Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[C:24]([CH3:33])=[CH:23][C:22]4=[O:34])[CH2:15][CH:14]3[C:35]([O:37]CC)=[O:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[C:24]([CH3:33])=[CH:23][C:22]4=[O:34])[CH2:15][CH:14]3[C:35]([OH:37])=[O:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CN(CCn2c(=O)cc(C)c3ccc(OC)cc32)CCN1CCc1ccc2c(c1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(C)cc(=O)n(CCN3CCN(CCc4ccc5c(c4)OCCO5)C(C(=O)O)C3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To 3.3 mL of a 90% aqueous methanol solution containing 58 mg of ethyl 1-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl)-4-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-2-carboxylate, 22 mg of sodium hydroxide was added and stirred at room temperature for 30 min. Further, 66 mg of sodium hydroxide and 1.1 mL of a 90% aqueous methanol solution were added and stirred at room temperature for 6 hours. After the solvent was removed under reduced pressure, water was added, and adjusted to pH 1 with 6.0 mol/L hydrochloric acid, thereafter ethanol was added and adjusted to pH 6.5 with aqueous saturated sodium hydrogen carbonate solution and 1.0 mol/L hydrochloric acid. The resulting solid was filtered to give 35 mg of 1-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl)-4-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-2-carboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[C:21]([O:28][CH3:29])[CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:34]1C=C(S(Cl)(=O)=O)C=C[C:39]=1Cl>>[CH2:34]([O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:30]=[CH:31][CH:32]=[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])[CH:14]=2)=[CH:20][C:21]=1[O:28][CH3:29])[CH3:39]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)ccc1C(=O)O
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)cc1OC

Procedure:
4-[3-(3,4-Dichloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid, MS (ISP): m/e=495.2 (M+H+), was prepared in analogy to example 17, steps A to D. Step C was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,4-dichloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:3]=1.[I:17]I>C(#N)C>[I:17][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:5]=1[CH3:7]
Reactant: II
Reactant: Cc1cc(C)n(-c2ccc(CCO)cc2)n1
Solvent: CC#N
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Yield: 129.4 %

Procedure:
A mixture of 2-[4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 1, 1.26 g, 5.8 mmol), iodine (883 mg, 3.5, mmol) and ceric ammonium nitrate (1.59 g, 2.9 mmol) was stirred in acetonitrile (58 mL) at room temperature for 1 h. Then, the solvent was evaporated under reduced pressure and the resulting residue was dissolved dichloromethane. The organic solution was washed with 5% aqueous solution sodium thiosulfate, then with brine, and finally dried (Na2SO4) and evaporated. The crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 1.54 g (78%) of the title compound as yellow solids: MS (ESI) m/z 343 [M+H]+, 1H-NMR (CDCl3) δ 7.32 (4H, s), 3.86 (2H, t, J=6.6 Hz), 2.91 (2H, t, J=6.6 Hz), 2.33 (3H, s), 2.30 (3H, s), 1.67 (1H, br.s).
Reaction SMILES: [N-]=C=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH2:50][C:51]([CH3:56])([CH3:55])[CH2:52][C:53]#[N:54])[CH:33]=[CH:34][C:35]=1[N:36]1[CH2:40][C:39](=[O:41])[N:38](CC[Si](C)(C)C)[S:37]1(=[O:49])=[O:48])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.Cl>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH2:50][C:51]([CH3:56])([CH3:55])[CH2:52][C:53]#[N:54])[CH:33]=[CH:34][C:35]=1[N:36]1[CH2:40][C:39](=[O:41])[NH:38][S:37]1(=[O:49])=[O:48])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(CC#N)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(CC#N)Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of PS-isocyanate resin (100 mg) in THF is added TBAF (1M in THF, 0.5 mL) and the mixture is stirred at RT for 2 h. The resin is filtered off and the TBAF solution is added to a solution of 4-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-3,3-dimethylbutyronitrile (25 mg, 0.047 mmol) in THF (5 mL). The mixture is stirred at RT for 18 h then is diluted with 1N HCl and extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4 and concentrated to give the title compound which is used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([OH:15])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:52]1[CH2:57][CH2:56][O:55][CH2:54][CH:53]1[C:58]1[C:66]2[S:65][C:64]([NH2:67])=[N:63][C:62]=2[C:61]([O:68][CH3:69])=[CH:60][CH:59]=1>C1COCC1.C(Cl)(Cl)Cl>[O:52]1[CH2:57][CH2:56][O:55][CH2:54][CH:53]1[C:58]1[C:66]2[S:65][C:64]([NH:67][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][N:18]=[C:10]([O:9][CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])[CH:11]=3)=[N:63][C:62]=2[C:61]([O:68][CH3:69])=[CH:60][CH:59]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(OCCN2CCCC2=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(OCCN4CCCC4=O)c3)nc12

