Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].[H-].[Na+].[Br:9][C:10]1[C:11](Cl)=[N:12][C:13]([Cl:16])=[N:14][CH:15]=1>C1COCC1>[Br:9][C:10]1[C:11]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])=[N:12][C:13]([Cl:16])=[N:14][CH:15]=1
Reactant: C[C@@H](O)[C@@H](C)O
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](C)Oc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.35 g (15.0 mmol) of (R,R)-(−)-2,3-butanediol in 50 ml of THF is mixed at 0° C. in portions with 480 mg (11.0 mmol) of sodium hydride (55% dispersion) and then stirred for 10 minutes at room temperature. The solution that is produced is added at 0° C. to 2.27 g (10.0 mmol) of 5-bromo-2,4-dichloropyrimidine in 25 ml of THF. The batch is slowly heated to room temperature and stirred for 12 hours. The solvent is drawn off, and the residue that is obtained is purified by chromatography (hexane/ethyl acetate 1:1). 2.29 g (8.1 mmol, corresponding to 81% of theory) of the product is obtained.
Reaction SMILES: [CH:1]1[C:6]([NH:7][NH2:8])=[CH:5][CH:4]=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:2]=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=O)[CH:20]([C:26](=O)[C:27]([F:30])([F:29])[F:28])[CH2:19][CH2:18]2>C(O)C>[CH3:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]3[N:7]([C:6]4[CH:1]=[CH:2][C:3]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][CH:5]=4)[N:8]=[C:26]([C:27]([F:28])([F:29])[F:30])[C:20]=3[CH2:19][CH2:18][C:17]=2[CH:16]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc2c(c1)CCC(C(=O)C(F)(F)F)C2=O
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(c1)CCc1c(C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Reaction time: 14.8 h
Yield: 63.9 %

Procedure:
4-Sulfonamidophenylhydrazine hydrochloride (1.80 g, 8.0 mmol) was added to a stirred solution of the diketone from Step 1 (1.86 g, 7.3 mmol) in ethanol (10 mL). The reaction was heated to reflux and stirred for 14.8 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo, dissolved in ethyl acetate, washed with water and with brine, dried over MgSO4 and reconcentrated in vacuo to give the pyrazole as a brown solid (1.90 g, 64%): mp 215°-218° C. 1H NMR (acetone-d6) 300 MHz 8.10 (d, 2H), 7.80 (d, 2H), 7.24 (s, 1H), 6.92 (d, 1H), 6.79 (br s, 2H), 6.88 (d,1H), 3.02 (m, 2H), 2.85 (m, 2H), 2.30 (s, 3H). 19F NMR (acetone-d6) 282 MHz -62.46 (s). High resolution mass spectrum Calc'd. for C19H17F3 O2S: 408.0994. Found: 408.0989.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34](I)=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34]([C:3]3[S:4][C:5]4=[CH:6][N:7]=[CH:8][CH:9]=[C:10]4[C:2]=3[CH3:1])=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: Cc1csc2cnccc12
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cnccc4c3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
149 mg of 3-Methyl-thieno[2,3-c]pyridine (1.0 mmol) is dissolved in 3.0 ml of dry THF and cooled to −78° C. 0.48 ml of n-BuLi 2.5M in hexane (1.2 mmol) is added at −78° C. and stirred at −78° C. for 10 min and room temperature for 10 min. The reaction vessel is cooled to −78° C. again and 2.6 ml of 0.5M ZnCl2 in THF (1.3 mmol) is added at −78° C. and stirred at room temperature for 15 min. 274 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2151431) (0.8 mmol) and 41 mg of PdCl2(pddf) (0.05 mmol) are added and the tube is capped. The tube is heated at 80° C. for 3 days. The reaction is quenched by NH4Claq. and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:4:1) to give 131 mg of the title compound. Yield 45%. mass spectrum (m/e): 365 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.O=[CH:13][CH2:14][C:15]1[C:23]2[C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[C:31]1([S:28]([N:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:23]=3[C:15]([CH2:14][CH2:13][NH:3][C@H:4]3[CH:9]4[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]4)[CH2:5]3)=[CH:16]2)(=[O:29])=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)c1cccc2c1c(CC=O)cn2S(=O)(=O)c1ccccc1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc2c1c(CCN[C@@H]1CN3CCC1CC3)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
A mixture of (S)-(−)-3-aminoquinuclidine dihydrochloride (202 mg, 1.01 mmol) and methyl 3-(2-oxoethyl)-1-(phenylsulfonyl)-1H-indole-4-carboxylate (330 mg, 0.92 mmol) from Step C above in 1% acetic acid in dichloromethane (20 mL) was stirred at ambient temperature for 16 h. Sodium triacetoxyborohydride (584 mg, 2.76 mmol) was added, and the resulting suspension was stirred for 2 h at ambient temperature. The solvent was removed under reduced pressure, and the crude material purified by column chromatography (silica gel, 10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 1-(phenylsulfonyl)-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-4-carboxylate (172 mg, 40%) as a yellow oil: MS (ESI+) m/z 468 (M+H).
