Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[H-].[CH2:6]([Al+]CC(C)C)C(C)C.[Nd].C(Br)C=C.[CH2:20](O)[CH2:21][CH2:22][CH3:23].[H-].C([Al+]CC(C)C)C(C)C>[Nd].CCCCCC>[CH2:1]=[CH:2][C:3](=[CH2:6])[CH3:4].[CH2:20]=[CH:21][CH:22]=[CH2:23]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CCCCO
Agent: C=CC=C
Agent: [H-]
Agent: [Nd]
Solvent: CCCCCC
Solvent: C=CCBr
Product: C=CC(=C)C
Temperature: 20 °C
Yield: 87 %

Procedure:
In this experiment, an isoprene-butadiene copolymer rubber was prepared using an alcohol modified neodymium catalyst system. In this procedure, a one gallon (3.78 liter) reactor was charged with 1,214 grams of hexane containing 81.3 grams of butadiene and 558.43 grams of 1.23 molar diisobutylaluminum hydride (DIBAH) in hexane, (i.e., 25% weight percent DIBAH). The reactor was maintained at 20° C. by cooling. N-butanol (11.16 grams) was added with stirring. After stirring for thirty minutes, 107.5 grams of 10.1% neodymium solution (neodymium neodecanoate) diluted with 160 grams of dry hexane, was charged to the reactor. The-solution was stirred for another thirty minutes after which time 18.2 grams of allyl bromide was added. The cooling was stopped and the solution was allowed to warm up. A delayed exothermic reaction was noted. After twenty minutes, bring the solution temperatures to about 10° C. above ambient temperature. When the temperature ultimately dropped, the catalyst solution was aged by heating at 65° C. for ninety minutes. The catalyst prepared had a butanol-DIBAH!Nd-allyl bromide-butadiene molar ratio of 2-13!-1-2-20, respectively, and a concentration of 0.025 molarity with respect to the neodymium.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=1)[C:6]([NH:8][NH2:9])=O.C(N(CC)CC)C.Cl.Cl.[CH3:28][O:29][C:30]1[N:35]=[C:34](/[CH:36]=[CH:37]/[C:38](=[NH:42])OCC)[CH:33]=[CH:32][C:31]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1>C(O)C>[CH3:28][O:29][C:30]1[N:35]=[C:34](/[CH:36]=[CH:37]/[C:38]2[N:42]=[C:6]3[CH:5]([C:10]4[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=4)[CH2:4][CH2:3][N:8]3[N:9]=2)[CH:33]=[CH:32][C:31]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)n1
Reactant: NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1nc(/C=C/c2nc3n(n2)CCC3c2cc(F)c(F)c(F)c2)ccc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 25 h
Yield: 23.8 %

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (120 mL) was added to tert-butyl N′-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate (6.6 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (6.03 g). A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (565 mg) and triethylamine (1.0 mL) in ethanol (10 mL) was added to a solution of ethyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate dihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10 mL) at room temperature. The reaction solution was stirred at 80° C. for 25 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 150 mg of the racemic title compound. The racemic title compound (150 mg) was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the title optically active compound with a retention time of 13 minutes and positive optical rotation (54 mg) and the title optically active compound with a retention time of 34 minutes and negative optical rotation (51 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][O:17][CH2:18][CH2:19]4)=[CH:31][CH:30]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Product: Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCOCC4)cc3)cc2)cc1

Procedure:
Compound 485 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-morpholinobenzoate. [M+H]+ calcd for C24H23N3O3: 402.08; found: 402.03.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=O)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.C(Cl)(=O)C(Cl)=O.CC[N:27]([CH:31]([CH3:33])[CH3:32])C(C)C.C1(N)CC1>CN(C=O)C.C(Cl)Cl>[CH:31]1([NH:27][C:16]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)=[O:18])[CH2:33][CH2:32]1
Reactant: COCCCc1cc(C(=O)O)c2ccccc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCCc1cc(C(=O)NC2CC2)c2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a CH2Cl2 solution (0.1 M) of 3-[3-(methyloxy)propyl]-1-naphthalenecarboxylic acid (1 eq.) from the previous step was added at 0° C. oxalyl chloride (1.2 eq.) followed by a few drops of DMF. The resulting solution was stirred at RT for 2 h before the volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane (0.1 M), cooled to 0° C. and added sequentially Hunig's base (1.2 eq.) an cyclopropylamine (1.1 eq.) dropwise. The resulting suspension was stirred at RT for 18 h. The reaction was quenched with 1 N aq. HCl and extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=1.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>CO.CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][N:15]([CH2:20][C@H:19]([OH:18])[CH2:21][O:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][NH:27]3)[CH2:16][CH:17]=1
Reactant: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CO
