Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1O[C@@H](C)C(O)=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH:30]=1>>[Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1[NH:21][CH:20]([CH3:30])[C:19]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[N:21][C:20]=2[CH:30]=1)=[O:23]
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Reactant: C[C@H](Oc1cccc(Cl)c1Cl)C(=O)O
Product: CC(Nc1cccc(Cl)c1Cl)C(=O)Nc1ccc2oc(-c3ccncc3)nc2c1

Procedure:
Similarly prepared as per compound 8 procedure, using (S)-2-(2,3-dichlorophenyl) propanoic acid 7 and compound 4 (4-pyridine) to obtained title compound Q60 as white solid (71%). 1H NMR (CDCl3, 400 MHz) δ 1.72 (d, J=6.8 Hz, 3H), 3.95 (dq, J=7.2 Hz, J=3.2 Hz, 1H), 4.79 (d, J=2.8 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.96 (d, J=8 Hz, 1H), 7.09 (t, J=8 Hz, 1H), 7.46 (dd, J=9.2 Hz, J2=2 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 8.06 (d, J=4 Hz, 2H), 8.09 (d, J=1.6 Hz, 1H), 8.56 (s, 1H), 8.8 (bs, 2H); 13C NMR (CDCl3, 100 MHz) δ 20.0, 56.4, 110.8, 111.1, 112.4, 118.6, 119.6, 120.9, 121.2, 128.4, 133.5, 134.3, 134.7, 142.4, 144.1, 148.0, 150.9, 161.7, 171.7; C21H17N4O2Cl2 (M+H)+ calcd. 427.0729 found 427.0724.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8]C(=O)CCCCl)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH2:19]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([OH:8])[CH:3]=1)[C:6](=[O:19])[CH2:7][CH:2]2[CH3:3]
Reactant: O=C(CCCCl)Oc1cccc(F)c1
Reactant: O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC1CC(=O)c2c(O)cc(F)cc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
After the obtained 4-chloro-butanoic acid 3-fluorophenyl ester (35.33 g) was heated to 80° C., aluminium chloride (24.0 g) was added. The reaction mixture started to foam. After the foaming was reduced the mixture was stirred during 2 hours at 100° C. After cooling water and ethyl acetate were added and the mixture was heated on a steam bath After all the oil was dissolved the organic layer was separated and washed with water and brine. The solvent was removed and the residue was crystallized from 2-propanol to give 21.2 g of 5-fluoro-2,3-dihydro-7-hydroxy-3-methyl-1H-inden-1-one, M.S. (C.I.) (M/Z): 181 [M+H]+.
Reaction SMILES: Cl.C1(C2CCN(C[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:29](=[O:30])[C:28]4[CH:31]=[CH:32][CH:33]=[C:26]5[C:27]=4[C:22](=[CH:23][CH:24]=[CH:25]5)[C:21]3=[O:34])CC=2)C=CC=CC=1.[Br:35]CCCCCBr.BrCCCCCCBr>>[Br:35][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:29](=[O:30])[C:28]2[CH:31]=[CH:32][CH:33]=[C:26]3[C:27]=2[C:22](=[CH:23][CH:24]=[CH:25]3)[C:21]1=[O:34]
Reactant: BrCCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCN1CC=C(c2ccccc2)CC1
Agent: BrCCCCCCBr
Agent: Cl
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
Following the procedure of part (a) of Example 56 but substituting 1,5-dibromopentane for the 1,6-dibromohexane, one obtains 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113°-115°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][C:13]=2Br)=[CH:8][CH:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][C:13]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(C2=C(Br)CCCc3ccccc32)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Yield: 62.3 %

Procedure:
To a solution of the bromide (2c) (6.85 g, 17.9 mmol) in DME (125 mL) was added benzene boronic acid (3.25 g, 26.8 mmol), tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol), and 2N aqueous sodium carbonate (13.5 mL). After refluxing overnight the solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 7.5 EtOAc/hexanes to 100% EtOAc) followed by recrystalization from EtOAc to give (2d) as a white solid (4.24 g, 62%): 1H NMR (CDCl3) δ 7.58 (d, J=16.1 Hz, 1H), 7.20 (m, 10H), 6.92 (d, J=8.1 Hz, 2H), 6.85 (dd, J=7.3, 1.1 Hz, 1H), 6.32 (d, J=16.1 Hz, 1H), 3.78 (s, 3H), 2.82 (t, J=7.0 Hz, 2H), 2.40 (t, J=7.0 Hz, 2H), 2.20 (m, 2H); APcI m/z: 422 (M+H+CH3CN+, 100%).
Reaction SMILES: C1C2N[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=C(C(OCC)=O)N=1.[H-].[Na+].[CH2:21]([N:28]1[C:40]2[C:39]([CH3:41])=[N:38][C:37]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)C1C=CC=CC=1>CN(C=O)C>[C:6]1([CH2:5][CH2:4][CH2:21][N:28]2[C:40]3[C:39]([CH3:41])=[N:38][C:37]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36][C:35]=3[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2c(C)n1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3ccccc3n(CCCc3ccccc3)c2c(C)n1
Temperature: 25 °C
Yield: 75 %

