Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([O:30]C)=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21](=[O:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([OH:30])=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21](=[O:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 90 °C
Yield: 92.7 %

Procedure:
Sodium hydroxide (0.2 mL of 1 N, 0.2 mmol) was added to a solution of the Methyl 13-cyclohexyl-6,7-dihydro-6-oxo -5H-indolo[2,1-a][2]benzazepine-10-carboxylate (20 mg, 0.052 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a microwave vial. The vial was sealed and the contents heated at 90° C. for 5 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (18 mg, 92%). ESI-MS m/z 374 (MH+); 1H NMR (500 MHz, ACETONE-D6) δ 1.22–1.35 (m, 1 H) 1.41–1.58 (m, 2 H) 1.59–1.70 (m, 1 H) 1.73–1.85 (m, 2 H) 1.92–2.00 (m, 1 H) 2.11–2.26 (m, 3 H) 3.04 (m, 1 H) 3.60 (d, J=14.04 Hz, 1 H) 3.97 (d, J=13.73 Hz, 1 H) 4.56 (d, J=18.31 Hz, 1 H) 5.19 (d, J=18.31 Hz, 1 H) 7.51 (m, 2 H) 7.57 (t, J=7.32 Hz, 1 H) 7.66 (d, J=7.63 Hz, 1 H) 7.81 (dd, J=8.39, 1.37 Hz, 1 H) 8.03 (d, J=8.24 Hz, 1 H) 8.23 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:30][CH2:29][CH2:28][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([O:25]CC)=O)=[N:21][N:22]=2)[N:19]=1.[CH2:31]1COCC1.C[Mg]Cl>O.C(Cl)Cl.[Cl-].[NH4+]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:30][CH2:29][CH2:28][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23](=[O:25])[CH3:31])=[N:21][N:22]=2)[N:19]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
A 100 mL round bottom flask was charged with ethyl 6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (3.04 g, 7.41 mmol). THF (37.0 mL) was added and the mixture was stirred at ambient temperature for about 15 min. The slurry was cooled to about −40° C. and a solution of methylmagnesium chloride (3 M in THF, 9.88 mL, 29.6 mmol) was added slowly while keeping the internal temperature between about −30° C. and −40° C. After about 15 min the mixture was cooled to about −55° C. followed by the slow addition of saturated ammonium chloride solution (about 10 mL). The mixture was then warmed to ambient temperature and diluted with water (50 mL), DCM (75 mL), and saturated aqueous ammonium chloride solution (50 mL). The layers were separated and the aqueous solution was extracted with DCM (2×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (2.74 g, 97%): LC/MS (Table 1, Method h) Rt=1.22 min; MS m/z: 381.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]CC)=O)=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:4]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>C(O)(C)C>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][N:33]1[C:9](=[O:11])[C:8]2[C:3](=[N:4][C:5]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:6][C:7]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH2:2]1
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1CBr
Reactant: CN(C)CCN
Solvent: CC(C)O
Product: CN(C)CCN1Cc2nc(-c3ccccc3)cc(-c3cccc([N+](=O)[O-])c3)c2C1=O
Yield: 35.8 %

Procedure:
A mixture of ethyl 2-bromomethyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (1.5 g) and 2-dimethylaminoethylamine (0.6 g) is isopropyl alcohol (15 ml) was refluxed for 1 hour. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of water (20 ml) and chloroform (40 ml). The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off. The residue was subjected to a column chromatography on silica gel, eluting with a mixture of chloroform and methanol (50:1 V/V). The fractions containing the desired compound were combined and evaporated in vacuo. The crystalline residue was recrystallized from ethanol to give 6-(2-dimethylaminoethyl)-4-(3-nitrophenyl)-5-oxo-2-phenyl-5,7-dihydro-(6H)-pyrrolo[3,4-b]pyridine (0.49 g).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Cl.[Cl:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[ClH:13].[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Nc1ccccc1OC(F)F
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: FC(F)Oc1ccccc1N1CCNCC1
Temperature: 0 °C
Yield: 13.6 %

