Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH3:12].[CH2:13]([CH2:15][NH2:16])[OH:14].C(N(CC)CC)C>C(O)(C)C>[OH:14][CH2:13][CH2:15][NH:16][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH3:12]
Reactant: NCCO
Reactant: Cc1c(Cl)n(C)c(=O)n(C)c1=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c(NCCO)n(C)c(=O)n(C)c1=O
Reaction time: 8 h

Procedure:
6-chloro-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione (3.4 g) was suspended in 30 ml of isopropanol, and the suspension was added with 1.26 ml of ethanolamine and 3.8 ml of triethylamine and then the resultant mixture was refluxed for 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and thereafter crystals formed were collected by filtration, washed with water and then recrystallized using a water-ethanol solution (1:1, v/v), thereby 2.9 g of 6-(2-hydroxyethylamino)-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione being obtained.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)C=[CH:7][CH:8]=1.CO.C(O)(=[O:21])C>C(OCC)(=O)C>[CH:13]1[C:14]2[C:9](=[CH:5][CH:4]=[C:3]([CH2:8][CH:7]=[O:21])[CH:2]=2)[CH:10]=[CH:11][N:12]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=CCc1ccc2ccncc2c1
Temperature: 2.5 °C

Procedure:
1.75 g (0.0077 mol) of 4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine, 30 ml of methanol, 1.15 ml of glacial acetic acid and 0.73 g of anhydrous ethyl acetate are mixed. The mixture is cooled to 0-5° C. and 1.14 g of 7-isoquinolylacetaldehyde (as obtained according to the Preparation) and, with care, 1.1 g (0.0175 mol) of sodium cyanoborohydride are added thereto. The mixture is stirred at 0-5° C. for 1.5 hours and subsequently at ambient temperature overnight. 7 ml of concentrated hydrochloric acid are added, the mixture is stirred for 10 minutes, the solvent is evaporated under reduced pressure and the residue is taken up in an ethyl acetate/dilute NH4OH mixture. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated. The residue is purified on a column of silica gel, elution being carried out with an ethyl acetate/methanol=9/1 mixture. The title compound is obtained. The dihydrochloride is prepared using a solution of isopropanol saturated with hydrochloric acid. 1.1 g of product are obtained.
Reaction SMILES: N#N.Cl.[F:4][C@@H:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:4][C@@H:5]1[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6]1
Reactant: N#CCCCBr
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: NCCCCN1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (R)-3-fluoropyrrolidin hydrochloride (400 mg, 3.09 mmol) and 4-bromobutyronitrile (0.32 mL, 3.09 mmol) in dry CH3CN (16 mL) was added K2CO3 (2.35 g, 16.99 mmol) at rt followed by KI (51 mg, 0.31 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (23 mL) and treated with LiALH4 (214 mg, 5.47 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Aq. 1N NaOH (7 mL) was then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (R)-4-(3-fluoropyrrolidin-1-yl)butan-1-amine as a colorless oil. GC-MS-conditions 01: tR=1.71 min; [M+H]+=161.10.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[C@H:10]([CH3:41])[NH:11][C:12](=[O:40])[C@H:13]([CH3:39])[N:14]([C:16](=[O:38])[C@H:17]([CH:35]([CH3:37])[CH3:36])[NH:18][C:19](=[O:34])[C@H:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:21](C(OC(C)(C)C)=O)[CH3:22])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:42])[C@H:10]([CH3:41])[NH:11][C:12](=[O:40])[C@H:13]([CH3:39])[N:14]([C:16](=[O:38])[C@H:17]([CH:35]([CH3:36])[CH3:37])[NH:18][C:19](=[O:34])[C@H:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:21][CH3:22])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)N[C@H](C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)C)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)C
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of 15.7 g (0.0266 mole) of Boc-N-methyl-L-leucyl-L-valyl-N-methyl-L-alanyl-L-alanine benzyl ester in 125 ml of dry dichloromethane was stirred and cooled to -10° C. while 70 ml trifluoroacetic acid, previously cooled at -15° C., was added. After 2 hours, the reaction was carefully added with good stirring to a mixture of 105 g of sodium bicarbonate, ice, and 200 ml of dichloromethane. The organic layer was separated and the aqueous layer was extracted with another 50 ml of dichloromethane. The combined organic layers were washed with 3×80 ml of saturated sodium bicarbonate solution, dried over magnesium fulfate, and evaporated leaving 11.85 g (91% of theory) of product. The FAB m.s. showed a molecular ion peak at 491.