Procedure:
Compound 10 (2.54 g, 10 mmol) was mixed with DMF (50 ml) and stirred at room temperature until the solution became clear. 60% NaH (1.2 g) was added and stirred for 5 minutes, followed by the addition of 1-bromine-3-phenyl propane (10 ml), and TLC track measurement. The mixture was reacted at room temperature for about 15 h. The subsequent steps were conducted according to those for synthesizing compound 58. Finally, white crystals (2.8 g, 75%) were obtained, mp 101-102° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.Cl[C:24]1[NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[N:25]=1>C(O)CCC.C(N(CC)CC)C>[NH:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[N:20]1[CH2:21][CH2:22][N:17]([C:5]2[N:4]=[C:3]([NH2:2])[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)[CH2:18][CH2:19]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4nc5ccccc5[nH]4)CC3)nc(N)c2cc1OC
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To 5.14 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride in 100 ml butanol, 11 ml of triethylamine was added. The mixture was stirred for 15 min and 2.65 g of 2-chloro-1H-benzimidazole was added. The mixture was refluxed for 18 hr and evaporated. Water was added to the residue and the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate and evaporated. The residue was crystallized from methanol to give 3.5 g of the title compound, which was recrystallized from methanol: mp>250° C.; ir (nujol mull) 3360 and 3180 cm-1 ; uv max (MeOH) 341 (ε=6,300), 284 (ε=28,500) and 251 nm (ε=66,800); nmr (DMSO-d6) ε 3.5 (m, 4H), 3.8 (m, 4H), 3.8 (s, 3H), 3.84 (s, 3H), 7.1 (m, 8H) and 10.7 (s, 1H); and Anal. Calcd for C21H23N7O2. 1/2 H2O: C, 60.86% H, 5.79% N, 23.67% and Found: C, 60.87% H, 5.98% N, 23.65%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:12][CH2:11]2)[C:3]=1[C:4]#[N:5].[S:13](Cl)(=[O:16])(=O)[NH2:14].[OH-:18].[Na+].Cl>CC(N(C)C)=O.O>[CH:10]1([C:6]2[C:3]3[C:4]([NH2:5])=[N:14][S:13](=[O:16])(=[O:18])[NH:1][C:2]=3[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12]1
Reactant: [OH-]
Reactant: N#Cc1c(N)cccc1C1CC1
Reactant: NS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC1=NS(=O)(=O)Nc2cccc(C3CC3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A solution of 2-amino-6-cyclopropylbenzonitrile (Example 92a) (1.0 eq., 626 μmol, 99 mg) and sulfamoyl chloride (1.5 eq., 939 μmol, 109 mg) in DMA (1 mL) was stirred in a scintillation vial at room temperature. After 2 hours, NaOH (1.5 eq., 939 μmol, 1N, 939 μL) and water (18 mL) were added and the resulting precipitated product stirred overnight at room temperature. The precipitate was filtered off and washed with water (3×5 mL). The wet precipitate was dissolved in EtOH (5 mL, 200 proof) and NaOH (2.5 eq., 1565 μmol, 1N, 1565 μL) was added. The reaction was heated to 80° C. with stirring overnight. The reaction mixture was cooled to room temperature and HCl (2.5 eq., 1565 μmol, 1N, 1565 μL) was added to the reaction vial. The ethanol and most of the water was removed on the rotary evaporator. The resulting precipitate was suspended in water (5 mL), stirred, filtered off, and washed with water (20 mL). The product was dried in a vacuum oven to give 5-cyclopropyl-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide (41 mg, 28%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.71 (m, 2H), 1.04 (m, 2H), 2.401 (m, 1H), 6.85 (d, J=8 Hz, 2H), 7.37 (t+br. s, J=8 Hz, 2H), 8.40 (br. s, 1H), 10.80 (s, 1H). 1H NMR (400 MHz, CD3OD) δ 0.89 (m, 2H), 1.15 (m, 2H), 2.36 (m, 1H), 6.90 (d, J=8 Hz, 1H), 6.97 (d, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H). MS 238 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][C:14]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])=[C:13]4[NH:25][C@H:26]3[CH2:31][CH2:30][C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28][CH2:27]3)=[CH:9][C:4]=2[N:3]=[CH:2]1.C(O)(C(F)(F)F)=O>>[NH2:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([NH:25][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:8]4[CH:7]=[CH:6][C:5]5[NH:1][CH:2]=[N:3][C:4]=5[CH:9]=4)[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:23][CH2:24]2)=[O:21])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc5[nH]cnc5c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc5[nH]cnc5c4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(1H-benzo[d]imidazol-5-yl)-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (45.3 mg, 0.086 mmol) was reacted with TFA (2 mL) to afford the desired product (21.3 mg, 58%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 9.16 (s, 1H), 8.48 (s, 1H), 8.27 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.99-7.93 (m, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 4.29 (s, 1H), 3.17 (s, 1H), 2.93-2.78 (m, 1H), 2.36 (d, J=11.1 Hz, 2H), 2.15 (d, J=11.2 Hz, 2H), 1.72-1.53 (m, 4H), 1.23-1.17 (m, 2H), 1.14-1.05 (m, 2H); ESI MS m/z 426 [C26H27N5O+H]+; HPLC 96.0% (AUC), tR=8.89 min.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:11]=[C:12]([CH3:15])[S:13][CH:14]=1.[NH4+].[Cl-]>CCOCC>[CH3:15][C:12]1[S:13][CH:14]=[C:10]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1cc(Br)cs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cc(-c2ccccc2)cs1

