Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH:11]1[C:16](=[CH:17][O:18]C)[CH2:15][CH2:14][O:13][CH2:12]1)=[O:4]>CO.FC(F)(F)C(O)=O>[CH:17]([CH:16]1[CH2:15][CH2:14][O:13][CH2:12][CH:11]1[CH2:10]/[CH:9]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:18]
Reactant: COC=C1CCOCC1C/C=C\CCCC(=O)OC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC/C=C\CC1COCCC1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[(Z)-6-methoxycarbonyl-2-hexenyl]-4-methoxymethylenetetrahydropyran in a mixture of methanol (10 ml) and 50% aqueous trifluoroacetic acid (10 ml) was stirred at room temperature for 1 hour and the solvent was evaporated in vacuo to give 4-formyl-3-[(Z)-6-methoxycarbonyl-2-hexenyl]tetrahydropyran as a residue. The residue was dissolved in methanol (10 ml). To the solution were added 4-phenylsemicarbazide (200 mg) and sodium cyanoborohydride (100 ml) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with chloroform (50 ml) and the solution was washed successively with saturated aqueous sodium hydrogen carbonate and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column (10 g) with a mixture of n-hexane and ethyl acetate (3:1) as an eluent to give 3-[(Z)-6-methoxycarbonyl-2-hexenyl]-4-(4-phenylsemicarbazidomethyl)tetrahydropyran (266 mg) as a pale yellow oil.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[NH:8].CS([C:19]1[N:24]=[C:23](/[CH:25]=[C:26]2/[C:27](=[O:32])[NH:28][C:29](=[O:31])[S:30]/2)[CH:22]=[CH:21][N:20]=1)(=O)=O.C(N(C(C)C)C(C)C)C>CS(C)=O>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[NH:8])[N:9]1[CH2:10][CH2:11][N:12]([C:19]2[N:24]=[C:23](/[CH:25]=[C:26]3/[C:27](=[O:32])[NH:28][C:29](=[O:31])[S:30]/3)[CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:14]1
Reactant: N=C(c1ccco1)N1CCNCC1
Reactant: CS(=O)(=O)c1nccc(/C=C2\SC(=O)NC2=O)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N=C(c1ccco1)N1CCN(c2nccc(/C=C3\SC(=O)NC3=O)n2)CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
The crude material from Step 2, furan-2-yl(piperazin-1-yl)methanimine hydrochloride (16.3 mg, 0.076 mmol) was diluted in DMSO (Volume: 0.75 mL) and added to (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (19.4 mg, 0.068 mmol) in a 2-dram vial. The reaction solution was then treated with N-ethyl-N-isopropylpropan-2-amine (50 mg, 0.387 mmol) and then shaken at 100° C. for 16 h. The reaction was then purified by RP-HPLC using TFA as the modifier to provide (Z)-5-((2-(4-(furan-2-yl(imino)methyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)=[CH:12][CH:11]=1.[C:25](Cl)(Cl)=[S:26]>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[NH:23][C:25](=[S:26])[NH:24][C:19]=3[CH:18]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Cc2ccc(N)c(N)c2)cc1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2ccc3[nH]c(=S)[nH]c3c2)cc1

Procedure:
To a solution of 0.51 g (5.0 mmoles) of triethyl amine, 1.14 g (5.0 mmoles) of 4-[(4-methoxyphenyl)-methyl]-o-phenylene-diamine and 35 ml of chloroform a solution of 0.58 g (5.0 mmoles) of thiophosgene and 10 ml of chloroform are added dropwise.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].FC(F)(F)S(O[C:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=1)(=O)=O>O.O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[C:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=1
Reactant: COc1nc2ccn(C)c2cc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc2ccn(C)c2cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
To 5-methoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (398 mg, 1.932 mmol) was added sodium carbonate (410 mg, 3.86 mmol), lithium chloride (164 mg, 3.86 mmol), tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (640 mg, 1.932 mmol) and deairared 1,4-Dioxane (15 mL) at rt temperature, followed by tetrakis (triphenylphosphine)pladdinum (0) (112 mg, 0.097 mol), and H2O (1 mL). The resulting light brown mixture was stirred at 80° C. for 2 hr. After cooling down to rt, the mixture was partitioned between H2O/EtOAc (30 mL/50 mL), and separated. The organic layer was washed with brine (10 mL), dried (Na2SO4), concentrated on rotary vacuo, purified on Biotage Flash Collector eluting with 30˜80% EtOAc/Hexanes (1200 mL) to afford the expected product, tert-butyl 4-(5-methoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (207 mg, 32%). 1H-NMR (400 MHz, MeOD) δ ppm 1.44-1.51 (m, 9 H) 2.51 (d, J=1.51 Hz, 2 H) 3.59 (s, 2 H) 3.78 (s, 3 H) 3.93 (s, 3 H) 4.04 (s, 2 H) 4.86 (s, 1 H) 5.82 (s, 1 H) 6.39 (d, J=2.52 Hz, 1 H) 7.27 (d, J=3.27 Hz, 1 H) 7.58 (s, 1 H); Mass spec 344.18 (MH+) Calc for C19H25N3O3 343.19.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[N:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1cnc2ccccc2n1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4cnc5ccccc5n4)cc3CC[C@@H]12
