Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[C:35]2[CH2:36][CH2:37][C@H:38]([OH:43])[C:39]=2[CH:40]=[CH:41][CH:42]=1)=[NH:33]>CN(C=O)C.O>[OH:43][C@@H:38]1[C:39]2[C:35](=[C:34]([C:32]3[N:31]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:33]=3)[CH:42]=[CH:41][CH:40]=2)[CH2:36][CH2:37]1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N=C(NO)c1cccc2c1CC[C@@H]2O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4O)no2)cc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
Prepared using General Procedure 1. To 3-cyano-4-isopropoxybenzoic acid (93.2 mg, 0.45 mmol) in DMF (3 mL) was added HOBt (104.3 mg, 0.68 mmol) and EDC (130.6 mg, 0.68 mmol). The reaction was stirred at room temperature for 16 h until the acid was fully activated. (S)—N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide INT-2 (97 mg, 0.5 mmol) was added in one portion and the reaction was stirred at room temperature for 2 h. The crude material was heated to 85° C. for 18 h. The reaction mixture was cooled to room temperature. Water (15 mL) was added and the mixture was allowed to stand and the dark brown precipitate was filtered. The precipitate was purified by silica gel chromatography (EA/hexane) to give 73 mg (40%) of (S)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 6 as a white solid. LCMS-ESI (m/z) calculated for C21H19N3O3: 361.1; found 362.1 [M+H]+, tR=3.63 min. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=2.1, 1H), 8.36 (dd, J=8.9, 2.2, 1H), 8.16 (dd, J=7.7, 0.5, 1H), 7.63 (d, J=7.5, 1H), 7.46 (t, J=7.6, 1H), 7.15 (d, J=9.0, 1H), 5.36 (dd, J=12.6, 6.8, 1H), 4.82 (hept, J=6.1, 1H), 3.54 (ddd, J=17.5, 8.7, 4.6, 1H), 3.31-3.18 (m, 1H), 2.63 (dddd, J=13.2, 8.4, 7.1, 4.7, 1H), 2.07 (dddd, J=14.1, 8.7, 6.6, 5.5, 1H), 1.84 (d, J=7.1, 1H), 1.50 (d, J=6.1, 6H). 13C NMR (101 MHz, DMSO) δ 173.07, 168.30, 162.46, 148.27, 142.29, 134.57, 133.77, 127.53, 127.28, 127.05, 122.26, 116.00, 115.25, 114.87, 102.43, 74.05, 72.49, 35.03, 30.80, 21.46. Chiral HPLC: (S)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile was eluted with 20% IPA in hexane: >99.9% ee, tR=25.07 min. (R)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 5 and racemic material were obtained in an analogous fashion from (R)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile and racemic 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile respectively using General Procedure 1. tR for (R)-enantiomer=17.60 min.
Reaction SMILES: [Na+].[CH3:2][S:3]([CH2-:5])=[O:4].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2C(=O)O[C:17](=[O:18])[C:16]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:15]23)=[CH:10][CH:9]=1.Cl.C(Cl)Cl>CS(C)=O>[CH3:2][S:3]([CH2:5][C:17]([C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[NH:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)=[O:18])=[O:4]
Reactant: COc1ccc(-n2c(=O)oc(=O)c3ccccc32)cc1
Reactant: [CH2-]S(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(Nc2ccccc2C(=O)CS(C)=O)cc1
Reaction time: 1 h

