Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH2:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:27][CH:26]=1)[CH3:24]
Reactant: CCc1ccc(C=O)cc1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCc1ccc(CNC2CCN(CCn3c(=O)cnc4ccc(OC)cc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 200 mg of 4-ethylbenzaldehyde, 100 mg of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 15 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.32 g of 1-(2-(4-(4-ethylbenzylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:23])[C:20]=2[CH2:21][OH:22])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]1(C)[C:27]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=1.[CH2:37](N(CC)CC)C>ClCCl>[C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:23])[C:20]=2[CH2:21][O:22][S:32]([C:27]2[CH:26]=[CH:31][C:30]([CH3:37])=[CH:29][CH:28]=2)(=[O:33])=[O:34])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CSc2oc3ccccc3c(=O)c2CO)cc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCc2c(SCc3ccc(C(C)(C)C)cc3)oc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 25 mL round bottom flask is introduced 2-(4-tert-butylbenzyl)thio-3-hydroxymethyl chromen-4-one (3 g, 8.47 mmol) and this is dissolved in dichloromethane (10 mL). Toluenesulfonyl chloride (12.7 mmol)and triethylamine (12.7 mmol) are then added to it and the reaction mixture is stirred for 4 hours at room temperature. The solvent is then removed in vacuo and the residue obtained is purified by silica gel flash chromatography (ethyl acetate:hexanes) to get the above-mentioned compound.
Reaction SMILES: N12CCCC1=NCCC2.Br[CH:11]([CH:22](Br)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:12](=[O:21])[CH2:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>CS(C)=O>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[O:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12](=[O:21])[CH:11]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(=O)CC(=O)C(Br)C(Br)c1ccc(OC)cc1
Agent: C1CN=C2CCCN2C1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cc(=O)cc(-c2ccc(OC)cc2)o1
Reaction time: 0.5 h

