Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][O:24][CH:25]([O:33][CH3:34])[CH2:26][NH:27][C@@H:28]([CH:30]([CH3:32])[CH3:31])[CH3:29]>>[CH3:23][O:24][CH:25]([O:33][CH3:34])[CH2:26][N:27]([C@@H:28]([CH:30]([CH3:31])[CH3:32])[CH3:29])[C:17](=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12][C:11]1[CH:20]=[CH:21][CH:22]=[C:9]([C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=2)[CH:10]=1
Reactant: COC(CN[C@H](C)C(C)C)OC
Reactant: CC(C)n1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C(C)C)c2)c1)[C@H](C)C(C)C)OC

Procedure:
The subtitled compound (105 mg) was prepared from 3-(3-(1-isopropyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 20, Step iii)] and (R)—N-(2,2-dimethoxyethyl)-3-methylbutan-2-amine, prepared as in Preparation 4 using a similar method to that described in Example 18, Step iii). MS [M+H-MeOH]+=428 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.01 and 8.00 (2×s, 1H), 7.78 (s, 1H), 7.42-7.33 (m, 2H), 7.23 and 7.22 (2×t, J=7.8 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 4.59 and 4.43 (2×t, J=5.1 Hz, 1H), 4.53 (septet, J=7.0 Hz, 1H), 3.76-3.63 (m, 5H), 3.37-3.27 (m, 8H), 2.85 and 2.84 (2×t, J=6.8 Hz, 2H), 2.75-2.49 (m, 2H), 1.97-1.85 and 1.78-1.66 (2×m, 1H), 1.51 (d, J=6.9 Hz, 6H), 1.15 and 1.14 (2×d, J=6.9 Hz, 3H), 0.90 and 0.87 (2×d, J=6.8 Hz, 3H), 0.79 and 0.74 (2×d, J=6.3 Hz, 3H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: C([O:9][C@@H:10]1[C@@:43]2([CH3:44])[C:14](=[CH:15][CH:16]=[C:17]3[C@@H:42]2[CH2:41][CH2:40][C@@:39]2([CH3:45])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:38])[CH2:23][CH2:24][CH:25]([O:29]C(=O)C2C=CC=CC=2)[CH:26]([CH3:28])[CH3:27])[CH2:13][C@@H:12]([O:46]C(=O)C2C=CC=CC=2)[CH2:11]1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>O>[CH3:38][C@@H:22]([C@@H:21]1[C@@:39]2([CH3:45])[CH2:40][CH2:41][CH2:42]/[C:17](=[CH:16]\[CH:15]=[C:14]3\[CH2:13][C@@H:12]([OH:46])[CH2:11][C@H:10]([OH:9])[C:43]\3=[CH2:44])/[C@@H:18]2[CH2:19][CH2:20]1)[CH2:23][CH2:24][CH:25]([OH:29])[CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](OC(=O)c5ccccc5)[C@]4(C)[C@H]3CC[C@]12C)OC(=O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)CCC(O)C(C)C)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
30 mg of 1α,3β,24-tribenzoyloxycholesta-5,7-diene was dissolved in 500 ml. of benzene, and the resulting solution was irradiated with ultraviolet rays in an atmosphere of argon at 10° C. for 2 minutes. After the reaction, isomerization was carried out for 2 hours in the argon atmosphere under reflux of benzene. After the reaction, most of the benzene was evaporated off at reduced pressure, and 2 ml. of 5% potassium hydroxide-methanol and 2 ml. of benzene were added to the residue. The mixture was maintained at room temperature for 28 hours in an atmosphere of argon to perform hydrolysis. The reaction product was diluted with water, and extracted with ethyl acetate. The ethyl acetate layer was repeatedly washed with water, and dried. The ethyl acetate was evaporated off at reduced pressure. The residue was subjected to the same separating and purifying procedure as in Example 20 to afford 1.9 mg of 1α,24-dihydroxycholecalciferol having the same properties as the product obtained in Example 20.
Reaction SMILES: [CH:1]1([N:4]2[C:9]([NH2:10])=[C:8]([NH2:11])[C:7](=[O:12])[NH:6][C:5]2=[O:13])[CH2:3][CH2:2]1.[CH:14](O)=O>>[CH:1]1([N:4]2[C:9]3[N:10]=[CH:14][NH:11][C:8]=3[C:7](=[O:12])[NH:6][C:5]2=[O:13])[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: Nc1c(N)n(C2CC2)c(=O)[nH]c1=O
Product: O=c1[nH]c(=O)n(C2CC2)c2nc[nH]c12

