Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1C2C(=CC(C3C=CC=CC=3OC)=CC=2)C(C(O)C)=CC1(C)C)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([CH3:50])([CH3:49])[CH:43]=[C:42]2[CH:51]([O:53][CH2:54][CH2:55][CH2:56][C:57]1C=CC=CC=1)[CH3:52].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CS(C)=O.C1COCC1.BrCCCC1C=CC=CC=1>[CH2:54]([O:53][CH:51]([C:42]1[C:41]2[C:46](=[CH:47][CH:48]=[C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[O:32][CH3:31])[CH:40]=2)[NH:45][C:44]([CH3:50])([CH3:49])[CH:43]=1)[CH3:52])/[CH:55]=[CH:56]/[CH3:57]
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)OCCCc1ccccc1)=CC(C)(C)N2
Agent: BrCCCc1ccccc1
Agent: COc1ccccc1-c1ccc2c(c1)C(C(C)O)=CC(C)(C)N2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C/C=C/COC(C)C1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Yield: 61.5 %

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-phenylpropoxy)ethyl]-1,2-dihydroquinoline 4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester (116 mg) in 2 mL of DMSO was treated with 334 μL of 1 M solution of sodium bis(trimethylsilyl)amide in THF and 52 μL of 1-bromo-3-phenylpropane to give the alkylated product, which was then deprotected (as above) to yield 31 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH:4](I)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]>C(O)(=O)C.[Zn]>[F:1][C:2]([F:21])([C:17]([F:18])([F:19])[F:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCCCCCCC(I)CC(F)(F)C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)CCCCCCCCCC(F)(F)C(F)(F)F
Temperature: 20 °C
Reaction time: 17 h
Yield: 93.9 %

Procedure:
To a stirred solution of the product from step (b) (2.5 g) in acetic acid (15 ml) was added zinc dust (0.75 g) and the reaction stirred at 20° C. for 17 hours. The reaction mixture was then filtered through a celite pad. The solvent was removed from the filtrate in vacuo to leave a dark orange residue that was partitioned between ethyl acetate (20 ml) and water (20 ml). The ethyl acetate layer was washed with saturated sodium bicarbonate solution (10 ml), dried and the solvent was removed in vacuo to leave the title compound as a dark red oil (1.66 g). A 1:6 mixture of elimination by-product:product, respectively, was produced.
Reaction SMILES: [Br:1][C:2]1[C:21]([F:22])=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[CH3:23][C:24]1([CH3:38])[C@@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][P:27]([OH:37])(=[O:28])[O:26][CH2:25]1>C(Cl)Cl.CC(O)C>[OH:37][P:27]1(=[O:28])[O:29][C@@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]([CH3:23])([CH3:38])[CH2:25][O:26]1.[Br:1][C:2]1[C:21]([F:22])=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CC1(C)COP(=O)(O)O[C@@H]1c1ccccc1
Agent: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3ccccc3[C@@H]12
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)COP(=O)(O)O[C@H]1c1ccccc1
Temperature: 86 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-(cis)-7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-amine (18.58 g, 51.18 mmol) in 300 mL of CH2Cl2 and 60 mL of 2-propanol at 50° C. was added a warm solution of (+)-phencyphos (6.19, 25.59 mmol) in CH2Cl2 (300 mL) and 2-propanol (75 mL). The mixture was heated at 86° C. About 500 mL of CH2Cl2 was removed by careful evaporation, and 310 mL of 2-propanol was added; the mixture was then further concentrated until a final weight of ca. 250 g, and then gradually cooled down to 35° C. After 1 h, the formed crystals were collected by filtration, washed with 2-propanol and dried to yield 12.7 g of crude product (e.e. =95%). This compound was further recrystallized from methanol:CH2Cl2:2-propanol (7:5:2) to give the title compound (12.3 g, 39%, e.e.=99.8%).
Reaction SMILES: [CH:1]1([C:7]([NH2:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>>[CH:1]1([C:7](=[S:19])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)C1CCCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: NC(=S)C1CCCCC1

