Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:23]([C:20]2([CH3:19])[CH2:22][CH2:21]2)(=[O:25])=[O:24])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC1(S(=O)(=O)Cl)CC1
Product: CC1(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)CC1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 1-methyl-cyclopropanesulfonylchloride to obtain the desired product. 1H NMR (300 MHz, CDCl3): δ 7.42 (dd, J=1.8 & 10.5 Hz, 1H), 7.36 (ddd, J=2.4, 4.5 & 9.0 Hz, 1H), 7.27 (d, J=6.0 Hz, 1H), 7.07 (dd, J=9.3 & 17.7 Hz, 1H), 6.24 (dt, J=2.1, 8.7 & 17.4 Hz, 1H), 5.86 (br s, 1H), 1.43 (s, 3H), 1.33 (t, J=5.4 Hz, 2H), 0.75 (dd, J=5.1 & 6.3 Hz, 2H); m/z=481 [M−1]−.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](Br)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH3:15])[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:24]=[O:25].O>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH3:15])[CH:24]=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCOc1cc(Br)ccc1OCOC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1cc(C=O)ccc1OCOC
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a solution of 3-butoxy-4-(methoxymethyl) oxybromobenzene (910 mg, 2.97 mmol) in tetrahydrofuran (15 ml) chilled at -72° C. was dropwise added n-butyllithium (2.22 ml, 3.56 mmol, 1.6M hexane solution) under nitrogen atmosphere, and 20 minutes later dimethylformamide (0.28 ml, 3.62 mmol) was added to the mixture, which was stirred for 30 minutes at the same temperature. The reaction mixture was mixed with water, and the product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on a column of silica gel to give 3-butoxy-4-(methoxymethyl) oxybenzaldehyde (556 mg, 84%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](=O)[CH2:13]Br)[N:7]=1)=[O:5])C.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[C:22]([NH2:24])=[S:23])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:22]2[S:23][CH:13]=[C:12]([C:8]3[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:11]=[CH:10][N:9]=3)[N:24]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[CH3:17]
Reactant: CCOC(=O)c1ccnc(C(=O)CBr)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3nccc(C(=O)O)n3)cs2)cc1OCC

Procedure:
4-Ethoxycarbonyl-2-(α-bromoacetyl)pyrimidine and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-pyrimidyl)thiazole.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>N1C=CC=CC=1.Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)S(=O)(=O)CC)cc2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 15.3 %

Procedure:
To a cold solution (0° C.) of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)-methyl]phenoxy}acetate (38 mg, 0.086 mmol) in anhydrous pyridine (2 mL) was added ethanesulfonyl chloride (Fluka, 40 ∞l, 0.43 mmol) and the reaction mixture was stirred at 0° C. for 4 hrs and at rt for an additional 15 hours. The reaction mixture was diluted with an aqueous solution of HCl (1N) and extracted with DCM (3×). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (cHex/EtOAc) gave 7 mg (15%) of the title compound as a colorless oil. LC/MS, M+(ESI): 534.3 (purity: 94.5%).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[Cl:16][C:17]1[CH:18]=[C:19]([O:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[N:21][CH:22]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:28][CH2:27][CH:26]([CH2:25][CH2:24][O:23][C:19]2[CH:20]=[N:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH2:31][CH2:30]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Reactant: Clc1cncc(OCCC2CCNCC2)c1
Product: CC(C)C(C#N)(CCCN1CCC(CCOc2cncc(Cl)c2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 4-[2-(5-chloro-3-pyridyloxy)ethyl]piperidine. The physico-chemical data of the compound was as below.
Reaction SMILES: C([O-])(=O)C1C=CC=CC=1.[CH3:10][C:11]1([CH3:38])[C:20]2[CH:19]=[CH:18][C:17]([C:21]#[C:22][C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=3)=[CH:16][C:15]=2[C:14]([C:34](C)(C)C)=[CH:13][CH2:12]1.FC(F)(F)S(OC1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:34][C:14]1[C:15]2[CH:16]=[C:17]([C:21]#[C:22][C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=3)[CH:18]=[CH:19][C:20]=2[C:11]([CH3:10])([CH3:38])[CH2:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Agent: O=C([O-])c1ccccc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)=CCC3(C)C)cc1
Yield: 0.5 %

