Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:15]=[CH:16][C:17]=1B1OC(C)(C)C(C)(C)O1>>[F:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]2[N:35]=[CH:36][CH:37]=[CH:38][N:39]=2)[CH:15]=[CH:16][C:17]=1[C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2[nH]cnc2c1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3Oc3ncccn3)cc2F)OC1(C)C
Product: Fc1cc(-c2ccccc2Oc2ncccn2)ccc1-c1ccc2[nH]cnc2c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 5-bromo-1H-benzo[d]imidazole and 2-((3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-yl)oxy)pyrimidine. MS (ESI): mass calcd. for C23H15FN4O, 382.12; m/z found, 383.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 9.31 (s, 1H), 8.52-8.45 (d, J=4.9, 2H), 7.95 (s, 1H), 7.92-7.87 (d, J=8.6, 1H), 7.79-7.70 (d, J=8.6, 1H), 7.59-7.55 (dd, J=7.7, 1.7, 1H), 7.55-7.47 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.32 (dd, J=12.0, 1.7, 1H), 7.30-7.23 (dd, J=8.1, 1.2, 1H), 7.13-7.08 (t, J=4.8, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4][CH2:3]1.O.NN>CCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:4][CH2:3]1
Reactant: CN1CCC(CCCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCC(CCCCN)CC1
Reaction time: 18 h
Yield: 89.8 %

Procedure:
To a stirred solution of 2-[4-(1-methyl-piperidin-4-yl)-butyl]-isoindole-1,3-dione (2.67 g, 8.89 mmol) in EtOH (50 mL) was added excess hydrazine hydrate (15 mL). After 18 h, the mixture was filtered and the filtrate was diluted with satd aq. NaHCO3 (20 mL) and water (20 mL). The mixture was extracted with CHCl3 (3×50 mL) and the combined organic layers were dried (Na2SO4) and concentrated to provide 1.36 g (90%) of a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][CH:9]([OH:12])[C:10]#[CH:11].[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[C:18]([Si:21]([O:12][CH:9]([CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[C:2]=1[Cl:1])[C:10]#[CH:11])([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC(O)CCc1sc2ccccc2c1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(CCc1sc2ccccc2c1Cl)O[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
A solution of alcohol 18 (2.20 g, 8.78 mmol) in dichloromethane (15 mL) was treated with DMAP (215 mg, 1.8 mmol), TBSCl (1.59 g, 10.5 mmol), and triethylamine (1.8 mL, 13.2 mmol). The reaction was stirred for 24 h and then saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (2×50 mL) and the combined dichloromethane solution dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (4% ethyl acetate/hexane) gave 3.06 g (6.4 mmol, 73%) of the protected alcohol (19).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[C:29](=[O:33])[N:30]([CH3:32])[CH2:31][C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[C:29](=[O:33])[N:30]([CH3:32])[CH2:31][C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CN1Cc2ccc(Cl)nc2C1=O
Product: CN1Cc2ccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)nc2C1=O

Procedure:
The title compound was prepared according to the procedure in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.32 mmol) and 2-chloro-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (52.6 mg, 0.29 mmol) as the starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](O)=[N:7][C:6]([NH:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1)=[CH:5]2.O=P(Cl)(Cl)[Cl:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:22])=[N:7][C:6]([NH:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1)=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Nc2cc3cc(Br)ccc3c(O)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(Br)ccc3c(Cl)n2)n[nH]1

Procedure:
Similar procedure as described in example 9B was used, starting from 6-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol and POCl3 to give (6-Bromo-1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 337 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1.[OH:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1>>[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:11](=[O:12])[CH:2]=[CH:3][CH2:4][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]4[CH2:26][OH:25])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:14]#[N:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: OCC1CCCCN1
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCCCC1CO
Yield: 83.6 %

Procedure:
By using the method of Example 89, 1.05 g (3.06 mmol) of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinoline-3-carbonitrile and 2.1 g (18.4 mmol) of 2-hydroxymethyl-piperidine were converted to 0.67 g the title compound. The free base was obtained as an off-white powder: mass spectrum (electrospray, m/e): M+H 524.3, (M+2H)+2267.7.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1ccc(F)cc1)OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Yield: 66.6 %