Procedure:
A solution of 12 g of 1-cyclopropyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (IV) in 50 ml of formic acid was refluxed for 2 hours. The hot solution was filtered and 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 11.2 g (V). The amide (V) was refluxed in 40 ml of 2N NaOH for 1 hour and then neutralized with 5N HCl. The crystals were filtered off. Yield 7 g (60%) (VI) NMR (see Table I).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C@@H:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[C@@H:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Yield: 76 %

Procedure:
3-(4-Benzyloxyphenyl)-(S)-2-ethoxypropanoic acid ethyl ester was hydrogenated at atmospheric pressure for 2 hours in ethyl acetate using Pd/C as catalyst. Purification by chromatography on silica gel using toluene:ethyl acetate as eluant gave 3.83 g (yield in 3 steps 76%) of (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:48][C:49]1[NH:50][C:51]2[C:56]([C:57]=1[CH2:58][C:59](O)=[O:60])=[CH:55][CH:54]=[CH:53][CH:52]=2>CN(C)C=O.ClCCl>[CH3:2][O:3][C:4](=[O:18])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:59](=[O:60])[CH2:58][C:57]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[NH:50][C:49]=2[CH3:48])=[CH:9][CH:8]=1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2)cc1
Reactant: Cc1[nH]c2ccccc2c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2C(=O)Cc2c(C)[nH]c3ccccc23)cc1
Reaction time: 16 h
Yield: 92 %

Procedure:
To a stirred solution of (E)-3-((S)-4-pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester hydrochloride (0.3 g, 1.12 mmol) in N,N-dimethylformamide (20 mL) was added sequentially triethylamine (0.5 mL, 3.58 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.24 g, 1.25 mmol), 1-hydroxybenzotriazole (0.17 g, 1.25 mmol) and 2-methylindole-3-acetic acid (0.235 g, 1.24 mmol). The reaction was stirred for 16 h and diluted with dichloromethane, and the solution was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (2% methanol in dichloromethane) to obtain (E)-3-(4-{(S)-1-[2-(2-methyl-1H-indol-3-yl)-acetyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester as a colorless oil (0.42 g, 1.03 mmol, 93% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 3 tR=1.111 min, m/z=478.23; 1H NMR (CDCl3) 1.15 (d, 6H), 1.55 (d, 3H), 2.17-2.29 (m, 4H), 2.42 (m, 1H), 2.91 (m, 1H), 3.95 (s, 3H), 5.70 (m, 1H) 6.80 (d, 1H), 7.03 (m, 4H), 7.30 (m, 4H), 7.71 (m, 1H), 8.30 (s, 1H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1B(O)O>OO>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(C2=CCCCC2)c(Cl)c1
Temperature: 80 °C