Procedure:
1,5-Diazabicyclo[4.3.0]non-5-ene (3.2 g) was added dropwise to a stirred solution of ethyl 5,6-dibromo-2,4-dioxo-6-(4-methoxyphenyl)hexanoate (5.6 g) in dimethylsulphoxide (30 ml) maintained at a temperature of 15°-20° C. After 30 minutes at room temperature, water (50 ml) and petroleum ether 40°-60° C. (20 ml) were added with cooling. The yellow solid which precipitated was filtered off and recrystallised from ethanol-water. A second recrystallisation from ethyl acetate-petroleum ether 60°-80° C. yielded the title product as yellow needles (mp 131°-133° C. with sublimation).
Reaction SMILES: C[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:13][CH:14]([CH3:19])[CH2:15][C:16](Cl)=[O:17].Cl[Sn](Cl)(Cl)Cl.O.Cl[CH2:27]Cl>>[CH3:13][CH:14]([CH3:19])[CH2:15][C:16]([C:4]1[S:3][CH:2]=[C:6]([C:7]2[CH:8]=[C:9]([CH3:27])[CH:10]=[CH:11][CH:12]=2)[CH:5]=1)=[O:17]
Reactant: Cc1sccc1-c1ccccc1
Reactant: ClCCl
Reactant: CC(C)CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: Cc1cccc(-c2csc(C(=O)CC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-methyl-3-phenylthiophene (102.8 g, 0.590 mol) and 3-methylbutanoyl chloride (72.3 g, 0.600 mol) in 60 mL of dichloromethane was added dropwise to a 1 M solution of SnCl4 in dichloromethane (640 mL, 0.640 mol) at 0° C. The solution was stirred for 6 h at room temperature then poured slowly into water (500 mL). The organic fraction was separated, washed with a saturated aqueous solution of NaHCO3, brine solution, and dried (MgSO4). Solvents were removed on a rotoevaporator and the product was distilled (145° C., ˜0.03 torr). Yield=132.9 g. 1H-NMR δ (CDCl3): 7.61 (s, 1H), 7.3–7.5 (m, 5H), 2.72 (d, 2H), 2.52 (s, 3H), 2.3 (m, 1H), 1.0 (d, 6H). EIMS: m/z (%) 258 (M+, 38), 243 (25), 216 (69), 201 (100), 174 (11), 129 (25), 115 (11).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]2[C:13]3[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=3[CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.C=[O:25].[CH:26]([OH:28])=[O:27]>O.C(=O)([O-])[O-].[Na+].[Na+]>[C:16]([OH:18])(=[O:25])/[CH:17]=[CH:12]\[C:26]([OH:28])=[O:27].[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]2[C:13]3[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=3[CH2:11][CH2:10][N:9]([CH3:26])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: COc1cc2c(cc1OC)C(Oc1ccc(Cl)cc1)CNCC2
Reactant: O=CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1OC)C(Oc1ccc(Cl)cc1)CN(C)CC2
Product: O=C(O)/C=C\C(=O)O
Temperature: 75 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
1-(4-Chlorophenoxy)-7,8-dimethoxy-2,3,4,5-tetrahydro-3-benzazepine (3 g, 6 mmole) was dissolved in 9 ml 95% formic acid and to this was added 8 ml 37% formaldehyde solution. The mixture was stirred at 75° C. for one hour, then was cooled, diluted with water and basified with sodium carbonate. The oil which separated was extracted with ether, washed with water, saturated NaCl, was dried (anhydrous MgSO4), filtered and evaporated to 2.1 g of an oil. This oil was converted to the maleate salt and recrystallized from isopropanol-ether to give 1.9 g (68%) of 1-(4-chlorophenoxy)-7,8-dimethoxy-3-methyl-2,3,4,5-tetrahydro-3-benzazepine maleate, d 153°-154° C.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][CH:17]2[O:21][C:20]3[CH:22]=[CH:23][C:24]([C:27](=[O:29])[CH3:28])=[C:25]([OH:26])[C:19]=3[CH:18]2[CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5](=[O:8])[O:6]C.[OH-].[Na+].O>C1COCC1>[O:1]=[C:2]([C:9]1[CH:10]=[CH:11][C:12]([S:15][CH2:16][CH:17]2[O:21][C:20]3[CH:22]=[CH:23][C:24]([C:27](=[O:29])[CH3:28])=[C:25]([OH:26])[C:19]=3[CH:18]2[CH2:30][CH2:31][CH3:32])=[CH:13][CH:14]=1)[CH2:3][CH2:4][C:5]([OH:8])=[O:6]
Reactant: CCCC1c2c(ccc(C(C)=O)c2O)OC1CSc1ccc(C(=O)CCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1c2c(ccc(C(C)=O)c2O)OC1CSc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 18 (430 mg, 0.9418 mmoles) was taken up in THF (5.8 ml) to which was added 1N NaOH (2.4 ml) and 2.5 ml H2O. The reaction mixture was stirred at room temperature under N2. After two hours, the THF was removed in vacuo and the reaction mixture was diluted to twice its volume with H2O and extracted with CHCl3. The aqueous phase was acidified with conc. HCl, extracted into CHCl3 and the organic phase was dried and concentrated. The residue was triturated with ether to afford the title compound, m.p. 110°-112°.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC([CH2:36][NH:37][C:38]([CH3:50])([CH3:49])[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=1)=O)(C)(C)C.C(OC(CNC(C)(C)CC1C=CC(C(CCNC2C=C(OC)C=CC=2C2CCC3C=C(OC(=O)C(C)(C)C)C=CC=3C2)=O)=CC=1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:44][C:43]1[CH:47]=[CH:48][C:40]([CH2:39][C:38]([CH3:50])([NH:37][CH3:36])[CH3:49])=[CH:41][CH:42]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(Cc1ccc(C(=O)O)cc1)NCC(=O)OC(C)(C)C
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCC(=O)c2ccc(CC(C)(C)NCC(=O)OC(C)(C)C)cc2)c1
Product: CCN(Cc1ccc(CC(C)(C)NC)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 38.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-[2-(tert-butoxycarbonylmethylamino)-2-methylpropyl]benzoic acid (120 mg) according to an analogous synthetic method to Preparation Example 86, pivalic acid 6-{2-{{4-[2-(tert-butoxycarbonylmethylamino)-2-methylpropyl]benzoyl}ethylamino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (97 mg) was used according to analogous synthetic method to the above-mentioned Example 215 and Example 337 to provide the title compound (48 mg).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]([N:17]1[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16].O.[OH-].[Li+].Cl>CO.O1CCCC1.O>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:33])=[O:2]
Reactant: COC(=O)COc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetic acid methyl ester (0.21 g, 0.46 mmol) in methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.039 g, 0.93 mmol). The resulting mixture was stirred at ambient temperature for three hours. The reaction was acidifed to pH 4 with 0.2 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by trituration with methylene chloride/diethyl ether to give the title compound (0.16 g).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][CH:39]=[C:40]([C:42]([NH:44][CH:45]2[CH2:47][CH2:46]2)=[O:43])[N:41]=1>>[CH:45]1([NH:44][C:42]([C:40]2[N:41]=[C:37]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)[S:38][CH:39]=2)=[O:43])[CH2:46][CH2:47]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=C(NC1CC1)c1csc(Br)n1
Product: C[C@@H](c1ccc(-c2nc(C(=O)NC3CC3)cs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-N-cyclopropylthiazole-4-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.252 min, m/z=542.1; 1H NMR (CDCl3) 0.61 (m, 2H), 0.81 (m, 2H), 1.04 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.06-2.24 (m, 5H), 2.29-2.40 (m, 1H), 2.71-2.89 (m, 2H), 5.62 (m, 1H), 6.94-7.01 (m, 2H), 7.19-7.31 (m, 5H), 7.35 (s, 1H), 7.61 (m, 2H), 8.01 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]([F:9])([CH3:8])[CH3:7])[CH2:3][OH:4].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C1C=CN=CC=1>[Si:10]([O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][C:6]([F:9])([CH3:8])[CH3:7])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(F)C[C@H](N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(F)C[C@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The amino alcohol (21.0 g) from Step 5 was dissolved in dichloromethane (300 mL) and the solution was cooled to 0° C. 4-(Dimethylamino)pyridine (0.051 g) and tert-butyldimethylsilyl chloride (21 g) were added followed by triethylamine (25 mL). The mixture was stirred at room temperature overnight. The reaction mixture was slowly poured into 0° C. saturated aqueous ammonium chloride and extracted with dichloromethane (3×300 mL). The organic layer was washed with brine, dried with sodium sulfate and the solvents were removed in vacuo to yield (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-fluoro-4-methylpentan-2-amine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:7]=2)=[N:2]1.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:49]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:51]=1)[NH2:48].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:48][C:47]1[CH:49]=[C:50]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[C:14]4[C:13]([NH:15][C@H:16]([C:18]5[N:23]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=6)[C:22](=[O:30])[C:21]6=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]6[N:19]=5)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=4[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[CH:7]=3)=[N:2]2)[CH:51]=[C:45]([O:44][CH3:43])[CH:46]=1
Reactant: COc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(N)cc(-n2ccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)n2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (67 mg, 0.12 mmol) was treated with 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (57 mg, 0.23 mmol), Cu(AcO)2 (32 mg, 0.18 mmol) and pyridine (20 μl, 0.25 mmol) in DMF (1.5 ml). The reaction mixture was submitted at vacuum-argon cycles and stirred at 100° C. under microwave conditions for 2 h. More pyridine and Cu(AcO)2 were added, and the reaction mixture stirred at 100° C. until the reaction was over. The solvent was cooled at room temperature and poured into ice-water, basified with potassium carbonate and extracted with ethyl acetate (×3). The organic phase was successively washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The residue (15.3 mg, 14% yield, 75% purity) was used in the next synthetic step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29][C:30]([F:33])([F:31])[F:32])=[CH:25][CH:24]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Solvent: CO
Product: NC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(SC(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 64 %

