Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[C:5]2[N:6]=[C:7]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)=[CH:31][CH:30]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1c(=O)c(Br)cc2cnc(S(C)=O)nc21
Product: CCn1c(=O)c(Br)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 40.5 %

Procedure:
6-Bromo-8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (4, 600 mg, 1.90 mmol) and 4-(4-methylpiperazino)aniline (363 mg, 1.90 mmol) were stirred at 120° C. for 3 h. The reaction mixture was purified by column chromatography using dichloromethane:methanol (100:3→100:5) to give the title compound (340 mg, 0.77 mmol, 40%) as a yellow solid. ESMS m/z 443 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.47 (s, 1H) 7.92 (s, 1H) 7.51 (d, J=8.8 Hz, 2H) 7.24 (br. s., 1H) 6.96 (d, J=8.8 Hz, 2H) 4.48 (q, J=7.0 Hz, 2H) 3.13-3.29 (m, 4H) 2.53-2.64 (m, 4H) 2.36 (s, 3H) 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH2:8][CH3:9])[C:3]=1[C:10]#[N:11].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>C1(C)C=CC=CC=1>[C:10]([C:3]1[C:4]([O:7][CH2:8][CH3:9])=[N:5][S:6][C:2]=1[NH:1][C:13](=[O:14])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:11]
Reactant: CCOc1nsc(N)c1C#N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1nsc(NC(=O)Oc2ccccc2)c1C#N
Reaction time: 24 h
Yield: 40.5 %

Procedure:
A solution of 16.6 g of 5-amino-4-cyano-3-ethoxyisothiazole and 30.7 g of phenyl chloroformate in 100 ml of toluene under nitrogen atmosphere was stirred and heated at 100° for about 16 hours. After this time, thin-layer chromatography indicated that the reaction was 50% complete. An additional 15 ml of phenyl chloroformate was added and heating (100°) continued for an additional 24 hours; at this time thin-layer chromatography indicated 80% reaction. After an additional 6 hours, 90% reaction was indicated. The mixture was allowed to cool to 5° and filtered. The solid filter cake was washed with toluene and recrystallized from acetic acid, then ethanol, to give 11.5 g of phenyl (4-cyano-3-ethoxy-5-isothiazolyl)carbamate, m.p. 252°-253°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:29]2[CH2:28][CH:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:31][CH2:30]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a dried flask, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (200 mg, 0.7 mmol) and 4-phenyl-1,2,3,5-tetrahydropyridine (160 mg, 0.81 mmol) were suspended in methylene chloride (4 mL) under N2. Triethylamine (0.22 g, 2.2 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.36 g, 0.81 mmol). The reaction was stirred overnight at room temperature and quenched by addition of saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (gradient: 0-45% B over 15 min. Bottle A=hexanes, bottle B=EtOAc) to give 234 mg (80%) of desired product. MS calculated for C25H36N2O3: (M+H) 413; found 413.2.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C@H:13]([C:18]([OH:20])=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH2:23][C:24]#[N:25].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:23]([CH2:24][NH:25][C:18](=[O:20])[C@H:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[NH:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][N:10]=1)#[N:22]
Reactant: CC(C)C[C@H](Nc1nnnn1-c1ccccc1)C(=O)O
Reactant: N#CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Nc1nnnn1-c1ccccc1)C(=O)NCC#N
Reaction time: 36 h
Yield: 55 %

Procedure:
To a solution of N-(1-phenyl-1H-tetraazol-5-yl)-L-leucine (100 mg, 0.36 mmol), aminoacetonitrile hydrochloride (62 mg, 0.68 mmol) and PyBOP (230 mg, 0.44 mmol) in DMF (3 mL) was added triethylamine (0.2 mL, 1.4 mmol). The solution was stirred 36 h, then partitioned between ethyl acetate and pH 3 phosphate buffer. The organic phase was washed with brine and concentrated. Purification by flash chromatography (60% to 90% ethyl acetate/hexanes) gave 62 mg of N1-(cyanomethyl)-N2-(1-phenyl-1H-tetraazol-5-yl)-L-leucinamide. MS (+APCI): 313.9 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:14]=1[C:10]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:8]2.[NH4+].[Cl-:16]>CO>[ClH:16].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:14]=1[C:10]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:8]2
Reactant: [Cl-]
Agent: COc1cccc2[nH]cc(CCN)c12
Agent: [NH4+]
Solvent: CO
Product: Cl
Reaction time: 0.5 h