Procedure:
A mixture of the crude triflate obtained above (3 g), 2,4-dichloro-benzeneboronic acid (3.2 g, 1.1 eq), 1,1′-bis(diphenylphosphino-ferrocene)PdCl2 (315 mg, 0.025 eq) and K2CO3 (4.2 g, 2 eq), in toluene/acetone/water (26/26/6,5 mL) was heated at 80° C. for 3 h. The mixture was then treated with 1N NaOH (15 mL) and H2O2 30% (10 mL) for 20 min at r.t. to reduce the residual borane. The product was extracted with toluene, washed with brine and dried over anh. Na2SO4. The solids were filtered, the solvent was evaporated and the residue was purified by flash chromatography (silica gel, 100% cHex). The title compound was obtained as a clear oil (2.18 g, 9.58 mmol, 62%)
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:16]([O:20][C:21]([NH:23][C@:24]([C:33]1[O:37][C:36]([C:38]2[CH:39]=[C:40]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:41]=[C:42]([CH2:44]Br)[CH:43]=2)=[N:35][N:34]=1)([CH3:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([NH:23][C@:24]([C:33]1[O:37][C:36]([C:38]2[CH:39]=[C:40]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:41]=[C:42]([CH2:44][O:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH:43]=2)=[N:35][N:34]=1)([CH3:32])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(c1cc(CBr)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reactant: OC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cc(COC2CCC2)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution of cyclobutanol (0.009 mL, 0.115 mmol) in 0.26 mL DMF, cooled to 0° C., was added sodium bis(trimethylsilyl)amide dropwise. After stirring for 5 min, a solution of 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(bromomethyl)-N-methyl-N-(methylsulfonyl)benzenamine (13.5 mg, 0.023 mmol) in 0.25 mL DMF was added and the reaction was stirred at 0° C. for 1 h. The reaction mixture was diluted with water, extracted with EtOAc and washed with brine. Drying, solvent evaporation and flash chromatography (15-55% EtOAc/hexanes) gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(cyclobutoxymethyl)-N-methyl-N-(methylsulfonyl)benzenamine. 1H NMR (CDCl3) δ 7.90 (d, J=9.0 Hz, 2H), 7.58 (s, 1H), 7.27 (m, 3H), 7.06 (m, 2H), 5.09 (bs, 1H), 4.47 (s, 2H), 4.05 (m, 1H), 3.57 (d, J=13.6 Hz, 1H), 3.43 (m, 1H), 3.38 (s, 3H), 2.90 (s, 3H), 2.24 (m, 2H), 2.02 (m, 2H), 1.73 (s, 3H), 1.56 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:6]=1)C.[O:26]1[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]1>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:7]2[C:8]3=[CH:9][N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[C:13]3[C:5]([CH2:4][O:32][CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[CH:6]2)=[CH:24][CH:23]=1
Reactant: OC1CCOCC1
Reactant: COC(=O)c1cc2c(CN(C)C)cn(Cc3ccc(F)cc3)c2cn1
Product: COC(=O)c1cc2c(COC3CCOCC3)cn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared as in example 116, step 1, using methyl 3-[(dimethylamino) methyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate and tetrahydro-2H-pyran-4-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:9]1[O:10][CH2:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH:13]=[C:8]1[CH:7]=[C:6]2[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1.[F:49][C:50]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:51]=1[C:52](O)=[O:53].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:9]1[O:10][CH2:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[CH:13]=[C:8]1[CH:7]=[C:6]2[C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48][C:52](=[O:53])[C:51]3[CH:55]=[CH:56][C:57]([F:59])=[CH:58][C:50]=3[F:49])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: COc1cc2c(cc1OC)C1OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C1C=C2c1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C1OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C1C=C2c1ccc(-c2ccc(OC(=O)c3ccc(F)cc3F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A solution of 8,9-dimethoxy-6-[4′-hydroxybiphen-4-yl]-3-phenyl-3-(4-pyrrolidinophenyl)-3H-naphtho[1,2-b]pyran (0.95 g, 0.5 mmol) and 2,4-difluorobenzoic acid (0.09 g, 0.5 mmol) in DCM (40 mL) containing 4-dimethylaminopyridine (0.01 g) and N,N′-dicyclohexylcarbodiimide (0.11 g, 1.6 mmol) under N2 was stirred at room temperature for 2 h. The resulting mixture was filtered through a short plug of silica using DCM as eluent. The solvent was removed under reduced pressure and the residue chromatographed on silica using EtOAc (0-20% gradient in toluene) as eluent. The solvent was removed under reduced pressure and the residue washed with acetone to give the title compound (0.29 g, 70%) as a pale violet powder, mp 249-250° C.
Reaction SMILES: [CH2:1]([CH:3]1[N:7]([CH2:8][CH2:9][C:10]#[N:11])[CH:6]([CH2:12][OH:13])[CH:5]([CH3:14])[CH2:4]1)[CH3:2].C(N(CC)[C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])C>>[CH2:1]([CH:3]1[N:7]([CH2:8][CH2:9][C:10]2[NH:11][C:18](=[O:27])[C:19]3[C:20]([CH:26]=2)=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)[CH:6]([CH2:12][OH:13])[CH:5]([CH3:14])[CH2:4]1)[CH3:2]
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: CCC1CC(C)C(CO)N1CCC#N
Product: CCC1CC(C)C(CO)N1CCc1cc2c(C)cccc2c(=O)[nH]1

