Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH:3]1([N:6]2[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:5][CH2:4]1.C([O-])(O)=[O:14].[Na+].[CH3:18][O:19][C:20]([C:22]1[CH:34]=[CH:33][C:25]2[NH:26][C:27]([C:29](Cl)(Cl)Cl)=[N:28][C:24]=2[CH:23]=1)=[O:21]>C1COCC1.O>[CH3:18][O:19][C:20]([C:22]1[CH:34]=[CH:33][C:25]2[NH:26][C:27]([C:29](=[O:14])[NH:12][CH:9]3[CH2:10][CH2:11][N:6]([CH:3]4[CH2:5][CH2:4]4)[CH2:7][CH2:8]3)=[N:28][C:24]=2[CH:23]=1)=[O:21]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Reactant: NC1CCN(C2CC2)CC1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C4CC4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 7.53 g (35.3 mmol) 1-cyclopropyl-piperidin-4-ylamine-dihydrochloride and 32.39 g (0.386 mol) NaHCO3 in 1300 mL THF and 370 mL water was added a solution of 11.79 g (32.1 mmol) 2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester in 360 mL THF. The reaction mixture was stirred vigorously for 2 h at room temperature. The THF was evaporated. The precipitate was filtered off and treated twice with approx. 300 mL of a saturated NaHCO3-solution under ultrasonic conditions. After filtration the resulting solid was washed twice with 150 mL water and dried under vacuo at 45° C. to give pure 2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic methyl ester in form of a light brown crystalline material. Yield: 9.9 g
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH3:18]O.Cl.N>ClCCl.C(OCC)(=O)C.C1CCCCC1.CO>[CH3:18][NH:8][C@@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]1[CH:4]=[C:3]([Br:2])[C:14]([O:15][CH3:16])=[C:13]([Br:17])[CH:12]=1
Reactant: CO
Reactant: COc1c(Br)cc(C[C@@H](N)C(=O)O)cc1Br
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CN[C@H](Cc1cc(Br)c(OC)c(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 5.5 g (14.12 mmol) of 3,5-dibromo-4-methoxy-D-phenylalanine-hydrochloride and 55 ml of methanol were added 150 ml of a saturated methanolic hydrogen chloride solution and the mixture was stirred for 20 hours at room temperature. The residue remaining after evaporation of the solvent was stirred with 50 ml of water and adjusted to pH 8 with saturated sodium hydrogen carbonate solution. The precipitate was suction filtered, stirred with 10 ml of isopropanol and left to stand overnight. The insoluble matter was filtered off and the filtrate was evaporated down in vacuo. The residue was further reacted as a crude product. Yield: 1.0 g (28.7% of theory) of a colourless oil , Rf=0.55 (eluant:dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia=300/80/25/25/3 (v/v/v/v/v)).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58][CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C.O>[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58][CH:59]1[CH2:64][CH2:63][N:62]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:61][CH2:60]1
Reactant: Brc1ccccc1SC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Sc2ccccc2Br)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.15 g, 0.000533 mol) in DMF (3 mL) was added DIPEA (0.206 g, 0.00160 mol), HOBt (0.0864 g, 0.00064 mol) and EDCI.HCl (0.122 g, 0.00064 mol) at ambient temperature. After 2 minutes 4-(2-bromo-phenylsulfanyl)-piperidine hydrochloride (0.197 g, 0.00064 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried. Purification by column chromatography using silica gel 60-120 mesh (40% ethyl acetate in hexane) afforded 0.097 g (36%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-bromo-phenylsulfanyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 499.07 (M+1)+, 95.7%, 1H NMR (DMSO-d6): δ 13.8 (d, 1H), 8.1 (t, 1H), 7.8 (d, 2H), 7.6 (dd, 1H), 7.58-7.3 (m, 6H), 7.22-7.06 (m, 2H), 4.3-4.1 (m, 3H), 3.9-3.6 (m, 2H), 3.0 (m, 1H), 2.0 (m, 2H), 1.7-1.4 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5](N)=[C:4]([F:11])[CH:3]=1.N([O-])=O.[Na+].C(Cl)Cl.C(OCC)(=O)C.[BrH:25]>O>[Br:25][C:5]1[CH:7]=[C:8]([O:9][CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=1[F:11]
Reactant: COc1cc(N)c(F)cc1Cl
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-2-fluoro-5-methoxyaniline (25.0 g, 0.143 mol) in 10% HBr (250 mL) was cooled to 0° C. and a solution of sodium nitrite (15.0 g, 0.218 mol) in water (20 mL) was slowly added. After addition, methylene chloride (50 mL) and cupric bromide (30.0 g, 0.244 mol) were added slowly. The reaction mixture was then warmed to ambient temperature, stirred for one hour, filtered through a bed of celite, and extracted with methylene chloride (2×100 mL). The combined organic phases were dried and concentrated. Chromatography of the dark oil (5% ethyl acetate in hexanes) gave 1-bromo-4-chloro-2-fluoro-5-methoxybenzene (16.6 g, 0.070 mol): 1H NMR (CDCl3): δ 7.20 (m, 1H), 7.05 (dd, 1H), 4.00 (s, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH2:16])[C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:6]=1.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(O)C.C(NCC)C>[NH:16]([C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@H:8]([C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Solvent: CC(C)O
Solvent: O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 64.6 %

