Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:26]([Br:27])=[CH:25][C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH2:23][CH3:24])=[O:22])[CH:16]=3)=[N:10][CH2:11][C:12](=S)[NH:13][C:7]=2[CH:6]=1)[CH2:2][CH3:3].[C:28]1([CH2:34][C:35]([NH:37][NH2:38])=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[CH2:1]([O:4][C:5]1[C:26]([Br:27])=[CH:25][C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH2:23][CH3:24])=[O:22])[CH:16]=3)=[N:10][CH2:11][C:12]3[N:13]([C:35]([CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:37][N:38]=3)[C:7]=2[CH:6]=1)[CH2:2][CH3:3]
Reactant: NNC(=O)Cc1ccccc1
Reactant: CCCOc1cc2c(cc1Br)C(c1cccc(S(=O)CC)c1)=NCC(=S)N2
Solvent: CCO
Product: CCCOc1cc2c(cc1Br)C(c1cccc(S(=O)CC)c1)=NCc1nnc(Cc3ccccc3)n1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 8-propoxy-7-bromo-1,3-dihydro-5-[m-(ethylsulfinyl)phenyl]-2H-1,4-benzodiazepine-2-thione is heated in ethanol with phenylacetic acid hydrazide and the resulting product heated to 250° C. to give 9-propoxy-8-bromo-1-benzyl-6-[ m-(ethylsulfinyl)phenyl]-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([CH:14]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1/[CH:28]=[CH:29]/[C:30]([OH:32])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:39][C:40]1([CH3:47])[CH2:45][CH:44]([NH2:46])[CH2:43][CH2:42][O:41]1.C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([CH:14]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1/[CH:28]=[CH:29]/[C:30]([NH:46][CH:44]1[CH2:43][CH2:42][O:41][C:40]([CH3:47])([CH3:39])[CH2:45]1)=[O:32])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n(C(c3ccccc3)c3ccc(F)cc3)c2n1
Reactant: CC1(C)CC(N)CCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)NC3CCOC(C)(C)C3)n(C(c3ccccc3)c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-1-[(4-fluorophenyl)(phenyl)methyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (1.00 g, 2.35 mmol) in THF (10 ml) were added DMF (0.10 ml) and oxalylchloride (0.246 ml, 2.82 mmol), which was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 2,2-dimethyltetrahydro-2H-pyran-4-ylamine (455 mg, 3.53 mmol), triethylamine (1.09 ml, 7.81 mmol) and THF (10 ml), the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to yield the objective product as a solid material.
Reaction SMILES: [CH3:1][C:2]([OH:26])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][N:5](CC1C=CC=CC=1)CC1C=CC=CC=1>C(O)C.[Pd]>[NH2:5][CH2:4][CH2:3][C:2]([CH3:1])([OH:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC(C)(O)CCN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(O)CCN
Reaction time: 72 h
Yield: 54.3 %

Procedure:
A solution of 3-methyl-1-(N,N-dibenzylamino)-nonan-3-ol (71 g) in ethanol (200 ml) was added to a slurry of 10% Pd/C (8 g) in ethanol. The mixture was hydrogenated at 70° and 200 psi for 3 days. The mixture was filtered through kieselguhr and evaporated. The oily product was fractionally distilled to give 1-amino-3-methyl-nonan-3-ol as a colourless liquid (18.9 g, 55% yield), b.p. 104°-106°/0.2 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH3:13])[C:9](N)=[O:10])=[CH:4][CH:3]=1.NC1C=CC(CCC[C:24](O)=[O:25])=CC=1.[S:27](=[O:31])(=[O:30])([OH:29])[OH:28]>CO>[S:27]([OH:31])([OH:30])(=[O:29])=[O:28].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH3:13])[C:9]([O:25][CH3:24])=[O:10])=[CH:4][CH:3]=1
Reactant: CCC(C(N)=O)c1ccc(N)cc1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC(C(=O)OC)c1ccc(N)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
The 4-aminophenylbutyramide used in this example was obtained according to patent literature WO 02/08247 A2 or WO 03/051909 A2. Procedure was as follow: Methanol (100 ml) was charged to 4-(4-Aminophenyl)-butyric acid (from Aldrich) CAS[15118-60-2] (FW=179.22, 1 eq, 15 g, 83.7 mmol). Sulphuric acid FW=98.08 (4 eq, 334.8 mmol, 33 g) was added maintaining the temperature below 20° C. The mixture was then refluxed for one hour and concentrated by distillation at atmospheric pressure until half of methanol will be removed. The reaction mixture was then cooled to 50° C. and t-butyl-methyl ether was added maintaining the temperature above 45° C. The mixture was then gradually cooled to 0-5° C. and held at this temperature for 1 hour. The resultant crystalline product was isolated by filtration and washed by cold mixture of methanol and t-butyl-methyl ether (4:10) and cold ether and then dried under vacuum and then dried under vacuum to give methyl 4-aminophenylbutyrate hydrogensulfate as a white crystal (20.0 g, 84%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[CH:31][C:30]=1[C:37](=[O:41])[C:38]#[C:39][CH3:40].CCN(C(C)C)C(C)C>CO>[CH3:40]/[C:39](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:38]/[C:37](=[O:41])[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[C:34]([F:35])[C:29]=1[F:28]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC#CC(=O)c1ccc(F)c(F)c1F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C/C(=C/C(=O)c1ccc(F)c(F)c1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Yield: 58.6 %

