Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[C:19]([NH:21][CH:22]1[CH2:24][CH2:23]1)=[O:20].[C:25]([N:44]1[CH:48]=[CH:47][N:46]=[C:45]1[CH:49]=O)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH:22]1([NH:21][C:19]([C:4]2[N:5]=[N:6][N:7]([C:8]3[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=3)[C:3]=2[CH2:2][NH:1][CH2:49][C:45]2[N:44]([C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:48]=[CH:47][N:46]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN)cc1
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CNCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a solution of 5-(aminomethyl)-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (164 mg, 0.5 mmol) obtained in Example 1197 in dichloroethane (10 ml) were successively added 1-trityl-1H-imidazole-2-carbaldehyde (169 mg, 0.5 mmol), acetic acid (30 mg, 0.5 mmol) and sodium triacetoxyborohydride (138 mg, 0.65 mmol) at 0° C., and the mixture was stirred at room temperature for 48 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution (5 ml) and, after partitioning, the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (130 mg, 40%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:25]3[CH2:31][CH2:30][CH:28]([CH:29]=2)[CH2:27][CH2:26]3)=[O:23])=[CH:17][C:16]=1[C:32]([F:35])([F:34])[F:33])([O-:14])=[O:13]>C(Cl)Cl>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]23[O:9][CH:29]2[CH:28]2[CH2:27][CH2:26][CH:25]3[CH2:31][CH2:30]2)=[O:23])=[CH:17][C:16]=1[C:32]([F:33])([F:34])[F:35])([O-:14])=[O:13]
Reactant: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)C1=CC2CCC1CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)C12OC1C1CCC2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
mCPBA (60% mixture, 518 mg, 3.00 mmol, 3 eq) was added to a solution of 11D (340 mg, 1.0 mmol, 1.0 eq) in CH2Cl2 (20 mL). The reaction mixture was stirred at rt overnight and then diluted with CH2Cl2 (40 mL). The organic solution was washed with sat. NaHCO3 (1×50 mL), brine (1×50 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 80% CH2Cl2/hexane gave 205 mg (0.58 mmol, 57.6%) of compound 11E. HPLC conditions: 95% at 3.70 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2% H3PO4, detecting at 220 nm).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C:15]4([C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:67][C:68]1([CH2:71]O)[CH2:70][CH2:69]1>O1CCCC1>[CH3:67][C:68]1([CH2:71][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C:15]5([C:25]6[CH:24]=[CH:23][N:22]=[CH:21][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:70][CH2:69]1
Reactant: O=C1OC2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccncc21
Reactant: CC1(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(COc2ccc(C3(C(=O)N4CCC5(C4)OC(=O)c4cnccc45)CC3)cc2)CC1

