Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([O:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[CH3:28][CH:29]1[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:25]([O:24][C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:35]2[CH:36]=[CH:37][C:31]3[O:30][CH:29]([CH3:28])[CH2:33][C:32]=3[CH:34]=2)=[C:3]([CH3:27])[N:4]=1)[CH3:26]
Reactant: CC1Cc2cc(B(O)O)ccc2O1
Reactant: CCOc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOc1nc(C)c(-c2ccc3c(c2)CC(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 68.4 %

Procedure:
To a solution of 4′-[(5-bromo-2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1 g) and 2-methyl-2,3-dihydro-1-benzofuran-5-ylboronic acid (0.63 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (2 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.77 g, 68%) as a pale-yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]1[C:13]2[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=3[S:16][C:12]=2[C:11](=O)[CH2:10]1>CO>[CH2:9]1[C:13]2[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=3[S:16][C:12]=2[C:11](=[N:2][OH:3])[CH2:10]1
Reactant: NO
Reactant: O=C1CCc2c1sc1c2CCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CCc2c1sc1c2CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a mechanical stirrer and nitrogen inlet was charged with hydroxylamine hydrochloride (573 mg, 8.25 mmol) and methanol (10 mL). The mixture was cooled to 0° C. using an ice bath. Sodium acetate (677 mg, 8.25 mmol) was added. The mixture was stirred at 0° C. for 30 min. After this time, 105c (319 mg, 1.65 mmol) was added, and the reaction was stirred at room temperature for 16 h. After this time, the mixture was concentrated, and the resulting residue was triturated with water (10 mL). The resulting solid was collected and dried in a vacuum oven at 45° C. to afford an 84% yield (287 mg) of 105d as an off-white solid: mp 173-174° C.; 1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 2.97 (m, 2H), 2.77-2.73 (m, 4H), 2.47 (m, 2H), 1.75 (m, 4H); MS (APCI+) m/z 208.3 (M+H)
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:23]=[CH:22][C:12]([CH:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>ClCCl.[Zn].II>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][CH:13]([C:12]1[CH:22]=[CH:23][C:9]([F:8])=[CH:10][CH:11]=1)[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH3:7]
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A suspension of zinc (5.7 g, 87.2 mmol) in dichloromethane (20 ml) was treated with iodine (0.1 g) and heated under reflux. A solution of ethyl bromoacetate (10.0 g, 59.8 mmol) in dichloromethane was then added dropwise over 15 min and the resulting mixture was heated for another 15 min. The thick paste was then cooled to 0-5° C. and treated dropwise with a solution of 4,4′-difluorobenzhydryl chloride (11.93 g, 50.0 mmol) in dichloromethane (20 ml). The cooling bath was then removed and the mixture was stirred at 22° C. for another 2 h. The reaction mixture was quenched by the addition of 1N hydrochloric acid and ethyl acetate. The organic phase was washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent under reduce pressure and distillation of the residue in vacuo gave 11.6 g (80%) of the title material as a clear oil: bp 95-100° C./0.1 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.14 (3H, t, J=7.1 Hz, CH3), 3.01 (2H, d, J=8.1 Hz, CH2), 4.06 (2H, q, J=7.1 Hz, CH2), 4.54 (1H, t, J=8.1 Hz, CH),7.0 (4H, m, aromatics), 7.2 (4H, m, aromatics). Anal. Calcd for C17H16F2O2: C, 70.34; H, 5.56. Found: C, 70.44; H, 5.50.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[N:14]1[NH:15][N:16]=[N:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]2[N:14]=[N:15][NH:16][N:17]=2)=[CH:24][CH:23]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1ccc(-c2nn[nH]n2)cc1
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Solvent: c1ccncc1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(-c3nn[nH]n3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2,4-dimethylphenyl)(2-methylpropyl)amine (100 mg, 0.564 mmol) in pyridine (2 mL) was added 4-(2H-tetrazol-5-yl)benzene-1-sulfonyl chloride (138 mg, 0.564 mmol) and the mixture stirred at 20° C. for 30 minutes, then stood at room temperature, in air, for 16 hours. The crude was then purified by flash silica (Si) chromatography (using a 25-100% ethyl acetate-cyclohexane gradient) to give a colourless gum. This was further dried under a stream of nitrogen, then under vacuum for 3 hours, to give the final product, 104.87 mg. LCMS (M+1) 386, RT 1.22 mins.
Reaction SMILES: [C:1]1([CH:7]([CH3:13])[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:14]>C(O)(C)(C)C>[C:1]1([C@@H:7]([CH3:13])[C:8]([NH2:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)c1ccccc1
Reactant: N
Solvent: CC(C)(C)O
Product: C[C@@H](C(N)=O)c1ccccc1
Yield: 90 %

