Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:7]=1[F:17])[CH3:2].[Li]C(CC)C.[I:24]I.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[C:7]([F:17])=[CH:8][CH:9]=[C:10]([O:12][C:13]([F:15])([F:14])[F:16])[C:11]=1[I:24])[CH3:2]
Reactant: CCOC(=O)Nc1cc(OC(F)(F)F)ccc1F
Reactant: II
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1c(F)ccc(OC(F)(F)F)c1I
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2 (31.34 g, 117.2 mmol) in THF (180 mL) at −78° C. is added sec-BuLi (1.4 M in cyclohexane, 200 mL, 280 mmol) dropwise over a 1 h period. After 20 min, a solution of I2 (44.6 g, 175.8 mmol) in THF (150 mL) is added dropwise over a 30 min period. This mixture is then stirred at −78° C. for 30 min. Saturated NH4Cl is added, and the cooling bath is removed. The reaction mixture is partitioned between H2O and EtOAc. The two layers are separated, and the organic layer is washed with 10% Na2SO3, H2O, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is suspended in DCM (50 mL), and heptane (300 mL) is added. The white powder 3 (18.1 g, 39%) from the resulting suspension is collected by suction filtration and air-dried. The filtrate is concentrated in vacuo, and the residue is suspended in heptane (200 mL). Another batch of 3 (3.8 g, 8%) is collected by suction filtration and air-dried. Additional product can be obtained by purifying the filtrate via silica gel chromatography. 1H NMR (CDCl3) δ 7.30-17.10 (m, 2H), 6.16 (br s, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H); 19F NMR (CDCl3) δ −56.90 (s, 3F), −114.35 (d, J=8.5 Hz, 1F); MS 394 (M+1, 100%), 374, 364, 321, 267.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[S-:19][C:20]1[CH:25]=[C:24]([C:26]([O-:28])=[O:27])[CH:23]=[CH:22][N:21]=1.[Na+].[Na+].C(=O)(O)[O-].[Na+].Cl>O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C([O-])c1ccnc([S-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3cc(C(=O)O)ccn3)CS[C@H]12
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 52.7 %

Procedure:
To a suspension of 7-aminocephalosporanic acid (9.30 g) and disodium 2-sulfido-4-pyridinecarboxylate (6.80 g) in water (160 ml) was dropwise added sodium bicarbonate (5.73 g) at room temperature. To the resulting mixture was added a saturated aqueous solution of sodium bicarbonate so that the pH was adjusted to 6.8. The resulting mixture was warmed to 65° C. and stirred for 1.5 hours during which period the temperature was allowed to rise from 65° to 75° C. The reaction mixture was cooled and then adjusted to pH 3.6 with 10% hydrochloric acid. The precipitates were collected by filtration, washed successively with water (x2), acetone (x2) and diethyl ether and then dried to give 7-amino-3-(4-carboxypyridin-2-yl)thiomethyl-3-cephem-4-carboxylic acid (6.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[F:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH2:63])(=[O:62])=[O:61])=[CH:56][CH:55]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([NH:63][S:60]([C:57]5[CH:56]=[CH:55][C:54]([F:53])=[CH:59][CH:58]=5)(=[O:61])=[O:62])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2(C(=O)O)CCC2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: NS(=O)(=O)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2(C(=O)NS(=O)(=O)c3ccc(F)cc3)CCC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.4 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.086 mmol) and CDI (28 mg, 0.17 mmol) in DMF (0.5 mL) was heated at 60° C. for 30 min, and then cooled to root temperature. To this solution was added a mixture of 4-fluoro-benzenesulfonamide (175 mg, 1 mmol) and NaH (40 mg, 60%, 1 mmol) in DMF (1 mL). The resulting mixture was stirred at room temperature for 10 min, purified by prep-HPLC to give the title compound as a white solid (20 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11]I)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][NH2:16].[ClH:17]>C(O)C>[ClH:17].[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11][NH:16][CH3:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OCCCI)cc1
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CNCCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(4-Nitrophenoxy)-3-iodopropane (4.76 g, 15.50 mmol) was added portionwise to a stirring solution of methylamine (33%) in ethanol (100 mL) at 0° C. The mixture stirred at room temperature for 4 hours and was then concentrated. The residue was partitioned between ethyl acetate/10% aqueous K2CO3. The organic phase was dried, decolorized and concentrated to afford an oil which was treated with ethanolic HCl. Yield: 2.5 g of hydrochloride salt which was used without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]#[C:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]#[C:23][CH2:24][CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CCC#CCBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CCC#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (4 g) is alkylated using 1-bromo-2-pentyne (3.1 ml; 30.4 mmol) and K2CO3 (4.2 g; 30.4 mmol) at 40° C. for 20 h. After aqueous work-up only a part of the crude material (1 g; 3.04 mmol) is de-acetylated under reflux using DBU (0.9 ml) in MeOH (80 ml). After aqueous work-up the crude 5-amino-3,3-dimethyl-6-nitro-1-(pent-2-ynyl)-1,3-dihydro-indol-2-one (0.87 g) is used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH2:7]([O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20])[CH3:8]>ClC1C=CC=CC=1Cl>[CH2:7]([O:9][CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:20]=[C:2]([OH:3])[C:1]1=[O:5])[CH3:8]
Reactant: CCOCCCNc1ccccc1N
Reactant: O=C(Cl)C(=O)Cl
Solvent: Clc1ccccc1Cl
Product: CCOCCCn1c(=O)c(O)nc2ccccc21
Yield: 55.5 %

