Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH3:16][Si:17](Cl)([CH2:19][CH2:20][Si:21](Cl)([CH3:23])[CH3:22])[CH3:18]>O1CCCC1>[F:8][C:9]1[CH:10]=[C:11]([N:12]2[Si:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][Si:17]2([CH3:18])[CH3:16])[CH:13]=[CH:14][CH:15]=1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: Nc1cccc(F)c1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of freshly distilled diisopropylamine (22.9 mL) in dry tetrahydrofuran (175 mL) at -78° C. under N2 is treated with n-butylithium (1.6 M in hexanes, 109 mL) dropwise over 15 minutes, and the resulting mixture is stirred at -78° C. for 45 minutes and is then added over ten minutes via cannula to a solution of 3-fluoroaniline (8.00 mL) in dry tetrahydrofuran (166 mL) at -78° C. under N2. The resulting reaction mixture is stirred at -78° C. for 50 minutes and is then treated with a solution of 1,1,4,4-tetramethyl-1,4-dichlorodisilethylene (18.3 g) in dry tetrahydrofuran (85 mL). The mixture is allowed to slowly warm to ambient temperature over four hours with stirring and is then washed with water (2×200 mL) and saline (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) 7.12, 6.65, 6.58, 0.86, 0.24 δ.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][C:9]3[C:16]4([CH3:19])[CH:17]([CH3:18])[CH:3]1[CH2:4][C:5]=2[C:10]=3[CH:11]=[CH:12][CH2:13][N:14]=[CH:15]4.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O>[CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][C:9]3[C:16]4([CH3:19])[CH:17]([CH3:18])[CH:3]1[CH2:4][C:5]=2[C:10]=3[CH:11]=[CH:12][CH2:13][NH:14][CH2:15]4
Reactant: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC1C2CC3=C(CCC4=C3C=CCNCC41C)N2C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a stirred solution of 2.24 g of 1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 23 ml of acetic acid, cooled to 15° C. under nitrogen, was added 1.70 g of sodium cyanoborohydride. The reaction mixture was stirred for an additional 2 hr and 90 ml of water was added. The solution was made basic (pH 12) with 50% aqueous sodium hydroxide solution and extracted with dichloromethane-ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, filtered and concentrated. The residue was purified by flash chromatography (alumina, ether). Recrystallization from ether/pentane gave 1.55 g (69%) of product, mp 126°-128° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([OH:18])[CH:12]=2)[CH2:9][CH2:8][O:7][CH:6]([CH3:10])[CH2:5]1)[CH3:2]>C(O)C.[Pd]>[CH2:4]([O:18][C:13]1[CH:12]=[C:11]([C:4]2([O:3][CH2:1][CH3:2])[CH2:9][CH2:8][O:7][CH:6]([CH3:10])[CH2:5]2)[CH:16]=[C:15]([F:17])[CH:14]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC1(c2cc(O)cc(F)c2)CCOC(C)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC1(c2cc(F)cc(OCc3ccccc3)c2)CCOC(C)C1