Procedure:
In the same manner as in the method described in Tetrahedron Lett., Vol. 32, No. 30, pp. 3727-3730 (1991), ethyl 5-ethyl-3-methylpyrrolidine-2-carboxylate hydrochloride is obtained. In the same manner as in Example 1b (a) and using ethyl 5-ethyl-3-methylpyrrolidine-2-carboxylate hydrochloride, ethyl 1-tert-butoxycarbonyl-5-ethyl-3-methylpyrrolidine-2-carboxylate is obtained. In the same manner as in Example 1b (b) and using ethyl 1-tert-butoxycarbonyl-5-ethyl-3-methylpyrrolidine-2-carboxylate, 1-tert-butoxycarbonyl-5-ethyl-2-hydroxymethyl-3-methylpyrrolidine is obtained. In the same manner as in Example 1b (c) and using 1-tert-butoxycarbonyl-5-ethyl-2-hydroxymethyl-3-methylpyrrolidine, 5-ethyl-2-hydroxymethyl-3-methylpyrrolidine hydrochloride is obtained. In the same manner as in Example 1b (d) and using 5-ethyl-2-hydroxymethyl-3-methylpyrrolidine hydrochloride, 3-(5-ethyl-2-hydroxymethyl-3-methylpyrrolidin-1-yl)propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-(5-ethyl-2-hydroxymethyl-3-methylpyrrolidin-1-yl)propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-[2-(5-ethyl-2-hydroxymethyl-3-methylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(C2CCCCC2)C2(CCNCC2)C1=O
Reactant: O=C(CCCI)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(C2CCCCC2)C2(CCN(CCCC(=O)c3ccccc3)CC2)C1=O
Yield: 65.5 %

Procedure:
tert-Butyl 2-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.30 g, 0.585 mmol), 4-iodobutyrophenone (0.17 g, 0.585 mmol), and potassium carbonate (0.12 g, 0.878 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.22 g, 65%); MS for C35H47N3O4 m/z 574 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.N[C@H:14](C(O)=O)C>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:14])[CH3:5]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: C[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 12 h

Procedure:
Site-specific mutagenesis was carried out according to standard techniques described by Kunkel (Kunkel T A. Rapid and efficient site-specific mutagenesis without phenotypic selection; Proc Natl Acad Sci, USA 1985, 82:488-492). Sequencing of the cDNA was carried out for assurance that the mutation was correct and that any new mutations had not been introduced. Expression of the recombinant FIX was obtained using “human embryonic kidney cell line 293” and the methods already reported in the literature (Chang J L, Jin J P, Lollar P, et al. Changing residue 338 in human factor IX from arginine to alanine causes an increase in catalytic activity. J. Biol. Chem. 1998; 273:12089-12094). The recombinant FIX was isolated from the supernatant (culture medium) by means of an immunoaffinity column, as aforedescribed. Briefly, the supernatant of the cell culture was collected every 24 hours for 10 days and conserved at −20° C. For the purification the supernatant was thawed out and benzamidine and EDTA were added to a final concentration of 5 milliMoles and 4 milliMoles respectively. After filtration through a Millipore filter, the supernatant was incubated with fast-flow Sepharose Q resin for 12 hours at 4° C. The resin was then re-equilibrated in Tris, NaCl and benzamidine buffer and loaded onto the column. Elution was undertaken with a 0-60 nM calcium gradient. The eluate was then dialyzed in a Tris-NaCl buffer. The preparation was then applied to the immunoaffinity column following the method described in example 2 (in the “in vitro” expression of the recombinant protein). Starting from the culture medium, the procedure was the same as for the plasma, except for the precipitation procedure using BaCl. The culture medium was centrifuged at 4000 g for 20 minutes then subjected to dialysis in Tris-NaCl and loaded onto the immunoaffinity column at a rate of 0.5 ml/min. The remaining steps were the same as those taken for the plasma.
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][CH:12]=2)=O)=[CH:7][CH:6]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[NH:23][NH2:24]>C(O)(=O)C>[CH2:27]([O:26][C:22]([NH:23][N:24]=[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][CH:12]=1)[C:8]1[CH:20]=[CH:21][C:5]([F:4])=[CH:6][CH:7]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)NN
Reactant: CSCc1ccc(C(=O)c2ccc(F)cc2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)NN=C(c1ccc(F)cc1)c1ccc(CSC)cc1
Yield: 61.7 %

