Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.O[NH:37][C:38](=[NH:55])[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:42]2>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:55]=[C:38]([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[NH:44][C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:42]4)[N:37]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CCOC(=O)CCc1cc2cc(C(=N)NO)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (150 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 10 min. ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D31) (193 mg) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was heated to 80° C. and stirred at that temperature for 6 hours. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL), and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was recrystallized from ethanol to afford ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D33) (95 mg) as a light pink solid. MS (ES): C24H24ClN3O4 requires 453; found 454.0 (M+H+).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17].[C:43]([O:53][CH2:54][CH:55]([CH2:57][O:58][C:59](=[O:68])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])O)(=[O:52])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].N1C=CC=CC=1>O1CCCC1>[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([O:37][CH:55]([CH2:54][O:53][C:43](=[O:52])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:57][O:58][C:59](=[O:68])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17]
Reactant: CCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCC
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)OCC(COC(=O)CCCCCCCC)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
Dicyclohexylcarbodiimide (6.5 g) was added to a stirred solution of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 8.6 g) and 2-n-nonanoyloxy-1-n-nonanoyloxymethylethanol (7.8 g) in a mixture of dry pyridine (80 ml) and dry tetrahydrofuran (25 ml) at 3° C., and then stirred at 0° to 5° C. for 4 hours and allowed to stand at room temperature overnight. The resultant mixture was poured into ice water (450 ml) and extracted with ethyl acetate (450 ml). Water (50 ml) was added to the extract and adjusted to pH 2 to 3 with 20% sulfuric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (100 ml×2) and an aqueous solution of sodium bicarbonate in turn, and dried over anhydrous magnesium sulfate. After removing the solution in vacuo, the residue was subjected to column chromatography on silica gel (370 g) with a mixture of chloroform and acetone (5:1). The eluate was evaporated in vacuo to give powder (4.62 g) of 2-n-nonanoyloxy-1-n-nonanoyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:13]([O-:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].[K+].[I-].[K+].C1(C=CC(O)=CC=1)O>CN(C)C=O>[C:13]([O:18][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: ClCCn1ccc2ccccc21
Reactant: C=C(C)C(=O)[O-]
Agent: Oc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCn1ccc2ccccc21
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 78.9 %

Procedure:
Subsequently, 1-(2-chloroethyl)indole (15.4 g), potassium methacrylate (21.3 g), potassium iodide (7.1 g), N,N-dimethylformamide (40 ml), and a small amount of hydroquinone were placed in a 200-ml flask equipped with a stirrer and a condenser tube. The mixture was heated to 100° C. and stirred for 2.5 hours. After completion of reaction, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. This reaction mixture was purified further by silica gel column chromatography to obtain 1-(2-methacryloyloxyethyl) indole (15.5 g).
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].CO.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[OH-].[Na+]>C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.CCOCC.CO>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7])=[CH:16][CH:15]=1
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of α-bromoisovaleric acid (2 g, 0.110 mole) and 5 ml of methanol is added one drop of phenolphthalein and then sufficient sodium hydroxide/methanol until adjusted to neutral pH. The solvent is then stripped off and p-chloroaniline (7 g, 0.055 mole) added. The mixture is melted in a 100° bath and stirred at 100° for 3 hours. The mixture is cooled and taken up in ether, and 10% aqueous sodium hydroxide is added. The aqueous phase is acidified to pH 4 and extracted with ether. The ether extracts are combined and washed with brine, dried over sodium sulfate and stripped to yield N-(p-chlorophenyl)valine.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[F:26][C:27]([F:33])([F:32])[C:28](OC)=[O:29].O>O1CCCC1>[C:1]([C:3]1[C:7]([C:28](=[O:29])[C:27]([F:33])([F:32])[F:26])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: COC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (4.62 g) in tetrahydrofuran (100 ml) at -75° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -75° C., n-butyllithium (4.7 ml of a 2.5M solution in hexanes). A solution of methyl trifluoroacetate (1.93 ml) in tetrahydrofuran (5 ml) was then added at such a rate that the temperature of the reaction mixture did not exceed -75° C. Upon completion of the addition the mixture was allowed to warm to room temperature. Water (100 ml) was added and the mixture extracted twice with ethyl acetate (80 ml). The combined organic layers were dried (Na2SO4) and evaporated to give a brown gum which was purified by column chromatography on silica gel (250 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a pale yellow solid, m.p. 124-125° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[NH+:11][CH:10]=[CH:9]2)([O-])=O.[H][H]>[Pt]=O.CO>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][NH:11][CH2:10][CH2:9]2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2cc[nH+]cc12
Agent: O=[Pt]
Solvent: CO
Product: Nc1cccc2c1CNCC2

