Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:23])=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.N#N.[CH:26]#[C:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.[Cu](I)I.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>[CH3:23][C:4]1[S:3][C:2]([C:26]#[C:27][CH2:28][CH2:29][CH3:30])=[N:6][C:5]=1[CH2:7][O:8][N:9]=[C:10]([C:17]1[N:21]([CH3:22])[N:20]=[N:19][N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCCC
Reactant: Cc1sc(Br)nc1CON=C(c1ccccc1)c1nnnn1C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC#Cc1nc(CON=C(c2ccccc2)c2nnnn2C)c(C)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.8 %

Procedure:
To a stirred solution of N-[(2-bromo-5-methyl-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.509 mmol, 1 eq.) in 3 ml dry THF “degassed” with N2, was added pentyne (0.069 g, 1.01 mmol, 2 eq.) followed by triethylamine (0.205 g, 2.03 mmol, 4 eq.), Copper Iodide (0.014 g, 0.076 mmol, 0.15 eq.) and Tetrakis(triphenylphosphine)palladium (0.029 g, 0.025 mmol, 0.05 eq.). The reaction was stirred for 20 hrs at room temperature for complete conversion. The reaction was diluted with EtOAc (50 ml), filtered through “Chem Elut” cartridge, washed with fresh EtOAc (2×20 ml) and the filtrate was evaporated. The residue was chromatographed on silica gel to give N-{[5-methyl-2-(pent-1-yn-1-yl)-1,3-thiazol-4-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.141 g, 69% yield) as a brown gum.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C1([O:23][C:24](=O)[NH:25][CH2:26][CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:24]([NH:25][CH2:26][CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[O:23])[CH2:5][CH2:4]1
Reactant: O=C(NCCc1c[nH]c2ccccc12)Oc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)NCCc2c[nH]c3ccccc23)CC1

Procedure:
4-Dimethylamino-4-phenyl-cyclohexylamine (more polar diastereomer) (218 mg, 1.0 mmole) was added to a solution of [2-(1H-indol-3-yl)ethyl]carbamic acid phenyl ester (280 mg, 1.0 mmole) in dioxane and refluxed for 12 h. Working up was performed by removing the dioxane by distillation and combining the residue with water. The batch was adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and evaporated. The product was obtained as a colorless oil in a yield of 404 mg (100%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7]2[CH:17]=[C:18]([CH2:21][N:22]([CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[C:23](=[O:34])CC3C4C(=CC=CC=4)NN=3)[CH:19]=[CH:20][C:6]1=2)[CH3:4].CI.O>CN(C=O)C>[CH2:3]([N:5]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9](=[O:15])[N:8]([CH3:16])[C:7]2[CH:17]=[C:18]([CH2:21][N:22]([CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[CH:23]=[O:34])[CH:19]=[CH:20][C:6]1=2)[CH3:4]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)C(=O)Cc3n[nH]c4ccccc34)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(C=O)CCc3cccnc3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
Sodium hydride (55% in oil) (52 mg) was suspended in DMF (7 ml), and cooled to 0° C. in an ice water bath. N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-2-(1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)acetamide (210 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 30 minutes followed at room temperature for 30 minutes. Methyl iodide (0.03 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=85:15). The purified product was condensed to dryness to give the title compound (17 mg) as a pale yellow white amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9]C(O)=O)=[CH:4][C:3]=1[F:13].C([N:16]([CH2:19]C)CC)C.ClC(OCC)=[O:23].[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:8]=[CH:9][NH:16][C:19]2=[O:23])=[CH:4][C:3]=1[F:13]
Reactant: O=C(O)C=Cc1ccc(Br)c(F)c1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]ccc2cc(F)c(Br)cc12
Temperature: 100 °C
Yield: 60.8 %

