Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:18][CH2:17][CH2:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([CH2:23][C:24]([OH:26])=[O:25])[CH2:18][CH2:17][CH2:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1CCCc2cc(OCc3cccc(Oc4ccccc4)c3)ccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CC1CCCc2cc(OCc3cccc(Oc4ccccc4)c3)ccc21
Temperature: 25 °C
Reaction time: 9 h
Yield: 80.6 %

Procedure:
To a solution of ethyl (6-((3-phenoxybenzyl)oxy)-1,2,3,4-tetrahydro-1-naphthalenyl)acetate (0.481 g, 1.15 mmol) in a mixed solvent of ethanol (4 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 9 hr. Water was added to the reaction mixture, and the mixture was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.360 g, yield 81%) as colorless needle crystals.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>>[CH:1]([CH:11]=[CH:10][C:9]#[N:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC#N
Reactant: C=Cc1ccccc1
Product: N#CC=CC=Cc1ccccc1
Yield: 684.5 %

Procedure:
Polymerization reaction was carried out in the same way as in Example 6 by employing 520 g of ethylene-propylene block copolymer (PEP), 430 g of styrene and 50 g of acrylonitrile to obtain 1001 g of styrene-acrylonitrile-modified ethylene-propylene block copolymer particles.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13](C(OCC2C=CC=CC=2)=O)[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:13][C@@H:12]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:31][CH:30]=1)[C@@H:11]([OH:15])[CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(-c2cccnc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution containing the product from Example 67A (0.130 g, 0.205 mmol) in methanol (3 mL) was treated with Pd(OH)2 on carbon (0.040 g, 20% Pd by wt.) and HCl solution (0.150 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) for 2.5 hours at 25° C., filtered through a bed of celite® and rinsed with methanol. The filtrate was concentrated to give the title compound as the hydrochloride salt.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[C:12]3/[C:13](=[O:18])[NH:14][C:15](=[S:17])[S:16]/3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.IC.[CH:21](N(CC)C(C)C)(C)C.O>C(O)C>[CH3:21][S:17][C:15]1[S:16]/[C:12](=[CH:11]\[C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)/[C:13](=[O:18])[N:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1NC(=S)S/C1=C\c1ccc2ncccc2c1
Solvent: CCO
Solvent: CI
Solvent: O
Product: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
The suspension of 5-[1-quinolin-6-yl-meth-(Z)-ylidene]-2-thioxo-thiazolidin-4-one (10.2 g, 37.5 mmol), iodomethane (4.65 mL, 75 mmol) and DIEA (N,N-diisopropylethylamine) (9.8 mL, 56.3 mmol) in anhydrous ethanol (100 mL) was stirred at room temperature for 12 h. After adding water (200 mL), the solid was collected by filtration, washed with water and dried to obtain 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one (8.76 g, 82%) as a grey solid. LC-MS m/e 287 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[C:26]([NH:28][NH:29][C:30](=[O:36])[CH2:31][O:32][CH:33]([CH3:35])[CH3:34])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1>C(OCC)C>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[C:26]2[O:36][C:30]([CH2:31][O:32][CH:33]([CH3:35])[CH3:34])=[N:29][N:28]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([CH3:6])([CH3:8])[CH3:7]
Reactant: CC(C)OCC(=O)NNC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC(C)OCc1nnc(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)o1

Procedure:
Thionyl chloride was added to a solution of 4-tert-butyl-N-{4-chloro-2-[N′-(2-isopropoxy-acetyl)-hydrazinocarbonyl]-phenyl}-benzenesulfonamide (150 mg, 0.312 mmol) and pyridine (66 μL, 0.811 mmol) in diethyl ether (3 mL). The resultant solution was stirred for 18 h at room temperature followed by removal of the volatiles in vacuo. 2 mL toluene was subsequently added and the reaction was heated at reflux for 5 h. The resultant solution was concentrated at reduced pressure and the residue purified via flash column chromatography (0-50% ethyl acetate in hexane) to afford 4-tert-butyl-N-[4-chloro-2-(5-isopropoxymethyl-[1,3,4]oxadiazol-2-yl)-phenyl]-benzenesulfonamide as a white solid.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[SH:15][C:16]1[N:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]#[N:32])=[CH:23][CH:22]=2)[CH:18]=[CH:19][N:20]=1>ClCCl>[C:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[S:15][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:22][CH:23]=1)#[N:32]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(-n2ccnc2S)c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSc1nccn1-c1ccc(C#N)c2ccccc12
Reaction time: 3 h