Procedure:
To a 2 molar solution of dimsyl sodium in dimethylsulfoxide (365 ml.), cooled to 10° C., was added a solution of 65 g. of N-(4-methoxyphenyl)isatoic anhydride in 150 ml. dimethylsulfoxide with stirring and stirring was continued 30 minutes at room temperature and 1 hour at 50° C. The reaction mixture was poured onto 1200 g. of ice, 70 ml. of concentrated hydrochloric acid was added, and the mixture was extrated with methylene dichloride. The extract was washed with water, dried (MgSO4), and concentrated under reduced pressure to give, after recrystallization from benzenecyclohexane 45 g. 2-(methylsulfinyl)-2'-(4-methoxyanilino)acetophenone; m.p. 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O)(=[O:11])=[O:10].[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:34]>>[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[C:26]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])=[C:25]1[CH3:34]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccc(Cl)cc1Cl
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccc(Cl)cc2Cl)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 27c using 2-(2,4-dichlorobenzenesulfonyl)benzaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH2:8][CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(c1O)CC(c1ccccc1)C(=O)N2Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(c1O)CC(c1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (22 mg, 0.057 mmol), β-alanine (657 mg, 7.4 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4, and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH 2 with 4 M HCl, and the resulting precipitate was collected by filtration to give 12.4 mg of the title compound as a white solid. MS: (+) m/z 446.40 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[C:12]1([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.O>C1COCC1.CCOCC>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)([OH:4])[CH2:21][S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: CS(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(CC(O)(CBr)c1cccc(Br)c1)c1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
In a manner identical with Example 57, 2,3'-dibromoacetophenone (7.8 g, 0.028 mole) is treated with 1 equivalent of the magnesium anion of methyl phenyl sulphone in THF at -70° C. The mixture is stirred for 2 h at -70° C., acetic acid (7 cc) is then added and the mixture is poured into water (100 g). It is reextracted with ether (3×100 cc), is washed with brine (2×100 cc) and is dried over MgSO4. The crude is precipitated with ether (50 cc) with warming and recrystallized from isopropyl ether to give white crystals of 1-bromo-2-[3'-bromophenyl]-3-phenylsulphonyl-2-propanol (2.4 g, 20%). Mp=132° C.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>CN(C)C=O.O.ClCCl>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:23]=[CH:24][C:25]([C:28]([N:10]2[CH2:11][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]=3[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]2=3)=[O:29])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5] benzodiazepine (1.0 g, 5.07 mmol) in N,N-dimethylformamide (10 mL) kept under nitrogen was added solid potassium carbonate (0.74 g, 5.35 mmol). The mixture was treated dropwise with a solution of 4-biphenylcarbonyl chloride (1.4 g, 6.46 mmol) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 1 hour. The mixture was then diluted with water and extracted with ethyl acetate. The organic extracts were combined and washed with 1N sodium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness to give a pink foam which was purified by flash chromatography. Elution with 25% ethyl acetate in hexane provided a white foam which was redissolved in dichloromethane, concentrated in vacuo to a foam, then crystallized by sonication from ethyl acetate/hexane to give the title compound (1.28 g, 66.9%) as a white solid, m.p. 175-177° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30](=[O:31])[C:27]4[CH:28]=[CH:29][C:24]([C:21]5[CH:20]=[CH:19][C:18]([CH3:17])=[CH:23][N:22]=5)=[CH:25][CH:26]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)nc1
Product: Cc1ccc(-c2ccc(C(=O)Nc3ccc4nc(C5CC5)c(C)n4c3)cc2)nc1

Procedure:
Operations similar to Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(5-methyl-2-pyridyl)benzenecarboxylic acid, to provide the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[C:39]([O:40][CH3:41])=[CH:38][C:28]([C:29]([C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[NH2:33])=[O:30])=[C:27]([CH3:42])[CH:26]=1>>[CH3:23][O:24][C:25]1[C:39]([O:40][CH3:41])=[CH:38][C:28]([C:29]([C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[NH:33][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])=[O:30])=[C:27]([CH3:42])[CH:26]=1
Reactant: COc1cc(C)c(C(=O)c2ccccc2N)cc1OC
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: COc1cc(C)c(C(=O)c2ccccc2NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1OC

Procedure:
N-[2-(4,5-Dimethoxy-2-methylbenzoyl)phenyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-(4,5-dimethoxy-2-methylbenzoyl)aniline using method I. LCMS; retention time 3.82 min, MH+ 548.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[O:30])[CH2:7]1)(=O)=O.[C:32]([SH:35])(=[O:34])[CH3:33].[H-].[Na+]>CN(C)C=O>[C:32]([S:35][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[O:30])[CH2:7]1)(=[O:34])[CH3:33]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCNC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](COCCNC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C

Procedure:
A solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (1.37 g) in dimethylformamide (3 ml) was added to a reaction mixture of thioacetic S-acid (0.32 ml) and sodium hydride (62.8% in oil suspension) (0.14 g) in dimethylformamide (7 ml) in a nitrogen stream, and the mixture was heated at 70°-75° C. for 5 hours. The reaction mixture was poured into ice-water (100 ml), extracted with ethyl, acetate (50 ml×2), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (1.02 g).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[Na].Cl.Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9]
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCCCCCCCO
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCCCCCCCOCc1ccc2ccccc2n1

