Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][S:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1.S(OC)(O[CH3:29])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]([CH3:29])[S:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NS(=O)(=O)/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)/C=C/c1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a suspension of sodium hydride (60%, 0.13 g (3.25 mmol)) in DMF (7.0 ml), 4-chloro-2-nitro-N-[(trans)-β-styrenesulfonyl]aniline (1.00 g (2,95 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.32 ml (3.38 mmol)) was added. The resulting mixture was stirred at 80° C. for 3 hours, and then poured into water, extracted with diethyl ether. The extract was washed with 1% sodium hydroxide solution, water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Small amount of diethyl ether was added to the residue and crystals separated was filtered and washed to give 0.99 g (95%) of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[N:24]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:11]3[N:10]=2)=[O:7])=[CH:4][N:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C(N(CC)C(C)C)(C)C>C(O)CCC>[CH:18]1([NH:17][C:16]2[N:11]3[N:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:25]=[CH:26][C:2]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])=[N:3][CH:4]=4)[N:24]=[C:12]3[CH:13]=[CH:14][CH:15]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCCCO
Reactant: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(Cl)nc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(NCCCO)nc1
Yield: 30.2 %

Procedure:
To a biotage initiator microwave vial (0.2-0.5 mL) containing 6-chloro-N-(5-cyclohexylamino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-nicotinamide ((B11), 0.27 mmol, 100 mg, 1 eq.), 3-aminopropan-1-ol (0.54 mmol, 0.028 mL, 2 eq.) and N,N-diisopropylethylamine (0.54 mmol, 0.094 mL, 2 eq.) in butanol (2 mL), was capped and heated in a biotage initiator 60 microwave for 30 minutes at 180° C., and a further 10 minutes at 210° C. The solvent was removed in vacuo and the residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (33.4 mg, 30%). HPLC, Rt: 2.37 min (purity: 92%). LC/MS M+(ESI): 410.2, M−(ESI) 408.2.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27].[NH2:31][OH:32]>CS(C)=O>[OH:32][N:31]=[C:26]([C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:20](=[CH:21][C:11]3=4)[CH2:19][CH2:18][O:17]5)[C:2]2=[O:1])[CH:24]=1)[NH2:27]
Reactant: NO
Reactant: N#Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: CS(C)=O
Product: NC(=NO)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a solution of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (1.15 g, 2.92 mmol) in dimethyl sulfoxide (20 mL) was added hydroxylamine (50% wt in H2O, 2 mL, 32.67 mmol). The reaction was stirred at 80° C. for 3 h, cooled to ambient temperature. The precipitate was collected by filtration and washed with water and diethyl ether and dried in vacuo to afford N′-hydroxy-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H) yl)methyl]benzenecarboximidamide (0.85 g, 68%): 1H NMR (300 MHz, CDCl3) δ7.61 (m, 1H), 7.96 (m, 1H), 7.51 (m, 1H), 7.38 (m, 2H), 7.16 (m, 2H), 7.01 (m, 1H), 6.75 (m, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 5.09 (d, 1H, J=15.7 Hz), 4.98 (d, 1H, J=9.0 Hz), 4.83 (m, 3H), 4.70 (d, 1H, J=9.0 Hz), 4.49 (t, 2H, J=8.6 Hz), 2.96 (m, 2H); MS (ES+) m/z 427.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=c1cc(C(F)(F)F)cc(-c2ccc(Cl)cc2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Cl)nc(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-4-trifluoromethyl-1H-pyridin-2-one (10.0 g, 37 mmol) and phosphoryl chloride (16.75 mL, 183 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as a light brown solid (10.14 g, 95%). MS (ISP) 292.1 [(M+H)+], 294 [(M+2+H)+] and 296 [(M+4+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[NH2:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(N)cc1OCc1ccccc1

Procedure:
3-Hydroxy-4-methoxy-1-nitrobenzene was benzylated by refluxing with benzyl bromide with potassium carbonate as a base in acetone which on reduction with sodium dithionite gave 3-benzyloxy-4-methoxy aniline. 4-Hydroxy-3-methoxy benzoic acid was converted to its methyl ester by refluxing in methanol in presence of an acid. The hydroxyl was benzylated using benzyl bromide and potassium carbonate. The ester was hydrolyzed with sodium hydroxide to provide the acid. The aniline and acid were coupled using N,N-1,3-diisopropylcarbodiimide in presence of 1-hydroxybenzotriazole to provide the amide. Finally the benzyl group was removed by hydrogenation in presence of palladium on carbon.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:27])([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH2:9][CH2:10][C:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)([CH3:27])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1C)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1ccc2c(c1C)OC(C)(COc1ccc(N)cc1)CC2
Yield: 91.3 %