Procedure:
A mixture of 1.6 g of ethyl 2-phenyl-propionate and 18 ml of tert-butanol is treated at 50° C. with stirring with 0.35 g of lipase from Candida antarctica (Novozym 435, activity 7000 PLU/g). Ammonia is then passed into the reaction mixture with stirring at 50° to 53° C. until it is saturated. The mixture is stirred at 50° to 53° C. for a further 8 hours and during the course of this a slow stream of ammonia is continuously passed through the apparatus. The mixture is then worked up in the manner indicated in Example 1. 0.6 g (90% of theory, conversion 46 area per cent GC) of (R)-2-phenyl-propionamide having an ee value of >98% is obtained.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl>CO>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(NC(C)=O)cc1
Agent: Cl
Solvent: CO
Product: CNS(=O)(=O)c1ccc(N)cc1
Yield: 91.9 %

Procedure:
The acetamide (1.6 g) was dissolved in methanol (5 ml) and refluxed, with an addition of 4N hydrochloric acid (7 ml), for 1 hour. After an evaporation of methanol under a reduced pressure, the residue was made basic with an addition of 1N sodium hydroxide, and extracted with ethyl acetate (30 ml), followed by drying over anhydrous sodium sulfate. Evaporation of the solvent under a reduced pressure gave N-methyl-4-(amino)benzenesulfonamide (1.2 g) (m.p. 110.9° C.-112° C.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:8].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:11][CH:12]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCCCCBr)Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CCCCCN1CCN(c2ccccc2)CC1)Nc1ccc(O)cc1

Procedure:
A solution of 45.7 g (0.16 mol) of 6-bromo-N-(4-hydroxyphenyl)hexanamide, 26.0 g (0.16 mol) of 1-phenylpiperazine and 22.4 ml (16.3 g, 0.16 mol) of triethylamine in 400 ml of ethanol was heated under reflux overnight and then concentrated under vacuum. The residue was mixed with sodium bicarbonate solution and trichloromethane. The resulting suspension was filtered. The solid was recrystallized from ethanol-water and then from acetonitrile to give the end product as tan crystals, mp 157°-159°.
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[C:9](=[O:28])[CH:8]=1.[H-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]OS(C)(=O)=O)=[CH:34][N:33]=1>C(OCC)(=O)C>[F:31][C:32]1[N:33]=[CH:34][C:35]([CH2:38][O:6][C:7]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:17][CH:18]=3)[C:9](=[O:28])[CH:8]=2)=[CH:36][CH:37]=1
Reactant: O=c1cc(O)ccn1-c1ccc(OCCN2CCCCC2)cc1
Reactant: CS(=O)(=O)OCc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)nc2)ccn1-c1ccc(OCCN2CCCCC2)cc1
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
Into a DMF solution (0.8 mL) of 4-hydroxy-1-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1H-pyridin-2-one (20 mg, 0.065 mmol), NaH (60% oiliness, 3 mg, 0.078 mmol) was added and stinred at room temeture for 20 minutes, followed by addition of DMF solution (0.2 mL) of 2-fluoro-5-methanesulfonyloxymethylpyridine (20 mg, 0.097 mmol), stirring at the same temperature for 2.5 hours and further an overnight stirring at 80° C. Ethyl acetate was added to the reaction liquid, which was then washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300; methanol:chloroform=1:10) to provide the title compound (12.5 mg, 45%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([NH:12]C=O)[CH2:4][CH2:3]1>Cl.CO>[NH2:12][C@H:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: O=CN[C@@H]1CCC(=O)c2ccccc21
Agent: Cl
Solvent: CO
Product: N[C@@H]1CCC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)—N-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)formamide (45 mg, 238 μmol) in 5 mL of HCl and 5 mL of MeOH was refluxed for 2 h and then stirred at RT overnight. The solvent was evaporated and the residue was neutralized with 10N NaOH and was extracted with EtOAc. The extracts was dried over Na2SO4 and evaporated. flash chomatograph (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:10 to 100:20) afforded crude (R)-4-amino-3,4-dihydronaphthalen-1(2H)-one as a sticky oil.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][S:5](=[O:16])(=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14].[OH-].[Na+]>O1CCOCC1>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[NH:6][S:5]([CH2:4][C:3]([OH:17])=[O:2])(=[O:15])=[O:16]
Reactant: COC(=O)CS(=O)(=O)Nc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.68 g (10.1 mmol) of 2-[N-(2,4-difluorophenyl)sulfamoyl]-acetic acid methyl ester is dissolved in 30 ml of dioxane, 15 ml of 2N sodium hydroxide solution is added and stirred for 30 minutes at room temperature. The reaction solution is then evaporated to dryness, the residue is dissolved in some water, the solution is again concentrated by evaporation, the residue is dissolved in 30 ml of water, acidified with 2N hydrochloric acid and the product is extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and evaporated to dryness in a vacuum The crude product is recrystallized from ether/hexane 1:1. 1.55 g (6.17 mmol)=61.1% of the theoretical yield is obtained as a crystallizate, melting point 110-111.5° C.
Reaction SMILES: O[CH2:2][C@@H:3]1[N:8]([CH2:9][C:10]([OH:24])([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[O:17][C@@H:16]([CH3:23])[CH2:15]3)[CH3:11])[CH2:7][CH2:6][N:5]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[CH3:11][C@:10]1([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[O:17][C@H:16]([CH3:23])[CH2:15]3)[O:24][CH2:2][C@@H:3]2[CH2:4][N:5]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][CH2:7][N:8]2[CH2:9]1
Reactant: C[C@H]1Cc2cc(C(C)(O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO)ccc2C(=O)O1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: C[C@@H]1Cc2cc([C@]3(C)CN4CCN(C(=O)OC(C)(C)C)C[C@H]4CO3)ccc2C(=O)O1

