Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].Cl[C:7]1[C:20]2[C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[NH:12][C:11]=2[C:10]([N+]([O-])=O)=[CH:9][CH:8]=1>CO.C1COCC1>[CH3:23][O:22][C:16]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:20]4=[C:7]([N:4]([CH2:3][CH2:2][OH:1])[N:5]=[C:19]4[C:18]=2[CH:17]=1)[CH:8]=[CH:9][CH:10]=3
Reactant: NNCCO
Reactant: COc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)-c1nn(CCO)c3cccc(c13)N2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.6 g of 2-hydroxyethyl hydrazine in 5 ml of methanol and 20 ml of THF was added over 1.5 hours to a mixture of 6.09 g of 1-chloro-7-methoxy-4-nitro-9(10H)-acridinone in 75 ml of methanol and 55 ml of THF, and the resulting suspension was stirred 20 hours at room temperature. The precipitate was collected and recrystallized from DMSO-methanol, Providing 9-methoxypyrazolo[3,4,5-kl]acridine-2(6H)ethanol, mp 275°-276° C.
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH:20]=[C:19]([CH2:22][OH:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+]>ClCCl>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][C:19]2([CH2:22][OH:23])[CH:20]([CH2:1]2)[CH2:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ICI
Product: CC(C)(C)OC(=O)N1CCC2(CO)CC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice-cooling, 15.3 ml of diethylzinc and 6.7 g of diiodomethane were added to 130 ml of dichloromethane. After further adding a solution of 1.07 g of 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-methanol in dichloromethane (20 ml), the resulting mixture was stirred at room temperature overnight. Then the reaction mixture was poured into saturated ammonium chloride, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 90 mg of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[N:5]=[C:4]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]2)[N:3]=1.[CH:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1.C(N(CC)CC)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C1COCC1>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[N:5]=[C:4]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([NH:33][S:37]([CH:34]3[CH2:36][CH2:35]3)(=[O:39])=[O:38])[CH2:29][CH2:28]2)[N:3]=1
Reactant: N[C@H]1CC[C@H](Nc2nc(Cl)cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)n2)CC1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(N[C@H]1CC[C@H](Nc2nc(Cl)cc(-c3c[nH]c4ncccc34)n2)CC1)C1CC1
Temperature: 85 °C

Procedure:
A mixture of Example 275a (350 mg, crude, 0.414 mmol), cyclopropanesulfonyl chloride (116 mg, 0.828 mmol), and triethylamine (0.058 mL, 0.414 mmol) in THF (5 mL) was stirred at room temperature for 1 day and concentrated in vacuo. To the residue was added dioxane (5 mL) and NaOH (20%, 1 mL) and the mixture was heated at 85° C. for 1 hour. The reaction mixture was concentrated and purified by reverse-phase HPLC performed on a Phenomenex Luna C8 AXIA column (30×75 mm, 100 Å) using a gradient of 10% to 95% acetonitrile: 0.1% aqueous trifluoroacetic acid over 12 minutes at a flow rate of 50 mL/minutes to give the title compound (17 mg, 9.2% yield) as trifluoroacetic acid salts. MS (ESI) m/e 447 (M+H)+; 1H NMR (400 MHz, DMSO-d6) ppm 0.94 (d, J=6.41 Hz, 4H) 1.35-1.53 (m, 4H) 1.99-2.11 (m, 4H) 2.50-2.57 (m, 1H) 3.15-3.25 (m, 1H) 3.71-3.82 (m, 1H) 6.66-6.79 (m, 1H) 7.08 (s, 1H) 7.18 (dd, J=7.93, 4.58 Hz, 1H) 8.29 (dd, J=4.73, 1.68 Hz, 1H) 8.35 (s, 1H) 8.79 (d, J=7.02 Hz, 1H) 12.03 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[CH2:57][CH2:56][N:48]2[C:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=3[CH:55]=[C:47]2[C:46]1=[O:58])(=[O:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:57][CH2:56][N:48]3[C:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=4[CH:55]=[C:47]3[C:46]2=[O:58])=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CCN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(-c4cccc(N5CCn6c(cc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)CC1

