Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH:7]([CH3:16])[CH2:6][C:5]2=[O:17].Cl[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].[OH-].[K+]>ClCCl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:22]([O:21][C:19]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([C:12]([F:14])([F:13])[F:15])[CH:10]=2)[C:5](=[O:17])[CH2:6][CH:7]1[CH3:16])=[O:20])([CH3:24])[CH3:23]
Reactant: CC(C)OC(=O)Cl
Reactant: CC1CC(=O)c2cc(F)c(C(F)(F)F)cc2N1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1c2cc(C(F)(F)F)c(F)cc2C(=O)CC1C
Reaction time: 8 h

Procedure:
6-Fluoro-2-methyl-4-oxo-7-trifluoromethyl-3,4-dihydro-2H-quinoline (1.01 g, 4.08 mmol) was dissolved in 10 mL of dichloromethane and 5 mL of pyridine, and stirred as isopropyl chloroformate (48 mL of a 1 molar solution in toluene, 48 mmol) was added slowly via syringe. After stirring overnight, 100 ml of a 1M aqueous potassium hydroxide solution was added and the aqueous phase was extracted with ethyl acetate (3×75 mL), the combined organics were washed with 1M HCl (2×50 mL), 100 mL each of a saturated sodium bicarbonate solution and brine, before being dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford 1.1 g of an oil, which was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexanes to afford 940 mg (69%) of the title compound as an oil. 1H NMR (CDCl3) δ 1.24 (d, 3H), 1.34 (d, 3H), 1.38 (d, 3H), 2.65 (dd, 1H), 3.05 (dd, 1H), 5.1-5.3 (m, 2H),
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:15]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O.C([N+](C)(C)C)C1C=CC=CC=1>CO.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[CH:26][C:25]2[CH:28]=[CH:29][C:22]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=2)[C:13]#[N:14])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(CC#N)cc1
Reactant: CCCCCCCc1ccc(C=O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: O
Solvent: CO
Product: CCCCCCCc1ccc(C=C(C#N)c2ccc(OCCCC)cc2)cc1
Temperature: 70 °C

Procedure:
9.4 g of p-butoxyphenylacetonitrile and 10.2 g of p-heptylbenzaldehyde are dissolved in 30 ml of methanol. 5 ml of a 40% solution of benzyltrimethylammoniumhydrate in water are added to the solution. The whole is heated at 70° C for 30 minutes and then cooled. The precipitate is sucked off and recrystallized from successively methanol and petroleum ether (60 : 80). Melting point of the resulting compound is 34.5°-35.5.° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([C@@H:16]2[O:24][CH2:23][C@@H:21]([OH:22])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:12](=[O:25])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(O)CC>CN(C)C=O.N1C=CC=CC=1>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]([C@@H:16]2[O:24][CH2:23][C@@H:21]([OH:22])[C@@H:19]([OH:20])[C@H:17]2[O:18][C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12](=[O:25])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccn([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2O)c(=O)n1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCO
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccn([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2OC(=O)c2ccccc2)c(=O)n1)c1ccccc1
Temperature: 124 °C
Reaction time: 8 h