Procedure:
1′-{[1-(4-Hydroxyphenyl)cyclopropyl]-carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (8.2 mg, 0.023 mmol), triethylamine (3.6 ul, 0.026 mmol), triphenylphosphine (15 mg, 0.056 mmol), and diisopropyl azodicarboxylate (11 ul, 0.056 mmol) were mixed in tetrahydrofuran (0.2 ml) at room temperature for 10 minutes. To the mixture, with stirring, was added (1-methylcyclopropyl)methanol (4.8 mg, 0.056 mmol). The resulting mixture then was stirred at room temperature overnight. The desired product was obtained from the mixture by prep-HPLC (5.8 mg, 59%). LCMS: m/z 419.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.O>CN(C=O)C.C(NCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][C:4]=2[CH:3]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Oc1ccc(Br)cc1I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(-c2cc3cc(Br)ccc3o2)cc1
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 4-Bromo-2-iodophenol [207115-22-8] (0.9 g, 3.0 mmol), 4-Methoxyphenylacetylene (0.43 g, 3.3 mmol), PdCl2P(PH3)2 (70 mg), and Cul (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give a solid which was triturated with MeOH, filtered to give a solid (0.4 g, 45%): Mp=192–194° C.; 1H NMR (CDCl3) δ 7.77 (d, 2 H, J=9.1 Hz), 7.66 (s, 1 H), 7.37–7.32 (m, 2 H), 6.98 (d, 2 H, J=9.1 Hz), 6.82 (d, 1 H, J=0.8 Hz), 3.87 (s, 3 H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[N:17]=[N:18][N:19]([CH2:21][Si](C)(C)C)[CH:20]=3)=[CH:14][C:13]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:37][CH2:36][C:35]([CH3:43])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]4)=[N:30][CH:31]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[N:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[CH:14][C:13]([C:26]3[CH:31]=[N:30][C:29]([N:32]4[CH2:37][CH2:36][C:35]([CH3:43])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]4)=[N:28][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3cn(C[Si](C)(C)C)nn3)c2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3cn(C)nn3)c2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-[1-(trimethylsilylmethyl)triazol-4-yl]-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (95 mg, 0.1529 mmol) in 1 mL of THF was cooled to 0° C. Water (5 drops) was added followed by tetra butyl ammonium fluoride (0.153 mL, 1.0 M solution in THF). The reaction was stirred at rt for 18 hours, another 0.2 mL of tetra butyl ammonium fluoride solution added and stirred for another 24 hours. The reaction was filtered through a pad of keiselguhr and the solvent removed under vacuum to yield a brown gum. The crude material was purified by preperative HPLC to give the product as a brown gum 63 mg, 75% yield.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[CH:23]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+]>>[O:37]1[C:36]2[CH:40]=[CH:41][C:33]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Yield: 84.2 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (200 mg, 0.28 mmol) and 1.0 N aqueous sodium hydroxide (5 mL) to afford 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (151 mg, 82%) as an amorphous white solid, mp=134-135° C.: ES(+)-HRMS m/e calcd for C34H40O10S (M+Na)+ 663.2234, found 663.2235.
Reaction SMILES: [CH3:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6](=[O:8])[C:5](=[O:9])[CH2:4][C:3]1=[O:10]>[OH-].[Na+]>[CH3:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][C:5]([C:6]([OH:7])=[O:8])=[CH:4][C:3]1=[O:10]
Reactant: CC1(c2ccccc2)OC(=O)C(=O)CC1=O
Agent: [Na+]
Agent: [OH-]
Product: CC1(c2ccccc2)OC(C(=O)O)=CC1=O
Reaction time: 24 h
Yield: 91.7 %

Procedure:
A mixture of 6-methyl-6-phenyltetrahydropyran-2,3,5-trione (2.18 g, described in Example 7) in aqueous sodium hydroxide (15 ml) at pH 11 is stirred for 24 hr and washed with diethyl ether. Hydrochloric acid (6N) is added until the solution becomes acidic at pH 1 to 4. The precipitate is collected and crystallized from diethyl ether to obtain the title compound (2.0 g), mp 174°-176° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[CH:5]=[N:4][CH:3]=1.[CH2:18]1[C@@H:22]2[CH2:23][NH:24][CH2:25][C@@H:21]2[CH2:20][N:19]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][C:6]1[N:7]=[C:2]([N:24]2[CH2:23][C@@H:22]3[CH2:18][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][C@@H:21]3[CH2:25]2)[CH:3]=[N:4][CH:5]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: Cc1cccc(C(=O)Nc2cncc(Cl)n2)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)Nc2cncc(N3C[C@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C3)n2)c1
Temperature: 110 °C

