Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[C:17]([C:20]([OH:22])=[O:21])[C:18]=3[CH3:19])[CH:15]([C:23]([OH:25])=[O:24])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.[CH2:26](O)[CH3:27]>>[CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[C:17]([C:20]([OH:22])=[O:21])[C:18]=3[CH3:19])[CH:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: Cc1c(C(=O)O)c2n(c1C(=O)c1ccc3n1CCC3)CCC2C(=O)O
Product: CCOC(=O)C1CCn2c(C(=O)c3ccc4n3CCC4)c(C)c(C(=O)O)c21

Procedure:
A stirred mixture of the diacid from Step C above (1.3 g, 0.0038 m), ethanol (30 ml) and resin catalyst (1.3 g; Biorad AG 50W-XB) was heated under reflux for 10 hours in an inert atmosphere, filtered hot, the solution allowed to cool, ice-bath cooled and filtered to yield ethyl 5-(2,3-dihydro-1H-pyrrolizine- 5-oyl)-7-carboxy-6-methyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate (0.73 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:44]=[N+:45]=[N-:46])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[NH:46][N:45]=[N:44][N:37]=3)=[CH:32][CH:31]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)Cc1ccc(C#N)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 80 °C

Procedure:
A solution of 1000 mg (1.91 mmol) of ethyl (7E)-8-{2-[(4-tert-butylbenzyl)oxy]phenyl}-6-(4-cyanobenzyl)oct-7-enoate in 70 ml of toluene is mixed with 3.8 ml (28.6 mmol) of trimethylsilyl azide and 713 mg (2.86 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: dichloromethane→dichloromethane/methanol 10:1). 800 mg (1.4 mmol, 74% of theory) of a white foam are obtained.
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[S:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12]OS(O)(=O)=O.C1(N=C=O)C=CC=CC=1>O>[C:3]([S:10][NH2:12])(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC(=S)c1ccccc1
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C=Nc1ccccc1
Product: NSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a stirred solution of KOH (560 mg, 10 mmol) in water (15 mL) was added thiobenzoic acid (690 mg, 5 mmol) and hydroxylamine-O-sulfonic acid (565 mg, 5 mmol). The solution was stirred for 20 min at room temperature. The white solid (S-benzoylthiohydroxylamine) was collected by filtration and then dissolved in CH2Cl2 (10 mL). To this mixture was added phenyl isocyanate (1.19 g, 10 mmol). The resulting solution was allowed to stir overnight at room temperature. The crude product was collected by the filtration and recrystallized in CH2Cl2/hexane. Pure compound 14 was obtained as a white solid (overall yield 60%). m.p. 184-186° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.99 (s, 1H), 7.88 (d, 7.5 Hz, 2H), 7.74 (t, J=8.1 Hz, 1H), 7.59 (t, J=7.5 Hz, 2H), 7.45 (d, J=7.5 Hz, 2H), 7.24 (t, J=7.8 Hz, 2H), 6.98 (t, J=7.2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 193.4, 155.0, 140.1, 135.2, 134.6, 130.1, 129.4, 127.2, 123.1, 119.3; IR (thin film) cm−1 3286, 3240, 1697, 1638, 1541, 1474, 1459, 1207; MS m/z 273.1 [M+H]+; calcd for C14H13N2O2S 273.1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[OH-].[K+]>O>[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CCOc1ccc(C(=O)O)cc1