Procedure:
The (2SR,4SR)-4-ethoxy-4-(5-fluoro-3-hydroxyphenyl)-2-methyltetrahydropyran, used as a starting material, was obtained by hydrogenolysis of a solution of (2SR,4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-ethoxy-2-methyltetrahydropyran (2.6 g, described in Note i. below Table X in Example 45) in ethanol (25 ml) in the presence of 10% palladium-on-charcoal catalyst (0.26 g). The mixture was filtered and the filtrate was evaporated. There was thus obtained the required starting material (1.69 g, 89%), as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCC2)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N2CCC2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-(3-bromo-4-methyl-benzenesulfonyl)-azetidine (Intermediate 155), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(F)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
1-Fluoro-4-t-butylbenzene (10 g, 65.79 mmol) was dissolved in concentrated sulfuric acid (40 ml) at 0° C. Solid potassium nitrate (6.64 g, 65.79 mmol) was added in small portions during 1 hour. The temperature was kept below 5° C. Following the addition stirring was continued for 2 hours. The reaction mixture was poured into ice-water (400 ml) and extracted with dichloromethane (3×50 ml). The organic phase was washed with water, aqueous sodium bicarbonate (1M) and water successively, dried over MgSO4 and filtered through silica gel (5 g). Evaporation of solvent left the crude product (10.32 g). Column chromatography on silica gel using petroleum ether containing 1% dichloromethane as the eluent afforded the pure product (7.6 g colorless oil).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([C:10]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=2[CH:12]=O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[CH3:23][O:24][CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.Cl>C1(C)C=CC=CC=1>[CH3:23][O:24][CH:25]=[CH:12][C:11]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:10]=1[C:8](=[O:9])[C:7]1[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)c(C(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC=Cc1ccc(OC)cc1C(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
10 g of 2-(4-nitrobenzoyl)-4-methoxybenzaldehyde is introduced together with 18 g of (methoxymethyl)triphenylphosphonium chloride in 400 ml of toluene and mixed in portions with 5.9 g of potassium-tert-butylate while being cooled with ice. After 1 hour of stirring while being cooled with ice and a subsequent 3.5 hours of stirring at room temperature, it is mixed with 200 ml of water, weakly acidified with 1N hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate phases are washed with saturated common salt solution, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with hexane:ethyl acetate=1:1 as an eluant. 6.9 g of 1-methoxy-2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)ethylene as a mixture of the E- and Z-forms is obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@@:9]1(C)[C:28]([O-:30])=[O:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[CH2:10][C@H:9]1[C:28]([OH:30])=[O:29])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@@H]2CN(C(=O)OC(C)(C)C)[C@](C)(C(=O)[O-])C2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
To a solution of 1-BOC 2-methyl (2S,4S)-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]pyrrolidine-2-carboxylate (1.02 g, 2.32 mmol) prepared in Step B in methanol (7 ml) and water (7 ml) was added LiOH (0.15 g, 6.99 mmol). The reaction mixture was stirred at rt for 3 h, concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (0.93 g, 95%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH2:9]1)=O)(C)(C)C.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[CH2:30]([NH:37][S:15]([CH2:14][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:16])=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CS(=O)(=O)Cl)Oc2ccc(C(F)(F)F)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(C[C@@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCNC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-[(S)-2-Chlorosulfonyl-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 109 μmol, 1.0 eq.) in DCM (1.0 mL) was combined with benzylamine (47.7 μL, 4.0 eq.) and the resulting mixture was stirred at room temperature for 2 hours. TFA (1.0 mL) was added and stirred for 1 minute. The mixture was then concentrated and purified by preparative HPLC to yield the title compound as a TFA salt (7.3 mg). MS m/z: [M+H]+ calcd for C20H23F3N2O3S, 429.14. found 429.0.
Reaction SMILES: CC(C)([O-])C.[Na+].CO[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[CH2:26][C:27]#[N:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH:9]=[C:26]([C:17]1[CH:18]=[CH:19][C:20]([C:22]([F:23])([F:24])[F:25])=[CH:21][C:16]=1[Cl:15])[C:27]#[N:28]
Reactant: COC=CC(=O)OC
Reactant: N#CCc1ccc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC=C(C#N)c1ccc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of sodium tert-butoxide (3.28 g, 34.2 mmol) in tetrahydrofuran (20 mL) at 0° C. was added a solution of methyl 3-methoxyacrylate (2.65 g, 22.8 mmol) and (2-chloro-4-trifluoromethyl-phenyl)-acetonitrile (5.00 g, 22.8 mmol) in tetrahydrofuran (20 mL) dropwise over 45 minutes. The red solution was stirred at 0° C. for 3 hours and then allowed to warm to 10° C. over another 2 hours. The reaction was then treated with 0.2 M aqueous citric acid (50 mL) and extracted with a 2:1 mixture of methyl tert-butyl ether and hexanes (75 mL). The organic layer was washed with an aqueous saturated solution of sodium chloride (50 mL). The organic solution was passed through a short column of silica gel, washing the residual material through the pad with additional methyl tert-butyl ether. The filtrate was concentrated in vacuo to afford 4-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-but-3-enoic acid methyl ester as a red oil (6.74 g, 97%). Major olefin isomer: 1HNMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.58 (d, 1H, J=8.3), 7.49 (d, 1H, J=8.3), 6.89 (t, 1H, J=7.1), 3.78 (s, 3H), 3.69 (d, 2H, J=7.1); 13C NMR (100 MHz, CDCl3) δ 169.4, 145.9, 136.1, 133.7, 133.0 (q, J=33.5), 131.5, 127.6 (q, J=3.8), 124.5 (q, J=3.8), 123.2 (q, J=292), 115.4, 114.7, 52.7, 36.7; IR (ATR, neat) 2957, 2224, 1740, 1438, 1395, 1319, 1268, 1172, 1128, 1080, 1010, 963, 892, 831, 719, 655 cm−1. Minor olefin isomer: 1H-NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.61 (d, 1H, J=7.8), 7.43 (d, 1H, J=7.8), 7.02 (t, 1H, J=7.8), 3.71 (s, 3H), 3.11 (d, 2H, J=7.8).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][C:8](=O)[CH2:7]1)=[O:5].[BH4-].[Na+].[CH2:20]([NH2:23])[CH2:21][NH2:22]>C1C=CC=CC=1>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([NH:22][CH2:21][CH2:20][NH2:23])[CH2:8][CH2:7]1)=[O:5]
Reactant: O=C1CC(C(=O)c2ccc(F)cc2F)CCN1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: NCCNN1CCC(C(=O)c2ccc(F)cc2F)CC1
Yield: 38 %