Procedure:
Triethylamine (4.92 mL, 35.32 mmol), followed by ethyl bromoacetate (3.74 mL, 33.72 mmol) were added to a stirring slurry of 4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile (8.07 g, 32.11 mmol) in dichloromethane (60 mL) and stirring continued for 3 h. The mixture was washed with aqueous HCl solution (0.2M 100 mL), 50% saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated. Hexanes (100 mL) were added and the mixture concentrated to provide ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate as a light-tan solid (10.47 g, (97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[NH:22][CH:21]=3)=[O:19])[CH:17]=2)=[O:10])=[CH:4][CH:3]=1.Br[CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])[CH:21]=3)=[O:19])[CH:15]=[N:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)Br
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 229 using 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308), methyl 2-bromopropionate and cesium carbonate. Purified using preparative HPLC (method 1) to afford the title compound.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[CH:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:27]=[S:19]1(=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:28])=[O:5])[CH:9]=2)[NH:18]1
Reactant: CC(C)(C)OC(=O)Cn1cc(C2NS(=O)(=O)c3ccccc32)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1cc(C2NS(=O)(=O)c3ccccc32)c2ccccc21
Reaction time: 13 h

Procedure:
The product of example 1, step d (32 mg, 0.08 mmol) was treated with trifluoroacetic acid (TFA) (neat) or 70% TFA in DCM. After stirring 2-24 h, the reaction was concentrated to dryness and purified by preparative LCMS to give the title compound. 1H NMR (DMSO-d6) δ 7.90-7.86 (m, 1H), 7.66-7.57 (m, 2H), 7.38 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.25-7.20 (m, 2H), 7.06 (t, J=7.2 Hz, 1H), 6.87 (t, J=7.2 Hz, 1H), 6.07 (s, 1H), 4.62 (s, 2H); MS: ESI (negative): 341 (M−H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[B-][N+](C)(C)C>C1C=CC=CC=1.[OH-].[Na+].O>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][NH:16][C:17]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [B-][N+](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C

Procedure:
To a solution of 1-Boc-piperidine-4-carboxaldehyde (3.5 g, 14 mmol) and 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (3.9 g, 14 mmol) in benzene (250 mL), a catalytic amount of pyridinium p-toluenesulfonate (0.35 g, 1.4 mmol) was added, followed by 4 A molecular sieves. The reaction mixture was heated at reflux for 48 h with azeotropic removal of water. The mixture was subsequently filtered through a pad of diatomaceous earth, washing well with ethyl acetate. The filtrate was concentrated in vacuo to a residue that was taken up in acetic acid (100 mL) and treated with borane-trimethylamine complex (3 g, 42 mmol). The mixture was heated at 70° C. for 24 h; then it was diluted with 2 N NaOH and extracted with dichloromethane. The water layer was neutralized with solid sodium bicarbonate, and further extracted with dichloromethane. The combined organic extracts were dried with MgSO4, filtered, and concentrated in vacuo to a solid residue (8 g, >100%) which was identified as the desired product and taken on directly to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1C(c2cnc3ccccc3c2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-6-(3-(piperazin-1-yl)propoxy)-2-(quinolin-3-yl)-1H-inden-1-one (40 mg, 1.2 eq, 0.1 mmol) obtained in Step 3 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (53%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1([OH:27])[CH2:7][N:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[O:9])[CH2:5]1)[CH3:3].[CH2:28]=O.[BH4-].[Na+]>CO.C=O>[F:17][C:12]1[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:10]([C:8]([N:6]2[CH2:7][C:4]([C@@H:2]([NH:1][CH3:28])[CH3:3])([OH:27])[CH2:5]2)=[O:9])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: C[C@H](N)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN[C@@H](C)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To 3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (87.4 mg, 0.18 mmol), prepared using procedures similar to those described in Example 28, was added formaldehyde (37% aqueous, 14 mg, 0.18 mmol) in methanol (2 mL) and sodium borohydride (7 mg, 0.18 mmol). The mixture was stirred for 3 h at rt, after which sodium borohydride (16 mg, 0.42 mmol) was added. Upon stirring an additional 1.25 h, more formaldehyde (37% aqueous, 1 drop) was added, and the mixture was stirred 3 days at rt. A further small spatula (˜50 mg) of sodium borohydride was then added, and the mixture was stirred at rt for 30 min. After quenching with 1 N HCl, the reaction mixture was purified directly by preparative HPLC. The clean material was converted to its hydrochloride salt to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol as a yellow solid (21.7 mg, 0.040 mmol, 22% yield). 1H NMR (400 MHz, CD3OD) δ 7.47 (dd, 1H), 7.36 (d, 1H), 7.31 (m, 1H), 7.06 (q, 1H), 6.62 (dt, 1H), 4.36 (dd, 1H), 4.21-3.91 (m, 3H), 3.44 (q, 1H), 2.66 (s, 3H), 1.29 (br m, 3H); MS (EI) for C19H19F3IN3O2: 506 (MH+).
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10]([O:12]C=O)C>CN(C)C=O>[CH:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:12]
Reactant: CCOC=O
Reactant: NCCCCCC(=O)O
Solvent: CN(C)C=O
Product: O=CCCCCCC(=O)O
Temperature: 100 °C
Yield: 95 %