Procedure:
A mixture containing 30 g. of ethyl 4-allyloxybenzoate and 180 ml. of 10% aqueous potassium hydroxide solution was stirred and heated on a steam bath for 21/2 hours. The resulting reaction mixture was diluted with one volume of water and filtered through a sintered glass funnel. The filtrate was stirred and acidified with excess concentrated hydrochloric acid. More water was added in order to facilitate stirring. The copious white solid precipitate was collected and dried in a vacuum oven at 60° C. to produce a quantitative yield of 4-allyloxybenzoic acid, m.p. 163°-164° C.
Reaction SMILES: [CH2:1]([CH:3]([N:7]1[C:11]2[N:12]=[C:13]([CH3:26])[N:14]=[C:15]([NH:16][C:17]3[C:18]([CH3:25])=[N:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:10]=2[N:9]=[N:8]1)[CH2:4][CH2:5][CH3:6])[CH3:2].[H-].[Na+].[CH2:29](I)[CH3:30]>CN(C)C=O.O>[CH2:29]([N:16]([C:17]1[C:18]([CH3:25])=[N:19][C:20]([CH3:24])=[CH:21][C:22]=1[CH3:23])[C:15]1[C:10]2[N:9]=[N:8][N:7]([CH:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH3:6])[C:11]=2[N:12]=[C:13]([CH3:26])[N:14]=1)[CH3:30]
Reactant: CCI
Reactant: CCCC(CC)n1nnc2c(Nc3c(C)cc(C)nc3C)nc(C)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC)n1nnc2c(N(CC)c3c(C)cc(C)nc3C)nc(C)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The product from Example 45, Part B (250 mg, 0.71 mmol) was treated with sodium hydride (26 mg, 0.85 mmol, 80%) and ethyl iodide (0.85 ml, 1.07 mmol) in dry dimethylformamide (7 ml) and stirred at room temperature for 15 h. The reaction was diluted with 150 ml water, and extracted with 3×30 ml ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (20 g, 1/3 hexanes/ethyl acetate) afforded the desired product, 221 mg (81%) as a clear viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([CH2:50]O)[CH2:46][CH2:45]1>>[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([CH2:50][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:46][CH2:45]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CN1CCC(CO)CC1
Product: COc1cc(C(=O)OCC2CCN(C)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with (1-methylpiperidin-4-yl)methanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-methyl-piperidin-4-ylmethyl ester. MS (ES+) m/z calcd. for C38H43Cl2F2N4O4: [(M+H)+]: 727. found: 727.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[NH3:24]>O1CCOCC1.CO>[NH2:24][C:2]1[C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C(=O)c3ccccc3OC)cc2c1
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2nc(N)c(C(=O)c3ccccc3OC)cc2c1

Procedure:
(2-Chloro-6-methoxyquinolin-3-yl)(2-methoxyphenyl)methanone (3.4 g, 10.4 mmol) was dissolved in dioxane (25 mL), mixed with 25% aqueous ammonia solution (15 mL) and heated for 30 hours to 150° C. under intrinsic pressure in the pressurized reactor. After cooling, the reaction mixture was diluted with methanol, prepurified with activated carbon and concentrated after filtration. The crude product was dissolved in dichloromethane and washed with water. The dichloromethane solution was dried (sodium sulfate) and concentrated. The crude product was purified chromatographically (silica gel, dichloromethane, 0-2% methanol). Yield: 1.4 g (4.5 mmol, 44%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([OH:11])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[F:13][C:2]([F:1])([F:12])[CH:3]([O:11][C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: OC(CN1CCOCC1)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)OC(CN1CCOCC1)C(F)(F)F
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
In a round bottomed reaction vessel, under argon, was placed 0.239 g (1.2 mmol) of 1,1,1-trifluoro-3-morpholin-4-yl-propan-2-ol and 0.203 g (1.3 mmol) of 4-chlorophenyl isocyanate. The vessel was capped, set in a bath at 85° C. and stirred. After 90 min, the mixture was cooled. The crude material was purified by chromatography on silica gel, eluting with hexanes-ethyl acetate (90:10), to give 0.250 g (59%) of (4-chloro-phenyl)-carbamic acid 2,2,2-trifluoro-1-morpholin-4-ylmethyl-ethyl ester as a white crystalline solid. (M+H)+=353 m/e.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:2]=1.[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])[NH2:17]>>[NH:8]([C:3]1[CH:2]=[CH:1][C:6]([NH:7][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:16]([NH2:17])=[O:18])=[CH:20][CH:21]=2)=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:16]([NH2:17])=[O:18])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Nc2ccc(N)cc2)cc1
Product: NC(=O)c1ccc(C(=O)Nc2ccc(Nc3ccc(NC(=O)c4ccc(C(N)=O)cc4)cc3)cc2)cc1

Procedure:
Compound 754 was prepared according to the procedure described in Scheme IV from 4,4′-diaminodiphenylamine and 4-carbamoylbenzoic acid. [M+H]+ calcd for C28H23N5O4: 494.18; found 494.00.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[N:15][CH:16]=2)[O:8][N:7]=1.[C:20](OCC)(=O)C.O>CO>[CH3:5][C:6]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[N:15][CH:16]=2)[O:8][N:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1noc(-c2cncc(C(=O)O)c2)n1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cncc(-c2nc(C)no2)c1
Temperature: 25 °C

