Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][C:8]2=[O:17])(=O)C.[BH4-].[Na+].O.[Cl-].[Na+].[CH2:23]([OH:25])[CH3:24]>Cl>[OH:25][CH:23]([C:5]1[CH:4]=[C:16]2[N:7]([C:8](=[O:17])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[N:6]=1)[CH3:24]
Reactant: CCO
Reactant: CC(=O)c1cnn2c(=O)[nH]c3ccccc3c12
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Product: CC(O)c1cc2c3ccccc3[nH]c(=O)n2n1
Reaction time: 2 h
Yield: 94 %

Procedure:
A suspension of 3.3 g (0.0146 mole) of acetylpyrazolo[1,5-c]quinazolin-5(6H)-one prepared as in part A above in 300 ml of absolute ethanol is cooled to 0° and 2.22 g (0.0584 mole) of sodium borohydride added. Stirring is continued at 0° for fifteen minutes and then at room temperature for 2 hours. The reaction mixture is treated with 150 ml of water, the solution stripped to about 100 ml, saturated with solid sodium chloride and adjusted to pH 6.0 (paper) with dilute (1 N) hydrochloric acid. The resultant precipitate is filtered and dried to give 3.1 g of product (94%) melting at 242°-245°. Recrystallization from chloroform-methanol gives 3.0 g of the title compound, m.p. 250°-252°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)Cc1cccc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1cccc(F)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a stirred solution of 3-fluorophenylacetic acid (5.0 g, 32.0 mmol) in diethyl ether (100 ml), at -10° C., was added lithium aluminium hydride (32.4 ml of a 1M solution in diethyl ether, 32.4 mmol), dropwise. The reaction mixture was allowed to warm to +25° C. and stirred for 1 h, before again cooling to -10° C., and quenching by addition of methanol (20 ml) and 4M sodium hydroxide (20 ml). The resulting slurry was filtered and the filtrate evaporated in vacuo. The crude product was chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (80:8:1) to give 3-(fluoro)phenethyl alcohol (3.80 g, 84%), δ (250 MHz, CDCl3) 2.87 (3H, t, J=6.5 Hz, CH2), 3.87 (3H, t, J=6.5 Hz, CH2), 6.89-7.02 (3H, m, Ar--H), 7.23-7.33 (1H, m, Ar--H).
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].O.[OH-].[Li+].O1CCCC1.CO>O>[CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)c1ccc(C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(C)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
A mixture of methyl 4-(pentan-2-yl)benzoate (634 mg, 3.1 mmol), lithium hydroxide monohydrate (646 mg, 15.4 mmol), tetrahydrofuran (12.0 mL), methanol (4.0 mL) and water (4.0 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=3-4. The mixture was extracted with ethyl acetate (20 ml×3). The organic phase was dried by sodium sulfate. The mixture was filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, petroleum/ethyl acetate=6:1) to gave 4-(pentan-2-yl)benzoic acid (E1-c) as a white solid (487 mg, 82%). LRMS (M−H)− m/z: 192.12. found 192.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][NH:9][C:8]2=O)=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: O=C1NCCC1Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Clc1ccc(CC2CCNC2)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
To a solution of 3-(4-chlorobenzyl)-2-pyrrolidinone (420 mg, 2 mmol) in dry THF (25 mL) and under N2 LAH (190 mg, 5mmol) was added in portions with stirring over a period of a couple of minutes. The temperature was increased to 60° C. and the stirring continued for 2.5 h. The mixture was quenched with 200 μL water, 200 μL 5M NaOH and 600 μL water. The solid Li- and Al-salts were filtered off and the filtrate was evaporated to give a colourless oil (387 mg, 99%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2[N:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+].B(O)(O)[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([NH2:43])=[O:42])[CH:36]=1>O1CCCC1.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>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[N:6]=[C:5]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH:21]=[CH:20]2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:35]3[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=3)[C:41]([NH2:43])=[O:42])[CH:3]=2)[N:8]=1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: Fc1ccccc1-c1nc(-n2ccc3cnccc32)c2cc(Br)ccc2n1
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: C1CCOC1
Product: NC(=O)c1cccc(-c2ccc3nc(-c4ccccc4F)nc(-n4ccc5cnccc54)c3c2)c1
Temperature: 80 °C
Yield: 26.5 %

