Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH2:21][CH2:20]5)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CCN(CC)CC.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>C(Cl)Cl>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:39]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([N:12]4[CH2:13][CH2:14][C:15]5[N:16]=[C:8]([C:5]6[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=6)[S:9][C:10]=5[C:11]4=[O:26])=[CH:25][CH:24]=3)[CH2:20][CH2:21]2)=[O:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1c2sc(-c3ccc(Cl)cc3)nc2CCN1c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCc3cc(N4CCc5nc(-c6ccc(Cl)cc6)sc5C4=O)ccc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-5-(2,3-dihydro-1H-indol-5-yl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (163 mg, 0.43 mmol) in CH2Cl2 (4.0 mL) and add (±)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (140 mg, 0.65 mmol), Et3N (0.09 mL, 0.64 mmol), and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (246 mg, 0.65 mmol). Stir the solution at room temperature for 2 h. Concentrate and purify by flash chromatography, using a 8% MeOH (2N NH3)/CHCl3 as eluent, to give the title compound (231 mg, 93%). 1H NMR (400 MHz, DMSO-d6): δ 8.10 (d, 1H, J=8.8 Hz), 8.05 (d, 2H, J=8.8 Hz), 7.62 (d, 2H, J=8.3 Hz), 7.29 (s, 1H), 7.19-7.15 (m, 1H), 4.22 (t, 2H, J=8.8 Hz), 4.07 (t, 2H, J=7.0 Hz), 3.54 (t, 1H, J=8.8 Hz), 3.47-3.36 (m, 3H), 3.29 (m, 1H), 3.26 (t, 2H, J=6.2 Hz), 3.18 (t, 2H, J=8.3 Hz), 2.16 (m, 1H), 2.01 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:22]1([O:28][CH2:29][CH2:30][Br:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC#N>[Br-:31].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:30][CH2:29][O:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: BrCCOc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOc3ccccc3)(CC1)C2
Product: [Br-]
Yield: 62.6 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (30.8 mg, 0.110 mmol) and 2-bromoethyl phenyl ether (35.7 mg, 0.177 mmol) in 2 CH3CN/3CHCl3 (2.5 mL) were reacted to give the desired product (33.1 mg, 62%). EI-MS m/z 400 (M+) Rt (1.86 min).
Reaction SMILES: C([O:8][C:9]([C:11]1([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]([CH3:41])[CH:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[O:32])[CH:25]=3)=[CH:19][C:18]=2[F:42])=[O:15])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.CO>O1CCCC1.[OH-].[OH-].[Pd+2]>[F:42][C:18]1[CH:19]=[C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]([CH3:41])[CH:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[O:32])[CH:25]=2)[CH:21]=[CH:22][C:17]=1[NH:16][C:14]([C:11]1([C:9]([OH:10])=[O:8])[CH2:13][CH2:12]1)=[O:15]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)OCc5ccccc5)CC4)c(F)c3)ccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-N-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)cyclopropanecarboxamide (510 mg) in tetrahydrofuran (20 ml)-methanol (20 ml) was added 20% palladium hydroxide on carbon (377 mg), followed by stirring under a hydrogen atmosphere at room temperature for 24 hr. The catalyst was removed by filtration, and washed with tetrahydrofuran-methanol(1:1). The filtrate was concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as white crystals (358.7 mg, 83%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12]/[CH:13]=[CH:14]/[CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:21]O)(C)(C)C>C1C=CC=CC=1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12][C@@H:13]2[O:21][C@H:14]2[CH2:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OO