Procedure:
6-Aminocaproic acid (100 g, 0.76 mol) was suspended in a mixture of ethylformate and N,N-dimethylformamide (1 l, 1:1) and heated at 100° C. for 18 h. The volatiles were evaporated in vacuo and the residue treated with ethyl acetate. The solid matter was filtered off and washed with ethyl acetate and air dried which afforded 115 g (95%) of 6-formyl hexanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8](Br)[CH:9]=1)=[O:4].CCN(CC)CC.[Br:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([S:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Reactant: Sc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Sc2cccc(Br)c2)c([N+](=O)[O-])s1
Yield: 99.8 %

Procedure:
4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 1 g, 3.75 mmol) and Et3N (523 μL, 3.75 mmol) were dissolved with THF (10 mL) into a round bottom flask with stir bar. To this 3-bromothiophenol (467 μL, 4.51 mmol) was added with stirring. The reaction became turbid therefore additional THF (12 mL) was added. The reaction was stirred at rt for 12 hours. The reaction mixture was concentrated in vacuo and then dissolved into EtOAc. The organic layer was washed several times with saturated NaHCO3 and brine. The combined organic layers were dried over sodium sulfate. Removal of the solvents in vacuo yielded the title compound (1.40 g, quantitative yield), which was used without further purification. 1H-NMR (CDCl3): δ 7.79 (t, 1H, J=1.8 Hz), 7.67–7.70 (m, 1H), 7.54–7.85 (m, 1H), 7.37–7.41 (t, 1H, J=7.9 Hz), 6.87 (s, 1H), 3.88 (s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]1[CH:67]=[CH:66][C:65]([C:68](O)=[O:69])=[CH:64][CH:63]=1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:68]([C:65]1[CH:64]=[CH:63][C:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[O:55][CH3:54])=[CH:67][CH:66]=1)=[O:69]
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 44.1 %

Procedure:
DIPEA (140 mg, 0.19 mL, 1.08 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method as described above) (119 mg, 0.38 mmol) in DMF (5 mL). HOBT (45 mg, 0.33 mmol) and EDCI (118 mg, 0.61 mmol) were then added at room temperature. After 2 minutes, 2′-Methoxy-biphenyl-4-carboxylic acid (70 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by preparative HPLC to afford 71 mg (44.1% yield) 2′-Methoxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 98.92%. 1H NMR (CDCl3): δ 7.94-7.84 (t, 1H), 7.8-7.72 (d, 1H), 7.7-7.56 (m, 4H), 7.5-7.44 (t, 1H), 7.4-7.3 (m, 3H), 7.1-7.0 (dd, 2H), 4.4-4.2 (m, 2H), 4.1-3.86 (m, 2H), 3.84-3.8 (s, 3H), 3.76-3.5 (m, 4H), 3.44-3.38 (t, 1H), 3.3-3.2 (bs, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]Cl.[OH-].[Na+].Cl>CCCCO>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[O:17][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:1][C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=3[CH2:9][C:10]=2[CH:15]=1
Reactant: Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1O
Reactant: ClCCOCCOCCOCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Clc1ccc2c(c1)Cc1cc(Cl)ccc1OCCOCCOCCOCCO2
Yield: 23.1 %