Procedure:
A mixture of 680 mg (1.85 mmol) of Intermediate 45, 367 mg (1.85 mmol) of Intermediate 36, and 0.67 mL (3.7 mmol) of DIEA in 15 mL of MeOH was refluxed overnight (14 h). The solvent was evaporated under reduced pressure and the residue purified directly by silica gel chromatography. Elution with 5%-20% MeOH in CH2Cl2 gave 612 mg (58% yield) of the title compound as a solid: TLC (DCM/MeOH, 4/1): Rf=0.50; 1H NMR (DMSO-d6, 300 MHz) δ11.35 (d, 1H, J=9.0), 7.87 (m, 2H), 7.48 (m, 4H), 7.3 (q, 1H, J=5.4), 7.10 (d, 2H, J=8.7), 6.78 (d, 2H, J=8.7), 5.25 (s, 1H), 4.18 (m, 3H), 3.19 (m, 2H), 2.86 (t, 2H, J=6.3), 2.74 (dd, 1H, J=13.8, 9.0), 2.32 (s, 3H), 1.64 (s, 3H); low resolution MS (ES+)m/e 564.9 (MH+);
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:6]([F:18])[CH2:5]1)=[N+]=[N-]>CO.[Pd]>[Si:11]([O:10][CH:7]1[CH2:8][CH2:9][CH:4]([NH2:1])[CH2:5][CH:6]1[F:18])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(N=[N+]=[N-])CC1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCC(N)CC1F
Reaction time: 8 h

Procedure:
To a stirred solution [(4-azido-2-fluorocyclohexyl)oxy](tert-butyl)dimethylsilane (1.0 g, 3.66 mmol) in MeOH (15 mL) was added Pd/C in MeOH. The flask was evacuated and filled with hydrogen several times, and left to stir overnight under hydrogen atmosphere. The mixture was diluted with DCM, filtered through a pad of Celite, and concentrated to afford the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>CO.[Pd]>[F:13][C:8]1[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Fc1ncccc1C1=CCOCC1
Agent: [Pd]
Solvent: CO
Product: Fc1ncccc1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-pyridine (260 mg, 1.45 mmol) in MeOH (20 mL) was added Pd/C (0.1 g), bubbled with H2 and stirred at RT overnight. The reaction mixture was filtered and the filtrate was concentrated to give 2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine (250 mg, 1.38 mmol, 95.3% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:18]2[C:19]([CH3:27])=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)[S:12][C:13]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:18]2[C:19]([CH3:27])=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)[S:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn2ccccc2c1-c1nc(-c2ccc(F)cc2F)c(C(=O)O)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a suspension of methyl 4-(2,4-difluorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (250 mg, 0.649 mmol) obtained above in THF (5 mL) and MeOH (5 mL), was added 2N aqueous solution of sodium hydroxide (1 mL) and the mixture was stirred for 2 h at 60° C. To the mixture, was added a 2:1 mixture of EtOAc and THF (60 mL) and 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with a 2:1 mixture of EtOAc and THF (10 mL). The combined organic layers were washed with brine (5 mL) and then dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain title compound (225 mg, 93%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH:10]([OH:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCC(O)c1ccc(OC)nc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(6-methoxy-2-methyl-pyridin-3-yl)-propan-1-ol (1.15 g, 6.35 mmol) in DCM (20 ml) is treated with Dess-Martin periodinane (2.96 g, 6.98 mmol) and the resulting suspension stirred at RT overnight. The reaction mixture is diluted with DCM (80 ml) and sat NaHCO3 (50 ml) added. The organic layer is separated and washed with H2O (20 ml), brine (20 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue is purified by chromatography on silica gel (2×70 ml) using 50% EtOAc/iso-hexane to give 1-(6-methoxy-2-methyl-pyridin-3-yl)-propan-1-one as a white solid. MS: m/z 180.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:7]([NH2:20])=[CH:8][CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)[CH:11]=1.S([O-])([O-])=O.[Na+].[Na+].[C:36](=[O:39])(O)[O-:37].[Na+]>C(O)C.O>[F:1][C:2]1[CH:24]=[C:23]([O:25][C:26]([F:27])([F:29])[F:28])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:6]2[CH:11]=[C:10]([O:12][CH2:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)[CH:9]=[CH:8][C:7]=2[N:20]=[C:4]1[C@H:3]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:2]1[C:36]([OH:37])=[O:39]
Reactant: Cn1ccc(COc2ccc(N)c(NCc3ccc(OC(F)(F)F)cc3F)c2)n1
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(OC(F)(F)F)cc4F)c3c2)n1
Temperature: 25 °C
Reaction time: 65 h
Yield: 60.2 %