Procedure:
Thionyl chloride (2.5 ml) was added dropwise in methanol (25 ml) under cooling at 7°-9° C. After the mixture was stirred for 30 minutes at the same temperature, 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyridinecarboxylic acid (2.5 g) was added thereto and the mixture was refluxed for 3 hours. After being cooled to room temperature, the mixture was poured into a mixture of ethyl acetate (100 ml) and water (100 ml). The organic layer was successively washed with 10% potassium carbonate aqueous solution and brine, and then dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from diethyl ether to afford methyl 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyridinecarboxylate (2.12 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.C(N(CC)CC)C.[CH3:29][C:30]1[CH:34]=[CH:33][N:32]([NH:35][C:36](=O)[C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH3:38])[C:31]=1[C:48](=[O:56])[NH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.N>ClCCl>[CH3:29][C:30]1[CH:34]=[CH:33][N:32]2[C:31]=1[C:48](=[O:56])[N:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:36]([C@@H:37]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH3:38])=[N:35]2
Reactant: Cc1ccn(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1C(=O)Nc1ccccc1
Agent: BrBr
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
Triphenylphosphine (6.8 g, 25.93 mmol) was dissolved in 50 mL dichloromethane. Bromine (1.33 mL, 25.97 mmol) was added dropwise and the reaction was stirred at room temperature for 30 min. Triethylamine (10.3 mL, 73.9 mmol) and (S)-tert-butyl (1-((3-methyl-2-(phenylcarbamoyl)-1H-pyrrol-1-yl)amino)-1-oxopropan-2-yl)carbamate (7.15 g, 18.5 mmol) suspended in 100 mL dichloromethane was added and the reaction mixture was stirred at 60° C. for 2 h. The mixture was concentrated to dryness and was re-dissolved in a pressure reactor with a solution of ammonia (7M in methanol, 350 mL, 2415 mmol). The mixture was heated at 100° C. for 32 h, then cooled at room temperature and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and dried over sodium sulphate, filtered and concentrated. The residue was purified using Isolera® Purification System (0% to 50%, hexane-ethyl acetate) to obtain 0.95 g (14% yield) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:32])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][NH:21]C(=O)OCC3C=CC=CC=3)[CH2:16]2)=[N:5][CH:4]=1>CO.[Pd]>[NH2:21][CH2:20][C@@H:17]1[CH2:18][CH2:19][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:32])[CH2:16]1
Reactant: COc1cnc2ccc(=O)n(CCN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CC[C@@H](CN)C3)c2c1

Procedure:
To a solution of phenylmethyl [((3S)-1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.33 g, 0.761 mmol) in MeOH (30 mL) was added catalytic 10% Palladium on carbon (0.20 g) and the resulting solution was subjected to H2 at 50 PSI on a Parr shaker. The solution was filtered through a pad of Celite® and concentrated under reduced pressure to yield a colorless oil, (0.100 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[C:44]([F:45])=[C:43]([F:46])[CH:42]=[CH:41][C:40]=1B(O)O.[F-].[Cs+]>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.C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:18][CH:19]=1)=[O:29])=[C:8]([C:42]1[CH:41]=[CH:40][C:39]([F:38])=[C:44]([F:45])[C:43]=1[F:46])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1ccc(F)c(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)c(F)c3F)ccc2c1
Temperature: 80 °C
Yield: 42.3 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.13 g, 4.0 mmol), 2,3,4-trifluorophenyl boronic acid (1.0 g, 5.7 mmol), trans-dichlorobis(triphenylphosphine)palladium II, (561 mg, 0.8 mmol) and cesium fluoride (5.5 g, 36 mmol) and add 50 mL of acetonitrile. Heat the mixture at 80° C. for 4 hours. Cool and filter the mixture and purify on an SOX column, eluting with 2N ammonia/ethanol. Purify further on a silica column eluting with 2% 2N ammonia/methanol/methylene chloride to give 880 mg (43%) of the title compound: 1H-NMR (CD3OD, 400 MHz) δ 7.93 (d, J=8.8 Hz, 1H); 7.50 (d, J=8.4 Hz, 3H); 7.39 (d, J=8.8 Hz, 1H); 7.35 (d, J=2.4 Hz, 1H); 7.07 (dd, J=9.2, 2.8 Hz, 1H); 6.96-6.87 (m, 2H); 6.80 (d, J=9.6 Hz, 2H); 4.10-4.07 (t, 2H); 3.91 (s, 3H); 2.72-2.69 (t, 2H); 2.48-2.48 (m, 4H); 1.61-1.55 (m, 4H); 1.46-1.43 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[CH2:7][O:8][C:4]=2[CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:18][OH:19]>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[N:18][OH:19])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: NO
Reactant: O=C1COc2cc(F)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1COc2cc(F)ccc21
Temperature: 23 °C
Yield: 79.6 %