Product: COc1ccc2[nH]cc(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.70 g, 3.1 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.58 g, 3.1 mmol). The product was isolated as a yellow foam. Yield 245 mg (19%). mp 105°-110° C. FDMS m/e=417 (M+ of free base). α[D]589 =+7.52 (c=1.01, methanol/dimethylsulfoxide).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:24]=1.[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH3:28][N:14]([C:11]1[N:10]=[CH:9][C:8]2[CH2:7][CH2:6][C:5]3[N:24]=[C:2]([CH3:1])[S:3][C:4]=3[C:13]=2[N:12]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: CI
Reactant: Cc1nc2c(s1)-c1nc(Nc3cccc([N+](=O)[O-])c3)ncc1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(s1)-c1nc(N(C)c3cccc([N+](=O)[O-])c3)ncc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of (2-methyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-8-yl)-(3-nitro-phenyl)-amine (100 mg, 0.3 mmol) in dry DMF (2 mL) was added NaH (7.8 mg, 0.3 mmol) under anhydrous conditions. Once H2 evolution had ceased, iodomethane (22 μL, 50 mg, 0.4 mmol) was added dropwise and the mixture was stirred at room temperature overnight. It was then concentrated under vacuum and H2O (20 mL) was added. The product was extracted with CH2Cl2 (3×30 mL). The combined extracts were dried, filtered, and concentrated under vacuum. Flash column chromatography (10% EtOAc:hexane) afforded the pure title product as a yellow solid (40 mg, 38%): mp 203-204° C. Anal. RP-HPLC: tR 17.1 min (10-70% MeCN, purity 85%). 1H-NMR (CDCl3): δ 8.30 (t, 1H, J 2.3, Ph-H), 8.11 (s, 1H, Py-H), 7.95 (ddd, 1H, J 8.2, 2.3, 1.0, Ph-H), 7.65 (ddd, 1H, J 8.2, 2.3, 1.0, Ph-H), 7.44 (t, 1H, J 8.2, Ph-H), 3.58 (s, 3H, N—CH3), 2.98 (m, 4H, CH2—CH2), 2.69 (s, 3H, CH3). 13C-NMR (CDCl3): δ 169.86, 160.70, 159.30, 157.05, 155.27, 148.71, 146.74, 131.42, 129.33, 120.81, 119.36, 116.63, 38.18, 25.68, 24.22, 20.17. MS (ESI+): m/z 354.09 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
17.64 g (128 mmol) of 4-hydroxybenzoic acid (Aldrich, purity 99%) and 14.32 g (255 mmol) of potassium hydroxide are dissolved in 30 ml of distilled water and added to 260 ml of ethanol. After addition of 33.0 g (29.7 ml, 0.17 mol) of 1-bromooctane (Aldrich, purity 99%), the solution is heated at the boil for 24 hours with stirring. A further 14.32 g (255 mmol) of potassium hydroxide are then added, and the mixture is refluxed with stirring for a further two hours. After the reaction batch has been cooled, the solvent is substantially removed under reduced pressure, and the residue is taken up in distilled water and strongly acidified using 2 M hydrochloric acid solution. The residue is extracted with chloroform, dried over magnesium sulfate, evaporated and recrystallized from acetone.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[C:6]([CH3:18])[C:7]=1OS(C1C=CC=CC=1)(=O)=O)#[N:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)#[CH:20]>CCCCCCC.CCOC(C)=O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[C:20][C:7]2[C:6]([CH3:18])=[CH:5][S:4][C:3]=2[C:1]#[N:2])=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Cc1csc(C#N)c1OS(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(C#Cc2c(C)csc2C#N)cc1

Procedure:
This product was prepared from benzenesulfonic acid 2-cyano-4-methyl-thiophen-3-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 9:1; yield (110 mg, 87%); 1H NMR δ (CDCl3): 7.51 (d, J=8.52 Hz, 2H), 6.88 (d, J=8.60 Hz, 2H), 6.81 (s, 1H), 3.84 (s, 3H), 2.51 (s, 3H); LCMS m/z: 253.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[CH:32][C:25]=12.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:32]2[C:25]3[C:26](=[N:27][CH:28]=[CH:29][N:24]=3)[NH:30][CH:31]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: O=Cc1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Reactant: c1cnc2[nH]ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1cccc(C(O)c2c[nH]c3nccnc23)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To N-(2-fluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (26, 162 mg, 0.47 mmol) in 1 mL of methanol, 5H-pyrrolo[2,3-b]pyrazine (3, 67 mg, 0.56 mmol) and potassium hydroxide (79 mg, 1.4 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 70% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (27, 150 mg, 69%). MS (ESI) [M+H+]+=465.4.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:21]([N:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:12]=2[C:11](=[O:13])[NH:10][C:9]1=[O:14])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Reaction time: 48 h
Yield: 68.7 %

Procedure:
A stirred solution of 7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (10 g, 52 mmol) in anhydrous DMF (100 ml) was treated with K2CO3 (7.91 g, 57.2 mmol) and, after 10 minutes, BuI (6.51 ml, 57.2 mmol). After reacting for 2 days the reaction mixture was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo to give an off-white solid. This was washed with hot cyclohexane and dried under vacuum to give the title compound (8.87 g, 68%); m/z 249.3[MH+].
