Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH2:11]=[O:12]>>[OH:12][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: Cn1cnc2ccccc21
Reactant: C=O
Product: Cn1c(CO)nc2ccccc21
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A solution of 1-methylbenzimidazole (2.5 g, 19 mmol), (J. Chem. Soc. 1929, 2820-2828), and paraformaldehyde (2 g) was heated at 165° C. for 30 minutes. Further paraformaldehyde (1 g) was added and heating continued for 2 hours. The mixture was allowed to cool and was purified by column chromatography eluting with methylene chloride, followed by methylene chloride/methanol (95/5) to give 2-hydroxymethyl-1-methylbenzimidazole (1.34 g, 45%). 1H NMR Spectrum: (DMSOd6) 3.84(s, 3H); 4.73(s, 2H); 5.57(br s, 1H); 7.19(t, 1H); 7.25(t, 1H); 7.54(d, 1H); 7.60(d, 1H) MS-ESI: 185 [MNa]+
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C(O)(=O)C.C(=O)(OCC)N.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:33])[CH:26]3[CH2:32][NH:31][CH2:30][CH:27]3[C:28]=2[CH:29]=1>ClCCCl>[Cl:8][C:29]1[C:28]2[CH:27]3[CH2:30][NH:31][CH2:32][CH:26]3[C:25](=[O:33])[C:24]=2[CH:23]=[CH:22][C:21]=1[O:20][CH3:19]
Reactant: COc1ccc2c(c1)C1CNCC1C2=O
Reactant: O=C1CCC(=O)N1Cl
Agent: CCOC(N)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2c(c1Cl)C1CNCC1C2=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
NCS (0.25 g, 1.9 mmol) and acetic acid (10 mL) were added to a solution of ethyl carbamate-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.52 g, 1.9 mmol) in DCE (10 mL), and stirred overnight at 60° C. The reaction was quenched with aqueous HCl (1 M) and washed with brine. The organic extracts were dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-60% EtOAc-hexanes gradient to afford the subtitle compound as a mixture of regioisomers. MS calculated for C15H16ClNO4+H: 310, observed: 310.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[N:41]1[CH:46]=[CH:45][CH:44]=[N:43][C:42]=1[CH2:47][C:48](O)=[O:49]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:48](=[O:49])[CH2:47][C:42]1[N:43]=[CH:44][CH:45]=[CH:46][N:41]=1)[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)Cc1ncccn1
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cc3ncccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using 2-pyrimidine acetic acid as the reacting carboxylic acid. LCMS: m/e 650.6 (M+H)+, 5.57 min (method 3). 1H NMR (599 MHz, <DMSO_CDCl3>) δ=8.78 (d, J=4.7 Hz, 2H), 7.88 (d, J=8.2 Hz, 2H), 7.29 (s, 1H), 7.22 (d, J=7.6 Hz, 2H), 5.28 (d, J=5.3 Hz, 1H), 4.75 (s, 1H), 4.62 (br. s., 1H), 3.93 (s, 1H), 3.82 (d, J=14.6 Hz, 1H), 2.77-2.72 (m, 1H), 2.63 (d, J=12.9 Hz, 1H), 2.40-2.32 (m, 1H), 2.16-2.04 (m, 1H), 2.00-1.81 (m, 2H), 1.73 (br. s., 2H), 1.71 (s, 3H), 1.67-1.52 (m, 4H), 1.50-1.39 (m, 7H), 1.36-1.20 (m, 7H), 0.99 (br. s., 6H), 0.98 (br. s., 3H), 0.93 (br. s., 3H), 0.93 (br. s., 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H][H]>CO.[Rh]>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc2cccnc2n1
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCc1ccc2c(n1)NCCC2
Yield: 68.9 %

Procedure:
A solution of naphthyridine 1-4 (2.72 g) in methanol (20 mL) was hydrogenated in the presence of 5% rhodium on carbon (2.1 g; containing 63% of water) under 40 psi of hydrogen at 5° C. for 10 hours. The catalyst was filtered through Solka Flok and washed with methanol (25 mL twice). The filtrate and washings were combined, concentrated in vacuo, and dissolved in methanol (6.8 mL). To the solution was added water (6.8 mL) slowly at ambient temperature. The resulting solid was collected by filtration, washed with a mixture of water and methanol (2:1; 5 mL), and dried under vacuum to give the desired crystalline tetrahydronaphthyridine 1-5 (1.9 g). The mother liquor yielded an additional 5% of 1-5; m.p. 95.2-96.3° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1I)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]1([CH3:34])[C:31]([CH3:33])([CH3:32])[O:30][BH:29][O:28]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[B:29]1[O:30][C:31]([CH3:33])([CH3:32])[C:27]([CH3:34])([CH3:26])[O:28]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(COCC(=O)OC(C)(C)C)c1I