Reaction SMILES: C[CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][CH2:64][O:65][P:66]([CH2:71][CH:72]=[CH2:73])([CH2:68][CH:69]=[CH2:70])=[O:67])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[Li+].[OH-]>C1COCC1>[CH2:68]([P:66]([O:65][CH2:64][O:63][C@@H:14]1[CH2:15][C@H:16]2[C@:21]([CH3:22])([CH2:20][CH2:19][C@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]3[CH:39]=[CH:38][C:37]([C@H:40]4[CH2:57][C@@:55]5([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]5([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]5[C:41]4=[C:42]4[C:47]([CH2:48][CH2:49]5)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]4)=[CH:36][CH:35]=3)[CH3:33])[CH2:17]2)[C@@H:23]2[C@@H:13]1[C@H:12]1[C@:26]([CH3:27])([C@@H:25]([OH:28])[CH2:24]2)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:2][C:3]([OH:5])=[O:4])[CH2:10][CH2:11]1)([CH2:71][CH:72]=[CH2:73])=[O:67])[CH:69]=[CH2:70]
Reactant: C=CCP(=O)(CC=C)OCO[C@@H]1C[C@@H]2C[C@@H](OCCN(C)c3ccc([C@H]4C[C@@]5(C)[C@@H](CC[C@]5(O)C#CC)[C@@H]5CCC6=CC(=O)CCC6=C54)cc3)CC[C@]2(C)[C@H]2C[C@H](O)[C@]3(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@H]3[C@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCP(=O)(CC=C)OCO[C@@H]1C[C@@H]2C[C@@H](OCCN(C)c3ccc([C@H]4C[C@@]5(C)[C@@H](CC[C@]5(O)C#CC)[C@@H]5CCC6=CC(=O)CCC6=C54)cc3)CC[C@]2(C)[C@H]2C[C@H](O)[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@H]3[C@H]12

Procedure:
The compound of Example 8C is dissolved in THF; an aqueous solution of LiOH is added, and the resultant mixture is stirred at ambient temperature for 3 hours. The reaction is quenched by addition of aqueous phosphoric acid (1N), and extracted with ethyl acetate. The crude material is carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH3:10])=[N:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:4].C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][Br:26])=[N:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(C)nc1-c1ccc(OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)nc1-c1ccc(OC)cc1
Temperature: 100 °C
Yield: 24.2 %

Procedure:
To the solution of 4-(4-Methoxy-phenyl)-2-methyl-thiazole-5-carboxylic acid methyl ester (0.25 g, 0.94 mmol) in the 20 ml of CCl4 was added NBS (0.16 g, 0.94 mmol) and AlBN 0.015 g, 0.094 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 10% ethyl acetate/hexane as a eluent to give the desired product (0.078 g, 24%).
