Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([OH:35])[C:17]2[C:12](=[CH:13][C:14](SC)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:24][C@H:25]2[CH2:28][C@H:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:26]2)[C:10]1=[O:34].OO.[S:38]([O-:42])([O-])(=[O:40])=S.[Na+].[Na+].[C:45](O)(=O)C>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1([OH:35])[C:17]2[C:12](=[CH:13][C:14]([S:38]([CH3:45])(=[O:42])=[O:40])=[CH:15][C:16]=2[C:18]([F:20])([F:21])[F:19])[N:11]([CH2:24][C@H:25]2[CH2:28][C@H:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:26]2)[C:10]1=[O:34]
Reactant: CC(=O)O
Reactant: O=S([O-])([O-])=S
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3c(F)cccc3Cl)c3c2cc(SC)cc3C(F)(F)F)C1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3c(F)cccc3Cl)c3c2cc(S(C)(=O)=O)cc3C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound of Example 32-1 (70 mg) in acetic acid (1 mL) were added sodium tungstate dihydrate (39 mg, 0.118 mmol) and 30% aqueous hydrogen peroxide (0.1 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate and washed with saturated saline, and the organic layer was dried over magnesium sulfate and filtered, and then the filtrate was evaporated and purified by silica gel column chromatography (chloroform/methanol=20/1 to 10/1) followed by hydrochloride salt formation to give the titled compound (29 mg, 31%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3([CH3:32])[CH2:31][O:30][CH2:29]3)=[CH:22][C:21]=1[N+:33]([O-])=O)[CH:15]=[CH:14]2)C1C=CC=CC=1.[CH2:36](N(CC)CC)C.C(O)=O.C(O)(=O)C.C(N)=N>[OH-].[OH-].[Pd+2].C(O)C>[CH3:32][C:28]1([CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]3[N:19]([C:16]4[CH:15]=[CH:14][C:13]5[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=5)[N:17]=4)[CH:36]=[N:33][C:21]=3[CH:22]=2)[CH2:31][O:30][CH2:29]1
Reactant: CC1(COc2ccc(Nc3ccc4cccc(OCc5ccccc5)c4n3)c([N+](=O)[O-])c2)COC1
Reactant: CCN(CC)CC
Agent: [Pd+2]
Agent: N=CN
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O=CO
Product: CC1(COc2ccc3c(c2)ncn3-c2ccc3cccc(O)c3n2)COC1
Temperature: 50 °C
Yield: 82 %

Procedure:
The compound (8-Benzyloxy-quinolin-2-yl)-[4-(3-methyl-oxetan-3-ylmethoxy)-2-nitro-phenyl]-amine (5 g, 10.6 mmol, 1.0 equivalent), ethanol (50 mL, 10 volumes)i triethylamine (7.8 mL, 56.2 mmol, 5.3 equivalents), and palladium hydroxide on carbon (500 mg, 0.1 weight equivalents) were charged to a 100 mL round bottom flask. The solution was deoxygenated and then heated to 50° C. Once the reaction reached 50° C., formic acid (2.2 mL, 56.2 mmol, 5.3 equivalents) was charged slowly to control any exotherm or off-gasing. The reaction was then heated at 55° C. for 15–25 hours. After nitro group reduction and benzyl group removal was noted by APCI MS, the reaction was cooled to 40° C. and filtered through a pad of Celite. The flask and the filter cake were washed once with ethanol (2.5 volumes). The filtrate was then charged to another 100 mL round bottom flask containing formamidine acetate (2.3 g, 22.3 mmol, 2.1 equivalents) and the reaction was heated at reflux for ˜8 hours. At reaction completion, the reaction was cooled to 20–25° C. and allowed to granulate for 10–20 hours. The solids were isolated by filtration and dried under vacuum at 40° C. with a slight nitrogen bleed to afford 3.14 g of 2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-ol as a yellow solid (82% yield). 1H NMR (d6-DMSO): δ 9.88 (s, 1H), 9.25 (s, 1H), 8.61 (d, 1H, J=9.1 Hz), 8.51 (d, 1H, J=9.1 Hz), 8.10 (d, 1H, J=9.1 Hz), 7.44 (m, 2H), 7.35 (d, 1H, J=2.5 Hz), 7.18 (dd, 1H, J=7.5, 1.7 Hz), 7.08 (dd, 1H, J=8.7, 2.5 Hz), 4.51 (d, 2H, J=5.8 Hz), 4.31 (d, 2H, J=5.8 Hz), 4.12 (s, 2H), 1.39 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][C@H:15]([C:17]([NH:19][C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18])[CH3:16].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][C@H:15]([C:17]([NH:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(C)(NC(=O)[C@H](C)N)c1ccccc1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccccc1