Procedure:
To a solution of 4.0 g (16.3 mmol) of 3-(4-bromo-3-fluoro-phenyl)-acrylic acid in 60 mL acetone were subsequently added at 0-5° C. 2.0 g (19.6 mmol) triethylamine in 10 mL of acetone followed by 2.3 g (21.2 mmol) of ethyl chloroformate in 10 mL of acetone. After stirring for 1 h at 0-5° C. a solution of 1.6 g (24.5 mmol) of sodium azide in 9 mL of water was added. After stirring for 1 additional h the reaction mixture was poured onto 200 mL ice water and extraced with chloroform twice. The organic phase was dried over magnesium sulfate, 24 mL of diphenylether were added and the chloroform was cautiously removed in vacuo. The residue was then added dropwise into 60 mL of diphenylether, which had been preheated to 250° C. After complete addition the reaction mixture was stirred for additional 30 minutes at 230-250° C. After cooling down to 100° C. the reaction mixture was poured into 100 mL of heptane and after further cooling in an ice bath the precipitated product was filtered by suction and 2.4 g of crude 7-bromo-6-fluoro-2H-isoquinolin-1-one were obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=[CH:33][C:26]1=2.[O:37]1[C:42]2([CH2:47][CH2:46][N:45]([CH2:48][C:49]3[C:50]([F:58])=[C:51]([CH2:55][CH2:56][OH:57])[CH:52]=[CH:53][CH:54]=3)[CH2:44][CH2:43]2)[CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)CC)C>CN(C=O)C>[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([C:34]([N:40]3[CH2:41][C:42]4([CH2:47][CH2:46][N:45]([CH2:48][C:49]5[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][CH2:56][OH:57])[C:50]=5[F:58])[CH2:44][CH2:43]4)[O:37][CH2:38][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:26]1=2
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: O=C(O)c1ccc2sccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc2sccc2c1)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.181 g) was added in one portion to a stirred solution at 0° C. of benzo[b]thiophene-5-carboxylic acid (0.065 g) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.113 g) and triethylamine (0.153 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.160 g.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH:44]=O)[CH:42]=[CH:43][C:36]1=2.[OH-].[K+]>C(O)C.[Pt]=O>[C@@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=2[C:32](=[O:34])[CH:33]=[CH:44][C:41]2[CH:42]=[CH:43][C:36]3[O:35][CH:39]=[CH:38][C:37]=3[CH:40]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: O=Cc1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=[Pt]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc2occc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
2'-(2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyloxy)-6'-hydroxyacetophenone (5 g) and benzo[b]furan-5-carbaldehyde (1.81 g) are (i) treated in the same manner as in Example 1 to give crude 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)acrylophenone, which is dissolved in a mixture of ethanol (50 ml) and a 10% aqueous potassium hydroxide solution (10 ml). The mixture is subjected to catalytic hydrogenation by using as a catalyst platinum oxide (120 mg) under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is neutralized with a 10% hydrochloric acid under ice-cooling, and concentrated under reduced pressure. To the residue is added ethyl acetate, and the mixture is stirred, and the organic layer is collected; (ii) treated in the same manner as in Example 1 to give crude 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)acrylophenone, which is dissolved in a mixture of ethanol (50 ml) and a 10% aqueous potassium hydroxide solution (10 ml). To the solution is added 4-N,N-diemethylaminopyridine (2.5 g) and the mixture is subjected to catalytic hydrogenation by using as a catalyst 10% palladium-carbon (1.1 g) under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is neutralized with a 10% hydrochloric acid under ice-cooling, and concentrated under reduced pressure. To the residue is added ethyl acetate, and the mixture is stirred, and the organic layer is collected; or (iii) treated in the same manner as in Example 2, and the organic layer is collected.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[C:4]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[CH:14][CH:13]=3)[C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl.CCOC(C)=O>[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]3[C:10](=[O:20])[N:11]([CH3:19])[C:12]4[C:17]([CH:18]=3)=[CH:16][N:15]=[CH:14][CH:13]=4)[C:3]=2[Cl:21])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cn1c(=O)c(-c2c(Cl)ccc(N)c2Cl)cc2cnccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Cl)ccc(NC(=O)c3ccc(CCl)cc3)c2Cl)cc2cnccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
To a solution of 3-(3-amino-2,6-dichloro-phenyl)-1-methyl-1H-[1,6]-naphthyridin-2-one (30 mg, 0.0937 mmol) in the dichloromethane (7 mL) is added 4-(chloromethyl)benzoyl chloride (53.2 mg, 0.28 mmol). After the mixture is stirred 24 hours at room temperature, it is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column elute with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (NH3, 2N)(95/5%) to give the titled intermediate as a solid (32.4 mg, 73.1%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[CH:5]=[CH:4][C:3]=1[CH3:15].C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1ccc(NC(=O)C(C)(C)C)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(N)nc1Cl
Temperature: 80 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
To N-(6-chloro-5-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (4.00 g, 17.7 mmol) was added 6 N HCl (20 mL) at room temperature. The mixture was stirred at 80° C. for 12 hours. The reaction mixture was basified with drop-wise addition of sat. NaHCO3 to pH 8-9, and then the mixture was extracted with CH2Cl2 (3×). The organic phases were dried over Na2SO4 and evaporated under vacuum to obtain the 6-chloro-5-methyl-pyridin-2-ylamine (900 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=8.0 Hz, 1 H), 6.35 (d, J=8.0 Hz, 1 H), 4.39 (br s, 2 H), 2.22 (s, 3 H). MS (ESI) m/z: 143 (M+H+).
Reaction SMILES: [CH:1]#[C:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[N:5]1.[C:9]([C:11]1[CH:27]=[CH:26][C:14]([CH2:15][NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20](I)[CH:19]=2)=[CH:13][CH:12]=1)#[N:10].C(N(C(C)C)CC)(C)C>CN(C)C=O.C1COCC1.[Cu]I.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>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:1]#[C:2][CH2:3][N:4]3[CH:8]=[CH:7][N:6]=[N:5]3)[CH:19]=2)=[CH:26][CH:27]=1)#[N:10]
Reactant: C#CCn1ccnn1
Reactant: N#Cc1ccc(CNC(=O)c2cccc(I)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CNC(=O)c2cccc(C#CCn3ccnn3)c2)cc1
Temperature: 55 °C
Reaction time: 5 h
Yield: 36.4 %