Procedure:
Following Method 3, cyclohexanecarboxamide and Lawesson's reagent were reacted, yielding cyclohexanecarbothioamide. LCMS (m/z): 144.1 (MH+); LC Rt=5.10 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CC(C)=O>[CH2:25]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 2,4-dihydroxybenzoate (i-1a) (1.68 g, 10 mmol) in acetone (30 mL) was added K2CO3 (2.76 g, 20 mmol). The mixture was stirred at rt for 5 h, followed by the addition of BnBr (1.88 g, 11 mmol). The mixture was heated at 60° C. for 24 h. The reaction mixture was cooled down, filtered. The filtrate was concentrated to afford the title compound. LCMS (ESI) calc'd for C15H14O4 [M+H]+: 259.1. found: 259.1.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[CH:4][C:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[N:6][CH:7]=1.C([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[O:32][C:3]3[CH:4]=[C:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])[N:6]=[CH:7][C:2]=3[N:1]=2)=[N:29][CH:30]=1
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c(N)cn1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)cn3)nc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.3 %

Procedure:
To a solution of N-((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)acetamide (1.80 g) in ethanol (20 mL) were added iron powder (1.84 g) and iron(III) chloride (1.07 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give N-((2S)-1-((5-amino-4-chloropyridin-2-yl)oxy)propan-2-yl)acetamide (1.46 g). To a solution of N-((2S)-1-((5-amino-4-chloropyridin-2-yl)oxy)propan-2-yl)acetamide (830 mg) and 5-(benzyloxy)pyridine-2-carboxylic acid (781 mg), diisopropylethylamine (1.19 mL) in DMF (10 mL) was added HATU (1.49 g), and the mixture was stirred at room temperature for 30 min. The precipitated solid was washed with ethyl acetate-hexane. A suspension of the obtained solid, potassium carbonate (1.22 g) and copper(I) iodide (84.0 mg) in DMF (10 mL) was stirred at 160° C. for 1.5 hr. The reaction mixture was subjected to silica gel chromatography (NH, ethyl acetate), and washed with saturated brine, and the solvent was evaporated. The obtained solid was washed with ethyl acetate/hexane. A mixture of the obtained solid, 10% palladium/carbon (containing water (50%), 200 mg) and THF (10 mL) was stirred at room temperature for 30 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (37.4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]([CH3:14])[CH2:12][S:11][C:10]2=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16](OCC)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:16](=[O:17])[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:10]3[S:11][CH2:12][CH:13]([CH3:14])[N:9]32)=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C(C(=O)OCC)=C1SCC(C)N1c1ccc(F)c(Br)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c2n(c3cc(Br)c(F)cc3c1=O)C(C)CS2
Temperature: 90 °C
Reaction time: 3 h
Yield: 16.5 %

Procedure:
Diethyl 3-(3-bromo-4-fluorophenyl)-4-methyl-1,3-thiazolidin-2-ylidenemalonate (4.2 grams) was dissolved in 40 grams of polyphosphoric acid and the solution was heated with stirring at 90° C. for three hours. After the reaction, the content was poured over into ice water and extracted with chloroform to give 3.5 grams of sirupy substance. This was subjected to a column chromatography on 350 grams of silica gel using chloroform as a developer and, from the initial distillate, 620 mg of ethyl 8-bromo-7-fluoro-1-methyl-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a) quinoline 4-carboxylate was obtained, Melting point was 211° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH2:8][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:10][C:4]=2[CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CC(N(C)C)=O>[CH3:22][S:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][C@@H:24]([CH3:29])[C:25]([F:27])([F:26])[F:28])=[C:13]([C:11]([N:9]2[CH2:10][C:4]3[CH:3]=[C:2]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:7]=[CH:6][C:5]=3[CH2:8]2)=[O:12])[CH:18]=1)(=[O:21])=[O:20]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cnc(Cl)cc2C1)C(F)(F)F
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cnc(N3CCOCC3)cc2C1)C(F)(F)F
Temperature: 180 °C
Yield: 13 %