Procedure:
1,7-Heptanediol (ex Lancaster) (1.7 g) was reacted with sodium (0.24 g) in toluene (50 ml) as in Stage A(ii). 2-Chloromethylquinoline hydrochloride (ex Aldrich) was added followed by triethylamine (0.7 ml). After heating under reflux for 6 hours, the reaction mixture was partitioned between water and diethyl ether and the organic phase washed with brine and dried. The crude material was purified by chromatography on silica (eluting with ether-hexane) to give 7-(2-quinolinylmethoxy)heptan-1-ol (0.43 g) which was used in Stage b.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:11]2[C:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([NH:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:3][CH:4]=3)=[O:9])=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[S:13][C:12]=2[CH:23]=1
Reactant: NCCN1CCCCC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(Cl)nc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(NCCN3CCCCC3)nc2)cc1

Procedure:
The coupling of the product from Step 1, Example 5 (6-Chloro-pyridin-3-yl)-[6-methoxy-2-(4-methoxy-phenyl) -benzo[b]thiophen-3-yl]-methanone) and 1-(2-Aminoethyl)-piperidine was carried out as in Example 5, Step 2 to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([C:10]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:19][C:18]2[C:13](=[C:14]([O:22]CC3C=CC=CC=3)[CH:15]=[C:16]([CH:20]=O)[CH:17]=2)[C:12](=[O:30])[CH2:11]1)[CH3:9]>>[CH2:8]([C:10]1([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:19][C:18]2[C:13](=[C:14]([OH:22])[CH:15]=[C:16]([CH2:20][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:17]=2)[C:12](=[O:30])[CH2:11]1)[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: CCC1(Cc2ccccc2)CC(=O)c2c(cc(C=O)cc2OCc2ccccc2)C1
Product: CCOC(=O)CCc1cc(O)c2c(c1)CC(CC)(Cc1ccccc1)CC2=O

Procedure:
Ethyl bromacetate is converted to the triphenyl phosphorone, reacted with the product of Example 36 and reduced catalytically to the desired compound using procedures analogous to those described in Example 24.
Reaction SMILES: S1C(C([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:10]([OH:12])=[O:11])=O)=CC2C=CC=CC1=2.[Cl:25][C:26]1[C:27]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:28]=2[S:29][C:30]=1[C:31](Cl)=[O:32]>>[Cl:25][C:26]1[C:27]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:28]=2[S:29][C:30]=1[C:31]([NH:8][C@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11])=[O:32]
Reactant: O=C(N[C@H](Cc1ccc(O)cc1)C(=O)O)c1cc2ccccc2s1
Reactant: O=C(Cl)c1sc2cc(F)ccc2c1Cl
Product: O=C(N[C@H](Cc1ccc(O)cc1)C(=O)O)c1sc2cc(F)ccc2c1Cl

Procedure:
Following the 9a synthetic method, using 3-chloro-6-fluorobenzo[b]thiophene-2-carbonyl chloride (249.09 mg, 1.0 mmol) instead of 3 gave 7a as a colorless oil; (145.32 mg, 36.9%). [α]D25: +18.3 (c=0.37, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.97-7.87 (m, 2H), 7.73 (d, J=6.6 Hz, 1H), 7.45-7.38 (m, 1H), 7.18-7.15 (m, 2H), 6.80-6.77 (m, 2H), 4.96-4.90 (m, 1H), 3.34-3.16 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.56, 163.89, 160.62, 159.45, 156.42, 139.16, 133.55, 130.54, 127.03, 124.94, 118.51, 115.22, 114.80, 109.29, 108.95, 54.14, 35.98; HRMS (ESI): calcd for: C18H13ClFNO4S [M−H]−=392.0165, obsd [M−H]−=392.0174.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=[O:13])[C:7](=[O:12])[N:8]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([N:31]([CH3:32])[CH3:33])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(Br)ccc2c1NC(=O)C2=O
Reactant: CN(C)S(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc2c1N(Cc1ccc(S(=O)(=O)N(C)C)cc1)C(=O)C2=O
Reaction time: 0.5 h
Yield: 10.8 %

