Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23].C(Cl)CCl>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[C:21]2[CH:29]=[CH:30][CH:31]=[C:19]([C:18]([F:17])([F:33])[F:32])[CH:20]=2)[C@H:11]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
(2S,4R)-4-(Benzyloxy)-2-isopropylpyrrolidine (0.410 g, 1.90 mmol) was dissolved in dichloromethane (30 mL) under nitrogen. (3-Trifluoromethyl-benzoylamino)-acetic acid (0.462 g, 1.90 mmol) was added followed by EDC (0.394 g, 2.06 mmol) and the mixture was stirred at room temperature-overnight. LC/MS revealed the reaction was not yet complete. More (3-Trifluoromethyl-benzoylamino)-acetic acid (0.12 g, 0.48 mmoles) and more EDC (0.30 g, 1.6 mmoles) were added and stirring continued for 3 hours at room temperature, then at reflux for 1.5 hours. The mixture was chromatographed on silica gel eluting with 30% ethyl acetate/hexane to provide 0.66 g (79%) of the coupled product as a colorless oil. LC/MS (M+H)+ m/z=449.2; 1H NMR (CDCl3) δ 8.03 (m, 1H), 7.76 (m, 1H), 7.58 (m, 2H), 7.34 (m, 5H), 4.52 (m, 2H), 4.03-4.34 (m, 4H), 3.65 (m, 1H), 3.48 (m, 1H), 2.54 (m, 1H), 2.12 (m, 1H), 1.92 (m, 1H), 0.92 (d, 3H), 0.77 (d, 3H).
Reaction SMILES: CC1(C)CC(=O)C=CC1.BrC1C=CC(CBr)=CC=1.[CH2:19]=[C:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[CH:21]1[CH2:28][C:29]1[CH:34]=[C:33](OC)[C:32]([Br:37])=[CH:31][C:30]=1O>>[CH2:19]=[C:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[CH:21]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Br:37])=[CH:31][CH:30]=1
Reactant: C=C1CCCC(C)(C)C1Cc1cc(OC)c(Br)cc1O
Agent: BrCc1ccc(Br)cc1
Agent: CC1(C)CC=CC(=O)C1
Product: C=C1CCCC(C)(C)C1Cc1ccc(Br)cc1

Procedure:
This compound was prepared from 5,5-dimethylcyclohex-2-en-1-one (8) and p-bromobenzyl bromide in three steps in the manner described for the synthesis of olefin (13). 1H NMR (400 MHz, CDCl3) δ 0.94 and 0.97 (2s, 2×3H, geminal-CH3 's), 2.62 and 2.82 (d of ABq, 2H, benzylic-CH2), 4.25 and 4.61 (2s, 2×1H, methylidene-CH2), 6.98 (d, 2H, Ar--H), 7.34 ppm (d, 2H, Ar--H). [This compound is also referred to as Compound "O" or 120130]
Reaction SMILES: C([NH:4][C@H:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7])(=O)C.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>>[NH2:4][C@H:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: O=C1c2ccccc2C(=O)C1(O)O
Product: CC(C)(C)[C@H](N)C(=O)O
Reaction time: 12 h

Procedure:
The above commercially available L-aminoacylase (Comparative Example 2) (0.5 mL) was added to the reaction reagent (9.5 mL) containing the above N-acetyl-L-tert-leucine and, after the above was gently stirred, the reaction was conducted at 25° C. for 12 hours. As a control test, the same reaction was conducted by adding 50 mM K-phosphate buffer (pH 7.5) to the reagent mixture in place of the L-aminoacylase solution. After the enzymatic reaction, the L-amino acid was directly detected by TLC and ninhydrin reaction by the same manner as in Example 2.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[C:23]5[CH2:31][CH2:30][NH:29][CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C([CH2:38][C:39]([O:41]Br)=[O:40])(C)(C)C>C(#N)C>[C:3]([O:41][C:39](=[O:40])[CH2:38][N:29]1[CH2:30][CH2:31][C:23]2[C:22]([O:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:10](=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=3)[CH:13]=[CH:14]4)=[N:27][CH:26]=[N:25][C:24]=2[CH2:28]1)([CH3:4])([CH3:8])[CH3:2]
Reactant: CC(C)(C)CC(=O)OBr
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CCNC4)ccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1