Procedure:
To a microwave tube equipped with a stirring bar, 138c (250 mg, 0.637 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (325.5 mg, 0.701 mmol), Pd(PPh3)4 (36.8 mg, 0.0319 mmol), Na2CO3 aqueous solution (1.0 N, 2.10 mL, 2.10 mmol), DME (2.0 mL) were added. The mixture was reacted in microwave at 135° C. for 15 min. CH2Cl2 (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:CH2Cl2=5:95) gave 2-(5-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 138d.
Reaction SMILES: N1C=CC=C[C:2]=1C(C1C=CC=CN=1)=O.[Br-].[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:18])=[O:17].CC([O-])(C)C.[K+]>C1COCC1>[C:16]([OH:18])(=[O:17])/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:2]
Reactant: O=C(c1ccccn1)c1ccccn1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC/C=C\C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
To a cooled (0° C.) solution of 293.6 mg (0.74 mmol) of the pyridyl ketone and 670.4 mg (1.48 mmol) of (5-carboxypentyl)-triphenylphosphonium bromide in 2.5 mL of THF was added dropwise 2.95 mL (2.95 mmol) of 1.0 M t-BuOK in THF over 10 min period. The dark brown solution was stirred at 0° C. for 1.5 h, and then the reaction was quenched with 20 mL of saturated aqueous NH4Cl . The mixture was extracted with 3×50 mL of CH2Cl2. The combined extract was dried over MgSO4, concentrated and purified by preparative HPLC with MeOH--AcOH--CH2Cl2 (2:1:97) as the eluent to afford 56.1 mg (8.4%) of the less polar (Z)-heptenoic acid and 434.9 mg of the (E)-isomer containing a byproduct from the Wittig salt. In order to purify it, the (E)-isomer was therefore esterified with CH2N2 which was generated by a standard method from MNNG and aqueous NaOH in Et2O. The ester was isolated cleanly by flash chromatography with EtOAc--hexanes--CH2Cl2 (2:1:1) as the eluent. The ester (102.5 mg) was then hydrolyzed with 1 N NaOH in THF-MeOH (1:1). Flash chromatography with EtOAc--MeOH--AcOH--CH2Cl2 (50:1:1:48) yielded 92.5 mg (25%) of the pure (E)-heptenoic acid: mp 56-61° C.; 1H NMR (CDCl3) δ 8.58 (s, 1H), 8.47 (d, J=4.1 Hz, 1H), 8.26 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.44 (dt, J=8.0, 1.5 Hz, 1H), 7.35-7.16 (m, 9H), 6.19 (t, J=7.4 Hz, 1H), 3.70 (dt, J=6.9, 6.7 Hz, 2H), 2.94 (t, J=7.2 Hz, 2H), 2.32 (t, J=7.8 Hz, 2H), 2.20 (ddd, J=7.3, 7.2, 7.0 Hz, 2H), 1.68-1.51 (m, 4H); FDMS 496 (M+1). Anal. (C30H29N3O4.0.1C2H4O2) C, H, N.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[C:28]([C:29]([OH:31])=O)=[C:27]([CH2:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][N:25]=1.C(N(C(C)C)C(C)C)C.[C:50]1([CH:56]2[CH2:60][CH2:59][NH:58][CH2:57]2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:23][C:24]1[C:28]([C:29]([N:58]2[CH2:59][CH2:60][CH:56]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:57]2)=[O:31])=[C:27]([CH2:32][C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40])[O:26][N:25]=1
Reactant: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(CC(=O)c2ccccc2)c1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of TBTU (0.48 g, 1.5 mmol, 1.5 eq.) in DMF (2 mL) was added to a mixture of 3-methyl-5-(2-oxo-2-phenylethyl)isoxazole-4-carboxylic acid (0.24 g, 1 mmol, 1 eq), N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1 eq) and 3-phenylpyrrolidine (0.15 g, 1 eq) in DMF (1 mL). The resulting solution was stirred at room temperature. Chloroform (25 mL) was added and the solution was washed with water and 1 M HCl, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2 1:2 heptane/EtOAc) to afford the title compound. MS (ESI, POS. ION) M/Z Calcd for C23H22N2O3: 374.1630, found 374.1632.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([Br:17])=[CH:12]2)=[O:5].[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>C(Cl)CCl.ClCCl>[C:22]([NH:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([Br:17])=[CH:12]2)=[O:5])(=[O:24])[CH3:23]
Reactant: Nc1ccccc1C(=O)Nc1cccc2cc(Br)cnc12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(=O)Nc1ccccc1C(=O)Nc1cccc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.1 %

Procedure:
A mixture of 8-(2-aminobenzoylamino)-3-bromoquinoline (200 mg), acetic anhydride (71.6 mg) and pyridine (139 mg) in ethylene chloride (4 ml) was stirred for 20 hours at ambient temperature. The mixture was diluted with dichloromethane, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was suspended in hot ethanol and allowed to cool to ambient temperature. The resulting precipitates were collected by filtration to give 8-(2-acetamidobenzoylamino)-3-bromoquinoline (200 mg) as yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([O:24]CC)=[O:23])[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([OH:24])=[O:23])[CH:5]=[CH:6][CH:7]=1)=[O:36]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Product: O=C(Nc1cccc(-c2c(C(=O)O)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1Cl

