Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([N+:19]([O-:21])=[O:20])=[CH:11][C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]1=2)#[N:7].[OH2:26]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([N+:19]([O-:21])=[O:20])=[CH:11][C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]1=2)(=[O:26])[NH2:7]
Reactant: O
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2 ml of concentrated sulphuric acid are added dropwise to a suspension of 4.0 g (0.015 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine in 40 ml of acetic acid and the mixture is stirred for a further 15 hours at room temperature. 100 ml of water are gradually added to the clear solution, the precipitated material is taken up in chloroform, and the chloroform layer is washed with water and evaporated to dryness. After recrystallisation of the residue from isopropanol, pure 5-carbamoyl-10-nitro-5H-dibenz[b,f]azepine is obtained; melting point 208°-212°, yield 2.2 g, 52.4% of the theoretical yield. The analytical and spectroscopic data agree with the given structure.
Reaction SMILES: [CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=3[NH:9][C:10](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=3[N:9]=[C:10]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Oc1cc([N+](=O)[O-])ccc1NC2=O
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(s1)Oc1cc([N+](=O)[O-])ccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 2-methyl-8-nitrothieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 2-methyl-4-(4-methylpiperazin-1-yl)-8-nitrothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [CH3:1][C:2]([S:12]([CH2:15][C@@H:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])([C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:3].[H][H]>CO.[Rh]>[CH3:3][C:2]([S:12]([CH2:15][C@@H:16]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[C:17]([OH:19])=[O:18])(=[O:13])=[O:14])([C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: [Rh]
Solvent: CO
Product: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)C[C@@H](CC1CCCCC1)C(=O)O

Procedure:
A solution of 610mg (1.59mmol) (S)-α-[[[1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnamic acid in 20 ml of methanol was hydrogenated in the presence of 60 mg of rhodium on aluminium oxide at 500 for 4 hours at a pressure of 106Pa of hydrogen. Subsequently, the catalyst was filtered off and rinsed with methanol. The methanolic solution was evaporated under reduced pressure, whereby 580 mg of (S)-α-[[[1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]cyclohexanepropionic acid, MS: 346 (M-C3H7)+ were obtained as a colourless crystalline solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(OC([NH:20][NH2:21])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH:20]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[NH2:21]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(CNN)c1

Procedure:
A solution of 3 g of methyl 3-bromomethylbenzoate (13 mmol), 2.6 g of tert-butoxycarbonylhydrazine (19 mmol) and 3.1 g of potassium carbonate (23 mmol) in 30 ml of DMF is stirred at RT for 24 h. After water has been added, the reaction mixture is extracted with dichloromethane. The organic phase is dried, filtered and evaporated, and the residue is purified chromatographically. The BOC protecting group is then eliminated using 30 ml of hydrochloric acid (4 M in dioxane). Yield: 1.25 g
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([NH:23][C:24]1[S:28][C:27]2[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=2[C:25]=1[C:33]([NH2:35])=[O:34])=[O:22]>CN(C=O)C.CO>[OH:10][CH2:9][CH2:8][C:7]1[C:3]([C:2]([F:1])([F:11])[F:12])=[N:4][N:5]([CH2:20][C:21]([NH:23][C:24]2[S:28][C:27]3[CH2:29][CH2:30][CH2:31][CH2:32][C:26]=3[C:25]=2[C:33]([NH2:35])=[O:34])=[O:22])[CH:6]=1
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Reactant: OCCc1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1c(NC(=O)Cn2cc(CCO)c(C(F)(F)F)n2)sc2c1CCCC2
Temperature: 60 °C
Yield: 40 %

Procedure:
To a solution of 2-(3-trifluoromethylpyrazol-4-yl)-ethanol (18 mg, 0.1 mmol) in DMF (0.5 mL) was added potassium carbonate (16 mg, 0.12 mmol). The reaction mixture was stirred at 60° C. for 25 min before 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (32 mg, 0.1 mmol) was added. Heating at 60° C. was maintained for 4 h before the reaction mixture was allowed to cool to RT. The whole was diluted with MeOH (0.5 mL), and filtered before being purified by preparative reverse phase HPLC to give the desired product as a white solid (17 mg, 0.04 mmol, 41%).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=[O:16])=[O:15])=[CH:9][C:8]=1[N+:27]([O-])=O)(=[O:3])[CH3:2].[H][H]>CO.COCCO.[Ni]>[C:1]([NH:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)(=[O:15])=[O:16])=[CH:9][C:8]=1[NH2:27])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: COCCO
Product: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N