Reactant: OC/C=C/C#CC#CC#Cc1ccccc1
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: c1ccccc1
Product: OC[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of 103 mg (0.50 mmole) of (E)-9-phenyl-2-nonen-4,6,8-triyn-1-ol in 20 ml of dry benzene was added 5 mg of vanadyl acetylacetonate and 0.095 ml (0.50 mmole) of a 5.24M solution of t-butylhydroperoxide in benzene. Further 0.095 ml potions of t-butyl hydroperoxide solution were added after 2 hours and 31/2 hours. After stirring for 18 hours, the benzene solution was concentrated and purified via preparative thin layer chromatography (Analtech, 2 mm, silica gel; ether-hexane 1:1) to afford 59 mg of the title compound, melting point 68°-70° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:21]2[S:25][C:24]([NH2:26])=[N:23][CH:22]=2)[N:9]=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:15])[CH3:16])[N:11]=[C:10]([C:21]2[S:25][C:24]([NH:26][C:28](=[O:29])[O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:23][CH:22]=2)[N:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(N)s2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(NC(=O)Oc3ccccc3)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
A mixture of 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-yl]-1,3-thiazol-2-amine (1.05 g, 2.6 mmol), phenyl chloroformate (618 mg, 3.9 mmol) and sodium hydrogen carbonate (311 mg, 3.9 mmol) in dioxane (10 mL) was stirred at RT for 2 hours then diluted with ethyl acetate and washed with water (150 mL) and brine (100 mL). The organics were dried over magnesium sulphate and concentrated in vacuo. The residue was recrystallised from diethyl ether and hexane to give the desired product as a beige solid (1 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+].O>CS(C)=O>[CH3:25][O:24][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:26][CH3:27])[N:14]=[C:13]([N:7]1[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[CH:12][C:3]=3[CH2:2][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:8]1)[NH:22][C:21]2=[O:23]
Reactant: C1COCCN1
Reactant: COc1cc2nc(N3CCc4c(CBr)cccc4C3)[nH]c(=O)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nc(N3CCc4c(CN5CCOCC5)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(5-bromomethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 23a (54 mg, 0.12 mmol), morpholine (12 mg, 0.13 mmol) and sodium bicarbonate (16 mg, 0.18 mmol) in dimethyl sulfoxide (0.5 mL) was heated to 80° C. with stirring for 18 h. After cooling to room temperature, water (2 mL) was added and the precipitated product was separated by filtration, rinsed with water and dried. 6,7-Dimethoxy-2-(5-morpholin-4-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-3H-quinazolin-4-one 701 was purified by flash chromatography eluting with 2% methanol in dichloromethane containing 0.2% of ammonium hydroxide. The product was converted to the hydrochloric acid salt. Yield 15 mg, mp. 227.9–229.6° C., [M+H]+=437.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH:16]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:11]3[O:10]2)=[O:8])=[CH:5][CH:4]=1.[CH2:25]([O:27][C:28](=O)C)C.CCCCCC>>[CH3:25][O:27]/[CH:28]=[C:18](\[C:9]1([C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:17][CH:16]=[C:12]2[CH:13]=[CH:14][CH:15]=[C:11]2[O:10]1)/[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC1(C(=O)c2ccc(OC)cc2)CC=C2C=CC=C2O1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CO/C=C(/C(=O)OC)C1(C(=O)c2ccc(OC)cc2)CC=C2C=CC=C2O1