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[N:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:27][C:26]=1[CH3:37])=[C:23]=[S:24]>CC(N(C)C)=O>[F:19][C:16]1[CH:17]=[CH:18][C:5]2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:23]([NH:22][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:27][C:26]=3[CH3:37])=[S:24])[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:15]=1
Reactant: Cc1cc(N2CCOCC2)ccc1N=C=S
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2cc(F)ccc21
Solvent: CC(=O)N(C)C
Product: Cc1cc(N2CCOCC2)ccc1NC(=S)NC1N=C(c2ccccc2)c2cc(F)ccc2N(C)C1=O
Temperature: 70 °C
Yield: 100.5 %

Procedure:
As illustrated in the scheme above, a solution of 3-amino-7-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (0.0056 g, 0.020 mmol) and 4-(4-isothiocyanato-3-methylphenyl)morpholine (0.0048 g, 0.020 mmol) in DMA (0.5 mL) was heated at 70° C. for 16 h. The reaction was cooled and concentrated in vacuo, and the residue was lyophilized to provide the title compound (0.0104 g, quantitative). 1H-NMR (CDCl3): δ 7.63-7.58 (m, 2H), 7.50-7.45 (m, 1H), 7.44-7.36 (m, 4H), 7.36-7.26 (m, 3H), 7.09 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 6.85-6.78 (m, 2H), 6.09-6.05 (m, 1H), 3.90-3.83 (br m, 4H), 3.41 (s, 3H), 3.21-3.15 (br s, 4H), 2.36 (s, 3H). MS (ESI) (M+H)+=518.HRMS calculated for (C28H28FN5O2S+H) (M+H)+: 518.2026. Found (ESI): 518.2117.
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[O:18])[C:9]2[C:8](=[O:19])[N:7]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:6](=[O:28])[N:5]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:4]=2[N:3]=1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C(Cl)(Cl)Cl>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:2]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:17]=[O:18])[C:9]3[C:8](=[O:19])[N:7]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[C:6](=[O:28])[N:5]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:4]=3[N:3]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2c(nc(Cl)n2-c2ccccc2C=O)n(COC(=O)C(C)(C)C)c1=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2nc3c(c(=O)n(COC(=O)C(C)(C)C)c(=O)n3COC(=O)C(C)(C)C)n2-c2ccccc2C=O)CC1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
2,2-Dimethylpropionic acid [8-chloro-1-(2,2-dimethyl-propionyloxymethyl)-7-(2-formylphenyl)-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl ester (2.0 g) and piperazine-1-carboxylic acid tert-butyl ester (2.15 g) were mixed, and the mixture was stirred at 150° C. for 1 hour and 10 minutes. The reaction mixture was diluted with chloroform and purified by silica gel column chromatography to give 1.94 g of the title compound from the elution fraction of hexane-ethyl acetate (1:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5](=[CH:26][CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[N:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[Cl:36][C:37]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:38]=1[CH:39]=O.N1C=CC=CC=1.N1C=CC=CC1>C(#N)C>[Cl:36][C:37]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:38]=1[C:39]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)C(=CC=Cc1ccc(Cl)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1=CCNC=C1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
The residue of 3-methoxycarbonyl-6-(4-chlorophenyl)-1,1,1-triphenyl-2-aza-1λ5-phosphahexa-1,3,5-triene (10.2 mmol) from Step D was dissolved in acetonitrile (40 mL) and 2,4-dichlorobenzaldehyde (1.78 g, 10.2 mmol) was added. The reaction was heated to 60° C. under a condenser (left open to the air) for 20 h. HPLC/MS indicated a mixture of the desired title pyridine and dihydropyridine intermediate 394 (M+1), 396 (M+3), Rt=4.75 min). The reaction was heated a further 4 h and was then concentrated. The residue was purified by flash column chromatography on silica gel eluted with 0 to 20% ethyl acetate in hexanes to afford methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-2-carboxylate. HPLC/MS: 392 (M+1), 394 (M+3); Rt=4.16 min. 1HNMR (CDCl3): δ 4.039 (s, 3H), 7.09 (br d, J=8.5 Hz, 2H), 7.26 (br d, J=8.4 Hz, 2H), 7.28 (d, J=2 Hz, 1H), 7.30 (dd, J=2.0 and 8.3 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[NH:7]1[C:15]2[C:10]3[C:11](=[CH:16][CH:17]=[CH:18][C:9]=3[C:8]1=[O:19])[CH:12]=[CH:13][CH:14]=2.C(Br)C#C.C(O)(=O)C>CN(C)C=O>[CH2:3]([N:7]1[C:15]2[C:10]3[C:11](=[CH:16][CH:17]=[CH:18][C:9]=3[C:8]1=[O:19])[CH:12]=[CH:13][CH:14]=2)[C:2]#[CH:1]
