Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[NH:30][C:31]3[CH:32]=[C:33]([NH3+:43])[CH:34]=[C:35]4[C:41](=[O:42])[NH:40][N:39]=[CH:38][C:37]=2[C:36]=34)=[CH:25][CH:24]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[NH:30][C:31]3[CH:32]=[C:33]([NH:43][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])[CH:34]=[C:35]4[C:41](=[O:42])[NH:40][N:39]=[CH:38][C:37]=2[C:36]=34)=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2[nH]c3cc([NH3+])cc4c3c2C=NNC4=O)cn1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2[nH]c3cc(NC(=O)[C@@H](CCc4ccccc4)NC(=O)OC(C)(C)C)cc4c3c2C=NNC4=O)cn1

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-4-phenylbutanoic acid and 2-(6-methylpyridin-3-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-aminium chloride 267(b) in 8 mL of anhydrous dimethylformamide containing triethylamine (0.3 mL, 2.3 mmol) stirred in an ice/water bath was added HATU (244 mg, 0.64 mmol), portion-wise. The mixture was then stirred overnight at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([C@H:17]3[CH2:22][CH2:21]C[CH2:19][C@@H:18]3[OH:23])[C:13]2=[O:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N[C@H]1CCCC[C@@H]1[OH:31]>>[Br:1][C:2]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([C@@H:17]3[C@@H:18]([OH:23])[CH2:19][O:31][CH2:21][CH2:22]3)[C:13]2=[O:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=c1c2cc(Br)c3cccnc3c2ccn1[C@H]1CCCC[C@@H]1O
Reactant: N[C@H]1CCCC[C@@H]1O
Product: O=c1c2cc(Br)c3cccnc3c2ccn1[C@H]1CCOC[C@@H]1O

Procedure:
1,5-Anhydro-3-(5-bromo-7-oxo-1,8-phenanthrolin-8(7H)-yl)-2,3-dideoxy-L-threo-pentitol was prepared by the procedure described for the synthesis of 5-bromo-8-[(1S,2S)-2-hydroxycyclohexyl]-1,8-phenanthrolin-7(8H)-one in Example 1, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (1S,2S)-2-aminocyclohexanol.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:32][CH2:31]1
Reactant: OC1CCNCC1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC(O)CC3)C[C@@H]12
Product: C[C@]12C[C@H](N3CCC(O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC(O)CC3)C[C@@H]12
Yield: 85.4 %

Procedure:
2α,3α-Epoxy-16β-(4-hydroxy-1-piperidinyl)-5α-androstane-17β-ol is reacted with 4-hydroxypiperidine as described in Example 3 to obtain the title compound in a yield of 85.4%, m.p.: 248°-250° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.C[Si]([CH:31]=[N+:32]=[N-:33])(C)C>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=[C:9]([C:10](=[O:12])[CH:31]=[N+:32]=[N-:33])[CH:8]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=CC(=O)c1cccc(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
A mixture of 3-phenylbenzoic acid (595 mg, 3 mmol) and thionyl chloride (1 mL) was heated at 60° C. for 2.5 hours. After this time, the thionyl chloride was removed under vaccum. Toluene was then added and the resulting solution was concentrated. This procedure was repeated two more times. The oily residue was then dissolved in dry THF. At 0° C., triethylamine (304 μL, 3 mmol) and trimethylsilyldiazomethane were added successively. The reaction was then stirred for 20 hours at room temperature. The reaction was concentrated. Purification of the residue by flash chromatography using CH2Cl2/AcOEt 95:5 to 85:15 gave the compound as a yellow thick oil (141 mg, 21%). NMR 1H (ppm, CDCl3): 7.98 (t., J3=1.37 Hz, 1H), 7.74-7.67 (m, 2H), 7.60-7.57 (m, 2H), 7.50-7.24 (m, 4H), 5.95 (s, 1H). MS (+ESI): M+H+: 222.9.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): • 7.99-7.97 (m, 2H), 7.47 (dd, 3H, J=5.08 Hz, 1.96 Hz), 7.18 (d, 2H, J=8.60), 7.07 (td, 1H, J=6.65 Hz, 1.56 Hz), 6.89-6.80 (m, 4H), 6.63 (dd, 1H, J=7.82 Hz, 1.56 Hz), 4.21 (t, 2H, J=6.26 Hz), 3.82 (s, 3H), 3.30 (d, 1H, J=14.1 Hz), 3.10-3.04 (m, 3H), 2.41 (s, 3H), 1.30 (s, 3H). MS [ES+] m/z exact mass calcd for C29H30NO6 488.2073, found 488.2086.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[CH:9]=[C:8]([Cl:20])[C:3]=1[O:4][CH2:5][CH2:6][OH:7].[H][H]>[Pd].C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([Cl:20])[C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: OCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCOc1c(Cl)cc(O)cc1Cl
Yield: 92.3 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1 Step B, by the treatment of 16.0 grams (0.051 mole) of 2-[2,6-dichloro-4-(phenylmethoxy)phenoxy]ethan-1-ol with hydrogen gas in the presence of a catalytic amount of 10% palladium on carbon in about 400 mL of ethanol using a Parr hydrigenaton apparatus. Following the theoretical uptake of hydrogen, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:2 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 10.5 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=3)=[N:17]2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:29])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:29])=[CH:3][C:2]([Cl:1])=[C:15]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:23]=[CH:24][C:25]([I:28])=[CH:26][CH:27]=3)=[N:17]2)[CH:14]=1
Reactant: O=C(NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Yield: 89.1 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-2-fluoro-5-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide (0.550 g, 1.01 mmol), KOH (0.285 g, 5.09 mmol), water (5 mL) and THF (15.0 mL) to afford 0.400 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.59 (m, 2H), 3.71 (s, 1H), 7.38 (d, J=9.6 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.60-7.69 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([CH2:40][C:41](O)=[O:42])[CH:37]=[CH:38][CH:39]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:44])([F:32])[F:45])[CH:35]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79 μmol), (3-trifluoromethyl-phenyl)-acetic acid (21.8 mg, 106 μmol) and DIPEA (48.94 μL, 277 μmol) in THF (3 mL), T3P (160 μL, 277 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as a white solid (87%, 43 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@@H:5]4[CH2:6][CH2:7][C@@H:2]([NH:1][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:3][C@H:4]4[F:35])=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CC[C@@H](N)C[C@H]1F
Product: COCC(=O)N[C@@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f67) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[CH:14][CH:13]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:31][NH2:32]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:32][CH3:31])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2occc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2occc2c1
Temperature: 85 °C
Yield: 49 %

