Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1>>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:28][CH:29]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(N)nc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, brown solid (46 mg, 58%), MS (ISP) m/z=318.5 [(M+H)+], mp 314.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C:26]([NH:25][C:22]([C:19]1[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:17][CH:18]=1)=[O:23])([CH3:30])[CH3:29]
Reactant: CC(C)(N)CO
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)(C)CO)nn1
Yield: 40 %

Procedure:
As described for example 42b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (67 mg, 0.20 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (37 mg, 40%) which was obtained as a white solid. MS: m/e=401.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].O>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1

Procedure:
A solution of 2.0 g (1 mmol) of 4-hydroxybenzophenone and 1.25 g (1.5 mmol) of trimethylacetyl chloride in 30 ml of pyridine was heated to 50° C. for 2 h. The reaction mixture was stripped of most of the pyridine and then slurried into water. The crude product obtained by filtration was air-dried and recrystallized from ethanol. The first crop (2.35 g, 79.9%, M.P.≅100°-102° C.) was used for analysis and biological evaluation.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.Cl[Sn]Cl>Cl>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]=1
Reactant: Cn1nnc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Product: Cn1nnc2ccc(N)cc21
Yield: 90.2 %

Procedure:
3-Methyl-5-nitrobenzotriazole (0.8 g) was reduced by SnCl2 (4.5 g) at 0° C. in 5 mL of conc. HCl. The pH of the reaction mixture was adjusted to basic and the mixture was extracted with EtOAc. The product, 5-amino-3-methylbenzotriazole (0.6 g), obtained after removal of the solvent, was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].Cl[CH2:29][CH:30]([OH:33])[CH2:31][OH:32]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Reactant: OCC(O)CCl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 57.5 g of sodium 4-(n-hexadecylamino)benzoate and 55.0 g of 3-chloro-1,2-propanediol in 350 ml of hexamethylphosphoramide is treated in the manner described in Example 3 to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate melting at 112°-113° C.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>[Pd].CO>[CH:15]1([N:12]2[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]2)[CH2:17][CH2:16]1
Reactant: c1ccc(CNC2CCN(C3CC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: NC1CCN(C2CC2)CC1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
N-benzyl-1-cyclopropyl-piperidin-4-amine (Intermediate 25; 2.3 g 10 mmol), 10% Palladium on Carbon (230 mg) and Methanol (230 mL) were combined and heated with stirring at 30° C. under Hydrogen at 5 bar pressure for 16 hours.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:10]([CH3:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:33]([CH2:35][CH2:36][C@H:37]([NH:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[C:38](O)=[O:39])=[O:34])=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:41]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:37]([C:38]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:10]([CH3:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:39])[CH2:36][CH2:35][C:33](=[O:34])[O:32][CH2:31][C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Reaction time: 6 h

Procedure:
25.7 g of H-Val-Thr(But)-OBut.HCl are reacted, in 250 ml of dimethylformamide, with 26.0 g of Z-Glu-(OBzl)-OH and 15 g of DCC in the presence of 9.5 g of HOBt. After stirring for 6 hours the mixture is filtered and the filtrate is evaporated to dryness in vacuo. The residue is taken up in ethyl acetate, the solution is washed as described under (A) and, after drying and evaporating off the solvent, 37.3 g of the title compound are obtained with a melting point of 140°-144° (decomposition). Elementary analysis correct (C, H and N).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[C:23]3=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[O:25][N:26]=[C:22]3[CH:21]=[CH:20][N:19]=2)[N:9]=[N:8]1>C(OCC)(=O)C.[Pt]>[NH2:26][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([C:10]2[N:9]=[N:8][N:7]([CH2:6][C:5]3[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:3]([C:2]([F:41])([F:1])[F:42])[CH:4]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:23]=1[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33])=[O:25]
Reactant: FC(F)(F)c1cc(Cn2nnc(-c3nccc4noc(-c5ccccc5Cl)c34)c2-c2ccccc2)cc(C(F)(F)F)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl

