Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)(C(C)(C)C)(C)C.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[H-].[K+]>[CH2:25]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[C:12]([CH:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)=[CH:13]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(O[Si](C)(C)C(C)(C)C)cc23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CCC(c2cn(Cc3ccccc3)c3ccc(O)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
By a method similar to Preparation 32, using 5-(t-butyldimethylsilanyloxy)-3-(1-methylpiperidin-4-yl)-1H-indol (350 mg, 1.02 mmol) in tetrahydrofuran (20 mL), potassium hydride (116 mg of a 35% dispersion in oil, 1.02 mmol) and benzyl bromide (121 μL, 1.02 mmol) and after stirring at room temperature overnight, the reaction mixture was directly treated with tetrabutyl ammonium fluoride (1.02 mL of a 1M solution in tetrahydrofuran, 1.02 mmol) and stirred at room temperature for three days. The solvent was then removed in vacuo, and the resulting residue was diluted with methanol (15 mL) and directly applied to a 5 g SCX column. After thoroughly washing with methanol, the column was eluted with a 8:2 mixture of dichloromethane and 2 N ammonia in methanol. The eluent was concentrated in vacuo, and the residue was further purified on silica gel. Elution with a 0% to 2% gradient of methanol in dichloromethane provided 323 mg (99%) of the title compound as an off-white gum: 1H NMR (400 MHz, CDCl3): 7.33-7.20 (m, 4H), 7.12-7.05 (m, 2H), 7.04 (d, 1H, J=8.4 Hz), 6.82 (s, 1H), 6.70 (dd, 1H, J=8.6, 2.6 Hz), 5.17 (s, 2H), 3.01 (br d, 2H, J=11.2 Hz), 2.71 (tt, 1H, J=11.8, 4.0 Hz), 2.38 (s, 3H), 2.22-1.98 (m, 4H), 1.98-1.88 (m, 2H): MS (ES+): m/e 321.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.NC1N=C(N)C(C2C=CC([N+:32]([O-:34])=[O:33])=C(Cl)C=2Cl)=CN=1.NC1N=C(N)C(C2C=C([N+]([O-])=O)C=C(Cl)C=2Cl)=C(C)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: Nc1ncc(-c2ccc([N+](=O)[O-])c(Cl)c2Cl)c(N)n1
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Agent: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])cc(Cl)c1Cl
Product: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 15 in an analogous manner to the compound of Example 39, mp. 265° C. Also obtained from this reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methyl pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][C:7]=2[CH:18]=1.C(=O)([O-])O.[K+].Br[CH2:25][C:26]#[N:27]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:25][C:26]#[N:27])[C:7]=2[CH:18]=1
Reactant: N#CCBr
Reactant: COc1ccc2c(c1)NC(c1ccccc1)CO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Product: COc1ccc2c(c1)N(CC#N)C(c1ccccc1)CO2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The compound obtained in Step B (480 mg; 1.99 mmol) is suspended in 8 ml of water (4 ml/l mmol). Potassium hydrogen carbonate (10 eq.; 19.89 mmol; 1.657 g), tetrabutylammonium bromide (1 eq.; 1.99 mmol; 641 mg) and bromoacetonitrile (8 eq.; 15.91 mmol; 1.11 ml) are then added. The mixture is stirred vigorously at 90° C. for 8 hours. After returning to ambient temperature, the product formed is extracted with dichloromethane. The organic phase is dried over MgSO4, filtered, and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (eluant: PE/AcOEt (8/2)). The title product is obtained in the form of a colourless oil.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH:6]([C:9]1[C:10]([O:19][CH3:20])=[C:11]([C:15](O)([CH3:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)([CH3:8])[CH3:7].[CH2:21]([O:23][C:24](=[O:32])[C:25]([O:27][Si](C)(C)C)=[CH2:26])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].Cl>ClCCl.O>[CH2:21]([O:23][C:24](=[O:32])[C:25](=[O:26])[CH2:27][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH:6]([CH3:8])[CH3:7])[C:10]=1[O:19][CH3:20])([CH3:17])[CH3:16])[CH3:22]
Reactant: C=C(O[Si](C)(C)C)C(=O)OCC
Reactant: COc1c(C(C)C)cccc1C(C)(C)O
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)CC(C)(C)c1cccc(C(C)C)c1OC
Temperature: -72 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
15.3 ml (129.71 mmol) of tin tetrachloride is added in drops to a mixture, cooled to −72° C., that consists of 28.16 g (135.19 mmol) of 2-(3-isopropyl-2-methoxyphenyl)-propan-2-ol and 50.9 g (270.38 mmol) of 2-trimethylsilanyloxy-acrylic acid ethyl ester in 420 ml of dichloromethane. In this case, the temperature increased to −65° C. After 30 minutes of stirring in this temperature interval, the reaction mixture is poured onto a mixture that consists of saturated sodium carbonate solution and dichloromethane (in each case 250 ml). After 30 minutes of stirring at room temperature, the batch is transferred into a spherical separating funnel, and a 1:1 mixture that consists of water and dichloromethane is added until a phase separation takes place. After the organic phase is shaken with sodium carbonate, 1N HCl and water, it is dried with sodium sulfate. After the usual procedure, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 20.44 g (48.35%) of the desired compound is obtained.