Procedure:
54.0 g (0.155 mol) of N4-benzoyl-1-(β-D-ribopyranosyl)cytosine 1 were dissolved in 830 ml of dimethylformamide (DMF) and 1.5 l of pyridine (both solvents dried and stored over molecular sieve 3 Å) with warming to 124° C. 23.0 g (0.163 mol; 1.05 eq.) of BzCl, dissolved in 210 ml of pyridine, were added dropwise at −58° to −63° C. in the course of 3.5 h. The batch was stirred overnight in a cooling bath. 90.3 g (1.5 mol; 10 eq.) of n-propanol were stirred in and the batch was concentrated at 40° C. in a high vacuum. Pyridine residues were removed by twice adding 150 ml of toluene and concentrating again. 124.3 g of residue were dissolved in 500 ml of CH2Cl2, extracted twice by stirring with 300 ml of half-concentrated NaHCO3 solution each time, and the precipitated solid was filtered off and dried: 60.7 g of residue. The CH2Cl2 phase was concentrated: 25.0 g. Separate chromatography on silica gel 60 (40×10 cm) with gradients (AcOEt/isohexane, 4:1, then pure AcOEt, then AcOET/MeOH, 19:1 to 2:1) yielded (TLC (silica gel, AcOET)):
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:23]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH:27]=[CH:26][N:25]=[CH:24]1.O>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NCCCCCCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCCCCCCCn1ccnc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.58 g of 6-chloronicotinic acid and 1.62 g of 1,1'-carbonyldiimidazole in 30 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then 1.95 g of 1H-imidazole-1-octanamine was added and the mixture was stirred at room temperature for 16 hours. The mixture was heated at reflux for 5 hours, 10 ml of water was added and heating was continued for one hour longer. The mixture was concentrated to remove tetrahydrofuran. Then 5 ml of 1N sodium hydroxide and dichloromethane was added. The mixture was shaken and the organic layer was separated, washed twice with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and gave an oil. The oil was treated with diethyl ether to crystallize the desired compound as white crystals, mp 79°-81° C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(O)C.Br[CH:19]([CH3:29])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH:19]([CH3:29])[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[O:21])[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: CC(Br)C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(CC2CCN(C(C)C(=O)c3ccc(O)cc3)CC2)cc1

Procedure:
7.57 g (0.04 mol) of 4-(4-methylbenzyl)-piperidine are introduced into 35 ml of ethanol, 9.15 g (0.04 mol) of 2-bromo-4'-hydroxypropiophenone and then 4.24 g (0.04 mol) of sodium carbonate are added and the mixture is heated under reflux for 2 hours. It is then cooled with an ice bath and 200 ml of iced water and 100 ml of toluene are added. The mixture is stirred and left to separate and the organic phase is separated off. The aqueous phase is extracted three times with 100 ml of toluene. The organic phases are combined, washed, dried and then evaporated. This gives 13 g of a pasty oil, which is purified by chromatography on silica using acetone as the eluant. 10 g of a pale oil are collected, which is used as such in the subsequent reduction.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17]CC4C=CC=CC=4)=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:25](=[S:28])[CH2:26][CH3:27])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.Cl.CCOCC>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:25](=[S:28])[CH2:26][CH3:27])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(=S)c1cc(-c2ccccc2)c2ccc(OCc3ccccc3)cc2c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCC(=S)c1cc(-c2ccccc2)c2ccc(O)cc2c1

Procedure:
A solution of methylthioacetyl derivative from Step 4 (140 mg) in AcOH (1 mL) and conc. HCl (1 mL) was stirred at r.t. 18 hr. The reaction mixture was diluted with Et2O, washed with H2O (2×), saturated NaHCO3 solution, brine, dried over MgSO4 and the solvent evaporated. The residue was flash chromatographed, eluting with hexane:EtOAc:CH2Cl2 (85:15:50) to afford the title compound as a foam.
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]C(N3C4C=CC=CC=4N=N3)(C3C=CC=CC=3)CC3C=CC(CP(OF)(OF)=O)=CC=3)=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:6])[O:4][CH3:5].[Br:52][Si](C)(C)C>C(Cl)Cl>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][Br:52])=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:6])[O:4][CH3:5]
Reactant: COc1ccc(-c2ccc(CC(Cc3ccc(CP(=O)(OF)OF)cc3)(c3ccccc3)n3nnc4ccccc43)cc2)cc1P(=O)(OC)OC
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CBr)cc2)cc1P(=O)(OC)OC