Procedure:
To a stirred solution of 4-(2-(benzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl) but-1-enyl)phenol (480 mg, 1.0 eq) in 15 mL MeOH was added 5 mL CH3NH2 (aq) and the mixture was heated at 85° C. for 48 h. The organic solvent was removed in vacuo, water was added to the residue and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (230 mg, 49%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=2.0 Hz, 1H), 7.36 (s, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 4.11 (t, J=4.8 Hz, 1H), 3.92 (t, J=4.8 Hz, 1H), 3.01 (t, J=5.2 Hz, 1H), 2.89 (t, J=5.2 Hz, 1H), 2.45-2.54 (m, 5H), 0.89-0.94 (m, 3H); m/z=414[M+1]+.
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@H:24]([C:31]([OH:33])=[O:32])[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1.[OH-].[Na+]>O.O1CCOCC1>[N:1]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([NH:23][C@H:24]([C:31]([OH:33])=[O:32])[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
1.25 g of Boc-Pro-OSu [G. W. Anderson et al., J. Amer. Chem. Soc. 86, 1839 (1964)] and 0.68 g of H-His-OH are suspended in 4 ml of H2O and 2 ml of dioxan. While stirring vigorously, 2N NaOH is added by means of a pH stat at a pH value of 9.0. After 45 minutes the absorption of NaOH ceases. The now clear solution is stirred for a further 10 minutes, the pH value is adjusted subsequently to 5.0 with 4N HCl, and the whole is concentrated to approximately 5 ml. After the addition of 20 ml of H2O, the whole is again concentrated to approximately 5 ml and then purified by chromatography over a column of absorber resin, diaion HP-20 (φ=1.6 cm; length=20 cm). The bulk of this product is eluted with 20% isopropanol in H2O. The fractions that are pure according to thin layer chromatography are combined, concentrated almost to dryness and, after the addition of H2O, lyophilised, yielding Boc-Pro-His-OH in the form of an amorphous powder; Rf (E)=0.45; Rf (A)=0.21.
Reaction SMILES: [OH-].[Na+].O.CC[O:6][C:7]([C@@H:9]([NH:18][C@H:19]([C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])[CH3:20])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8].Cl>C(O)C>[CH3:20][C@H:19]([NH:18][C@H:9]([C:7]([OH:8])=[O:6])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Reaction time: 18 h