Procedure:
A solution of 5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, Example 33-C, (250 mg, 0.55 mmol), bromo tert-butylacetate (204 μL, 1.38 mmol), TEA (384 μL, 2.76 mmol) and ACN (5 mL) is stirred at room temperature. Following completion of the reaction the contents of the flask are partitioned between DCM and brine. Organic layer is dried over anhydrous Na2SO4, concentrated, and the residue is separated via FCC (50-100% EtOAc/heptane) to give the title compound. MS (ESI) m/z 568.1 (M+1).
Reaction SMILES: C(OC(=O)N[C@H]1C[C@H:10]([NH:12][C:13]2S[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)C1)(C)(C)C.Cl.[NH2:24][C@H:25]1[CH2:28][C@H:27]([N:29]2[C:33]3=[N:34][CH:35]=[CH:36][CH:37]=[C:32]3[N:31]([CH3:38])[C:30]2=[O:39])[CH2:26]1.ClC1N(C)C2C=CC=CC=2N=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.CS(C)=O>[CH3:38][N:31]1[C:32]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:29]([C@H:27]2[CH2:28][C@H:25]([NH:24][C:13]3[N:12]([CH3:10])[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH2:26]2)[C:30]1=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: Cn1c(Cl)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1c(N[C@H]2C[C@H](n3c(=O)n(C)c4cccnc43)C2)nc2ccccc21

Procedure:
The title compound was synthesized following the procedure described for INTERMEDIATE 10, using 3-(trans-3-aminocyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.147 g, 0.577 mmol), 2-chloro-1-methyl-1 h-benzoimidazole (0.096 g, 0.577 mmol), diisopropylethylamine (1 ml, 5.75 mmol) and 4-dimethylaminopyridine (7.05 mg, 0.058 mmol) in DMSO (0.5 mL) and purified by ISCO on silica gel column using 0-80% EtOAc/hexanes to afford 1-methyl-3-(trans-3-((1-methyl-1H-benzo[d]imidazol-2-yl)amino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.103 g, 0.296 mmol, 51.2% yield). m/z: 366.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ: ppm 8.04 (dd, J=5.28, 1.17 Hz, 1 H), 7.50 (dd, J=7.82, 1.17 Hz, 1 H), 7.19-7.24 (m, 1 H), 7.13-7.18 (m, 1 H), 7.10 (dd, J=7.73, 5.18 Hz, 1 H), 7.02 (d, J=6.46 Hz, 1 H), 6.88-6.98 (m, 2 H), 5.32 (t, J=8.41 Hz, 1 H), 4.51-4.69 (m, 1 H), 3.56 (s, 3 H), 3.26-3.40 (m, 5 H), 2.41-2.57 (m, 2 H).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=O>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)[CH3:44]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 55.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-diethylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.6 mg) was obtained.
Reaction SMILES: [C@@H]12N([CH2:10][CH2:11][NH:12][C@:13]34[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]3[C@@H:15]3[C@@:28]([CH3:31])([CH2:29][CH2:30]4)[C@@:27]4([CH3:32])[C@@H:18]([C@:19]5([CH3:44])[C@@H:24]([CH2:25][CH2:26]4)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]4[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=4)=[CH:21][CH2:20]5)[CH2:17][CH2:16]3)[C@@H](CCC1)COC2.[C@@H:51]12[O:58][C@@H:55]([CH2:56][CH2:57]1)[CH2:54][NH:53][CH2:52]2>>[CH:55]12[O:58][CH:51]([CH2:57][CH2:56]1)[CH2:52][N:53]([CH2:10][CH2:11][NH:12][C@:13]13[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:14]1[C@@H:15]1[C@@:28]([CH3:31])([CH2:29][CH2:30]3)[C@@:27]3([CH3:32])[C@@H:18]([C@:19]4([CH3:44])[C@@H:24]([CH2:25][CH2:26]3)[C:23]([CH3:33])([CH3:34])[C:22]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)=[CH:21][CH2:20]4)[CH2:17][CH2:16]1)[CH2:54]2
Reactant: C1C[C@H]2CNC[C@@H]1O2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3[C@@H]4CCC[C@H]3COC4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CC4CCC(C3)O4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane as the alkylating amine in step 3. The product was isolated as a white solid (8 mg, 28%). LCMS: m/e 669.7 (M+H)+, 2.11 min (method 4). 1H NMR (500 MHz, ACETONITRILE-d3) δ 8.17-7.83 (m, 2H), 7.43-7.12 (m, 2H), 5.32 (dd, J=6.2, 1.8 Hz, 1H), 4.80 (d, J=1.7 Hz, 1H), 4.72 (d, J=1.4 Hz, 1H), 4.37 (br. s., 2H), 3.14 (br. s., 4H), 2.99 (br. s., 4H), 2.92-2.81 (m, 1H), 2.68-2.44 (m, 2H), 2.27-1.15 (m, 24H), 1.75 (s, 3H), 1.21 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH3:20]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:20])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1
Solvent: CCO
Product: CC(=O)N1CCC(c2ccc(S(N)(=O)=O)cc2)CC1

