Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][OH:3].[CH3:4][CH2:5][CH2:6][C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C>[ClH:1].[CH3:4][CH2:5][CH2:6][C:7](=[N:2][OH:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(=O)CCC
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCCCCC(CCC)=NO
Temperature: 25 °C
Yield: 75.3 %

Procedure:
Hydroxylamine hydrochloride (2.1 g) was added to a solution of 1-azabicyclo[3.2.2.]nonan-4-one (2.77 g) in ethanol (30 ml) and the mixture was heated under reflux for 2 h. On cooling the reaction mixture to room temperature, the white solid was collected by filtration and dried in vacuo to give the title compound (2.84 g, 75%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]2[CH2:9][CH:10]([OH:12])[CH2:11][CH:5]1[CH2:6][CH2:7]2.Cl[C:14]1[N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3([CH3:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=2[N:15]=1>CN(C=O)C>[CH3:3][N:4]1[CH:8]2[CH2:7][CH2:6][CH:5]1[CH2:11][CH:10]([O:12][C:14]1[N:18]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4([CH3:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[C:17]3[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=3[N:15]=1)[CH2:9]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: CC1(N2CCC(n3c(Cl)nc4ccccc43)CC2)CCCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C2CCC1CC(Oc1nc3ccccc3n1C1CCN(C3(C)CCCCCCC3)CC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
To a stirred suspension of NaH (60% oil suspension, 102.8 mg, 2.57 mmol was used after washing with n-hexane) in DMF (1.5 ml) was added a solution of tropine (190.6 mg, 1.35 mmol) in DMF (1.5 ml) dropwise at 0° C. After 0.5 hour stirring, a solution of 2-chloro-1-[1-(1-methylcyclooctyl)-4-piperidinyl]-1H-benzimidazole (162 mg, 0.45 mmol) in DMF (3 ml) was added to the reaction mixture at 0° C. The resulting mixture was stirred at room temperature for 23 hours and then at 120° C. for 19 hours. After cooling down to 0° C., the reaction mixture was quenched with water and extracted with CH2Cl2. The extracts combined were washed with brine, dried (Na2SO4), filtered, and concentrated to give 391.1 mg of crude oil, which was purified by preparative TLC (1 mm thick plate×3, CH2Cl2/MeOH:10/1) to afford 42.3 mg (20%) of title compound as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH2:34]1N2CCN(CC2)C1.C(=O)(OC)OC>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[N:25]([CH3:34])[CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OCC)c(OCC)c4)n3)cccc12
Reactant: C1CN2CCN1CC2
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cc1OCC
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Ethyl 3-(7-{5-[3,4-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (100 mg) (D66), DABCO (13 mg) and N,N-dimethylformamide (4 mL) was added to dimethyl carbonate (10 mL) successively. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 150° C. for 2 h. After cooling the reaction, the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and then NaOH (27 mg) in water (5 mL) was added. The mixture was stir at 50° C. for 8 h. The organic solvent was evaporated off and the mixture was acidified with HCl (1 M) solution to pH around 1. Extracted with EtOAc (60 mL), the organic layer was separated and the organic solvent was evaporated off. The residue was purified by Mass Directed Auto Prep to afford 3-(7-{5-[3,4-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1-methyl-1H-indol-3-yl)propanoic acid (E42) (50 mg). δH (DMSO-d6, 400 MHz): 1.35-1.39 (6H, m), 2.61 (2H, t), 2.97 (2H, t), 3.63 (3H, s), 4.12-4.19 (4H, m), 7.15-7.22 (3H, m), 7.43 (1H, dd), 7.65 (1H, d), 7.78 (1H, dd), 7.79 (1H, dd), 12.06 (1H, br s). MS (ES): C24H25N3O5 requires 435; found 436.2 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[I-].[Na+].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[S:30]>CC(C)=O.C(=O)([O-])O.[Na+].O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([C:3]3[N:31]=[C:29]([NH:28][CH2:27][CH2:26][CH:22]4[CH2:23][CH2:24][CH2:25][N:21]4[CH3:20])[S:30][CH:2]=3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:12][CH:13]=1
Reactant: CN1CCCC1CCNC(N)=S
Reactant: O=C(CCl)C1(c2ccc(Cl)cc2)CCCCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CN1CCCC1CCNc1nc(C2(c3ccc(Cl)cc3)CCCCC2)cs1
Temperature: 50 °C