Procedure:
6-Bromo-2-(2-fluoro-phenyl)-4-pyrrolo[3,2-c]pyridin-1-yl-quinazoline from Step E, Example 3 (0.1 g, 0.23 mmol) was dissolved in tetrahydrofuran (5 ml). Sodium carbonate (0.075 g, 0.7 mmol) and benzamide-3-boronic acid (0.040 g, 0.24 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (0.005 g, 0.004 mmol) after degassing for 5 mins. Water (0.5 ml) was added drop wise and the mixture was magnetically stirred and heated to 80° C. for 4 hrs. Water was added and product extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated in a rotary evaporator and the residue further purified using a HPLC reverse phase column using an acetonitrile and water gradient containing 0.1% trifluoroacetic acid to yield the title compound (0.028 g, 25%). MS (ES) 460.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:18][O:19][C:20](=[O:31])[C@@H:21]([NH2:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[CH3:18][O:19][C:20](=[O:31])[C@@H:21]([NH:30][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[NH:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1
Reactant: CCC(C)CNc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)CNc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Yield: 75 %

Procedure:
As per Procedure A, 5-chloro-2-(2-methyl-butylamino)-benzoic acid (12.44 mmol, 3 g) was treated with (2S)-amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride (12.44 mmol, 3.66 g), HBTU (14.92 mmol, 5.66 g) and diisopropylethylamine (37.32 mmol, 4.82 g) to yield 3-(4-bromo-phenyl)-(2S)-[5-chloro-2-(2-methyl-butylamino)-benzoylamino]-propionic acid methyl ester. (4.4 g, 75% yield). LC-MS m/z: 482.8 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].ClC(N(C)C)=C(C)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][C:25]=1[C:34]([N:36]1[CH2:41][CH2:40][CH:39]([O:42][CH3:43])[CH2:38][CH2:37]1)=[O:35].Cl>C(Cl)Cl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([C:3]2[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:6][C:2]=2[CH3:1])=[O:32])=[CH:26][C:25]=1[C:34]([N:36]1[CH2:37][CH2:38][CH:39]([O:42][CH3:43])[CH2:40][CH2:41]1)=[O:35]
Reactant: COC(=O)c1c[nH]c(C)c1
Reactant: COC1CCN(C(=O)c2cc(CC(=O)O)ccc2F)CC1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(C)c1C(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
A solution of methyl 5-methyl-1H-pyrrole-3-carboxylate (61) (0.104 g, 0.74 mmol) in anhydrous DCM (5 mL) was added dropwise to a stirred suspension of aluminum trichloride (0.226 g, 1.69 mmol) in anhydrous DCM (10 mL) at 0° C., under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of the requisite acid chloride [prepared earlier; 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.090 mL, 0.68 mmol) was added to a solution of 2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetic acid (0.200 g, 0.68 mmol) in anhydrous DCM (5 mL) at 0° C. and stirred for 2 hours] was added dropwise to the stirred suspension at 0° C. The resulting suspension was allowed to warm to room temperature and then stirred at room temperature for a further 18 hours. The reaction was incomplete and further aluminum trichloride (0.226 g, 1.69 mmol) was added and the solution was stirred at room temperature for a further 1 hour. The reaction mixture was poured onto ice (50 mL) and conc HCl (2 mL). The layers were separated and the aqueous layer extracted with DCM (2×50 mL). The combined organics were washed sequentially with 2M HCl (2×75 mL), water (50 mL), and saturated NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a colourless gum (0.117 g, 41.5% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.44-1.77 (3H, m), 1.85 (1H, m), 2.10 (3H, s), 3.08 (1H, m), 3.29 (3H, s), 3.36-3.55 (3H, m), 3.75 (3H, s), 3.92 (1H, m), 4.16 (2H, m), 6.93 (1H, t), 7.07-7.12 (2H, m), 7.21 (1H, m), 8.82 (1H, s); m/z (LC-MS, ESI+), RT=1.72 min (M+H=417.20).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:10]=1[CH:11]=[O:12].[BH4-].[Na+]>CO>[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:10]=1[CH2:11][OH:12]
Reactant: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To form 2,3-dichloro-6-nitrobenzylalcohol (compound XX) from 2,3-dichloro-6-nitro benzaldehyde (compound XIX), compound XIX is preferably solubilized in a solvent or solvent mixture such as toluene and methanol. The solution of compound XIX is added to a reducing solution such as sodium borohydride in an organic solvent over a period of time to maintain a reaction temperature below about 40° C., preferably 25° C. The reaction is preferably stirred for 24 hours at room temperature under nitrogen and then washed with water. After removing the aqueous layer the organic layer is azeotropically dried and concentrated forming 2,3-dichloro-6-nitrobenzylalcohol (compound XX).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C@:12]1([CH2:23][CH2:24][N:25]([CH3:33])C(=O)OC(C)(C)C)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[C:14](=[O:22])[NH:13]1.C(N(CC)CC)C.[CH3:41][O:42][C:43](Cl)=[O:44].C(O)(C(F)(F)F)=O>ClCCl.CO>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15]([C:14](=[O:22])[NH:13][C@@:12]2([CH2:11][CH2:10][CH2:9][NH:8][C:43](=[O:44])[O:42][CH3:41])[CH2:23][CH2:24][NH:25][CH3:33])=[CH:16][CH:17]=1
Reactant: COC(=O)Cl
Reactant: CN(CC[C@]1(CCCN)NC(=O)c2ccc(Cl)cc21)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC[C@]1(CCCNC(=O)OC)NC(=O)c2ccc(Cl)cc21
Reaction time: 1.5 h