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cccc(COCC(=O)OC(C)(C)C)c1B1OC(C)(C)C(C)(C)O1

Procedure:
The procedure used in Example 3: step b was followed using (2-iodo-3-methyl-benzyloxy)-acetic acid tert-butyl ester ((Example 299: step a) 571 mg, 1.6 mmol), PdCl2(PPh3)2 (55 mg, 0.08 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL) at a reaction temperature of 80° C. Analogous aqueous workup and purification by SiO2 flash column chromatography yielded the title compound contaminated with the product resulting from halide reduction (542 mg, 95%). The material was used without further purification. 1H-NMR (CDCl3): δ 7.20 (t, 1H, 7.4 Hz), 7.11 (d, 1H, J=7.4 Hz), 7.07 (d, 1H, J=7.4 Hz), 4.72 (s, 2H), 3.86 (s, 2H), 2.43 (s, 3H), 1.46 (s, 9H), 1.39 (s, 12H).
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].N1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[C:9]([NH:2][C:3]1[N:4]=[C:5]([Br:8])[S:6][CH:7]=1)(=[O:12])[CH:10]=[CH2:11]
Reactant: Nc1csc(Br)n1
Reactant: C=CC(=O)Cl
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)Nc1csc(Br)n1
Yield: 5 %

Procedure:
4-Amino-2-bromothiazole hydrobromide (15.6 g) and acryloylchloride (7 g) were suspended in methylene chloride (100 ml) with stirring and treated with pyridine (16 ml), maintaining reaction temperature at 0° C. with an ice bath. After addition was complete, the reaction mixture was stirred at room temperature for 3 hours, then poured onto 20% aqueous sodium acetate and stirred for 30 minutes. The mixture was filtered and separated and the organic layer washed with 2N hydrochloric acid, water, sodium carbonate solution and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo. The residue was recrystallised from carbon tetrachloride to give the title compound (0.7 g) m.p. 152°-4° C. (Found: C, 30.5; H, 2.2; N, 11.8. C6H5BrN2OS requires C, 30.9; H, 2.2; N, 12.0%).
Reaction SMILES: [F:1][C:2]([F:42])([C:38]([F:41])([F:40])[F:39])[CH2:3][CH2:4][CH2:5][S:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:35][C:34]2[CH:33]=[C:32]([OH:36])[CH:31]=[CH:30][C:29]=2[C@@H:28]2[C@@H:19]1[C@H:20]1[C@@:24]([CH2:26][CH2:27]2)([CH3:25])[C@@H:23]([OH:37])[CH2:22][CH2:21]1.C(OC(=O)C)(=O)C.B1([O-])OO1.[OH2:54].[OH2:55].O.O.[Na+]>>[F:42][C:2]([F:1])([C:38]([F:39])([F:40])[F:41])[CH2:3][CH2:4][CH2:5][S:6]([CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:35][C:34]2[CH:33]=[C:32]([OH:36])[CH:31]=[CH:30][C:29]=2[C@@H:28]2[C@@H:19]1[C@H:20]1[C@@:24]([CH2:26][CH2:27]2)([CH3:25])[C@@H:23]([OH:37])[CH2:22][CH2:21]1)(=[O:55])=[O:54]
Reactant: O
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)OC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CS(=O)(=O)CCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Under the conditions of Example 3, 76 mg of 7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol (Example 26f) is acetylated with acetic anhydride, and the crude product is oxidized, as described in Example 4, with sodium perborate tetrahydrate, worked up and chromatographed. 31 mg of the title compound is obtained as oil. [α]D22 =30.6°(c=0.515 in methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[Br:11]Br.N>CC(O)=O>[Br:11][C:3]1[C:4]2[NH:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: BrBr
Agent: N
Solvent: CC(=O)O