Procedure:
The product from Example 24A (130.5 mg, 0.53 mmol) was reacted with the product from Example 1C (149.6 mg, 0.70 mmol) and N,N-diisopropylethylamine (110 μL) in DMSO as described in Example 19A, except that the mixture was heated to 110° C. overnight, to afford the title compound. MS (DCI/NH3) m/z 424 (M+H)+.
Reaction SMILES: O(C=C)S(C(F)(F)F)(=O)=O.[CH3:11][C:12]([O:14][C@@H:15]1[CH2:28][C:27]2[C@@:18]([CH3:34])([C@@H:19]3[C@@H:24]([CH2:25][CH:26]=2)[C@@H:23]2[CH2:29][CH2:30][C:31](=O)[C@@:22]2([CH3:33])[CH2:21][CH2:20]3)[CH2:17][CH2:16]1)=[O:13].C(B(CC)[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)C.FC(F)(F)S(OC1[C@]2(CC[C@H]3[C@@H](CC=C4[C@]3(C)CC[C@H](OC(=O)C)C4)[C@@H]2CC=1)C)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C.O1CCCC1>[CH3:11][C:12]([O:14][C@@H:15]1[CH2:16][C:17]2[C@@:18]([CH3:34])([C@@H:19]3[C@@H:24]([CH2:25][CH:26]=2)[C@@H:23]2[CH2:29][CH:30]=[C:31]([C:42]4[CH:43]=[CH:38][CH:39]=[N:40][CH:41]=4)[C@@:22]2([CH3:33])[CH2:21][CH2:20]3)[CH2:27][CH2:28]1)=[O:13]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reactant: CCB(CC)c1cccnc1
Agent: C=COS(=O)(=O)C(F)(F)F
Agent: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: 25 °C

Procedure:
The crude vinyl triflate thus obtained (about a 4:1 mixture of vinyl triflate and prasterone acetate) is taken up with tetrahydrofuran (3.7 L). Diethyl(3-pyridyl)borane (90 g), bis(triphenylphosphine)palladium II chloride (3.8 g) and a 2M sodium carbonate aqueous solution (1 L) are loaded under inert gas environment. The resulting mixture is refluxed for about 1 h, then cooled to room temperature, and ethyl acetate (2.5 L) and water (2.5 L) are added. The aqueous phase is back-extracted with ethyl acetate (1.4 L), the combined organic phases are treated with decolourising carbon (about 100 g), and then concentrated under vacuum to obtain crude abiraterone acetate as an oil (320 g; purity about 87%; assay 51%).
Reaction SMILES: [CH:1]([O:14][C:15]([CH:17]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:18]([NH:20][CH:21]1[C:40](=[O:41])[N:23]2[CH:24]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:30])[CH:25]([CH3:28])[C:26](=[O:27])[C@H:22]12)=[O:19])=[O:16])([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.C(OC(C(C1C=CC=CC=1)C(NC1C(=O)N2C(C(OCOC(=O)C(C)(C)C)=O)C(C)C(O)[C@H]12)=O)=O)C1C=CC=CC=1.OC1[C@@H]2C(NC(=O)C(C(OCC3C=CC4C(=CC=CC=4)C=3)=O)C3C=CC=CC=3)C(=O)N2C(C(OCOC(=O)C(C)(C)C)=O)C1C>>[CH:1]([O:14][C:15]([CH:17]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:18]([NH:20][CH:21]1[C:40](=[O:41])[N:23]2[CH:24]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:38])[CH3:36])=[O:30])[CH:25]([CH3:28])[CH:26]([OH:27])[C@H:22]12)=[O:19])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1C(=O)[C@@H]2C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Agent: CC1C(O)[C@@H]2C(NC(=O)C(C(=O)OCc3ccc4ccccc4c3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Agent: CC1C(O)[C@@H]2C(NC(=O)C(C(=O)OCc3ccccc3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Product: CC1C(O)[C@@H]2C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C

