:19])=[N:5][N:4]=1
Reactant: CSc1nnc(-c2cccs2)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(-c2cccs2)nnc1S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 4-methyl-5-methylthio-3-(2-thienyl)-4H-1,2,4-triazole (4.85 g, 2.29×10-2 mole) and CH2Cl2 (170 ml) was added portionwise m-chloroperoxybenzoic acid (4.95 g, 2.29×10-2 mole). After stirring at room temperature overnight the reaction was washed two times with saturated aqueous NaHCO3 and one time with saturated aqueous NaCl, and dried over anhydrous N2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure yielding an off-white solid which was purified by flash chromatography (40% acetone/EtOAc). Crystallization from EtOAc afforded small colorless plates: 2.78 g (53%), mp 105°-107° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.O>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:17][CH2:18][C@@H:14]([OH:13])[CH2:15]1
Reactant: OC1CCNC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1N1CC[C@@H](O)C1
Temperature: 110 °C
Yield: 81.2 %

Procedure:
A mixture of 2-chloro-5-nitroanisole (0.59 g, 3.1 mmol) and 3-hydroxy pyrrolidine (0.55 g, 6.2 mmol) was heated neat to 110° C. over night. Reaction mass was diluted with ethyl acetate and the organic layer was given water and brine wash, dried over Na2SO4, concentration yields dark red solid (0.6 g, 82% yield). LC-MS, [M+H]+=239.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[Si:33]([O:40][CH2:41][CH:42]=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[BH3-]C#N.[Na+].CC(O)=O>CO.C(Cl)Cl>[C:36]([Si:33]([CH3:35])([CH3:34])[O:40][CH2:41][CH2:42][N:30]1[CH2:31][CH2:32][CH:27]([N:25]2[CH:26]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([CH2:12][C:3]5[CH:4]=[C:5]6[C:10](=[CH:11][C:2]=5[F:1])[N:9]=[CH:8][CH:7]=[CH:6]6)=[CH:14][N:15]=4)[N:18]=3)[CH:23]=[N:24]2)[CH2:28][CH2:29]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 70 mg, 0.164 mmol), tert-butyldimethylsilyloxy-acetaldehyde (47 μL, 0.246 mmol) and NaBH3CN (52 mg, 0.246 mmol) in MeOH (2 mL) was stirred at rt for 2 h. The pH was then adjusted to 5-6 with AcOH and the RM was stirred at rt for 2 h more. The mixture was diluted with DCM and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound as a foam (tR 4.27 min (conditions 3), MH+=586.1).
Reaction SMILES: [N:1]1([CH:7]2[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd].O>[N:1]1([C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)[C@@H]1CC(N2CCCCC2)CN1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](N2CCCCC2)CN1

Procedure:
A solution of 10.0 g of [4S]-1-[phenylmethoxy)carbonyl]-4-(1-piperidinyl)-L-proline, methyl ester in 100 ml of methanol is treated with a suspension of 2 g of 5% palladium on charcoal in 10 ml of water and placed under 3 atmospheres of hydrogen. After an equivalent quantity of hydrogen is consumed, the suspension is filtered and the solvent evaporated to give the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[C:11]([CH2:12][OH:13])=[C:10]([CH3:14])[O:9][N:8]=1)[CH2:4][CH2:5][CH3:6].[CH:15]([NH:18][C:19]([C:21]1[S:25][C:24](Cl)=[N:23][CH:22]=1)=[O:20])([CH3:17])[CH3:16].O>C1COCC1>[CH:15]([NH:18][C:19]([C:21]1[S:25][C:24]([O:13][CH2:12][C:11]2[C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][O:9][C:10]=2[CH3:14])=[N:23][CH:22]=1)=[O:20])([CH3:17])[CH3:16]
Reactant: CCCCc1noc(C)c1CO
Reactant: CC(C)NC(=O)c1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1noc(C)c1COc1ncc(C(=O)NC(C)C)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a suspension of NaH (55%, 58 mg, 2.4 mmol) in THF (3 mL) at 0° C., was added a solution of (3-butyl-5-methyl-isoxazol-4-yl)-methanol (169 mg, 1.0 mmol) in THF (3 mL) dropwise. The resulting mixture was stirred for 1 h and then cooled to 0° C. and then a solution of 2-chloro-thiazole-5-carboxylic acid isopropylamide (205 mg, 1.0 mmol) in THF (3 mL) added dropwise and the resulting mixture stirred at room temperature overnight. Water was then added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 30% methanol in dichloromethane, then 0 to 60% ethyl acetate in heptane) gave the title compound (145 mg, 43%) as a white solid. MS: m/e=338.4 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][SH:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:14][CH2:15][CH2:16][OH:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][S:13][S:14][CH2:15][CH2:16][OH:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: SCCCc1ccc2c(c1)OCO2
Reactant: OCCS
Product: OCCSSCCCc1ccc2c(c1)OCO2
Yield: 43.8 %