Procedure:
An ethanol solution (100 ml) of 4-fluoro-4'-methylmercaptomethylbenzophenone (7.8 g), ethyl carbazate (9.4 g) and acetic acid (9 ml) was heated for 20 hours with refluxing. The solvent was distilled off under reduced pressure, and then the obtained oily substance was diluted with dichloromethane, and washed successively with an aqueous 5% sodium hydroxide solution, water and an aqueous saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off to obtain 4-fluoro-4'-methylmercaptomethylbenzophenone ethoxycarbonylhydrazone (6.4 g) as an isomer mixture.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6](=N)[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[S:20])[N:3]1[CH2:21][CH2:22][CH2:23][OH:24].Cl.C[OH:28]>>[CH3:1][C:2]1([CH3:25])[C:6](=[O:28])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:18])([F:19])[F:17])[CH:9]=2)[C:4](=[S:20])[N:3]1[CH2:21][CH2:22][CH2:23][OH:24]
Reactant: CO
Reactant: CC1(C)C(=N)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1CCCO
Agent: Cl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1CCCO
Temperature: 0 °C
Yield: 68 %

Procedure:
To a solution of compound 4a (627 mg, 1.7 mmol) in methanol (27 mL) was added 2N aqueous hydrogen chloride (5.2 mL). The solution was refluxed for 90 min and then poured in an ice/water solution. The solution was extracted with ethyl acetate (3×30 mL), washed with brine, and dried over magnesium sulphate to give 428 mg (68%) of desired compound 5a. 1H NMR (400 MHz, Acetone-d6) δ: 1.65 (s, 6H), 3.67 (q, 2H, J=5.7 Hz), 3.75 (t, 1H, J=5.01 Hz), 3.90 (m, 2H), 8.03 (d, 1H, J=6.4 Hz), 8.18 (s, 1H), 8.26 (d, 1H, J=8.26 Hz).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:18][C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc[nH]1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: S=C(NN=Cc1ccc[nH]1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and pyrrole-2-carboxaldehyde (53 mg, 0.56 mmol) similar to Example 3 and isolated as a yellow oil (3 mg, 2%). 1H NMR (CDCl3): 9.28 (s, 1H), 8.99 (s, 1H), 7.68 (s, 1H), 7.22 (d, J=7.8 Hz, 1H), 6.94 (s, 1H), 6.53-6.51 (m, 1H), 6.29-6.26 (m, 1H), 6.22-6.13 (m, 2H), 4.30-4.24 (m, 1H), 3.04 (s, 1H), 2.94 (s, 1H), 1.92-1.84 (m, 1H), 1.65 (d, J=9.0 Hz, 1H), 1.50 (d, J=9.0 Hz, 1H), 1.45-1.38 (m, 1H).
Reaction SMILES: NC1C=C(C(F)(F)F)C(OC)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[C:47]2[CH:48]=[C:49]([O:56][CH3:57])[C:50]([C:52]([F:55])([F:54])[F:53])=[CH:51][C:46]=2[N:45]=[C:44]2[N:58](CC=C)[NH:59][C:60]([CH3:61])=[C:43]2[N:42]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[C:47]2[CH:48]=[C:49]([O:56][CH3:57])[C:50]([C:52]([F:54])([F:55])[F:53])=[CH:51][C:46]=2[N:45]=[C:44]2[NH:58][NH:59][C:60]([CH3:61])=[C:43]2[N:42]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(OC)c(C(F)(F)F)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1C(F)(F)F
Product: COc1cc2c(cc1C(F)(F)F)N=C1NNC(C)=C1N=C2c1ccccc1Cl

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-8-trifluoromethyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVee) was prepared by reacting 0.0023 moles of (2-amino-5-methoxy-4-trifluoromethylphenyl)-(2-chlorophenyl)-methanone (Xee) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-1-(2-propenyl)-8-trifluoromethyl-pyrazolo[3,4-b][1,4]benzodiazepine (XIVee) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=407.