Procedure:
1.1 g (5 mmol) of Phe-Gly (manufactured and sold by PEPTIDE INSTITUTE INC., Japan) was dissolved in a mixture of 2 ml of water, 2 ml of 2-propanol and 1.5 ml of diethylamine to obtain a solution. To the obtained solution was gradually added 1.8 g (6.5 mmol) of trityl chloride, followed by stirring for one hour. To the resultant reaction mixture was added water, to thereby generate a precipitate. The generated precipitate was collected, washed with water and then dissolved in 5 ml of acetic acid, to thereby obtain an acidic solution. The solvents were distilled off from the obtained acidic solution under reduced pressure, to thereby obtain 1.5 g of Trt-Phe-Gly. 604 mg (1.3 mmol) of the obtained Trt-Phe-Gly, 158 mg (1.3 mmol) of DMAP and 853 mg (1.0 mmol) of paclitaxel were dissolved in 20 ml of methylene chloride to obtain a solution. To the obtained solution was added 164 mg (1.3 mmol) of DIPC and stirred overnight at room temperature to effect a reaction. After completion of the reaction, the solvents were distilled off from the resultant reaction mixture under reduced pressure. The resultant residue was purified by silica gel column chromatography (silica gel: Art No. 9385, Silica gel 60, 200-400 mesh, manufactured and sold by Merck KGaA, Germany; column: 4.0×30 cm; eluent: methylene chloride/acetonitrile ratio=80/20), to thereby obtain 980 mg of 2′-Trt-Phe-Gly-paclitaxel. 800 mg of the obtained 2′-Trt-Phe-Gly-paclitaxel was treated with 10 ml of 90% acetic acid to effect a reaction for removing an N-trityl group. The resultant product was purified by silica gel column chromatography (silica gel Art No. 9385, Silica gel 60, 200-400 mesh, manufactured and sold by Merck KGaA, Germany; column 4.0×30 cm; eluent: methylene chloride/methanol/acetonitrile ratio=95/5/5), and subsequently converted from an acetate to a corresponding hydrochloride with an ion exchange resin, to thereby obtain 450 mg of 2′-Phe-Gly-paclitaxel hydrochloride (186).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=2)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28].[Cl:31]CCl>>[Cl:31][C:16]1[N:17]=[CH:18][C:13]([NH:12][CH:8]([C:4]2[CH:3]=[C:2]([NH:1][C:27](=[O:29])[CH3:28])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10][CH3:11])=[N:14][CH:15]=1
Reactant: ClCCl
Reactant: CC(=O)Cl
Reactant: CCCC(Nc1cncc(Cl)n1)c1cccc(N)c1
Solvent: CCN(CC)CC
Product: CCCC(Nc1cnc(Cl)cn1)c1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a stirred solution of N-[1-(3-aminophenyl)butyl]-6-chloropyrazin-2-amine (0.10 g, 0.36 mmol) and triethylamine (100 μl, 0.72 mmol) in dichloromethane (3 mL) cooled to 0° C. was added acetyl chloride (31 μL, 0.43 mmol). The resulting mixture was stirred at room temperature for 18 h. then diluted with dichloromethane (10 mL) and washed with H2O (10 mL) and brine (10 mL). The organic phase was collected, dried and concentrated and the residue purified by flash chromatography eluting with ethyl acetate-hexane (1:1) to give pure product (94 mg, 82%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28](C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1CCC(N)CC1)CC>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([CH:1]4[CH2:6][CH2:5][CH:4]([CH2:25][CH2:24][CH3:28])[CH2:3][CH2:2]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: CCCC1CCC(N)CC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CCCC1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 69.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 4-propylcyclohexylamine (0.148 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 105.7 mg (0.30 mmol, 69.7% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][NH:33][CH2:34]2)=[O:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][N:33]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:34]2)=[O:29]
Reactant: COC(=O)c1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 26.1 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 109 mg of 4-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 65 mg of the target compound.
Reaction SMILES: C(OC([N:10]([CH3:12])C)N(C)C)(C)(C)C.[C:13]([C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([NH:25][C:26](=[O:48])[C:27]3[C:32]([F:33])=[CH:31][CH:30]=[C:29]([N:34]([S:41]([CH2:44][CH2:45][CH3:46])(=[O:43])=[O:42])S(CCC)(=O)=O)[C:28]=3[F:47])[CH:23]=2)[N:18](S(CCC)(=O)=O)[CH:17]=1)(=O)[CH3:14].[NH2:55]N>C1COCC1>[NH:10]1[CH:12]=[CH:14][C:13]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([NH:25][C:26](=[O:48])[C:27]4[C:32]([F:33])=[CH:31][CH:30]=[C:29]([NH:34][S:41]([CH2:44][CH2:45][CH3:46])(=[O:42])=[O:43])[C:28]=4[F:47])[CH:23]=3)[NH:18][CH:17]=2)=[N:55]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)Nc2cnc3c(c2)c(C(C)=O)cn3S(=O)(=O)CCC)c1F)S(=O)(=O)CCC
Reactant: NN
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(-c4cc[nH]n4)c3c2)c1F
Temperature: 25 °C
Yield: 14.1 %