Procedure:
Stir a mixture of 4-[1-(3,5-bistrifluoromethylbenzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chlorophenyl)-isoxazolo[4,3-c]pyridine (350 g, 0.583 mol) and 5% Pt—C (35 g) in ethyl acetate (3.5 L) under a H2 (˜5 psi) atmosphere for 20 hours. Filter through hyflo, wash with ethyl acetate (3.5 L) and concentrate to a solid. Dissolve in ethyl acetate (7 L) and add Darco® (600 g). Stir for 2 hours then filter through hyflo. Rinse filter cake with ethyl acetate (3.5 L) and concentrate filtrates to give the title compound. Exact Mass 601.1: mass spectrum (IS): m/z=602.0 (M+1); 1H NMR (250 MHz, CDCl3) 8.0 (d, J=6.0 Hz, 1H), 7.23 (s, 1H), 7.45-7.29 (m, 5H), 7.22 (m, 1H), 7.13-7.03 (m, 2H), 6.96 (m, 1H), 6.90-6.80 (m, 2H), 6.48 (d, J=6.0 Hz, 1H), 7.79 (bs, 2H), 5.31 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14](=[O:29])[C:15]2[CH:24]=[CH:23][C:22]3[C:21](C)([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO.[CH2:32]1COCC1.[BH4-].[Na+]>O>[OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]([OH:29])[C:15]2[CH:24]=[CH:23][C:22]3[CH:21]([CH3:25])[CH:20]([CH3:32])[CH2:19][C:18]([CH3:27])([CH3:28])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CC(C)C3C)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.9 g (7.4 mmol) of methyl 2-hydroxy-4-[3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate and 100 ml of a methanol/THF (50/50) mixture were introduced into a round-bottomed flask and 140 mg (3.7 mmol) of sodium borohydride were added in small amounts. The reaction mixture was stirred at room temperature for 2 hours, poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporation of the solvents, 1.6 g (55%) of the expected compound, with a melting point of 92°-93° C., was recovered.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:43]2[N:42]=[C:41]([Cl:44])[N:40]=[C:23]([NH:24][C@H:25]([CH3:39])[CH2:26][S:27][C:28]3[N:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[NH:30][N:29]=3)[C:22]=2[N:21]=[CH:20]1)(=O)C.C[O-].[Na+]>CO>[C:16]([O:15][CH2:14][C@H:8]1[O:7][C@@H:6]([N:19]2[C:43]3[N:42]=[C:41]([Cl:44])[N:40]=[C:23]([NH:24][C@H:25]([CH3:39])[CH2:26][S:27][C:28]4[N:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[NH:30][N:29]=4)[C:22]=3[N:21]=[CH:20]2)[C@H:5]([OH:4])[C@@H:9]1[OH:10])(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4n[nH]c(-c5ccccc5)n4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4n[nH]c(-c5ccccc5)n4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 8 %

