Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(CCO)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(C#N)cc2)cc1
Yield: 67 %

Procedure:
2-(4-Cyanophenyl)ethanol (1.46 g; 9.9 mmol) and 4-toluenesulfonyl chloride (1.9 g; 10 mmol) were stirred in pyridine (20 mL) at 5° C. for 3 hours. Work-up was performed by removing the solvent, addition of 2M aqueous HCl and extraction with EtOAc. The organic phase was washed with aqueous citric acid, then passed through a short plug of silica gel with Et2O. Removal of the solvent in vacuo afforded a colourless oil, containing ca. 30% of unreacted 2-(4-cyanophenyl)ethanol according to 1H NMR. The oil was further subjected to the reaction conditions above for 2 hours. Work-up as above afforded 2.0 g (66%) of the sub-title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].CN(C=O)C.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[O:30][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CBr
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To (E)-2-(2-bromomethylphenyl)-2-methoxyimino-N-methylacetamide (0.72 g, 2.5 mmol), added were dry DMF (5.0 ml), 2,5-dimethylphenol (0.46 g, 3.75 mmol) and potassium carbonate (0.69 g, 5.0 mmol), and the reaction mixture was stirred at room temperature for 4 hours. Then, water (100 ml) was added to the reaction mixture which was then extracted with ethyl acetate (100 ml). The extract was washed with water (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.57 g) as colorless crystals (yield, 69.8%).
Reaction SMILES: C[C:2]([CH3:18])(C)[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[NH:9]2.[CH3:19][CH:20](C)[CH2:21]CCO>>[CH3:19][CH:20]([CH3:21])[CH2:18][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[NH:9]2
Reactant: CC(C)CCCO
Reactant: CC(C)(C)COc1cccc2[nH]c(C(=O)O)cc12
Product: CC(C)CCCOc1cccc2[nH]c(C(=O)O)cc12

Procedure:
This compound is synthesized analogously to (85) from 4-methyl-pentan-1-ol.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:39]1[CH2:40][CH2:41][CH:36]([C:33]2[CH:34]=[CH:35][C:30]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCBr)Nc1ccccc1Cc1ccccc1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: O=C(CCCCCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (12) synthesized in Reference Example 12 and the compound (4) synthesized in Reference Example 4 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:26](Cl)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>CN(C)C=O.C(Cl)Cl.C(N(CC)CC)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:26]([OH:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: CCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(O)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4.3 g (20 mmol) 1,5-diacetyl-2-indolinone (Ex. II) are dissolved in 20 ml of dimethylformamide and 490 mg dimethylaminopyridine (DMAP) and 6 ml triethylamine added and the mixture is cooled in the ice bath. 3.8 ml (22 mmol) octanoic acid chloride in 20 ml of dimethylformamide are added to this solution and the mixture is stirred for a further 10 min. Then the reaction mixture is added to 150 ml of methylene chloride and 150 ml 1 N hydrochloric acid. The organic phase is separated off, dried over sodium sulphate and concentrated by rotary evaporation. The residue is chromatographed through a silica gel column with methylene chloride/methanol 95:5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[N:6]=[C:5]2[NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:28]=[CH:27]2.Cl[CH2:41][CH2:42][N:43]([CH3:45])[CH3:44].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:44][N:43]([CH3:45])[CH2:42][CH2:41][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[N:6]=[C:5]2[NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:28]=[CH:27]2
Reactant: CN(C)CCCl
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN(C)C
Temperature: 85 °C