Procedure:
A solution of NaOH (144.8 g, 3.42 mol; assay=94.5%), water (2573 ml), ethanol (2187 ml) and Trandolapril (680 g, 1.58 mol; assay=99.81%) was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 18 hours. After an in process control showed an almost complete saponification (by HPLC), the pH of the clear solution was adjusted to 3.8 by addition of 2N aqueous hydrochloric acid at a temperature ranging from about 20° C. to about 25° C. (The solution was seeded according to the general seeding procedure, see Example 2). The suspension was stirred at a temperature ranging from about 20 to about 25° C. for 5.5 hours, and then filtered off, and the wet product was washed with water (2149 ml) and ethanol (2198 ml). Then, a suspension of the wet product in ethanol (6046 ml) was stirred at a temperature ranging from about 38° C. to about 43° C. for 14 hours, and then at a temperature ranging from about 20° C. to about 25° C. for 2 hours. After filtration, the wet product was washed with ethanol (2224 ml) and dried in vacuo (<1 mbar) at 40° C. until the ethanol content was <0.5% (4 days) to give Trandolaprilat as crystalline Form E (yield: 582 g, 1.44 mol, 91.3%; assay (NaOH)=99.74%; HPLC purity: 99.33%, Trandolaprilat diketopiperazine: 0.52%; water content: 0.54%, ethanol content: 955 ppm, chloride content=not detected).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[C:5]([C@@:9]2([CH3:19])[NH:14][C:13](=S)[CH2:12][N:11]3[N:16]=[CH:17][CH:18]=[C:10]23)[CH:6]=[CH:7][CH:8]=1.CO>O.C([O-])([O-])=O.[Na+].[Na+]>[Br:2][C:3]1[CH:4]=[C:5]([C@@:9]2([CH3:19])[N:14]=[C:13]([NH2:1])[CH2:12][N:11]3[N:16]=[CH:17][CH:18]=[C:10]23)[CH:6]=[CH:7][CH:8]=1
Reactant: N
Reactant: C[C@]1(c2cccc(Br)c2)NC(=S)Cn2nccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@]1(c2cccc(Br)c2)N=C(N)Cn2nccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
32% aqueous ammonia solution (11.9 mL, 201.1 mmol) was added to a stirred mixture of (R)-4-(3-bromo-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazine-6-thione (1.8 g, 5.59 mmol) in 7 N solution of ammonia in methanol (11.97 mL, 83.79 mmol) in a sealed tube. The mixture was stirred at 60° C. for 90 minutes. After cooling to room temperature the mixture was diluted with water and Na2CO3 (aq. sat. solution) and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M solution of ammonia in methanol in DCM 0/100 to 2/98 to 3/97 to 10/90). The desired fractions were collected and concentrated in vacuo to yield (R)-4-(3-bromo-phenyl)-4-methyl-4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-ylamine (1.4 g, 82% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:48][CH2:49][CH2:50][CH3:51])[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:6]=1[C:7]([O:9][CH3:10])=[O:8]>C(O)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH2:48][CH2:49][CH2:50][CH3:51])[N:5]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCc1nc(N)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nc(N)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
To a solution of 47 mg (0.070 mmol) 4-amino-2-butyl-5-carbomethoxy-1-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methylimidazole (Example 1, Step I) in 1 mL glacial acetic acid was added 1 mL distilled water and the mixture stirred at room temperature for 14 hours. All volatiles were removed in vacuo and the residue purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/acetonitrile/methanol (9:1:.5), to afford 24 mg (0.056 mmol, 79%) of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[S:8][C:9]2[C:10](=[CH:12][C:13]3[N:14]=[C:15]([NH2:19])[S:16][C:17]=3[CH:18]=2)[N:11]=1>CN(C)C=O>[Cl:1][CH2:2][C:3]([NH:19][C:15]1[S:16][C:17]2[C:13](=[CH:12][C:10]3[N:11]=[C:7]([NH2:6])[S:8][C:9]=3[CH:18]=2)[N:14]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1nc2cc3nc(N)sc3cc2s1
Solvent: CN(C)C=O
Product: Nc1nc2cc3nc(NC(=O)CCl)sc3cc2s1

Procedure:
1.2 gm of chloroacetyl chloride were added to a stirred solution of 2.2 gm of 2,6-diamino-benzo[1,2-d:5,4-d']bisthiazole in 20 ml of dimethylformamide at 5° C. The resulting suspension was heated for 1 hour on a waterbath, then cooled, and the solid 2,6-bis-(chloroacetyl-amino)-benzo[1,2-d:5,4-d']bisthiazole was filtered off. While stirring, 0.5 gm of an aqueous saturated sodium carbonate solution was added to the filtrate. After 1 hour the precipitate was filtered off, dissolved in 30 ml of dimethylformamide/dioxan (1:1), freed from traces of insoluble material and precipitated again with water. The crystals were dissolved in dimethylformamide and the solution was treated with an excess of 2 N hydrochloric acid. The hydrochloride obtained thereby was washed and dried.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[CH3:21][C:22]1([CH3:29])[CH2:27][C:26](=[O:28])[O:25][C:23]1=[O:24]>O1CCOCC1>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[C:26](=[O:28])[CH2:27][C:22]([C:23]([OH:25])=[O:24])([CH3:29])[CH3:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: C1COCCO1
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CC(C)(C)C(=O)O

Procedure:
A solution of 3.6 g (13.5 mmol) of N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 1.75 g (13.5 mmol) of 2,2-dimethylsuccinic acid anhydride in 50 ml of dioxane is heated under reflux for 5 hours. Concentration of the reaction mixture by evaporation yields crude 3-carboxy-3-methyl-butanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide that melts at from 125° to 131° and is further used in crude form.
Reaction SMILES: [Br:1][C:2]1[C:11]([Br:12])=[C:10]([N+:13]([O-:15])=[O:14])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O>>[Br:1][C:2]1[C:11]([Br:12])=[C:10]([N+:13]([O-:15])=[O:14])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:16]([Cl:21])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Product: O=C(Cl)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Yield: 91 %

Procedure:
96 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid and 200 ml of thionyl chloride were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was heated under reflux and then the excess thionyl chloride was removed under vacuum. The residue was dissolved in 100 ml of isopropyl ether and then the solvent removed and the product air-dried. 91 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 215° C.; yield: 91%).