Procedure:
Following a procedure similar to that described in Preparation 4, 1.6 g of 7-acetoxy-2,8-dimethyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 39) was hydrogenated, using 0.2 g of 10% w/w palladium-on-carbon and 15 ml of methanol, to afford 1.35 g of the title compound as a pale brown oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8](O)([OH:13])[C:9]([F:12])([F:11])[F:10]>>[F:10][C:9]([F:12])([F:11])[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[OH:13]
Reactant: Oc1ccccc1
Reactant: OC(O)C(F)(F)F
Product: Oc1ccccc1C(O)C(F)(F)F
Temperature: 50 °C

Procedure:
9.3 g (100 mmol) of phenol and 3.9 g (25 mmol) of 75% fluoral hydrate are introduced into a 100 ml reactor. 5.0 g of a catalyst are added and the mixture is heated at 50° C. for 5 hours. The nature of the catalyst employed and the yields of monocondensed products obtained, with their ortho/para ratio, are reported in Table I below.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:46]3[O:45][C:44]([NH2:47])=[N:43][C:42]=3[C:41]([O:48][CH3:49])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[C:46]3[O:45][C:44]([NH:47][C:4](=[O:6])[CH2:3][O:2][CH3:1])=[N:43][C:42]=3[C:41]([O:48][CH3:49])=[CH:40][CH:39]=2)=[CH:36][CH:37]=1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COCC(=O)Nc1nc2c(OC)ccc(-c3ccc(F)cc3)c2o1

Procedure:
From methoxyacetic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:25][CH3:26])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)=O.[NH2:33][OH:34]>C(O)C>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4](=[N:33][OH:34])[C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:25][CH3:26])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1
Reactant: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)c3ccccc3F)cc2)cc1)C(=O)O
Reactant: NO
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=NO)c3ccccc3F)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionic acid from Example 10, (0.01 mmol, 1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with ethyl acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C26H22FNO5 [M+H]+: 448.2, [M−H]−: 446.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][C:15]([NH2:17])=[NH:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[O:19][C:20](=O)/[C:21](/[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[C:22](\O)/[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(OC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C)(C)C>>[C:26]([O:25][C:23]([C:22]1[C:21]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:20]([OH:19])[N:17]=[C:15]([CH2:14][C:9]2([C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:16]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: N=C(N)CC1(c2ccc(Cl)cc2)CCCC1
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 55.1 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (27-02) (12 g, 55%) was synthesized from [1-(4-chlorophenyl)-cyclopentyl]-acetonitrile (26-02) (12 g, 44.03 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (23.49 g, 76.27 mmol) as a yellow solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-01).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].O.[CH3:14][N:15]=[C:16]=[O:17].[Cl-].[Na+]>C(O)(=O)C>[CH3:14][NH:15][C:16]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:17]
Reactant: CN=C=O
Reactant: NC(C(=O)O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)NC(C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.1 mole of α-amino-4-hydroxybenzeneacetic acid dissolved in 500 ml of water containing 0.05 mole of acetic acid is added 0.11 mole of methyl isocyanate. This mixture is stirred for 30 minutes at room temperature. The reaction mixture is saturated with sodium chloride and then extracted with ethyl acetate. The ethyl acetate is washed with water, dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [C:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:3][CH:2]=1.ClC(OC)=O.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].Cl>CCOCC.O.C(N(CC)CC)C>[CH2:18]([N:20]([CH2:21][CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]1[CH2:3][CH:2]=1)[CH3:19]
Reactant: CCNCC
Reactant: O=C(O)CCCCCCC1=CC1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)C(=O)CCCCCCC1=CC1
Reaction time: 1.5 h