Procedure:
The titled compound was prepared in 64% yield from (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (100 mg, 0.316 mmol) and 1-bromomethyl-4-trifluoromethylsulfanyl-benzene (90 mg, 0.332 mmol) according to the procedure described in Example 3: 1H NMR (400 Mz, DMSO-d6) δ 7.79 (d, 2 H, J=8.8), 7.61 (d, 2 H, J=8.8), 7.59 (d, 2 H), J=8.1), 7.43 (d, 2 H, J=8.1), 7.32 (br s, 1 H), 6.65 (br s, 1 H), 4.62 (ABq, 2 H, Δv=73.1, Jab=17.3), 3.88 (dt, 1 H, Jd=12.7, Jt=3.9), 2.79 (m, 1 H), 2.43 (m, 1 H), 1.79 (m, 1 H), 1.65 (m, 2 H), 1.42–1.19 (m, 3 H), 0.94 (m, 1 H); MS m/e 529.1 (M+Na)+. Optical rotation: [α]D=−28.6 (c=5.87 mg/mL, MeOH).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].[C:20]([O-:23])([O-])=O.[Na+].[Na+].[C:26]([C:30]1C(C)=C(B(O)OO[SiH3])C=[CH:34][C:35]=1C)(C)(C)[CH3:27].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[F:1][C:2]1[C:3]([C:26]2[CH:30]=[CH:35][CH:34]=[C:20]([OH:23])[CH:27]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: Cc1ccc(B(O)OO[SiH3])c(C)c1C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(-c3cccc(O)c3)c21

