Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[CH:3]=1.[CH2:13](C(CC)(CC)C([O-])([O-])[O-])[CH3:14]>C1(C)C(C)=CC=CC=1>[CH3:13][C:14]1[O:8][C:7]2[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[CH:3][C:2]=2[N:1]=1
Reactant: Cc1cc(N)c(O)cc1[N+](=O)[O-]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: Cc1ccccc1C
Product: Cc1nc2cc(C)c([N+](=O)[O-])cc2o1

Procedure:
To a stirred solution of 2-amino-5-nitro-p-cresol (3.3 g, 0.0146 mol) in xylene (35 ml) was added the triethylorthoacetate (6.4 g, 0.0392 mol) in one portion. The mixture was refluxed for one hour, filtered through a pad of decolorizing carbon and concentrated to dryness under reduced pressure. The residue was triturated with ligroin and 2.7 g (71 percent) of white solid was collected. NMR was consistent for the product.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1>C(#N)C>[O:32]=[S:29]1(=[O:33])[CH2:30][CH2:31][N:26]([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][C@H:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Solvent: CC#N
Product: O=C(CN1CCS(=O)(=O)CC1)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 11.7 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and thiomorpholine 1,1 dioxide (190 mg, 1.405 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (15 mg, 12%), MS (ISP) m/e=455.3 [(M+H)+].
Reaction SMILES: [CH2:1]([N:13]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](OC)([O:30]C)[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>FC(F)(F)C(O)=O>[CH2:1]([N:13]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])=[CH:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Yield: 77.7 %

Procedure:
A solution of 4[N-Dodecyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]amino]-butanoic acid, ethyl ester (315 mg, 0.53 mmol) in trifluoroacetic acid (5 ml) was heated to 70° C. for 2 h, and then concentrated in vacuo. The residue was diluted with ethyl acetate (100 ml), washed with sat. sodium bicarbonate (30 ml), brine (30 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 2:1 to 1.5:1) to afford the title compound (224 mg, 77%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH3:37])=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:34](=[O:35])[O:36][CH3:37])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C)c1ccc(-c2cnc(Oc3ccc(OC)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of Example 11D ((110 mg, 0.337 mmol) and diisopropylethylamine (0.5 mL) in methylene chloride (1 mL) cooled to 0° C. was added methyl chloroformate (67 μL, 0.76 mmol, 2.3 eq.). The mixture was stirred at room temperature overnight. The reaction mixture was purified directly on silica gel eluting with an ethyl acetate/hexane gradient (0-30%) to give the title compound (112 mg, 86%). 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.45 (m, 3 H), 7.27-7.33 (m, 2 H), 7.21-7.26 (m, 2 H), 6.91-7.01 (m, 2 H), 4.73-498 (m, 1 H), 3.83 (s, 3 H), 3.66 (s, 3 H); 1.47 (d, J=6.62 Hz, 3 H) MS (DCI): m/e 385 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:29]([CH3:30])[C:28](=[O:31])[N:27](C(OC(C)(C)C)=O)[C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.[C:39]([N:43]=C(N(C)C)N(C)C)(C)(C)[CH3:40].BrCC#N.[NH4+].[Cl-].C(O)(C(F)(F)F)=O>C1COCC1>[NH2:1][C:2]1[C:3]2[C:29]([CH2:40][C:39]#[N:43])([CH3:30])[C:28](=[O:31])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: CC1C(=O)N(C(=O)OC(C)(C)C)c2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Agent: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(CC#N)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of the intermediate from Step B above (102 mg, 0.182 mmol) stirred in THF (3566 μl) was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (34.2 μl, 0.182 mmol) followed by 2-bromoacetonitrile (19.02 μl, 0.273 mmol). After stirring for 5 minutes at room temperature, saturated aqueous NH4Cl was added. The reaction mixture reaction was then partitioned between EtOAc and water. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The crude material was taken up in DCM (1 mL) and TFA (280 μl, 3.64 mmol) was added. After 3 hours the reaction was quenched with aq. NaHCO3 and partitioned between water and EtOAc. The organic layer was dried, concentrated in vacuo and purified by silica gel column chromatography using a hexanes/EtOAc gradient to afford the product as a white solid. Chiral separation using SFC provided both enantiomers of the title compound. 1H NMR (500 MHz, CHCl3-d): δ 8.45 (d, J=8.72 Hz, 1H); 7.43 (s, 1H); 7.18 (dd, J=8.75, 1.62 Hz, 1H); 5.48 (s, 2H); 4.71 (t, J=7.69 Hz, 2H); 2.99 (d, J=16.98 Hz, 1H); 2.81-2.68 (m, 2H); 2.67 (d, J=16.98 Hz, 1H); 1.68 (s, 3H). m/z=500.0 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:35].CCOCC>>[ClH:35].[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][S:16][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])=[CH:19][CH:20]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(OCc3ccc(F)cc3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(SCc1ccc(OCc2ccc(F)cc2)cc1)N1CCNCC1