Procedure:
1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (0.0132 mL, 0.0607 mmol) was added to N-(3-acetyl-1-(propylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzamide (0.0197 g, 0.0304 mmol) in THF (0.3 mL). The solution was stirred at reflux for 4 hours, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in EtOH (0.3 mL), and hydrazine (0.00973 g, 0.304 mmol) was added. The solution was stirred at reflux for 8 hours. The solution was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography (5% to 10% MeOH/DCM), then purified again with reversed phase (C-18) chromatography using gradient elution with 1% to 50% CH3CN/water to afford N-(3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.002 g, 0.0043 mmol, 14.3% yield). 1H NMR (400 MHz, CD3OD) δ 8.71-8.75 (m, 1H), 8.49-8.51 (m, 1H), 7.78 (s, 1H), 7.66-7.70 (m, 1H), 7.50-7.58 (m, 1H), 6.93-6.99 (m, 1H), 6.12-6.14 (m, 1H), 2.96-3.02 (m, 2H), 1.80-1.89 (m, 2H), 1.00-1.05 (m, 3H); m/z (APCI-pos) M+1=461.1.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:2]1[CH2:11][C:12]([CH:14]1[S:18][CH2:17][NH:16][C@@H:15]1[C:19]([OH:21])=O)=[O:13].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:2]1[CH2:11][C:12]([CH:14]1[S:18][CH2:17][NH:16][C@@H:15]1[C:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:13]
Reactant: O=C(C[C@@H]1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)O
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C(C[C@@H]1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCCC1
Yield: 31 %

Procedure:
Colorless crystals of 1-{3-[(R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-thioprolyl}pyrrolidine were prepared in the same manner as in Example 1, except that 3-[(R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-thioproline prepared in Reference Example 34 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 31%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:36][C@H:35]2[NH:37][CH2:38][C@@H:30]1[CH2:31][CH:32]=[CH:33][CH2:34]2.CCN(C(C)C)C(C)C>C(O)C>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:37]2[CH2:38][CH:30]3[N:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)[CH2:36][CH:35]2[CH2:34][CH:33]=[CH:32][CH2:31]3)=[CH:7][CH:8]=1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: O[C@H](COc1cccc2[nH]c3ccccc3c12)CN1CC2C/C=C\CC1CN2c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]c3ccccc3c12)CN1CC2CC=CCC1CN2c1ccc2ccccc2c1
Temperature: 95 °C

Procedure:
(S)-4-Oxiranylmethoxy-9H-carbazole (18.5 mg, 0.077 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.189 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was evaporated and the residue was purified via silica chromatography (30% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:41](COCC[Si](C)(C)C)[CH:40]=[N:39][C:5]=2[C:6]([CH2:30][C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:38])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[C:12]([CH3:29])[CH:11]=1)#[N:2].C(=O)(O)[O-:51].[Na+]>S(=O)(=O)(O)O.O>[Cl:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[CH2:30][C:6]1[C:5]2[N:39]=[CH:40][NH:41][C:4]=2[C:3]([C:1]([NH2:2])=[O:51])=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)=[C:12]([CH3:29])[CH:11]=2)[N:7]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(Nc2nc(Cc3c(Cl)cccc3Cl)c3ncn(COCC[Si](C)(C)C)c3c2C#N)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Nc2nc(Cc3c(Cl)cccc3Cl)c3nc[nH]c3c2C(N)=O)ccc1N1CCNCC1
Temperature: 95 °C