Procedure:
From 2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+57.3° (c=1.03, CHCl3), ES-MS m/e (%): 499 (M+H+, 100).
Reaction SMILES: C([BH-](CC)CC)C.[Li+].C([O:11][C:12]([C@@H:14]1[N:18]([CH3:19])[C:17](=[O:20])[CH2:16][C@@H:15]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[OH:11][CH2:12][C@@H:14]1[N:18]([CH3:19])[C:17](=[O:20])[CH2:16][C@@H:15]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccccc2)CC(=O)N1C
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1CO
Temperature: 0 °C

Procedure:
Lithium triethylborohydride solution (4.24 L, 1.0M/THF) was steadily added (over 45 minutes) to a cold (−20° C.), stirred solution containing (±)-(4R*,5R*)-5-(Ethoxycarbonyl)-1-methyl-4-phenylpyrrolidin-2-one (500 g, 2.02 mole) in tetrahydrofuran (4L). The internal temperature was kept below −15° C. during the addition; the reaction was then allowed to warm to 0° C. and stirred for 1 hour. The reaction mixture was then cooled back down to −5° C. and cold 4N hydrochloric acid solution (made from 1000 mL ice water and 500 mL conc. HCl) was added over a 7-8 minute period with vigorous stirring. After stirring for 30 minutes (internal temp. ˜12° C.) the pH was adjusted to 7-8 by adding solid potassium carbonate. The reaction mixture was allowed to warm to room temperature, at which time the organic layer was separated and washed with brine (4 L). The organic layer was concentrated to near dryness, and hexane (200 ml) was added to precipitate a yellow solid. The solid was filtered, washed with hexane (500 ml) and dried under vacuum to give 345.12g (83%) of (±)-(4R*,5R*)-5-(hydroxymethyl)-1-methyl-4-phenylpyrrolidin-2-one. NMR (CDCl3) δ 2.35 (br s, 1H, OH), 2.56 (m, 1H, CH2), 2.94 (s, 3H, CH3), 3.01 (m, 1H, CH2), 3.34 (dd, J=13.5, 3.1 Hz, 1H, CH), 3.63 (dd, J=12.2, 3.4 Hz, 1H, CH), 3.75 (m, 2H, CH2), 7.31 (m, 5H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[N+:15]([CH3:18])([O-:17])=[O:16].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])/[CH:6]=[CH:18]/[N+:15]([O-:17])=[O:16]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc(/C=C/[N+](=O)[O-])cc(OC)c1OC
Yield: 41 %

Procedure:
A mixture of 3,4,5-trimethoxybenzaldehyde (9.80 g, 50 mmol), nitromethane (18 ml), ammonium acetate (4.11 g) and acetic acid (38 ml) was heated and refluxed for 2 hours. After the reaction mixture was concentrated under reduced pressure, 10% aqueous sodium hydroxide solution was added to the residue and the reaction mixture was extracted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel chromatography (dichloromethane) and recrystallized to yield trans-3,4,5-trimethoxy-β-nitrostyrene (4.96 g, 41%). Properties: mp 116-118° C. (ethanol)
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:8][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:9][CH2:10][CH2:11][CH2:12]2
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1ccc2c(c1)CCCN2
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.5 %