Procedure:
Using the procedure of Example 1, methyl 2-(4-methoxy-benzoyl) -7-benzofuranacetate, prepared hereafter, was reacted to obtain the desired product with a Rf 0.07 (eluant: hexane - ethyl acetate (75-25)).
Reaction SMILES: CS[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].OO.[S:18]([O-:21])([O-])=[O:19].[Na+].[Na+].O=O.[C:26](O)(=O)C>>[CH3:26][S:18]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:21])=[O:19]
Reactant: O=S([O-])[O-]
Reactant: CC(=O)O
Reactant: CSCCCCCCCCCCC(=O)O
Agent: O=O
Agent: OO
Agent: [Na+]
Product: CS(=O)(=O)CCCCCCCCCCC(=O)O
Temperature: 25 °C

Procedure:
Into a three-neck round-bottom flask fitted with an overhead mechanical stirrer, thermometer and addition funnel were added 12.3 g of 11-(methylthio)undecanoic acid and 53 mL of acetic acid. The mixture was warmed slightly to help all of the solid to dissolve in the acetic acid. At a temperature of approximately 30° C., the dropwise addition of 24 g of 30% hydrogen peroxide was started. After the addition was completed, the reaction mixture was stirred without heating for an hour. The mixture was then heated at slow reflux for an hour. The reaction mixture was cooled first to room temperature and then in an ice bath. Aqueous sodium sulfite (5%) was added to decompose all active oxygen present. The solid was filtered and washed several times with cold deionized water. The solid was then dried overnight on a watchglass. The product weighed about 7.7 g (55% of theoretical) based upon the weight of starting acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:38](=[O:52])([O:40][CH2:41][CH:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51])[CH2:43][NH2:44])[NH2:39]>CN(C=O)C>[C:38](=[O:52])([O:40][CH2:41][CH:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51])[CH2:43][NH:44][C:21](=[O:22])[CH2:20][N:10]1[C:11](=[O:19])[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[NH2:39]
Reactant: NCC(COC(N)=O)c1ccccc1Cl
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)OCC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 47 mg (135 μmol) of the compound of Example 33A, 34 mg (176 μmol) of EDC and 24 mg (176 μmol) of HOBt in 1 ml of DMF was stirred at RT for 1 h, and 34 mg (149 μmol) of the compound of Example 15A were then added. The mixture was stirred at RT for 16 h and then separated directly by preparative HPLC [Method 9] into its components. This gave 28 mg (37% of theory) of the title compound.
Reaction SMILES: Cl.Cl.N[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH2:12][N:13]1[CH2:17][CH2:16][C@H:15]([NH2:18])[C:14]1=[O:19].[S:20]1[C:24]([S:25](Cl)(=[O:27])=[O:26])=[CH:23][C:22]2[CH:29]=[CH:30][CH:31]=[CH:32][C:21]1=2.C(#[N:35])C>>[NH2:35][C:10]1[CH:11]=[CH:4][C:5]([CH2:12][N:13]2[CH2:17][CH2:16][C@H:15]([NH:18][S:25]([C:24]3[S:20][C:21]4[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=4[CH:23]=3)(=[O:27])=[O:26])[C:14]2=[O:19])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC#N
Reactant: N#Cc1ccc(N)c(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Agent: Cl
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3cc4ccccc4s3)C2=O)ccc1N

Procedure:
The title compound (0.131 g, 0.307 mmol) is prepared as in EXAMPLE 1, Part E from 4-amino-3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)benzonitrile dihydrochloride (0.135 g, 0.445 mmol) and benzo[b]thiophene-2-sulfonyl chloride (0.114 g, 0.49 mmol) in acetonitrile.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:13]=1)=[O:11])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:14]2[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH:17]=[CH:16][C:15]=2[OH:18])=[CH:25][CH:24]=1)[CH3:28]
Reactant: CCOc1ccc(Cc2cc(C(=O)CP(=O)(OCC)OCC)ccc2O)cc1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc(C(=O)CP(=O)(O)O)ccc2O)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 83.5 %

Procedure:
To a solution of {2-[3-(4-ethoxybenzyl)-4-hydroxyphenyl]-2-oxoethyl}phosphonic acid diethylester (1.00 g) in dichloromethane (4.7 mL) was added bromotrimethylsilane (1.6 mL) at 0° C., and the reaction mixture was stirred for 9 hr at room temperature. Methanol (4.0 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. Evaporation and crystallization from ethyl acetate-n-hexane gave the title compound (0.72 g) as a pale brown crystal.
Reaction SMILES: C([C:5]1[C:10]([NH2:11])=[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13]2)[CH:8]=[CH:7][N:6]=1)(C)(C)C.[NH2:26][C:27]1[C:28]([C:34](O)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1>>[NH2:26][C:27]1[C:28]([C:34]([NH:11][C:10]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[CH2:13]2)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)c1nccc(N2CCCC(O[Si](C)(C)C(C)(C)C)C2)c1N
Product: CC(C)(C)[Si](C)(C)OC1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, tert-butyl (+/−)-4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-amine was coupled to 3-amino-6-bromopicolinic acid yielding 3-amino-6-bromo-N-(4-(3-(tert-butyldimethylsilyloxy)-piperidin-1-yl)pyridin-3-yl)picolinamide. LCMS (m/z): 506.2 (MH+); LC Rt=4.03 min.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[O:31][C:32]([F:35])([F:34])[F:33]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[C:24]([O:31][C:32]([F:33])([F:34])[F:35])[CH:25]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: COc1ccc(C=O)cc1OC(F)(F)F
Product: COc1ccc(CN2C(=O)C(C)CC2c2c(OC)cccc2OC)cc1OC(F)(F)F