Procedure:
8.4 g of the title compound was prepared from 27.8 g 3-(1,3-benzodioxol-5-yl)propanethiol and 5.5 g of 2-mercaptoethanol as a colorless oil according to the same procedure as that described in Example 1.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[NH:7][C:8]2[C:13]([C:14](=[O:16])[N:15]=1)=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[CH:10][CH:9]=2)[CH2:4][CH3:5].[H][H].[CH3:22][O:23][C:24]1[CH:39]=[CH:38][C:27]([CH:28](Cl)[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:26][CH:25]=1.[OH-].[Na+]>CN(C=O)C>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH:28]([N:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=3)[N:7]=[C:6]2[CH2:3][CH2:4][CH3:5])[C:27]2[CH:38]=[CH:39][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:34][CH:33]=1
Reactant: CCCc1nc(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: [H][H]
Reactant: COc1ccc(C(Cl)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1C(c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 82.3 %

Procedure:
To a suspension of 1.01 g (33.7 mmol) of 80% sodium hydride in 20 mL of dry DMF was added at 0° C. 7.5 g (32 mmol) of the product of Step A as a solid. The reaction mixture was diluted with a further 50 mL of DMF to assist stirring. After hydrogen evolution was complete, a solution of 8.8 g (33.7 mmol) of 4,4'-dimethoxybenzhydryl chloride in 20 mL of dry DMF was added dropwise. The reaction mixture was stirred overnight and then poured into 300 mL of 0.1N NaOH. The precipitate was collected by filtration and dried under vacuum to give 12.1 g (94%) of a yellow solid.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.Cl[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=O>>[CH3:45][N:44]([CH3:46])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(=O)CCl
Product: COc1cc(NCCCc2ccc(OCCN(C)C)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 29.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N,N-dimethylacetamide (8.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.7 mg) was obtained.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:17](Cl)(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:23]=1>O1CCCC1.O>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][S:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=2)(=[O:19])=[O:18])=[C:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1ccc(Cl)cc1Cc1ccccn1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2ccccn2)cc1OC
Reaction time: 72 h

Procedure:
0.7 ml of pyridine and then 2.27 g of 3,4-dimethoxybenzenesulfonyl chloride are successively added at room temperature to 1.86 g of 4-chloro-2-(pyridin-2-ylmethyl)aniline in solution in 20 ml of tetrahydrofuran. After 72 hours at room temperature, the reaction medium is taken up in water and extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and concentrated in order to obtain 2.12 g of the expected product.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.[N+:69]([CH3:72])([O-:71])=[O:70]>>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]([CH2:72][N+:69]([O-:71])=[O:70])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Reactant: C[N+](=O)[O-]
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C[N+](=O)[O-])C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Temperature: 0 °C
Yield: 97.2 %

Procedure:
A 31.07 g (82.75 mmol) portion of ethyl (E)-3-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]acrylate was dissolved in 300 ml of nitromethane to which, while cooling in an ice bath with stirring, was subsequently added dropwise 13.37 ml (82.75 mmol) of diazabicycloundecene. After 10 minutes of stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 1 hour. While cooling in an ice bath with stirring, the reaction solution was acidified by gradually adding 10% citric acid aqueous solution and then mixed with ethyl acetate to effect separation of layers. The resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and then with saturated brine. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure to give 35.12 g (97.2%) of the title compound. This compound was used in the following reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[C:11](O)=[O:12])=[CH:7][CH:6]=1)=[O:4].[Cl-].[NH4+]>C1COCC1.O.C(OCC)(=O)C>[OH:12][CH2:11][CH:10]([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:21]=1)[CH2:9][C:8]1[CH:26]=[CH:27][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCC(Cc2ccc(C(=O)OC)cc2)C(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(CO)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
112.8 ml (112.8 mmol) of a 1 M boran-THF complex solution are added dropwise to a solution of 20.9 g (56.4 mmol) of 2-[4-(methoxycarbonyl)benzyl]-4-[4-(methoxycarbonyl)phenyl]butanoic acid in 600 ml of THF at −10° C. The reaction mixture is then warmed to 0° C. and stirred at this temperature for 4 h. After reaction is complete, saturated ammonium chloride solution is added to the reaction mixture, which is diluted with water and ethyl acetate, the phases are separated, and the aqueous phase is back-extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and, after filtration, freed of solvent in vacuo. 20.11 g (94% purity, 100% of theory) of a colourless solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)=[O:4].S(Cl)(Cl)=O.O.[NH2:18][NH2:19]>>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([C:10]([NH:18][NH2:19])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)s1
Reactant: NN
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)NN)s1
Yield: 72 %