Procedure:
A mixture of 0.33 mmol (6-Chloro-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (example 167), 0.67 mmol morpholine in 2 ml dimethylacetamide is heated at 180° C. for 30 minutes in a microwave oven. The solvent was removed in vacuo. Chromatography of the residue (silica gel; ethyl acetate/heptane) yields the title compound as a white solid. Yield=13%. MS (m/e): 500.1 [M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([N:15]([O:16][CH3:17])[CH3:14])=[O:6]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(F)c(F)c(F)c1

Procedure:
Following the procedure of Example 29, step (b), reaction of 3,4,5-trifluoro-benzoic acid with N,O-dimethylhydroxylamine HCl in present of HOBT, EDA, TEA in DCM followed the column purification gave the title compound; Calcd MW 219.16. Found MH+ 220.1.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH:14]=[O:15])=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[BH4-].[Na+].O>CO>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][OH:15])=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cnc(C=O)s2)OCCO1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(c2cnc(CO)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 5-(2-methyl-[1,3]dioxolan-2-yl)thiazole-2-carbaldehyde (5.12 g, 25.70 mmol) was dissolved in MeOH (60 mL). NaBH4 (1.26 g, 31.89 mmol) was added portionwise at 0° C. and the reaction mixture stirred at 0° C. for 1 h. Water was added and the mixture extracted with EA (3×). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil. TLC:rf (1:1 hept-EA)=0.31. LC-MS-conditions 02: tR=0.64 min; [M+H]+=202.52.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12][OH:13])C1C=CC=CC=1>[Pd].C(O)C>[NH2:10][C@@H:11]([CH2:12][OH:13])[CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)NC[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)NC[C@@H](N)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a mixed liquid of 3.10 g of benzyl[(1R)-2-hydroxy-1-{[(methylsulfonyl)amino]methyl}ethyl]carbamate and 50 ml of ethanol was added 500 mg of 5% palladium/carbon, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. The palladium/carbon was separated by filtration and the solvent was then evaporated to obtain 1.72 g of N-[(2R)-2-amino-3-hydroxypropyl]methanesulfonamide as a colorless oily substance.
Reaction SMILES: C(OC([N:11]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47]CC2C=CC=CC=2)=[CH:43][CH:42]=1)[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:24](=[O:28])[NH:25][CH2:26][CH3:27])[CH:21]=2)[NH:16][C:15]=1[C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=1)=O)C1C=CC=CC=1.C(O)(=O)C.[H][H]>O1CCCC1.CO.[OH-].[OH-].[Pd+2].O>[CH3:35][C:33]1[CH:34]=[C:29]([C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][CH2:12][NH:11][CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=2)=[CH:21][C:20]([O:23][C:24](=[O:28])[NH:25][CH2:26][CH3:27])=[CH:19][CH:18]=3)[CH:30]=[C:31]([CH3:36])[CH:32]=1
Reactant: CCNC(=O)Oc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(OCc4ccccc4)cc3)C(=O)OCc3ccccc3)c2c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNC(=O)Oc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccc(O)cc3)c2c1
Temperature: 25 °C