Procedure:
To a solution of the product of Example 29A (120 mg, 0.17 mmol) in concentrated sulfuric acid (5 mL) was added water (1 mL) at 0° C. and the mixture was heated at 95° C. for 20 minutes. After cooling to ambient temperature, the mixture was diluted with water (3 mL), and the pH was adjusted to pH 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3×20 mL). The combined organic phase was concentrated and the residue was purified via preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 3 00 MHz): δ 13.55 (br, 1H), 11.66 (s, 1 H), 9.58 (s, 1 H), 8.67 (s, 1 H), 8.57 (s, 1 H), 7.81 (s, 1 H), 7.57-7.54 (m, 1 H), 7.41-7.36 (m, 1 H), 7.11 (dd, J=8.4, 2.1 Hz, 1 H), 7.05 (d, J=2.1 Hz, 1 H), 6.62 (d, J=8.4 Hz, 1 H), 4.69 (s, 2H), 3.23-3.22 (m, 4 H), 2.94-2.92 (m, 4 H), 2.14 (s, 3 H). MS: 510 (M+H+).
Reaction SMILES: C([O:5]O)(C)(C)C.[Cl:7][C:8]1[C:13]([Cl:14])=[C:12]([S:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22]>CCCCCCCCCC.C(Cl)(Cl)Cl>[Cl:7][C:8]1[C:13]([Cl:14])=[C:12]([S:15]([CH2:16][CH3:17])=[O:5])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:22])([F:23])[F:24]
Reactant: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Reactant: CC(C)(C)OO
Solvent: ClC(Cl)Cl
Solvent: CCCCCCCCCC
Product: CCS(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Reaction time: 18 h

Procedure:
t-Butyl hydrogen peroxide (2.4 ml of a 5.5M solution in decane) was added to a solution of (R)-N-[2,3-dichloro-4-ethylsulphanylphenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide Method 1) (0.23 g) and d-10-camphorsulphonic acid (0.018 g) in chloroform (10 ml) and the mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-50% EtOAc/isohexane to give the title compound (0.22 g) as a white solid. NMR (CDCl3+1 drop DMSO): 1.21-1.28 (m, 3H), 1.71 (s, 3H), 2.77-2.89 (m, 1H), 3.04-3.16 (m, 1H), 7.14 (s, 1H), 7.78 (d, 1H), 8.66 (d, 1H), 9.73 (s, 1H); m/z: 376.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccccc1Br
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccccc1Br
Yield: 3.5 %

Procedure:
A mixture of 2-amino-3-(2-bromobenzyloxy)pyridine (5.58 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave a residue which was purified by chromatography (silica, chloroform/methanol) and recrystallisation from ethanol/ether to obtain the product (0.28 g), m.p. 158°-169° C.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]([C:22]1([CH3:28])[CH2:27][CH2:26][N:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1(C)CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Temperature: 210 °C
Yield: 40.5 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethyl-pyridazine (1.0 g, 4.3 mmol) in NMP (10 mL) is added 4-methyl-piperidine-4-carboxylic acid ethyl ester (2.0 g, 8.6 mmol) and DIPEA (3.7 mL, 21.6 mmol). The mixture is heated in microwave at 210° C. for 1.5 h. The mixture is concentrated at 80° C. by rotovaporation. The crude product is purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (0.64 g, 41%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: COc1ccccc1CC(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: CC#N
Product: COc1ccccc1CC(=O)N1CC[C@@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-methoxyphenyl)acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])([CH3:3])[CH3:2].CN(C)C=O.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[CH:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([Cl:23])=[O:9])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1SC(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1SC(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 3-isopropylthio-4-methoxybenzoic acid (2.5 g; that is prepared as described in Reference Example 49) in toluene (25 mL), and dimethylformamide (0.2 mL) is treated with thionyl chloride (2.5 mL) and the solution is stirred at 60° C. for 3 hours. The solution is concentrated, treated with toluene (10 mL) and again evaporated to dryness, to give 3-isopropylthio-4-methoxybenzoyl chloride (2.7 g), in the form of a light brown oil.