Procedure:
To a solution of N1-(2-fluoro-4-(trifluoromethoxy)benzyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)benzene-1,2-diamine (74.5 g, 0.18 mol) in ethanol (750 mL) was added a solution of racemic cis-3-hydroxyhexahydroisobenzofuran-1(3H)-one (28.4 g, 0.18 mol) and sodium sulfite (46.7 g, 0.36 mol) in H2O (750 mL). The reaction mixture was left open to air and stirred vigorously at RT. After 65 h, saturated sodium bicarbonate (600 mL) was added and the organic solvents were concentrated to dryness. The resulting suspension was partitioned between TBME (1.5 L) and H2O (1.5 L). The aqueous layer was partitioned between EtOAc (1.5 L) and HCl was added (160 mL, 6 M). The organic layer was separated and the aqueous was further extracted with ethyl acetate (500 mL). The combined organic layers were dried with MgSO4, filtered and concentrated to dryness. The resulting residue was dissolved in ethanol (450 mL) and H2O (100 mL), seeded (500 mg, 0.9 mmol) and stirred at room temperature for 1 h. H2O (300 mL) was then added portion wise over 30 min. The precipitate was filtered, rinsed with H2O/ethanol (2:1, 2×120 mL) and hexanes (2×200 mL) yielding the title compound as a light pink solid (59.8 g, 60.2%). The racemic material was separated into its constituent enantiomers through chiral stationary phase chromatography (stationary phase 600 g of Chiralpak IC, diameter: 110 mm, detector: Knauer superpreparative cell (0.5 mm), temperature: 35° Celsius, eluent: 0-20 min 40% heptane, 40% ethanol, 20% DCM (500 ml/min) (there was 0.10 v/v % acetic acid added to the eluents) to provide the title compound. MS (ESI): mass calcd. for C27H26F4N4O4, 546.2; m/z found, 547.0 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 7.63-7.59 (d, J=8.9, 1H), 7.34-7.30 (d, J=2.2, 1H), 7.11-7.06 (m, 1H), 7.06-7.02 (dd, J=8.9, 2.3, 1H), 6.95-6.90 (d, J=8.6, 1H), 6.88-6.84 (d, J=2.3, 1H), 6.81-6.74 (m, 1H), 6.31-6.28 (d, J=2.2, 1H), 5.38-5.28 (s, 2H), 5.09-5.04 (s, 2H), 3.89-3.84 (s, 3H), 3.24-3.14 (d, J=11.5, 1H), 3.08-3.02 (d, J=3.0, 1H), 2.65-2.51 (m, 1H), 1.90-1.78 (m, 2H), 1.78-1.70 (m, 1H), 1.69-1.58 (d, J=14.2, 2H), 1.56-1.39 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.9 %

Procedure:
Into a 250 mL round bottomed flask were added 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (8.00 g, 40.6 mmol) and 120 mL dry THF. The solution was cooled in an ice bath at 0° C. and NaH (2.40 g, 60.0 mmol) was added in three portions. After 20 min, p-toluene-sulfonyl chloride (8.70 g, 45.63 mmol) was added, and the reaction mixture was allowed to warm to rt over 30 min. The reaction mixture was concentrated and hexanes was added to obtain a precipitate, which was collected and washed with ice cold 2M NaOH. The crude product was recrystallized from EtOAc/hexanes to afford 17.8 g (92%) of the title compound as a light tan powder. 1H-NMR (500 MHz, d6-DMSO) δ 8.49 (d, J=2.5 Hz, 1H), 8.21 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 2.32 (s, 3H); MS: m/z 476.8/478.8 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23](Cl)=[N:22][C:21]=12.[Cl-].[NH4+]>CN(C=O)C>[Br:16][C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([N:9]3[C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:12][O:11][C:10]3=[O:13])=[N:22][C:21]=12
Reactant: O=C1N[C@@H](c2cccc(Cl)c2)CO1
Reactant: Clc1ccn2ncc(Br)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1OC[C@H](c2cccc(Cl)c2)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To (S)-4-(3-chlorophenyl)oxazolidin-2-one (278 mg, 1.41 mmol) in DMF (10 mL) was added sodium hydride (56.8 mg, 1.42 mmol) and the reaction was stirred at ambient temperature for 1 hour. 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (300 mg, 1.29 mmol) was added at once and the reaction was stirred at ambient temperature for 18 hours. Ice was added followed by ammonium chloride (aqueous), and the resulting suspension filtered and washed with water. After drying, (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(3-chlorophenyl)oxazolidin-2-one (231 mg, 45.5% yield) was isolated as a pale yellow solid.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16](O)(=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O>[C:1]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCO
Solvent: O
Product: CCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCC
Reaction time: 24 h