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-methoxy-3-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 439.85 g/mol.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[C:24](OC)=[N:23][S:22](=[O:27])[N:21]=1>CO>[NH2:19][C:20]1[C:24]([NH:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)=[N:23][S:22](=[O:27])[N:21]=1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Reactant: COC1=NS(=O)N=C1N
Solvent: CO
Product: NC1=NS(=O)N=C1NCCCOc1cc(CN2CCCCC2)ccn1
Yield: 66.8 %

Procedure:
A solution of the product of Step A (6.5 g; 26.0 mmoles) in 90 ml of methanol was reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (3.84 g; 26.0 mmoles) according to the general procedures described in U.S. Pat. No. 4,374,248 to give 6.33 g of product. Recrystallization from methanolacetonitrile yielded the title compound, mp 154°-158° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]=1[CH2:14][CH:15]=[O:16])([CH3:3])[CH3:2].[CH2:17]1C(=O)N(Br)C(=O)C1.C1(S(O)(=O)=O)C=CC=CC=1>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(C=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH:11]([CH3:12])[CH3:13])[C:5]=1[CH:14]([CH3:17])[CH:15]=[O:16])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1CC=O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)c1cc(Br)cc(C(C)C)c1C(C)C=O
Yield: 70.4 %

Procedure:
To a dry DMF solution of 2,6-diisopropyl-4-bromophenylacetaldehyde (7.3 g, 25.8 mmol) at 0° C. was added 2,6-ditert-butyl-4-methylphenol (0.056 g, 0.26 mmol), followed by NBS (4.59 g, 25.8 mmol). After stirring for few minutes, benzenesulfonic acid (8.16 g, 51.6 mmol) was added. The resulting mixture was stirred at 35° C. for 12 h under nitrogen. After regular work up, the crude product was purified by column chromatography to afford 2-(2,6-diisopropyl-4-bromophenyl)propionaldehyde (5.4 g).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][C:48]=2[S:50](Cl)(=[O:52])=[O:51])[CH:43]=[CH:42][CH:41]=1.O>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:50]([C:48]1[CH:47]=[CH:46][CH:45]=[C:44]3[C:49]=1[N:40]=[CH:41][CH:42]=[CH:43]3)(=[O:51])=[O:52])[C:12](=[O:17])[C:11]2([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:22][CH2:23]1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COc1ccc(C2(N3CCN(c4ccncc4)CC3)C(=O)Nc3ccc(Cl)cc32)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2(N3CCN(c4ccncc4)CC3)C(=O)N(S(=O)(=O)c3cccc4cccnc34)c3ccc(Cl)cc32)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
Potassium tert-butoxide (26.6 mg, 0.24 mmol) was added to a solution of 5-chloro-3-(2,4-dimethoxyphenyl)-3-(4-pyridin-4-ylpiperazin-1-yl)-1,3-dihydroindol-2-one (0.10 g, 0.22 mmol) in dimethylformamide (4 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hour. Then 8-quinolinesulfonyl chloride (53.9 mg, 0.24 mmol) was added to the reaction solution while cooling in ice, and the mixture was stirred at room temperature for 12 hours. Water was cautiously added to the mixture, which was extracted twice with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatographic purification of the residue on silica gel (mobile phase gradient 0-7% methanol in dichloromethane) afforded 57.0 mg of the title compound.
Reaction SMILES: CO[C:3]1[CH:11]=[C:10](NC(C)=O)[C:9](S(C)=O)=[CH:8][C:4]=1[C:5](O)=[O:6].CC(C)=O.ClC(OCC(C)C)=O.C1([N:37]2CCCC2CN)CCCCC1>O.C(N(CC)CC)C>[C:5]([NH2:37])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:3]=1
Reactant: NCC1CCCN1C1CCCCC1
Reactant: COc1cc(NC(C)=O)c(S(C)=O)cc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 116.9 %