Procedure:
A solution of 2-chloro-1-[1-(4-chloro-phenyl)-cyclohexyl]-ethanone (144.8 mg, 0.53 mmol) and sodium iodide (80 mg, 0.53 mmol) in acetone (4 mL) was stirred at room temperature for 10 min. Next, [2-(1-methyl-pyrrolidin-yl)ethyl] thiourea (100 mg, 0.71 mmol) was added. The resulting mixture was heated at 50° C. overnight. After the mixture was allowed to cool to room temperature, it was diluted with 5% sodium hydrogen carbonate in water and then extracted with ethyl acetate (3×20 mL). The extracts were combined, and dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. The crude was purified by column chromatography on silica gel using dichloromethane/2 N ammonia in ethanol (95:5) to give {4-[1-(4-chloro-phenyl)-cyclohexyl]-thiazol-2-yl}-[2-(1-methyl-pyrrolidin-2-yl)-ethyl] amine, 95, as an oil (150 mg, 70%). 1H (CDCl3, 300 MHz) δ 7.30-7.21 (m, 4H), 6.02 (s, 1H), 5.67 (s, 1H), 3.67-1.52 (m, 24H) ppm; 13C (C6D6, 75 MHz) δ 22.9, 23.5, 26.9, 29.4, 30.8, 36.7, 40.8, 43.2, 46.4, 57.4, 64.9, 101.2, 128.7, 129.4, 132.0, 146.8, 160.1, 169.5 ppm.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[Br:25]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([Br:25])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccc(F)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 1-benzenesulfonyl-7-fluoro-1H-indole (1.00 g, 3.63 mmol) in CCl4 (20 mL) was added a solution of saturated sodium bicarbonate (40 mL) and bromine (0.19 mL, 3.81 mmol) at room temperature. After stirring at room temperature for 16 hours, the reaction was diluted with DCM and water. The organic extract was washed with saturated sodium bicarbonate, 10% aqueous sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated. The product was obtained as an off-white solid (1.22 g, 95%)
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:42][CH2:43]OS(C)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:49]=[N+:50]=[N-:51].[Na+].CN(C=O)C>O>[N:49]([CH2:43][CH2:42][C:15]1[N:14]([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:22]2[C:17]([C:16]=1[CH2:24][CH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)=[N+:50]=[N-:51]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 60 °C
Yield: 96 %

Procedure:
Ethyl 3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate (1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together under N2 and heated to 60° C. After 1 hour the reaction was cooled and water was added. Extracted with EtOAc/Et2O mix and washed with water and brine and dried over sodium sulfate. Removed solvent to obtain ethyl 3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (light-brown solid) in 96% yield.
Reaction SMILES: [O-:1][P:2]([O-:5])([O-:4])=[O:3].[O-][P:7]([O-:10])([O-:9])=[O:8].[O-][P:12]([O-:15])([O-])=[O:13].[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[P:22](=[O:26])([OH:25])([OH:24])[OH:23].S(=O)(=O)(O)O>>[O:3]=[P:2]12[O:5][P:7]3([O:10][P:12]([O:15][P:22]([O:9]3)([O:4]1)=[O:23])(=[O:13])[O:1]2)=[O:8].[P:22](=[O:23])([OH:26])([OH:25])[OH:24]
Reactant: O=P([O-])([O-])[O-]
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Product: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Yield: 30 %

Procedure:
A 30% P2O5 wet process phosphoric acid was prepared from North Florida phosphate rock, dilute phosphoric acid and sulfuric acid. The metallic impurity content of the phosphoric acid analyzed as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:26](Cl)(=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([NH:15][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ncccc2NC(=O)OC(C)(C)C)cc1
Reaction time: 0.1 h
Yield: 34.2 %