Procedure:
To a stirred solution of ethylcarbamic acid 3-(2-[benzyloxycarbonyl-[4-(4-benzyloxyphenyl)butyl]amino]-ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl ester (12 mg in a mixture of 1.5 mL tetrahydrofuran and 0.5 mL methanol) was added 12 mg of 10% palladium hydroxide on carbon catalyst followed by acetic acid (0.010 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 1.5 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol: ammonium hydroxide, 90:7:1) gave the title compound (8.2 mg). m/e=500 (M+H)
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:29])[NH:9][C:10]2([CH:17](C)[C:18]([NH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:19])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH2:11]2)=[CH:3][CH:2]=1.[C:36]1(C2C=CC=CC=2)C=CC(NC(=O)NC(C2C=CC(C)=CC=2)CC(O)=O)=CC=1.N1(CCN)CCCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:29])[NH:9][C@@H:10]([C:15]2[CH:36]=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[CH2:17][C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:19])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(CC(=O)O)NC(=O)Nc2ccc(-c3ccccc3)cc2)cc1
Reactant: CC1=CC=CC(NC(=O)Nc2ccc(-c3ccccc3)cc2)(C(C)C(=O)NCCN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NCCN1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc([C@@H](CC(=O)NCCN2CCCC2)NC(=O)Nc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
3-(3-Biphenyl-4-yl-ureido)-N-(2-pyrrolidin-1-yl-ethyl)-3-tolyl-propionamide. To a solution of 3-(3-biphenyl-4-yl-ureido)-3-p-tolyl-propionic acid (0.15 g, 0.40 mmol), 2-pyrrolidin-1-yl-ethylamine (0.05 g, 0.40 mmol) and HOBt (0.081 g, 0.60 mmol) in DMF (4 mL), was added EDCl (0.12 g, 0.60 mmol). The resulting solution was stirred under N2 at rt for 20 h. The solution was diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The combined extracts were washed with brine (40 mL), dried (Na2SO4), and filtered, and the solvent was removed. The crude product was purified by column chromatography on silica gel using a gradient of 0–20% (MeOH(1% NH4OH)/CH2Cl2) to afford 0.12 g (63%) of the desired product as a white solid. Racemic compound: Rf=0.11 (10% MeOH (1% NH4OH)/CH2Cl2). MS (electrospray): mass calculated for C29H34N4O2, 470.27; m/z found, 471.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.57–7.50 (m, 4H), 7.43–7.37 (m, 4H), 7.29–7.25 (m, 3H), 7.16 (d, J=7.9 Hz, 2H), 5.22 (t, J=6.9 Hz, 1H), 3.28–3.23 (m, 2H), 2.68 (d, J=6.4 Hz, 2H), 2.52–2.48 (m, 6H), 2.31 (s, 3H), 1.77–1.75 (m, 4H).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([OH:9])([C:7]#[N:8])[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1.C(Cl)Cl.O>[NH2:8][CH2:7][C:4]1([OH:9])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: N#CC1(O)CCCCC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: NCC1(O)CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a stirred solution of cyclohexanone cyanohydrin (2 g, 15.98 mmol) in anhydrous THF (40 mL) at rt was added portion-wise LiAlH4 (1.82 g, 47.94 mmol). The reaction vessel was sealed and the mixture was heated at 80° C. for 5 h. The mixture was cooled to 0° C. and water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. To the resulting mixture was added DCM and saturated aq sodium potassium tartrate, and the mixture stirred for 3 h. The organic layer was separated and further washed with brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 1-(aminomethyl)cyclohexanol (1.3 g) which was not purified further. LCMS (ESI) m/z 130 (M+H)+.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:2]1.[O-:26][CH2:27]C.[Na+]>C(O)C>[CH3:27][O:26][CH2:2][C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:13][CH:14]=2)[CH2:7][CH2:8]1
Reactant: CC[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)cc2)C(=O)O1
Agent: [Na+]
Solvent: CCO
Product: COCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)CC1
Yield: 50 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol) with sodium ethoxide (1.6 mmol) in ethanol (10 ml) at a temperature 60° C. for 6 hours and by purifying the compound by silica gel column chromatography in 50% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[C:12]([O-])=[O:13].[Na+].C=O>CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:12][OH:13])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(=O)[O-]
Reactant: Clc1ccc2nccn2n1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1cnc2ccc(Cl)nn12
Yield: 72.3 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine (1.5 g, 9.8 mmol) in AcOH (50 mL) was added NaOAc (1.4 g, 17.1 mmol) and paraformaldehyde (1.5 g). The mixture was heated at reflux overnight and then concentrated under reduced pressure. The residue was basified to pH=12. Then the mixture was filtered and the solid was washed with EtOH to afford (6-chloro-imidazo[1,2-b]pyridazin-3-yl)methanol (1.3 g) in 72% yield.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([F:27])[C:14]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:15]([F:21])[C:16]=2[F:20])[N:11]([CH2:28][CH3:29])[C:10]1=[O:30])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3]>FC(F)(F)C(O)=O>[CH2:28]([N:11]1[C:12]2[C:17](=[C:16]([F:20])[C:15]([F:21])=[C:14]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:13]=2[F:27])[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:30])[CH3:29]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2c(F)c(F)c(N3CCCC3)c(F)c21
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)n(O)c(=O)c2c(F)c(F)c(N3CCCC3)c(F)c21
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A solution of 3-benzyloxy-1-ethyl-5,6,8-trifluoro-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example X-3, 0.15 g, 0.36 mmol) in trifluoroacetic acid (5.0 mL) was reacted with a 1.0 M solution of boron tris(trifluoroacetate) (1.8 mL, 1.8 mmol) in TFA and allowed to stir for 1 hour. The mixture was then concentrated and the residue dissolved in methanol and concentrated. This process was repeated three times. The residue was then triturated from diethyl ether and filtered to provide 0.11 g of the title compound as a solid, mp 223-225° C.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[C:17]1([CH2:23]OOC(=NC(C)C)NC(C)C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]([O:1][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:7]=1
Reactant: CC(C)N=C(NC(C)C)OOCc1ccccc1
Reactant: COC(=O)c1oc2ccc(OC)cc2c1O
Solvent: CC#N
Product: COC(=O)c1oc2ccc(OC)cc2c1OCc1ccccc1
Yield: 64 %

