Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([CH:10]=1)[C:8]#[N:9].P(Br)(Br)[Br:16]>C1(C)C=CC=CC=1.ClCCl>[Br:16][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: BrP(Br)Br
Reactant: CS(=O)(=O)c1ccc(CO)cc1C#N
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CBr)cc1C#N
Temperature: 40 °C

Procedure:
A flask is charged with 5-hydroxymethyl-2-methylsulfonyl-benzonitrile (0.788 g, 3.73 mmol) in toluene (5 mL) and heated at 40° C. PBr3 (0.175 mL, 1.86 mmol) is added and the reaction is refluxed for 0.5 h. It is then cooled to room temperature, diluted with dichloromethane and washed with water. The aqueous layer is extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and concentrated in vacuo to afford 5-bromomethyl-2-methanesulfonyl-benzonitrile as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.28 (s, 3H), 4.89 (s, 2H), 7.80 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 8.18 (d, J=8.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)=[O:8].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=1)[CH2:5][NH:6][C:7](=[O:8])[C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][CH:14]=1
Reactant: Cc1cc(-c2ccc(CNC(=O)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cc2F)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(N4CCNCC4)nc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude tert-butyl 4-(5-((3-fluoro-4-(2-methylpyridin-4-yl)benzyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate 20-2 in dichloromethane (2 mL) was treated with trifluoroacetic acid (TFA, 0.5 mL), and the solution was stirred overnight at room temperature. Evaporation under reduced pressure (with the addition of some toluene to aid evaporation of the residual TFA) followed by lyophilization gave crude N-(3-fluoro-4-(2-methylpyridin-4-yl)benzyl)-6-(piperazin-1-yl)nicotinamide 20-3.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:7]([N+:12]([O-])=O)=[N:8][CH:9]=[CH:10][CH:11]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NCCc1cccnc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCCc1cccnc1N
Yield: 90.7 %

Procedure:
A solution of 3-(2-azidoethyl)-2-nitropyridine (0.190 g, 0.98 mmol) in methanol (5 mL) was stirred at 20° C. with 10% palladium on carbon (50 mg) under 1 atm hydrogen for 96 h. The mixture was filtered through celite and the filtrate concentrated to give the title compound (0.122 g).
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:21]([N:23]1[CH2:32][CH2:31][CH2:30][C@H:24]1[C:25]([N-:27][CH2:28][CH3:29])=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=O)C1C=CC=CC=1.CO.[H][H]>[Pd].O>[ClH:1].[NH2:12][C@H:13]([C:21]([N:23]1[CH2:32][CH2:31][CH2:30][C@H:24]1[C:25]([N-:27][CH2:28][CH3:29])=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20]
Reactant: [H][H]
Reactant: CC[N-]C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC[N-]C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N

Procedure:
L-Arginyl-L-prolyl-N-ethylamide, hydrochloride is prepared by the following procedure. A solution of 8.7 g. of Nα -benzyloxycarbonyl-L-arginyl-L-prolyl-N-ethylamide hydrochloride in 100 ml. of methanol is stirred with 500 mg. of 20% palladium-on-carbon under one inch water pressure of hydrogen for three hours. The catalyst is removed by filtration and the filtrate evaporated under reduced pressure and at 35°-40° C. The residual foam is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([N:8]([CH2:10][CH2:11]Cl)[CH3:9])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH3:9])[CH2:10][CH2:11][NH:13]2
Reactant: CN(CCCl)c1ccc(Br)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCNc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
A solution of 4-bromo-N1-(2-chloroethyl)-N1-methylbenzene-1,2-diamine (25D) (0.611 g, 2.3 mmol) and K2CO3 (0.634 g, 4.6 mmol) in DMF (7 mL) was heated to 80° C. for 1 hour and then at 100° C. for 1.5 hours, cooled to rt, diluted with water and extracted with EtOAc. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 0.528 g (100%) of the desired product 6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (25E): 1H NMR (300 MHz, CDCl3) δ 6.72 (1H, dd), 6.56 (1H, d), 6.38 (1H, d), 3.74 (1H, bs), 3.47 (2H, t), 3.22 (2H, t), 2.82 (3H, s).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:9]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(#N)C>[C:1]([CH2:2][CH2:3][O:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[N:9]1)#[N:4]
Reactant: C=CC#N
Reactant: NC(=NCC(F)(F)F)Nc1ccn(CCO)n1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC#N
Product: N#CCCOCCn1ccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
Acrylonitrile (0.8 g.) was added to a solution of 1-(2-hydroxyethyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (2.51 g.) in acetonitrile (10 ml.). Benzyltrimethylammonium hydroxide (40% w/v aqueous solution; 10 μl) was added. After stirring at room temperature for 1 hour, the solution was evaporated to dryness in vacuo, and the residue purified by medium pressure chromatography using triethylamine/EtOH/EtOAc 1:1:9 v/v/v as eluant to give 1-[2-(2-cyanoethoxy)ethyl]-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (1.0 g.) having the following n.m.r. spectrum in d6DMSO: 7.6 (d, 1H); 5.8 (d, 1H); 4.2 (m, 2H); 4.1 (t, 2H); 3.8 (t, 2H); 3.6 (t, 2H); 2.7 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](F)=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[CH3:22][S-:23].[Na+].C[S-].O>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([S:23][CH3:22])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(-c2cc(C(C)C)nc(N)n2)c2ccccc12
Reaction time: 2 h
Yield: 98 %