Reaction SMILES: C([N:3]1[CH2:18][CH2:17][CH2:16][C:6]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([Cl:15])=[C:5]2[CH2:4]1)C.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>>[C:23]1([O:22][C:20]([N:3]2[CH2:18][CH2:17][CH2:16][C:6]3=[N:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]([Cl:15])=[C:5]3[CH2:4]2)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN1CCCc2nc3ccccc3c(Cl)c2C1
Reactant: O=C(Cl)Oc1ccccc1
Product: O=C(Oc1ccccc1)N1CCCc2nc3ccccc3c(Cl)c2C1
Yield: 18.5 %

Procedure:
11-Chloro-2,3,4,5-tetrahydro-1H-2-azepino[4,3-b]quinoline-carboxylic acid phenyl ester was prepared analogous to Example 98 from 2-ethyl-11-chloro-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and phenyl chloroformate.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[CH2:44]([CH2:46][NH2:47])[OH:45]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:23]=[C:20]([CH2:21][NH:47][CH2:46][CH2:44][OH:45])[CH:19]=[N:18][C:17]=2[NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: NCCO
Product: COc1ccc(Nc2ncc(CNCCO)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.200 g, 0.346 mmol) and ethanolamine (Aldrich, St. Louis, Mo.) (0.031 mL, 0.519 mmol). 1H NMR (400 MHz, d6-DMSO) δ 11.79 (s, 1H); 8.89 (d, J=2.35 Hz, 1H); 8.55 (d, J=2.54 Hz, 1H); 8.34 (d, J=2.35 Hz, 1H); 8.13 (dd, J=8.90, 2.64 Hz, 1H); 7.74-7.93 (m, 1H); 6.84 (d, J=9.00 Hz, 1H); 5.08 (br. s., 1H); 4.08 (s, 2H); 3.82-3.88 (m, 3H); 3.63 (q, J=4.96 Hz, 2H); 2.95 (t, J=5.09 Hz, 2H); 2.44 (s, 3H). m/z (ESI, +ve ion) 383.1 (M+H)+.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH:6]=1.[C:20]1([C:26]2[C:34]3[C:33]([N:35]4[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]4)=[N:32][CH:31]=[N:30][C:29]=3[S:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[OH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:41][CH:38]2[CH2:39][CH2:40][N:35]([C:33]3[C:34]4[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:27][S:28][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:36][CH2:37]2)[CH:6]=1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: COCOc1ccc(C(=O)OC)c(OCC2CO2)c1
Product: COC(=O)c1ccc(O)cc1OCC(O)CNC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Yield: 51 %

Procedure:
Synthesis followed SP6 (3 h), using 300 μmol methyl 4-(methoxymethoxy)-2-(oxiran-2-ylmethoxy)benzoate and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give MOM intermediate upon purification by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 10:6:1) with 51% yield. Product was obtained by MOM-removal according to SP8 with 32% yield upon purification by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 6:4:1) and subsequent prep. HPLC (reversed phase).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]1[C:9]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[CH:8][C:7]([CH:18]=[O:19])=[N:6]1)[CH3:4].[NH4+].[Cl-]>CCO>[CH2:3]([N:5]1[C:9]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[CH:8][C:7]([CH2:18][OH:19])=[N:6]1)[CH3:4]
Reactant: CCn1nc(C=O)cc1-c1cccc(C#N)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCn1nc(CO)cc1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
NaBH4 (252 mg, 6.6 mmol) was added portionwise to a stirred solution of 3-(1-ethyl-3-formyl-1H-pyrazol-5-yl)-benzonitrile (1.5 g, 6.6 mmol) in EtOH (25 mL) at 0° C. The mixture was warmed to RT and stirred for a further 30 min., NH4Cl solution (10 ml) was added, the EtOH removed under reduced pressure, H2O (30 mL) added, and the aqueous mixture extracted with EtOAc (2×70 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSO4) and concentrated under reduced pressure to yield the crude alcohol (1.49 g, quant.). 1H NMR (CDCl3, 360 MHz) δ 7.78-7.54 (4H, m), 6.31 (1H, s), 4.72 (2H, s), 4.11 (2H, q, J=7.3 Hz), 1.42 (3H, t, J=7.3 Hz). MS (ES+) C13H13N3O requires: 227, found: 228 (M+H+, 70%).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.[C@@H:44]12[NH:52][C@@H:48]([CH2:49][CH2:50][CH2:51]1)[CH2:47][O:46][CH2:45]2.CCN(C(C)C)C(C)C>CS(C)=O>[C@@H:48]12[N:52]([CH2:2][CH2:3][NH:4][C@:5]34[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]3[C@@H:7]3[C@@:20]([CH3:23])([CH2:21][CH2:22]4)[C@@:19]4([CH3:24])[C@@H:10]([C@:11]5([CH3:37])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[C@@H:44]([CH2:51][CH2:50][CH2:49]1)[CH2:45][O:46][CH2:47]2