Procedure:
A solution of 4′-{2-benzotriazol-1-yl-3-[4-(difluorophosphonomethy)phenyl]-2-phenylpropyl}-4-methoxybiphenyl-3-yl-phosphonic acid dimethyl ester (330 mg, 0.39 mmol) and bromotrimethylsilane (1 mL) in CH2Cl2 (5 mL) was stirred at r.t. overnight. Volatile mateials were removed in vacuo. The residue was co-evaporated with ˜90% aqueous EtOH (3×) to give the title compound as a light brown foam.
Reaction SMILES: ClC(OCC)=O.CN1CCOCC1.COC(C=C([NH:21][C@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([O-:25])=O)C)=O.[Na+].[CH3:33][C:34]1([CH3:46])[S:38][C@@H:37]2[C@H:39]([NH2:42])[C:40](=[O:41])[N:36]2[C@H:35]1[C:43]([OH:45])=[O:44].O.[C:48]1([CH3:58])[CH:53]=[CH:52][C:51]([S:54]([OH:57])(=[O:56])=[O:55])=[CH:50][CH:49]=1.[OH-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(=O)C.O>[CH3:33][C:34]1([CH3:46])[S:38][C@@H:37]2[C@H:39]([NH:42][C:23]([C@H:22]([NH2:21])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:25])[C:40](=[O:41])[N:36]2[C@H:35]1[C:43]([OH:45])=[O:44].[C:48]1([CH3:58])[CH:49]=[CH:50][C:51]([S:54]([O-:57])(=[O:55])=[O:56])=[CH:52][CH:53]=1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)C=C(C)N[C@@H](C(=O)[O-])c1ccccc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: CN1CCOCC1
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
Meanwhile, 4-methylpentan-2-one (70 ml) was stirred and cooled to 0° and ethyl chloroformate (2.0 ml, 0.0208 mole) and a 1% solution of N-methylmorpholine in 4-methylpentan-2-one (3 ml) were added. The solution was cooled to -5° and sodium (R)-N-(1-methoxycarbonylpropen-2-yl)-α-aminophenylacetate (5.42 g, 0.02 mole) was added. The suspension was stirred at 0° to -5° for 30 minutes and then cooled to -30°. The 6-APA solution prepared above was added so as to keep the temperature of the mixture between -25 and -30°. The mixture was stirred for 30 minutes at -30° when water (50 ml) was added. Aqueous 2.53 M toluene-p-sulphonic acid monohydrate solution (17 ml, 0.043 mole) together with 10 M aqueous sodium hydroxide solution (ca. 0.1 ml) were added to the stirred two-phase mixture to adjust the pH to and maintain it at 1.5. The mixture was stirred at 5° for 1 hour when more toluene-p-sulphonic acid solution was added to readjust the pH from 2.5 to 1.6. The resulting suspension was stirred for a further 2 hours at 5° and filtered. The wet cake was washed with 4-methylpentan-2-one (50 ml), sucked as dry as possible and washed by slurrying with ice-cold water (50 ml). The solid was refiltered, washed with ethyl acetate (20 ml) and dried in vacuo at 45° to give ampicillin toluene-p-sulphonate (8.51 g, 81.7% th.), [α]D25 + 173° (c 0.97; 0.2 M pH 7 phosphate buffer). We claim:
Reaction SMILES: [Sn:1]([Br:3])[Br:2].[C:4]([CH2:7][C:8](=[O:10])[CH3:9])(=O)[CH3:5].C([Br:14])(=O)C>C(OCC)C>[CH3:5][C:4]([Sn:1]([Br:14])([Br:3])[Br:2])=[CH:7][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: CC(=O)Br
Reactant: Br[Sn]Br
Solvent: CCOCC
Product: CC(=O)C=C(C)[Sn](Br)(Br)Br
Yield: 96.3 %

Procedure:
The procedure was analogous to Example 6. 22.4 g (0.08 mol) of tin(II) bromide and 8.0 g (0.08 mol) of acetylacetone were reacted with 9.8 g (0.08 mol) of acetyl bromide in 200 ml of diethyl ether and the reaction solution was concentrated to give 34.0 g (96% of theory) of 1-methylbut-1-en-3-onyltin tribromide (Br3 Sn--C(CH3)=CH--CO--CH3) melting at 110°-112° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CO.[CH3:14][Si](C=[N+]=[N-])(C)C.C(OCC)C>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: Cc1ccc(O)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cc(O)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 49 %