Procedure:
20 g of (2,2-dimethoxy-ethyl)-(4-fluoro-benzyl)-amine (1) were dissolved in 120 ml of dichloromethane. 20 mL of pyridine were added. At 0° C. a solution of 23.8 g p-toluenesulfonic acid chloride in dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirring is continued until conversion was completed. For workup, the reaction mixture was extracted twice with 2M hydrochloric acid, twice with sodium bicarbonate and once with brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product was purified by silica gel chromatography to yield 22.95 g of compound 2 as an orange oil. Rt=1.71 min (Method C). Detected mass: 336.1 (M-OMe−).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH2:8][CH2:7]2.S(Cl)([Cl:19])(=O)=O>C(O)(=O)C>[ClH:19].[Cl:1][C:5]1[C:4]([O:3][CH3:2])=[C:13]([O:14][CH3:15])[C:12]([Cl:19])=[C:11]2[C:6]=1[CH2:7][CH2:8][NH:9][CH2:10]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: CC(=O)O
Product: COc1c(Cl)c2c(c(Cl)c1OC)CNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (200 mg, 0.870 mmol) was suspended in glacial acetic acid (5 mL) and sulphuryl chloride (154 μL, 1.92 mmol) was added slowly. The resulting mixture was stirred at room temperature for 3 hours and then evaporated to give the title compound (quant) as a yellowish mass.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]([CH3:25])([CH3:24])[CH2:10]1>CC(C)=O>[CH:18]1([O:17][N:12]2[C:11]([CH3:24])([CH3:25])[CH2:10][CH:9]([NH:8][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:14][C:13]2([CH3:16])[CH3:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Reactant: O=C1CCC(=O)O1
Solvent: CC(C)=O
Product: CC1(C)CC(NC(=O)CCC(=O)O)CC(C)(C)N1OC1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 1.0 gram (10.0 mmol) of succinic anhydride in 25 ml of acetone is added to a solution of 2.64 gram (10.0 mmol) of 4-amino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine (as prepared in Example 6B) in 10 ml of acetone. The reaction mixture is stirred for sixteen hours at room temperature and then concentrated to form a white solid. Purification by flash chromatography (silica gel; 9:1 ethyl acetate:ethanol) and recrystallization from heptane:ethyl acetate affords the title compound as a white solid melting at 136°-138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[N:15]=[C:14](Cl)[N:13]=[C:12]([CH2:17][CH3:18])[N:11]=1>O1CCOCC1>[CH2:17]([C:12]1[N:13]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[N:15]=[C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[N:11]=1)[CH3:18]
Reactant: Nc1cccc(O)c1
Reactant: CCc1nc(Cl)nc(Cl)n1
Solvent: C1COCCO1
Product: CCc1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)n1
Reaction time: 3 h

Procedure:
After dissolving 3-aminophenol (2.18 g, 20 mmol) in 1,4-dioxane (20.0 mL), 2,4-dichloro-6-ethyl-1,3,5-triazine (1.78 g, 10 mmol) was added and stirring carried out for 3 hours at 100° C. under a nitrogen atmosphere.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1.[C-:16]#[N:17].[Na+]>CS(C)=O.O>[C:16]([CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1)#[N:17]
Reactant: O=C1Nc2ccccc2SC1CCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCC1Sc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a solution of 2.86 g of 2-(3-bromopropyl)-2H-1,4-benzothiazin-3(4H)-one in 10 ml of dimethyl sulfoxide was added 0.54 g of sodium cyanide. The mixture was stirred at room temperature for 3 hours and diluted with water. The resulting crystals were collected by filtration and washed with water. Recrystallization from methanol gave 1.55 g (66.7%) of 2-(3-cyanopropyl)-2H-1,4-benzothiazin-3(4H)-one as prisms, m.p. 107°-108° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].[OH-:23].[Na+].II.C(Cl)Cl>C1COCC1>[OH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:23][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]
Reactant: OCCOCCOCCOCCCCCCCCCCCS
Reactant: [OH-]
Agent: II
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCCOCCOCCOCCCCCCCCCCCSSCCCCCCCCCCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
To a solution of 2-{2-[2-(11-mercapto-undecyloxy)-ethoxy]-ethoxy}-ethanol (145 mg, 0.43 mmol) dissolved in 5 mL of THF was added 1 mL of a NaOH solution (0.1 M), followed by iodine (5 crystals). The solution was stirred at room temperature for 24 h and added to 20 mL of CH2Cl2. After the solution was rinsed with H2O (2×5 mL), the organics were dried over MgSO4 and concentrated. The crude residue was purified by flash chromatography (CH2Cl2/MeOH, 20:1, v/v) to afford 78 mg (54%) of 2. 1H NMR 400 MHz (CDCl3) d 3.72-3.52 (br, 24 H), 3.44 (t, J=7.2 Hz, 4 H), 2.66 (t, J=7.0 Hz, 2 H), 2.41 (br s, 2H), 1.65 (m, 4H), 1.57 (m, 4H), 1.41-1.20 (br, 28H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:5])[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[SH:35]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:35][C:29]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=2[Cl:27])[CH2:8][C@H:7]1[CH2:16][O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1COCc1ccc(OC)cc1
Reactant: Fc1ccc(S)c(Cl)c1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(F)cc2Cl)C[C@H]1COCc1ccc(OC)cc1

