Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([CH2:23][CH2:24][CH2:25]O)=[CH:20][C:19]=2[CH:27]=1.[C-:28]#[N:29].[Na+]>>[C:28]([CH2:25][CH2:24][CH2:23][C:21]1[O:22][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[O:6][C:2]=3[CH3:1])=[CH:27][C:19]=2[CH:20]=1)#[N:29]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2oc(CCCO)cc2c1
Reactant: [C-]#N
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2oc(CCCC#N)cc2c1
Yield: 80 %

Procedure:
In the same manner as in Example 13, 3-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]propanol was mesylated and then reacted with sodium cyanide to yield 2-(3-cyanopropyl)-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran (yield 80%), which was then recrystallized from acetone-isopropyl ether to yield colorless prisms having a melting point of 114° to 115° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:20][CH:19]([CH2:21]O)[CH2:18]1)=[O:16])[CH:12]=[CH2:13].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:30]([CH3:34])[C:31](=[O:33])[CH3:32])C=CC=CC=1>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:11]([O:14][C:15]([N:17]1[CH2:18][CH:19]([CH:21]=[C:30]([CH3:34])[C:31](=[O:33])[CH3:32])[CH2:20]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1CC(CO)C1
Reactant: CC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)N1CC(C=C(C)C(C)=O)C1
Yield: 89.1 %

Procedure:
To a solution of oxalyl chloride (6.3 g) in methylene chloride (85 ml) was added dimethyl sulfoxide (3.87 g) at -60° C. and stirred was stirred for 15 minutes. A solution of 1-allyloxycarbonyl-3-hydroxymethylazetidine (6.8 g) in methylene chloride (21 ml) was then added thereto and the mixture was stirred at -60° C. for 30 minutes. Triethylamine (20 g) was dropwise added thereto. To the mixture was added water (50 ml) and organic layer was separated washed with water, dried over magnesium sulfate, evaporated and coevaporated with benzene to give an oily residue. The residue was dissolved in methylene chloride (160 ml) and 3-triphenylphosphoranylidenebutan-2-one (11.8 g) was added thereto and the mixture was stirred overnight at room temperature. The evaporated residue was triturated with ethyl acetate and the insoluble material was filtered. The filtrate was applied on silica gel column using a mixture of n-hexane and ethyl acetate. The main fractions were evaporated to give 1-allyloxycarbonyl-3-(2-methyl-3-oxo-1-butenyl)azetidine (7.06 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=[O:6].C(Cl)CCl.C1C=CC2N(O)N=[N:22][C:20]=2C=1.Cl.CN>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([NH:22][CH3:20])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1ccc(O)c(Br)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 3-bromo-4-hydroxybenzoic acid (Commercial eg Aldrich) (2.0 g), EDC (2.65 g), HOBT (1.41 g) and TEA (6.2 ml) in DCM (60 ml) was added methylamine hydrochloride (1.87 g). This was stirred at 25-30 C. for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The organics were dried (sodium sulphate) and concentrated in vacuo to yield the title compound, 0.57 g
Reaction SMILES: ClC1C=C(C=CC=1)C[N:6]1[C:14]2[N:13]=[C:12](C(C)C)[NH:11][C:10]=2[C:9](=[O:18])[NH:8][C:7]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24].[OH-].[Na+]>N1C=CC=CC=1>[NH:8]1[C:9](=[O:18])[C:10]2[NH:11][CH:12]=[N:13][C:14]=2[NH:6][C:7]1=[S:24]
Reactant: CC(C)c1nc2c([nH]1)c(=O)[nH]c(=O)n2Cc1cccc(Cl)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Temperature: -5 °C
Yield: 226.7 %