Procedure:
A sealed tube containing tert-butyl (3R)-3-(hydroxymethyl)-4-{2-hydroxy-2-[(3S)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]propyl}piperazine-1-carboxylate (175 mg, 0.403 mmol) and cyanomethylenetributylphosphorane (117 mg, 0.483 mmol) dissolved in anhydrous benzene (3 mL) was degassed twice with nitrogen and then heated using a microwave to 135° C. for 2.5 hours. The reaction was allowed to cool and the crude mixture was concentrated and purified on MPLC (30-75% EtOAc/Hex) to afford the minor isomer as the faster eluting peak and the major isomer as the slower eluting peak: Major, slower eluting isomer: LC-MS: (M+1)+417.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18].[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][C@@H:32]([F:33])[C@@H:28]([CH2:27][NH:26][CH:23]3[CH2:24][CH2:25]3)[CH2:29]2)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Product: Cc1c(N2C[C@H](CNC3CC3)[C@H](F)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Yield: 33.3 %

Procedure:
Using 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (20.0 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (15.2 mg), the same procedure was followed as in Example 36 to give 5-amino-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid as a yellow solid (9.6 mg).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[N:13]=[CH:14][C:15]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])=[N:16][C:17]=1[C:18]([NH:20][CH3:21])=[O:19]>>[NH2:11][C:12]1[C:17]([C:18]([NH:20][CH3:21])=[O:19])=[N:16][C:15]([C:22]2[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:10][CH2:9][CH2:8][NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:26])[CH:23]=2)=[CH:14][N:13]=1
Reactant: NCCNc1ccccc1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Product: CNC(=O)c1nc(-c2cccc(C(=O)NCCNc3ccccc3)c2)cnc1N
Yield: 45 %

Procedure:
3-amino-N-methyl-6-[3-({[2-(phenylamino)ethyl]amino}carbonyl)phenyl]pyrazine-2-carboxamide was synthesized according to the procedure described in above from N-phenylethane-1,2-diamine and 3-{5-amino-6-[(methylamino)carbonyl]pyrazine-2-yl}benzoic acid. Yield 45%: 1H NMR (400 MHz, CDCl3): 8.90 (s, 1H), 8.82 (br d, 1H), 8.70 (br t, 1H), 8.45 (br s, 1H), 8.32 (br d, 1H), 7.82 (br d, 1H), 7.52 (t, 1H), 7.02 (t, 2H), 6.62 (d, 2H), 6.50 (t, 1H), 5.72 (br t, 1H), 3.52 (d, 2H), 3.20 (d, 2H), 2.92 (d, 3H); MS (EI) for C21H22N6O2: 391 (MH+)
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]([NH:12][CH:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3]1>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:22]=[C:20]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:12][C:4]2[O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[C:3]1=2
Reactant: CCOC(=O)C(=CNc1cc(=O)c2ccccc2o1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2oc3ccccc3c(=O)c2c1=O
Yield: 81.6 %

Procedure:
Diethyl {[(4-oxo-4H-1-benzopyran-2-yl)amino]methylene}malonate (36 g, 0.11 mole) is added to diphenyl ether (300 ml) at 200° C. The reaction mixture is refluxed under nitrogen for 90 min. The product, which crystallized out on cooling, is filtered off and washed with ethyl acetate. Recrystallization from DMF gives white crystals (25.6 g, 83%), mp 174°-175° C.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=2[OH:22])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.OC1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([O:36][CH3:37])[C:30]([CH3:39])([CH3:38])[CH2:29]1>C1(C)C(C)=CC=CC=1>[N:1]1[N:2]([C:10]2[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=2[OH:22])[CH2:13][CH2:14][C:15]([O:17][CH:18]2[CH2:35][C:32]([CH3:34])([CH3:33])[N:31]([O:36][CH3:37])[C:30]([CH3:39])([CH3:38])[CH2:29]2)=[O:16])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)CCc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1C
Product: CON1C(C)(C)CC(OC(=O)CCc2cc(-n3nc4ccccc4n3)c(O)c(C(C)(C)C)c2)CC1(C)C
Temperature: 100 °C
Yield: 56.7 %