Procedure:
The title compound was prepared in analogy to example 68 step 8 using (1R,2R,4R)-4-methanesulfonyloxy-2-(4-methoxy-benzyloxymethyl)-cyclopentanecarboxylic acid ethyl ester (example 153 step 6) and 2-chloro-4-fluorothiophenol. Yellow oil (95%). MS (EI): 452 (M)−.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[O:31][N:30]=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[C:38]([F:41])([F:40])[F:39])[O:24][N:23]=2)=[CH:18][CH:17]=1)[C:3]([NH:5][CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C)=[O:4].[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>ClCCl>[NH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[O:31][N:30]=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[C:38]([F:41])([F:40])[F:39])[O:24][N:23]=2)=[CH:18][CH:17]=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.5 h

Procedure:
(R/S)-tert-Butyl 2-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)ethylcarbamate (Example 51, 80 mg, 0.139 mmol) was dissolved in dichloromethane (5 mL). TFA (1 mL, 12.98 mmol) was added. The reaction mixture was stirred for 30 min. All solvent was removed to provide (R/S)-N-(2-aminoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide, TFA (70 mg, 0.116 mmol, 83% yield): LCMS=474.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.62 (1 H, t, J=5.93 Hz), 8.19 (2 H, d, J=8.35 Hz), 7.55-7.76 (7 H, m), 5.20 (1 H, s), 3.39-3.64 (2 H, m), 3.07 (2 H, t, J=6.15 Hz); HPLC peak RT=6.3 min (Method A).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH:15]=[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]4)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>CO.[H][H].O=[Pt]=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][CH:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17]4)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2c(c1)OCCO2)N1C2C=C(c3ccccc3)CC1CC2
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: O=C(c1ccc2c(c1)OCCO2)N1C2CCC1CC(c1ccccc1)C2

Procedure:
PtO2 (40 mg) is added to a solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-phenyl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)-methanone (0.40 g) in methanol (5 mL). The resulting mixture is shaken in hydrogen atmosphere (1 bar) at room temperature for 6 h. Then, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→9:1) to give the title product as a ca. 1:1 mixture of endo and exo isomer.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][O:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1>>[NH:30]1[CH2:29][CH2:28][CH:27]([CH2:26][O:25]/[N:24]=[C:21](/[C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)\[CH3:22])[CH2:32][CH2:31]1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CON)CC1
Product: C/C(=N\OCC1CCNCC1)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 15 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and t-butyl 4-(aminooxymethyl)piperidine-1-carboxylate (intermediate J) in 15% yield using the same procedure as described in the synthesis of example 29. 1H-NMR (400 MHz, CDCl3), δ ppm 9.43 (s, 1H), 8.93 (m, 1H), 8.13 (m, 2H), 7.92 (s, 1H), 7.83 (dd, 1H), 7.43 (dd, 1H), 6.10 (s, 2H), 4.20 (d, 2H), 3.18 (d, 2H), 2.68 (t, 2H), 2.37 (s, 3H), 1.98 (br s, 1H), 1.80 (d, 2H), 1.37 (q, 2H). LCMS (method A): [MH]+=417, tR=1.66 min.
Reaction SMILES: [C:1]1([CH2:6][OH:7])([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11]>COCCOC.O>[Si:14]([O:5][CH2:4][C:1]1([CH2:6][OH:7])[CH2:3][CH2:2]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: OCC1(CO)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1(CO)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of cyclopropane-1,1-diyldimethanol (3.7 g) dissolved in ethylene glycol dimethyl ether (50 mL) was treated with 60% sodium hydride (1.449 g) at 0° C. under nitrogen. The resulting mixture was stirred at 20° C. for 1 h, treated with tert-butylchlorodimethylsilane (5.46 g) and stirred at room temperature overnight. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (2×250 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution 100% DCM). Pure fractions were evaporated to dryness to afford the subtitle compound (5.50 g) as an oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[Br:15]Br.Br.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:15][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:10][CH:9]=1
Reactant: BrBr
Reactant: CCCCC(CC)Cc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC(CC)Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
The procedure was adapted from Weinshenker, N. M. et al., J. Org. Chem. 1975, 40, 1966. A 100-mL round bottom flask was charged with (2-ethylhexyl)-benzene (12 g, 0.063 mol), carbon tetrachloride (20 mL), and anhydrous ferric chloride (0.10 g). A 3.9 mL solution of bromine (0.076 mol) in 10 mL of carbon tetrachloride was added. The resultant mixture was exothermic and proceeded with evolution of hydrogen bromide gas (and some bromine gas) that was neutralized with sodium hydroxide. The reaction was completed as the evolution of hydrogen bromide was finished. The solution was stirred at ambient temperature for an additional hour. After addition of aqueous sodium hydroxide (10%), the mixture was extracted with diethyl ether (3×100 mL). The combined organic layer was washed with aqueous sodium hydroxide (10%) until no yellow/brown color in the aqueous phase was observed. The organic phase was dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was distilled under vacuum to yield 13.8 g (81%) of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10]I>O1CCCC1>[CH3:10][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: CI
Reactant: N#Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: CNc1ccc(C#N)cc1
Yield: 76 %