Reaction SMILES: [N:1]1([S:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[N:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C1CC[C@@H](c2ccc(C=CS(=O)(=O)N3CCOCC3)cc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H](c2ccc(CCS(=O)(=O)N3CCOCC3)cc2)C1

Procedure:
A solution of (3R)-3-{4-[2-(morpholine-4-sulfonyl)-vinyl]-phenyl}-cyclopentanone (210 mg) in EtOAc (10 ml) containing Pd/C (10%, 50 mg) was hydrogenated over night at r.t. The mixture is filtered and solvents are removed in vacuo to afford the 1H NMR (300 MHz, CDCl3) δ 7.25-7.17 (m, 4H), 3.75 (m, 4H), 3.48-3.34 (m, 1H), 3.32-3.23 (m, 4H), 3.21-3.07 (m, 4H), 2.72-2.61 (m, 1H), 2.53-2.22 (m, 4H), 2.01-1.89 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3c(F)cc(F)cc23)CC1

Procedure:
(8.5 mg, 54%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and phenylsulfonylchloride (10.6 mg, 0.06 mmoles) with 1M NaN(TMS)2 (60 μL, 0.06mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=O.[OH-].[K+]>>[F:12][C:13]1[CH:14]=[C:15](/[CH:16]=[CH:2]/[C:1]([C:4]2[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)=[O:3])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: COc1ccc(C(C)=O)cn1
Reactant: O=Cc1cc(F)cc(F)c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C(=O)/C=C/c2cc(F)cc(F)c2)cn1

Procedure:
In analogy to example 170, step 1, 5-acetyl-2-methoxypyridine was reacted with 3,5-difluorobenzaldehyde in the presence of potassium hydroxide to give the title compound as a colourless solid. MS (ESI+): m/z=276.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccccc2c1Cl
Reactant: NCc1ccccc1
Solvent: O
Product: N#Cc1c(N)nc2ccccc2c1NCc1ccccc1
Temperature: 130 °C

Procedure:
5 g of 2-amino-3-cyano4-chloroquinoline and 11 ml of benzylamine are heated under stirring at 130° C. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale-yellow precipitate is recrystallized from dimethylformamide to obtain 5.2 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](=[O:33])(=[O:32])[NH:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](=[O:33])(=[O:32])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
Reactant: OB(O)c1ccncc1
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: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
Yield: 53.9 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 2-(4-bromo-2-trifluoromethyl-phenylsulfamoyl)-5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester (0.108 g), 4-pyridineboronic acid (0.036 g) in 1,2-dimethoxyethane (5.0 ml), ethanol (0.4 ml) and 2 M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0.023 g) to obtain the desired compound (0.058 g) as a brownish foam. MS (ISN): 548.3 (M−H)−
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30](O)[CH:29]=1>CO.C(Cl)Cl>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([O:1][CH:2]2[C:3]3[C:8](=[N:7][CH:6]=[C:5]([C:12]4[CH:13]=[CH:14][C:15]([C:18]([N:20]5[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]5)=[O:19])=[CH:16][CH:17]=4)[CH:4]=3)[NH:9][CH2:10][CH2:11]2)[CH:29]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1ccc(F)cc1OC1CCNc2ncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)cc21