Procedure:
Partial deacylation of the purified 2',3',5'Tri-O-acetyl-2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3-yl)]thio-2-propyl}adenosine (described in Example 27) using sodium methoxide in methanol to provide the title 5'-O-acetyl-2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3yl)]thio-2-propyl}adenosine (0.035 g, 8%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ1.34 (3H, d, --CHCH3), 2.02 (3H, s, --COCH3), 4.53-4.68 (2H, q, H-2'and --CHCH3), 5.40, 5.61 (2H, 2d, 2'- and 3'-OH), 5.86 (1H, d, H-1'), 7.38-8.01 (5H, 3m, Ar--H), 8.37 (1H, s, H-2). HPLC retention time 16.9 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: C[C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C(S[NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]CCCCCCC(O)=O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:61]1([N:67]=[C:68]=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:61][N:67]([C:51]1[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=1)[CH3:68]
Reactant: O=C(O)CCCCCCCCCCCNSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 500 mg of radicicol, 2.013 g of 12-tritylthioaminododecanoic acid, 60 ml of dry tetrahydrofuran, 848 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 965 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:15]2[CH2:14][CH2:13]S[CH2:11][C:10]=2[S:9][C:8]=1[NH:16][C:17]([CH:19]1[C:21]([CH3:23])([CH3:22])[C:20]1([CH3:25])[CH3:24])=[O:18])=[O:6])[CH2:2][CH3:3].O[O:27][S:28]([O-:30])=O.[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:1]([NH:4][C:5]([C:7]1[C:15]2[CH2:14][CH2:13][S:28](=[O:30])(=[O:27])[CH2:11][C:10]=2[S:9][C:8]=1[NH:16][C:17]([CH:19]1[C:20]([CH3:25])([CH3:24])[C:21]1([CH3:23])[CH3:22])=[O:18])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1c(NC(=O)C2C(C)(C)C2(C)C)sc2c1CCSC2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1c(NC(=O)C2C(C)(C)C2(C)C)sc2c1CCS(=O)(=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 133D (0.16 g, 0.41 mmol) in 40 mL acetone was added OXONE® (1 g, 1.29 mmol) in one portion. The resulting suspension was allowed to stir at room temperature for 16 hours. The reaction was diluted with ethyl acetate and washed with water (2×), brine (1×), dried (MgSO4), filtered and concentrated. The crude material was chromatographed (15% ethyl acetate/hexanes) to afford the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 0.81-0.97 (m, 3H) 1.10-1.30 (m, 12H) 1.39-1.66 (m, 3H) 3.09-3.25 (m, 4H) 3.36 (t, J=6.10 Hz, 2H) 4.41 (s, 2H) 7.93 (t, J=5.49 Hz, 1H) 10.83 (s, 1H). MS (ESI+) m/z 413.1 (M+H)+. Anal. calcd. for C19H28N2O4S2: C, 55.31; H, 6.84; N, 6.79. Found: C, 55.31; H, 7.13; N, 6.54.
Reaction SMILES: C=O.[CH:3](O)=O.[OH:6][CH2:7][CH:8]1[CH:13]([OH:14])[CH:12]([OH:15])[CH:11]([OH:16])[CH2:10][NH:9]1>O>[OH:6][CH2:7][CH:8]1[CH:13]([OH:14])[CH:12]([OH:15])[CH:11]([OH:16])[CH2:10][N:9]1[CH3:3]
Reactant: O=CO
Reactant: OCC1NCC(O)C(O)C1O
Agent: C=O
Solvent: O
Product: CN1CC(O)C(O)C(O)C1CO

Procedure:
A mixture of 7 ml of aqueous formalin, 15 ml of formic acid, 1.5 g of 2-hydroxymethyl-3,4,5-trihydroxypiperidine, m.p. 204°-205°, [α]D25 +45° (H2O), is heated under reflux for 20 hours. The reaction mixture is then concentrated to dryness under reduced pressure, the residue is dissolved in water and the insolubles are removed by filtration. The filtrate is passed over ion exchange resin column (Dowex 50 W×4). The column is rinsed with water and the absorved material is eluted with 0.28% aqueous ammonia. The eluate is concentrated to dryness under reduced pressure and the crystalline residue is recrystallized from ethanol to yield 2-hydroxymethyl-3,4,5-trihydroxy-N-methylpiperidine, m.p. 142°-143°, [α]D24 +15.5° (H2O), yield 1.2 g. Treatment with an equimolar amount of p-toluenesulfonic acid gives the corresponding p-toluenesulfonate which, in turn, is recrystallized from methanol. m.p. 198°-199°, [α]D24 +12.2° (methanol).
Reaction SMILES: [N:1]([N:3](C)[C:4](N)=O)=O.[OH-].[K+].[CH3:10][O:11][C:12]([O:14][C@@H:15]1[C@@:36]2([CH3:37])[C:19](=[CH:20][CH:21]=[C:22]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[CH:27]([C:29]([OH:31])=[O:30])[CH3:28])[CH2:18][C@@H:17]([O:39][C:40]([O:42][CH3:43])=[O:41])[CH2:16]1)=[O:13].[N+](=[CH2:46])=[N-]>C(OCC)C.C(O)(=O)C>[N+:3](=[CH2:4])=[N-:1].[CH3:10][O:11][C:12]([O:14][C@@H:15]1[C@@:36]2([CH3:37])[C:19](=[CH:20][CH:21]=[C:22]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[CH:27]([C:29]([O:31][CH3:46])=[O:30])[CH3:28])[CH2:18][C@@H:17]([O:39][C:40]([O:42][CH3:43])=[O:41])[CH2:16]1)=[O:13]
Reactant: CN(N=O)C(N)=O
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)OC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1