Procedure:
This compound was prepared by treating 4-aminobenzonitrile with a slight excess, on a molar equivalents basis, of methyl iodide in tetrahydrofuran solvent for 4 hrs at room temperature. Removal of the THF and other volatiles, followed by recrystallization, gave a 76% yield of 4-(N-methyl)aminobenzonitrile, mp 85-87° C. Using Example 1 procedure, the aforesaid substituted nitrile was treated with ethanolamine to obtain a 70% yield of 2-[4-(N-methyl) aminophenyl]oxazoline, mp 145-147° C. Following the Example 6 procedure, the aforesaid compound was treated with TDO to form the oxazoline shown below, having a methyl group attached to the nitrogen in the acetoacetanilide segment. The product was recrystallized from ethyl acetate, mp 102-105° C. Elemental analysis, FT-IR, exhibiting 1726 (C—O) and 1635 (—C═N—) cm−1 absorptions, and with 1H NMR confirmed the below drawn structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5](=[O:8])[NH:6][CH:7]=1.[CH2:12]([OH:14])[CH3:13]>[Pd].C(O)(=O)C>[C:12]([NH:9][C:4]1[C:5](=[O:8])[NH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:14])[C:13]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: O=c1[nH]cc(Cl)cc1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(Nc1cc(Cl)c[nH]c1=O)c1ccccc1
Temperature: 25 °C

Procedure:
5-Chloro-3-nitro-2-pyridone (5.3 g.) was hydrogenated in 225 ml. of ethanol and 6 ml. of acetic acid in the presence of 0.6 g. of 5% palladium-on-carbon. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was dissolved in 75 ml. of pyridine, cooled in ice and treated over 15 minutes with 4.8 g. of benzoyl chloride. The ice bath and reaction mixture were allowed to warm to room temperature spontaneously. The mixture was poured onto 200 g. of ice. On dilution with 500 ml. of water an oil separated which on washing with water solidified (4 g.). The crude 3-benzoylamino-5-chloro-2-pyridone was used directly in the next step.
Reaction SMILES: FC(F)(F)C(N[C@@H:6]1[C:14]2C(=CC=C(OC)C=2)C(=O)[CH2:7]1)=O.[CH3:20][O:21][C:22]1[CH:31]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[C:25]([OH:32])=[CH:24][CH:23]=1.C(Br)C=C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:14]([O:32][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])[CH:6]=[CH2:7]
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)CC2=O
Reactant: COC(=O)c1cc(OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCOc1ccc(OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Step AS (1). A mixture of 10 g (55 mmol) of methyl 5-methoxysalicylate, 9.3 mL (110 mMol) of allyl bromide and 36 g (110 mmol) of cesium carbonate in 100 mL of acetonitrile was stirred at rt for 2 h. The reaction was filtered to remove cesium carbonate and concentrated under vacuum to yield 13.3 g (100%) of methyl 2-allyloxy-5-methoxybenzoate as a yellowish solid, which was used directly in the next reaction without purification. LC-MS (M+H)+=223; 1H NMR (400 MHz, CDCl3) δ ppm 3.77 (s, 3H) 3.88 (s, 3H) 4.49-4.58 (m, 2H) 5.20-5.29 (m, 1H) 5.39-5.50 (m, 1H) 5.96-6.11 (m, 1H) 6.89 (d, J=9.06 Hz, 1H) 6.98 (dd, J=9.07, 3.27 Hz, 1H) 7.32 (d, J=3.02 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1O.[N+:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[C-:13]>>[CH:13]1[N:1]2[C:10]3[C:5]([N:4]=[CH:3][C:2]2=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: Oc1cnc2ccccc2n1
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1ncn2c1cnc1ccccc12

Procedure:
M.p. 195°-196° C., from 2-quinoxalinol and ethyl isocyanoacetate. (Compound 2)