Procedure:
NBS (28 g, 158 mmol) was added to a solution of 1,2,3,4-tetrahydroquinoline (20 g, 150.16 mmol) in carbon tetrachloride (200 mL). The resulting solution was stirred for 3 h at 0° C., extracted with dichloromethane (3×50 mL) and concentrated in vacuo to give a residue, which was applied onto a silica gel column with 1% ethyl acetate in petroleum ether to give 6-bromo-1,2,3,4-tetrahydroquinoline as a yellow solid (11 g, 35%).
Reaction SMILES: I([O-])(=O)=O.[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1.[I:17]I.S(=O)(=O)(O)O>O>[I:17][C:11]1[CH:12]=[C:7]([Cl:6])[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[CH3:13]
Reactant: II
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+2]([O-])[O-]
Solvent: O
Product: Cc1c(I)cc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Sodium iodate (158 g, 0.800 mol, 0.4 eq.) was added portionwise, under nitrogen atmosphere, to an ice-cooled mixture of 4-chloro-2-nitrotoluene (343 g, 2.00 mol), iodine (204 g, 0.800 mol, 0.4 eq.) and conc. sulfuric acid (1960 g, 20.0 mol, 10 eq.) and the resulting mixture was stirred at a temperature of 5° C. to 10° C. for 6 hours. Water (2 L) was added dropwise thereto with stirring in an ice-water bath, and the mixture was extracted with toluene (2.5 L). The combined organic layer was treated with aqueous 10% sodium thiosulfate solution, washed with water (1 L×2) and aqueous sat. sodium hydrogencarbonate solution (1 L×2) successively, dried over sodium sulfate and concentrated to give crude A-1 (548 g, purity 62%) as a yellow oil. This product was used in the following reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:26])([CH3:25])[C:10]([NH:12][C@@H:13]1[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:24])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]O)=[C:41]([Br:47])[CH:40]=1)=[O:30]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:26])([CH3:25])[C:10]([NH:12][C@@H:13]1[CH2:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:45][C:42]2[CH:43]=[CH:44][C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][NH:31][C:29]([NH:28][CH3:27])=[O:30])=[CH:40][C:41]=2[Br:47])[C:14]1=[O:24])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H]1CCc2ccccc2NC1=O
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)c(Br)c1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)c(Br)c1

Procedure:
Prepared from 2-t-butoxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]propanamide (Step K) and 2'-[[(methylamino)carbonyl]amino]methyl-3-bromo-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step J) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CDCl3): δ 1.39 (s, 12H), 1.41 (s, 3H), 1.92 (m, 1H), 2.48-2.75 (m, 6H), 4.20 (d, 6 Hz, 2H), 4.52 (m, 2H), 4.70 (m, 1H), 4.92 (m, 2H), 7.08-7.35 (m, 10H) 7.42 (m, 1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH:10]([C:12]([OH:14])=[O:13])[CH3:11])[C:4]1=[O:15].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.O=[C:35]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:36]([O:38]CC)=[O:37].C([BH3-])#N.[Na+]>O.C(O)C>[C:12]([CH:10]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:3]([NH:2][CH:35]([C:36]([OH:38])=[O:37])[CH2:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:4]1=[O:15])[CH3:11])([OH:14])=[O:13]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C(=O)O)N1CCCC[C@H](N)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)N1CCCC[C@H](NC(CCc2ccccc2)C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 422 mg of 3-(S)-amino-1-(1-carboxyethyl)perhydroazepin-2-one hydrochloride in water and adjust the pH to 6.8 with 2M tetrabutylammonium hydroxide. Lyophilize the solution and dissolve the residue in 10 ml absolute ethanol. Add 1.98 g ethyl 2-oxo-4-phenylbutyrate and 7 g. powdered 4 A molecular sieves. Add a solution of 357 mg. sodium cyanoborohydride in 3 ml absolute ethanol at a rate of 0.5 ml/hour. After the addition is complete, stir the reaction mixture overnight at room temperature. Filter the reaction mixture, wash the filter cake with ethanol and concentrate the combined filtrate and washings at aspirator pressure. Dissolve the residue in water and add 20 ml ether and 20 ml Dowex 50 (H+). Stir the mixture for 1 hour then draw off the ether layer.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.C(=O)(O)[O-].[Na+].[C:21]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[C:21]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:33])=[O:34])=[CH:28][CH:27]=1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)cc1

Procedure:
6.3 grams (0.03 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile are dissolved in 70 ml of acetone, and 30 ml water are added thereto. Sodium bicarbonate (2.6 g, 0.03 mol) is added with stirring, followed by a solution of 7 g (0.03 mol) of 4-carbethoxybenzenesulfonyl chloride in 30 ml acetone. The reaction mixture is stirred overnight, filtered and the filtrate diluted with 750 ml water. The dark, cream-colored solid which separates and which is recovered by filtration and drying constitutes 3-[4-(4-carbethoxyxbenzenesulfonamido)benzenesulfonyl]acrylonitrile: ##SPC31##
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O>>[NH2:12][C:11]1[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([CH3:13])[C:2]=2[N:1]=[C:16]([CH3:18])[C:15]=1[C:14]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Cn1c(N)c(C#N)c2ccccc21
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2c(c1N)c1ccccc1n2C