Product: Nc1ccc2nc[nH]c2c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 5-aminobenzimidazole (0.3 g, 2.3 mmol) in 30 ml of AcOH was added bromine. (0.055 ml, 1.1 mmol) in a portion and resulting reaction mixture was stirred for 0.5 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a dark brown solid which was subjected to silica gel column chromatography (NH3 saturated 10% MeOH/EtOAc) to yield 0.22 g (0.97 mmol, 42%) of the desired product.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15](F)[CH:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5])[CH3:2].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][NH:28][CH3:29]>CS(C)=O>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][N:28]([CH3:29])[C:15]1[CH:14]=[C:13]([C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH3:12])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CNCCN(C)C
Reactant: CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(N(C)CCN(C)C)c2)s1
Temperature: 120 °C

Procedure:
A stirred mixture of 1-Ethyl-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 73) (0.05 g, 0.14 mmol) and N,N,N′-Trimethylethylenediamine (0.25 ml, 2.1 mmol) in dry DMSO (0.5 ml) is heated under argon at 120° C. for 2 hours. The solvent is in vacuo removed and the product is purified by chromatography on silica eluting with ethanol-triethylamine (98:1) to give the titled compound. MH+: 440.1051
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:8]2[S:18][CH3:19].I[CH3:21].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:21])[C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:8]2[S:18][CH3:19]
Reactant: COC(=O)c1[nH]c2ccc(OC)cc2c1SC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(SC)c2cc(OC)ccc2n1C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A suspension of 60% sodium hydride in mineral oil (0.30 g, 7.5 mmol) in 3.0 mL of N,N-dimethylformamide is cooled in ice while a solution of methyl 5-methoxy-3-(methylthio)-1H-indole-2-carboxylate (1.3 g, 5.2 mmol) in 10 mL of N,N-dimethylformamide is added dropwise. The mixture is stirred for 45 minutes, then iodomethane (0.50 mL, 1.1 g, 8.0 mmol) is added in one portion. After stirring at room temperature for 8 hours, the mixture is added to 100 g of ice and water. The solid is filtered and washed with 10% methanol-water to yield 1.2 g (88%) of product. A sample purified by flash chromatography (silica gel, 25% hexane in dichloromethane elution) and recrystallized from hexane has mp 89°-91° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O:14][CH:15](OC)[C:16]1[C:40]([O:41]COC)=[C:39]([C:45]([F:48])([F:47])[F:46])[CH:38]=[CH:37][C:17]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:27]=2)=[CH:22][CH:21]=1.O>CC(C)=O>[CH:15]([C:16]1[C:40]([OH:41])=[C:39]([C:45]([F:46])([F:48])[F:47])[CH:38]=[CH:37][C:17]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:27]=2)=[CH:22][CH:21]=1)=[O:14]
Reactant: COCOc1c(C(F)(F)F)ccc(COc2ccc(-c3cccc(CC(=O)OC)c3)cc2)c1C(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)Cc1cccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C=O)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
After p-toluenesulfonic acid monohydrate (0.716 g, 3.77 mmol) was added to a solution of methyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-3-yl)acetate (1.83 g, 3.43 mmol) obtained in Example (8-2) in acetone (20 ml), the mixture was stirred at room temperature for 6 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate (twice), the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a residue. The obtained residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=80/20-70/30) to give methyl (4′-{[2-formyl-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-3-yl)acetate (1.26 g, yield: 83%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][C:8]2=[O:13].I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[C:2]([F:1])([F:14])[F:15])[C:8]1=[O:13]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2c1cccc2C(F)(F)F
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2c(cccc2C(F)(F)F)C1=O
Yield: 24.2 %

Procedure:
Using analogous reaction conditions as described in Example 1, 5-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-22d: 0.090 g, 0.4186 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.091 g, 0.4186 mmol), 1,4-dioxane (10 mL), copper iodide (0.007 g, 0.04186 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.017 g, 0.1255 mmol) and potassium phosphate (0.221 g, 1.0465 mmol) to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 0.031 g of the product (24% yield).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[C:5]([Br:8])[C:6]=1[CH3:7].[Li][CH2:11]CCC.S(OC)(OC)(=O)=O>C(OCC)C>[Br:1][C:2]1[S:3][C:4]([CH3:11])=[C:5]([Br:8])[C:6]=1[CH3:7]
Reactant: [Li]CCCC
Reactant: Cc1c(Br)sc(Br)c1Br
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: Cc1sc(Br)c(C)c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
A solution of 2,4,5-tribromo-3-methylthiophene (50.2 g, 0.15 mol; Gronowitz, S.; Moses, P. Hakansson Arkiv. f. Kemi. 1960, 14, 267) in 400 mL of diethyl ether was cooled to -78° C., and a solution of nBuLi (100 mL, 1.6M) was added dropwise. The starting material precipitated out of solution, but when n-BuLi added, the reaction mixture became stirrable again. When the addition was complete, the reaction mixture was stirred for 20 min, and then a solution of dimethyl sulfate (75.7 g, 0.600 mol) in 200 mL of diethyl ether which was cooled to -50° C. was added by cannulation. When addition was complete, the reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction was quenched with 100 mL of 6N NaOH solution and stirred for 2h. The mixture was transferred to a separatory funnel, and the aqueous layer was separated and extracted with additional ether. The organic layers were combined, washed with water and brine and dried (MgSO4). The suspension was filtered and concentrated to give an oil. Vacuum distillation provided 22.1 g (55%) of 2,4-dibromo-3,5-dimethylthiophene, A8, b.p. 71°-72° C. @ 0.4 mmHg. The 1H NMR in CDCl3 supported the assigned structure. ##STR58##
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.ClC(OCC(C)C)=O.Cl.[CH3:24][NH:25][O:26][CH3:27]>C1COCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([N:25]([O:26][CH3:27])[CH3:24])=[O:14]
Reactant: O=C(O)c1cccc2c(Br)cccc12
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1cccc2c(Br)cccc12
Reaction time: 0.42 h
Yield: 30 %

Procedure:
Step 1 A solution of 5-bromo-1-naphthoic acid (prepared according to the procedure of Hausamann, Chem. Ber., 1876, 9, 1519; 2.00 g, 7.97 mmol) in THF (50 mL) was treated with TEA (2.22 mL, 15.93 mmol), then with isobutyl chloroformate (1.088 g, 7.97 mmol) and the resulting suspension was stirred at rt. After 25 min, the mixture was treated with additional TEA (2.22 mL, 15.93 mmol), then with a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (0.777 g, 7.97 mmol) in water (5 mL), and the mixture was stirred at rt. After 2.5 h, the mixture was concentrated and the residue was taken up in EtOAc and water. The mixture was filtered, the layers were separated, and the organic phase was washed with NaHCO3 (aq), dried and concentrated to provide 5-bromo-N-methoxy-N-methyl-1-naphthamide as a pasty solid (1.03 g, 30%) contaminated with ca. 30% isobutyl 5-bromo-1-naphthoate. Mass spectrum m/z 294, 296 (M+H)+. Without further purification, a solution of this material (1.01 g, 2.404 mmol) in THF (15 mL) was stirred on ice and treated with (4-fluorophenyl)magnesium bromide, 2M in ether (7.21 mL, 14.42 mmol). The solution was stirred on ice and allowed to slowly warm to rt. After 16 h, the mixture was treated with 1 M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 85:15 hexane-EtOAc) to provide (5-bromonaphthalen-1-yl)(4-fluorophenyl)methanone as a pale yellow viscous oil (658 mg, 83%). 1H NMR (400 MHz, methanol-d4) δ 8.49 (1 H, d, J=8.6 Hz), 7.95 (1 H, d, J=8.6 Hz), 7.86-7.93 (3 H, m), 7.74 (1 H, dd, J=8.5, 7.2 Hz), 7.64-7.68 (1 H, m), 7.40 (1 H, dd, J=8.5, 7.6 Hz), 7.25 (2 H, t, J=8.8 Hz). Mass spectrum m/z 329, 331 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH2:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH:34][C:28]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=1[C:26](=[O:35])[NH:25][C@H:4]([C:3]([O:2][CH3:1])=[O:36])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Reactant: COC(=O)CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)CCCCCNc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)C(=O)OC