Procedure:
A solution of N3-(tert-butoxycarbonyl)-2,3-pyridinediamine (446 mg, 2.13 mmol) in tetrahydrofuran (7 mL) was treated with potassium hexamethyldisilazide (894 mg, 4.48 mmol). After 0.1 hr, the mixture was treated with p-anisoyl chloride (0.365 mL, 2.13 mmol). After 0.5 hr, the mixture was poured into aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed three times with water, once with saturated sodium chloride solution, dried (magnesium sulfate), and filtered. Concentration in vacuo and purification of the residue by flash chromatography (silica gel, hexanes/ethyl acetate) yielded 250 mg (34%) of the title compound.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH:25]C(=O)CCl)[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31].CSC(=S)N.[Na]>O>[C:1]([S:4][C@@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1SC(C)=O)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1SC(C)=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 0.11 g of sodium (3R,4S)-4-acetylthio-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate in 5 ml of water is added under ice-cooling 0.036 g of sodium monomethyldithiocarbamate, and the mixture is stirred at room temperature for 2 hours. The same procedure as Example 3B yields 0.032 g of sodium (3R,4S)-4-acetylthio-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[I:20]C1C=CC=CC=1N>>[I:20][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Reactant: Nc1ccccc1I
Product: O=C(Nc1ccccc1I)C1CCCCC1
Yield: 84 %

Procedure:
This compound was prepared following the procedure described for compound 26A in example 26, except that 2-iodoaniline was used in place of 2-trifluoromethylaniline. Yield 84%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([CH2:28][OH:29])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23]2)=[O:20])[N:10]=[N:9]1.[CH2:41](N(CC)CC)C.CS(Cl)(=O)=O.C[O-].[Na+]>C1COCC1.O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([CH2:28][O:29][CH3:41])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:23]2)=[O:20])[N:10]=[N:9]1
Reactant: CCN(CC)CC
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](COC)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate (165 mg) and triethylamine (215 μl) were dissolved in THF (4 ml), and methanesulfonyl chloride (60 μl) was added under ice-cooling. The mixture was stirred at 0° C. for 2 hr, and sodium methoxide (28% methanol solution, 600 mg) and methanol (2 ml) were added, and the mixture was further stirred at 75° C. for 3 hr. The mixture was cooled to room temperature and diluted with water and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-80:20) was concentrated under reduced pressure to give the object product (142 mg).
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][C:22]1[C:23]([N:38]2[CH2:43][C@@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:24]([F:37])[C:25](F)=[C:26]([C:28](=[N:34][OH:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:27]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CN(C=O)C>[Si:3]([O:20][CH2:21][C:22]1[C:23]([N:38]2[CH2:43][C@@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:24]([F:37])[C:25]2[O:35][N:34]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26]=2[CH:27]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(=NO)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@H](C)C2)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
Sodium hydride (0.723 g, 18.07 mmol) was suspended in 60 ml of DMF and cooled in an ice bath. Ethyl 2-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6R)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-(hydroxyimino)acetate (Intermediate 166, 8.827 g, 14.45 mmol) was dissolved in 30 ml of DMF and added to the reaction flask. The ice bath was removed and the reaction stirred at room temperature for 2 hours. LCMS analysis indicated that the reaction was incomplete, so an additional 100 mg of NaH was added and the reaction stirred for 30 minutes. LCMS analysis indicated that the reaction was incomplete, so an additional 100 mg of NaH was added and the reaction stirred for 30 minutes. The reaction was cooled in an ice bath and quenched drop wise with 5 ml of saturated NH4Cl. The reaction was diluted with water and extracted three times with ethyl acetate. The organic layers were combined, washed 5× with brine, dried over MgSO4 and concentrated to give an oil. The oil was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate. Fractions were combined and concentrated to give the title compound (5.156 g, 8.73 mmol, 60.4%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][NH:14][CH3:15]>CO>[CH3:13][N:14]([CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClCCCCOc1cccnc1
Reactant: CNC
Solvent: CO
Product: CN(C)CCCCOc1cccnc1
Temperature: 100 °C