Procedure:
A mixture of 30.0 grams (84.9 mmol) of methyl 3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate, 19.1 grams (102 mmol) of 4-hydroxy-1-methoxy-2,2,6,6-tetramethylpiperidine, and 200 ml of xylene is heated at reflux in a round-bottomed flask equipped with a fractionating column and an adjustable still head. Approximately 25 ml of wet xylene is distilled from the reaction mixture. The reaction mixture is then cooled to 100° C., treated with 1.4 gram of lithium amide, and diluted with 100 ml of xylene. The mixture is heated at reflux for sixteen hours while methanol is removed by fractional distillation. The reaction mixture is diluted with 200 ml of toluene, and washed successively with 1N hydrochloric acid (200 ml) and saturated sodium bicarbonate solution (300 ml). Solids are removed by filtration, and the filtrate is dried over anhydrous magnesium sulfate and then concentrated to obtain a brown solid. The crude product is passed through a layer of silica gel (2:1 heptane:ethyl acetate). The eluent is evaporated to give a solid which is recrystallized from isopropanol to afford 24.5 grams (57% yield) of the title compound as a white solid melting at 135°-137° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]([N:4]1[CH2:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CC(COc2ccc(C3(C#N)CCOCC3)cc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N1CC(COc2ccc(C3(CN)CCOCC3)cc2)C1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 4-{4-[(1-isopropylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-carbonitrile (1.8 g, 5.73 mmol) in THF (80 ml) was cooled to 0° C. under an atmosphere of nitrogen. A solution of lithium aluminium hydride (1.0M solution in Et2O, 17 ml, 17 mmol) was added dropwise over 5 min. The mixture was stirred whilst warming to ambient temperature over 18 hours. The reaction was cooled to 0° C. and quenched with water (0.5 ml) then 2M NaOH (0.5 ml) and then water (1.5 ml). Celite® (3 g) was added and the mixture stirred at ambient temperature for 0.5 hour. Diluted with ethyl acetate (50 ml), filtered and concentrated in vacuo to give a colourless oil (1.8 g). The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 88:12:1.2 by volume) to give the title compound as a white crystalline solid (1.55 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.18 (d, 2H), 6.89 (d, 2H), 4.18 (d, 2H), 3.77 (m, 2H), 3.54 (m, 2H), 3.41 (t, 2H), 3.02 (t, 2H), 2.88 (m, 1H), 2.75 (s, 2H), 2.31 (quintet, 1H), 2.11 (m, 2H), 1.80 (m, 2H), 0.95 (d, 6H). LRMS ESI+ m/z 319 [M+H]+. HRMS ESI+ m/z 319.2375 [MH]+.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][O:4][CH:5]([CH2:7][OH:8])[CH3:6].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([CH:1]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)[CH:2]([OH:9])[CH2:3][O:4][CH:5]([CH2:7][OH:8])[CH3:6])=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(O)COC(C)CO
Product: CC(CO)OCC(O)C(C(=O)c1ccc([N+](=O)[O-])cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 51.7 %

Procedure:
Dipropylene glycol (40.2 g, 0.3 mole) was treated with p-nitrobenzoyl chloride (116 g, 0.625 mole), following the general procedure described in Example 1, Part A. After treatment with saturated aqueous sodium bicarbonate in the usual manner, the ethyl acetate solution of the product was dried (MgSO4), filtered and crystallization effected by the addition of hexanes. The product, bis-(4-nitrobenzoyl)-dipropylene glycol (67 g), was isolated as a pale yellow solid, m.p. 96°-100° C. which was homogeneous by TLC.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=2[C:23](O)=[O:24])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:15][CH2:16][CH:17]([NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=2[CH2:23][OH:24])[CH2:18][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1c(F)cccc1NC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1c(F)cccc1NC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 60.1 %

Procedure:
To a solution of lithium aluminium hydride (0.9 g) in anhydrous tetrahydrofuran (160 ml) is added 2-(1-benzyl-4-piperidinylamino)-6-fluorobenzoic acid (8.0 g) and the mixture is refluxed for 1 hour. After cooling, the reaction solution is poured into ice-water and then extracted with dichloromethane. The solvent is concentrated and to the resulting residue is added diethyl ether/n-hexane. The precipitated crystal is collected by filtration to give N-(1-benzyl-4-piperidinyl)-2-hydroxymethyl-3-fluoroaniline (4.6 g) as light yellow powders, m.p.: 167°-170° C.