Procedure:
A mixture of tert-butyl 5-(6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.475 g, 0.898 mmol), 2-chloro-N,N-dimethylethanamine (0.28 g, 1.94 mmol) and K2CO3 (1.18 g, 2.54 mmol) in DMF (8 mL) was heated at 85° C. for 3 h. The volatiles were removed in vacuo and the residue was taken up in CHCl3/MeOH. The solid was removed via filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, CHCl3/MeOH 93:7 then 90:10) to give tert-butyl 5-(6-(2-(dimethylamino)ethoxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.087 g, 0.145 mmol, 16%). MS 600.4 (M+1).
Reaction SMILES: [CH3:1][C:2]([C@:4]1([OH:26])[C@@:8]2([CH3:25])[CH2:9][CH2:10][C@@H:11]3[C@:22]4([CH3:23])[C:15](=[CH:16][C:17]([C@H:19]5[C@@H:21]4[CH2:20]5)=[O:18])[C:14]([Cl:24])=[CH:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].CS(C)=[O:29]>>[Cl:24][C:14]1[C:15]2[C@:22]([CH3:23])([C@H:21]3[CH2:20][C@H:19]3[C:17](=[O:18])[CH:16]=2)[C@@H:11]2[C@H:12]([C@H:7]3[C@:8]([CH3:25])([CH2:9][CH2:10]2)[C@@:4]([OH:26])([C:2](=[O:3])[CH3:1])[CH2:5][C@H:6]3[OH:29])[CH:13]=1
Reactant: CS(C)=O
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Product: CC(=O)[C@@]1(O)C[C@@H](O)[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Yield: 36 %

Procedure:
Under the culturing and fermentation conditions of Example 1, a 50-liter fermentor is prepared with 28 l. of a Bacillus megaterium culture and, after a culture period of 12 hours, combined with 6 g. of cyproterone (6-chloro-17-hydroxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione), dissolved in 400 ml. of dimethyl sulfoxide. After a contact period of 60 hours, the content of the fermentor is extracted with methyl isobutyl ketone and worked up as described in Example 1. The thus-obtained crude product is chromatographed over a silica gel column with the use of the solvent gradient methylene chloride-methylene chloride/acetone and recrystallized from acetone/hexane, thus obtaining in a 36% yield pure 6-chloro-15β,17-dihydroxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione, m.p. 251°-253° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[CH:36]=[C:35]([C:37](O)=[O:38])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:37]([C:35]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]([C:23]5[O:22][CH:26]=[CH:25][CH:24]=5)[CH:36]=4)=[O:38])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cc(-c2ccco2)nc2ccccc12
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(-c3ccco3)nc3ccccc23)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (42 mg, 0.15 mmol) and 2-fur-2-ylquinoline-4-carboxylic acid (95.7 mg, 0.4 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 30 min at room temperature. Carbodiimde resin (442 mg, 0.5 mmol) was added and shaking continued for 18 h. The solution was filtered off, the resin washed with THF and methanol and the combined filtrate and washings reduced to dryness under vacuum. The residue was dissolved in ethyl acetate, washed with hydrochloric acid (1M) and aqueous sodium hydrogen carbonate. The solvent was evaporated from the organic fraction under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-fur-2-ylquinoline-4-carboxamide. NMR; δH [2H6]—DMSO 10.85,(1H, s), 8.62,(1H, t), 8.12-8.07,(3H, m), 7.97,(1H, m), 7.94,(2H, d), 7.82,(1H, m), 7.72,(2H, m), 7.63,(1H, m), 7.49-7.45,(3H, m), 7.34,(1H, d), 6.75,(1H, m), 3.16,(2H, t), 2.23,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.69 min, MH+502.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:10]([CH3:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[Br-].[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=O>O1CCCC1.BrCCBr>[Br:24][C:20]1[CH:19]=[C:18]([C:16]([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH:10]([CH3:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=2)=[CH2:15])[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(Br)ccc1OC(C)C
Reactant: CC(=O)c1cccc(Br)c1
Agent: [Br-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc(OC(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of magnesium turnings (811 mg, 33.38 mmol, 1.2 eq) in 5 mL of dry tetrahydrofuran, 0.1 mL of 1,2-dibromoethane were added followed by 5 mL of a tetrahydrofuran solution of 4-bromo-1-isopropoxy-2-methyl-benzene (7.0 g, 30.6 mmol, 1.1 eq in 25 mL tetrahydrofuran). The resulting mixture was gently heated to initiate the reaction. The remaining solution of bromide was added dropwise at such a rate that the reaction could reflux without external heating. After the addition the reaction mixture was heated at reflux for further 2 hours. The mixture was cooled to 0° C. and a solution of 3-bromoacetophenone (5.54 g, 27.81 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added dropwise. After 2 hours LC-MS showed complete conversion to the desired product. 50 mL of water were added followed by 35 mL of 1 M aqueous HCl. The organic fraction was washed with brine, dried over sodium sulfate and concentrated to give a yellow oil. The oil was dissolved in 10 mL of acetic acid. 0.3 mL of 98% sulfuric acid were added and the dark solution was stirred at room temperature. After 30 min LCMS showed complete conversion to the desired product. Crushed ice was poured in the reaction mixture which was then extracted with dichloromethane. The organic fraction was collected, washed with water, aq. NaHCO3 and dried with over sodium sulfate. The crude product was purified by flash chromatography eluting with cyclohexane. 6.8 g of clean product was obtained as colorless liquid (yield: 66%)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=O)[C:7]2=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=[C:6]2[O:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=[S:22])[C:7]2=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=[C:6]2[O:5]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2cc3ccccc3nc2C1=O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2cc3ccccc3nc2C1=S
Yield: 86.9 %