Procedure:
A mixture of 6-fluoro-benzofuran-3-one (CAS 351528-80-8) (5.93 g, 39 mmol), sodium acetate (6.587 g, 80 mmol) and hydroxylamine hydrochloride (5.553 g, 80 mmol) in ethanol (70 ml) was refluxed for 4 h. Cooled to 23° C., filtered the precipitate off, washed with aqueous ethanol and dried in high vacuum to give the title compound as a white solid (5.19 g, 80%, HPLC 1.489 min); MS (ISN) m/e=168.1 [(M−H)−].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([NH2:42])[N:39]=[CH:38][N:37]=2)[CH:31]=1)=O)(C)(C)C>>[NH2:42][C:40]1[N:39]=[CH:38][N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(N)ncn2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(N)ncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (116 mg, 0.4 mmol) and 3-[3-(6-amino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K53) (138 mg, 0.44 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (90 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.C(O)(C)C.O>C1(C)C=CC=CC=1>[CH3:13][C:8]1([C:5]2([CH2:3][OH:2])[CH2:7][CH2:6]2)[O:9][CH2:10][CH2:11][O:12]1
Reactant: COC(=O)C1(C2(C)OCCO2)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC1(C2(CO)CC2)OCCO1
Temperature: 0 °C

Procedure:
11.2 g of 5 is dissolved in 150 ml of toluene and cooled under nitrogen to 0° C. 125 ml of DIBAH solution (1.2 M in toluene) is now slowly added in drops and stirred for 2 more hours. Then, 1.25 ml of isopropanol and 25 ml of water are added in drops and stirred overnight. The precipitate is filtered off, the filtrate is concentrated by evaporation and chromatographed on silica gel with ethyl acetate/hexane, whereby 9.1 of title compound 6 accumulates as a colorless oil.
Reaction SMILES: [OH:1][C:2]1([C:20]([F:23])([F:22])[F:21])[C:14]2[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=[C:10]([CH3:19])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O1CCCC1.[OH-].[Na+]>CO>[OH:1][C:2]1([C:20]([F:21])([F:22])[F:23])[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[C:10]([CH3:19])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: COC(=O)c1cc(C)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc2c1-c1ccccc1C2(O)C(F)(F)F
Temperature: 25 °C
Yield: 110.1 %

Procedure:
A mixture of methyl 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylate (1.000 g), tetrahydrofuran (4 ml), methanol (6 ml) and 4N aqueous sodium hydroxide solution (1.6 ml) was stirred with heating under reflux for 3 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water (30 ml) was added to the obtained residue, and the mixture was adjusted to pH 1 with 6N hydrochloric acid (2 ml), and extracted with ethyl acetate (30 ml). The organic layer was successively washed with water and saturated brine. After addition of anhydrous magnesium sulfate and activated carbon (0.2 g), the mixture was stirred at room temperature for 10 min. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.053 g). The residue was directly used for the next reaction without further purification.
Reaction SMILES: [I:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9]/[C:10](=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[CH2:11][OH:12].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[I:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9]/[C:10](=[CH:13]\[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)/[CH:11]=[O:12]
Reactant: OC/C(C#CCCCCC#CI)=C/c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C/C(C#CCCCCC#CI)=C/c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
To a solution of Compound 4 (399.4 mg, 1.10 mmol) in dry CH2Cl2 (50 mL) cooled at 0° C. in an ice-water bath was added PCC (591.3 mg, 2.74 mmol) followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with Et2O and filtered through a short silica gel plug with rinsing by EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 17 percent EtOAc in hexane) to give 296.6 mg (75 percent) of Compound 5: pale yellow oil; Rf=0.36 (17 percent EtOAc in hexane); IR (neat) 2942, 2230, 1690, 1596, 1450, 1324, 1180 cm−1; 1H NMR (300 MHz, CDCl3) δ9.55 (s, 1H), 8.10-8.04 (m, 2H), 7.48-7.44 (m, 3H), 7.42 (s, 1H), 2.60 (td, J=6.66, 2.46 Hz, 2H), 2.44 (t, J=6.75, 2H), 1.83-1.66 (m, 4H); 13C NMR (75 MHz, CDCl3) δ192.4, 151.9, 134.8, 132.1, 131.0, 129.4, 124.0, 103.3, 94.7, 75.4, 28.3, 28.0, 21.1, 20.3, −5.9; MS (+CI) m/z (relative intensity) 363 (M+H+, 40), 207 (100); HRMS (+EI) calcd for C17H15IO 362.0168 (M+), found 362.0107.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([C:22]([F:25])=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:18]2[CH:17]=[N:16][C:15]([C:19](O)=[O:20])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.Cl.[CH3:28][O:29][NH2:30]>>[Cl:1][C:2]1[C:3]([F:26])=[C:4]([C:22]([F:25])=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:18]2[CH:17]=[N:16][C:15]([C:19]([NH:30][O:29][CH3:28])=[O:20])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CON
Reactant: O=C(O)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1
Agent: Cl
Product: CONC(=O)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1

Procedure:
The title compound is prepared by coupling of 9-(3-chloro-2,6-difluorobenzyl)-9H-β-carboline-3-carboxylic acid and O-methyl hydroxylamine hydrochloride under conditions similar to those provided in step (b) of example 7.