Procedure:
10 g (0.037 mole) bis(2-hydroxy-5-chlorophenyl)-methane and 8.6 g (0.037 mole) 1,11-dichloro-3,6,9-trioxaundecane are dissolved in 100 ml n-BuOH. To this is added 6.5 g 50% aqueous sodium hydroxide. The resulting solution is heated to reflux for 15 hours, acidified with ethereal HCl, and solvent stripped in vacuo. The resulting gum is chromatographed on Neutral Alumina IV, eluting with ether/ethyl acetate. Appropriate fractions are collected, combined and recrystallized from methanol to yield 3.65 g white crystalline solid; m.p. 143.5°-144°. Yield: 23%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:37]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:37]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccc(C(F)(F)F)cc3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)(F)F)cc3)sc3cc(O)ccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a 2-dram vial containing (E)-tert-butyl 3-(4-((6-methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3 yl)oxy)phenyl)acrylate (59.4 mg, 0.113 mmol) in anhydrous DCM (1.5 mL) at 0° C. was added BBr3 (1.0 M in DCM, 451 μL, 0.451 mmol) dropwise. The resulting mixture was stirred at 0° C. for 1 h after which the reaction was quenched with 3 drops of water, diluted with DCM, and extracted with sat. aq. NaHCO3 (added a few drops of 2-propanol). The organic layer was dried over anhydrous MgSO4, filtered concentrated in vacuo to afford the crude material which was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 10-100% CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (33.8 mg, 0.074 mmol, 66% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=6.36 (d, J=16.17 Hz, 1H), 6.78-6.89 (m, 1H), 6.98 (d, J=8.59 Hz, 2H), 7.17-7.30 (m, 2H), 7.51-7.70 (m, 5H), 7.88 (d, J=8.08 Hz, 2H). HRMS (m/z, MH+): 457.0710.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10]>C1COCC1>[OH:12][C:8](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH:9]([CH3:11])[CH3:10]
Reactant: N#CCC#N
Reactant: CC(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(O)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A solution of malononitrile (4.0 g, 60 mmol) in THF (30 mL) was added dropwise over 1 h to a suspension of NaH (95%, 3.0 g, 120 mmol) in THF (75 mL) at 0° C. The reaction was then warmed to room temp and stirred for 1 h. The suspension was then cooled to 0° C. and treated dropwise with a solution of isobutyryl chloride (6.3 mL, 60 mmol) in THF (25 mL). The addition was controlled so that the internal temp does not rise above 10° C. Upon completion of the addition the reaction was warmed to room temp and stirred for 24 h. The reaction was then quenched with H2O (10 mL) and evaporated. The residue was then partitioned between EtOAc (100 mL) and 1 N HCl (75 mL). The aqueous layer was extracted again with EtOAc (50 mL) and the combined organic layers were washed with brine (100 mL), dried (c), filtered, and evaporated to yield the desired product (7.95 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:16]([C:17](O)=[O:18])[CH2:15][C:14]2([CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].C1C2(OCCCO2)C[C@@H](C2NC=C([C:42]3[CH:47]=[CH:46][C:45]([C:48]4[CH:53]=[CH:52][C:51]([C:54]5[N:55]=[C:56]([C@@H:59]6[CH2:63][CH2:62][CH2:61][N:60]6[C:64]([C@@H:66]([NH:70][C:71](=[O:74])[O:72][CH3:73])[CH:67]([CH3:69])[CH3:68])=[O:65])[NH:57][CH:58]=5)=[CH:50][CH:49]=4)=[CH:44][CH:43]=3)N=2)N1>>[CH3:68][CH:67]([CH3:69])[C@H:66]([NH:70][C:71](=[O:74])[O:72][CH3:73])[C:64]([N:60]1[CH2:61][CH2:62][CH2:63][C@H:59]1[C:56]1[NH:57][CH:58]=[C:54]([C:51]2[CH:50]=[CH:49][C:48]([C:45]3[CH:44]=[CH:43][C:42]([C:10](=[O:11])[CH2:6][NH:5][C:17]([CH:16]4[CH2:15][C:14]5([CH2:20][CH2:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24]5)[CH2:13][N:12]4[C:10](=[O:11])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:9])[CH3:8])=[O:18])=[CH:47][CH:46]=3)=[CH:53][CH:52]=2)[N:55]=1)=[O:65]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1C(=O)NCC(=O)c1ccc(-c2ccc(-c3c[nH]c([C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)n3)cc2)cc1)C(C)C
Yield: 49 %

Procedure:
Prepared in 49% yield from 2-{N-[(methyloxy)carbonyl]-L-valyl}-8-thia-2-azaspiro[4.5]decane-3-carboxylic acid 8,8-dioxide (107) (100 mg, 0.26 mmol) and methyl {(1S)-[((2S)-2-{4-[4′-(aminoacetyl)-4-biphenylyl]-1H-imidazol-2-yl}-1-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate dihydrochloride (1) (148 mg, 0.26 mmol), in an analogous fashion as described in Example 15.