Procedure:
A solution of PhMgBr (prepared from 1.65 g of Mg (0.0678 mol) and 10.64 g of PhBr (0.0678 mol) in 40 mL of diethyl ether) was added to a mixture of 10 g (0.0565 mol) of 4-bromo-2-methylthiophene and 0.62 g (0.0012 mol) of NiCl2dppp in 50 mL of ether under stirring at reflux. The reaction mixture was refluxed for additional 3 h and then stirred overnight. The resulting mixture was treated with 10% aqueous NH4Cl, the organic layer was separated, washed with 10% aqueous NH4Cl and then dried with anhydrous Na2SO4. Solvent was evaporated, the residue was recrystallized from methanol. Yield 6.8 g (70%) of colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([NH:24][C:25](=[O:34])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[S:23])[CH:5]=[CH:6][C:7]=1[O:8]C1C2=C(C)C(OC)=CN2N=CN=1.Cl[C:36]1[N:44]=[CH:43][N:42]=[C:41]2[C:37]=1[N:38]=[C:39]([CH2:52][CH3:53])[N:40]2[CH:45]([CH:49]1[CH2:51][CH2:50]1)[CH:46]1[CH2:48][CH2:47]1.N12CCN(CC1)CC2>CC#N>[CH:46]1([CH:45]([CH:49]2[CH2:51][CH2:50]2)[N:40]2[C:39]([CH2:52][CH3:53])=[N:38][C:37]3[C:41]2=[N:42][CH:43]=[N:44][C:36]=3[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:21][C:22]([NH:24][C:25](=[O:34])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[S:23])=[CH:3][C:2]=2[F:1])[CH2:48][CH2:47]1
Reactant: COc1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Reactant: CCc1nc2c(Cl)ncnc2n1C(C1CC1)C1CC1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCc1nc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncnc2n1C(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To a mixture 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (24 mg, 0.075 mmol, Compound A of Example 3), 6-chloro-9-(dicyclopropylmethyl)-8-ethyl-9H-purine (20.7 mg, 0.075 mmol, PCT Appl. WO 99/01454, U.S. Pat. No. 6,143,743, example 831, the disclosure of which is herein incorporated by reference) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 8.4 mg, 0.075 mmol) was added MeCN (2 mL). The reaction was stirred at RT for 4 h and concentrated in vacuo. The residue was purified by reverse phased preparative HPLC to give the title compound (15.3 mg, 36%) as a white solid. 1H NMR (CDCl3) δ 12.43 (m, 1H), 8.48 (m, 1H), 8.40 (m, 1H), 7.92 (m, 1H), 7.28 (m, 4H), 7.13 (m, 2H), 3.72 (s, 2H), 3.34 (m, 3H), 1.53 (m, 3H), 0.81 (m, 2H), 0.46 (m, 4H), 0.23 (m, 2H), MS(ESI+) m/z 489 (M+H)+.
Reaction SMILES: C(CC(O)=O)C.[C:7]([N:14](C(OC(C)(C)C)=O)[C@H:15]([C:22]([OH:24])=O)[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C[N:33]1CCOCC1.ClC(OCC(C)C)=O.N[C@@H](CC(C)C)CSCC>C(OCC)(=O)C>[C:7]([NH:14][C@H:15]([C:22]([NH2:33])=[O:24])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCSC[C@@H](N)CC(C)C
Solvent: CCOC(C)=O
Solvent: CCCC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Reaction time: 0.25 h