Procedure:
The 2-lower alkyl-5,6,7, or 8-nitroisoquinolinium salt can be catalytically hydrogenated directly to a 2-lower alkyl-5,6,7 or 8-amino-1,2,3,4-tetrahydroisquinoline. The hydrogenation can be readily effected by use of a platinum oxide catalyst in methanol and a hydrogen pressure of about 25 to 100 psi. The hydrogenation proceeds at room temperature. After filtering to remove the catalyst, the filtrate can be worked up to obtain the 2-lower alkyl-5,6,7 or 8-amino-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:17]([O-])=O.C(NS(C1C(Cl)=C([N+]([O-])=O)C=C(C=1)C(O)=O)(=O)=O)CCC.N[C:42]1[CH:43]=[C:44]([CH:48]=[C:49](S(=O)(=O)NC)[C:50]=1[O:51]C1C=CC=CC=1)C(O)=O.CNC.C(N)CCC.NC1CC(S(=O)(=O)NCCCC)(OC2C=CC=CC=2)C=C(C(O)=O)C=1>>[NH2:17][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])[C:2]=1[O:51][C:50]1[CH:49]=[CH:48][CH:44]=[CH:43][CH:42]=1)[C:6]([OH:8])=[O:7]
Reactant: CNS(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: CCCCNS(=O)(=O)C1(Oc2ccccc2)C=C(C(=O)O)C=C(N)C1
Agent: CCCCNS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: CNC
Solvent: CCCCN
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1

Procedure:
The starting materials, 4-chloro-5-dimethylsulphamyl-3-nitro-benzoic acid and 5-n-butylsulphamyl-4-chloro-3-nitro-benzoic acid, were new and were obtained as described for the starting material of Example 2 by substituting aqueous dimethylamine (3.6 g containing 1.5 g of dimethylamine) and n-butylamine (2.2 g), respectively, for the aqueous methylamine, and had melting points of 233-235° C, and 196-198° C, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[CH:27][NH:26][N:25]=2)[N:12]=1>>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])=[N:12][C:13]([NH:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1)=[CH:14]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: N#Cc1cccc(O)c1
Product: COc1ccc2c(Oc3cccc(C#N)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-hydroxy-benzonitrile and (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine to give 3-[6-methoxy-3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 358(MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31](O)=[O:32])[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40](=[O:54])[NH:41][C:42]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C>ClCCl>[C:35]([O:39][C:40](=[O:54])[NH:41][C:42]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:43][CH2:44][N:45]([C:31]([C:17]2[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[F:34])[CH:16]=2)=[O:32])[CH2:46][CH2:47]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCC(NC(=O)OC(C)(C)C)(c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 120 h
Yield: 15.9 %