Procedure:
Dissolve 4-methoxytryptamine (1 g, 5.26 mmol) in MeOH and add of NH4Cl (0.97 eq, 0.27 g, 5.10 mmol). After 30 minutes, evaporate in vacuo to remove the MeOH leaving a thick orange oil. Dissolve the oil in MeOH and add dropwise to Et2O (200 mL) with vigorous stirring giving a gummy white precipitate. Stir with heating to give the title compound as a solid: 1H NMR (d6-DMSO, 300 MHz): 3.06 (bs, 4H); 3.86 (s, 3H); 6.46 (dd, 1H); 7.06-6.9 (m, 3H); 7.93 (bs, 1H); 10.9 (s, 1H); MS (ES+): m/z 191 (M+H)+; 175 (M−CH3)+; 174 (M−NH2)+; (ES−): 189 (M−H)−; Analysis for C11H15ClN2O: Calcd.: C, 58.2788; H, 6.6692; N, 12.3566. found C, 58.18; H, 6.73; N, 12.15.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Br.Br.Br.[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][NH:37][CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]>>[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][N:37]([CH2:6][C:5]6[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=6)[CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=Cc1ccc(O)cc1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc(O)cc3)C4)n[nH]c2c1
Yield: 49.2 %

Procedure:
The title compound was prepared from 4-hydroxy-benzaldehyde (24.2 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 18. The crude material was purified by HPLC Method A to afford 31.4 mg of the title compound.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[O:20]1C[CH2:23][CH2:22][CH2:21]1.C(Cl)(=O)C=C>O>[C:21]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:20])[CH:22]=[CH2:23]
Reactant: C1CCOC1
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a mixture of 10 mmole of 1,3-adamantanediol, 15 mmole of triethylamine, and 100 ml of tetrahydrofuran, 13 mmole of acrylic chloride was added drop wise over about 30 minutes. After the completion of addition, the resulting mixture was stirred at 50° C for 1.5 hours. Water was added to the reaction mixture; the mixture was then extracted with ethyl acetate; the organic layer was concentrated; and the concentrate was subjected to column chromatography on a silica gel to yield the title compound in a yield of 63%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[Li]CCCC.[CH:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCCCCC>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1Br
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)c1cc(OCc2ccccc2)ccc1C(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethylacetal (Tet. Lett., 22, 5027 (1981)) (130 g) in THF (2.0 L), cooled to -78° C., was added dropwise a solution of n-BuLi (210 ml, 1.91M) in hexane. After 15 min., a solution of benzaldehyde (48 mL) in THF (50 ml) was added dropwise. The cooling bath was removed, then the reaction mixture was warmed slowly (40 min.) to -10° C. and quenched with a saturated NH4Cl solution. The reaction mixture was diluted with Et2O (2.0L). The organic phase decanted, washed with H2O (3×), brine, dried over MgSO4 and the solvents evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 95:5 to 85:15) to give the title product as a foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:10]1[O:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:19]3[CH:20]=[CH:21][S:17][CH:18]=3)[CH:3]=2)=[N:12][C:11]=1[CH2:13][CH2:14][OH:15]
Reactant: Cc1oc(-c2cccc(Br)c2)nc1CCO
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Product: Cc1oc(-c2cccc(-c3ccsc3)c2)nc1CCO
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-[2-(3-Bromo-phenyl)-5-methyloxazol-4-yl]ethanol (1.0 g, 3.54 mmol) (see Ex. 2, Part D) and 3-thiophene boronic acid (5.32 mmol) were stirred in n-PrOH (10 mL) under nitrogen, to which 2M Na2CO3 (3.54 mL) was added. The mixture was heated at 85° C., and after Pd(PPh3)4 (41 mg, 0.0354 mmol) was added, the reaction proceeded for 0.5 h. Once the reaction mixture had cooled to room temperature, it was concentrated and taken up in CH2Cl2 (20 mL), then washed with 0.5M NaOH (20 mL). The aqueous layer was back-extracted with CH2Cl2 (10 mL), combined organics were washed with 1M NaOH (10 mL), followed by H2O (10 mL), then dried over Na2SO4, and concentrated to a crude solid. Recrystallized from ethyl acetate:hexanes (1:1) and vacuum oven-dried at 50° C. to yield a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.48 (t, J=8.0 Hz, 1H) 7.46(m, 1H), 7.41 (m, 1H), 3.95 (t, J=5.6 Hz, 2H), 2.74 (t, J=5.6 Hz, 1H), 2.36 (s, 3H); MS (EI) 286.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH:19]=[O:20])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH:19]([OH:20])[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: c1ccsc1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cccs2)CC1