Procedure:
Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and ethyl N-(L-alaninyl)-2-amino-2-phenylpropionate hydrochloride (prepared from N-BOC-L-alanine (Sigma) and D,L-α-methylphenylglycine ethyl ester (from Example D9 above) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=128-130° C.). The reaction was monitored by tlc (Rf=0.2 in 3% MeOH/CHCl3) and the product was purified by silica gel chromatography using 3% MeOH/CHCl3 as the eluent.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CCN(CC)CC.[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:26][C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1)#[N:15]>C(Cl)Cl>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:26][C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)=[C:20]([S:22]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:23])=[O:24])[CH:21]=1)#[N:15]
Reactant: CN(C)CCN
Reactant: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCNS(=O)(=O)c1cc(C#N)ccc1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of N1,N1-dimethyl-ethane-1,2-diamine (74.0 mg, 0.84 mmol) and Et3N in dry CH2Cl2 (3 ml) was added the solution of 5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylchloride (90%, 282 mg, 0.7 mmol) in dry CH2Cl2 (6 ml) dropwise. The resulting solution was stirred at room temperature for 1 hour. CH2Cl2 (60 ml) was added and the mixture was washed with water, brine, and dried over MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (CH2Cl2/CH3OH=10:1) to give 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-benzene-sulfonamide as white solid (220 mg, 75.9%): HPLC-MS (ESI): Calcd for C19H21Cl2N3O4S [M+H]+ 414, Found: 414
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41](=O)[NH:40][N:39]=2)=[CH:33][CH:32]=1.N>C(Cl)(Cl)Cl.O>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:38]([CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)=[N:39][N:40]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Agent: Cl
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 200 °C

Procedure:
A mixture of 14.19 g (0.1 mol) phosphorus pentoxide, 13.77 g (0.1 mol) triethylamine hydrochloride and 12.76 g (0.1 mol) 4-chloroaniline is heated and stirred in a nitrogen atmosphere at 200° C. until a homogeneous melt has formed (about 20 min). To the melt, 5.93 g (0.025 mol) 4-(4-pyridylmethyl)-1(2H)-phthalazinone (for preparation see German Auslegeschrift no. 1 061 788 [published 23 Jul. 1959]) is added, and the reaction mixture is stirred for 3 h at 200° C. After the reaction mixture has cooled to about 100° C., 200 ml of water is added. Stirring is continued until the temperature reaches about 30° C., and then 20 ml conc. ammonia (30% aqueous ammonium hydroxide solution) and 900 ml chloroform are added consecutively. As soon as a diphasic mixture has formed, the organic phase is separated off, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated on a RE to a volume of about 50 ml, to which 100 ml acetate is then added, and the mixture is cooled in an ice bath. The crystallizate obtained is filtered off and washed with acetate and ether. After recrystallization from methanol and drying under HV for 8 h at 120° C., the title compound is obtained; m.p. 194-195° C.; ESI-MS: (M+H)+=347.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:18][C:19]=1[NH:20][CH:21]([CH3:23])[CH3:22])=[O:14]>ClCCCl>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:10])=[O:9])[CH2:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[CH:18][C:19]=1[N:20]([CH:21]([CH3:23])[CH3:22])[C:8]([CH:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)=[O:9])=[O:14]
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)cc1NC(C)C
Agent: CC1=CCC(C(=O)Cl)CC1
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccc(F)cc2)cc1N(C(=O)C1CC=C(C)CC1)C(C)C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
4-Methyl-cyclohex-3-enecarbonyl chloride was prepared according to the procedure reported in Journal of Organic Chemistry (1986) 51(23), PP4485-8. This 4-Methyl-cyclohex-3-enecarbonyl chloride (0.121 g, 0.77 mmol) was dissolved along with 5-(4-Fluoro-phenyl)-3-isopropylamino-thiophene-2-carboxylic acid methyl ester (0.150 g, 0.51 mmol) in anhydrous 1,2-dichloroethane (2 mL). The reaction mixture was stirred for 16 h at reflux. Then, the solvents were removed and the residue was purified by flash chromatography (8:2 Hexane/EtOAc) to obtain 140 mg (66%) of 5-(4-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester. 1H NMR(CDCl3, 400 MHz): δ 7.60 (m, 2H), 7.15 (m, 2H), 7.02 (d, 1H), 5.42-5.20 (m, 1H), 4.99 (m, 1H), 3.83 (d, 3H), 2.41-1.50 (m, 10H), 1.20 (m,3H), 0.98 (d, 3H).
Reaction SMILES: [C:1]1(C)C=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C1C[O:27][CH:21]2[C@:22]34OCCOC3([CH2:15][CH2:16][C@H:17]4[C@@H:18]3[CH2:36][CH:35]=[C:34]4[C@:29]([CH3:37])(CC[CH2:32][CH2:33]4)[C@H:19]3[CH2:20]2)O1.CC(C)=[O:40]>O>[C:2]([C@:3]12[CH2:32][CH2:33][C@@H:34]3[C@:29]4([CH3:37])[C:17]([CH2:16][CH2:15][C@H:35]3[C@@H:36]1[CH2:18][CH2:5][C:4]2=[O:40])=[CH:22][C:21](=[O:27])[CH2:20][CH2:19]4)#[CH:1]
Reactant: CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC2OCCOC34CC[C@@H]1[C@]23OCCO4
Solvent: O
Product: C#C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CCC2=O