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.281 g) was dissolved in dimethyl sulphoxide (DMSO) (10 mL) and sodium thiomethoxide (0.070 g) was added. The reaction mixture was stirred at room temperature for 2 hours at which time another equivalent of thiomethoxide was added and the reaction stirred for another 2 hours. The mixture was poured into water (100 mL) and the product was extracted into ethyl acetate/hexane (3×50 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The reaction product was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate to give 2-amino-4-(4-methylthionaphth-1-yl)-6-isopropylpyrimidine (0.303 g), m.p. 139-140° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][CH2:20]O>C1C=CC=CC=1.S(=O)(=O)(O)O>[CH3:17][O:18][CH2:19][CH2:20][O:16][CH2:15][C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: COCCO
Reactant: OCc1c2ccccc2cc2ccccc12
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COCCOCc1c2ccccc2cc2ccccc12
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-methoxyethanol (1 l) in benzene (1.5 l), conc. sulfuric acid (3 ml) was added and the mixture was heated to 80° C. A solution of 9-anthracenemethanol (45 g, 0.22 mole) in 2-methoxyethanol (450 ml) was added to the mixture under reflux and stirring was continued for 1.5 hours under reflux. After standing at room temperature overnight, the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried over anhydrous MgSO4 and evaporated. The residual crude oil (63 g) was chromatographed on silica gel (Wakogel C-200, manufactured by Wako Pure Chemical Industries, Ltd.) with n-hexane/ethyl acetate [50/1→25/1→8/1 (V/V)] as eluent to give 47.6 g of 9-(2-methoxyethoxy)methylanthracene as orange yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([CH3:32])[CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CNCCN1CCOCC1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CCN1CCOCC1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(2-morpholin-4-yl-ethyl)-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and Methyl-(2-morpholin-4-yl-ethyl)-amine following General Procedure C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>CN(C=O)C.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Temperature: 100 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
A mixture of ethyl 5-bromothiophene-2-carboxylate (1.0 g, 4.25 mmol), 4-chlorophenylboronic acid (0.998 g, 6.38 mmol), 2.0 M aq NaHCO3 (6.38 ml, 12.76 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.492 g, 0.425 mmol) in DMF (40 ml) under nitrogen was stirred at 100° C. under nitrogen in a sealed tube for 18 hours as described in WO 2007/011284. The reaction was then cooled to RT, diluted with saturated aq NaHCO3 (40 ml) and extracted with EtOAc (40 ml). The EtOAc extracts were dried over Na2SO4 and concentrated. The crude product was purified by ISCO chromatography on a silica gel column (120 g) employing a 10 min gradient ranging from hexane to 30% EtOAc to elute ethyl 5-(4-chlorophenyl)thiophene-2-carboxylate (1.05 g, 3.94 mmol, 93% yield) as a white solid. LC MS at t=2.70 min. (m+H=267) PHENOMENEX® 55 C18 4.6×30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. 1H NMR (400 MHz, CD3OD) 8 ppm 1.39 (t, J=7.18 Hz, 3H), 4.37 (q, J=7.22 Hz, 2H), 7.43-7.51 (m, 3H), 7.71 (d, J=8.56 Hz, 2H), 7.78 (d, J=4.03 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:17][C:10]=12.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:45](C)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([CH3:45])[CH2:22][CH2:23]3)[S:17][C:10]=12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4CCNCC4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 154, Step C, 20.0 mg, 0.0357 mmol), formaldehyde (8.68 mg, 0.107 mmol, 37%), NaBH(OAc)3 (37.9 mg, 0.179 mmol) and THF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (dichloromethane/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (19.1 mg, 93.2%). LRMS (APCI pos): >99% purity, 254 nm, m/e 573 (M). 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 8.44 (d, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 7.94 (dd, 1H), 7.61 (m, 2H), 7.38 (m, 1H), 7.21-7.28 (m, 4H), 6.46 (d, 1H), 2.99 (m, 2H), 2.91 (m, 1H), 2.34 (s, 3H), 2.06-2.17 (m, 4H), 1.94 (m, 2H).
Reaction SMILES: [Mg].Br[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[C:4]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:3]([CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:29])[N:7]([CH3:8])[N:6]=2)=[CH:10][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1C(O)c1ccccc1
Temperature: 40 °C
Yield: 12 %