Procedure:
To 3.0 g (0.01 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-b]-quinolin-5(4H)-one in 30 ml of acetonitrile was added 1.3 g (0.006 mole) of phosphorus pentasulfide. The mixture was stirred vigorously at reflux for 2 hr. After cooling, the reaction mixture was diluted with 60 ml of toluene and filtered. The residue on the filter paper was washed with 50 ml of additional toluene/acetonitrile, 3/1, V/V. The filtrate was washed with 3×50 ml saturated sodium carbonate (caution: gas evolved), dried over anhydrous sodium sulfate, filtered, treated with activated charcoal, filtered again and concentrated by rotary evaporation (90° C., 30 mm). The residual syrup was crystallized from isopropyl alcohol, yielding 1.6 g (52%) of yellow crystals, m.p. 114°-116° C.
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH3:9][C:4]1([CH3:10])[CH2:3][C:2](=[O:1])[CH2:11][C:6](=[O:7])[CH2:5]1
Reactant: CC(=O)CC(C)(C)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)CC(=O)C1
Yield: 82.3 %

Procedure:
A solution of 5 parts of 5-keto-3,3-dimethylhexanoic acid and about 15 parts of 73% sulfuric acid was heated for one hour in a 130°-135° oil bath. The cooled solution was then poured into a separatory funnel containing ice and chloroform. The aqueous phase was then washed three times with additional chloroform. The combined organic extractions were then dried and evaporated. There was obtained an 82.3% yield of dimedone. It was further recrystallized from toluene.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCNCC1CCNC1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)c(C)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A mixture of 0.80 g (2.70 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.41 g (3.20 mmol) of N-ethyl-3-pyrrolidinemethanamine, 0.82 g (8.10 mmol) of triethylamine, and 25 mL of acetonitrile was refluxed for 4 hours, then stirred at room temperature overnight. The precipitate was collected by filtration, washed with acetonitrile and ether, and dried to give 0.90 g of the title compound, mp 198°-199° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:18])[C:6]1[C:11]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:9]=[CH:8][C:7]=1[F:17].[OH:19]OS([O-])=O.[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CO.O>[Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:18])[C:6]1[C:7]([F:17])=[CH:8][CH:9]=[CH:10][C:11]=1[S:12]([C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19]
Reactant: CC(C)(C)Sc1cccc(F)c1C(=O)NCCCl
Reactant: O=S([O-])OO
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)S(=O)c1cccc(F)c1C(=O)NCCCl
Reaction time: 0.03 h
Yield: 98 %