Procedure:
A solution of diazomethane in diethyl ether was prepared by adding N-nitroso-N-methylurea to a mixture of 50% aqueous potassium hydroxide solution and diethyl ether in accordance with the method described in Organic Syntheses Collective Volume 2, p. 165 (1943) and this solution was added to a solution of 85 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylic acid (prepared in Example 6 above) in 5 ml of diethyl ether until the yellow color of diazomethane would be persistent. After the excess diazomethane was decomposed by addition of acetic acid, the reaction mixture was washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 79 mg of methyl 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylate.
Reaction SMILES: [Cl-].[C:2]([C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH+:15]([CH:18]([CH3:31])[CH2:19][CH2:20][CH2:21][N:22]3[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[NH:24][C:23]3=[O:30])[CH2:14][CH2:13]2)[CH:9]=[C:8]([CH2:32][CH2:33][CH3:34])[N:7]=1)([CH3:5])([CH3:4])[CH3:3].CCCCCC.C(O)C.C(N(CC)CC)C>CCCCCC.C(O)(C)C>[C:2]([C:6]1[N:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]([CH3:31])[CH2:19][CH2:20][CH2:21][N:22]3[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[NH:24][C:23]3=[O:30])[CH2:16][CH2:17]2)[CH:9]=[C:8]([CH2:32][CH2:33][CH3:34])[N:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CCCc1cc(N2CC[NH+](C(C)CCCn3cc(C)c(=O)[nH]c3=O)CC2)nc(C(C)(C)C)n1
Agent: [Cl-]
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCCc1cc(N2CCN(C(C)CCCn3cc(C)c(=O)[nH]c3=O)CC2)nc(C(C)(C)C)n1
Yield: 43.2 %

Procedure:
For racemate resolution, a solution of 4-(2-tert-butyl-6-propylpyrimidin-4-yl)-1-[1-methyl-4-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)butyl]piperazin-1-ium chloride from Example 38 (200 mg) in 3 ml of hexane/isopropanol (9:1 (V/V)) was loaded onto a chiral column (DAICEL ChiralPAK AD, length: 50 cm, internal diameter: 5 cm, particle size: 20μ); eluent: hexane/ethanol/triethylamine (85:15:0.1 (V/V)). 0.08 g of the title compound was obtained after concentration of the resulting filtrate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:25])=[C:12]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22](O)=[O:23])[C:13]=1[Cl:14].C[N:27](C)C=O.[OH-].[NH4+]>C(Cl)Cl.O1CCCC1>[Cl:14][C:13]1[C:8]([CH3:7])=[CH:9][CH:10]=[C:11]([Cl:25])[C:12]=1[NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:22]([NH2:27])=[O:23]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Nc2ccccc2C(N)=O)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (1.90 g, 14.8 mmol) is added dropwise to a 0° C. suspension of meclofenamic acid (2.00 g, 6.7 mmol) and dimethylformamide (530 μl, 6.7 mmol) in 100 ml of methylene chloride. The clear yellow solution is stirred at 0° C. for one hour and then added by cannula to 3.6 ml of ammonium hydroxide (29% aqueous solution) in tetrahydrofuran at room temperature. After one hour the volatiles are removed and the residue partioned between ethyl acetate and water. The organic layer is washed with brine and dried over magnesium sulfate and concentrated. The white solid is recrystallized from ethyl acetate and isopropanol to give 1.30 g (69%), mp 185°-187° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[C:5]2[CH2:15][S:16][CH2:17][C:4]1=2)[CH3:2].N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[C:5]2=[CH:15][S:16][CH:17]=[C:4]12)[CH3:2]
Reactant: CCN1C2=C(CSC2)C(=O)Nc2ccccc21
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Product: CCN1c2ccccc2NC(=O)c2cscc21