Procedure:
3.19 g of 3-(3-chlorobenzyl)-8-isopropyl-xanthine and 2.67 g of phosphorus pentasulfide were heated under reflux in 35 ml of pyridine for 5 hours. After cooling to −5° C., 13.2 ml (26.4 mM) of 2N NaOH were added over 15 minutes. The reaction mixture was evaporated to dryness, the residue suspended in water, the pH adjusted to 7.5 and the solid collected. The product was redissolved in 100 ml of 1N NaOH, treated with charcoal (5%), filtered and neutralized to pH 7.5. The solid was collected, washed and dried to give 2.29 g of crude thioxanthine. The product was dissolved in 250 ml of chloroform and filtered through 15 g of silica gel. The collected material was reprecipitated from NaOH by neutralization with HCl to give the title compound (2.38 g) as an off-white solid mp 218-20° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25])[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:24]([C:23]1[N:22]=[C:21]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:27])[NH:20][C:19]=1[CH2:17][CH3:18])[CH3:25]
Reactant: CCc1nc(C(=O)O)[nH]c1CC
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1nc(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)[nH]c1CC

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (120 mg, 0.52 mmol), 4,5-diethyl-1H-imidazole-2-carboxylic acid obtained in Example (43c) (36.7 mg, 0.22 mmol), WSC hydrochloride (145 mg, 0.76 mmol) and HOBT (35 mg, 0.26 mmol), to obtain 55.0 mg of the title compound as a white foamy substance (66%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[CH2:11][N:10]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:9]1)(C)(C)C.O1CCOCC1>Cl>[CH3:19][S:16]([N:10]1[CH2:9][CH:8]([NH2:7])[C:12]2([CH2:13][CH2:14][CH2:15]2)[CH2:11]1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)NC1CN(S(C)(=O)=O)CC12CCC2
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CC(N)C2(CCC2)C1
Reaction time: 0.83 h

Procedure:
(+/−)-tert-butyl-(6-(methylsulfonyl)-6-azaspiro[3.4]octan-8-yl)carbamate (0.195 g, 0.641 mmol) was dissolved in 4.0 M HCl in dioxane (3.0 mL, 12.00 mmol) and stirred at r. t. for 1 hr 5 min. +/−MS analysis after 50 min. indicated a the reaction had essentially proceeded to completion (m/e 205.2, M+H for desired product; no sm was detected). HCl/dioxane was removed under vacuum, and the residue co-evaporated with ether. The initially obtained oil was dried under vacuum over P2O5 to yield 0.153 g of the HCl salt of the title compound as a pale tan solid. +/−MS: m/e 205.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (br. s., 2H), 3.74 (br. s., 1H), 3.58-3.49 (m, 1H), 3.45-3.34 (m, 2H), 2.95 (s, 3H), 2.36-2.22 (m, 1H), 2.09-1.92 (m, 2H), 1.91-1.81 (m, 3H).
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH2:23][CH2:24][O:25][CH2:26][CH:27]=2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[O:25]1[CH2:26][CH:27]=[C:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23][CH2:24]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C2=CCOCC2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C2=CCOCC2)c(-c2cncnc2)c1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
5-Bromo-6-(3,6-dihydro-2h-pyran-4-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.1, 160 mg, 0.361 mmol), pyrimidin-5-ylboronic acid (89 mg, 0.722 mmol), Pd(PPh3)2Cl2 (25 mg, 0.036 mmol), aq. 2 M NaHCO3 (0.541 mL, 1 mmol) and DME (1.5 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 90° C. for 1.5 h. The RM was diluted with EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2 to 5% MeOH) and treated with Si-Thiol (90 mg) in MeOH to afford the title product as a solid. HPLC (Condition 3) tR=4.99 min, UPLC-MS (Condition 2) m/z=443.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.39-2.60 (m, 2H) 3.74 (t, J=5.47 Hz, 2H) 3.90-4.00 (m, 2H) 5.58 (s, 1H) 7.39 (d, J=8.99 Hz, 2H) 7.77-7.92 (m, 2H) 8.40 (d, J=1.96 Hz, 1H) 8.94 (s, 2H) 9.12 (d, J=1.00 Hz, 1H) 9.21 (s, 1H) 10.60 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3ccc(C(F)(F)F)cn3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-(trifluoromethyl)pyridine in dimethylsulfoxide at 100° C. in the presence of potassium carbonate. LC (method 4): tR=1.04 min; Mass spectrum (ESI+): m/z=523 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([NH:12][CH2:13][CH2:14][CH3:15])[CH2:7]2.C1(C)C(S(O[CH2:26][CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:12]([CH2:13][CH2:14][CH3:15])[CH2:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[CH2:7]2
Reactant: CCCNC1CCc2c(O)cccc2C1
Reactant: Cc1ccccc1S(=O)(=O)OCCc1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN(CCc1cccs1)C1CCc2c(O)cccc2C1
Reaction time: 24 h