Yield: 53 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (30 mg) was reacted with 1-(4-fluoro-2-hydroxyphenyl)ethanone (39.4 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (53% yield). LCMS: m/z=489.14 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.11-2.25 (m, 2H), 2.32 (s, 3H), 2.32-2.58 (m, 4H), 2.45 (s, 3H), 3.40-3.68 (m, 4H), 3.70-3.90 (m, 2H), 5.31 (bs, 1H), 5.51 (t, J=3.3 Hz, 1H), 6.75-6.82 (m, 1H), 6.89 (dd, J=2.1 and 10.7 Hz, 1H), 7.41-7.51 (m, 4H), 7.57-7.61 (m, 1H), 7.80 (dd, J=7.1 and 8.6 Hz, 1H, 8.33 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[N:12]([CH2:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH:25]([O:29][CH2:30][C:31]4[N:32]=[C:33]([C:37]5[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=5)[O:34][C:35]=4[CH3:36])[CH2:24]3)[C:9]2=[CH:10][N:11]=1>C1COCC1.CO.[OH-].[Li+]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]([CH2:20][CH2:21][O:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([O:29][CH2:30][C:31]4[N:32]=[C:33]([C:37]5[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=5)[O:34][C:35]=4[CH3:36])[CH2:24]3)[C:9]2=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2n1CCOC1CCCC(OCc2nc(-c3cccc(C)c3)oc2C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cc2cc(C(=O)O)n(CCO[C@@H]3CCC[C@H](OCc4nc(-c5cccc(C)c5)oc4C)C3)c2cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
60 mg of ethyl 5-(2-methoxyethoxy)-1-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxylate are dissolved in 2 ml of THF/methanol 3:1, and 0.15 ml of a 1 N lithium hydroxide solution is added. The mixture is stirred at room temperature for 24 h. All volatile components are removed under reduced pressure, the residue is taken up in DMF/acetonitrile, 70 μl of TFA are added and the mixture is filtered and purified by RP-HPLC. This gives 14 mg of (1R,3S)-5-(2-methoxyethoxy)-1-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid as a colorless oil. C31H37N3O7 (563.66), MS (ESI): 564 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([O:28]C)=[O:27])[CH:21]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][S:16]C(=O)C)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[OH-].[K+].Cl>C1COCC1>[C:26]([C:22]1[CH:21]=[C:20]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]([CH2:14][CH2:15][SH:16])=[C:5]2[C:3]([OH:4])=[O:2])[CH:25]=[CH:24][CH:23]=1)([OH:28])=[O:27]
Reactant: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCSC(C)=O)c3ccccc32)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-n2c(C(=O)O)c(CCS)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of 3-(2-acetylsulfanyl-ethyl)-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid methyl ester (0.32 g, 0.73 mmol) in THF (10 mL) was dropwise added 0.5 N KOH (10 mL) and the resulting mixture was stirred at room temperature overnight. The reaction acidified with 3 N HCl and the resulting white precipitate was washed with H2O and dried under vacuum to give 0.22 g of a white solid (85% yield over 2 steps): 1H NMR (DMSO-d6, 300 MHz) δ 2.81 (t, J=6 Hz, 2H), 3.37 (t, J=6 Hz, 2H), 7.02 (d, J=9 Hz, 1H), 7.19 (t, J=6 Hz, 1H), 7.28 (t, J=6 Hz, 1H), 7.63 (m, 2H), 7.77 (s, 1H), 7.83 (d, J=9 Hz, 1H), 8.01 (d, J=9 Hz, 1H); 13C NMR (DMSO-d6, 300 MHz) δ 25.18, 29.62, 111.11, 121.26, 123.93, 126.18, 127.13, 127.28, 128.35, 129.10, 129.86, 132.24, 138.93, 139.48, 162.78, 167.07. Anal. Calcd for C18H15NO4S: C, 63.33; H, 4.43; N, 4.10; S, 9.39. Found: C, 63.03; H, 4.6; N, 4.09; S, 9.16.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH3:22][N:23]([CH3:43])[C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:40]3[CH2:41][CH2:42][N:37]([S:34]([C:29]4[C:30]5[C:25](=[C:24]([N:23]([CH3:43])[CH3:22])[CH:33]=[CH:32][CH:31]=5)[CH:26]=[CH:27][CH:28]=4)(=[O:36])=[O:35])[CH2:38][CH2:39]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)N3CCNCC3)cccc12
