Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]([N:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]1[CH2:36][O:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[ClH:1].[ClH:1].[C:16]1([C:15]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[CH2:36][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1)N1CCNCC1COc1cccnc1
Reaction time: 12 h
Yield: 98 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(benzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (89.5 mg, 0.175 mmol). After 12 h, the reaction mixture was concentrated under reduced pressure, yielding 63.8 mg (98%) of the desired product as a white solid. LC-MS: RT=3.05 min, [M+H]+=298.1.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[C:33]([C:37]1[CH:38]=[C:39]([CH3:55])[C:40](=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=1)([CH3:36])([CH3:35])[CH3:34].Cl>C(OCC)C>[C:33]([C:37]1[CH:38]=[C:39]([CH3:55])[CH:40]([C:42]([C:10]2[C:9]3[CH2:8][C:7]4[C:15](=[CH:16][CH:17]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=4)[C:14]=3[CH:13]=[CH:12][C:11]=2[C:18]([CH3:21])([CH3:20])[CH3:19])([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:41]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccccc1)(c1ccccc1)c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 2.53 g of 2,7-di-tert-butyl-fluorene (9.10 mmol) was dissolved in 70 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 6.4 ml of a n-butyl lithium/hexane solution (1.56M: 9.98 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, a solution prepared by dissolving 3.01 g of 3-tert-butyl-1-methyl-6,6-diphenyl fulvene (10.0 mmol) in 40 ml of dehydrated diethyl ether was added and stirred with refluxing for 7 days. The reaction mixture was added to 100 ml of a hydrochloric acid aqueous solution (1N) and thereafter diethyl ether was added to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a reddish-brown liquid. The liquid was purified by a column chromatography using 180 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. The remainder was re-crystallized using methanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.65 g (2.85 mmol) as a pale yellow solid (yield: 31%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12].O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[C:10]2[C:9]([Cl:15])=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1sc2ncnc(O)c2c1Br
Product: Cc1sc2ncnc(Cl)c2c1Br
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a 25-mL round-bottom flask containing 5-bromo-6-methylthieno[2,3-d]pyrimidin-4-ol (100 mg, 0.41 mmol, 1.00 equiv) in POCl3 (10 mL) was stirred for 1 h at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was then quenched with saturated aqueous sodium carbonate, extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After concentrated under vacuum, this resulted 5-bromo-4-chloro-6-methylthieno[2,3-d]pyrimidine (79 mg, 73%) as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:31](=[O:34])[CH2:32][CH3:33])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (4.60 g, 15.8 mmol) and N,N-diisopropylethylamine (1.40 mL, 15.8 mmol) in 25 mL of dry methylene chloride was added propionyl chloride (1.40 mL, 15.8 mmol) dropwise at 0° C. After being stirred at room temperature overnight, the reaction mixture was quenched with 30 mL of H2O and extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with aqueous HCl (5%, 20 mL), NaHCO3 (sat., 2×30 mL), brine (50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography (silica gel, hexane:ethyl acetate) to afford N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 as a colorless oil (4.50 g, 82%). IR (film, cm−1) 2975, 2934, 2854, 1690, 1663, 1591, 1496, 1422, 1402, 1365, 1265, 1242, 1176, 1149, 1038, 962,775, 702; 1H NMR (CDCl3, ppm) 7.44–7.22 (m, 5H), 4.09–3.22 (m, 4H), 2.80–2.09 (m, 2H), 2.06 (q, 2H, J=7.5 Hz), 1.75–1.19 (m, 5H), 1.48(s, overlap, 9H), 1.06 (t, 3H, J=7.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]3[CH2:19][O:18]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[N-:20]=[N+:21]=[N-:22].[Na+].[NH4+].[Cl-].O>CCO>[N:20]([CH2:19][CH:17]([OH:18])[CH2:16][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21

Procedure:
3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (500 mg, 1.3 mmol), NaN3 (111 mg, 1.7 mmol), NH4Cl (91 mg, 1.7 mmol), were combined in 4 ml of EtOH and 1 ml of H2O and heated to 80° C. overnight. Upon completion, the EtOH was evaporated and the mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine and dried over Na2SO4 and concentrated. The material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].Cl.[N:11]([O-])=O.[Na+].[F:15][B-:16]([F:19])([F:18])[F:17].[Na+]>O>[F:15][B-:16]([F:19])([F:18])[F:17].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N+:6]#[N:11])=[CH:4][C:3]=1[CH3:9]
Reactant: O=N[O-]
Reactant: Cc1cc(N)ccc1Cl
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: Cc1cc([N+]#N)ccc1Cl
Yield: 95.2 %