Procedure:
To a suspension of 0.246 g. of 4-ethyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 2 ml. of dry pyridine is added in portions a total of 0.133 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15 minutes, cooled and diluted with water. The solid is collected and recrystallized from methanol-water to give off-white crystals, m.p. 201°-202° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Si](C)(C)C)[CH:4]=1.[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(OC(=O)C)(=O)C>[N+:15]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Si:2]([CH3:14])([CH3:13])[CH3:1])[CH:4]=1)([O-:17])=[O:16]
Reactant: C[Si](C)(C)c1cccc([Si](C)(C)C)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)c1cccc([N+](=O)[O-])c1
Yield: 36 %

Procedure:
To a solution of 1.50 g (6.75 mmol) of m-bis(trimethylsilyl)benzene in 4.0 ml of acetic anhydride was added dropwise a solution of 1.6 ml (35.6 mmol) of 94% nitric acid in 5 ml of acetic anhydride at 130° C. with stirring. The mixture was stirred for 30 minutes. The reaction mixture was poured into a mixture of ice and 2% potassium carbonate solution and methylene chloride and separated. The aqueaus layer was extracted with methylene chloride. The organic layer was washed successively with water and 2% potassium hydroxide solution, dried and evaporated. The residue was purified by column chromatography on silica gel [eluent: methylene chloride-cyclohexane (1:3-1:5)] to give 475 mg of pale yellow liquid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[CH2:5][C@@H:4]([C:15]([OH:17])=[O:16])[NH:3]1>C(O)(=O)C.O=[Pt]=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[CH2:5][C@@H:4]([C:15]([OH:17])=[O:16])[NH:3]1
Reactant: O=C1N[C@H](C(=O)O)Cc2ccc([N+](=O)[O-])cc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)C(=O)N[C@H](C(=O)O)C2
Yield: 99.7 %

Procedure:
(3S)-1-Oxo-7-nitro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1 g) is suspended in acetic acid (50 g), and PtO2 (50 mg) is added thereto. The mixture is subjected to catalytic reduction. The catalyst is filtered off, and the filtrate is distilled to remove the solvent, whereby (3S)-1-oxo-7-amino-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (870 mg) is obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4](Cl)=[O:5].[CH3:15][OH:16]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]([O:16][CH3:15])=[O:5]
Reactant: CO
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Product: COC(=O)c1c(F)cccc1C(F)(F)F
Reaction time: 18 h

Procedure:
2-Fluoro-6-(trifluoromethyl)benzoyl chloride (Sigma-Aldrich; 950 mg, 4.19 mmol) was added drop-wise to dry methanol (5 mL) under nitrogen. After 18 hours LCMS indicated that no starting material remained. The reaction solution was partitioned between DCM (˜50 mL) and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with further DCM and the combined DCM extracts were dried (sodium sulfate) and evaporated to give the title product as a colourless liquid (786 mg). This material was used in the next step without further purification. LCMS (System 3): tRET=1.05 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:16]>CO.C(Cl)(Cl)Cl.CCOCC>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid (2.02 g, 9.71 mmol, Aldrich) in methanol and chloroform (1:1, 32 ml) was added a 2 M TMS-diazomethane in ether (˜7 ml) in portions, over about 2 h, allowing the solution to cool down between additions. The solution was evaporated in vacuo and the residue dissolved in chloroform (˜20 ml). The solution was evaporated in vacuo to give methyl 4-fluoro-2-(trifluoromethyl)benzoate as a slightly yellow-brown liquid (2.07 g).