Procedure:
A mixture of NαNim -bis BOC-(S)-histidine ethyl acetate solvate (0.96 g, 2.50 mmol), 4 methyl-morpholine (0.28 mL, 2.50 mmol) and isobutyl chloroformate (0.33 mL, 2.50 mmol) in ethyl acetate (35 mL) is stirred in an ice bath under N2 for 15 minutes. A solution of (S)-2-amino-1-ethylthio-4-methyl pentane (0.40 g, 2.50 mmol) in ethyl acetate (2 mL) is then added and the reaction stirred at room temperature for 18 hours. After washing with 10% citric acid, brine, saturated NaHCO3 solution and brine, the ethyl acetate extract is dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is flash chromatographed over silica gel. Elution with a mixture of 2% methanol- 98% chloroform affords pure BOC-protected histidineamide.
Reaction SMILES: Cl.[C:2]([O:5][CH2:6][C:7](=[O:31])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C@@H:23]([OH:27])[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[CH2:18][CH2:19]2)[C@@H:14]([Cl:29])[CH2:13]3)[CH2:10][C@H:9]1[CH3:30])(=[O:4])[CH3:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:2]([O:5][CH2:6][C:7](=[O:31])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C@@H:23]([OH:27])[CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[CH:18]=[CH:19]2)[C:14]([Cl:29])=[CH:13]3)[CH2:10][C@H:9]1[CH3:30])(=[O:4])[CH3:3]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
A hydrogen chloride stream is introduced into a solution of 1.0 g. of 21-acetoxy-6α-chloro-11β-hydroxy-16α-methyl-4-pregnene-3,20-dione in 100 ml. of dioxane for 30 minutes at 25° after adding 1.5 g. of dichlorodicyanobenzoquinone. The solution is then heated for 15 hours to 120°. After cooling, the solution is filtered, the filter cake washed with dichloromethane, and the filtrate evaporated under vacuum. The residue of the evaporation is chromatographed on silica gel. With 32-40% acetone-hexane, after recrystallization from acetone-diisopropyl ether, 380 mg. of 21-acetoxy-6-chloro-11β-hydroxy-16α-methyl-1,4,6-pregnatriene-3,20-dione is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: Ic1c[nH]cn1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (1.31 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure IVa. Obtained as a pink solid (1.88 g, 97%). MS (ISP) 485.3 [(M+H)+]; mp 194° C.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:13])[NH:9][N+]([O-])=O.[H][H].Cl>CO.[Pd].CC(O)C>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:13]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=N)N)C(=O)O

Procedure:
Boc-hArg(NO2)-Amp (1.5 g) was dissolved in HPLC grade MeOH (120 ml) and to the clear solution was added the Pd—C catalyst (10%, Aldrich). A small stir bar was placed in the flask and the reaction mixture was stirred under a slow stream of hydrogen overnight after incorporating the 5-6N HCl in 2-propanol solution (1.5 ml). After the overnight reaction, the solution was filtered and the solvent evaporated. The white crystalline product was dried under vacuum to give 1.61 g of the Boc-hArg-Amp intermediate product.
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:5][CH:4]=[C:3]([NH:19][CH2:20][CH2:21][C:22]2[N:27]=[C:26]3[C:28]([N:30]=[C:31]([NH2:33])[NH:32][C:25]3=[N:24][CH:23]=2)=[O:29])[CH:2]=1.[CH2:34]1NC2NC(N)=NC(=O)C=2NC1CCNC1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1.[H][H].C=O.[BH4-].[Na+]>>[CH3:34][N:27]1[C:26]2[C:28]([N:30]=[C:31]([NH2:33])[NH:32][C:25]=2[NH:24][CH2:23][CH:22]1[CH2:21][CH2:20][NH:19][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])=[CH:1][CH:2]=1)=[O:29]
Reactant: Nc1nc(=O)c2c([nH]1)NCC(CCNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)N2
Reactant: Nc1nc(=O)c2nc(CCNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2[nH]1
Reactant: [H][H]
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Product: CN1c2c([nH]c(N)nc2=O)NCC1CCNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1