Procedure:
20 mg of p-toluenesulphonic acid are added to a solution of 327 mg of 13-ethinyl-3,3;17,17-bis-(ethylenedioxy)-10-methyl-gon-5-ene in 15 ml of acetone and 0.5 ml of water and the mixture is heated under reflux for 5 hours. The reaction mixture is concentrated to about 5 ml, diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried and evaporated. Chromatography on silica gel using a mixture of hexane/ethyl acetate (3:1) as the eluant gives only 13-ethinyl-10-methyl-gon-4-ene-3,17-dione, which is recrystallised from ether/hexane; melting point 148°-150° C, [α]D25 = +63°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18](=[O:24])[CH:17]=[CH:16]2.[BH4-].[Na+]>CO.O>[CH3:23][N:19]1[C:20]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][NH:9][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]1=[O:24]
Reactant: O=Cc1cccnc1
Reactant: Cn1c(=O)ccc2cc(OCCN)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1c(=O)ccc2cc(OCCNCc3cccnc3)ccc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
3-Pyridine carbaldehyde (0.99 ml) and 6-(2-Aminoethoxy)-1-methyl-1H-quinolin-2-one (2.18 g) were added to methanol (50 ml). The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride (0.757 g) was added thereto. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure to give the title compound (3.063 g) as a yellow oil.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-:16].[Na+].[Na+].O>C(OCC)(=O)C>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:3]#[C:2][C:1]([NH2:4])=[O:16])=[O:11])=[CH:8][CH:7]=1
Reactant: C#CCN
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)C#CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
A solution of propargylamine (3.55 g) in ethyl acetate (25 ml) was added over a period of 15 minutes to a stirred mixture of 4-bromobenzoyl chloride (14.2 g) and sodium carbonate (10.6 g) in ethyl acetate (100 ml) at ambient temperature. The mixture was heated at reflux for 1 hour. The mixture was cooled to ambient temperature and water (200 ml) was added. The mixture extracted with ethyl acetate (2×100 ml). The ethyl acetate extracts were combined, washed with saturated aqueous sodium bicarbonate solution, saturated with brine, dried (MgSO4) and evaporated. The solid residue was recrystallised from ethyl acetate to give 4-bromobenzoyl propargyl amide (8.9 g), m.p. 281°-288° C.; NMR: 3.10(1H,m), 4.05(2H,m), 7.69(2H,m), 7.80(2H,m), 9.0(1H,m); m/z 238(M+H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH3:36][NH:37][CH2:38][CH3:39].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][N:37]([CH2:38][CH3:39])[CH3:36])=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: CCNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(C)Cc1ccc2c(c1)cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 61.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with N-methylethylamine (0.160 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (211 mg, 0.996 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(N-methylethylaminomethyl)indol-2-yl]isoindolinone (67.0 mg, yield 62%).
Reaction SMILES: [CH2:1]([O:19][CH2:20][C@H:21]([CH2:23][OH:24])[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:25]1([C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)Cl)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1COCC1.C(#N)C>C(N(CC)CC)C>[CH2:1]([O:19][CH2:20][C@H:21]([CH2:23][O:24][C:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOC[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
39 grams (113 mmol) of (S)-1-octadecyl-glycerol and 40 grams (137 mmol) of triphenylchloromethane were added to a mixture of 500 ml of dry THF and 130 ml of dry acetonitrile. 32 ml of dry triethylamine was added and the reaction mixture was refluxed for 17 hours. The reaction mixture was then cooled to room temperature, poured on ice (1 kilogram), transferred to a separatory funnel and extracted twice with 200 ml diethyl ether. The organic phase was washed consecutively with 200 ml water, twice with 100 ml dilute (1.5%) H2SO4, 200 ml water, 200 ml concentrated aqueous sodium bicarbonate, and again with 200 ml water. The solution was then dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue, a brown oil, was dissolved in 250 ml ethyl acetate and cooled to −20° C. overnight. The mixture was centrifuged (3,500 rotations per minute) at a temperature of −10° C. (3500 RPM), and the mother liquid was then poured off. The remaining solid was dissolved in hexane and refrigerated (5±3° C.) overnight. Filtration of the precipitate yielded 50 grams of pure (R)-1-octadecyl-3-trityl-glycerol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16](C(OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)CC(OCC)=O.CS(C)=O.[Li+].[Cl-]>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)cc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)Cc1cc(F)cc(OCc2ccccc2)c1
Yield: 57 %