Procedure:
A solution of 7-cycloprop-1-enyl-heptanoic acid (0.25 g, 1.5 mmol) in 10 ml of ether was cooled in an ice bath and treated with 0.3 mL of triethyl amine. Methyl chloroformate (0.16 g, 17 mmol) was added, and the reaction was stirred for 1.5 hours. Excess diethylamine was added while the reaction was still cooled in an ice bath, and the reaction was stirred for one half hour. Additional ether and water were added, and the aqueous phase was acidified to pH 1 with aqueous HCl. The phases were separated, and the organic phase was washed with water, 1N sodium hydroxide, water and brine. The organic phase was dried over magnesium sulfate, filtered and stripped. Column chromatography gave 70 mg of colorless liquid 7-cycloprop-1-enyl-heptanoic acid diethylamide (Compound 48) in 74% purity.
Reaction SMILES: [Cl-].[CH3:2]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].C(C1C=CC([C@H]2CC[C@H](CCCC=O)CC2)=CC=1)#N.[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C@H:57]2[CH2:62][CH2:61][C@H:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH:67]=[O:68])[CH2:59][CH2:58]2)=[CH:53][CH:52]=1)#[N:50]>O1CCCC1.O.C1(C)C=CC=CC=1>[CH3:2][O:68][CH:67]=[CH:66][CH2:65][CH2:64][CH2:63][C@H:60]1[CH2:61][CH2:62][C@H:57]([C:54]2[CH:55]=[CH:56][C:51]([C:49]#[N:50])=[CH:52][CH:53]=2)[CH2:58][CH2:59]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CCCCC=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: N#Cc1ccc([C@H]2CC[C@H](CCCC=O)CC2)cc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC=CCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
Commercially available methoxymethyltriphenylphosphonium chloride (120.8 g, 0.35 mol) was added to tetrahydrofuran (400 ml), followed by adding potassium t-butoxide (39.5 g, 0.35 mol) in argon atmosphere with stirring at -10° C. over 20 minutes, agitating the reaction mixture at 0° C. for one hour, dropwise adding a solution of 4-[trans-4-(4-cyanophenyl)cyclohexyl]-1-butanal (60.0 g, 0.23 mol) obtained according to the method of Example 4 (i), in tetrahydrofuran (300 ml) at -10° C. over one hour, agitating the reaction mixture at 0° C. for one hour, further agitating at 20° C. for 2 hours, adding toluene (1 l) and water (1 l) to the reaction mixture at 0° C., 4 times washing the resulting toluene solution with water (1 l), drying over anhydrous magnesium sulfate, separating the drying agent, distilling off toluene, purifying the residue according to silica gel column chromatography using heptane as an eluent to obtain trans-1-(5-methoxy-4-pentenyl)-4-(4-cyanophenyl)cyclohexane (52.6 g, 0.19 mol), adding to the total quantity of this compound, tetrahydrofuran (750 ml) and 2N-hydrochloric acid (190 ml), heating the mixture under reflux with stirring for one hour, cooling the resulting solution, adding diethyl ether (0.5 l) and water (1 l) to the reaction mixture, three times washing the resulting diethyl ether solution with water (0.5 l), drying over anhydrous magnesium sulfate, separating the drying agent, concentrating under reduced pressure, recrystallizing the resulting residue (50 g) from a mixed solvent of heptane and ethyl acetate (3:1), and drying to obtain 5-[trans-4-(4-cyanophenyl)cyclohexyl]-1-pentanal (43.1 g, 0.16 mol).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1.[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](Br)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Br:29][C:30]1[CH:31]=[C:32]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:15]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2cccc(-c3cccc4c3sc3ccccc34)c2)OC1(C)C
Reactant: Brc1cccc(Br)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Yield: 79.3 %

Procedure:
2-(3-(dibenzo[b,d]thiophen-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.80 g, 22.78 mmol) and 1,3-dibromobenzene (21.49 g, 91 mmol) were dissolved in toluene (300 mL), and potassium carbonate (9.44 g, 68.3 mmol) in 50 mL of water and the Pd(PPh3)4 catalyst (0.263 g, 0.228 mmol) were then added. The reaction mixture was degassed and refluxed under N2 overnight. The organic layer was then separated, evaporated and subjected to column chromatography on silica gel, eluted with hexane/DCM 9:1 v/v mixture, providing 4-(3′-bromo-[1,1′-biphenyl]-3-yl)dibenzo[b,d]thiophene (7.5 g, 18.06 mmol, 79% yield) as white solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:22])[C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:5])([CH3:4])[CH3:3].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCO.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl>[C:2]([O:6][C:7](=[O:22])[C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])([CH3:5])([CH3:3])[CH3:4]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 53.7 %