Procedure:
By the same method, the other 4-oxocarbapenam esters of Example 53 are converted to the corresponding pivaloyloxymethyl 6-(2-benzyloxycarbonyl-2-phenylacetamido)-1-hydroxy-2-methylcarbapenam-3-carboxylate and pivaloyloxymethyl 1-hydroxy-2-methyl-6-[2-(2-naphthylmethoxycarbonyl)-2-phenylacetamido]carbapenam-3-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[CH:23]([OH:32])([C:29]([OH:31])=[O:30])[CH:24]([OH:28])[C:25]([OH:27])=[O:26].C([OH:35])C>O>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[C@H:23]([OH:32])([C:29]([OH:31])=[O:30])[C@@H:24]([OH:28])[C:25]([OH:27])=[O:26].[OH2:35]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CCO
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Solvent: O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
A sample of 149.4 g of hydrocodone bitartrate containing 2.1 wt % of ethanol was placed in a crystallisation dish. The sample was placed in a vacuum oven along with a crystallisation dish containing water (ca 200 ml). A vacuum was applied (16665 pascals (approximately 10 mm to 1 mm Hg)) and the sample was dried at 60° C. for 24 hours to afford 151.7 g of ethanol-free (as defined below) product. The water content measured by Karl Fisher titration was 9.66% which indicated that the final product was a hemi-pentahydrate.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH3:7])[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH2:8][O:9]CC=C)[C:4](=[O:20])[N:3]1[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:1]=[C:2]1[N:6]([CH3:7])[C:5]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)([CH2:8][OH:9])[C:4](=[O:20])[N:3]1[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:31])([F:32])[F:30])[CH:22]=1
Reactant: C=CCOCC1(c2ccc(F)cc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The crude mixture of 4-[2,5-dioxo-4-(4-fluorophenyl)-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile obtained in step 5 is solubilised in 5 mL of DCM under argon atmosphere. 0.9 mL of trifluoroborane-dimethylsulfide complex is added. The mixture is stirred at rt for 7 hours. A saturated aqueous sodium bicarbonate solution is added slowly, the product is extracted with DCM and the organic layer is dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 4/1 DCM/ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].Br[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OCC)(=O)C>[OH:16][CH2:15][CH2:14][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(OCCO)c(C)c1
Temperature: 60 °C
Yield: 25.6 %

Procedure:
To a solution of methyl 4-hydroxy-3-methyl-benzoate (5.77 g, 34.7 mmol) in DMF (17 mL) was added 2-bromoethanol (6.51 g, 3.7 mL, 52.1 mmol) and cesium carbonate (33.95 g, 104.2 mmol) and the reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and then partioned between water (250 mL) and ethyl acetate (2×100 ml). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to yield a crude oil that was purified by silica gel column chromatography using EtOAc/hexanes (10 to 100%) as eluent to give methyl 4-(2-hydroxyethoxy)-3-methyl-benzoate (1.87 g, 26%) as a white solid. ESI-MS m/z calc. 210.1. Found 211.1 (M+1)+; Retention time: 1.08 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.94-7.79 (m, 2H), 6.84 (d, J=8.5 Hz, 1H), 4.23-4.08 (m, 2H), 4.08-3.96 (m, 2H), 3.88 (s, 3H), 2.34-2.18 (m, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=S)([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17]([C:16]1[CH:21]=[CH:22][C:23]2[NH:24][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:1]([CH3:3])[CH3:2])=[N:13][C:14]=2[CH:15]=1)=[O:18]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CC(C)c1ccccc1N=C=S
Product: COC(=O)c1ccc2[nH]c(Nc3ccccc3C(C)C)nc2c1

Procedure:
1-Isopropyl-2-isothiocyanatobenzene (5 mmol) and methyl 3,4-diaminobenzoate (5 mmol) were reacted, following general procedure B, to yield 2-(2-Isopropylphenylamino)-1H-benzimidazole-5-carboxylic acid methyl ester, which was purified by silica gel chromatography using DCM/ethyl acetate as eluent.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]([C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1)=[O:12].[CH:19]1([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl>[CH:19]1([CH2:25][S:26]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]2[C:11]([O:10][CH3:9])=[O:12])(=[O:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Reactant: COC(=O)[C@@H]1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Reaction time: 18 h
Yield: 70.5 %