Reaction SMILES: [CH:1]1[N:12]2[C:13]3[C:9]([C:10]4[CH2:16][CH2:15][CH2:14][C:11]=42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][NH:3][CH:2]=1.B.C1COCC1>C(O)(C(F)(F)F)=O>[CH2:1]1[N:12]2[C:13]3[C:9]([CH:10]4[CH2:16][CH2:15][CH2:14][CH:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][NH:3][CH2:2]1
Reactant: C1=Cn2c3c(c4cccc(c42)CN1)CCC3
Agent: B
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: c1cc2c3c(c1)C1CCCC1N3CCNC2
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To a solution of 3,4,9,10-tetrahydro-8H-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole (61 mg, 0.29 mmol) in TFA (2 mL) being cooled in an ice-bath, BH3.THF (0.7 mL, 0.7 mmol, 1 M THF) was added slowly under Ar. After 4 h, the reaction mixture was concentrated in vacuo then CHCl3 (3 mL) and 1 N HCl (3 mL) were added. The mixture was stirred for 1 h before separating the two layers. The aqueous layer was basified to pH 13-14 with 5 N NaOH then extracted with CHCl3 (3×3 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give 36 mg (58%) of the title compound as a thin white film.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])C(OC)=O.Cl(O)(=O)(=O)=O.C(OCC)(=O)C.CO>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)C(C(=O)OC)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
10.08 g (33.8 mmol) of dimethyl-2-(2,6-dinitrophenyl)-malonate is mixed in 54 ml of glacial acetic acid with 2.7 ml of perchloric acid and refluxed at 125° C. In this case, the ethyl acetate that is produced is distilled off. After 90 minutes, the reaction is brought to a halt, since starting material is no longer present according to TLC. The reaction mixture is poured into ice water and extracted three times with ethyl acetate. The combined organic extracts are shaken with 5% sodium bicarbonate solution, with water and with brine. After the organic phase is dried, the desiccant is filtered off and the solvent is spun off, a residue remains that is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 4.69 g of the (2,6-dinitrophenyl)-acetic acid, which then is esterified with methanol (16 ml) and concentrated sulfuric acid (0.4 ml), is isolated. To this end, the acid and the reagents are refluxed for seven hours. The methanol is spun off, and the residue is worked up in the usual way. After chromatography on silica gel (mobile solvent ethyl acetate/hexane), 4.43 g (89%) of the desired ester is obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[S:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.ClCCl>C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:39][C:35]2[S:34][CH:38]=[CH:37][N:36]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=Cc1nccs1
Reactant: CC(C)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CCN(Cc1nccs1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Sodium triacetoxyborohydride (0:30 g, 1.42 mmol) is added to a stirred solution of 4-(3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.71 mmol), 2-thiazolecarboxaldehyde (0.12 ml, 1.42 mmol), and dichloromethane (3.5 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is diluted with ethyl acetate, washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered, and concentrated. Water is added to the residue, and the solution loaded onto a SCX-2 (10 g) column and washed with water (20 ml) and methanol (20 ml). The product is then eluted with 2M ammonia in methanol (30 ml). The filtrate is concentrated and the crude material purified on silica gel eluting with 0-50% ethyl acetate/hexanes to yield (0.20 g) of 4-{(3-methyl-butyl)-[(thiazol-2-yl)-methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=368 (M+1); 1H NMR (CDCl3): δ=7.67 (1H, d), 7.23 (1H, d), 4.17 (2H, brs), 3.93 (2H, s), 2.72-2.54 (5H, m), 1.78 (2H, brd), 1.7-1.57 (2H, m), 1.45-1.41 (10H, m), 1.40-1.32 (2H, m), 0.87 (6H, d).