Procedure:
59 g of 2-(3-acetylureido)-5-(3-trifluoromethylphenylsulfonyloxy)nitrobenzene in 200 ml of methanol and 200 ml of 2-methoxyethanol are hydrogenated under normal pressure with a catalytic amount of Raney nickel. After hydrogen uptake is complete, the catalyst is filtered off with suction, washed with warm 2-methoxyethanol and the solution is evaporated under reduced pressure. Water is added to the residue and it is then filtered off with suction, washed with water and dried over sodium hydroxide, melting point 182° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]3[CH2:12][CH2:13][NH:14][CH2:15][CH:6]3[C:5]=2[CH:4]=1)[CH3:2].[F:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([CH2:23][CH2:24][CH2:25]Cl)=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]3[CH2:12][CH2:13][N:14]([CH2:25][CH2:24][CH2:23][C:21](=[O:22])[C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:28][CH:27]=4)[CH2:15][CH:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C1CNCCC1N2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCc1ccc2c(c1)C1CN(CCCC(=O)c3ccc(F)cc3)CCC1N2
Reaction time: 9 h

Procedure:
To methyl ethyl ketone (120 ml) are added 8-ethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (9 g), γ-(p-fluorobenzoyl)propyl chloride (12 g), potassium carbonate (12 g) and potassium iodide (11 g), and the mixture is refluxed with stirring for 9 hours. After cooling, the insoluble materials are filtered off and the filtrate is concentrated. The resulting residue is dissolved in a dilute hydrochloric acid and the solution is washed with benzene. The dilute hydrochloric acid layer is made alkaline with aqueous ammonia and extracted with benzene. The benzene layer is dried over anhydrous sodium sulfate and concentrated. The resulting residue is treated with ethanolic hydrochloric acid in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (12 g), m.p. 192° - 195°C (recrystallized from aqueous ethanol).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7](O)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.FC(F)(F)CO.B(F)(F)F>C(OCC)C>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C:6]([CH3:20])=[CH:7][O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: FB(F)F
Solvent: OCC(F)(F)F
Solvent: CCOCC
Product: CC1=CO[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 6 h
Yield: 33.3 %

Procedure:
To a solution of dihydroartemisinin (426 mg, 1.50 mmol) and 2,2,2-trifluoroethanol (220 μl, 3.00 mmol) in diethyl ether (30 ml) at room temperature under nitrogen was added boron trifluoride dietherate (3 drops). The mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. Flash chromatography (SiO2: 8% ethyl acetate/hexanes) gave 10β-[(2′,2′,2′-trifluoroethyl)oxy]dihydroartemisinin (157 mg, 29%) and 9,10-anhydrodehydroartemisinin (133 mg, 46%) both as white solids. Ether: M.p. 113.4-114.2° C.; [α]D20: +133° (c 0.30/CHCl3); νmax (film): 2984, 2960, 2928, 2870, 1454, 1414, 1378, 1308, 1278, 1174, 1150, 1110, 1052, 1036, 990, 972, 918, 874, 824; δH: 5.43 (1H, s, H-12), 4.90 (1H, d, J=3.46 Hz, H-10), 4.15 (1H, dq, J=12.2, 8.87 Hz, H-1′), 3.89 (1H, d, J=12.2, 8.67 Hz, H-1′), 2.65-2.75 (1H, m, H-9), 2.40 (1H, ddd, J=17.5, 13.4, 4.02 Hz), 2.07 (1H, ddd, J=14.6, 4.83, 3.01 Hz), 1.64-1.96 (5H, m), 1.22-1.58 (4H, m), 1.46 (3H, s, H-14), 0.98 (3H, d, J=5.94 Hz, H-16), 0.97 (3H, d, J=7.69 Hz, H-15); δC: 104.13, 102.41, 87.93, 80.73, 64.91 (d, J=34.3 Hz), 52.32, 43.99, 37.29, 36.17, 34.39, 30.44, 25.90, 24.47, 24.11, 20.13, 12.47; m/z (CI, NH3): 384 (M+NH4+, 16%), 367 (M++1, 2), 284 (100), 267 (72).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[OH:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)=[O:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
MnO2 (20 g, 231 mmol, 5 equivalent) was added to a stirred solution of the crude (3,5-dimethoxy-phenyl)-(4-methoxy-3-nitro-phenyl)-methanol in CH2Cl2 (100 mL). The reaction mixture was stirred at room temperature for 2 days and MnO2 [6 equivalent (3×2 eq.)] was added during this period of time. The reaction mixture was then filtered through celite and washed with CH2Cl2 (3×60 mL). Removal of solvent from the filtrate and chromatography (Silica Gel) gave (3,5-dimethoxy-phenyl)-(4-methoxy-3-nitro-phenyl)-methanone as a solid (9.61 g, 79% yield): 1H NMR (CDCl3) δ 3.83 (s, 6H, 2OCH3), 4.06 (s, 3H, OCH3), 6.68-6.70 (t, J=2.2 Hz, 1H, Ar), 6.85-6.86 (d, J=2.3 Hz, 2H, Ar), 7.16-7.20 (d, J=8.9 Hz, 1H, Ar), 8.06-8.10 (dd, J=2.3 and 8.9 Hz, 1H, Ar), 8.33-8.34 (d, J=2.1 Hz, 1H, Ar); 13C NMR (CDCl3) δ 55.64, 56.91, 104.96, 107.57, 113.10, 127.86, 129.69, 135.78, 138.66, 139.20, 155.85, 160.79, 193.07.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:15][C:11]=2[N:12]=[CH:13][N:14]=1)C.Cl.O>CC(C)=O>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]2[C:10]3[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:3])=[N:14][CH:13]=[N:12][C:11]=3[O:15][C:16]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:22]=1
Reactant: CCOC(CCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12)OCC
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCC=O)c23)cc1
Reaction time: 1 h