Procedure:
In a solution containing 26.9 g of oxalyl chloride in 200 ml of o-dichlorobenzene at 60° C. under stirring, a solution containing 35.5 g of N-(3-ethoxypropyl)-o-phenylenediamine in 220 ml of o-dichlorobenzene is added for 42 minutes in several times. The mixture is then heated and stirred at 130° C. for 1.1 hours. The mixture is subjected to filtration during hot and the filtrate is cooled. Ether is added to the filtrate and the crystals are filtered, washed and dried, followed by combining second crystals to obtain 25.2 g of (1).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:14][C:15]([O:17]C)=[O:16])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[H][H]>CO.[OH-].[Na+]>[C:15]([CH2:14][CH:3]([CH2:2][SH:1])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])([OH:17])=[O:16]
Reactant: [H][H]
Reactant: COC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a solution of the product from Example 62, Step (d) (3.0 g) in methanol (60 ml), 1N sodium hydroxide (60 ml) is added. After 4 hours, the solution is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle, and the desired material is eluted with water to yield 2.3 g of the named product, Rf =0.2 (silica gel-benzene:acetic acid, 75:25).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[OH:16][C:17]1[N:18]=[N:19][C:20]([OH:23])=[CH:21][CH:22]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:18]1[C:17](=[O:16])[CH:22]=[CH:21][C:20]([OH:23])=[N:19]1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Oc1ccc(O)nn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2nc(O)ccc2=O)[C@@H]1O

Procedure:
A mixture containing I g of 6-cyano-2,2-dimethyl-3,4-epoxychromane, 1.1 g of 3,6-dihydroxypyridazine and 0.20 ml of a methanolic solution containing 357. of benzyltrimethylammonium hydroxide, in 5 ml of dioxane and 5 ml of dimethylformamide, is refluxed for 50 hours. It is concentrated under vacuum and the residue is then triturated in 15 ml of water. The precipitate formed is filtered off and washed with water and then isopropyl ether.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:12][CH2:13][C:14]([OH:16])=[O:15].Cl>O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: Oc1cccc(F)c1
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1cccc(F)c1