Procedure:
To a stirred solution of 5-hydroxy-2-methylbenzoic acid (WO 9619437, 1.11 g, 6.69 mmol), in dichloromethane (6 mL) and methanol (6 mL) was added a 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether (7.31 mL, 14.7 mmol) at 0° C. The mixture was stirred at room temperature for 3 days, and the mixture was diluted with dichloromethane (200 mL). The solution was washed with water and brine, dried over magnesium sulfate, and evapolated. The residue was purified by column chromatography on silica gel (40 g) eluting with hexane/ethyl acetate (10/1) to afford 545 mg (49%) of the title compound:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C=O)C.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:32][CH2:33][N:34]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:35][CH2:36]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(n2cc(C(=O)c3cccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Yield: 19 %

Procedure:
A solution of 1-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-(3,5-dichloro-phenyl)-urea (100 mg, 0.19 mmol) and methanesulfonylchloride (22 mg, 0.19 mmol) in DMF/CH2Cl2 (2/3, 5 mL) was stirred in a sealed tube for 1.5 hours at room temperature. The reaction mixture concentrated in vacuo. Purification by reverse phase preparative HPLC (HPLC method 2) provided the title compound as a white solid (21.8 mg, 19%). MS: 603.5 (MH+); HPLC Rf: 2.3 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH:4]=[C:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCO.CCOC(C)=O.CO.[Pd]>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[CH:15]2)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]c(C)cc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: CNC(=O)CC(c1ccccc1)c1ccc2[nH]c(C)cc2c1
Reaction time: 48 h

Procedure:
To a solution of N-methyl-3-(2-methyl-1H-indol-5-yl)-3-phenyl-acrylamide LXVIII (990 mg, 3.41 mmol) in EtOH/EtOAc/MeOH (5/2/1, 40 ml) was added Pd/C (5%, 90 mg). The mixture was hydrogenated in a Parr apparatus at 60 psi of H2 for 48 hours. Degoussa-type catalyst (10% Pd/C, catalytic amount) was added to the mixture. The mixture was hydrogenated in a Parr apparatus at 60 psi of H2 for additional 6 hours. The reaction mixture was filtered through celite, and the filter cake was washed with MeOH, hot EtOH and DCM. The filtrate was concentrated affording N-methyl-3-(2-methyl-1H-indol-5-yl)-3-phenyl-propionamide LXIX as a light orange foamy solid in quantitative yield (1.05 g).
Reaction SMILES: C(OC(Cl)=O)C(C)C.[N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)[CH2:32][CH2:31]1>C1COCC1>[NH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:19]([C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:9]=[CH:10][CH:11]=[CH:12]4)=[O:21])[CH2:35][CH2:34]2)=[CH:39]1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccc2ncccc2c1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of isobutylchloroformate (0.65 g, 5.01 mmol) in dry THF (10 cm3) was added dropwise to a suspension of quinoline-6-carboxylic acid (0.87 g, 5.03 mmol) and triethylamine (0.6 g, 5.94 mmol) in dry THF (10 cm3) with stirring and cooling at -20° C. Stirring was continued while the temperature rose to ambient over 2 hours, then the mixture was cooled to -20° C. again and a solution of 3-[2-(4-amino-1-piperidyl)ethyl]indole (1.20 g, 4.94 mmol) in dry THF (20 cm3) was added dropwise. The mixture was stirred at room temperature overnight then evaporated to dryness and the residue triturated with water, aqueous potassium carbonate and water to give 1.4 g. of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:18][C:13]2[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:19]=[CH:20][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Using the procedure described in Example 102, Part A, N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (3.1 mmol) and 4-nitrobenzoic acid (3.0 mmol) yielded the title product, which was used directly in the next step without additional purification.
Reaction SMILES: C[C:2]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](O)([CH2:17][C:18](OCC)=O)[CH2:12][CH2:11][C:10]3([CH3:25])[CH3:24])[O:6][CH2:5][CH2:4][O:3]1.[CH3:26][C:27]1C=CC(S(O)(=O)=O)=CC=1.[OH2:37]>C1C=CC=CC=1>[CH3:24][C:10]1([CH3:25])[C:9]2[C:14](=[CH:13][CH:17]=[C:18]([C:26](=[O:37])[CH3:27])[CH:8]=2)[C:15]([CH2:16][CH2:7][C:2]([O:3][CH2:4][CH3:5])=[O:6])=[CH:12][CH2:11]1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C3(C)OCCO3)ccc21
Solvent: c1ccccc1
Product: CCOC(=O)CCC1=CCC(C)(C)c2cc(C(C)=O)ccc21