Procedure:
Synthesized according to General Procedure 1. 4-chloro-3-methylaniline (5 g, 35.3 mmol) in water (15 mL) and conc. HCl (9.5 mL, 116.5 mmol) at −5° C. was added a freshly prepared aqueous solution of sodium nitrite (3.2 g, 45.9 mmol) in water (8 mL) slowly over 10 minutes. After stirring for 15 minutes at −5° C. a freshly prepared aqueous solution of sodium tetrafluoroborate (5.4 g, 49.4 mmol) in water (14 mL) was added in one portion causing the formation of a precipitate. The solid was filtered and washed with cold (5° C.) diethyl ether (10 mL). The solid was dissolved in acetone (15 mL) and filtered. To the filtrate was added diethyl ether (15 mL) causing the precipitation of the arenediazonium tetrafluoroborate. The solid was filtered, washed with cold (5° C.) diethyl ether (5 mL) and then air dried overnight to provide 4-chloro-3-methylbenzenediazonium tetrafluoroborate (8.07 g, 33.6 mmol, 95% yield) as a tan solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.68 (d, J=2.2 Hz, 1H), 8.56 (dd, J=2.4, 8.8 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H) and 3.47 (s, 3H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=125.0; tR=0.24 min.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH3:14][O:15][CH2:16][C:17](O)=O>>[CH3:14][O:15][CH2:16][C:17]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1
Reactant: COCC(=O)O
Reactant: NC(C(=O)O)C(O)c1ccccc1
Product: COCc1nc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures Y, Z with methoxyacetic acid, Z1 and Z2. LC-MS-conditions 02: tR=0.81 min; [M+H]+=234.45.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:7][CH2:6][C:3]2([C:2]([F:9])([F:8])[F:1])[CH2:5][CH2:4]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1(C(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A 0° C. solution of (1-(trifluoromethyl)cyclopropyl)methanol (2.46 g, 17.56 mmol), TEA (2.94 mL, 21.1 mmol) and DMAP (0.215 g, 1.76 mmol) in DCM (35 mL) was treated with p-toluenesulfonyl chloride (3.38 g, 17.7 mmol), allowed to warm to RT and stirred overnight. The mixture was treated with additional DCM, washed with 2N HCl (3×), followed by satd. NaHCO3, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (3.42 g, 66%). 1H NMR (400 MHz, DMSO-d6): δ 7.77 (m, 2H), 7.48 (m, 2H), 4.16 (s, 2H), 2.41 (s, 3H), 1.04 (m, 2H), 0.92 (m, 2H); MS (ESI) m/z: 295.1 (M+H+).
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:3]=[CH2:4].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.C(OCC)(=O)C>CN(C=O)C>[Si:21]([O:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH:3]=[CH2:4])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: C=C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
To the resultant compound from Example 4 (0.264 g, 0.932 mmol) in DMF (4 ml) was added tert-butyldimethylsilyl chloride (0.300 g, 1.99 mmol) and imidazole (0.269 g, 3.95 mmol). The mixture was stirred at room temperature for 12 hours, poured into ethyl acetate and washed sequentially with 0.5M H3PO4, saturated NaHCO3 solution and brine, then dried over Na2SO4 and evaporated to afford 0.355 g (96%) of the desired compound. Mass spectrum: (M+H)+ =398.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>O1CCCC1>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1)[C:19]([CH3:20])=[O:21]
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 5-amino-2-benzoxazolinone (3.39 g, 22.5 mmol) and triethylamine (3.17 ml, 22.5 mmol) in dry tetrahydrofuran (50 ml) was dropwise added acetylchloride (1.6 ml, 22.6 mmol). The reaction mixture was stirred for additional 2 hours at room temperature, whereafter the precipitate was filtered off The crystals were treated with water (100 ml), filtered off and washed with water. This treatment left the product as white crystals, M.p. 295°-300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:9][CH2:10][CH2:11][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Chlorophenol (500 mg, 3.89 mg), 2-bromoethanol (0.28 ml, 3.89 mmol), triphenylphosphine (1.02 g, 3.89 mmol) were dissolved in tetrahydrofuran (8 ml). The solution was added dropwise with diisopropylazodicarboxylate (0.84 ml, 3.89 mmol) and stirred at room temperature for 3 hours. The solvent of the reaction mixture was evaporated, and then solids were precipitated by using diethyl ether-hexane and removed by filtration. The filtrate was evaporated under reduced pressure to obtain the title compound as crude product (1.18 g). The crude product was used for the next reaction without purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[C:4]([CH3:18])[CH:3]=1.[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].C1CCN2C(=NCCC2)CC1>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:12])=[C:4]([CH3:18])[CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1Nc1cnccc1C(=O)NS(C)(=O)=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
3-[(4-Iodo-2-methylphenyl)amino]isonicotinic acid (example 3) (50 mg, 0.141 mmol) was dissolved in 4 ml dry THF followed by the addition of 1,1″-carbonyldiimidazole (CDI) (0.311 mmol, 50 mg), methanesulfonamide (0.169 mmol, 16.1 mg) and DBU (0.169 mmol, 26 mg). The mixture was stirred for 16 h at 40° C. and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 20.3 mg (47 μmol; 33% yield) of pure desired product. LC-MS (method III): rt=2.74 min; m/z [M+H]+ 432.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[O:21][CH3:22])[CH2:6][CH2:7][CH3:8])[CH2:3][CH2:2]1.ClCCl.CO.N>>[CH:1]1([CH2:4][N:5]([CH2:6][CH2:7][CH3:8])[CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[O:21][CH3:22])[CH2:3][CH2:2]1
Reactant: CCCN(CCOc1ccc([N+](=O)[O-])cc1OC)CC1CC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCCN(CCOc1ccc(N)cc1OC)CC1CC1