Procedure:
A portion of the 4-chloro-1-(3-pyridyloxy)butane was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of dimethylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.26 g of an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH3:10])[C:7](Br)=[O:8].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20]>C(=S)=S>[Br:5][CH:6]([CH3:10])[C:7]([C:18]1[CH:17]=[CH:16][C:15]2[O:11][C:12](=[O:20])[NH:13][C:14]=2[CH:19]=1)=[O:8]
Reactant: CC(Br)C(=O)Br
Reactant: O=c1[nH]c2ccccc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2oc(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of aluminum chloride (40 g) and 2-bromopropionyl bromide (32.4 g) in carbon disulfide (100 ml) was refluxed with stirring for 30 minutes. To the resultant mixture was added 2-benzoxazolinone (13.5 g) and the mixture was refluxed under stirring for 7 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diethyl ether to give 5-(2-bromopropionyl)-2-benzoxazolinone (13.5 g). mp. 191°-193° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.O[CH2:26][C@@H:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)C>C1COCC1>[Br:24][CH2:21][C@@H:27]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:26]
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CBr)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (12.54 g, 47.8 mmol) was dissolved in 100 ml of anhydrous THF and at 0° C. tetrabromomethane (15.85 g, 47.8 mmol) in 100 mL of anhydrous THF was added dropwise. This was followed by the dropwise addition, after 15 min, of benzyl ((S)-2-hydroxy-1-methylethyl)carbamate (5.0 g, 23.9 mmol), dissolved in 150 ml of THF. After 10 min at 0° C. the cooling bath was removed and the mixture was stirred at room temperature overnight. The precipitate which had formed was separated off and washed with ethyl acetate and the combined organic phases were concentrated. The residue obtained was purified over silica gel (ethyl acetate-n-heptane=20:80). Yield: 3.41 g (52%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][N:4]([C@@H:12]1[CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=2[CH2:14][CH2:13]1)[CH2:5][CH2:6][C:7]1[S:11][CH:10]=[CH:9][CH:8]=1.[N:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[N+:24]=[N-:25].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][CH2:2][CH2:3][N:4]([C@@H:12]1[CH2:22][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=2[CH2:14][CH2:13]1)[CH2:5][CH2:6][C:7]1[S:11][CH:10]=[CH:9][CH:8]=1.[N:23]([CH2:26][CH2:27][C:28]([O-:30])=[O:29])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NCCC(=O)O
Agent: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: [N-]=[N+]=NCCC(=O)[O-]
Reaction time: 8 h

Procedure:
In a 50 mL round bottom flask, rotigotine (500 mg, 1.56 mmol, 1 equiv.), 3-azidopropionic acid (447 mg, 3.73 mmol, 2.4 equiv.—in 5 mL DCM), and pyridine (302 μL, 3.73 mmol, 2.4 equiv.) were dissolved in 50 mL anhydrous DCM and allowed to stir under argon. The solution was cooled in an ice-water bath for 5 min, and the bath was removed. To the solution DCC was added (778 mg, 3.73 mmol, 2.4 equiv.). The solution was allowed to stir at room temperature under argon. Following overnight reaction, reverse phase HPLC analysis of the reaction mixture showed complete conversion of free rotigotine to the ester form. The reaction mixture was filtered and the filtrate was concentrated to dryness on a rotary-evaporator. The crude product was then purified by silica gel chromatography. The crude product was dissolved in a mixed solvent of hexane-ethyl acetate (6 mL, 4:1 v/v) and then loaded onto a 300 mL silica gel column (30 mm id). The column was eluted with hexane-ethyl acetate (4:1 v/v). The fractions (10 mL each) were analyzed by TLC and reversed phase HPLC. The product fractions were pooled, evaporated by rotary-evaporation, and then dried under vacuum overnight. Yield: 292 mg.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH2:24]([N:27]([CH2:31][C:32]#[CH:33])[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[C:9]=2[C:8](=[O:17])[N:7]([CH2:18][CH2:19][C:20]([OH:22])([CH3:21])[C:33]#[C:32][CH2:31][N:27]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26])[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCC(C)=O)c(=O)c2c1ncn2CCC
Reactant: C#CCN(CCC)CCC
Product: CCCCn1c(=O)n(CCC(C)(O)C#CCN(CCC)CCC)c(=O)c2c1ncn2CCC
Yield: 28 %

Procedure:
3-Butyl-1-(6-dipropylamino-3-hydroxy-3-methyl-4-hexynyl)-7-propylxanthine was prepared in 28% yield using 3-butyl-1-(3-oxobutyl)-7-propylxanthine and N,N-dipropyl-2-propynylamine as as in Example 6C1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]=[C:16]([C:26]([F:29])([F:28])[F:27])[CH:15]=2)=[CH:10][CH:9]=1)(=O)=O.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:34]4[C:30](=[O:40])[C:31]5[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:33]4=[O:35])=[CH:9][CH:10]=3)=[CH:15][C:16]([C:26]([F:28])([F:27])[F:29])=[N:17]2)=[CH:20][CH:21]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 2-{4-[1-(4-chlorophenyl)-3-(trifluorom ethyl)-1H-pyrazol-5-yl]phenyl}ethyl methanesulfonate obtained by Example 51 (3.2 g) and Potassium phthalimide (1.6 g) was stirred at 80° C. for 5 hrs.