Procedure:
The known procedure disclosed in the literature (J. Heterocyclic Chem., 28, 17, (1991).) was followed using 5-methoxycarbonyl-2-thiophenecarboxylic acid, thionyl chloride and hydrazine monohydrate to give 144 mg of a white solid (yield 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([O:15]C(=O)CC)(=[O:14])[CH2:12][CH3:13].C([O-])(=O)CC.[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[C:12]([CH3:13])[C:11]([OH:15])=[O:14]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CCC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=Cc1ccc(F)c(F)c1)C(=O)O

Procedure:
A mixture of 2.88 g. (0.02 mole) of 3,4-difluorobenzaldehyde, 3.24 g. (0.025 mole) of propionic anhydride and 0.92 g. (0.02 mole) of sodium propionate under nitrogen is heated at 135° with a magnetic stirrer for 20 hours. The reaction mixture is poured onto 50 ml. of water. A solid precipitates that dissolves when 50 ml. of saturated K2CO3 is added with stirring. The basic solution is extracted with ether (2×100 ml.). The aqueous phase is then poured into an excess of concentrated HCl and ice. The precipitated white solid is filtered and dried to give 3,4-difluoro-α-methylcinnamic acid, M.P. 122°-125°.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:48]([O:52][C:53]([NH:55][C@@H:56]1[CH2:61][C@H:60]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:59][N:58]([C:70]2[CH:75]=[C:74]([NH:76][C:77]3[CH:82]=[CH:81][C:80]([NH2:83])=[CH:79][CH:78]=3)[CH:73]=[C:72]([N:84]3[CH2:89][C@@H:88]([NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][C@@H:86]([NH:98][C:99]([O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:100])[CH2:85]3)[N:71]=2)[CH2:57]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>CN(C=O)C.CCOC(C)=O>[C:48]([O:52][C:53]([NH:55][C@@H:56]1[CH2:61][C@H:60]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:59][N:58]([C:70]2[CH:75]=[C:74]([NH:76][C:77]3[CH:82]=[CH:81][C:80]([NH:83][C:12]([C:3]4[CH:4]=[CH:5][C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]=4[OH:1])=[O:14])=[CH:79][CH:78]=3)[CH:73]=[C:72]([N:84]3[CH2:89][C@@H:88]([NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][C@@H:86]([NH:98][C:99]([O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:100])[CH2:85]3)[N:71]=2)[CH2:57]1)=[O:54])([CH3:49])([CH3:50])[CH3:51]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2cc(Nc3ccc(N)cc3)cc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2cc(Nc3ccc(NC(=O)c4ccc5ccccc5c4O)cc3)cc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
1-Hydroxy-naphthalene-2-carboxylic acid (142) (0.028 g, 0.148 mmol) was dissolved in DMF (1 mL), iPr2EtN (0.222 mmol) was added followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU) (0.062 g, 0.163 mmol) and the mixture was shaken in an 8 mL Teflon septum capped vial at room temperature for 20 minutes. N-(2,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-pyridin-4-yl)-benzene-1,4-diamine (141) (0.08 g, 0.0986 mmol) was added and the mixture was shaken at room temperature for 16 h. LC-MS indicated complete coupling at this point. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), NaHCO3 (aqueous sat., 15 mL) and brine (15 mL) via extraction, dried over MgSO4 and concentrated to give an orange/green oil. Purification by flash chromatography using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc in hexane in 30 minutes) gave the desired product (143) as a greenish-white powder upon concentration (0.063 g, 0.064 mmol, 65% yield). LC-MS (ESI): (exact mass: 981.53) m/e=982.6 [M+1]+ (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[CH3:10].[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[CH2:18][Cl:17])=[C:3]([C:9]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)([OH:11])[CH3:10])[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: CC(O)(c1ccco1)c1cc(Br)ccc1N
Product: CC(O)(c1ccco1)c1cc(Br)ccc1NC(=O)CCl

Procedure:
Prepared from 1-(2-amino-5-bromophenyl)-1-(2-furyl)ethanol and chloroacetyl chloride generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.84 (s, 1H), 8.07 (d, J=8.76 Hz, 1H), 7.57 (bs, 1H), 7.50 (dd, J=2.33, 8.76 Hz, 1H), 7.12 (s, 1H), 7.09 (d, J=2.31 Hz, 1H), 6.46-6.42 (m, 2H), 4.35 (d, J=1.69 Hz, 2H), 1.85 (s, 3H); MS (ES) m/z 356/358 ([M−H]−, 100%).