Procedure:
A solution of 4.89 g (10.6 mmol) 4-[4-(4-fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carboxylic acid tert-butyl ester in 120.6 ml 1.5M HCl/Et2O and 24.1 ml abs. MeOH was stirred at rt for 6 h. Evaporation of the reaction mixture provided 3.96 g piperazine-1-carbothioic acid S-[4-(4-fluoro-benzyloxy)-benzyl] ester hydrochloride as colourless powder, mp. 169–169.5° C. 1H-NMR(d6-DMSO): 3.05 m, 4H and 3.58–3.75 m, 4H; 4.09 s, 2H; 5.06 s, 2H; 6.94 d, 2H, 7.17–7.30 m, 4H and 7.43–7.55 m, 2H; 9.2 br, 2H. MS (ISP): 361.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][NH:13][NH2:14]>C(O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:10])[N:13]([CH3:12])[NH2:14])=[C:4]([CH3:11])[CH:3]=1
Reactant: CNN
Reactant: Cc1cc(I)ccc1N=C=S
Solvent: CCO
Product: Cc1cc(I)ccc1NC(=S)N(C)N
Yield: 64.2 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 22.3 g (0.0810 mole) of 4-iodo-2-methylphenyl isothiocyanate with 3.74 g (0.0811 mole) of methylhydrazine in 175 ml of ethanol yielded 16.7 g of 4-(4-iodo-2-methylphenyl)-2-methyl-3-thiosemicarbazide as a solid, mp 160°-161° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:24]=[C:23]([NH:25][C:26]3[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([Cl:33])[N:27]=3)[CH:22]=[CH:21][C:11]=2[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[N:6][CH:7]=1.C([O-])(=O)C.[Na+]>C1COCC1.O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:24]=[C:23]([NH:25][C:26]3[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([Cl:33])[N:27]=3)[CH:22]=[CH:21][C:11]=2[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2nc(Cl)ncc2Cl)cc1/C=C/c1cncc(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2nc(Cl)ncc2Cl)cc1CCc1cncc(N)c1
Temperature: 90 °C
Yield: 61.9 %

Procedure:
To a solution of tert-butyl {2-[(E)-2-(5-aminopyridin-3-yl)vinyl]-4-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}carbamate (90.0 mg, 0.185 mmol) in THF (4 mL) was added p-toluenesulfonylhydrazide (0.515 g, 2.76 mmol). The reaction solution was heated to reflux at 90° C., then a solution of sodium acetate (0.363 g, 4.42 mmol) in water (3.7 mL, 20 mmol) was added dropwise over 4 h period. Another portion of p-toluenesulfonylhydrazide (0.343 g, 1.84 mmol) was added to reaction flask, then a solution of sodium acetate (0.242 g, 2.95 mmol) in water was added dropwise overnight under reflux. The reaction solution was diluted with ethyl acetate. Aqueous layer was extracted with ethyl acetate twice. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to yield the desired product (56 mg, 62%). LCMS for C24H29Cl2N6O2 (M+H)+: m/z=503.3, 505.3.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:15])([F:14])[C:8]([OH:13])([CH2:11][CH3:12])[C:9]#[N:10].[OH2:16]>C(OCC)C>[F:6][C:7]([F:15])([F:14])[C:8]([OH:13])([CH2:11][CH3:12])[C:9]([NH2:10])=[O:16]
Reactant: O
Reactant: CCC(O)(C#N)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCC(O)(C(N)=O)C(F)(F)F
Temperature: 115 °C
Reaction time: 0.33 h