Product: CN(C)c1cccc2c(S(=O)(=O)N3CCN(C(=O)Oc4ccc(Oc5ccc(C(F)(F)F)cn5)cc4)CC3)cccc12
Yield: 32 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperazine and purified by flash chromatography (ethyl acetate—heptane 1:4), yield 32%. Pale crystals, HPLC-MS: m/z: 601(M+1) at Rt=5.2 min.; m.p. ° C.; IR (KBr): ν 1723 (C═O) cm−1.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH:7]1[CH2:12][CH2:11][C:10](=[N:13][S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH:22]1([Mg]Br)[CH2:24][CH2:23]1>C(OCC)C>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH:7]1[CH2:8][CH2:9][C:10]([NH:13][S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])([CH:22]2[CH2:24][CH2:23]2)[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Br[Mg]C1CC1
Reactant: CC(C)(C)S(=O)N=C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Solvent: CCOCC
Product: CC(C)(C)S(=O)NC1(C2CC2)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 3.00 g (9.05 mmol) of 2-methyl-propane-2-sulfinic acid [4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylidene]-amide (25) in 15 mL of diethyl ether was added dropwise to 54.3 mL (27.1 mmol) of a 0.5 M solution of cyclopropylmagnesium bromide in diethyl ether precooled to −78° C. The reaction solution was stirred at −78° C. for 1 h and was allowed to warm to room temperature overnight. The reaction was quenched by dropwise addition of saturated aqueous Na2SO4, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography to yield 800 mg of the title compound (26) as diastereomeric mixture. Rt=2.22 min, 2.25 min (Method C). Detected mass: 374.3 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([CH:17]([OH:19])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8].N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:21])[C:14]([CH:17]([O:19][C:44](=[O:46])[CH3:45])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(C)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 0.535 g. of benzhydryl 7-(2-thienylacetamido)-3-(1-hydroxyethyl)-2-cephem-4-carboxylate, 6 ml. of pyridine, and 2 ml. of acetic anhydride in 30 ml. of methylene chloride was refluxed at 42° C. for 2 hours. The reaction mixture was then evaporated in vacuo to dryness, and the resulting residue was dissolved in ethyl acetate and washed with 1N.HCl and brine, and dried over anhydrous sodium sulfate. Evaporation in vacuo of the dried solution to dryness provided 0.571 g. (99 percent) of the title product as a white froth. The product was identical to that prepared above via the reaction of ketene with the cephem carbinol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:7]=[C:6]2O.O=P(Cl)(Cl)[Cl:22]>CN(C)C1C=CC=CC=1>[Cl:22][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2nc(-c3cccnc3)nc(O)c2c1
Solvent: CN(C)c1ccccc1
Product: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a mixture of 6-methoxy-2-(pyridin-3-yl) quinazolin-4-ol (600 mg, 2.37 mmol) in POCl3 (5 mL) was added N,N-dimethyl aniline (1 drop). The resulting mixture was stirred at 120° C. for 30 min. After the reaction was completed, POCl3 was removed in vacuo, and the residue was added to ice-water slowly. The pH was adjusted to ˜7 by slowly adding NaHCO3 (sat.) at 0° C. and then a precipitate formed. The solid was collected and was purified by chromatography on silica gel eluted with petroleum ether/ethyl acetate (v/v=4:1 to 1:1) to give 260 mg of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline as a pale yellow solid (40.4%). LCMS m/z=272.1, 274.0 (M+1) (Method B) (retention time=1.90 min).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Li][CH2:10][CH2:11][CH2:12][CH3:13]>CCOCC>[CH2:10]([C:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)[CH2:11][CH2:12][CH3:13]