Procedure:
A solution of 1-propyn-3-yl-1H-[1,2,3]triazol (0.086 g, 0.8 mmol) in N,N-dimethylformamide (“DMF”, 1 mL) was treated with the N-(4-cyano-benzyl)-3-iodo-benzamide (0.225 g, 0.62 mmol) prepared in Step (1), diisopropylethylamine (0.32 g, 2.5 mmol), copper (I) iodide (0.024 g, 0.013 mmol), and dichlorobis(triphenylphosphine)palladium (II) (0.025 g, 0.004 mmol), respectively. The reaction mixture was stirred under nitrogen atmosphere for 5 hours at 55° C., then cooled to room temperature. The crude reaction mixture was diluted with THF (5 mL) and passed through a pad of silica gel (elution with THF). The partially purified product obtained was further purified using silica gel chromatography (elution with THF/hexane [3:1]) to give the title compound (0.077 g, 36%) as cream color solid. 1H-NMR (CDCl3/DMSO-d6) δ 8.3 (m, 1H), 7.9 (s, 1H), 7.8 (m, 2H), 7.6 (s, 1H), 7.4 (m, 3H), 7.3 (m, 2H), 5.3 (s, 2H), 4.5 (d, 2H) ppm. Mp 145° C.-147° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(OC(=O)C1C=CC=CC=1F)C1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([F:9])=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C(OCc1ccccc1)c1ccccc1F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(F)cc1
Reaction time: 18 h

Procedure:
Benzyl alcohol (4.05 mL, 39.1 mmol) was added slowly to a stirring solution of 4-fluorobenzoic acid (5.00 g, 35.7 mmol), 4-(dimethylamino)pyridine (432 mg, 3.53 mmol), and 1,3-dicyclohexylcarbodiimide (8.15 g, 39.5 mmol) in anhydrous CH2Cl2 at room temperature under an argon atmosphere. After 18 h the reaction was worked up according to procedures as outlined for the synthesis of 16. Flash chromatographic purification over silica (10% EtOAc in hexanes) afforded 17 as a clear, colorless liquid (7.75 g, 94%). 1H-NMR (500 MHz, CDCl3) δ 5.35 (s, 2H), 7.06-14 (m, 2H), 7.32-7.41 (m, 3H), 7.41-7.47 (m, 2H), 8.06-8.12 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 66.84, 115.5 (d, JC-F=22.0 Hz), 126.4 (d, JC-F=2.9 Hz), 128.2, 128.3, 128.6, 132.3 (d, JC-F=9.6 Hz), 135.9, 165.5, 165.8 (d, JC-F=253 Hz); GC-MS 230 m/z [M]+, C14H11OF2 requires 230.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17](=O)[C:16](=O)[CH:15]=1.C1C2C(=NC3C(N=2)=CC=CC=3)C=CC=1.IC>C(O)(=O)C.C(O)C>[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]2[N:1]=[C:2]3[C:11](=[N:12][C:16]=2[CH:15]=1)[CH:10]=[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[CH:3]3
Reactant: Nc1cc2ccccc2cc1N
Reactant: CC1=CC(=O)C(=O)C=C1C
Agent: c1ccc2nc3ccccc3nc2c1
Solvent: CCO
Solvent: CI
Solvent: CC(=O)O
Product: Cc1cc2nc3cc4ccccc4cc3nc2cc1C

Procedure:
The 2,3-dimethylbenzo(B)phenazine was prepared by the condensation of 2,3-diaminonapthalene with 4,5-dimethyl-1,2-benzoquinone in 4:1 ethanol to acetic acid at reflux for 2 hours. The phenazine was alkylated by the procedure of Synthesis Example 8, using iodomethane. Electrochemical analysis was consistent with an N,N'-dialkylated phenazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].CN(C)C.CCCCCC.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)N1CCCC1=O
Agent: CN(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCCN1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 30.5 h
Yield: 56.1 %