Procedure:
A mixture of 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (384 mg), (4-phenylpiperidin-4-yl)-carbamic acid tert-butyl ester (230 mg), DIPEA (427 μL) and BEP (456 mg) in dichloromethane (10 mL) was stirred at r.t. for 5 d. The solvent was distilled off in vacuo, the residue was re-dissolved in MTBE/ethyl acetate (v/v=1/1, 40 mL) and washed once with water, twice with saturated sodium bicarbonate solution, once with 1N sodium hydroxide solution and with brine. After evaporation of the solvents, the residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) giving 95 mg (16%) of the title compound.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([OH:5])=[O:4].[CH3:13][CH2:14][CH2:15][N:16]([C@@H:24]1[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([OH:34])[C:27]=2[CH2:26][CH2:25]1)[CH2:17][CH2:18][C:19]1[S:23][CH:22]=[CH:21][CH:20]=1.Cl.FC(F)(F)C(O)=O>ClCCl>[NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:13][CH2:14][CH2:15][N:16]([C@@H:24]1[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([OH:34])[C:27]=2[CH2:26][CH2:25]1)[CH2:17][CH2:18][C:19]1[S:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCCN(CCc1cccs1)[C@H]1CCc2c(O)cccc2C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The Boc-Gly-Rotigotine HCl was deprotected by first dissolving the product (1.258 g, 2.55 mmol) in dichloromethane (64 ml). After addition of trifluoroacetic acid (9.83 ml, 128 mmol), the reaction mixture was stirred for 1 hour at room temperature and then all the volatiles were removed using a rotary evaporator. The residue (dark yellow) was dissolved in methanol and precipitated by adding into diethyl ether (40 mL). The pale yellow precipitate was filtered using a glass frit and dried to give Gly-Rotigotine.2TFA (1.140 g, 79% yield).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>C1COCC1>[C:1]([Si:5]([O:8][C:9]1[CH:10]=[C:11]([F:16])[C:12]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[C:13]([F:15])[CH:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(F)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2c(F)cc(O[Si](C)(C)C(C)(C)C)cc2F)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of tert-butyl(3,5-difluorophenoxy)dimethylsilane (1.0 eq) in dry THF (0.2M) under an atmosphere of N2 at −78° C. was added n-butyllithium (1 eq, 1.6M in hexanes) slowly keeping the internal temperature below −65° C. The reaction was stirred for 1 hr at −78° C., followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHCO3 (sat) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield tert-butyl(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane in 91% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.21 (s, 6 H) 0.97 (s, 9 H) 1.37 (s, 12 H) 6.33 (d, J=9.39 Hz, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
Substituted benzyl bromide compounds can also be prepared from commercially available substituted benzaldehydes, benzoic acids and benzoic esters by first converting these compounds to the corresponding alcohol. Exemplary synthetic methodology to provide substituted benzyl bromide from benzyl aldehyde is described below. For example, as illustrated in Scheme 12, treatment of 4-hydroxy-3-nitro-benzaldehyde 73 with benzyl bromide in the presence of K2CO3 in DMF at 65° C. gives 4-benzyloxy-3-nitro-benzaldehyde 74. Reduction of compound 74 in methanol with NaBH4 affords the alcohol 75 and subsequent bromination using PBr3 in diethyl ether provides the desired bromide compound 76.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=C[C:52]2[N:53](C3CCCCC3)[C:54](C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.CN(C)C1C=CC(B(O)O)=CC=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:41]=[CH:42][C:43]([N:53]([CH3:54])[CH3:52])=[CH:2][CH:3]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: CN(C)c1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(N(C)C)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 26 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-dimethylaminophenylboronic acid (44 mg, 0.2625 mmol) to produce the title compound (27 mg, 26% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:17](=[O:21])[CH2:18][CH2:19]Cl)[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C.CCOCC>O1CCOCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:17](=[O:21])[CH2:18][CH2:19][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: C1CCNC1
Reactant: CN1C(=O)c2cc(Cl)ccc2N(C(=O)CCCl)c2ccccc21
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN1C(=O)c2cc(Cl)ccc2N(C(=O)CCN2CCCC2)c2ccccc21

Procedure:
3.5 gm (0.01 mol) of 2-chloro-5-(3-chloro-propionyl)-5,10-dihydro-10-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one and 3.5 gm (0.05 mol) of pyrrolidine were refluxed in 50 ml of dioxane for 4 hours. After addition of activated charcoal, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform, the solution was extracted with water, and the organic phase was evaporated in vacuo. The oily residue was obtained as crystals after addition of ether. After recrystallization from cyclohexane 2.6 gm of the crystalline title compound, m.p. 118°-120° C., were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[C:13]([O:17][C:18](=[O:28])[NH:19][C:20]1[S:21][C:22]([CH2:25][CH2:26][NH2:27])=[CH:23][N:24]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(O)C>[C:13]([O:17][C:18](=[O:28])[NH:19][C:20]1[S:21][C:22]([CH2:25][CH2:26][NH:27][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[CH:10]=[CH:11][S:12][C:3]=23)=[CH:23][N:24]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCN)s1
Reactant: N#Cc1cnc2ccsc2c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ncc(CCNc2c(C#N)cnc3ccsc23)s1
Yield: 40.9 %