Procedure:
(S)-6-{4-Chloro-2-[1-methoxycarbonyl-2-(4′-phenoxy-biphenyl-4-yl)-ethylcarbamoyl]-phenylamino}-hexanoic acid methyl ester was prepared following Procedure G using (S)-2-(2-amino-5-chloro-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)propionic acid methyl ester (401 mg, 0.8 mmol), 6-oxo-hexanoic acid methyl ester (231 mg, 1.6 mmol), acetic acid (2.4 mmol), sodium triacetoxyborohydride (437 mg, 97%, 2 mmol) and DCE (6 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:3) gave the title compound as yellow oil (418 mg).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.C(=O)(O)O.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[CH:17][CH:16]=1.CN(C)C=O>C(OCC)C>[CH3:5][C:3]1[N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[N:24]=[C:1]([OH:7])[CH:2]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)Nc1ccc(F)cc1
Agent: O=C(O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(O)nc(Nc2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A mixture solution of ethyl acetoacetate(3.8 ml, 30.3 mmol), 4-fluorophenylguanidine carbonate(5 g, 26.3 mmol), and dimethylformamide(5 ml) was refluxed for 2 hours and cooled to a room temperature. Ethyl ether was added to the reaction mixture and the resulting solid was filtered, washed with ethyl ether, and concentrated under a reduced pressure to give 1.74 g of the titled compound. (Yield 30%)
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+:32].C(O)(C)C>O>[C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][K:32])=[O:27])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCCN(CCCCCC(=O)OCC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCN(CCCCCC(=O)O[K])S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A round bottom flask fitted with an overhead stirrer was charged with C4F9SO2N(C3H7)(CH2)5COOC2H5 (63.0 g; 0.143 mole), KOH (13.1 g; 0.234 mole; pellets) isopropanol (26 mL) and deionized water (21 mL). The ensuing mixture was refluxed overnight, cooled to room temperature, yielding a solution of C4F9SO2N(C3H7)(CH2)5COOK (61.3% solids).
Reaction SMILES: [CH:1]([C:9]1=[CH:10][C:11]([O:13][C:14]1=[O:15])=O)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=CC1C=CC=CC=1.C1C(=O)OC(=O)C=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>CN(C)C=O>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][N:36]1[C:14](=[O:15])[CH:9]=[CH:10][C:11]1=[O:13]
Reactant: CN(C)CCCN
Reactant: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Agent: O=C1C=CC(=O)O1
Solvent: CN(C)C=O
Solvent: C=Cc1ccccc1
Product: CN(C)CCCN1C(=O)C=CC1=O
Temperature: 110 °C

Procedure:
A solution of 250 g of copoly(styrene-maleic anhydride (commercially available from the Monsanto Chemical Company under the tradename of Lytron 810) in 2500 ml of dry dimethylformamide is made by stirring in a 5-liter flask, containing a reflux condenser, thermometer, stirrer, and dropping funnel. The mixture is heated to 110°C and 230 g of N,N-dimethyl-1,3-propanediamine is added slowly at a rate to keep the mixture boiling slightly. Polymer precipitates as a gummy mass at first but goes back into solution after about half of the amine is added. The condenser is replaced by a distillation column and about 500 ml of material is removed by distillation with stirring. The residue is cooled, precipitated in water, collected by filtration and air-dried at room temperature for 2 days. The solid is dissolved in acetone, and again precipitated in water and air-dried. Yield = 260 g of off-white, friable solid.