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 3-tert-butyl-dimethyl-silyloxy-phenylboronic acid (0.14 g, 0.54 mmol) in 5 ml of a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 3 days. The reaction mixture was concentrated and the crude material was washed with methanol to give (Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxyphenyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 22%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:7][N:6]=[CH:5]2.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:7][N:6]=[CH:5]2
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(Oc1nncc2cc(Cl)ccc12)C(F)(F)F
Product: Cc1ccc(N)cc1-c1ccc2c(OC(C)C(F)(F)F)nncc2c1

Procedure:
The title compound was prepared according to a procedure similar to that described in Example 225, using 6-chloro-1-(1,1,1-trifluoropropan-2-yloxy)phthalazine and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine as starting materials. MS (ESI, pos. ion) m/z: 348.1 (M+1). The racemic material was subjected to Preparative SFC separation using a chiral column to afford its (R)- and (S)-enantiomers.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[NH:6]1)=[O:4].CCN(CC)CC.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCCl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:6]1[S:31]([C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32])=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@H]1CC[C@@H](c2cccc(F)c2)N1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)[C@H]1CC[C@@H](c2cccc(F)c2)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 75.4 %

Procedure:
(2R,5S)-5-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester (0.33 g, 1.5 mmol) was dissolved in 1,2-dichloroethane (2 mL) and Et3N (1.0 mL, 7.4 mmol, 5 eq) was added followed by 4-chlorobenzenesulfonyl chloride (0.78 g, 3.7 mmol, 2.5 eq). The mixture was heated at 100° C. for 16 hr. Solvent was removed under vacuum and the residue was dissolved in EtOAc (10 mL), washed with 10% NaHCO3 and brine, dried (Na2SO4) and concentrated under vacuum. Chromatography on silica gel (5–10% EtOAc/hexanes) yielded 0.45 g (75%) of pure (2R,5S)-1-(4-chloro-benzenesulfonyl)-5-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester as yellowish solid. 1H NMR (CDCl3, 300 MHz) δ 7.67 (2H, d), 7.42 (2H, d), 7.24 (3H, m), 6.98 (1H, m), 4.95 (1H, t), 4.82 (1H, q), 3.94 (3H, s), 2.45–2.25 (3H, m), 2.05 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](Cl)(Cl)=[S:10]>C1(C)C=CC=CC=1.CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]=[C:9]=[S:10]
Reactant: Nc1ccncc1Br
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: S=C=Nc1ccncc1Br
Temperature: 25 °C
Yield: 57 %

Procedure:
3-bromopyridin-4-amine (5 g, 28.90 mmol) was suspended in dry toluene (100 mL) and cooled in an ice-bath. A solution of thiophosgene (6.646 g, 4.407 mL, 57.80 mmol) in dry toluene (100 mL) was added dropwise over 25 mins. The resulting orange/red suspension was stirred at reflux overnight. The red suspension was allowed to cool to RT and concentrated under reduced pressure to give a dark brown/red solid. This material was partitioned between saturated NaHCO3 and DCM. The aqueous layer was extracted with further DCM (3×50 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a dark red solid/gum. This material was suspended in MeOH/DCM, adsorbed onto silica under reduced pressure and purified by column chromatography (75% EtOAc in hexanes, ˜300 mL silica) to give 3-bromo-4-isothiocyanatopyridine as a red oil which solidified on standing (3.513 g, 57% Yield). MS (ES+) 216.9.
Reaction SMILES: [C:1]1(=[O:6])O[C:3](=[O:4])[CH2:2]1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C1CC(=O)O1
Reactant: Nc1ccccc1
Product: O=C(CC(=O)Nc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To the cold solution of malonic anhydride, prepared as above, was added aniline (700 μl, 6 equivalents). The reaction mixture was allowed to warm to room temperature. It was then extracted with 5 ml saturated aqueous NaHCO3, and the aqueous extract was washed with 5 ml ether, acidified with H2SO4, and extracted with 3-4-ml portions of ether. The ether extracts were combined and dried over Na2SO4, and the ether was removed under reduced pressure, to leave a residue of malonanilide (mp 127°-130° C., 180 mg, 72% isolated yield, based on diketone).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].C1(P(=[CH:30][CH:31]=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:30][CH:31]=[O:32])[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: N#Cc1cccc(C=CC=O)c1
Yield: 91.8 %

Procedure:
A mixture of 3-cyanobenzaldehyde (2.0 g) and (triphenylphosphoranylidene) acetaldehyde (5.0 g) in 100 mL CH2Cl2 was stirred at reflux for 16 hours. The reaction was cooled, concentrated and purified on silica gel column (ethyl acetate/hexane=3/7) to afford 2.2 g of 3-cyano-1-(2-formylethenyl)benzene as a yellow oil.