Procedure:
From thiophene (130 mg) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (300 mg) by procedure D. Yield: 167 mg (40%). Yellow oil. MS (m/z): 298.1 ([M+H]+).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15]1[CH2:16][N:17]=[C:18]([O:21][CH2:22][CH3:23])[CH2:19][N:20]=1)[CH3:13].[CH3:24][O:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][C@H:31]([CH:34]([CH3:36])[CH3:35])[CH2:32]Br)=[CH:28][C:27]=1[O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44]>O1CCCC1>[CH3:24][O:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][C@H:31]([CH:34]([CH3:36])[CH3:35])[CH2:32][C@@H:16]2[C:15]([O:14][CH2:12][CH3:13])=[N:20][CH2:19][C:18]([O:21][CH2:22][CH3:23])=[N:17]2)=[CH:28][C:27]=1[O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44].[CH2:12]([O:14][C:15]1[CH2:16][N:17]=[C:18]([O:21][CH2:22][CH3:23])[CH2:19][N:20]=1)[CH3:13]
Reactant: COCCCOc1cc(C[C@@H](CBr)C(C)C)ccc1OC
Agent: CCOC1=NCC(OCC)=NC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC1=N[C@H](C[C@H](Cc2ccc(OC)c(OCCCOC)c2)C(C)C)C(OCC)=NC1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
1 6M n-butyllithium in hexane (788 ml, 1.26 mol) is added dropwise at -40° C. under an inert atmosphere over a period of 20 minutes to a solution of 3,6-diethoxy-2,5-dihydro-pyrazine (229.8 g, 1.35 mol) in tetrahydrofuran (3.0 liters). The batch is stirred for a further 15 minutes at -40° C. and then a solution of 2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butyl bromide (323.4 g, 0.90 mol) in tetrahydrofuran (1.0 liter) is added dropwise thereto over a period of 20 minutes. When the addition is complete, the temperature of the mixture is allowed to rise to -20° C. and the mixture is then stirred at that temperature over a period of 18 hours. The reaction mixture is concentrated and the residue is partitioned between ethyl acetate (1 liter) and water (1 liter). The organic phase is washed with 2×1 liter of water, and the aqueous phases are each back-extracted with 1 liter of ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution (1 liter) and dried over magnesium sulfate. After concentration, the residue is dried under a high vacuum over a period of 1 hour at 35° C. The crude title compound is obtained in admixture with a small amount of epimeric 2(R)-{2(S)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]3-methylbutyl}-3,6-diethoxy-2,5-dihydro-pyrazine (approx. 95:5 diastereoisomeric mixture) and excess 3,6-diethoxy-2,5-dihydro-pyrazine in the form of a colourless oil (472 g): Rf (ethyl acetate/hexane 1:2)=0.20. The 2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butyl bromide used as starting material can be prepared, for example, as described below:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[O:9][C:10]1[CH:22]=[CH:21][C:13]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][O:16][C:12]=2[C:11]=1[CH2:23][CH2:24][CH3:25].CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH3:33][S:34]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[O:9][C:10]1[CH:22]=[CH:21][C:13]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][O:16][C:12]=2[C:11]=1[CH2:23][CH2:24][CH3:25])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1c(O[C@@H]2CCCC[C@@H]2CO)ccc2c(C(F)(F)F)noc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(O[C@H]2CCCC[C@H]2COS(C)(=O)=O)ccc2c(C(F)(F)F)noc12
Reaction time: 4 h