Procedure:
81.3 g of 2-methoxy-4-acetamino-5-methylsulphinylbenzoic acid (0.30 mole), 600 ml of acetone, 120 ml of water and 41.7 ml of triethylamine with a density of 0.726 (0.30 mole) are placed in a 1 liter flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The mixture is cooled to 0° C. and 40.8 g of isobutyl chloroformate (0.30 mole) is poured in drop by drop. It is agitated for 30 minutes with the cooling bath removed, cooled to 0° C. again and 54.6 g of 1-cyclohexyl-2-aminomethyl-pyrrolidine (0.30 mole) is poured in drop by drop. The mixture is reacted for 1 hour at room temperature with agitation, and left to stand. The solution is evaporated to dryness. A paste is obtained and is dissolved in 200 ml of soda and 400 ml of water. It is heated to reflux for 2 hours, and 50 ml of a mixture distilling over at low temperature is distilled off then put back under reflux. The reaction medium is left to stand, then the suspension is extracted four times with 200 ml of methylene chloride. The organic phase is washed twice with 300 ml of 10% hydrochloric acid, the aqueous phase is filtered with carbon black and the filtrate is made alkaline with 300 ml of 40% soda. The suspension is extracted 3 times, each time with 300 ml of methylene chloride. The organic solution is washed with water and dried over magnesium sulphate. The solution is filtered and evaporated to dryness. 42.5 g (36%) of benzamide is obtained; this does not crystallise.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[O:17][CH2:16][C:15]4([CH3:22])[CH2:18][NH:19][CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:23])[O:3]1.C[C@@H]1CC2C(=CC=C(C3CO3)C=2)C(=O)O1>>[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[O:17][CH2:16][C:15]4([CH3:22])[CH2:18][NH:19][CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:23])[O:3]1
Reactant: C[C@H]1Cc2cc(C3CN4CCNCC4(C)CO3)ccc2C(=O)O1
Agent: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Product: C[C@@H]1Cc2cc(C3CN4CCNCC4(C)CO3)ccc2C(=O)O1

Procedure:
The title compound was prepared in an analogous fashion to that described for (3S)-3-Methyl-6-(9a-methyloctahydropyrazino[2,1-c][1,4]oxazin-3-yl)isochroman-1-one starting from (3R)-3-methyl-6-(oxiran-2-yl) isochroman-1-one. LC/MS: m/e 317.2 (M+H)+.
Reaction SMILES: C(OC(=O)C)(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]([OH:21])=[O:20])[C:13]([C:22]([OH:24])=O)=[C:12]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N#N.N1C=CC=CC=1>C(COC)OC>[Cl:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]3[C:19](=[O:21])[O:20][C:22](=[O:24])[C:13]3=[C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:11]=2[CH:10]=1
Reactant: O=C(O)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O
Agent: N#N
Solvent: CC(=O)OC(C)=O
Solvent: COCCOC
Solvent: c1ccncc1
Product: O=C1OC(=O)c2c1nc1ccc(Cl)cc1c2-c1ccccc1

Procedure:
Acetic anhydride (288 μl, 3.0 mmol) was added to a stirred suspension of 6-chloro-4-phenylquinoline-2,3-dicarboxylic acid (100 mg, 0.31 mmol) in dimethoxyethane (1 ml) in an inert N2 atmosphere followed by the addition of pyridine (49 μl, 0.61 mmol) at room temperature.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:16][CH2:17][C:18]([OH:20])=O)[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.C(Cl)[Cl:29]>>[CH2:12]([N:16]1[CH2:17][C:18](=[O:20])[N:9]([C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[C:7]([Cl:29])[CH:2]=2)[C:10]1=[S:11])[CH2:13][CH2:14][CH3:15]
Reactant: Cc1cccc(Cl)c1N=C=S
Reactant: ClCCl
Reactant: CCCCNCC(=O)O
Solvent: CCN(CC)CC
Product: CCCCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S

Procedure:
The title compound was prepared by the procedure described in Example 54 using 6.5 g of 2-chloro-6-methylphenyl-isothiocyanate, 8.5 g of N-butyl glycine, 10.0 g of triethyl amine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (3.85 g) as a light pink solid, m.p. 97°-100° C. Anal. Calcd. for. C14H17Cl N2O S: C, 56.65; H, 5.77; N, 9.44. Found: C, 56.45; H, 5.67; N, 9.33. Mass spectrum (+FAB, [M+H]+) m/z 297.