Procedure:
700 mg (3.4 mmol) (−)-5-hydroxy-N-n-propyl-2-aminotetralin made by the process described in U.S. Pat. No. 5,382,596, 4.8 g (17 mmol) 2-(2-thienyl)ethanol toluenesulfonate, 216 mg (2 mmol) sodium carbonate (0.6 molar ratio Na2CO3/amine starting material), and 40 mL xylenes (mixture, Aldrich Chemical Co.) were mixed and brought to reflux. The reaction was halted at 24 hours, and worked up in the usual manner well known to those skilled in the art without chromatographic purification to yield the product, (−)-5-hydroxy-2-[N-n-propyl-N-2-(2-thienyl)ethylamino]tetralin, that was converted to its hydrochloride salt form, with a yield of 1 g (84%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Br:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]1[CH:17]=[CH:18][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:26]1[CH:25]([CH2:24][C:22]([OH:23])=[O:21])[CH2:30][CH2:29][CH2:28][C:27]2=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: Cl
Product: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(Br)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-bromophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[C:26]([CH3:30])=[N:27][NH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[C:26]([CH3:30])=[N:27][NH:28][CH:29]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1n[nH]cc1-c1ccc2c(c1)CCNC2C
Product: Cc1n[nH]cc1-c1ccc2c(c1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][CH:20]([O:22][CH3:23])[CH3:21])[CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][NH2:14].Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][N:26]=1>C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][CH:20]([O:22][CH3:23])[CH3:21])[CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][NH:14][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][N:26]=1
Reactant: COC(C)Cc1ccc(OCCN)c(C)c1
Reactant: Clc1ncnc2ccccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(C)Cc1ccc(OCCNc2ncnc3ccccc23)c(C)c1
Reaction time: 3 h
Yield: 63.5 %

Procedure:
1.0 g of triethylamine and 2.2 g of 2-[2-methyl-4-(2-methoxypropyl)phenoxy]ethylamine were added to 1.7 g of 4-chloroquinazoline dissolved in 50 ml of toluene. The mixture was then heated under reflux, whilst stirring, for 3 hours. At the end of this time, the reaction product was washed with water and dried over anhydrous sodium sulfate. Toluene was removed by distillation under reduced pressure. The oily product thus obtained was subjected to column chromatography (Wakogel C-200, eluted with a 1:1 by volume mixture of toluene and ethyl acetate) to isolate the product, and the crystals obtained were recrystallized from hexane, to give 2.2 g of the title compound as a colorless crystalline powder, melting at 95°-97° C.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[Na].[C:21]([OH:29])(=[S:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>O1CCOCC1.C(OCC)(=O)C.O.[Cl-].[Zn+2].[Cl-]>[C:21]([S:28][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH3:11])(=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1
Reactant: OC(=S)c1cccnc1
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1SC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
To a solution of 4-(R)acetoxy-3(R)-[1(R)t-butyldimethylsilyloxyethyl]azetidin-2-one (2.87 g) in dioxane (40 ml), the sodium salt of thionicotinic acid (1.94 g) was added. Zinc chloride (1.7 g) was added to the resulting mixture and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulphate, and evaporated in vacuo. The residue was purified by column chromatography to give 1.9 g of the title product (52% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CN=C1>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc2ccc(O)cc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Product: CC(C)(C)OC(=O)Nc1cccc2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 8-(tert-butoxycarbonylamino)-2-naphthol, as described above in Step A, (35 g, 0.135 mol), tert-butyldiphenylsilyl chloride (40.9 g, 0.149 mmol), and imidazole (18.4 g, 0.270 mmol) in dry, degassed DMF (300 mL) was stirred, under argon, at 50° C. for 18 hrs. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (500 mL) and EtOAc (1 L). The aqueous layer was extracted further with EtOAc (300 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane −25% to 45% CH2Cl2 to yield the desired product as a pale solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Product: CC(CNC(=O)c1cccnc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and nicotinoyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was, consistent with the proposed title structure.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1>C(OCC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[NH:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: Cc1ccc(CC2CCN(C(=O)C(=O)O)CC2)cc1
Solvent: CCOCC
Product: Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)[nH]c4c3)CC2)cc1