Procedure:
A solution of (+/-) 6-(2-methyl-1,3-dioxolan-2-yl)-1,2,3,4-tetrahydro-4,4-dimethyl-1-hydroxy-1-(carboethoxymethyl)-naphthlene ((Compound D16, 321 mg, 0.90 mmol) and catalytic amount of TsOH in 20 ml of benzene was refluxed for 12 h. During the reaction the water generated from the reaction was periodically removed by a Dean-Stark trap. The solvent was removed and the residue was purified by column chromatography (silica, ethyl acetate/hexane (1/3)) to give the title compound as an oil (215 mg).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)=[O:19]
Reactant: C[S+](C)(C)=O
Reactant: CON(C)C(=O)C=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(4-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (13 g) as an oil.
Reaction SMILES: C[CH2:2][N:3]([CH:7]([CH3:9])C)[CH:4](C)C.CNC.BrC[C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=C[C:16]=1[F:24].CCOC(C)=O>C1COCC1>[F:24][C:16]1[CH:15]=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:9]=1[CH2:7][N:3]([CH3:2])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
A −20° C. solution of DIEA (771 mg, 5.97 mmol) and dimethylamine (2.0M in THF, 1.94 mL, 3.88 mmol) in THF (5 mL) was treated drop-wise with a solution of 2-(bromomethyl)-1-fluoro-4-nitrobenzene (698 mg 2.98 mmol) in THF (5 mL) and stirred at RT overnight as the cooling bath expired. The mixture was treated with EtOAc, washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 1-(2-fluoro-5-nitrophenyl)-N,N-dimethylmethanamine (494 mg, 84% yield). MS (ESI) m/z: 199.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:22])=[CH:10][CH:11]=2)[C:6]1=[O:23].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:20]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:22])=[CH:10][CH:11]=2)[C:6]1=[O:23]
Reactant: OB(O)c1ccccc1
Reactant: O=c1c2cc(F)ccc2cc(-c2ccc(O)cc2)n1Cc1ccc(F)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2cc(F)ccc2cc(-c2ccc(Oc3ccccc3)cc2)n1Cc1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of 2-(2,4-difluorobenzyl)-7-fluoro-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (54 mg, 0.14 mmol), a compound of formula (Id), in CH2Cl2 (8 mL) was added phenylboronic acid (35 mg, 0.28 mmol), copper (II) acetate (51 mg, 0.28 mmol), and powdered activated 4 Å molecular sieves (500 mg). The mixture was stirred for 10 minutes then treated with triethylamine (99 μL, 0.71 mmol). The resulting suspension was stirred for 72 hours at ambient temperature. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography on silica gel eluting with 25% EtOAc/hexanes to afford 2-(2,4-difluorobenzyl)-7-fluoro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one, a compound of formula (Id), (29 mg, 45% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.11 (1H, dd, J=9.4, 2.8 Hz), 7.52 (1H, dd, J=8.6, 5.1 Hz), 7.45-7.36 (3H, m), 7.19-7.14 (1H, m), 7.14-7.09 (2H, m), 7.08-7.03 (2H, m), 7.02-6.93 (3H, m), 6.78-6.72 (1H, m), 6.70-6.64 (1H, m), 6.47 (1H, s), 5.24 (2H, s) ppm.