Reactant: O=C1Nc2cccc3cccc1c23
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)c2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Potassium-t-butoxide, 6.17 g (0.055 mol) was added to a solution of 8.46 g (5 mmol) of benz[cd]indol-2(1H)-one in 100 ml of dimethylformamide. After stirring for 10 minutes at room temperature, 4.9 ml (0.055 mol) of propargyl bromide was added and the mixture was stirred for 1 hour at room temperature. The reaction mixture was acidified with acetic acid and partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was dried and evaporated and the residue was crystallized from tetrahydrofuran/ethanol to leave 8 g (77%) of product with m.p. 183°-186° C. The title compound was recrystallized for analysis twice from methylene chloride/ethyl acetate and had m.p. 185°-187° C.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccc(F)cc1)[C@@H]1CCC(F)(F)C1
Product: O=C(O[C@H]1CCNC1)[C@](O)(c1ccc(F)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)acetic acid and t-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:30])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25](Br)[N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:30])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([NH:36][CH2:35][CH2:34][O:33][CH3:32])[N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COCCN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(Br)n2)cc1
Solvent: CN1CCCC1=O
Product: COCCNc1cccc(COc2ccc(C(=O)Nc3cc(C(=O)NC4CC4)ccc3C)cc2)n1
Temperature: 190 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-({4-[(6-bromo-2-pyridinyl)methoxy]benzoyl}amino)benzamide (100 mg, 0.21 mmol), 2-methoxyethylamine (500 μL) and NMP (500 μL) was heated to 190° C. in the microwave for 90 min. The cooled reaction mixture was eluted through a silica cartridge with isohexane then ethyl acetate to give the crude product which was triturated with diethyl ether to give the title compound as a solid (36 mg); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 3.28 (m, 2H), 3.31 (m, 3H), 5.08 (s, 2H), 6.47 (d, 1H), 6.61 (d, 2H), 7.14 (d, 2H), 7.32 (m, 2H), 7.40 (m, 1H), 7.63 (m, 1H), 7.80 (m, 2H), 7.97 (m, 2H), 8.37 (m, 1H), 9.84 (s, 1H); Mass Spectrum: M+H+ 475.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](O)=O.C=O.O>CC(C)=O>[CH2:1]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@H](NCc1ccccc1)C(=O)O
Reactant: O=CO
Agent: C=O
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H](C)[C@@H](C(=O)O)N(C)Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To 110.7 g of above described N-benzyl-isoleucine (0.50 mol) were added 69.0 g formic acid (1.50 mol) and 49.4 g formaldehyde 36.5% in water (0.60 mol) and the clear, colorless reaction mixture was heated under stirring to ˜90° C. for 2 h. The reaction mixture was concentrated by rotary evaporation (60° C./25 mbar) and the residue was triturated under stirring (˜15 min) with 250 ml acetone. After evaporation of the solvent, triturating was repeated twice using a total of 500 ml acetone. Evaporation of the solvent (50° C./10 mbar) gave 129.9 g white, crystalline residue which was stirred with 200 ml acetone for 1 h at RT and 3 h at −20° C. The crystal suspension was filtered, washed with cold acetone and dried (16 h/50° C./10 mbar) affording 103.9 g (88.3%) product as a white, crystalline powder.