Procedure:
To solid magnesium (60 mg, 5 mmol) under nitrogen was added a solution of 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (450 mg, 1.35 mmol) (prepared in accordance with Example A-214) in tetrahydrofuran (7 mL). The mixture was heated at 40° C. for 2 hours. Benzaldehyde (1 mL) was added. The mixture was heated to 45° C. for 2 hours. It was quenched with HCl (10 mL, 1N) and washed with ethyl acetate. The aqueous acid layer was basified and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated to give a residue. The residue was purified with a silica gel column to give the title compound (59 mg, 12% yield). MS: m/z=360 (M+1); 1H NMR was consistent with the proposed structure. Anal. Calc'd for C22H18N2OF.0.6EtOAC: C, 71.1; H, 5.6; N, 10.2; Found: C, 70.9; H, 5.47; N, 10.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C@@H:7]([NH:10]C(=O)OCC1C=CC=CC=1)[CH2:8][CH3:9].O=[C:27]([CH3:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[NH2:25][C:24]1[C:3]2[C:2](=[CH:23][CH:22]=[CH:21][C:4]=2[O:5][CH2:6][C@@H:7]([NH2:10])[CH2:8][CH3:9])[N:1]=[C:27]([CH3:34])[C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC[C@@H](COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N

Procedure:
Prepared as in Example 2a from (S)-benzyl 1-(3-amino-2-cyanophenoxy)butan-2-ylcarbamate (Example 97c) and ethyl 3-oxobutanoate as brown solid (75%). MS 318 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].C(O)C.[ClH:16]>[Pd].O>[ClH:16].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C#N)nc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(CN)nc1
Yield: 82 %

Procedure:
To 5-Methanesulfonyl-pyridine-2-carbonitrile (22 kg, 1.0 mol eq, limiting reagent) was charged palladium on carbon (2.0 kg, 5% w/w), ethanol (110 L, 5 rel vol), water (14 L, 0.64 rel vol) and hydrochloric acid (25.04 kg, 32% w/w). An ethanol line rinse (16 L, 0.7 rel vol) followed. The reaction mixture was heated and subjected to an atmosphere of hydrogen until the reaction was complete as judged by HPLC analysis. Water (108 L, 4.9 rel vol) was charged, the catalyst filtered off and washed with water (36 L, 1.6 rel vol). The combined filtrates were concentrated under reduced pressure to approximately 2.5 rel vols. The reaction was then heated and ethanol (126.3 L, 5.7 rel vol) was charged. The reaction mixture was cooled, stirred and isolated by filtration. The solid was washed with ethanol (73.7 L, 3.3 rel vol) and dried to constant weight to yield the title compound (20.1 kg, 9.05 mol, 82%).
Reaction SMILES: [CH:1]([O-:3])=[O:2].C([NH+](CC)CC)C.[CH3:11][O:12][C:13](=[O:24])/[C:14](/[CH2:22]Br)=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH3:11][O:12][C:13](=[O:24])/[C:14](/[CH2:22][O:3][CH:1]=[O:2])=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)/C(=C/c1ccccc1)CBr
Reactant: O=C[O-]
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: COC(=O)/C(=C/c1ccccc1)COC=O