Procedure:
A mixture of 2-difluoromethoxyaniline (5.14 g, 32.3 mmol) and bis(chloroethyl)amine hydrochloride (5.8 g, 32.5 mmol) in 50 mL of n-butanol was heated at reflux for 48 hours. Potassium carbonate (8.9 g, 64.5 mmol) was added and heated at reflux for approximately 24 hours. The mixture was extracted with 2N hydrochloric acid and the extract cooled to approximately 0° C. and then basified with sodium hydroxide to give a precipitate. The precipitate was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting with 5% methanol/methylene chloride. Product fractions were combined and concentrated. The residue was crystallized from hydrochloric acid in methanol to give 1-[2-(difluoromethoxy)phenyl]piperazine hydrochloride (1.32 g, 4.38 mmol), m.p. 165°-176° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([NH:18][CH:19]1[CH2:23][CH2:22][N:21]([CH:24]([C:34]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:35])[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[C:20]1=[O:42])(=[O:17])=[O:16])[CH:7]=[CH:6]2.[SH2:43].Cl>C(N(CC)CC)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([NH:18][CH:19]1[CH2:23][CH2:22][N:21]([CH:24]([C:34]([N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:35])[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[S:43])=[CH:28][CH:27]=3)[C:20]1=[O:42])(=[O:17])=[O:16])[CH:7]=[CH:6]2
Reactant: COc1cc2ccc(S(=O)(=O)NC3CCN(C(Cc4ccc(C#N)cc4)C(=O)N4CCCCC4)C3=O)cc2cc1OC
Reactant: S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1cc2ccc(S(=O)(=O)NC3CCN(C(Cc4ccc(C(N)=S)cc4)C(=O)N4CCCCC4)C3=O)cc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.6 g (7.78 mmol) of 3-(6,7-dimethoxynaphthalene-2-sulfonylamino)-1-[2-(4-cyanophenyl)-1-piperidinocarbonylethyl]-2-pyrrolidinone were dissolved in 5 ml of triethylamine and 80 ml of pyridine, and hydrogen sulfide was passed into saturation. The mixture was left to stand overnight and subsequently added dropwise to a mixture of 600 g of ice and 100 ml of concentrated hydrochloric acid. The precipitate was filtered off with suction and dissolved in THF, and the solution was dried over magnesium sulfate and concentrated. The residue was mixed with ether and, after stirring at room temperature for 30 min, the precipitate was filtered off with suction. The slightly impure 3-(6,7-dimethoxynaphthalene-2-sulfonylamino)-1-[2-(4-aminothiocarbonylphenyl)-1-piperidinocarbonylethyl]-2-pyrrolidinone was used without further purification in the next stage.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:20]=[C:19]([F:21])[C:18]([Br:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(OCC)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Br:22][C:18]1[C:19]([F:21])=[CH:20][C:12]([O:10][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1ccc(O)c(F)c1
Reactant: O=C(O)c1cc(Br)c(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2cc(F)c(Br)cc2C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 2 L RB flask was charged with 2-fluoro-4-methoxyphenol (49.6 g, 349 mmol), 2,5-dibromo-4-fluorobenzoic acid (80 g, 269 mmol), ethyl acetate (1.316 mL, 13.43 mmol), cesium carbonate (192 g, 591 mmol) and toluene (1200 mL). To the mixture at was added copper(I) triflate toluene complex (2:1) (1.713 g, 8.06 mmol) and it was stirred at room temperature for 20 minutes. The solution was then heated to 75° C. for 16 hours at which point the toluene was removed under reduced pressure. The solution was dissolved in 1.5 liters of water and washed with 250 ml of EtOAc. The aqeuous layer was acidified to pH 1 with concentrated HCl and the resulting precipitant was collected by filtration and washed with water. The derived solid was washed with a 1:1 solution of ethyl acetate and hexane, then dried under vacuum to afford 5-bromo-4-fluoro-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a light brown solid. MS m/z=358.8 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:21]([C:23]1[CH:24]([CH3:33])[CH:25]=[C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:27]=1)=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:21][C:23]4[NH:27][C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=4[CH3:33])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Reactant: CC1C=C(CCC(=O)O)N=C1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(CCC(=O)O)[nH]c1C=C1C(=O)N(C)c2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol) was condensed with 3-(5-formyl-4-methyl-4H-pyrrol-2-yl)-propionic acid (62 mg, 0.41 mmol) and piperidine (2 drops) in ethanol (3 mL) stirred at 80° C. for 2 hours to give 31 mg (20%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.14 (br s, 1H, NH), 9.14 (s, 1H), 8.34 (s, 1H), 7.69 (m, 1H), 7.30-7.40 (m, 3H), 6.08 (s, 1H), 3.32 (s, 3H, CH3), 2.89 (m, 2H, CH2), 2.53 (m, 2H, CH2), 2.16 (s, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:49]1([NH:52][CH2:53][C@@H:54]2[C@@H:58]([OH:59])[CH2:57][CH2:56][NH:55]2)[CH2:51][CH2:50]1>CN(C=O)C>[CH:49]1([NH:52][CH2:53][C@@H:54]2[C@@H:58]([OH:59])[CH2:57][CH2:56][N:55]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:51][CH2:50]1
Reactant: O[C@H]1CCN[C@@H]1CNC1CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CC[C@H](O)[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (250 mg, 0.48 mmol), HOBt (78 mg, 1.2 eq.), EDC (110 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (2R,3S)-2-cyclopropylaminomethyl-pyrrolidin-3-ol (300 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give 100 mg of the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH2:8]([O:15][CH2:16][CH:17]=[CH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.COCCOC>[Cu].[Zn].C(OCC)C>[CH2:8]([O:15][CH2:16][CH:17]1[CH2:18][C:3](=[O:4])[C:2]1([Cl:7])[Cl:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CCOCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: COCCOC
Product: O=C1CC(COCc2ccccc2)C1(Cl)Cl