Procedure:
Nα-BOC-L-lysine t-butyl ester hydrochloride salt (23) (25.97 g, 76.64 mmol) was dissolved in CHCl3 (300 ml) and washed with saturated aqueous Na2CO3 solution (2×100 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resultant oil (the free amine) was combined with benzaldehyde (10.42 g, 98.13 mmol), EtOH (150 ml) and activated 3 Å molecular sieves (46.0 g). The mixture was stirred under N2 for 6 hours. Sodium cyanoborohydride (2.41 g, 3 8.4 mmol) was added and the mixture was stirred overnight at room temperature. The brown mixture was filtered and the filtrate acidified to pH, 2 with 1 N HCl (110 ml). The yellow solution was concentrated to dryness, dissolved in CHCl3, washed with saturated Na2CO3 solution and water. The organic layer was separated, dried (MgSO4) and concentrated. Flash column chromatography (10% EtOH/CHCl3, Rf=0.30) afforded the Nε-benzyl-Nα-BOC-L-lysine t-butyl ester (24) (16.16 g, 54%) as a colorless oil. 1H NMR (CD3OD) δ 7.34-7.20 (m, 5H), 3.91 (dd, 1H, J=9.0, 5.1 Hz), 3.72 (s, 2H), 2.58 (t, 2H, J=7.2 Hz), 1.82-1.30 (m, 6H), 1.45 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 171.9, 155.3, 140.1, 128.3, 128.1, 126.9, 81.6, 79.5, 53.9, 48.9, 32.7, 29.5, 28.3, 27.9, 22.9. HRMS m/z calcd. for C22H36N2O4 392.2675, found 392.2676. Anal. calcd. for C22H35N2O4: C67.32, H, 9.24, N, 7.14. Found: C67.40, H, 9.28, N, 7.16. [α]25D+6.9° (c=1.00, CDCl3).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[C:6]([F:18])[CH:5]=1)[CH3:3].Cl[C:20]1[N:25]=[C:24]([N:26]2[C@@H:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][O:28][C:27]2=[O:34])[C:23]([F:35])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:35][C:23]1[C:24]([N:26]2[C@@H:30]([CH:31]([CH3:32])[CH3:33])[CH2:29][O:28][C:27]2=[O:34])=[N:25][C:20]([NH:1][C@H:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:11])=[C:6]([F:18])[CH:5]=2)[CH3:3])=[N:21][CH:22]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1nc(Cl)ncc1F
Reactant: C[C@H](N)c1ccc(C(=O)N2CCCCC2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)[C@H]1COC(=O)N1c1nc(N[C@@H](C)c2ccc(C(=O)N3CCCCC3)c(F)c2)ncc1F
Temperature: 107.5 °C
Yield: 12.5 %

Procedure:
To (S)-(4-(1-aminoethyl)-2-fluorophenyl)(piperidin-1-yl)methanone (0.019 g, 0.076 mmol) was added (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (0.030 g, 0.114 mmol), NMP (0.5 ml) and Hunig's Base (0.033 ml, 0.190 mmol). The reaction was heated at 105-110° C. for 8 hours or until done by LCMS. The reaction was let cool, 0.5 ml of NMP added, filtered, purified by prep LC and lyophilized to give 4.5 mg of (S)-3-(5-fluoro-2-((S)-1-(3-fluoro-4-(piperidine-1-carbonyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one as TFA Salt. LCMS m/z 474.2 (M+H)+, Rt 0.91 min.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([O:18]CC)=[O:17])=[N:15][N:6]3[C:5](=[O:21])[C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:6]3[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2n(C)c3ccc(F)cc3c(=O)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c2ccc(F)cc2c(=O)n2nc(C(=O)O)cc12

Procedure:
From 3.5 g of 7-fluoro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid, ethyl ester, 50 ml of 1 N aqueous sodium hydroxide and 175 ml of methanol, following the procedure of Example 14, there is obtained 7fluoro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid; mp 295° C., after crystallization from dimethylformamide/methanol.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH:6]([C:9]1[O:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N+:11]([O-])[C:10]=1[CH3:23])([CH3:8])[CH3:7].COC(C)(C)C.[OH-].[Na+]>ClCCl.O>[Cl:5][CH2:23][C:10]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[O:13][C:9]=1[CH:6]([CH3:8])[CH3:7]
Reactant: COc1cccc(-c2oc(C(C)C)c(C)[n+]2[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: COC(C)(C)C
Product: COc1cccc(-c2nc(CCl)c(C(C)C)o2)c1
Temperature: 42.5 °C

Procedure:
75 g (648 mmol) of methanesulfonyl chloride were added at a temperature of 20° C. to a solution of 135 g (435 mmol) of 5-isopropyl-2-(3-methoxyphenyl)-4-methyloxazole 3-oxide in 500 ml of dichloromethane. The reaction was stirred at 40-45° C. up to full conversion. 500 ml of tert-butyl methyl ether and 300 ml of water were added. Addition of 20% sodium hydroxide solution established a pH of 8. After phase separation, the organic phase was washed with 3×200 ml of water. The organic phase was concentrated fully under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=2[C:17](OC)=[O:18])([CH3:4])([CH3:3])[CH3:2].ClCCl.CC(C[AlH]CC(C)C)C>O>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=2[CH2:17][OH:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2cc(C(C)(C)C)[nH]c12
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(CO)c2[nH]1
Yield: 72.2 %

Procedure:
To a solution of methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (6.15 g, 22.3 mmol) and dichloromethane (30 ml) was added DIBAL-H (1.0 M, 20 mL, 20 mmol) at 78° C. The mixture was stirred for 1 h before water (10 mL) was added slowly. The resulting mixture was extracted with EtOAc (120 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give (2-tert-butyl-5-nitro-1H-indol-7-yl)methanol (4.0 g, 73%), which was used in the next step directly.