Procedure:
To a solution of 8.4 g of 4-chlorobenzenesulfonyl chloride (0.04 mole) and 6.9 g of N-trimethylsilyl-2-pyrrolidone (0.044 mole) in 50 ml of anhydrous tetrahydrofuran was added 0.2 ml of trimethylamine, and the mixture was stirred at the reflux temperature for 30.5 hours. The solvent was removed from the reaction under reduced pressure, and the residue was dissolved in 50 ml of chloroform. After addition of 15 g of silica gel (Wako Gel C-200) to the solution, chloroform was again removed under reduced pressure. The powdery residue thus obtained was supended in a mixed solvent of hexane-ethyl acetate (7:3). The suspension was subjected to chromatography on a column (D 40 mm×L 500 mm) of 300 g of silica gel (Wako Gel C-200). Elution with a mixed solvent of hexane-ethyl acetate (7:3) followed by a mixed solvent of hexane-ethyl acetate (3:2) gave a crystalline product, which was recrystallized from a mixed solvent of chloroform-ether to give 5.83 g of N-(4'-chlorobenzenesulfonyl)-2-pyrrolidone as crystals.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].[H-].[Na+].Br[CH2:37][C:38]([O:40]CC)=[O:39].[OH-].[Na+]>O1CCCC1.C(O)C>[F:1][C:2]([F:32])([F:33])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:37][C:38]([OH:40])=[O:39]
Reactant: OCCOCCOCCOCCOCCOCCOCCOCCOCCOCC(F)(F)F
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)COCCOCCOCCOCCOCCOCCOCCOCCOCCOCC(F)(F)F
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product of step (c) (750 mg) in tetrahydrofuran (15 mL) was added sodium hydride (60% dispersion in mineral oil, 91 mg). The reaction was stirred at 20° C. for 30 minutes then ethyl bromoacetate (335 μl) was added and the reaction was stirred for a further 15 hours. Ethanol (1 mL) was then added and the stirring continued for 5 minutes. Sodium hydroxide solution (2M, 10 mL) was added and the resulting mixture was stirred at 20° C. for 30 minutes. The reaction mixture was then partitioned between dichloromethane (40 mL) and water (40 mL). The aqueous layer was acidified to pH 1 by the addition of hydrochloric acid (2M) and then extracted with dichloromethane (2×40 mL). The combined organic layers were dried and the solvent removed in vacuo to give the title compound as a yellow oil (612 mg).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][CH:10]2[NH:12][CH:7]([CH2:8][CH2:9]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[CH3:19][N:20]([CH:22]=[O:23])[CH3:21]>>[CH2:1]([CH:5]1[CH2:6][CH:7]2[N:12]([CH2:9][C@@H:10]([CH3:11])[CH2:19][N:20]3[C:21]4[C:6](=[CH:5][CH:1]=[CH:2][CH:3]=4)[CH2:7][CH2:8][C:22]3=[O:23])[C@@H:10]([CH2:9][CH2:8]2)[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC1CC2CC[C@@H](C1)N2C[C@@H](C)CN1C(=O)CCc2ccccc21

Procedure:
Crude (R,S)-1-(3-chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (107LH63)(0.094 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), NAI (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-c4)(0.025 g), HPLC-MS (ammonium acetate) [M+H]+=369.33.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[C:7]([C:10]([S:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)C([O-])=O)([OH:9])=[O:8].O1CCC[CH2:31]1>CN(C=O)C>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]2[CH2:14][C@H:10]([C:7]([O:9][CH3:31])=[O:8])[S:22][C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:2](=[O:3])[C:16]=2[CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(CC(SCc2ccccc2)(C(=O)[O-])C(=O)O)cc1
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1Cc2ccc(C)cc2C(=O)[C@H](c2ccccc2)S1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30 %

Procedure:
Oxalyl chloride (11.3 g) and DMF (3 drops) were successively added dropwise to a solution of 2-(carboxy)(phenyl)methylthio-3-(4-methylphenyl)propionate (25.5 g) in tetrahydrofuran (THF) (150 ml), followed by stirring for 1.5 hours at room temperature and concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (50 ml). The solution was added dropwise to a suspension of aluminum chloride (AlCl3)(21.7 g) and dichloromethane (200 ml) with ice-cooling. The reaction mixture was stirred for 2 hours with ice-cooling and poured into ice-water. The dichloromethane layer was separated, washed with water, dried (MgSO4) and distilled off to give crystals of methyl trans-7-methyl-5-oxo-4-phenyl-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxylate (7.2 g, 30%). Recrystallization from ethyl acetate-hexane gave colorless prisms.