Procedure:
Trichloroacetyl chloride (108 ml, 0.96 mol) was added slowly to a stirred suspension of freshly activated zinc-copper couple (56 g), allyl benzyl ether (50 ml, 0.32 mol), dry 1,2-dimethoxyethane (95 ml) and dry diethyl ether (550 ml) in a 2 L three-neck flask under argon. The reactants were heated under gentle reflux for 3d. The products were then filtered and the residue was washed with ether. The combined filtrate and washings were concentrated under reduced pressure. Light petroleum ether was added and the mixture was stirred vigorously. The supernatant was decanted and more light petroleum ether was added. After vigorous stirring the supernatant was again decanted and mixed with the original supernatant. The resulting solution was washed with saturated NaHCO3 twice and brine once. The organic phase was dried over MgSO4 and the solvent was evaporated to give a light yellow oil which was used directly in the next step. 1H NMR (CDCl3, 300 MHz): δ 3.10-3.25 (m, 2H), 3.36-3.57 (m, 1H), 3.65-3.75 (m, 1H), 3.83-3.88 (m, 1H), 4.57 (s, 2H), 7.27-7.40 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[CH:4]=1.[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:15][N:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[CH:4]=1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc2sc(CCl)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1cc2cc([N+](=O)[O-])ccc2s1
Reaction time: 20 h

Procedure:
A mixture of the product of part (A) above (3.20 g), N-methyl-4-nitrophenethylamine (2.52 g), anhydrous potassium carbonate (4.0 g) and acetonitrile (40 ml) was heated under reflux with stirring for 20 hours and then cooled and filtered. The residue was washed with acetonitrile, and the combined filtrate and washings were evaporated to give an oil which was chromarographed on silica gel. Elution with dichloromethane first gave impurity followed by pure product. The Product-containing fractions were evaporated to give the title compound (4.17 g), m.p. 76°-78° (from isopropanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:25])[CH2:9][CH3:10])=[CH:4][CH:3]=1.I[C:27]1[CH:32]=[CH:31][N:30]([CH3:33])[C:29](=[O:34])[CH:28]=1>>[CH2:23]([C@@:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12](=[O:25])[N:11]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:32]=[CH:31][N:30]([CH3:33])[C:29](=[O:34])[CH:28]=3)=[CH:3][CH:4]=2)[CH2:9][CH3:10])[CH2:16][CH2:15]1)[CH3:24]
Reactant: Cn1ccc(I)cc1=O
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CC)(c2ccccc2)OC1=O
Product: CC[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 32 Method 2 Steps 3 and 4 using 4-iodo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 1 tR=1.58 min, m/z=431 (M+1); 1H NMR (CDCl3) 7.33 (1H, d, J=7.03 Hz), 7.29-7.21 (7H, m), 7.01 (2H, d, J=8.20 Hz), 6.75 (1H, d, J=2.05), 6.39 (1H, dd, J=2.05, 7.03), 5.48 (1H, ap dd, J=6.44, 9.66), 3.58 (3H, s), 2.95-2.87 (1H, m), 2.37-2.14 (3H, m), 2.06-1.81 (m, 4H), 1.00 (3H, t, J=7.32), 082 (3H, t, J=7.61).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].[SH2:13].C(NCC)C>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[S:13])[NH2:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12]
Reactant: S
Reactant: CCCc1cc(C#N)ccc1O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCCc1cc(C(N)=S)ccc1O
Temperature: 7 °C
Reaction time: 54 h
Yield: 93 %