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71), 250 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (HPLC Partisil 10, 0.5% EtOAC-hexanes) using 70.2 mg (0.78 mmol) of cuprous cyanide, 33.2 mg (0.78 mmol) of lithium chloride and 34.5 mg (1.28 ml, 1.57 mmol) of methyllithium (1.22M solution in Et2O).
Reaction SMILES: O1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].O1CCCC1.CC(C)([O-])C.[K+]>O>[F:17][C:12]([F:18])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:21][F:22])([CH2:19][F:20])[CH:2]=[C:7]([N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])[C:6]=2[CH:8]=1)[C:13]([F:15])([F:16])[F:14]
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Reactant: O=C1CCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Yield: 16.2 %

Procedure:
To a mixture of 0.41 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.18 g of 2-pyrrolidinone and 8 ml of tetrahydrofuran was added 0.22 g of potassium tert-butoxide with stirring under ice-cooling and the mixture was stirred for 3.5 hours under ice-cooling and then stirred at room temperature for 4 days. Water was added and the mixture was extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain from the first eluted fraction 0.08 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzopyran represented by the following formula having a melting point of 104-105° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[C:42]([O:50][C:51]([F:54])([F:53])[F:52])[CH:41]=1>CCOC(C)=O.C(Cl)Cl>[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]3[N:25]=[C:24]([N:26]([CH3:27])[CH3:28])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:12][CH2:13]2)(=[O:48])=[O:47])=[C:42]([O:50][C:51]([F:53])([F:52])[F:54])[CH:41]=1
Reactant: CN(C)c1nc(NCC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)c1nc(NCC2CCN(S(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a suspension of 4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.30 mmol) in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated to give a white solid. To a suspension of the above solid in CH2Cl2 (5 mL) was added diisopropylethylamine (480 μL, 2.76 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (462 mg, 1.36 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 3 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 14% to 20% EtOAc in hexane) to give N2-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-ylmethyl]-N4,N4-dimethyl-quinazoline-2,4-diamine (420 mg, 55%) as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2([OH:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:25])=[CH:11][C:10]=1[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.N1C=CC=CC=1>ClCCl.ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C:9]1[C:10]([CH3:27])=[CH:11][C:12]([C:16]2([OH:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:30]3[CH:29]=[C:28]([CH3:37])[CH:33]=[CH:32][CH:31]=3)[C:17]2=[O:25])=[CH:13][C:14]=1[CH3:15])([CH3:6])([CH3:5])[CH3:7]
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cccc(N2C(=O)C(O)(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)c3ccccc32)c1
Temperature: 32 °C
Yield: 123.5 %

Procedure:
Using a method similar to Preparation 38, with 3-[4-(tert-Butyl-dimethylsilanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (11.51 g, 30 mmol), m-tolylboronic acid (8.16 g, 60 mmol), copper (II) acetate (5.45 g, 30 mmol), pyridine (4.9 ml, 60 mmol) and powdered 4A sieves (15 g) in dichloromethane (100 mL) and heat at 32° C. for 1 day stirring mechanically. Add more m-tolylboronic acid (4.08 g, 30 mmol), copper (II) acetate (2.73 g, 15 mmol), pyridine (5.0 ml, 62 mmol) and powdered 4A sieves (15 g) and continue heating for 1 day. Dilute with dichloromethane/ethyl acetate and filter slowly through a pad of Celite and silica gel. Use three such pads to filter the entire reaction washing liberally with ethyl acetate. After the filtration is complete stir the pads in additional ethyl acetate and refilter. Evaporate the organics in vacuo to obtain 17.55 g of a yellow oil. Purify by preparative HPLC (5% ethyl acetate/hexanes for 5 minutes and then use gradient up to 25% ethyl acetate/hexanes) to obtain 9.05 g (64%) of a yellow gum. MS (ES): m/z=474 (M+1); 1H NMR (DMSO-d6); δ7.47 (t, 1H), 7.30-7.23 (m, 5H), 7.09 (t, 1H), 6.77 (d, 1H), 6.72 (s, 1H), 2.39 (s, 3H), 2.14 (s, 6H), 0.99 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(C1CCCCC1=O)(=O)C(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[C:44]([NH:51][CH:52]1[CH2:56][CH2:55][NH:54][CH2:53]1)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>[Cu]I.CN(C)C=O>[C:47]([O:46][C:44](=[O:45])[NH:51][CH:52]1[CH2:56][CH2:55][N:54]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:3]=2)[CH2:53]1)([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3s2)CC1
Agent: [Cu]I
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCC(OC(c2cccc(N3CCC(NC(=O)OC(C)(C)C)C3)c2)c2nc3ccccc3s2)CC1
Temperature: 55 °C
Reaction time: 96 h