Procedure:
To a solution of (S)-tert-butyl 2-(1-(3-aminopropyl)-6-chloro-3-oxoisoindolin-1-yl)ethyl(methyl)carbamate trifluoroacetic acid salt (71 mg, 0.14 mmol) in dry dichloromethane (10 mL) at room temperature was added triethylamine (56 mg, 0.56 mmol) and methylchloroformate (26 mg, 0.3 mmol). After stirring for 1.5 h, methanol (2 mL) was added. The reaction mixture was stirred for 2 h and then concentrated. The residue was dissolved in dichloromethane (3 mL) and added trifluoroacetic acid (5 mL). After stirring for 2 h, the solvent and excess reagent were evaporated under reduced pressure. The residue was purified by preparative HPLC (C-18 column, 5 to 70% CH3CN in H2O containing 0.01% CF3CO2H over 20 min, 20 mL min−1) to afford product and a minor amount of (R) isomer as TFA salt (45 mg, 69%). 1H NMR (CD3OD) δ 7.73 (d, J=7.9 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.56 (dd, J=8.2, 1.2 Hz, 1H), 3.58 (s, 3H), 3.00 (t, J=7.0 Hz, 2H), 2.80-2.88 (m, 1H), 2.60 (s, 3H), 2.40-2.49 (m, 1H), 2.26-2.37 (m, 2H) 1.90-2.02 (m, 2H) 1.24-1.38 (m, 1H) 0.83-0.96 (m, 1H); MS EI m/z 340 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([C@H:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[S:29])[CH3:27])[NH:24][C:23]1=[O:36])[CH3:21])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].P(=O)(O)(O)O>CN(C)C=O.C(OCC)C>[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([C@H:26]([C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[S:29])[CH3:27])[N:24]([CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:23]1=[O:36])[CH3:21])([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccccc1
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=S)c1ccccc1

Procedure:
To a suspension of sodium hydride (31 mg) in dry dimethylformamide (4.3 ml), there were added successively t-buty alpha-bromoacetate (835 mg) and (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]azetidin-2-one (0.42 g), and the resultant mixture was stirred at room temperature for 1 hour under a nitrogen stream. The reaction mixture was diluted with diethyl ether and adjusted to pH 6.86 with a phosphoric acid buffer solution. The aqueous layer was separated from the organic layer and extracted with diethyl ether three times. The extracts were combined with the organic layer, washed three times with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](OCC)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[N:4]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][OH:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1ccn2c(C(=O)Nc3cccc4c3c(CC)nn4Cc3cccc(C)n3)cnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CO)ccn34)c12
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To ethyl 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carboxylate (201 mg, 0.417 mmol; prepared as in Example 23) in THF (20 mL) was added lithium aluminum hydride (47.4 mg, 1.25 mmol). The reaction mixture was stirred overnight, quenched with sodium sulfate decahydrate, filtered through Celite and the filter pad was washed with EtOAc. The filtrate was concentrated under reduced pressure to give the product (156 mg).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:12]=[N:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)C>C(O)(=O)C>[C:1]1([N:7]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[N:13][CH:12]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=NC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 5.4 g. of phenylhydrazine in 70 ml. of 30% aqueous acetic acid is added 10.0 g. of N-(dimethylaminomethylene)-p-nitrobenzamide. The reaction mixture is stirred at 90° C. for one hour and then cooled. The solid is collected and recrystallized from ethanol giving 9.1 g. of the desired product as colorless crystals, mp. 130°-132° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:17]([O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH2:31][CH2:32]Cl)[CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([O:21][C:22]1[CH:23]=[C:24]2[C:25](=[CH:29][CH:30]=1)[C:26](=[O:27])[N:16]([C:13]1[CH:14]=[CH:15][C:10]([N:7]3[CH2:8][CH2:9][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6]3)=[CH:11][CH:12]=1)[CH2:32][CH2:31]2)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1ccc(C(=O)Cl)c(CCCl)c1
Reactant: Nc1ccc(N2CCC3(C2)OCCO3)cc1
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CCC4(C3)OCCO4)cc1)C2=O