Procedure:
A solution of 4-hydroxy-3-propylbenzonitrile (35.63 g, 0.221 mol) (Example 29 in DMF (300 mL) was saturated with hydrogen sulfide at rt (moderate flow over 45 min). Temperature was monitored (increase of about 7° C.). Diethylamine (45.73 mL, 0.442 mol) was added to the solution. The temperature rose to 10° C. and the already green reaction mixture became darker green. Hydrogen sulfide was passed through the solution for another 30 min (at this point the reaction temperature was 40° C.). The reaction mixture was warmed to 60° C. (gaseous evolution noted). Hydrogen sulfide was again passed through the solution at 60° C. over 2 h. The reaction mixture was cooled and stirred at rt for 54 h, and most of the solvent removed under reduced pressure. The resultant residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (4×100 mL), then brine, and dried over sodium sulfate, filtered, and concentrated. The resultant orange oil was triturated in hexanes (300 mL) and ether (25 mL) to give a yellow solid (39.97 g, 93%) after drying for 1 h under suction. LC/MS m/z 196.1 (M+H)+, RT 2.16 min. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.44 (s, 1H), 9.14 (s, 1H), 7.73-7.65 (m, 2H), 6.73 (d, 1H), 2.51-2.47 (m, 2H), 1.59-1.50 (m, 2H), 0.90 (t, 3H).
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>C(OCC)(=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:10]1[CH:19]=[CH:20][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=1
Reactant: Brc1ccc(COc2ccccn2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(COc2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran solution (120 mL) of 2-(4-bromo-benzyloxy)-pyridine (34 g, 128 mmol) described in Manufacturing Example 2-2-1 was added n-butyl lithium (50 mL, 2.6 M, hexane solution, 134 mmol) dropwise at −78° C. After 30 minutes of stirring, to the reaction solution was added N,N-dimethylformamide (10 mL, 134 mmol) dropwise at −78° C., which was stirred at room temperature. The reaction solution was partitioned into water and ethyl acetate, and the ethyl acetate layer was washed with water (2 times) and aqueous sodium chloride (once). The water layers were combined and extracted with ethyl acetate. The resulting ethyl acetate layer was washed with water (2 times) and aqueous sodium chloride (once). The ethyl acetate layer thus obtained was combined with the ethyl acetate layer obtained previously, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was then concentrated under a reduced pressure to obtain the title compound (26.8 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16](OC)=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.[CH3:22][NH2:23].[H-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]([NH:23][CH3:22])=[O:17])=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 61A (100 mg, 0.3135 mmol) and methylamine (2M solution in THF, 0.467 mL, 0.941 mmol) in THF (2 mL) at 0° C. was treated with NaH (12 mg, 0.47 mmol), stirred at room temperature for 1 hour, treated with water (0.1 mL), and concentrated. The residue was purified by flash chromatography on silica gel with 20% acetone/hexane to provide the title compound.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:4]1[CH:3]=[CH:2][N:28]([CH2:29][CH:30]([OH:32])[CH3:31])[C:5]=12
Reactant: CC(O)CN
Reactant: COc1cccc2c1CC(CC=O)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1Cc1ccn(CC(C)O)c1-2
Reaction time: 0.58 h
Yield: 28.8 %

Procedure:
A solution of 2.04 g of (RS)-2-(2-oxoethyl)-4-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.13 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:4). There was obtained 0.7 g (29%) of (RS)-1-(5-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[C:20]([CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32])#[N:21].N12CCCCC1C=NCCC2.Cl>O1CCOCC1.O>[C:20]([CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C:11]([NH:10][C:5]1[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([CH3:9])[N:6]=1)=[O:13])(=[O:33])=[O:32])#[N:21]
Reactant: N#CCC=Cc1ccccc1S(N)(=O)=O
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CCC#N)n1
Reaction time: 15 h
Yield: 66.9 %

Procedure:
5.2 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate are added to a solution of 4.45 g of 2-(3-cyano-1-propen-1-yl)phenylsulfonamide and 3.3 ml of 1,5-diazabicyclo[5,4,0]undec-5-ene in 80 ml of dioxan, and the mixture is stirred for 15 hours at 20°-25° C. The reaction mixture is then taken up in 350 ml of water and the aqueous solution is acidified to pH 2 with 2N HCl and extracted with ethyl acetate. The organic extracts are combined and concentrated. The oily orange-coloured residue is dissolved in a very small amount of acetone. About 20 ml of diethyl ether are added to this solution, which is diluted dropwise with hexane until the onset of crystallisation. The mixture is subsequently further cooled and the precipitated crystals are isolated by filtration. Yield: 5.2 g of the title compound with a melting point of 142°-143° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:17])=O>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCCOc1ccc(C(=O)Cl)cc1

Procedure:
Heated at reflux a solution of 75 g (0.39 mole) of 4-n-butoxybenzoic acid in 250 ml of thionyl chloride for 3 hrs. Removed by vacuum distillation the excess thionyl chloride to give 84 g of a brown colored liquid.