Procedure:
A stirred mixture of 7-chloro-thieno[3,2-b]pyridine-6-carbonitrile (47.8 mg, 0.25 mmol), [5-(2-amino-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (J Med Chem, 1992, 35, 3239-3246) (54.6 mg, 0.22 mmol), and triethylamine (0.04 ml, 0.28 mmol) in 3 ml of ethanol was heated to reflux for 17 hr. Ethanol was evaporated, and the residue was partitioned between dichloromethane and aqueous NaHCO3. The organic layer was washed with H2O, dried over MgSO4, filtered, and concentrated in vacuum. The resulting residue was purified by silica gel chromatography (MeOH/CH2Cl2/NH3=1/20/0.1) to give 36.1 mg (40%) of yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.82 (d, J=5.4 Hz, 1H), 7.52 (d, J=5.4 Hz, 1H), 7.18 (s, 1H), 5.32 (m, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H), 1.55 (s, 9H); LC-MS (ESI) m/z 402.1 (M+1).
Reaction SMILES: C([O:9][C@H:10]1[C@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@H:12]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:11]1[F:34])(=O)C1C=CC=CC=1.C(N)CCC>CO>[F:34][C@@H:11]1[C@@H:10]([OH:9])[C@H:14]([CH2:15][OH:16])[O:13][C@@H:12]1[N:25]1[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: Cc1cn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2F)c(=O)[nH]c1=O
Solvent: CO
Solvent: CCCCN
Product: Cc1cn([C@H]2O[C@@H](CO)[C@H](O)[C@H]2F)c(=O)[nH]c1=O

Procedure:
A solution of 23 (47 mg, 0.1 mmol) and n-butylamine (0.74 g, 1.0 mL, 10 mmol) in methanol (2 mL) was heated at reflux for 3 hours. The solution was evaporated to dryness and triturated with ethyl ether to afford a solid that was filtered, washed with ether and dried to afford 24 (20 mg, 0.077 mmol, 77% as a white solid: mp 188° C. (lit. value: mp 185-187° C., 184-185° C., 187-188° C. for the D-isomer); [α]D20=−93 (c 0.25 MeOH); (lit. value: [α]D20=−111 (c 0.23 MeOH), [α]D20=−122 (c.023 MeOH)); 1H-NMR (DMSO-d6) δ 11.0 (1H, bs, N—H, 7.58 (1H, s, C-H thymine), 6.09 (1H, dd, J=4.2 and J=15.6, H-1), 5.85 (1H, bs, OH), 5.10 (1H, bs, OH), 5.02 (1H, dt, J-4.0, J-3.8 and J-52.8, H-2), 4.22 (1H, dt, J-3.8, J-4.0 and J=20.3, H-3), 3.76 (1H, q, J=4.0 and J-9.5, H4), 3.69-3.57 (2H, m, H-5 and H-5′), 1.77 (3H, s, Thymine CH3).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CCN(CC)CC>C1COCC1>[C:16]([C:20]1[N:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cn1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cn1
Yield: 65 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (158 mg, 0.62 mmol) was reacted with (6-tert-butyl-pyridin-3-yloxy)-acetic acid (130 mg) DMTMM (1.2 eq, 206 mg) and NEt3(2.5 eq, 220 μl) in THF to give the title compound (165 mg, 65%) after purification by column chromatography (Hex/EtOAc=1/3).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[CH2:25][C:26]([NH:28][CH:29]1[C:34]([CH3:36])([CH3:35])[CH:33]2[CH2:37][C:30]1([CH3:38])[CH2:31][CH2:32]2)=[O:27].O>O1CCCC1>[CH:8]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][C:26]([NH:28][CH:29]2[C:34]([CH3:36])([CH3:35])[CH:33]3[CH2:37][C:30]2([CH3:38])[CH2:31][CH2:32]3)=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC12CCC(C1)C(C)(C)C2NC(=O)CCl
Reactant: c1ccc(NC2CCCCC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC12CCC(C1)C(C)(C)C2NC(=O)CN(c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-cyclohexylaniline (100 mg, 0.56 mmol) in tetrahydrofuran (4 ml) at −78° C. was added LiHMDS (1 ml of a 1M solution in tetrahydrofuran) dropwise. The solution was allowed to warm to 0° C., then recooled to −78° C., and a solution of 2-chloro-N-(1,3,3-trimethylbicyclo[2,2,1]hept-2-yl)acetamide (124 mg, 0.56 mmol) in tetrahydrofuran (1 ml) added dropwise. The mixture was allowed to warm to room temperature, and was stirred for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. The ethyl acetate solution was absorbed onto silica gel, which was eluted with 3% methanol/methylene chloride, to yield 2-(cyclohexylphenylamino)-N-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)acetamide.