Procedure:
Dissolve 640 mg (1.39 mmol) N-(4,4-diethoxybutyl)-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine-4-amine in 5 ml acetone and, at RT, add 1 ml 1 N hydrochloric acid. After 1 h, add the reaction mixture to water and extract three times with dichloromethane. Combine the organic phases and wash with buffer solution (pH 7) and saturated sodium chloride solution, dry over magnesium sulphate and concentrate under vacuum. Purify the raw product by chromatography on silica gel (solvent: dichloromethane/ethyl acetate 2:1). 191 mg (35.6% of theor.) of the target compound is obtained.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6].[CH3:9][C:10]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:9][C:10]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:11][CH2:12][CH2:13][O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]
Reactant: OCC(O)CO
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=CCCOCC(O)CO)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
0.27 g (55%, 6.2 mmol) of sodium hydride was added to a solution of glycerol 0.57 g (6.2 mmol) in dry N,N-dimethylformamide (6 mL) with cooling on ice. After the mixture was stirred for 30 min at 50° C., the above (4,8,12-trimethyltridec-3-enyl)tosylate was added dropwise, with additional stirring for 10 hours at the same temperature. After addition of water at 0° C., the reaction mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 79 mg of the title compound (6% yield in 2 steps). The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:19][CH:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:2]1([CH:8]([CH3:11])[CH2:9][NH:10][S:22]([CH:20]([CH3:21])[CH3:19])(=[O:24])=[O:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CN)c1ccccc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
To a solution of 2-phenyl-propylamine HCl salt (1.0 g, 5.8 mmol), DMAP (35 mg, 0.3 mmol) and Et3N (1.77 g, 17.5 mmol) in DCM (25 mL) was added propane-2-sulfonyl chloride (1.25 g, 8.7 mmol) dropwise at 0° C. The mixture was stirred at r.t. for 16 h, and was then concentrated under vacuum. The residue was partitioned between EtOAc (100 mL) and H2O (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, filtrated and concentrated to give an oil residue. This residue was purified with silica gel column (Hexane/EtOAc=2/1 to 1/1) to obtain the desired product (1.2 g, 86%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.30-7.32 (m, 2H), 7.18-7.24 (m, 3H), 3.90-3.94 (m, 1H), 3.30-3.35 (m, 1H), 3.18-3.22 (m, 1H), 2.99-3.04 (m, 1H), 2.91-2.95 (m, 1H), 1.27 (d, 3H, J=7.2 Hz), 1.25 (d, H, J=7.8 Hz), 1.22 (d, 1H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([S:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:18]#[N:19])[CH2:2][CH2:3][CH3:4].COC1C=CC(/C=[C:35]2/[C:36]([NH:38][C:39]([S:41]/2)=[NH:40])=[O:37])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:40][C:39]1[S:41]/[C:35](=[CH:16]\[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:18]#[N:19])=[C:6]3[S:5][CH2:1][CH2:2][CH2:3][CH3:4])/[C:36](=[O:37])[N:38]=1
Reactant: CCCCSc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCSc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 4-butylsulfanyl-6-formyl-quinoline-3-carbonitrile (example 53b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-butylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 367 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[N:23]([CH2:27]Cl)[CH:24]=[N:25][N:26]=1.O>CN(C)C=O>[Cl:21][C:22]1[N:23]([CH2:27][O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[CH:24]=[N:25][N:26]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: ClCn1cnnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nncn1COc1ccc(Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
5.6 g of p-phenoxyphenol and 4.2 g of potassium carbonate are heated for 1 hour at 70° C. in 50 ml of anhydrous dimethylformamide. Subsequently, 5.6 g of 2-chloro-1-chloromethyl-1,3,4-triazole is added and the mixture stirred for 6 hours at 70° C. and overnight at room temperature (about 20° C.). The mixture is then poured into 500 ml of water and extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated. The residue is purified by chromatography over silica gel using n-hexane/ethyl acetate (2:1) as eluant. There is obtained 2.8 g of 2-chloro-1-[(p-phenoxyphenoxy)-methyl]-1,3,4-triazole as an oil.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Br:19][C:20]1[CH:24]=[CH:23][N:22]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=1.[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O.O>C1COCC1.CN(C1C=CN=CC=1)C>[C:39]([O:38][C:36]([N:22]1[CH:23]=[CH:24][C:20]([Br:19])=[CH:21]1)=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
A solution of TBAF (1.0 M in THF, 3.6 mL) was added to a solution of 3-bromo-1-triisopropylsilanyl-1H-pyrrole (1.0 g, 3.308 mmol) in THF (10 mL) and the mixture was stirred at room temperature for 30 minutes. (BOC)2O (0.866 g, 3.965 mmol) and DMAP (40 mg, 0.3308 mmol) were added to the reaction and the resulting mixture was stirred for 2 additional hours. Water was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and with brine; dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc) to give 0.197 g (24% yield) of 3-bromo-pyrrole-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(/[CH:34]=[CH:35]/[CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:1]([C:8]1[N:9]=[C:10](/[CH:34]=[CH:35]/[CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(/C=C/CCN2CCCCC2)OC1(C)C
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3ccccc3)nc(Cl)c12
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: [K+]
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3ccccc3)nc(/C=C/CCN3CCCCC3)c12
Temperature: 110 °C
Reaction time: 24 h
Yield: 42.6 %