Procedure:
Concentrated sulfuric acid (15.3 g) was added, under an argon atmosphere, to a 100 ml flask and the starting compound 3,3,3-trifluoro-2-hydroxy-2-ethylpropiononitrile (Fluorchem) (8 g) was then added dropwise. The reaction mixture was heated at 115° C. for 15 min and then cooled down to 8° C.; distilled water (21.8 g) was then added slowly. Diethyl ether was then added and the whole was stirred for 20 min.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N+]=[N-].[H][H]>CCO.CC(O)=O.[Pd]>[NH2:1][CH2:4][C@H:5]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CN=[N+]=[N-])COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)[C@@H](CN)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-yl(methyl)carbamate (4 g, 11.66 mmol) in EtOH (100 mL) and AcOH (10 mL) was added Pd/C (10%, 1.0 g). The resulting mixture was transferred to an autoclave and charged with hydrogen (45 psi). The reaction mixture was stirred at RT for 1 h and filtered. The filtrate was concentrated to give (S)-tert-butyl 1-amino-3-(benzyloxy)propan-2-yl(methyl)carbamate, which was used without further purification. LRMS (M+Na+) m/z 317.2.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:21]=[CH:20][C:11]3[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=3[CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[O:25]([NH2:27])[CH3:26].CO.[NH4+].[OH-]>O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6](=[N:27][O:25][CH3:26])[C:8]2[CH:21]=[CH:20][C:11]3[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Nc1nc2cc(C(=O)c3ccc(F)cc3)ccc2[nH]1
Reactant: CON
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CON=C(c1ccc(F)cc1)c1ccc2[nH]c(NC(=O)OC)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl [5-(4-fluorobenzoyl)-1H-benzimidazol-2-yl]carbamate (Janssen Pharmaceutica, U.S. Pat. No. 3,657,267, Apr. 18, 1972) (31.61 g, 0.11 mole) and methoxylamine hydrochloride (0.35 mole) were added to abs. methanol. After heating under reflux for 48 hrs a clear solution was obtained. After 72 hrs this mixture was filtered hot through Celite then allowed to cool to room temperature. Removal of solvent under reduced pressure gave a solid residue. This material was suspended in H2O and adjusted to pH 12 with conc NH4OH. After stirring for 10 min the precipitate was isolated by filtration, washed repeatedly with H2O, then dried at 50° C. under reduced pressure to give the title product as a white solid. Yield: 33.08 g (96%). Mp: 290°-295° C., TLC: Rf=0.66,0.77 (CHCl3 --MeOH,10:1,SiO2) syn and anti isomers. IR (KBr): 3350, 2939, 1735 cm-1. 1H NMR (DMSO-d6): δ 3.73-3.75 (D, 3H, CH3); 3.85-3.87 (d, 3H, CH3); 6.95-7.46 (m, 7H, Ar); 11.74 (brd, s, 2 H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[CH:10]([C:38]([OH:40])=O)[CH:11]2[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([CH3:37])[CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][OH:42]>>[OH:42][NH:41][C:38]([CH:10]1[CH:11]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:12]2[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:9]1[CH2:14][CH2:13]2)=[O:40]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3C(C(=O)O)C4CCC3N4C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3C(C(=O)NO)C4CCC3N4C(=O)OC(C)(C)C)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 24, Step 3, 0.15 g (0.26 mmol) of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-7-aza-bicyclo[2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester and hydroxylamine gave tert-butyl 2-[(hydroxyamino)carbonyl]-3-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]-7-azabicyclo[2.2.1]heptane-7-carboxylate as an amorphous off yellow solid (0.0162 g, 14.7%) after Biotage Flash 40S chromatography, eluting with 5% methanol in ethyl acetate. MS: 583 (M+H)+
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].[BH4-].[Na+].Cl>O1CCCC1>[OH:14][C@H:13]([CH3:15])[CH2:12][C:11]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](C)O
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A solution of 2.33 g (15.5 mmol) of L-(+)-tartaric acid in 50 ml of tetrahydrofuran (THF) was cooled in a cryostat at -20° C., and a solution of 0.5 g (3.8 mmol) of ethyl acetoacetate in THF (2 ml) was added. To the resulting solution, there was further added 0.59 g (15.5 mmol) of sodium borohydride, all at one and with stirring, and the mixture was stirred for 13 hours. The reaction mixture was cooled in an ice bath, 25 ml of 1N HCl was added, and stirring was continued for 30 minutes. After distilling off THF under reduced pressure, the aqueous layer was extracted twice with ether (50 ml and 30 ml), and the combined extract was washed first with 30 ml of a saturated aqueous solution of sodium bicarbonate and then with 30 ml of a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure from the dried solution, and the residue was purified by silica gel column chromatography, giving 0.30 g ethyl (R)-(-)3-hydroxybutanoate as a fraction of ethyl acetate:n-hexane (1:5). Its specific rotation [α]D22 was -34.1° (cl. 20, CHCl3). The synthesis yield was 59% and the optical yield was 79% e.e. (see Reference 2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=4)[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Product: O=C(NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1)c1cccnc1

Procedure:
Following a similar procedure to that described in example 245, but starting from 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (obtained in example 90) and nicotinoyl chloride hydrichloride (obtained in section a), the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13]C)=[C:11]2[C:6]([CH:7]=[CH:8][C:9](C(O)=O)=[N:10]2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[OH:13][C:12]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COc1ccc2ccc(C(=O)O)nc2c1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2cccnc2c1O
Yield: 53.1 %