Procedure:
4-(1,4-Dioxa-7-azaspiro[4.4]non-7-yl)phenylamine was reacted with 4-butoxy-2-(2-chloroethyl)benzoyl chloride by method A. The product with the molecular weight of 438.57 (C26H34N2O4) was obtained in this way; MS (ESI): 439 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:10]#[CH:11])[CH:7]=[N:6][CH:5]=1.[CH3:13][O:14][C:15](=[O:40])[CH2:16][CH2:17][C:18]1[C:23]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:22][CH:21]=[C:20](I)[N:19]=1>>[CH3:13][O:14][C:15](=[O:40])[CH2:16][CH2:17][C:18]1[C:23]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[CH:22][CH:21]=[C:20]([C:11]#[C:10][C:8]2[CH:7]=[N:6][CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=2)[N:19]=1
Reactant: C#Cc1cncc(C(=O)OC)c1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Product: COC(=O)CCc1nc(C#Cc2cncc(C(=O)OC)c2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 2.8 %

Procedure:
Under the conditions of example 5A, 184 mg of the crude 5-ethinylnicotinic acid methyl ester is reacted with 500 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-30% ethyl acetate and for complete purification subjected to high-pressure liquid chromatography on reversed-phase silica gel (Nova-Pak HR C18) with acetonitrile/water=75/25. 15 mg of 3-{6-[2-(5-methoxycarbonyl-3-pyridyl)-ethinyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:25].[Na+]>CO>[NH2:25][CH:16]1[CH2:17][CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][C:15]1([CH2:22][CH3:23])[CH2:20][CH3:21]
Reactant: [BH3-]C#N
Reactant: CCC1(CC)CN(Cc2ccccc2)CCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1(CC)CN(Cc2ccccc2)CCC1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (7.85 g, 102 mmol) was added to the stirred solution of 1-benzyl-3,3-diethyl piperidin-4-one (5.0 g, 20.40 mmol) in methanol (100 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (1.3 g, 20.40 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,3-diethyl piperidine. Yield 8.2 g (82%), C16H26N2, m/z 247 (M+1), PMR (CDCl3): 0.84 (s, 3H), 0.98 (s, 3H), 1.48 (bs, 2H, D2O exchangeable), 1.66 (m, 2H), 2.04 (m, 2H), 2.42 (m, 2H), 2.86 (m, 1H), 3.46 (dd, 2H), 7.32 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]C)[CH:5]=[CH:4][C:3]=1[C:10](=[O:18])[CH:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].ClC1C=C(C=CC=1)C(OO)=O.CO.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[C:10](=[O:18])[CH:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC(C)C(=O)c1ccc(SC)cc1Br
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)C(=O)c1ccc(S)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of the sulfide obtained in step B (3.59 g) in chloroform (30 c.c.) was added m-chloroperoxybenzoic acid (1.87 g) and the suspension was stirred for 1 hr. It was than warmed up to R.T. and Ca(OH)2 (1.11 g) was added and stirred for 45 min. Insolubles were filtered off and trifluoroacetic anhydride (10 g) was added to the filtrate and the mixture heated to reflux for 1 hr. Volatiles were removed in vacuo to yield a residue to which was added a solution of MeOH (50 c.c.) and triethylamine (50 c.c.); the mixture was then concentrated in vacuo to dryness and this process was repeated 3 times. The residue was finally taken up in ethyl acetate (100 c.c.) and washed with 1N HCl (3×25 c.c.), brine, dried and evaporated to dryness to yield the title compound as an oil which was used immediately in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([CH2:29][CH3:30])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:7]=1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:5])[CH3:2].[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:42]3[CH:43]=[CH:44][C:39]([C:38]([F:49])([F:48])[F:37])=[CH:40][CH:41]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([CH2:29][CH3:30])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:7]=1[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc2c(c1)c1ccccc1n2CC
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc2c(c1)c1ccccc1n2CC

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-1-(9-ethylcarbazol-3-yl)-5-hydroxyindole-3-carboxylic acid ethyl ester (170 mg, 0.35 mmol, see step (b) Example 14) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol. Yield 130 mg (60%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=[C:25]([Cl:34])[CH:24]=1.Cl>CCO>[Cl:34][C:25]1[CH:24]=[C:23]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([C:9]([F:20])([F:21])[C:10]([F:18])([F:19])[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13])=[CH:8][C:2]=2[F:1])[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=1
Reactant: Nc1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1F
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1F
Yield: 30 %

Procedure:
2-Fluoro-4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl) aniline and ethyl 4,6-dichloronicotinate were reacted in a mixture of EtOH and conc. HCl for 36 h as for example 33, step A. The resultant solid was purified by flash chromatography on silica gel (Hexane—10% EtOAc/Hexane gradient elution) to give ethyl 6-chloro-4-[2-fluoro-4-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)anilino]nicotinate (30%). 1H NMR [400 MHz, CDCl3] δ 10.11 (br s, 1H), 8.86 (s, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.46 (d, J=9.7 Hz, 2H), 6.98 (d, J=0.7 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H).