Yield: 55.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloroquinoxaline (76 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 82 mg (55%) of the title compound as an amorphous foam. FDMS: m/e=589. α[D]589 =+68.96 (c=0.81, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Agent: Cl
Solvent: CCO
Product: OCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 138.8 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (150 mg) in ethanol (2 mL) was added 2 N hydrogen chloride-ethanol solution (3.0 mL), and the mixture was stirred at room temperature for 14 hr. The oil obtained by concentration under reduced pressure was crystallized from ethyl acetate-ethanol, and the crystals were recrystallized from ethyl acetate-ethanol to give the title compound (86.5 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:37]([OH:38])[C@@H:36]([CH3:39])[C@@H:35]([OH:40])[C@@H:34]([CH3:41])[C@H:33]([O:42][C:43]([CH3:45])=[O:44])[C@H:32]([CH3:46])[C@@H:31]([O:47][CH3:48])[CH:30]=[CH:29][O:28][C@:25]2([CH3:49])[C:26](=[O:27])[C:15]3[C:16]([O:24]2)=[C:17]([CH3:23])[C:18]([OH:22])=[C:19]2[C:20](=[O:21])[C:10](=[C:11]([NH2:50])[C:12]([C:14]=32)=[O:13])[NH:9][C:7](=[O:8])[C:6]([CH3:51])=[CH:5][CH:4]=[CH:3]1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>COCCOCCOC.O>[CH3:1][C@@H:2]1[C@H:37]([OH:38])[C@@H:36]([CH3:39])[C@@H:35]([OH:40])[C@@H:34]([CH3:41])[C@H:33]([O:42][C:43]([CH3:45])=[O:44])[C@H:32]([CH3:46])[C@@H:31]([O:47][CH3:48])[CH:30]=[CH:29][O:28][C@:25]2([CH3:49])[C:26](=[O:27])[C:15]3=[C:16]([O:24]2)[C:17]([CH3:23])=[C:18]([OH:22])[C:19]2=[C:14]3[C:12]([OH:13])=[C:11]([NH2:50])[C:10](=[C:20]2[OH:21])[NH:9][C:7](=[O:8])[C:6]([CH3:51])=[CH:5][CH:4]=[CH:3]1
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C\O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(N)c(O)c4c3C2=O)NC(=O)/C(C)=C\C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: COCCOCCOC
Solvent: O
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(N)c(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C

Procedure:
8 g 3-amino-rifamycin S were dissolved in 30 ml diglyme and the solution was then added with 2 g sodium ascorbate dissolved in 5 ml water. The solution of 3-amino-rifamycin SV thus obtained was heated to 50° C. and then added with 4.4 g 4-carboxybenzoic aldehyde. The solution was stirred at this temperature for 15 minutes and then after adding 30 ml chloroform was again stirred at 50° C. for 4 hours. The reaction mixture was then added with 300 ml chloroform, washed with an aqueous solution of sodium metabisulphite and then with water.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[C:1]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cccnc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
In a typical run, nicotinic acid (2.0 g, 16.2 mmol) was taken up in CH2Cl2 (20 mL) along with oxalyl chloride (1.4 mL, 16.2 mmol). After a few drops of DMF were added, the reaction mixture was stirred at room temperature until all the solids had dissolved and all gas evolution had ceased (1 h). This freshly prepared solution of the acid chloride was added dropwise at 0° C. to a solution containing tert-butyl 2-aminoethylcarbamate (2.6 g, 16.2 mmol) and Et3N (3.4 mL, 24.2 mmol) in CH2Cl2 (200 mL). The resulting reaction mixture was warmed to room temperature and stirred for 2 h. It was then washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded tert-butyl 2-(nicotinamido)ethylcarbamate (3.1 g, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29]>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:15])[NH:29][C:24]3[C:23]([N:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1N
Solvent: CO