Procedure:
Prepared analogously to Example 3.1.b. from 950 mg (3.1 mmol) of cyclopropylmethyl-[2-(2-methoxy-4-nitrophenoxy)ethyl]propylamine. Yield: 0.74 g (86% of theory); C16H26N2O2 (M=278.39); calc.: molecular ion peak (M+H)+: 279; found: molecular ion peak (M+H)+: 279; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].I[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>[Cu](I)I.C(OCC)(=O)C>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[N:4]([C:1](=[O:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Ic1cccs1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N(c1ccccc1)c1cccs1
Temperature: 150 °C
Yield: 18.4 %

Procedure:
A mixture of acetanilide (6.0 g), 2-iodothiophene (18.6 g), copper iodide (864 mg), and potassium carbonate (12.2 g) was heated for 2 hours at 150° C. After the mixture was allowed to cool, water and ethyl acetate were added thereto. The resulting mixture was stirred, then filtered with celite. The aqueous phase was extracted. The organic phase was washed with water and saturated brine, and dried over sodium sulfate. The resulting solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:5) to obtain N-(2-thienyl)acetanilide (1.77 g; yield, 18%) as a light brown solid.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17](C(OCC1C=CC=CC=1)=O)[C@H:16]([CH3:31])[CH2:15]2)=O)C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:31][C@@H:16]1[CH2:15][C:14]2[C:18](=[CH:19][CH:20]=[C:12]([NH2:11])[CH:13]=2)[NH:17]1
Reactant: C[C@@H]1Cc2cc(NC(=O)OCc3ccccc3)ccc2N1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1Cc2cc(N)ccc2N1

Procedure:
A mixture of benzyl (2R)-5-{[(benzyloxy)carbonyl]amino}-2-methyl-2,3-dihydro-1H-indole-1-carboxylate (PCT/US00/08224; WO00/73301, 3.36 g, 8.07 mmol) and 10% palladium-on-carbon (108 mg) in THF/MeOH (1:1, 60 mL) is shaken on a Parr apparatus under a 36 psi hydrogen atmosphere overnight. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure. Purification by chromatography on a Biotage Flash 40M 90 g silica gel cartridge (1–2% MeOH/CH2Cl2) affords the title compound, MS (ESI+) for C9H12N2 m/z 149 (M+H)+.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:36])[CH2:7][C@@H:8]([OH:35])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH2:13][CH2:12]1)=[O:10].Cl>C1COCC1.O>[OH:35][C@@H:8]([C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[CH2:7][C:6]([OH:36])=[O:5]
Reactant: COC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(=O)O)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
LiOH.H2O (19.8 mg, 0.47 mmol) was added to a solution of (R)-3-hydroxy-4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-butyric acid methyl ester (71 mg, 0.16 mmol) in 2 mL THF:H2O (1:1) and stirred at room temperature for 3 h. The reaction mixture was acidified with 1 M HCl and then extracted with EtOAc. After drying the organic layer over Na2SO4, it was concentrated and then purified via silica gel chromatography using 0-15% MeOH/CH2Cl2 to provide (R)-3-hydroxy-4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-butyric acid (52 mg, 75%). LC/MS: m/z 437.3 (M+H)+ at 2.04 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)c(F)c2)cs1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(CCc2ccc(CCl)c(F)c2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of N-(4-{2-[3-fluoro-4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (196.6% mg, 0.668 mmol) in chloroform (10 ml) was added thionyl chloride (0.144 ml, 2.00 mmol), and the mixture was stirred at room temperature for 1 hr. Thionyl chloride (0.077 ml, 1.00 mmol) was added, and the mixture was stirred at room temperature for 1 hr and concentrated. Ethyl acetate (10 ml) was added to the residue, and the mixture was concentrated again under reduced pressure. The operation was performed 3 times to remove thionyl chloride azeotropically. A mixture of ethyl acetate (1 ml) and diisopropyl ether (10 ml) was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give N-(4-{2-[4-(chloromethyl)-3-fluorophenyl]ethyl}-1,3-thiazol-2-yl)acetamide (205.3 mg, 0.656 mmol, yield 98.3%) as a slightly yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCNc2ccccc2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCNc2ccccc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
489 mg (2.5 mol) of 5-chloro-1H-indole-7-carboxylic acid, 706 mg (2.5 mmol) of N-(4-tert-butyl-benzyl)-N′-phenyl-ethane-1,2-diamine and 541 mg (2.75 mmol) of EDC.HCl were dissolved in 20 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed with 1N aqueous HCl solution, once with 1N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel; diethyl ether/heptane 1:1) to yield 460 mg (40%) product as a white solid. MS (ISP) 460.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:51][CH2:52][CH:53]([CH3:55])[CH3:54])[CH:48]([CH3:50])[CH3:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:51]([CH2:52][CH:53]([CH3:55])[CH3:54])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CC(C)CNCC(C)C
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CC(C)C)CC(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with diisobutylamine (Alfa) to give the title product. LC-MS (ES+) 776 [(M+H)+].