Procedure:
A solution of sodium hydroxide (6.7 gm, 167 mmol) in water (20 mL) was added slowly to a neat mixture of 3-fluorophenol (8.9 gm, 79.5 mmol) and 3-bromopropionic acid (12.26 gm,80 mmol) as the reaction became exothermic. The mixture was refluxed gently for two hours and then allowed to cool and become semi-solid. Water was added to dissolve the semi-solid and then was acidified with concentrated HCl. The product was extracted into diethyl ether and the ethereal extract was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was slurried in 4:1 hexanetbenzene to give crystalline 3-(3-fluorophenoxy) propionic acid. m.p.: 90-91° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:59][C:60]([CH3:62])=O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH:60]([CH3:62])[CH3:59])[C@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=O
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To crude (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-((R)-3-methylpiperazin-1-yl)pyrimidin-4-yl)benzo[d]thiazol-6-yl)acetate (45.8 mg, 0.079 mmol) and sodium triacetoxyborohydride (83.7 mg, 0.395 mmol) in DMF (1 mL) was added acetic acid (23.7 mg, 22.6 μL, 0.395 mmol) and acetone (18.3 mg, 23.2 μL, 0.316 mmol). The reaction mixture was heated at 60° C. for 6.5 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent) and concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](Cl)=[N:14][OH:15])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[C:17]([C:19]1[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[O:15][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(CC(Cl)=NO)c1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOc1cccc(Cc2cc(-c3ccc(N)nc3N)on2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-butoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Manufacturing Example 65-1-4 and 3-ethynyl-pyridin-2,6-diamine (52.8 mg, 0.396 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (216 μL, 1.55 mmol). This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=1:1˜ethyl acetate) to obtain the title compound (43 mg, 21%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>ClCCl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
To a solution of 133e (180 mg, 0.287 mmol) in dichloromethane (5 mL) and methanol (5 mL) was added NaBH4 (21.7 mg, 0.574 mmol). After stirring at room temperature for 1 h, it was quenched with aqueous NH4Cl (5 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×20 mL) The combined organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by reverse-phase prep-HPLC to afford 133 (50 mg, 27%) as a white solid. MS-ESI: [M+H]+ 629.3. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=5.5 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.22 (s, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.78 (dd, J=1.5, 13.5 Hz, 1H), 7.51 (d, J=5.5 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 5.89 (s, 1H), 4.90-4.88 (m, 1H), 4.42 (s, 2H), 3.92 (t, J=5.5 Hz, 2H), 3.61 (s, 2H), 3.59 (s, 3H), 3.50 (t, J=5.0 Hz, 2H), 3.25 (s, 3H), 2.90 (t, J=5.5 Hz, 2H), 2.67 (t, J=5.0 Hz, 2H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(O)C.[C:15]([CH2:17][C:18](OCC)=[O:19])#[N:16]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:18](=[O:19])[CH2:17][C:15]#[N:16])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)CC#N
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: CCO
Product: N#CCC(=O)Nc1ccc(N)c([N+](=O)[O-])c1

Procedure:
15.3 gm (0.1 mol) of 1,4-diamino-2-nitrobenzene were heated to boiling in 150 ml of ethyl cyanoacetate. Simultaneously therewith the ethanol formed during the reaction was removed by distillation. After the reaction mixture was cooled, the precipitate formed was vacuum filtered, washed with ether and recrystallized from dilute acetic acid. The product had a melting point of 218°-221°C.
Reaction SMILES: [F:1][CH:2]([F:27])[N:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[N:14]=[N:15][N:16]([C:19]4[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=4)[C:17]=3[CH3:18])[CH:9]=2)[C:4]1=[O:26].[H][H]>[C].[Pd].C(O)C>[F:27][CH:2]([F:1])[N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[N:14]=[N:15][N:16]([C:19]4[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=4)[C:17]=3[CH3:18])[CH:9]=2)[C:4]1=[O:26]
Reactant: [H][H]
Reactant: Cc1c(-c2ccc3c(=O)n(C(F)F)ccc3c2)nnn1-c1cccnc1F
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)CCN(C(F)F)C3=O)nnn1-c1cccnc1F
Yield: 28.4 %