Product: O=c1[nH]c2ccccc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A mixture of 396.0 mg of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 137.6 mg of 1,2-phenylenediamine is heated to 120° for 60 minutes. Thereafter, the mixture is suspended in methanol, filtered under suction and recrystallized from N,N-dimethylformamide/water. There is obtained 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone of m.p. >300°.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C:20]3[N:21]=[C:22]([N:25]4[CH2:28][CH:27]([S:29][C:30]5[C@H:31]([CH3:54])[C@@H:32]6[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]6[C:34]=5[C:35]([O:37]CC5C=CC([N+]([O-])=O)=CC=5)=[O:36])[CH2:26]4)[O:23][CH:24]=3)=[O:19])[CH2:13]2)=O)=CC=1)([O-])=O>O1CCCC1>[NH:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C:20]2[N:21]=[C:22]([N:25]3[CH2:28][CH:27]([S:29][C:30]4[C@H:31]([CH3:54])[C@@H:32]5[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]5[C:34]=4[C:35]([OH:37])=[O:36])[CH2:26]3)[O:23][CH:24]=2)=[O:19])[CH2:13]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N[C@H]5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)C5)co4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SC3CN(c4nc(C(=O)N[C@H]5CCNC5)co4)C3)[C@H](C)[C@H]12
Reaction time: 4.5 h
Yield: 32.9 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-(1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (650 mg, 0.821 mmol) (obtained as described in Example 80(1)) in a mixture of tetrahydrofuran (33 ml) and distilled water (33 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (650 mg) at room temperature for 4.5 hours. After checking the completion of the reaction, the reaction mixture was filtered and to the filtrate were added ethyl acetate and distilled water. The resulting mixture was shaken in a separatory funnel and the aqueous layer was separated and concentrated under reduced pressure. The residue was purified by chromatography on a Cosmosil column (eluant: distilled water distilled water:acetonitrile (76:24)),and the eluate was lyophilized to afford the desired compound (1R,5S,6S)-2-{1-[4-((3S)-pyrrolidin-3-ylcarbamoyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (129 mg, yield 33%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]4)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)N[C@H]3CC[C@H](O)CC3)c2n1

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and (trans)-4-aminocyclohexanol. The crude material was purified by reverse phase chromatography, eluting with 0-60% acetonitrile/water to yield the title compound as a white solid (32 mg, 97% yield). MS (apci) m/z=454.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CN=C1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1c2cc(Br)ccc2CC12CCC(O)CC2
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](OC1CCC2(CC1)Cc1ccc(Br)cc1C2=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.4 %

Procedure:
To a 4 mL vial was placed 6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (41 mg, 0.139 mmol) and it was azeotroped with toluene twice (1 mL/each). The solid was dissolved in DMF (1.5 mL). To this solution was added TBDPS-Cl (40 μL, 0.154 mmol) followed by imidazole (24 mg, 0.353 mmol). The reaction was allowed to stir overnight (˜14 hours) at room temperature. The reaction was quenched with H2O (1 mL) and diluted with diethyl ether (1 mL). The phases were separated and the aqueous phase was back extracted twice with diethyl ether (2 mL/each). The combined organic phases were washed with H2O, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 6′-bromo-4-(tert-butyldiphenylsilyloxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (58 mg, 0.109 mmol, 78% yield). M+H=did not ionized. 1H NMR=(CDCl3, 400 MHz) δ 7.83 (d, J=1.6 Hz 1H), 7.69-7.66 (m, 5H), 7.45-7.32 (m, 7H), 3.73 (m, 1H), 2.98 (s, 2H), 1.93-1.89 (m, 2H), 1.62-1.47 (m, 4H), 1.37 (m, 2H), 1.08 (s, 9H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Brc1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Temperature: 85 °C
Yield: 62 %

Procedure:
Compound 4 [Xu, H.; Yin, K.; Huang, W. Chem. Eur. J. 2007, 13(36), 10281-10293] was prepared as follows: a mixture of N-phenylnaphthalen-1-amine (2.767 g, 12.62 mmol), 1-bromo-4-iodobenzene (7.140 g, 25.24 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.578 g, 0.631 mmol), tri-tert-butylphosphine (10 wt. % in hexanes) (5.83 mL, 1.89 mmol), sodium tert-butoxide (NaOtBu) (3.032 g, 31.55 mmol) and anhydrous toluene (80 mL) was degassed with argon for about 40 min while stirring. The reaction mixture was then maintained under argon at about 85° C. while stirring. Upon confirming consumption of the starting material by TLC (SiO2, 100% hexanes), the reaction was cooled to RT and poured over EtOAc (ca. 300 mL). The organics were then washed with sat. NaHCO3, H2O (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product via flash chromatography (SiO2, 8:1-hexanes:CH2Cl2) provided Compound 4 (2.93 g, 62%) as a white foam: confirmed by LCMS (APCI): calculated for C22H16BrN (M+): 374; Found: 374.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Br:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH2:4].[C:15](OCC)(=[O:17])C>>[F:1][C:2]1[CH:8]=[C:7]([Br:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[N:4]=[C:15]=[O:17]
Reactant: COC(=O)Oc1cc(N)c(F)cc1Br
Reactant: CCOC(C)=O
Product: COC(=O)Oc1cc(N=C=O)c(F)cc1Br
Temperature: 80 °C
Yield: 94 %

Procedure:
A solution of trichloromethyl chloroformate trichloromethyl (15 ml, 125 mmol) in ethyl acetate was charged into a 500 ml-three neck flask equipped with a dropping funnel and distillation apparatus and, a solution of 2-fluoro-4-bromo-5-methoxycarbonyloxyaniline (28.0 g,113 mmol) in ethyl acetate (100 ml) was added dropwise over 20 minutes. After dropping, the mixture was heated at 80° C. and ethyl acetate was removed by distillation. After cooling, carbon tetrachloride (150 ml) was added and the undissolved substances were removed by filtration. The solvent was then removed from the filtrate by distillation under reduced pressure, whereby a brown solid of 2-fluoro-4-bromo-5-methoxycarbonyloxyphenyl isocyanate (29.1 g, yield 94%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:15]2)[N:3]=1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:15]2)[N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: COC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N(CC(F)(F)F)c1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 142 mg (0.33 mmol) of the compound from example 1 were initially charged in THF (9.5 ml), the mixture was cooled to 0° C. and 13 mg (0.33 mmol) of sodium hydride (60% suspension in mineral oil) were then added. The mixture was stirred at 0° C. for 30 min, and 96 μl (0.67 mmol) of 2,2,2,-trifluoroethyl trichloromethanesulfonate were then added dropwise. The reaction mixture was stirred at RT overnight. The mixture was then diluted with ethyl acetate and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase dichloromethane:methanol 60:1) and the product fractions were concentrated. The crude product obtained in this manner was re-purified by means of preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)−gradient), then suspended in acetonitrile/water and finally dried by lyophilization. This gave 68 mg (40% of theory) of the title compound as a solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:8]=1[CH2:21][N:22]([CH3:24])[CH3:23].[CH3:25][Si:26]([CH3:29])([CH3:28])Cl.O>C1COCC1>[CH3:23][N:22]([CH2:21][C:8]1[CH:9]=[C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH:12][C:7]=1[Si:26]([CH3:29])([CH3:28])[CH3:25])[CH3:24]
Reactant: C[Si](C)(C)Cl
Reactant: CN(C)Cc1cc(NC(=O)OC(C)(C)C)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cc(NC(=O)OC(C)(C)C)ccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At −78° C., n-butyl lithium (2.5 ml/L, 3 ml) was slowly added dropwise into a solution of tert-butyl 4-bromo-3-((dimethylamino)methyl)phenylcarbamate (compound 28) (2.7 g, 8 mmol) in THF. The reaction mixture was stirred at low-temperature for 30 minutes, followed by adding trimethylchlorosilane (1.1 g, 9.6 mmol). And then the reaction mixture was stirred at low-temperature for 1 hour. After the mixture was warmed to RT and stirred overnight, three times of water was added into the reaction solution. The reaction mixture was extracted by ethyl acetate. The solvent was dried and evaporated to give a crude product, which can be directly used for the next step.