Procedure:
A solution of 4-(2,4-difluorobenzoyl)piperidinone (1.50 g, 6.27 mmol) in benzene (40 mL) and ethylenediamine (4.0 mL) was refluxed for 6 hours. The resulting mixture was concentrated to a residue which was dissolved in MeOH (30 mL). The mixture was cooled (0° C.) and NaBH4 (1.0 g, 26.4 mmol) was slowly added. After stirred for an hour, the mixture was concentrated and quenched with 1 N NaOH (50 mL). The mixture was extracted with CH2Cl2 (5×20 mL), dried (K2CO3), and was concentrated. The residue was purified by flash chromatography (CHCl3-MeOH-2 M NH3 in MeOH 100:10:2 to 100:20:5) to afford the product as an pale yellow solid (670 mg, 38%).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6].Cl[C:21]1[N:22]=[CH:23][C:24]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[N:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:21]2[CH:26]=[N:25][C:24]([C:27](=[O:28])[N:29]([CH3:30])[CH3:31])=[CH:23][N:22]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6]
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)COC(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
A mixture of methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-benzoate (0.25 g, 0.91 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (168 mg, 0.91 mmol) and potassium carbonate (250 mg, 1.81 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4) and reduced in vacuo. The residue was chromatographed on silica, eluting with 20 to 70% ethyl acetate in isohexane, to give the desired compound (0.3 g).
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.[C:19]([NH:22][CH2:23][C:24]1[S:28][C:27]([SH:29])=[N:26][N:25]=1)(=[O:21])[CH3:20].C(=O)(O)[O-].[Na+]>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:29][C:27]3[S:28][C:24]([CH2:23][NH:22][C:19](=[O:21])[CH3:20])=[N:25][N:26]=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: CC(=O)NCc1nnc(S)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 60 °C
Reaction time: 5 h
Yield: 51.4 %

Procedure:
7-Aminocephalosporanic acid (1.36 g.), 5-acetamidomethyl-1,3,4-thiadiazole-2-thiol(1.04 g.) and sodium bicarbonate (885 mg.) were dissolved in water (70 ml.), and the solution was stirred at 60° C for 5 hrs. After the reaction, the reaction mixture was adjusted to pH5, and then allowed to stand overnight in a refrigerator. The precipitating crystals were collected by filtration to give 7-amino-3-(5-acetamidomethyl-1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (1.03 g.) m.p. 195°-197° C (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20](O)=[O:21])=[CH:17][CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].Cl.[CH3:27][NH:28][CH3:29].C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:28]([CH3:29])[CH3:27])=[O:21])=[CH:17][CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(C(=O)O)ccc32)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(C(=O)N(C)C)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 4-(5-carboxy-3-cyanoindol-1yl)benzoic acid ethyl ester (0.084 g), dimethylamine hydrochloride (0.061 g), triethylamine (0.13 g) and 4-dimethylaminopyridine (0.006 g) in dichloromethane (2.5 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide (0.058 g) at room temperature, and this mixture was stirred at room temperature overnight. This reaction mixture was poured into 1 mol/L hydrochloric acid, and this mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/2) to give the title compound (0.020 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)OC)[CH:5]=[CH:4][C:3]=1[Cl:13].[OH-].[K+]>CO.O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:13]
Reactant: COC(=O)Nc1ccc(Cl)c(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(Cl)c(Br)n1
Yield: 82.3 %