Reaction SMILES: C(=O)(O)O.ClC(Cl)C.C([N:16]1[CH2:20][C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C@@H:18]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:17]1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[Si:32]([O:31][CH2:30][C@@H:18]1[C@@H:19]([C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[CH2:20][NH:16][CH2:17]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
1-Chloroethyl chloride carbonate was added to 4 ml of a 1,2-dichloroethane solution of 390 mg of (3R,4S)-1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(4-nitrophenyl)pyrrolidine under cooling with ice bath, and this was warmed up to room temperature and stirred for 2Hours. This was again cooled in an ice bath, mixed with saturated sodium carbonate aqueous solution, warmed up to room temperature and stirred for 30 minutes. This was extracted twice with chloroform, and the combined organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The oily residue was dissolved in 4 ml of methanol and heated under reflux for 5Hours. After concentration under a reduced pressure, the residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 290 mg of (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(4-nitrophenyl)pyrrolidine as an orange oily substance.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C(Cl)(C([Cl:18])=O)=O>C(Cl)Cl>[C:1]([Cl:18])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 10-undecenoic acid (5.055 mL, 25 mmol) in CH2Cl2 (50 mL) was slowly added (COCl)2 (4.364 mL, 50 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give 10-undecenoyl chloride (25 mmol). The product was used for the next reaction without further purification. 1H NMR (500 MHz, CDCl3) δ 1.29-1.48 (m, 10H), 1.71 (m, 2H), 2.05 (m, 2H), 2.88 (t, J=7 Hz, 2H), 4.98 (m, 2H), 5.80 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(OC([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:26](=[O:36])[CH2:27][O:28][C:29]2[N:34]=[CH:33][C:32](Br)=[CH:31][N:30]=2)[CH2:20]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:26](=[O:36])[CH2:27][O:28][C:29]2[N:30]=[CH:31][C:32]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:33][N:34]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)COc2ncc(Br)cn2)C1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: COc1ccc(-c2cnc(OCC(=O)NCC3CCNC3)nc2)cc1
Reaction time: 1 h

Procedure:
4-Methoxyphenylboronic acid (1.0 g, 6.8 mmol, 1.05 equiv.) was added to a solution of N-(1-tert-butoxycarbonylpyrrolidin-3-(RS)-ylmethyl)-2-(5-bromopyrimidin-2-yloxy)acetamide (2.7 g, 6.5 mmol) in 1-propanol (30 mL). The suspension was stirred until all ingredients had dissolved (~10 min). The resulting solution was treated with palladium acetate (29 mg, 0.13 mmol, 0.02 equiv.), triphenylphosphine (103 mg, 0.39 mmol, 0.06 equiv.), 2 M aqueous sodium carbonate (3.9 mL, 7.8 mmol, 1.2 equiv.) and deionized water (9 mL). The reaction mixture was heated at reflux under N2 for 1 h. Water (20 mL) was added and the N2 inlet was removed. After stirring at room temperature overnight, the reaction mixture was thoroughly extracted with ethyl acetate. The combined organic phase was washed with saturated sodium bicarbonate solution and brine. The organic phase was stirred with activated charcoal for 15 min, dried over sodium sulfate and concentrated. Recrystallization of the residue from ethyl acetate in hexane afforded clean N-(1-tert-butoxycarbonylpyrrolidin-3-(RS)-ylmethyl)-2-(5-(4-methoxyphenyl)pyrimidin-2-yloxy)acetamide (2.1 g). The solid was dissolved into methylene chloride (30 mL) and neat trifluoroacetic acid (5 mL) added dropwise. After about 1 h, the solution was concentrated to an oil on a Teflon dryvac, then under high vacuum to give N-(pyrrolidin-3-(RS)-ylmethyl)-2-[5-(4-methoxyphenyl)pyrimidin-2-yloxy]acetamide.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:18]C)[CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.B(Br)(Br)Br.ClCCl.CO>ClCCl>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CC(NC(=O)c1ccc(F)cc1)C2
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1Cc2ccc(O)cc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.45 g (5.08 mmol) 4-fluoro-N-(5-methoxy-indan-2-yl)-benzamide were dissolved in 50 ml of dichloromethane, 13 ml (12.7 mmol) boron tribromide (1M in dichloromethane) were added, the whole was stirred for 30 min at RT. The resulting mixture was poured onto 200 ml of ice water, the organic phase was washed twice with water, dried, evaporated and the residue obtained was subjected to chromatography on silica with a mixture of dichloromethane/methanol 98:2.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([CH3:22])=[CH:7][CH2:8][C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[C:11](=[O:20])[C:10]=1[CH3:21])([OH:3])=[O:2].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:9]([CH2:8][CH:7]=[C:6]([CH3:22])[CH2:5][CH2:4][C:1]([O:3][CH3:23])=[O:2])=[C:10]([CH3:21])[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COC1=C(OC)C(=O)C(CC=C(C)CCC(=O)O)=C(C)C1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCC(C)=CCC1=C(C)C(=O)C(OC)=C(OC)C1=O