Procedure:
A 0° C. solution of N-(2-chloroethyl)-2-fluoro-6-(1,1-dimethylethylthio)benzamide (2.0 g, 7.0 mmol) in methanol (50 mL) was combined with a 0° C. solution of OXONE® (4.24 g, 7.0 mmol) in water (50 mL). This mixture was stirred for 2 min, then was poured into 25% aq sodium metabisulfite (100 mL) and extracted with ether (3×100 mL). The combined organics were washed with brine followed with water, then were dried (MgSO4), concentrated, and purified by HPLC with 7:3 ethyl acetate/hexanes to afford 2.1 g of the title compound as a white solid, a 98% yield. m.p. 80-90° C.
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:13][C:9]3[S:10][CH:11]=[CH:12][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: O=Cc1sccc1Oc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3sccc3Oc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-phenoxy-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 435.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(#N)C.ClCCl>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH:5]2[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: COc1cccc(C2CCCN2CCN)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cccc(C2CCCN2CCNC(=O)c2ccc(Cl)cc2)c1
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of N-(2-aminoethyl)-2-(3-methoxyphenyl)pyrrolidine (0.58 g) in acetonitrile (15 ml) was added milled potassium carbonate (1.10 g) followed by 4-chlorobenzoyl chloride (0.33 ml) at ambient temperature, under nitrogen. The reaction mixture was stirred for 1.5 hrs, diluted with dichloromethane, and filtered. The filter cake was washed with dichloromethane, and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, 0-20% methanol/dichloromethane). The appropriate fractions were collected and concentrated to afford 0.80 g (85%) of product. Trituration with ether/petroleum ether gave the analytical sample, mp 96°-98° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: OB(O)c1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2ccccc2F)nc1

Procedure:
5 g (24.6 mmol) of 2-bromo-5-nitro-pyridine, 3.79 g (27.1 mmol) of 2-fluoro-phenylboronic acid, 276.5 mg (1.23 mmol) of palladium acetate, 646 mg (2.46 mmol) of triphenylphosphine and 24.6 ml of a 1 M aqueous sodium carbonate solution in 150 ml of toluene and 37 ml of ethanol were heated under reflux for 5 h. After cooling, the mixture concentrated under reduced pressure to half of its volume, poured onto water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The product was purified by chromatography (silica gel, n-heptane/ethyl acetate 5:1). Yield: 4.2 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1C([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH+](CC)CC)C>C(O)(=O)C>[CH2:15]([O:14][C:13]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:12]=1[C:22]([N:23]([CH3:24])[CH3:25])=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(-n2c(C(=O)[O-])c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Agent: CC[NH+](CC)CC
Solvent: CC(=O)O
Product: COc1ccc(-n2cc(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of triethylammonium 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (7) (3.5 g, 6.70 mmol) in acetic acid (100 mL) was stirred at RT for 4 h and then 110° C. for 1 h. The volatiles were removed in vacuo and the crude material partitioned between EtOAc (100 mL) and 1M NaOH (aq.) (20 mL)/brine (50 mL), the organic layer was then dried (MgSO4), filtered and concentrated in vacuo to afford 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (9) (3.05 g, 100%) as a yellow oil: m/z 457 (M+H)+ (ES+).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[NH:8][CH2:7][CH2:6]2.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>CN1CCCC1=O>[ClH:14].[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[C:11]([CH3:12])[C:10]=2[CH3:13])[CH2:6][CH2:7]1
Reactant: Cc1c(O)cc2c(c1C)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCc4cc(O)c(C)c(C)c43)c2cc1OC
Yield: 40 %

Procedure:
Utilizing a procedure analogous to that described in Example 47 this product (with conversion to the HCl salt as outlined for Example 2) was prepared in 40% yield from 5-hydroxy-6,7-dimethyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (M.P. 207°-209° C. (dec); LC-MS: 352 (MH+); anal. RP18-HPLC RT: 3.48 min.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:17][C:18](=[O:32])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:12]=[CH:13][C:14]=1[CH2:15]Cl>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:17][C:18](=[O:32])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=2[Cl:31])[CH:12]=[CH:13][C:14]=1[CH2:15][N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCl)c(Cl)c1
Reactant: CC1CCNCC1
Solvent: C1CCOC1
Product: CC1CCN(Cc2ccc(NC(=O)COc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
0.24 mL (2.000 mmol) 4-methylpiperidine was added to a solution of 0.206 g (0.500 mmol) N-(3-chloro-4-chloromethyl-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z32b) in 5 mL abs. THF and the mixture was refluxed for 2 h. The reaction mixture was poured onto ice water, the precipitate was filtered off, washed with water and dried in a HV.