Procedure:
Triethylamine (22.15 ml) was added to a solution of (2S)-2-(methoxycarbonyl)piperidine hydrochloride (10 g) [see Preparation 24] and cyclohexylmethanesulfonyl chloride (16.42 g) [King. J. F. et al,. J. Am. Chem. Soc., 1992, 114(5), 1743-9] in dichloromethane (100 ml). The reaction mixture was stirred for 18 hours after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 95:5 changing to 80:20, by volume, hexane:ethyl acetate to afford methyl (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboxylate (11.9 g) as a white solid.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]3[N:12]([CH:27]([CH3:29])[CH3:28])[C:13](=[O:26])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:15](=[O:16])[C:9]3=[CH:8][N:7]=2)[CH:5]=[CH:4]N=C1.[CH2:30]([N:32]([CH2:43][CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=CC(N)=[CH:38][CH:37]=1)[CH3:31].C1(=O)OC(=O)CC1.CN(C)C=O>C(Cl)(Cl)Cl>[CH2:43]([N:32]([CH2:30][CH3:31])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=[CH:4][C:5]([NH:1][C:6]2[N:11]=[C:10]3[N:12]([CH:27]([CH3:28])[CH3:29])[C:13](=[O:26])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:15](=[O:16])[C:9]3=[CH:8][N:7]=2)=[CH:38][CH:37]=1)[CH3:44]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: COc1ccc(Cn2c(=O)c3cnc(-n4ccnc4)nc3n(C(C)C)c2=O)cc1
Agent: O=C1CCC(=O)O1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(=O)n(Cc4ccc(OC)cc4)c(=O)n(C(C)C)c3n2)cc1
Temperature: 180 °C
Yield: 62.2 %

Procedure:
A mixture of 700 mg (1.78 mmol) of 7-(imidazol-1-yl)-1-isopropyl-3-(4-methoxybenzyl)-1H-pyrimido[4,5-d]pyrimidine-2,4-dione and 1.1 g (5.35 mmol) of 4-(2-diethylaminoethoxy)aniline is heated at 180° C. for 4 hours, then cooled. To the reaction mixture is added 357 mg (3.6 mmol) of succinic anhydride, 1 mL of chloroform, and 3 mL of dimethylformamide. The reaction mixture is heated at 50° C. for 2 hours, cooled, and diluted with chloroform. The mixture is washed with a saturated solution of sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue is chromatographed on silica eluting with 5:95 methanol/chloroform to give a yellow solid which is crystallized from methanol/water to give 590 mg (61%) of the title compound: mp 139-141° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13]C)=[O:12]>[OH-].[Na+]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)CCc1cccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1cccc(Cl)c1Cl

Procedure:
Methyl 3-(2,3-dichlorophenyl)propionate was refluxed in 10% aqueous sodium hydroxide (1 l.) for two hours and the reaction mixture was cooled, acidified and filtered. The filter cake was dissolved in hot aqueous sodium bicarbonate, and filtered. The filtrate was acidified and filtered to yield 3-(2,3-dichlorophenyl)propionic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.C[O-].[Na+]>>[CH3:5][C:4]1[CH:3]=[CH:2][N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:4][CH:5]=2)[N:8]=1
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Product: Cc1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 45.6 %

Procedure:
To a solution of 4-trifluoromethylbenzamidine (45 g) was added sodium methoxide (11.9 g) as a solid in portions, followed by acetylaldehyde dimethylacetal (34.3 g). The mixture was refluxed overnight, then filtered, the solvent evaporated from the filtrate under reduced pressure, and the residue was partitioned between methylene chloride and water, the organic layer separated, washed with brine, dried over sodium sulfate, the solvent evaporated under reduced pressure, and the residue flash-chromatographed on silica gel, eluting with 20% ethyl acetate in heptane, to yield 13 g of 4-methyl-2-(4-trifluoromethylphenyl)pyrimidine m.p. 50° C.