Procedure:
A screw-capped tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (example 41, 200 mg), copper(I) iodide (7 mg), 2-isobutyrylcyclohexanone (25 mg), cesium carbonate (280 mg), 3-(Boc-amino)pyrrolidine (160 mg) and anhydrous N,N-dimethylformamide (1 mL). The tube is evacuated, filled with argon and sealed. After stirring at 55° C. for 4 days, the mixture is diluted with ethyl acetate, water and ammonia. After decantation, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5), to afford (1-{3-[benzothiazol-2-yl-(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([Si:5]([CH3:35])([CH3:34])[O:6][CH:7]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([CH2:26][OH:27])=[C:23]([CH3:28])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C1COCC1>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:27][CH2:26][C:24]1[S:25][C:21]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:35])[CH3:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:11]([CH3:29])[CH:12]=2)([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:22][C:23]=1[CH3:28]
Reactant: COC(=O)CBr
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(CO)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(COCC(=O)OC)s1
Temperature: 25 °C
Yield: 30.8 %

Procedure:
T a 0° C. solution of 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophen-2-yl-methanol (0.96 g, 1.85 mmol) in THF (10 mL) is added 60% NaH (81 mg, 2.0 mmol) and stirred for 20 m. The mixture is added methyl bromoacetate (0.21 mL, 2.22 mmol)warmed to RT, and stirred overnight. The reaction is quenched with satd NH4Cl (10 mL), diluted with H2O (10 mL), and extracted with EtOAc (2×20 mL). The combined organic layers is MgSO4 dried and concentrated. The resulting residue is chromatographed to give the title compound (0.33 g, 0.57 mmol, 31%). 1H NMR (CDC3), δ 0.06 (s, 3H), 0.12 (s, 3H), 0.70 (t, J=7.3 Hz, 6H), 0.91 (s, 9H), 0.97 (s, 9H), 2.01-2.10 (m, 4H), 2.19 (s, 3H), 2.20 (s, 3H), 3.67 (dd, J=5.8, 3.4 Hz, I H), 3.76 (s, 3H), 3.85 (dd, J=9.8, 5.8 Hz, 1H), 3.98 (dd, J=9.8, 3.4 Hz, 1H), 4.09 (s, 2H), 4.64 (s, 2H), 6.53 (s, 1H), 6.67 (d, J=8.3 Hz, I H), 7.00-7.06 (m, 2H). LC/MS (m/z): calcd for C 10 33H58NO5SSi (M+NH4)+: 608.9; found: 608.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:56])[C:7]([O:10]/[N:11]=[C:12](/[C:43]1[N:44]=[C:45]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[S:46][CH:47]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18][CH2:19][C:20]([CH2:41][Cl:42])=[C:21]2[C:25]([O:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:62].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:56])[C:7]([O:10]/[N:11]=[C:12](/[C:43]1[N:44]=[C:45]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[S:46][CH:47]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18](=[O:62])[CH2:19][C:20]([CH2:41][Cl:42])=[C:21]2[C:25]([O:27][CH:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)cs1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS(=O)[C@H]23)cs1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a solution of (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (3 g, 3.63 mmol) in dichloromethane (DCM) (100 mL) at −40° C. was added dropwise a solution of 3-chlorobenzoperoxoic acid (0.976 g, 4.36 mmol) in dichloromethane 20 mL) over 1 min. The mixture was stirred at the same temperature over 30 min. LCMS indicated completion of the reaction. Dichloromethane (60 mL) was added and the mixture was treated with 15% aqueous sodium thiosulfate (40 mL). The organic solution was separated and washed with 5% sodium bicarbonate (80 mL), brine (80 mL), dried over sodium sulfate, and concentrated. The residue was purified by ISCO automated silica gel chromatography (120 g column, 0-50% ethyl acetate/hexanes) to afford (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (2.44 g, 2.90 mmol, 53.2% yield) as a white solid. LCMS: (M+H)+: 842.2.
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH:3]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC(F)(F)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(F)(F)c1ccccc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Intermediate 19 (0.88 g, 5.64 mmol) was dissolved in THF (12 mL) and (carbethoxymethylene) triphenylphosphorane (1.96 g, 5.64 mmol) was then added. The solution was stirred at 50° C. for 12 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel using n-hexane/AcOEt (5:1) as eluent. The title compound was obtained (1.10 g, 89%) as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[O:12])=[CH:5]2
Reactant: OCc1cc2cc(F)ccc2[nH]1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.9 %