Procedure:
The title compound was prepared from 2-amino-1-methyl-1H-indole-3-carbonitrile (D22) and ethyl acetoacetate using a method similar to that described in Description 2.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][S:45]([C:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1)(=[O:47])=[O:46]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:54][C:51]3[CH:50]=[CH:49][C:48]([S:45]([CH3:44])(=[O:47])=[O:46])=[CH:53][CH:52]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(S(C)(=O)=O)cc3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-methanesulfonyl-phenylamine according to procedure B followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=433.3 [M+H]+.
Reaction SMILES: CO.[NH2:3][C:4]1[C:9](Cl)=[C:8]([F:11])[N:7]=[C:6](Cl)[C:5]=1[F:13]>[C].[Pd].C(N(CC)CC)C>[NH2:3][C:4]1[C:5]([F:13])=[CH:6][N:7]=[C:8]([F:11])[CH:9]=1
Reactant: Nc1c(F)c(Cl)nc(F)c1Cl
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1cc(F)ncc1F
Reaction time: 288 h
Yield: 90.8 %

Procedure:
To 40 ml of methanol were added 4.5 g of 4-amino-2,5-dichloro-3,6-difluoropyridine and 4.5 g of triethylamine together with 0.40 g of 10% palladium carbon, and the mixture was hydrogenated at 50° C. for 12 days. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 100 ml of chloroform, and the mixture was washed with 10 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue were added 1.5 g of triethylamine, 0.35 g of 10% palladium on carbon, and 30 ml of methanol, and the mixture was hydrogenated at 50° C. for 41 hours. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 100 ml of chloroform, and the mixture was washed with 10 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2.67 g of the title compound as precipitate as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH:12]([CH2:21][CH3:22])[C:13](=O)[CH2:14][C:15]([O:17]CC)=[O:16]>>[CH2:21]([C:12]1[O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8][C:13]=1[CH2:14][C:15]([OH:17])=[O:16])[CH3:22]
Reactant: NC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)C(Br)CC
Product: CCc1oc(-c2ccc(F)cc2)nc1CC(=O)O

Procedure:
The title compound was prepared from 5 g of 4-fluorobenzamide and 5.67 g of ethyl 4-bromo-3-oxo-hexanoate as described in example 2B to give 1.8 grams of intermediate 3B as a solid: 1H NMR (CDCl3, 300 MHz) δ7.96 (dd, 2H, J=8.8, 5.3), 7.11 (t, 2H, J=8.6), 3.61 (s, 2H), 2.69 (q, 2H, J=7.5), 1.27 (t, 3H, J=7.5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]2[O:13][C:14]([CH2:17]Cl)=[N:15][N:16]=2)=[CH:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[I-].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]2[O:13][C:14]([CH2:17][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:15][N:16]=2)=[CH:4][N:3]=1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(CCl)o1
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(CN2CCOCC2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-chloro-5-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-N-isopropylpyridin-4-amine (46) (60 mg, 0.2 mmol) was taken in a rbf, added morpholine (4 mL) to the rbf followed by the addition of potassium iodide (0.2 mmol), stirred the reaction mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure to remove excess of morpholine. The crude material obtained was taken to next step as such, without purification. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.608 min; LCMS (ES-API), m/z 338.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[C:28]([O:42][CH3:43])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:42][CH3:43])=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Product: CCOc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxy-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 92.1.1) to give the title compound as a white solid. (HPLC: tR 2.63 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.98-7.94 (m, 1H), 7.92-7.90 (m, 1H), 7.54-7.53 (m, 1H), 7.22-7.21 (m, 1H), 4.16-4.09 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H), 1.41 (t, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=3)=[N:20][N:21]=2)=[O:16])[CH2:12]1)[CH:5]=O.Cl.[CH3:31][C:32]1([OH:36])[CH2:35][NH:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][N:34]2[CH2:35][C:32]([OH:36])([CH3:31])[CH2:33]2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:20][N:21]=2)=[O:16])[CH2:12]1
Reactant: CC1(O)CNC1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4Cl)C3)o2)cc1
Agent: Cl
Product: CC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)c(Cl)c2)C1
Yield: 31 %

Procedure:
Using a similar protocol as described in Example 70 employing 79A and 3-methylazetidin-3-ol hydrochloride as starting materials afforded 29 mg (31%) of 79 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.51 (s, 3H), 3.04 (d, 2H), 3.28 (d, 2H), 3.57 (s, 2H), 3.89 (s, 3H), 4.41 (m, 1H), 4.65 (m, 1H), 4.80 (m, 1H), 5.10 (m, 2H), 5.30 (s, 1H), 7.01 (d, 2H), 7.13 (s, 1H), 7.36 (s, 1H), 8.09 (d, 2H), MS (APCI+) m/z 485 [M+H]+, LC purity: 88%.