Procedure:
To a solution of methyl 6-bromo-5-chloropyridin-2-ylcarbamate (1.1 g, 4.1 mmol) in methanol (50 mL) was added KOH (700 mg, 13 mmol) at room temperature. The mixture was heated at reflux for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography on silica gel (5% to 10% EtOAc in petroleum ether) to give 6-bromo-5-chloropyridin-2-amine (700 mg, 81%). 1H NMR (400 MHz, CDCl3) 7.54 (d, J=8.0 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:21])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:11][C:10](Cl)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(OCC)(=O)C.O>[Cl-].[Na+].O>[C:1]([NH:5][C:6](=[O:21])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:11][C:10]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NC(C)(C)C
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)NC(C)(C)C
Temperature: 100 °C
Yield: 93.8 %

Procedure:
A mixture of 6.0 g (19 mMol) of N-tert.-butyl-6-chloro-4-o-tolyl-nicotinamide and 12 ml (138 mMol) morpholine was heated at 100° C. for 4 hours. After cooling to room temperature, extractive work-up with ethyl acetate, water and brine yielded 6.3 g (91%) of N-tert.-butyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide as a brown crystalline foam.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58]F)[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][C@@H:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:69]1CCC[CH2:70]1>CO.Cl[Pd]Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58][O:69][CH3:70])[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][CH:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CF)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C1CCOC1
Agent: Cl[Pd]Cl
Solvent: CO
Product: C=CCOC1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](COC)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
The compound (1.80 g, 1.92 mmol) synthesized in Example 8 (8a) was dissolved in methanol (30 mL) and tetrahydrofuran (6 mL) and palladium chloride (II) (67.4 mg, 0.38 mmol) was added thereto, followed by stirring of the mixture at room temperature for 14 hours. After the reaction mixture was subjected to celite filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-4:1-3:1, V/V) to obtain the desired title compound (1.43 g, yield 83%) as colorless amorphous matter.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([O:27][CH3:28])[C:19]=4[S:20][C:3]=1[C:4]=23.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][O:34][C:33]1=[O:37]>>[CH2:14]([N:13]([CH2:16][CH3:17])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][O:34][C:33]3=[O:37])=[C:3]3[S:20][C:19]4[C:21]([O:27][CH3:28])=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:15]
Reactant: O=C1OCCN1CCCl
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1c(OC)ccc(OC)c1-2
Product: CCN(CC)CCn1nc2c3c(c(NCCN4CCOC4=O)ccc31)Sc1c(OC)ccc(OC)c1-2
Yield: 56.9 %

Procedure:
A mixture of 2.2 g (0.0055 mol) of 5-amino-N,N-diethyl-7,10-dimethoxy-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine and 1.6 g (0.011 mole) of 3-(β-chloroethyl)-2-oxazolidinone was treated in the manner described in Example 42 to furnish 1.6 g of the title compound, mp greater than 250° C. dec.
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12]C=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][C:17]([OH:19])=[O:18].OS(O)(=O)=O>O>[C:6]([C:8]1[CH:13]=[CH:12][C:16]([C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1)(=[O:7])[C:5]1[CH:14]=[CH:15][CH:2]=[CH:3][CH:4]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 100 °C

Procedure:
To a mixture of 4-methylbenzophenone (25 g, 0.127 mole) with HOAc (130 mL) was added successively CrO3 (35 g), H2O (80 mL) and conc. H2SO4 (25 mL). The mixture was heated for 3 hours at 100±5° C. and then quenched by adding ice water (500 mL) to yield a crude 4-benzoylbenzoic acid solid which was dissolved in a 10% KOH solution and filtered. The filtrate was acidified with diluted HCl to pH 2.0 and precipitate by subjected to ice bath. The precipitate was collected to obtain 21.3 g 4-benzoylbenzoic acid in a yield of 74.1%.