Procedure:
To a solution of 6-{[cis-2-(hydroxymethyl)cyclohexyl]oxy}-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (388 mg, 1.09 mmol), from this Example step 3, in CH2Cl2 (11 mL) was added Et3N (0.230 ml, 1.635 mmol) at 0° C., followed by methanesulfonyl chloride (0.093 mL, 1.2 mmol). The reaction mixture was stirred from 0° C. to room temperature for four hours. The mixture was diluted with CH2Cl2, washed with 5% HCl, followed by H2O then NaHCO3. Organic extracts were dried over NaSO4 and filtered. The solvent was evaporated in vacuo to give title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCOC(C)=O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(Cl)c1N1CCCCC1
Temperature: 80 °C
Yield: 66 %

Procedure:
To a flask containing 2,3-dichloronitrobenzene (387 mg, 2.01 mmol) was added 3 mL of piperidine, and the result was heated to 80° C. overnight. The reaction was diluted with EtOAc (30 mL), washed with water (2×30 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative tlc (20% EtOAc-hexane) yielded 320 mg (66%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 7.56-7.50 (m, 2H), 7.04 (t, 1H, J=8.1 Hz), 3.04 (br s, 4H), 1.69 (br s, 4H), 1.59 (br s obscured by water, 2H).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([CH3:28])([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)C.O.[OH-].[K+]>C(O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:10]([N:11]1[CH2:16][CH2:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[CH2:12]1)[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:28])([CH3:27])[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCC(c1ccccc1Cl)N1CCc2sccc2C1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.5 %

Procedure:
7-(2-Chlorophenyl)-7-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid ethyl ester (2.80 g, 7.23 mmol) was dissolved in ethanol (40 mL) and water (25 mL) containing potassium hydroxide (10 g, 250 mmol). The mixture was heated to reflux for 24 hours. After 24 hours, the flask was cooled to room temperature and concentrated. Water (50 mL) was added and extracted with 10% ethyl acetate in heptane. The aqueous fraction was acidified (to pH=6) with concentrated hydrochloric acid and the product was extracted with dichloromethane (2×100 mL). The dichloromethane extracts were combined, dried over sodium sulfate, filtered and concentrated. The remaining tan oil (3.0 g) was purified by flash column chromatography on silica gel (100 g), eluting with heptane-ethyl acetate (2:1) to provide 7-(2-chlorophenyl)-7-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid as a white solid (2.1 g, 71.6% yield). The product was dissolved in water (ASTM 1, 200 mL) containing hydrochloric acid (1%) and acetone (25 mL). Most of the acetone and excess hydrochloric acid was removed under reduced pressure. The remaining water (200 mL) was freeze-dried to provide 7-(2-chlorophenyl)-7-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethylheptanoic acid, hydrochloride salt (Compound Ig hydrochloride, 2.2 g, mp 97-100° C., 99.47% purity by HPLC) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ=12.25 (br s, 0.5H), 12.12 (br s, 0.5H), 8.24 (br s, 1H), 7.60-7.38 (m, 4H), 6.94 (d, 1H, J=4.5 Hz), 6.77 (d, 1H, J=4.5 Hz), 4.90-4.68 (m, 1.5H), 4.38 (dd, 0.5H, J=14.4, 5.4 Hz), 4.01 (m, 1H), 3.80 (dd, 0.5H, J=14.4, 5.1 Hz), 3.60-3.30 (m, 1.5H), 3.20-2.85 (m, 2H), 2.42 (m, 1H), 2.23 (m, 1H), 1.40-1.0 (m, 5H), 1.01 (s, 6H), 0.79 (m, 1H). (mixture of rotational isomers). 13C NMR (75 MHz, DMSO-d6): δ=178.41, 134.70, 134.60, 131.83, 131.49, 131.23, 131.05, 129.93, 129.75, 128.38, 128.35, 128.10, 125.43, 125.26, 124.87, 124.86, 64.35, 63.17, 49.87, 48.70, 48.00, 47.13, 41.16, 30.78, 30.30, 30.12, 25.77, 25.02, 24.14, 21.78, 21.37. (mixture of rotational isomers). HRMS (MMI-TOF): Calculated for C22H29Cl2NO2S (MH+): 406.1202. found 406.1594.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].C([CH2:14][C:15]([O-])=[O:16])(C)=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:10][O:9][C:7]([C:3]1[C:2]([O:1][C:15](=[O:16])[CH3:14])=[CH:6][S:5][CH:4]=1)=[O:8]
Reactant: C=C(C)CC(=O)[O-]
Reactant: COC(=O)C1CSCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1cscc1OC(C)=O
Temperature: -25 °C