Procedure:
In the preparation of N5 -methyltetrahydrohomofolic acid from homofolic acid, the steps consisting of reducing homofolic acid to tetrahydrohomofolic acid in the dark with a slight overpressure of hydrogen in the presence of reduced platinum oxide, immediately reacting tetrahydrohomofolic acid with formaldehyde to product the intermediate 5,11-methylenetetrahydrohomofolic acid and reducing without isolation the formed 5,11-methylene intermediate with sodium borohydride to give the desired 5-methyltetrahydrohomofolic acid (5-MeTHHF) and removing by precipitation at a pH of about 3.8 with acetic acid the side products, refrigerating the product filtrate containing 5-MeTHHF overnight and separating and recovering 5-MeTHHF.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13](=[C:15]3[C:20](=[O:21])OC(C)(C)OC3=O)[OH:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1>CN(C1C=CN=CC=1)C.C1C=CC=CC=1>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:29]=[C:30]([NH:34][C:20](=[O:21])[CH2:15][C:13](=[O:14])[CH2:12][O:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)[CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: CC1(C)OC(=O)C(=C(O)COC23CC4CC(CC(C4)C2)C3)C(=O)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: COC(=O)c1cccc(NC(=O)CC(=O)COC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A mixture of 5-[2-(adamantan-1-yloxy)-1-hydroxy-ethylidene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (27.27 g, 81.1 mmol), 3-amino-benzoic acid methyl ester (11.68 g, 77.2 mmol) and DMAP (cat.) in benzene (550 mL) was heated at reflux for 2 hours. The mixture was allowed to cool to room temperature. The solvent was removed by evaporation at reduced to give the crude product as a red oil. Purification by flash column chromatography (DCM:ethyl acetate 6:1) yielded the title compound as a yellow foam (20.34 g, 68%). 1H NMR (CDCl3) 9.22 (1H, br s), 8.08-8.07 (1H, t), 7.91-7.88 (1H, m), 7.81-7.77 (1H, m), 7.43-7.38 (1H, m), 4.14 (2H, s), 3.91 (3H, s), 3.74 (2H, s), 2.19 (3H, br s), 1.83-1.58 (12H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br.[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27]Br)[CH2:21]1)=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(CC(C)C)=O>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: Oc1ccccc1-c1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)[C@@H]1CCCN(CCOc2ccccc2-c2ccccc2)C1
Yield: 43.4 %

Procedure:
A mixture of 2-hydroxybiphenyl (3.0 g, 17.6 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (6.1 g, 17.6 mmol, EP 374801), potassium carbonate (9.7 g, 71 mmol) and methyl isobutylketone (50 ml) was heated at reflux for 22 h. The reaction mixture was allowed to cool, diluted with methyl isobutylketone and filtered. The solvent was evaporated in vacuo and the residue was purified by column chromatography (heptane/ethyl acetate=2/3) to give 2.7 g of (R)-1-(2-(2-phenylphenoxy) ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1.[OH:14][CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1>>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([N:17]2[CH2:18][CH2:19][CH2:20][CH:15]([OH:14])[CH2:16]2)=[O:12])=[CH:6][C:5]([Cl:13])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)cc1/C=C/C(=O)O
Reactant: OC1CCCNC1
Product: Nc1ncc(Cl)cc1/C=C/C(=O)N1CCCC(O)C1

Procedure:
The title compound was prepared from (E)-3-(2-amino-5-chloro-3-pyridinyl)-2-propenoic acid and 3-hydroxypiperidine as a white solid:
Reaction SMILES: [C:1]1([SiH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:23][CH2:24][CH:25]=[CH2:26])(=O)C>>[OH:23][CH2:24][CH2:25][CH2:26][Si:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc([SiH](c2ccccc2)c2ccccc2)cc1
Reactant: C=CCOC(C)=O
Product: OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The above-mentioned compounds (G-1), (G-2) and (G-3) are prepared by hydrolyzing an adduct (C) of commercially available triphenylsilane (A) and allyl acetate (B) with an alkali to obtain 3-hydroxypropyltriphenylsilane (D) and reacting this compound (D) with acryloyl chloride (E), methacryloyl chloride (E-2) or allyl chloroformate (E-3) in the presence of a dehydrochlorinating agent such as pyridine or triethylamine. ##STR5##