Procedure:
The title compound was prepared from ethyl 4-(3-aminophenyl)-8-(trifluoromethyl)quinoline-3-carboxylate and 2-chlorophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 483.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[ClH:11].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][Cl:16].Cl>CN(C=O)C.O>[ClH:16].[ClH:11].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: CN(C)CCCl
Reactant: Nc1cccc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To 3-aminophenol (10.9 g, 100 mmol) in DMF (100 mL) cooled with an ice/H2O bath was added NaH (8.90 g, 222 mmol) in 4 portions. 2-(Dimethylamino)ethylchloride hydrochloride (15.8 g, 110 mmol) was then added in 3 portions and the reaction was stirred at rt overnight. The reaction was poured into H2O (600 mL) and extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (flash chromatography), treatment with HCl (50.0 mL, 4M in dioxane, 200 mmol) and concentration provided the title compound (14.0 g, 56.0 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.80 (s, 6H), 3.46 (t, J=4.8 Hz, 2H), 4.30 (t, J=4.9 Hz, 2H), 6.58-6.66 (m, 3H), 7.18 (t, J=8.2 Hz, 1H), 8.55 (br.s., 2H), 10.70 (br.s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[NH:5][CH3:6].N1C=CC=CC=1.[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[N:5]([CH3:6])[C:20](=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: C=C1CC(=O)O1
Reactant: CNc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)CC(=O)N(C)c1ccc(Cl)c(Cl)c1

Procedure:
Dissolved in toluene were 3.5 g (0.02 mole) of 3,4-dichloro-N-methylaniline and a catalytic amount of pyridine, followed by a dropwise addition of 1.9 g (0.022 mole) of diketene at 50° C. After completion of the the dropwise addition, the resultant mixture was heated under reflux for 3 hours. The reaction mixture was cooled, and its organic layer was then washed with water, water, a 10% aqueous solution of hydrochloric acid and a 5% aqueous solution of sodium hydrogencarbonate in order. The thus-washed organic solution was dried and concentrated to obtain 3',4'-dichloro-N-methylacetoacetoanilide.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>CCOC(C)=O.[Pt](=O)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C2CCC3(CC2)OCCO3)cc1
Reaction time: 1 h

Procedure:
A solution of the title compound from Example 10 Step A (907 mg, 3.15 mmol) in EtOAc was degassed via nitrogen sparge. Platinum(IV) oxide (225 mgs, 0.991 mmol) was then added. The reaction flask was fitted with a 3-way adapter equipped with a hydrogen balloon. After 3 vacuum/hydrogen cycles, the reaction mixture was placed under a hydrogen atmosphere. After 1 h, the reaction mixture was filtered through a pad of Celite, rinsing with EtOAc, and concentrated in vacuo. The unpurified product was used in the subsequent step: LCMS m/z 291.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]#[N:16].[H-].[Na+].Cl[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O)C>CN(C)C=O.O>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:13]([CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]=2[CH:1]=1)#[N:16]
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Reactant: CCOC(=O)C(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-phenothiazinecarbonitrile (224.5 g) in dimethylformamide (1 liter) is introduced, with stirring and in the course of 2 hours 30 minutes, into a suspension of sodium hydride (24 g) in dimethylformamide (1 liter) at a temperature in the region of 25° C., and the mixture is left stirred for a further 1 hour 15 minutes until the evolution of gas has ceased. The fine suspension obtained is introduced, with stirring and at a temperature in the region of 25° C., in the course of 4 hours 30 minutes, into a solution of ethyl 2-chloropropionate (255 cc) in dimethylformamide (1 liter), and stirring is continued for 16 hours. Ethanol (100 cc) is then poured into the reaction mixture, and thereafter the whole is poured into a mixture of ice (2 kg) in distilled water (4 liters): a gum precipitates and then crystallizes. The solid formed is drained, washed successively with distilled water (6×500 cc) and petroleum ether (2× 500 cc) and dried in the air. Ethyl (2RS)-2-(2-cyano-10-phenothiazinyl)propionate (296.5 g) is thereby obtained in the form of yellowish brown crystals, m.p. 117°-8° C., which are used as they are in the next stage.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21].[Si](C#N)(C)(C)C.[N:28]1([C:33](N2C=CN=C2)=[O:34])C=CN=[CH:29]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:16]([C:15]4[CH:18]=[CH:19][C:12]([F:11])=[C:13]([O:20][CH3:21])[CH:14]=4)[CH2:29][NH:28][C:33]3=[O:34])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: COc1cc(C=O)ccc1F
Agent: C[Si](C)(C)C#N
Product: COc1cc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)ccc1F

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 4-fluoro-3-methoxybenzaldehyde (0.616 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA 1.21 mL, 8.7 mmol), di-(imidazol-1-yl)methanone (0.767 g, 4.7 mmol) as described in method 2.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:7]=1.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17](/[CH:18]=[CH:25]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: Cc1ccnc(OCc2ccc(C=O)cc2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccnc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 109.4 %