Procedure:
A 320 g. portion of methyl tetrahydro-4-oxo-3-thiophenecarboxylate [Hromatka et al., Monat. Chemie, 104, 1520 (1973)] is dissolved in 650 ml. of isopropenylacetate, 2.0 g. of p-toluenesulfonic acid is added and the mixture is refluxed overnight. The mixture is concentrated, dissolved in 750 ml. of methylene chloride, cooled to -25° C. and 160 ml. of sulfuryl chloride is added over a one hour period. The methylene chloride is distilled off giving 4-acetoxy-3-thiophenecarboxylic acid methyl ester.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][C:2]1=[N:6]O.[C:9]1(=O)[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]1>C(O)(=O)C.[Zn]>[CH2:5]1[C:1]2[CH:2]([NH:6][CH:13]3[C:12]=2[C:11](=[O:15])[CH:10]=[CH:9][CH2:14]3)[CH2:3][CH2:4]1
Reactant: O=C1CCCC1=NO
Reactant: O=C1CCCC(=O)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1C=CCC2NC3CCCC3=C12
Temperature: 25 °C

Procedure:
To a mechanically stirred solution of 1,2-cyclopentanedione-2-oxime (25.0 g, 0.22 mol) and 1,3-cyclohexanedione (25.0 g, 0.22 mol) in 70% acetic acid (250 mL) was added zinc dust (43.0 g, 0.66 g-atom) in about 5-g portions (moderately exothermic) over a 30 minute period. After the addition, the mixture was heated to reflux for 2 hours and was then cooled to room temperature. The solution was decanted from excess zinc and poured into ice water (250 mL). The mixture was extracted with dichloromethane (1×200 mL, 2×100 mL) and the combined extracts were washed with saturated sodium bicarbonate to neutrality, then washed with brine, and dried (Na2SO4). The solution was concentrated to about 1/4 the original volume, whereupon the title cyclopent[b]indolone (8.3 g) separated as a light tan solid: mp 236°-238° C. (recrystallized from ethyl acetate); IR (KBr) 3210 (NH), 1620 cm-1 (C=O); NMR (CDCl3) δ 2.07 (m, 2, CH2), 2.30-2.90 (m, 10, CH2), 10.17 (br s, 1, NH); MS m/e 175 (M+). Anal. Calcd for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.36; H, 7.38; N, 7.84.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.Br[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH:32]=[O:33])[CH2:28][CH2:27]1.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH:32]=[O:33])[CH2:28][CH2:27]4)[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: O=CN1CCC(CBr)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC4CCN(C=O)CC4)CC3)cc21
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of norfloxacin (0.96 g, 3 mmol), 4-bromomethyl-1-formylpiperidine (1.26 g 6.1 mmol) and triethylamine (0.44 g, 0.6 mL, 4.3 mmol) in anhydrous dimethylformamide (15 mL) was heated at 100° C. for 2 hours. The solvent was removed under high vacuum and the residue was dissolved in methanol, filtered and precipitated by the addition of diethyl ether to give the product as a white solid (1.0 g, 75% yield).