Procedure:
To a stirred solution of crude (5-fluoro-1H-indol-2-yl)methanol 46 (1.55 g, 9.39 mmol) in anhydrous CH2Cl2 (50 mL) at cold-bath temperature (0° C.) was added portionwise pyridinium chlorochromate (PCC) (2.22 g, 10.29 mmol). Reaction was stirred at ambient temperature for 4 hours. Reaction was diluted with CH2Cl2 and filtered through a pad of celite and washed with CH2Cl2. After evaporation of solvent, crude product was silica-column chromatographed (Biotage) using Acetone:Hexane as an eluent to yield 5-fluoro-1H-indole-2-carbaldehyde 47 (0.627 g, 41% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+].[NH4+].[OH-]>CN1CCCC1=O>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: Brc1cccnc1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: CN1CC=C(c2cn(-c3cccnc3)c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 160 °C
Reaction time: 2.5 h

Procedure:
3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (4.5 g), 3-bromopyridin (6.0 g), CuBr (4.5 g) and K2CO3 (8.0 g) in N-methyl-2-pyrrolidone (25 ml) were heated under stirring at 160° C. for 2.5 h. After cooling the reaction mixture was poured into diluted NH4OH (500 ml) and extracted with ethyl acetate (3×300 ml). The combined organic phases were dried (MgSO4) and the solvent evaporated. The title compound was obtained by recrystallization from acetone. Yield: 3.4 g (58%). M.p. 175°-177° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:17]([NH2:19])=[N:16][CH:15]=[N:14][C:13]=3[S:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:20]Br>C(O)(=O)C.CN(C=O)C.C([O-])(O)=O.[Na+]>[Br:20][C:11]1[S:12][C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:19])[C:18]=2[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: Nc1ncnc2scc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1ncnc2sc(Br)c(-c3ccc([N+](=O)[O-])cc3)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of Example 58C (50 mg, 0.18 mmol) in acetic acid (1 mL) and DMF (3 mL) was heated with a heat gun to obtain a clear solution, cooled to 0° C., and treated with bromine (0.02 mL). The reaction mixture was stirred at 0° C. for 1 hour, diluted with saturated NaHCO3, and filtered. The filter cake was dried to provide 56 mg of the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]4[O:22][CH2:23][O:24][C:17]=34)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:25][CH3:26].[I-].[Na+].[CH3:29][N:30]([CH:32]=O)C>C(#N)C>[N:30]1([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]5[O:22][CH2:23][O:24][C:17]=45)=[N:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:25][CH3:26])[CH2:32][CH2:7][CH2:6][CH2:5][CH2:14][CH2:29]1
Reactant: CN(C)C=O
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCN1CCCCCC1
Temperature: 45 °C

Procedure:
A mixture of 7-(2-bromoethoxy)-4-(2,3-methylenedioxyanilino)-6-methoxyquinazoline (0.48 g) homopiperidine (0.322 ml), sodium iodide (0.002 g), DMF (5 ml) and acetonitrile (6 ml) was stirred and heated to 45° C. for 5 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether to give the title compound as a solid (0.4 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.65 (m, 4H), 1.9 (m, 4H), 3.35 (m, 2H), 3.55 (m, 2H), 3.7 (m, 2H), 4.0 (s, 3H), 4.6 (m, 2H), 6.1 (s, 2H), 7.0 (m, 3H), 7.45 (s, 1H), 8.15 (s, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 437.