Procedure:
The product of (i) above (21.0 g) was added portionwise to a stirred mixture of concentrated aqueous ammonia solution (160 ml) and ethanol (160 ml). The mixture was warmed at 35° until solution was complete and then evaporated. The residue was triturated with water and the solid was filtered off and dried to give the title compound, (18.0 g), m.p. 196°-197° (from ethanol).
Reaction SMILES: [NH:1]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:2]([C:10]([N:12]([CH3:32])[C@H:13]([C:17]([NH:19][C@H:20]([C:29]([NH2:31])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[N+:51]([O-])([OH:53])=[O:52]>C(Cl)Cl.C(O)(=O)C>[NH:1]([C:33]([O:35][CH2:36][CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:34])[C@H:2]([C:10]([N:12]([CH3:32])[C@H:13]([C:17]([NH:19][C@H:20]([C:29]([NH2:31])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N+:51]([O-:53])=[O:52])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of Fmoc-Phe-N-Me-Val-Tyr-NH2(230 mg, 0.340 mmol) in methylene chloride (1 ml) and acetic acid (1 ml), fuming nitric acid (0.03 ml) was added under cooling with ice, followed by stirring at room temperature for 1 hour. The reaction mixture was mixed with water and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1) to give the titled compound (204 mg, 83%).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].CN(C)CCCN(C)C.[NH2:23][C:24]1[N:29]=[C:28]([OH:30])[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:34][C:33]=2[O:50][CH3:51])=[C:26]([CH3:52])[N:25]=1>C1COCC1.O>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:30][C:28]1[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:47])[CH3:48])([CH3:44])[CH3:45])=[CH:34][C:33]=2[O:50][CH3:51])=[C:26]([CH3:52])[N:25]=[C:24]([NH2:23])[N:29]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1Cc1c(C)nc(N)nc1O
Agent: CN(C)CCCN(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 95.4 %

Procedure:
2-Mesitylenesulfonyl chloride (4.96 g, 22.7 mmol) was added to a solution of N,N,N′,N′-tetramethyl-1,3-propanediamine (3.79 mL, 22.7 mmol) and the product of example 8 step (v) (6.55 g, 15.1 mmol) in THF (66 mL) and the mixture was stirred at RT for 3 h. The resulting mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with brine, dried and concentrated. The residue was purified via chromatography on silica to give 8.87 g of the subtitle compound as a white solid; 1H NMR (CDCl3); 6.93 (2H, s), 6.71 (1H, d), 6.41 (1H, d), 6.33 (1H, dd), 4.66 (2H, br s), 4.02 (2H, t), 3.78 (3H, s), 3.77-3.82 (2H, m), 3.75 (2H, s), 2.59 (6H, s), 2.31 (3H, s), 2.25 (3H, s), 1.93-2.01 (2H, m), 0.89 (9H, s), 0.05 (6H, s); LC-MS: m/z 616.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:25]Br>CO>[Br:25][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:24])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:23])[CH2:16]2)[C@:19]2([CH3:22])[C@@H:4]([CH2:3][C@H:2]([OH:1])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: BrBr
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: CO
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A stirred solution of 3α-hydroxy-5β-pregnane-11,20-dione (10 g.) in dry methanol (700 ml.) was treated at 0° with a solution of bromine (1.9 ml.) in methanol (45 ml.) at such a rate that the yellow colour disappeared before further addition. The solution was then partitioned between water and chloroform. The organic layer was washed with water, dried (Na2SO4) and evaporated. Chromatography of the residue (with benzene/ethyl acetate, 2.5:1) gave title compound (7.2 g.) as a white foam; [α]D + 100°(c 1.1).
Reaction SMILES: [CH:1]([Si:3]([CH:8]=[CH2:9])([CH:6]=[CH2:7])[CH:4]=[CH2:5])=[CH2:2].[CH3:10][SiH:11]([CH3:16])[O:12][SiH:13]([CH3:15])[CH3:14]>>[CH:1]([Si:3]([CH:8]=[CH2:9])([CH:6]=[CH2:7])[CH2:4][CH2:5][Si:11]([CH3:16])([CH3:10])[O:12][Si:13]([CH2:9][CH2:8][Si:3]([CH:6]=[CH2:7])([CH:4]=[CH2:5])[CH:1]=[CH2:2])([CH3:15])[CH3:14])=[CH2:2]
Reactant: C[SiH](C)O[SiH](C)C
Reactant: C=C[Si](C=C)(C=C)C=C
Product: C=C[Si](C=C)(C=C)CC[Si](C)(C)O[Si](C)(C)CC[Si](C=C)(C=C)C=C
Temperature: 70 °C
Yield: 28.8 %