Reactant: C1C[C@@H]2COC[C@H](C1)N2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: 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)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)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)benzoate (20 mg, 0.033 mmol), (1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonane (16.78 mg, 0.132 mmol) and Hunig's Base (0.029 mL, 0.165 mmol) in DMSO (1 mL) was heated to 120° C. for 1 h. The reaction mixture was quenched with distilled water (2 mL), extracted with dichloromethane (2×2 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide methyl 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)benzoate as a brown solid which was taken to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[OH:30][C@@H:31]([CH3:34])[CH2:32][NH2:33]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:16])([CH3:17])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:33][CH2:32][C@@H:31]([OH:30])[CH3:34])=[O:21])=[O:5]
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and commercially available (S)-2-hydroxypropylamine using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.01 (d, J=6.1 Hz, 3H), 1.48 (s, 6H), 1.46 (s, 6H), 3.07-3.20 (m, 2H), 3.65-3.73 (m, 1H), 4.68 (d, J=4.4 Hz, 1H), 7.68-7.81 (m, 4H), 11.60 (br s, 1H). MS (ESI+) m/z 489 (M+H)+. Anal. calcd. for C22H24F4N2O4S: C, 54.09; H, 4.95; N, 5.73. Found: C, 53.91; H, 4.89; N, 5.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:5][C:6]2[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[N:11][CH2:10][C:9](=[O:21])[NH:8][C:7]=2[CH:22]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:8]1[C:7]2[CH:22]=[C:3]([O:2][CH3:1])[C:4]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:5][C:6]=2[C:12]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[N:11][CH2:10][C:9]1=[O:21])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccccc1-c1cc2c(cc1OC)NC(=O)CN=C2c1cccc(C#N)c1
Product: COc1ccccc1-c1cc2c(cc1OC)N(Cc1ccccc1)C(=O)CN=C2c1cccc(C#N)c1
Yield: 90 %

Procedure:
Prepared from 3-[8-methoxy-7-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzonitrile Example 10 using the same method described for Example 35 using benzyl bromine instead of hexyl bromine, we. The title compound (95 mg) was obtained as a yellow solid, (yield=90%).
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].C(N(CC)CC)C.Cl>C(O)C>[Cl:20][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:19])[C:14]3[C:15]([OH:17])=[N:32][N:31]([C:28]4[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=4)[C:3](=[O:4])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: CC(C)c1ccc(NN)cc1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)c1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (2.01 g, 6.80 mM) and 4-isopropylphenylhydrazine hydrochloride (8.90 g, 47.6 mM) in ethanol (72 mL) was added triethylamine (7.6 mL, 54.5 mM) to give a brown solution. This solution was refluxed for 16 hours, cooled to room temperature, and then added slowly to a mixture of hydrochloric acid (12N, 100 mL) and ice (100 mL) with vigorous stirring whereupon a pink suspension formed. The suspension was filtered, and the collected solids were washed with a cold solution made by mixing methanol (100 mL), hydrochloric acid (100 mL, 12N) and ice (100 g) to give the 4-isopropylphenylhydrazine salt of the title compound as a purple powder (1.80 g). This material was refluxed in glacial acetic acid (15 mL) for 3 hours to give a tan suspension. The suspension was cooled to room temperature and filtered. The collected solids were washed with glacial acetic acid (10 mL) and ether to give the title compound (1.125 g, 43%) as a tan powder, mp 367-369° C.; MS(CI): 382 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.