Procedure:
329 g of myristyl alcohol and 351 g of myristic acid were heated to 60° C. in a 1 L initial charge vessel and mixed by means of a magnetic stirrer. 2.72 g of Novozym 435 were added and the water of reaction formed was removed by applying a vacuum of 5 mbar, and the water was distilled off. The course of the reaction was monitored for ˜24 h by means of acid number titration (cf. Table 1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[NH:9][CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:31][CH2:32]Cl)[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:32][O:31][CH2:29][CH3:30])[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2
Reactant: CCOCCl
Reactant: CCOC(=O)c1c[nH]c2nc3cc(Cl)c(F)cc3cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1cc(C(=O)OCC)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Temperature: 15 °C
Reaction time: 5 h

Procedure:
A suspension of 6 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 5.16 g of potassium carbonate in 120 cm3 of dimethylformamide is heated at a temperature close to 110° C. for 1 hour. After cooling to about 15° C., 5.44 cm3 of chloromethyl ethyl ether are added and the mixture is stirred for 5 hours at between 15° and 20° C. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at about 60° C. The residue is taken up in 3 times 150 cm3 of trichloromethane. The combined organic extracts are filtered in order to remove the insoluble matter. The filtrate is dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at about 40° C. The residue is recrystallized from 55 cm3 of dimethylformamide. 5.6 g of 8-chloro-3 -ethoxycarbonyl-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a beige solid melting at 261° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:32]([BH3-])#N.[Na+]>CO.ClC(Cl)C>[CH3:32][N:16]([CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccc(Oc3ccccc3)cc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 17 h

Procedure:
A solution of 1,1-dimethylethyl 4-((2-(4-phenoxyphenyl)ethyl)amino)-1-piperidinecarboxylate (about 9.4 mmol) in a mixture of methanol and dichloroethane (30 mL) was treated with a formaldehyde (37% solution in water). After the addition of sodium cyanoborohydride (710 mg, 11.26 mmol), the reaction was stirred for 17 hours. The reaction was concentrated. Purification on silica gel using a gradient of ethyl acetate in hexane gave 1,1-dimethylethyl 4-(methyl(2-(4-phenoxyphenyl)ethyl)amino)-1-piperidinecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1S[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[F:19][C:20]1C=C(O)C=C(F)[C:21]=1B(O)O.BrC1N=C(C(OC)=O)C=CC=1F>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:21][C:20]=1[F:19]
Reactant: OB(O)c1c(F)cc(O)cc1F
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Agent: COC(=O)c1ccc(F)c(Br)n1
Product: O=C(O)c1ccc(F)c(-c2c(F)cc(O)cc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2,6-difluoro-4-hydroxyphenyl)boronic acid and replacing methyl 2-bromothiazole-4-carboxylate with methyl 6-bromo-5-fluoropicolinate (see US2012/225062) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])=[O:16]
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1ccc(Cl)s1

Procedure:
N-[(tert-Butoxy)carbonyl]-5-chlorothiophene-2-sulfonamido 2,2-dimethylpropanoate (74) is synthesised from 5-chlorothiophene sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. (1.89 g, 100%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.65 (1H, d, 4.1 Hz), 6.99 (1H, d, 4.1 Hz), 1.48 (9H, s), 1.35 (9H, s).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.[OH-].[Na+].[BH4-].[Na+].O>C(O)(=O)C>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(O)c1ccccc1CO2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 5.0 g. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in 16 ml. of 5% sodium hydroxide is added dropwise to a cold solution of 1.36 g. of sodium borohydride in 40 ml. of water. The reaction mixture is stirred at 0° C. for 4 hours, poured onto ice, and acidified with glacial acetic acid. The precipitate is filtered and washed with water to provide colorless crystals, m.p. 132°-133.5° C. of 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](OC(C)=O)=[O:17]>CC(O)=O.[Fe]>[NH:12]([C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][CH:8]=1)[C:16]([CH3:15])=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccc2c(Cl)cccc12
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c(Cl)cccc12
Yield: 95.1 %

Procedure:
The above synthesized 1-chloro-5-nitronaphthalene (540 mg, 2.6 mmol) was dissolved in 10 mL AcOH, followed by treatment with 415 mg (7.43 mmol) iron powder and subsequently acylated with Ac2O (0.26 mL, 2.73 mmol) according to the procedure described in Example 209A to give 543 mg (95%) of 1-acetamino-5-chloronaphthalene.