Procedure:
To the 25 ml round bottomed flask equipped with a reflex condenser was charged 10.17 g of tetravinylsilane (75 mmol), 1 g of 1,1,3,3-tetramethyldisiloxane (7.5 mmol) and 10 μL of platinumdivinylmethyldisiloxane (5% Pt). The mixture was stirred and heated at 70° C. until it turned light yellow. (Scheme 5) . From this mixture, 0.88 g (29% yield) of 1,3 -di- [2 - (trivinylsilyl)ethyl ]-1,1,3,3-tetramethyldisiloxane (7) was isolated by distillation at 115° C and 0.1 nun Hg. 1H NMR 300 MHz, CDCl3 :δ6 6.22** (AXY,JAX =18 Hz, JAY =2 HZ, Z.Z H) , 6.20** (AXY, JAX =18 HZ, JAY =2 HZ), 6.15 (AXY,JAX =18HZ, JAY =2 HZ), 6.12 (AXY,JAX =7 HZ, JAY =2 HZ), 6.11(AXY, JAX = 7 HZ, JAY =2 Hz), 6,08* (AXY,JAX =7 Hz, JAY =2 Hz), 6.07** (AXY,JAX =7HZ,JAY=HZ), 5.82** (AXY,JAX =18 HZ, JAY =7 Hz), 5.80* (AXY,JAX =18 HZ, JAY =7 HZ), 5.79 (AXY,JAX =18 Hz, JAY =7 HZ), 5.76** (AXY,JAX =18 Hz, JAY=7HZ), 5.75* (AXY,JAX=18 Hz, JAY=7 Hz), 1.09* (d, 0.1 H), 1.07(d,l.5 H), 0.67 (m 1.2 H), 0.47 (m 1.2 (H), 0.12, (m, 0.1 H), 0.08, (s, 1H), 0.06, (s, 1 H) , 0.05 (s, 5 H) . 13C NMR 75 MHz, CDCl3 : δ135.089,, (CH); 134,628, (CH); 134,4, (CH2); 10.137, (CH 2); 6.869,, (CH); 4.21,, (CH2); 4.131, (CH2); 1.347,, (CH3); -0.34, (CH3) . 29Si NMR 99.4 MHz, CDCl3 with Cr (acac)3 δ-18.12, 8.00. IR (neat liquid on NaC1): cm-1 3180 (w) , 3050 (s) , 3010 (m) , 2960(s) , 2910(m) , 2880(m) , 2790(w) , 1610(m) , 1400(s) , 1250(s), 1130(s), 1050(s), 1010(s), 955(s), 840(s), 800(m), 770(s) , 730(s) , 625(w) , 550(m) , 525(m). C20H/38Si4O calc. C 59.04, H 9.41, Si 27.61, 0 3.96; found C 57.76, H 9.02. ##STR11##
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[CH2:18][CH2:17]1)[CH2:5][CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[C@H:9]([OH:15])[CH2:8]1.[BH4-].[Li+]>>[Cl:32][C:28]1[CH:27]=[C:26]([NH:25][C:24]([N:19]2[CH2:20][CH2:21][C:22](=[O:23])[N:16]([C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][N:7]3[CH2:14][CH2:13][C:10]4([CH2:12][CH2:11]4)[C@H:9]([OH:15])[CH2:8]3)[CH2:17][CH2:18]2)=[O:33])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2cccc(Cl)c2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: O=C(Nc1cccc(Cl)c1)N1CCC(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CC1
Yield: 27 %

Procedure:
In analogy to the procedure described in Example 2, (S)-2-[4-(3-chloro-phenyl-carbamoyl)-7-oxo-[1,4]diazepan-1-yl]-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyric acid methyl ester and lithium borohydride gave the title compound in 27% yield as an off-white powder. MS: 465.3 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([O:3][O:4][P:5]([CH:11]([OH:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([O:7][O:8][CH2:9][CH3:10])=[O:6])[CH3:2].[N:21]([CH2:24][C:25]([O:27][CH2:28]C)=[O:26])=[N+:22]=[N-:23].CO.C[O-].[Na+]>C>[N:21]([C:24](=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([CH:11]([P:5]([O:7][O:8][CH2:9][CH3:10])([O:4][O:3][CH2:1][CH3:2])=[O:6])[OH:20])=[CH:13][CH:14]=1)[C:25]([O:27][CH3:28])=[O:26])=[N+:22]=[N-:23]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CCOOP(=O)(OOCC)C(O)c1ccc(C=O)cc1
Agent: C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOOP(=O)(OOCC)C(O)c1ccc(C=C(N=[N+]=[N-])C(=O)OC)cc1
Temperature: -78 °C
Yield: 48.1 %