[Li]CCCC.CN([CH:31]=[O:32])C.Cl>C1COCC1>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([CH:31]=[O:32])[CH:11]=[CH:10]3)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (2.249 g, 6.25 mmol, 1.0 eq.) was dissolved in THF (10 mL) under nitrogen atmosphere. Then the mixture was cooled down to −78° C. and a solution of n-BuLi in THF (2.5 M, 7.5 mL, 18.8 mmol, 3.0 eq.) was added to the mixture dropwise. The mixture was stirred at −78° C. for 15 min. Then DMF (2.4 mL, 31.2 mmol, 5.0 eq.) was added to the mixture and stirred at −78° C. for 1 h. When the reaction completed, 1 M HCl was added to adjust the pH to 6. The mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using petroleum ether/ethyl acetate (10/1) as eluent to give 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde as a white solid (1.16 g, 60%). EDI-MS: 311.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.24 (s, 1H), 7.92-7.87 (m, 2H), 7.77 (d, 1H), 7.22-7.19 (m, 2H), 4.42-4.30 (m, 1H), 2.30-2.28 (m, 2H), 1.93-1.90 (m, 2H), 1.48-1.11 (m, 5H), 0.82 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]([NH:26][CH:27]([C:29]1[NH:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:33]=1)[CH3:28])([CH3:25])[CH3:24].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[N:26]([CH:23]([CH3:25])[CH3:24])[CH:27]([C:29]1[NH:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:33]=1)[CH3:28])[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)NC(C)c1nc(-c2ccccc2)c[nH]1
Reactant: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N(C(C)C)C(C)c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
Into a solution of 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid (0.18 g, 0.6 mmol) in DMF (7 mL) was added isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine (0.11 g, 0.5 mmol), 1-hydroxybenzotriazole (0.22 g, 1.6 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.12 g, 0.6 mmol). The resulting mixture was stirred under an Argon atmosphere at rt overnight. The reaction mixture was extracted with EtOAc and the combined organic extracts were washed sequentially with saturated aqueous NaHCO3 solution, 1N HCl, saturated aqueous NaHCO3 solution, and brine. The organic phase was then dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (eluent: EtOAc) to afford the product (2-(4-hydroxy-2,6-dimethyl-phenyl)-1-{isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-ethyl)-carbamic acid tert-butyl ester (0.13 g, 50%). MS (ES+): 521.5 (100%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:7][CH3:8])[C:4]([NH2:6])=[O:5].[OH-].[K+].Cl[CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:7]([C@H:3]([N:2]1[CH2:12][CH2:13][CH2:14][C:15]1=[O:16])[C:4]([NH2:6])=[O:5])[CH3:8]
Reactant: CC[C@H](N)C(N)=O
Reactant: O=C(Cl)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: CC[C@@H](C(N)=O)N1CCCC1=O
Yield: 60 %

Procedure:
The compound (−)-(S)-α-ethyl-2-oxo-1-pyrrolidineacetamide is prepared by suspending 50 grams of (S)-2-aminobutyramide hydrochloride in 500 mL of dichloromethane at room temperature, then cooling to temperatures between −5 and 0° C. and adding 81.2 grams of potassium hydroxide and 23.3 grams of tetrabutylammonium bromide at those temperatures. A 66.4 gram amount of 4-chlorobutyryl chloride is added at the same temperatures. After completion of the reaction, solids are removed by filtration, the solution is adjusted to pH 7-7.5 with acetic acid, and dichloromethane is partially evaporated by the application of a vacuum. 150 mL of ethyl acetate are added to precipitate the product, which is isolated by filtration and washed with ethyl acetate and then with acetone; the product has a chiral purity of 99.8 percent by high performance liquid chromatography. The final product is purified by recrystallization from ethyl acetate, giving a yield of 60-65 percent.