Procedure:
To a solution of 6-bromo-7-methyl-1H-indole-2,3-dione (2.0 g, 8.33 mmol) in DMF (25 ml) was added potassium carbonate (2.3 g, 16.6 mmol). After stirring at this temperature for 30 minutes, was added 4-bromomethyl-N,N-dimethyl-benzenesulfonamide (3.0 g, 10.83 mmol). The reaction mixture was stirred at room temperature for six hours. It was then partitioned between water and ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to give the crude product which was chromatographed on flash silica gel eluting with 20% ethyl acetate in hexane, providing the title compound of 12A (0.392 g, 11% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH2:26][CH2:27][N:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:29][CH:30]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1
Reactant: Cc1cc(C2=CCNCC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CC=C(c2cc(C)cn3nc(NC4CCN(c5cc(C)ncn5)CC4)nc23)CC1

Procedure:
Prepared in analogy to example 164b, starting from 6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidin-4-yl)-8-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine and ethyl chloroformate. The title compound was obtained as a light yellow solid (yield: 36%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (v/v) as eluent.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=N/S(C2SC=CC=2)(=O)=O)/[CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:32]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11](=[O:12])[C:2]([Cl:1])=[CH:3]2)(=[O:30])=[O:31])=[CH:27][CH:28]=1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C1C(Cl)=CC(=NS(=O)(=O)c2ccc(Cl)cc2)c2ccccc21

Procedure:
5.2.34 4-chloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)benzenesulfonamide (12e) was prepared according to the procedure for 12a except using 4-chlorobenzenesulfonamide, TiCL4.2THF and THF as solvent which afforded the title compound 452.2 mg (61.8%) as a yellow solid, m.p.: 138-140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8][CH2:7][C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8][CH2:7][C:6]1=[S:26]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)CN1C(=O)CN=C(c2ccccn2)c2cc(Br)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CN1C(=S)CN=C(c2ccccn2)c2cc(Br)ccc21

Procedure:
A mixture of 0.01 mole of 7-bromo-2,3-dihydro-5-(2-pyridyl)-2-oxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-bromo-2,3-dihydro-5-(2-pyridyl)-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])[CH:2]=1.B(Br)(Br)Br.ClCl>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])[CH:2]=1
Reactant: COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Agent: BrB(Br)Br
Agent: ClCl
Product: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Yield: 86.5 %

Procedure:
By the method used in Example 1, Part D, 1.25 g (3.8 mmol) of 1-([1,1'-biphenyl]-3-ylmethyl)-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 15.2 mL of 1M BBr3 /CH2 Cl2 to give 1.03 g (87% yield) of crude 1-([1,1'-biphenyl]-3-ylmethyl)-4-hydroxy-2-methyl-1H-indole.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8](=[S:28])[NH:9][C:10]=2[C:11]2[C:20]([F:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.Cl[C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:21][C:20]1[C:11]([C:10]2[N:9]=[C:8]([S:28][C:30]3[N:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=23)=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:16]=[CH:15]2
Reactant: Clc1ncccn1
Reactant: Nc1nccn2c(=S)[nH]c(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nccn2c(Sc3ncccn3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A 10 mL microwave vessel was charged with a solution of 8-amino-1-(8-fluoro-2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazine-3-thione (10 mg, 0.00002 mol), 2-chloropyrimidine (0.0059 g, 0.000052 mol) and potassium carbonate (0.011 g, 0.000077 mol) in DMF. The reaction mixture was heated in the microwave at 100° C. for 10 min followed by 120° C. for 10 min to get full consumption of SM. The reaction mixture was concentrated in vacuo. Purification by Gilson HPLC eluting with 10→60% acetonitrile: H2O afforded the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ=7.07 (t, J=4.93 Hz, 1H), 7.21 (d, J=5.05 Hz, 1H), 7.48-7.59 (m, 4H), 7.74-7.85 (m, 2H), 8.04 (d, J=8.59 Hz, 1H), 8.25 (dd, J=8.21, 1.39 Hz, 2H), 8.31 (dd, J=8.72, 1.39 Hz, 1H), 8.50 (d, J=4.80 Hz, 2H). MS(ES+): m/z 465.98 (100)[MH+]. HPLC: tR=2.75 min (Open Lynx polar—5 min).