Procedure:
To a dry 1 L round bottom flask was added 10.9 g (40 mmol) of 37, 52 g (400 mmol, 10 equivalents) of ethyl α-azidoacetate and 200 mL of anhydrous MeOH and the solution stirred under argon at -78° C. To this was added via syringe over 10 minutes, 59 mL (320 mmol, 8 equivalents) of NaOMe, 5.4M in MeH. The reaction was stirred briefly (5 minutes) at -78° C., then at 0° C. (1 hour). The yellow suspension was partitioned between ice-cold brine (400 mL) and EtOAc (3×250 mL). The combined EtOAc was washed with brine (1×400 mL); dried well (MgSO4) and rotovapped (20° C.) to a light yellow solid. Trituration with ether:petroleum ether (35°-60° C.) provided 38 as a light yellow solid (7.72 g, 52%), mp 106°-110° C. 1H NMR (250 MHz, DMSO-d6) δ: 7.86 (d, 2H, J=8.2 Hz, aromatic) , 7.48 (dd, 2H, J=8.2, 1.8 Hz, aromatic), 6.95 (s, 1H, vinylic), 6.30 (dd, 1H, J=15.3, 5.5 Hz, OH), 5.01 (dd, 1H, J=14.3, 5.5 Hz, P--CH), 3.98 (m, 4H, OCH2), 3.87 (s, 3H, CO2CH3), 1.18 (t, 3, J=7.0 Hz, CH3), 1.16 (t, 3H, J=7.0 Hz, CH3); mp 106°-110° C. (dec).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12](Cl)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]([OH:24])[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1.O>C(OCC)C>[CH2:3]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([O:24][CH2:18][C:19]2[O:23][CH:22]=[CH:21][CH:20]=2)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccco1
Reactant: Clc1ncc(Br)c(Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Brc1cnc(OCc2ccco2)nc1Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
14.1 mg of 60% oily sodium hydride was added to a mixture of 73.3 mg of 4-benzyl-5-bromo-2-chloropyrimidine (Production Example 15), 1 ml of furfuryl alcohol and 14.8 mg of cuprous iodide at room temperature, followed by stirring at 90° C. for 2 hours. Water and diethyl ether were added to the reaction solution, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 10% ethyl acetate/hexane, to give 50.9 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2=[N:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13](Cl)=[C:4]2[CH:3]=1.C1(O)C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[K+]>C(OCC)C>[NH:25]([C:13]1[C:12]2[CH2:11][N:10]([CH3:15])[CH2:9][CH2:8][C:7]=2[N:6]=[C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=12)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: CN1CCc2nc3ccc(Cl)cc3c(Cl)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CN1CCc2nc3ccc(Cl)cc3c(Nc3ccccc3)c2C1

Procedure:
By the method described for Example 14, a mixture of the compound of Example 6 (15.0 g, 0.0562 mol), 10.69 (0.115 mol) of phenol and 10.3 mol (0.115 mol) of aniline is reacted. Thereafter, the reaction mixture is slurried with a mixture of 10% aqueous potassium hydroxide and diethyl ether. The insoluble product is filtered and recrystallized from acetonitrile giving the title compound (13.0 g, 72%), m.p. 137°-139° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:32][OH:33])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=1)[CH2:32][O:33][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: C[C@@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@@H]1Cn2c(cc(OCc3ccc(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:5]=2[S:4][CH:3]=1.[H][H]>[Pd].O1CCCC1.C(N(CC)CC)C>[S:4]1[C:5]2[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:2]=[CH:3]1
Reactant: O=Cc1cccc2c(Br)csc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1cccc2ccsc12

Procedure:
2 g of 5% palladium-on carbon catalyst are added to a solution of 10.4 g (43.15 mmoles) of 3-bromo-7-benzothiophene-carbaldehyde in 130 ml of tetrahydrofuran and 5.6 ml of triethylamine and the mixture is hydrogenated with hydrogen in a hydrogenating apparatus for 45 hours at 20°-22° C. under atmospheric pressure. The catalyst is then filtered off and the solvent is evaporated in vacuo from the filtrate. The residue is dissolved with 50 ml each of water and ethyl acetate, and 5.2 g (67.5% of the theoretical amount) of 7-benzothiophene-carbaldehyde are obtainable as residue from the separated organic phase after evaporation of the solvent in vacuo.