Procedure:
To an acetic acid (20.0 mL) solution of 4-(4-methyl-pyridin-2-yloxymethyl)-benzaldehyde (2.60 g, 11.5 mmol) described in Manufacturing Example 43-1-2 were added nitromethane (3.50 g, 57.3 mmol) and ammonium acetate (1.76 g, 22.9 mmol) at room temperature under nitrogen atmosphere, which was stirred for 4 hours at 100° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. 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 to obtain the title compound (3.40 g) as a crude product.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15](I)[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:15]2[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([C:1]34[CH2:8][CH:7]5[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]5)[CH2:10]3)[CH2:2]4)[CH:16]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(I)cc1C12CC3CC(CC(C3)C1)C2
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(Br)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 42.8 %

Procedure:
To a stirred solution of 2-(1-admantanyl)-4-iodo-1-methoxybenzene (0.19 g; 0.5 mmol) and 4-bromophenylboronic acid (0.1 g, 0.47 mmol) in 1,4-dioxane (10 ml) Pd(PPh3)4 (0.04 g) was added at 80° C., followed by the addition of the solution of NaHCO3 (0.2 g) in H2O (2 ml). The mixture was stirred at reflux for 2 h and the solvents were evaporated. The residue was diluted to 100 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4, filtered and the filtrate was evaporated to dryness to give The residue was purified by FCC (SiO2) to give the title product (0.08 g; 39%), as creamy gum. 1H-NMR (CDCl3) 1.77 (s, 6H); 2.07 (s, 3H); 2.12 (s, 6H); 3.86 (s, 3H); 6.92 (d, 1H, J=8.39 Hz); 7.34 (dd, 1H, J=2.42, 8.42 Hz), 7.38-7.42 (m, 3H); 7.50 (d, 2H, J=8.57 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:10])[CH3:9])[CH:7]=1.F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([CH3:25])(=[O:24])=[O:23].C(N(C(C)C)CC)(C)C.ClCCl>CN(C)C=O>[F:21][C:19]1[CH:20]=[CH:15][C:16]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([NH:10][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([CH3:13])[C:5]=2[O:11][CH3:12])[CH3:9])[CH:18]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: COc1c(C)cc(F)cc1C(C)N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(C)cc(F)cc1C(C)Nc1cc(F)ccc1S(C)(=O)=O
Yield: 15 %

Procedure:
A solution of 1-(5-Fluoro-2-methoxy-3-methylphenyl)ethanamine (0.34 g, 1.87 mmol), 2,4-difluoro-1-methanesulfonyl-benzene (0.3 g, 1.56 mmol) and diisopropylethylamine (1.4 mL, 7.81 mmol) in N,N-dimethylformamide (10 mL) was stirred at 110° C. for 18 h. Dichloromethane was added (20 mL) and washed with water (2×20 mL), brine (20 mL), dried, and concentrated under reduced pressure to the crude compound which was purified by silica gel column (20% ethyl acetate in hexanes) to afford 5-fluoro-N-(1-(5-fluoro-2-methoxy-3-methylphenyl)ethyl)-2-(methylsulfonyl)benzenamine (83 mg, 14%): 1H NMR (400 MHz, CDCl3): δ 7.78 (dd, 1 H), 7.07 (dd, 1H), 7.03 (dd, 1H), 6.53 (dd, 1H), 6.32 (dd, 1H), 4.82 (bs, 1H), 4.45 (m, 1H), 3.75 (s 3H), 3.07 (s, 3H), 2.41 (s, 3H), 1.48 (d, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCN(CC)CC.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]=[C:18]=[O:20])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccccc1N=C=O

Procedure:
The compound was prepared substantially in accordance with the procedure detailed in Example 27A, using 2-ethylaniline (1.5 ml, 12.2 mmol), Et3N (4.3 ml, 30.4 mmol) and triphosgene (1.2 g, 4.0 mmol) in 45 ml of CH2Cl2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH2:6][NH:5]1.[OH-].[Na+].[C:19](=[S:21])=[S:20].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>C(OCC)(=O)C.C(O)C>[OH:1][CH2:2][CH2:3][C@H:4]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH2:6][N:5]1[C:19]([S:21][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=1)=[S:20]
Reactant: OCC[C@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCC[C@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Yield: 34 %

Procedure:
In the same manner as described in Example 13 by using (3R)-3-(2-hydroxyethyl)-1,2,3,4-tetrahydro-β-carboline (100 mg), 2N NaOH (0.23 ml), CS2 (0.028 ml), 4-chlorobenzyl chloride (82 mg) and 70% ethanol (2.5 ml), there is prepared the title compound (66 mg, 34%) as white powder, [α]D20 -115.8° (c=1.0, ethyl acetate). Mass m/e: 416 (M+), 258 (M+ --p--Cl--C6H4 --CH2SH).