Reactant: [Li]CCCC
Reactant: O=C1C=CCCCC1
Solvent: CCOCC
Product: CCCCC1(O)C=CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
To a clear solution of 2-cyclohepten-1-one (5 g, 45.5 mmol) in ether (50 mL), cooled to 0° C., was added n-BuLi (2.0 M in hexanes, 25 mL, 50.0 mmol) dropwise to produce an opaque yellow solution. The reaction stirred for 2 h at 0° C. and then warmed to room temperature. After 1 h, the reaction was complete as determined by TLC, and quenched in 50 mL NH4Cl. The organic layer was separated and the aqueous layer was extracted with 50 mL of ether (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (10% Et2O/pentane) to afford the title compound as a light yellow oil (2 g, 26% yield). IR (film) 3377, 3015, 2930, 2860, 1456, 1378, 1335, 1223, 1121, 1103, 1043, 997 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.69 (tt, 1H, J=5.6, 11.9 Hz, CCH═CH), 5.59 (d, 1H, J=11.9 Hz, CCH═CH), 2.17-2.09 (m, 2H), 1.84-1.45 (m, 9H), 1.38-1.27 (m, 4H), 0.93-0.88 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 139.1, 130.0, 76.1, 41.1, 38.5, 27.6, 27.5, 25.6, 24.1, 23.2, 14.1; HRMS (EI+) exact mass calculated for [M]+ (C11H20O) requires m/z 168.1514, found m/z 168.1516.
Reaction SMILES: Br[C@@H:2](C)[C:3](OC)(OC)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.[C:21]([O-:24])(=[O:23])C.[K+].CN(C)C=O>O>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([C@H:3]([CH3:2])[C:21]([OH:24])=[O:23])[CH:13]=[CH:12]2
Reactant: COc1ccc2cc(C(OC)(OC)[C@H](C)Br)ccc2c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 97 %

Procedure:
A mixture of (+)(S)2-bromo-1,1-dimethoxy-1-(6-methoxy-2-naphthyl)-propane (3.39 g; 10 mmol), potassium acetate (1.2 g; 12 mmol), N,N-dimethylformamide (14 ml) and of water (8 ml) is heated at 100° C. under stirring. The reaction mixture is worked up as described in example 1 to provide (+)(S)2-(6-methoxy-2-naphthyl)-propionic acid (2.23 g; 9.7 mmol; yield 97%), m.p. 155°-157° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]([C:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:50]=[CH:49][CH:48]=2)=[O:46])[CH2:41][C@@H:40]1[CH2:57][CH2:58]O)=[O:38])([CH3:35])([CH3:34])[CH3:33].[S:60]1C=C[CH:62]=[C:61]1CC(O)=O>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]([C:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:50]=[CH:49][CH:48]=2)=[O:46])[CH2:41][C@@H:40]1[CH2:57][CH2:58][C:61](=[S:60])[CH3:62])=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)Cc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)CC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Triphenylphosphine (0.65 g, 2.5 mmol), in tetrahydrofuran (7 mL) was cooled to 0° C. and diethylazodicarboxylate (0.41 mL, 2.5 mmol) added. The reaction was stirred for 30 min, and 1-tert-butoxycarbonyl-2(S)-(2-hydroxyethyl)-4-naphthoylpiperazine (0.50 g, 1.3 mmol) and thiolacetic acid (0.18 mL, 2.5 mmol) were added in tetrahydrofuran (8 mL). After stirring at 20° C. for 16 h, the solvent was removed in vacuo and the residue chromatographed on silica with 30% ethyl acetate in hexane to give the title compound.