Procedure:
The title compound is prepared from [4-(4-methyl-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 119b) and 5-amino-1,3-dihydro-benzimidazole-2-one according to the method described in Example 1c. Melting Point: >280° C. (diethylether)
Reaction SMILES: Br[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:38]1([CH3:44])C=CC=C[CH:39]=1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:15]([O:14][C:12]([C:8]1[N:9]=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([N:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]1)[C:2]=2[CH:44]1[CH2:38][CH2:39]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Br)c2cn1
Reactant: Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CCOC(=O)c1cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C3CC3)c2cn1
Temperature: 95 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)piperazin-1-yl)isoquinoline-3-carboxylate (464 mg, 1 mmol), C3H4B(OH)2 (860 mg, 10 mmol), Pd(dppf)Cl2 (73 mg, 0.1 mmol) and K3PO4 (636 mg, 3 mmol) in toluene (20 ml) and H2O (2 ml) was stirred at 95° C. overnight. After extraction by EA, the residue was dried with anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to afford ethyl-7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-8-cyclopropylisoquinoline-3-carboxylate as a yellow solid (350 mg, yield: 85%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=O)[CH3:12]>>[F:2][C:3]1[CH:4]=[C:5]([NH:9][N:10]=[C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(F)c1
Reactant: CC(=O)c1cccs1
Agent: Cl
Product: CC(=NNc1cccc(F)c1)c1cccs1

Procedure:
This compound is prepared from commercial 3-fluorophenylhydrazine hydrochloride (Aldrich) and from commercial 2-acetylthiophene (Aldrich), according to the procedure 1.
Reaction SMILES: [S:1]([N:11]=[C:12]1[NH:16][CH2:15][CH2:14][NH:13]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:17](Cl)([Cl:19])=[O:18].C(N(CC)CC)C>O1CCCC1>[Cl:19][C:17]([N:16]1[CH2:15][CH2:14][N:13]=[C:12]1[NH:11][S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)N=C2NCCN2)cc1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC2=NCCN2C(=O)Cl)cc1
Temperature: 0 °C

Procedure:
12 parts by weight of 2-tosylimino-imidazolidine (produced as described by Gompper and Hagele, Ber. 99, 2892 [1966]) were partly dissolved by 10 minutes' boiling in 150 parts by volume of absolute tetrahydrofurane, and thereafter rapidly cooled to 0°C by swirling in an ice bath. 6 parts by weight of phosgene were added to the suspension while stirring, the mixture was stirred for 30 minutes at 0°C, 5 parts by weight of triethylamine were then added dropwise and the whole was then stirred for a further 3 hours at room temperature. The excess phosgene was blown out by means of a stream of dry air and the precipitated triethylamine hydrochloride was removed from the tetrahydrofurane solution by filtration and was thoroughly eluted with absolute tetrahydrofurane. The combined solutions were evaporated to dryness in vacuo and the residual oil was caused to crystallize by trituration with methylene chloride and ether, filtered off and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([OH:21])=[O:20].[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:22][O:20][C:19]([C:3]1[N:4]([CH3:18])[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)=[N:6][C:2]=1[Br:1])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(Br)c1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(Br)nc(-c2cccc(OC(F)(F)F)c2)n1C
Reaction time: 70 h
Yield: 93.4 %

Procedure:
A stirred solution of 1.826 g (5.0 mmol) of 5-bromo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid (example 72) in 20 ml of DMF was treated at RT with 2.073 g (15.0 mmol) of potassium carbonate, followed by addition of 0.62 ml=1.42 g (10.0 mmol) of iodomethane. After 70 hours, the reaction mixture was poured into crashed ice and extracted twice with Et2O; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane/CH2Cl2 1:0 to 0:1) to give 1.77 g (93%) of the title compound as light yellow oil. MS: 379.0 (MH+, 1Br).