Procedure:
The above mixture of a mixture of diethyl 3-benzyloxy-5-fluorophenylmalonate and diethyl malonate (ca. 1:1.2, 1.0 g), DMSO (10 ml), water (0.1 ml), and LiCl (346 mg) were placed in a 50 ml round-bottom flask equipped with a magnetic stirrer and fitted with a condenser. The mixture was heated at reflux for 5 hr. The mixture was poured into water (50 ml) and the whole extracted with n-hexane (2×50 ml). The combined organic extracts were washed with water (50 ml), brine (50 ml) and dried over Na2SO4. Removal of solvent gave 283 mg (57%) of ethyl 3-benzyloxy-5-fluorophenylacetate as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH2:11][OH:12]>>[CH2:11]([O:12][C:6](=[NH:7])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCO
Reactant: N#Cc1ccc(Br)cc1
Product: CCOC(=N)c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 5 h

Procedure:
4-Bromo-benzonitrile (5 g) was suspended in absolute EtOH (100 ml) and cooled to 0-5° C. HCl gas was bubbled through, initially vigorously for several minutes and later slowly for 5 hours. The resulting solution was allowed to stir overnight. Most of solvent was removed and the precipitate was filtered, washed with EtOH twice and dried to afford compound 2BO (4.1 g) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.[CH3:46]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:46])[C:6]=1[N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][NH2:14])[CH2:11][CH2:12]1)=[O:44]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2[nH]ncc2N)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(CN)CC1
Yield: 21 %

Procedure:
Following the procedures as described in Example 113, tert-butyl (1-(4-amino-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 133 as a white solid (40 mg, 21%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.76 (d, J=6.8, 1H), 7.62-7.38 (m, 4H), 7.38-7.16 (m, 2H), 3.63 (s, 3H), 3.15-2.94 (m, 5H), 2.88 (t, J=6.4, 1H), 1.86-1.60 (m, 2H), 1.42-1.05 (m, 3H). ESIMS m/z=448.1 (M+1)
Reaction SMILES: [CH:1]([C:5](O)([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C#C)=[C:2]([CH3:4])[CH3:3].O1CC[CH2:16][CH2:15]1.[N+]([O-])([O-])=O.[K+].[OH2:24]>[N+]([O-])([O-])=O.[Ag+]>[CH3:4][C:2]([CH2:1][CH:5]=[CH:8][C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:15][CH3:16])=[CH2:3]
Reactant: C1CCOC1
Reactant: C#CC(O)(C=C(C)C)CCCCC
Reactant: O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: C=C(C)CC=CC(=O)CCCCC
Reaction time: 8.5 h

Procedure:
3-Isobutenyl-1-octyn-3-ol (0.180 g; 10-3 mole) is kept at the reflux temperature of tetrahydrofuran and protected from light, in the presence of silver nitrate (0.017 g; 10-4 mole) and potassium nitrate (0.101 g; 10-3 mole) in a mixture (6 cc) of tetrahydrofuran and water (2:1 by volume). After 6 hours of reaction silver nitrate (0.017 g) is again added. Refluxing is continued for another 8.5 hours and the reaction mixture is then treated under the conditions described in Example 1. 2-Methyl-1,4-undecadien-6-one (0.104 g) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH3:61])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:44][CH:43]([NH2:59])[C:42]2=[O:60])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>O1CCCC1.O>[C:32]1([CH3:61])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:58])[C:54]([CH3:55])([CH3:56])[CH3:57])[CH2:44][CH:43]([NH:59][C:14]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=3)=[O:16])[C:42]2=[O:60])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1Cl
Reaction time: 0.17 h
Yield: 268.4 %

Procedure:
Methyl 5-amino-2-chlorobenzoate (223 mg) was dissolved in tetrahydrofuran (50 ml), triphosgene (135 mg) was added under ice-cooling, triethylamine (116 μl) was added thereto five times every 3 minutes, the mixture was stirred for 10 minutes at same temperature. A solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (500 mg) in tetrahydrofuran (10 ml) was added dropwise, the resultant mixture was stirred for 30 minutes at same temperature and additionally stirred for 2 hours at room temperature. The reaction mixture was poured into water (400 ml), extracted with methylene chloride. The organic layer was washed with 1N hydrochloric acid, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 756 mg of the titled compound.