Procedure:
To a stirred solution of triethylammonium formate (1.87 g) in acetonitrile (4 ml) was added (Z)-2-bromomethyl-3-phenylacrylic acid methyl ester (1.30 g) and the mixture heated at reflux for 2 hours. The reaction was cooled and extracted into diethyl ether (3×10 ml). The combined organics were dried (MgSO4) and concentrated under reduced pressure to afford the title compound as a crude oil.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@@H:12]([N:25]2[C:29]([N:30]3C(=O)C4=CC=CC=C4C3=O)=[C:28]([C:41](=[O:44])[CH2:42][Cl:43])[N:27]=[CH:26]2)[C@H:11]1[F:45])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>ClCCl>[NH2:30][C:29]1[N:25]([C@@H:12]2[O:13][C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@H:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:11]2[F:45])[CH:26]=[N:27][C:28]=1[C:41](=[O:44])[CH2:42][Cl:43]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N2C(=O)c3ccccc3C2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: NN
Solvent: ClCCl
Solvent: O
Product: Nc1c(C(=O)CCl)ncn1[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1F
Reaction time: 1 h
Yield: 95 %

Procedure:
Compound (15) obtained in step (6) above (220 mg) was dissolved in dichloromethane (9 ml), to which was then added hydrazine monohydrate (0.02 ml) under cooling at 0° C., and the resultant mixture was allowed to effect the reaction under stirring at the same temperature for 1 hour to produce the titled compound (16). The reaction solution obtained was filtered and the filtrate was concentrated to leave a solid. The solid was purified by silica gel column chromatography (developer solvent:toluene-ethyl acetate, 1:1), to afford the titled compound (16) as a colorless solid (166 mg). Yield: 95%.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([OH:12])=O.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:13]([CH2:20][CH2:21][NH:22][C:10]([C:2]1[NH:1][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc2ccncc2[nH]1
Reactant: NCCOc1ccccc1
Product: O=C(NCCOc1ccccc1)c1cc2ccncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 15) and 2-phenoxyethylamine to give the title compound as a pale yellow solid. δH (CD3OD): 3.81 (2H, t), 4.18 (2H, t), 6.89-6.97 (3H, m), 7.14 (1H, s), 7.26 (2H, t), 7.65 (1H, d), 8.10 (1H, d), 8.78 (1H, s); m/z (ES+)=282 [M+H]+.
Reaction SMILES: O[CH:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30]>[Pd].C(O)(=O)C>[CH2:2]([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(O)c1ccccc1)OCC2c1ccc(C(C)C)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1c(Cc2ccccc2)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 66.9 %

Procedure:
A solution of N-(7-(hydroxy(phenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (512 mg, 1.05 mmol) obtained in Example 94 and 10% palladium on carbon (water content: 50%, 50 mg) in acetic acid (20 mL) was stirred at 80° C. for 1.5 hours under an argon atmosphere. The catalyst was removed and the reaction solution was concentrated under reduced pressure. Water was added to the residue and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from hexane-ethyl acetate to obtain 330 mg (yield: 67%) of the title compound. Melting point: 153-154° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH3:27])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:19]1[CH3:27])[CH3:17]
Reactant: CCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a stirred suspension of 9.66 g (0.017 mole) of tetrachlorophthalic anhydride and 13.5 g (0.034 mole) of 80 percent active 1-ethyl-2-methylindole in 30 ml of benzene maintained at 0°-5° C. by means of an ice bath, 10.6 g (0.079 mole) of aluminum chloride was added in small increments. The reaction mixture was then maintained at 0° to 5° C. for an additional twenty minutes, allowed to warm to room temperature and stirred overnight. The mixture was transferred to a beaker and triturated successively with hexane, 10 percent hydrochloric acid, and lastly with 5 percent aqueous sodium hydroxide which had been heated to 70° C. The residual oil was filtered, acidified with dilutes hydrochloric acid and allowed to stand overnight. On standing, the oil gave way to a solid which was collected by filtration, washed with water and dried to yield 6.8 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: Ro =R1 =R2 =R3 =Cl; R5 =CH3 ; R6 =CH3CH2 ; Y1 =H), an off white solid melting at 214°-216° C. Analysis by mass spectrum showed m/e peaks at 443 (M+, Cl=35) and 398 (M+ --COOH).