Procedure:
After adding 20 mg of palladium carbon to 10 ml solution of ethanol with 7 mg of 4-(2-difluoromethyl-1-oxo-isoquinoline-6-yl)-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole, hydrogen was added under 4 atm of hydrogen pressure. 8 hours later, the reaction solution was filtrated and after distilling out the solvents of the filtrate under reduced pressure, the residues were separated and purified by thin-layer chromatography (chloroform/methanol=10/1) to obtain 2 mg of the above compound as a white solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[C:2]=[S:3].Cl.[NH2:15][CH2:16][C:17]#[N:18]>C(N(CC)CC)C>[NH2:15][C:16]1[N:1]([CH:4]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)[C:2](=[S:3])[NH:18][CH:17]=1
Reactant: S=C=NC1CCc2ccccc2C1
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Product: Nc1c[nH]c(=S)n1C1CCc2ccccc2C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-isothiocyano-1,2,3,4-tetrahydronaphthalene (1.92 g, 10.1 mol), prepared as in Example 10, and aminoacetonitrile hydrochloride (0.94 g, 10.1 mmol) in 1.41 mL of triethylamine was heated at 60° C. for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography (elution: methylene chloride followed by 3% methanol in methylene chloride). The purified residue was recrystallized from ethyl acetate/hexane. The residue (1.06 g) and 44 mL of 0.1N potassium hydroxide was stirred under nitrogen for 15 minutes. The residue was isolated by filtration, washed with water, air dried and then stirred with methylene chloride. Filtration and drying gave 5-amino-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione, m.p. 169°-171° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2)=O.[OH-].[Na+].O>CO>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2
Reactant: COC(=O)c1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc2cc(CO)ccc2c1
Reaction time: 18 h

Procedure:
A mixture of 25.8 g. of 6-methoxycarbonyl-2-naphthyl-α-methylacetic acid, 4 g. of sodium hydroxide, 10 ml. of water, and 500 ml. of methanol are heated to 50° C, cooled, and evaporated. The residue is taken up in 500 ml. of diethylene glycol dimethyl ether and diborane is bubbled through. The resulting mixture is saturated with diborane and then is allowed to stand for 18 hours. The reaction mixture is acidified by the addition of aqueous 1N hydrochloric acid. The mixture is extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to give 6-hydroxymethyl-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:24](=[O:25])[CH:23]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:27]3[CH2:28][CH2:4][CH2:3][CH2:2][CH2:1]3)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Product: O=C(N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)C(C1CCCCC1)C1CCCCC1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and substituting 2,2-dicyclohexylacetic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.27 (m, J=6.3, 4H), 7.24-7.18 (m, 1H), 5.22 (d, J=6.9, 1H), 4.11-3.99 (m, 1H), 3.62 (d, J=13.0, 1H), 3.46 (d, J=13.0, 1H), 2.67-2.58 (m, 2H), 2.54 (dd, J=4.2, 9.4, 1H), 2.51-2.43 (m, 1H), 2.31 (dt, J=4.0, 7.6, 1H), 2.25 (dd, J=4.2, 9.0, 1H), 2.08-1.99 (m, 1H), 1.87-1.76 (m, 1H), 1.67 (dd, J=15.7, 26.7, 10H), 1.55 (s, 3H), 1.50-1.38 (m, 2H), 1.31-1.02 (m, 8H), 1.00-0.85 (m, 2H); MS (ESI+) m/z 423 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[CH3:31][O:32][C:33]1[C:34]([CH3:43])=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2.C[Si](Cl)(C)C.CCOC(C)=O>CN(C=O)C>[CH3:31][O:32][C:33]1[C:34](/[CH:43]=[CH:1]/[C:3]2[N:4]=[C:5]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[N:7][N:6]3[C:17]=2[C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:20][CH:19]=2)=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: COc1cc2ccccc2nc1C
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ccccc2nc1/C=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a mixture of compound 5f (100 mg, 0.245 mmol) and 3-methoxy-2-methylquinoline (212 mg, 1.22 mmol) in 4 mL of DMF was added TMSCl (312 μL, 2.45 mmol) dropwise. The resulting mixture was stirred at 90° C. for 24 h. After cooling to rt, the mixture was treated with 60 mL of EtOAc and washed with water (3×20 mL), brine (15 mL) and then dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0:1-1:9 EtOAc/DCM) to afford compound 63a as a yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.10-8.25 (m, 4H), 7.99 (d, J=5.9 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.1 Hz, 1H), 7.49-7.55 (m, 1H), 7.39-7.47 (m, 1H), 7.37 (s, 1H), 6.11 (d, J=5.6 Hz, 1H), 4.04-4.12 (m, 4H), 3.96-4.04 (m, 4H), 4.01 (s, 3H), 1.64 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C33H33N5O4, 564.3 (M+H). found 564.5.