Procedure:
A mixture of 8.0 g (0.036 mole) of 3-hydroxy-5-methoxy-2-benzofurancarboxylic acid, methyl ester and 10.0 g (0.043 mole) of O-phenylmethoxy-N,N'-diisopropylisourea (L. J. Mathias, Synthesis, 561 (1979)) in 200 ml of acetonitrile is stirred at reflux under a nitrogen atmosphere for 22 hours. The mixture is cooled and filtered to remove by-product 1,3-diisopropylurea. The insoluble material is washed with hexane and the combined filtrates are evaporated (vacuum). The residue is treated with 250 ml of diethyl ether, and the mixture is again filtered and evaporated. The crude oil residue is chromatographed over silica gel using dichloromethane/hexane (2:1) elution to obtain 7.2 g 64% yield) of the purified 5-methoxy-3-(phenylmethoxy)2-benzofurancarboxylic acid, methyl ester as an oil. The ester is saponified without additional purification.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:16]3[CH:31]=[CH:30][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=4)=[CH:18][CH:17]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: c1ccc(C2CCCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC(c4ccccc4)C3)cc2)nc1
Yield: 314.4 %

Procedure:
Using a method similar to Example 345, using 3-phenyl-piperidine hydrochloric acid salt (0.413 g, 2.09 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.50 g, 0.417 mmol), sodium triacetoxyborohydride (0.656 g, 3.10 mmol), and acetic acid (0.172 mL, 3.00 mmol) in 1,2-dichloroethane (20.0 mL) provides, after reverse-phase HPLC, 0.508 g (64%) of the title compound as a white solid: mass spectrum (electrospray): m/z=388.1 (M+1); 1H NMR (DMSO-d6): 8.65 (d, 1H, J=2.2 Hz), 8.29 (dd, 1H, J=2.6, 8.8 Hz), 8.05 (s br, 1H), 7.50 (s br, 1H), 7.39 (d, 2H, J=8.4 Hz), 7.35-7.17 (m, 5H), 7.16-7.06 (m, 3H), 3.55 (s, 2H), 2.91 (d, 2H, J=10.6 Hz), 2.80 (t, 1H, J=11.3 Hz), 2.05 (q, 2H, J=8.4 Hz), 1.86 (d, 1H, J=11.3 Hz), 1.81-1.56 (m, 2H), 1.48 (dq, 1H, J=4.0, 12.1 Hz).