Procedure:
Finely ground 7,8-dimethoxyquinoline-2-carboxylic acid (1.00 g, 4.3 mmol) (W. Ried, A. Berg and G. Schmidt, Chem. Ber., 85, 204 (1952)) was heated under nitrogen in a flask submerged in an oil batch at 185° until the evolution of gases had ceased from the melt. The reaction was cooled and 75% aqueous sulfuric acid (8.1 mL) was carefully added. The resulting solution was heated at 105°-125° for 2 hr, cooled, poured over ice and taken to pH 5 with 5N sodium hydroxide. The mixture was filtered, and the filtrate was extracted with methylene chloride (4×50 mL). The extracts were dried (MgSO4) and concentrated in vacuo to give 8-hydroxy-7-methoxyquinoline (0.40 g, 53%), mp 113°-115° after recrystallization from 95% ethanol. Anal. Calcd for C10H9NO2 : C, 68.56; H, 5.18; N, 8.00. Found: C, 68.33; H, 5.17; N, 7.97.
Reaction SMILES: [NH2:1][S:2]([CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([NH:10][NH2:11])=[O:9])(=[O:4])=[O:3].[OH-].[K+].[C:18](=S)=[S:19]>C(O)C.O>[SH:19][C:18]1[O:9][C:8]([C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[CH2:5][S:2]([NH2:1])(=[O:3])=[O:4])=[N:10][N:11]=1
Reactant: NNC(=O)c1ccccc1CS(N)(=O)=O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)Cc1ccccc1-c1nnc(S)o1
Yield: 22 %

Procedure:
To a suspension of 11.5 g of the hydrazide prepared in Example 1 in 100 ml of absolute ethanol was added a solution of 2.8 g of potassium hydroxide in 20 ml of water. After stirring several minutes, 4.8 g of carbon disulfide was added in one portion. The suspension was refluxed 4.5 hours then concentrated in vacuo. After water (about 100 ml) was added to the residue and the suspension stirred several minutes, the suspension was filtered and the filtrate was acidified with concentrated hydrochloric acid (red to litmus paper). The mixture was filtered and the residue was washed sequentially with 1×25 ml water, 1×10 ml 2-propanol and 1×10 ml ethyl ether. The suction-dried residue was recrystallized from methanol to give 3 g of the subject compound; m.p. 224°-227° C.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3F)CC2)cc1
Solvent: O=CO
Product: O=C(NCc1ccc(F)cc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1

Procedure:
4-[4-(2-aminoethyl)anilino]-N-(2,4-difluorobenzyl)-1-piperidinecarboxamide formate (0.477 g, 1.1 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to give the title compound (0.25 g, 0.032 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[N:30]([CH3:31])[C:29]([CH:32]5OCC[O:33]5)=[CH:28][N:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[N:30]([CH3:31])[C:29]([CH:32]=[O:33])=[CH:28][N:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C2OCCO2)cnc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl
Solvent: CC(C)=O
Product: Cn1c(C=O)cnc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1

Procedure:
(4-Benzyloxy-phenyl)-(6-(4-(1,3-dioxolan-2-yl)-3-methyl-3H-imidazol-2-yl)-quinazolin-4-yl)-amine (0.06 g) was treated with acetone (5 ml) and 2N HCl at reflux for 2 hours. The mixture was cooled, partitioned between ethyl acetate and 2N sodium carbonate. The organic phase was dried and concentrated in vacuo to give the title compound which was used directly in any subsequent synthetic step; m/z (M+1)+ 436.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C.Cl[C:36]1[O:37][C:38]2[C:39](=[C:41]([C:53]#[N:54])[C:42]([CH3:52])=[C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:44]=2[F:45])[N:40]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:45][C:44]1[C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:42]([CH3:52])[C:41]([C:53]#[N:54])=[C:39]2[C:38]=1[O:37][C:36]([C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[N:40]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3nccs3)nc2c1C#N
Temperature: 125 °C
Yield: 29.9 %

Procedure:
2-Tri-n-butylstannylthiazole (392 mg, 1.05 mmol), dichlorobis(triphenylphosphine)palladium(II) (49.0 mg, 0.070 mmol) and 2,6-di-tert-butylcresol (30.7 mg, 0.14 mmol) were added to a toluene (20 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (200 mg, 0.698 mmol), followed by heating under reflux in an oil bath at 125° C. for 5 hours in an argon atmosphere. The solvent was evaporated away under reduced pressure, then the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=9:1→2:1) to obtain the entitled compound (70.0 mg, 29.9%) as a pale yellow solid.