Reaction time: 4 h
Yield: 448.7 %

Procedure:
To a solution of 6-(5-carboxy-3-methyl-2-pentenyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (93 mg) in methanol (3 ml) was added p-toluene sulfonic acid (10 mg). The mixture was stirred for 4 hours. The solvent was evaporated off under reduced pressure. The residue was dissolved in diethylether. The solution was washed with water and then dried. The solvent was evaporated off under reduced pressure. The residue was subjected to a column chromatography using silica-gel (3 g). From the fractions eluted with carbon tetrachloride-ethyl acetate (5:1) was obtained 2,3-dimethoxy-6-(5-methoxycarbonyl-3-methyl-2-pentenyl)-5-methyl-1,4-benzoquinone (84 mg). This product was treated in a conventional manner to produce 2,3-dimethoxy-6-(5-methoxycarbonyl-3-methyl-2-pentenyl)-5-methylhydroquinone, which was dissolved in pyridine (0.4 ml). The solution was cooled to about -10° C., to which was added chlorosulfonic acid (120 μl). The mixture was stirred for two days at room temperature. The reaction solution was made to pH 8- 9 with 1N potassium carbonate, then unreacted substances were removed by extraction with diethylether. The aqueous phase was subjected to evaporation to dryness under reduced pressure. The residue was subjected to column-chromatography using silica-gel (3 g). From the fractions eluted with methanol-chloroform (2:5) was obtained a mixture (24 mg) of potassium salts of 2,3-dimethoxy-6-(5-methoxycarbonyl)-3-methyl-2-pentenyl)-5-methylhydroquinone 1-sulfate and 4-sulfate.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.C1COCC1.[Pd]>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][CH:30]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 49.5 %

Procedure:
A mixture of intermediate (5) (0.19 mole) in methanol (600 ml) and THF (600 ml) was hydrogenated overnight with Pd/C 10% (3 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE. The precipitate was filtered off, dried, and dissolved in water. The mixture was alkalinized with Na2CO3 and then extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 40 g of N-[4-(1-piperazinyl)phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 6).
Reaction SMILES: [K].Br[CH:3]([CH:7]([CH3:9])[CH3:8])[C:4]([OH:6])=[O:5].[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([F:18])[CH:12]=1.[OH-].[Na+]>CCOCC.C(Cl)(Cl)Cl>[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C@H:3]([C:4]([OH:6])=[O:5])[CH:7]([CH3:9])[CH3:8])=[C:13]([F:18])[CH:12]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(C)C(Br)C(=O)O
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](Nc1ccc(Br)cc1F)C(=O)O
Temperature: 25 °C

Procedure:
To the potassium salt of α-bromoisovaleric acid (1.42 g) is added 4-bromo-2-fluoroaniline (1.9 g). The mixture is heated at 125° under nitrogen for 3.5 hr and then cooled to RT. The reaction product is poured into 2 M NaOH and ether/chloroform. The basic phase is separated and acidified with conc. HCl and then extracted into ether, washed with saturated NaCl solution, dried over calcium sulfate and evaporated to yield N-(4-bromo-2-fluorophenyl)valine.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:27]4[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:16][C:17]=3[C:18]32[N:25]=[C:24]([NH2:26])[CH2:23][O:22][CH2:21]3)=[C:9]([F:34])[CH:8]=1)(=O)=O.[F:37][C:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40][N:39]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:34][C:9]1[C:10]2[O:11][C:12]3[C:17](=[CH:16][C:15]([C:27]4[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:14][CH:13]=3)[C:18]3([N:25]=[C:24]([NH2:26])[CH2:23][O:22][CH2:21]3)[C:19]=2[CH:20]=[C:7]([C:42]2[CH:41]=[CH:40][N:39]=[C:38]([F:37])[CH:43]=2)[CH:8]=1
Reactant: NC1=NC2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1=NC2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(-c3ccnc(F)c3)cc12
Temperature: 85 °C
Yield: 84.9 %

Procedure:
A 10 ml resealable tube was charged with 5-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (385 mg, 0.730 mmol), 2-fluoropyridin-4-ylboronic acid (165 mg, 1.168 mmol), PdCl2(dppf)-DCM adduct (59.6 mg, 0.073 mmol), dioxane (3650 pt) and potassium carbonate (1M solution) (2190 μL, 2.190 mmol). The mixture was flushed with argon, sealed and heated at 85° C. for 1 hr. The mixture was diluted with EtOAc, organic layer was filtered through Celite and concentrated. The brown residue was purified by chromatography (10-80% DCM/MeOH/NH4OH in DCM) to afford 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (294 mg, 85% yield) as off-white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=[O:30]>>[CH:37]([C:34]1[CH:35]=[CH:36][C:31]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH:18]([C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])[CH:17]=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[CH:32][CH:33]=1)([CH3:39])[CH3:38]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C(C)C)cc3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 4-chloro-1-(4-isopropylphenyl)-1-butanone: ESMS m/e: 435.2 (M+H)+.