Procedure:
In a 2-5 mL microwave vial was added methyl 2-benzyl-4-chloro-9H-pyrimido[4,5-b]indole-7-carboxylate (0.100 g, 0.284 mmol), (E)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)piperidine (0.113 g, 0.426 mmol), potassium carbonate (0.106 g, 0.768 mmol) and Pd(Ph3P)4 (0.05 g, 0.044 mmol). The vial was purged with N2 (3 vacuum+refill cycles). DME (2.84 mL) and water (0.398 mL) were added and the vial was flushed with N2 (one vacuum+refill) and then heated to 110° C. while stirred for 24 hours. After cooling, the mixture was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography to give (E)-methyl 2-benzyl-4-(4-(piperidin-1-yl)but-1-en-1-yl)-9H-pyrimido[4,5-b]indole-7-carboxylate (55 mg, 0.121 mmol, 42.6% yield) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 2H) 1.50-1.61 (m, 4H) 2.30-2.47 (m, 4H) 2.53-2.59 (m, 2H) 2.59-2.70 (m, 2H) 3.91 (s, 3H) 4.27 (s, 2H) 7.16-7.24 (m, 1H) 7.29 (t, J=7.6 Hz, 2H) 7.34-7.43 (m, 4H) 7.88 (dd, J=8.2, 1.4 Hz, 1H) 8.07 (d, J=1.4 Hz, 1H) 8.41 (d, J=8.2 Hz, 1H) 12.48 (s, 1H); HRMS m/z 455.2442 (M+H)+; HPLC 100% @ 220 nm and 99.4% @ 254 nm, RT=1.84 minutes.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[CH3:7].ClC(Cl)C.Cl>C1COCC1>[C:16]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:6][CH3:7])=[CH:10][CH:11]=2)[CH2:2][CH2:1]1)#[N:17]
Reactant: CCOc1ccc(CC#N)cc1
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: CCOc1ccc(C2(C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6M n-Butyllithium (680 ml) is added over 5 min to a stirred solution of 4-ethoxyphenyl acetonitrile (56 g) in anhydrous THF (600 ml) at 25° C. under an atmosphere of nitrogen. After 1 h, a solution of 1.2 dichloroethane (111 g) in anhydrous THF (300 ml) is added dropwise over 2 h and the mixture stirred at 25° C. for 16 h. The mixture is then poured onto 3N HCl (1 l ), concentrated under reduced pressure, extracted with diethyl ether (x3), washed with water, dried over anhydrous sodium sulphate, the solvent removed under reduced pressure and the residue distilled to give the product, b.p. 116°-120° C., yield 40 g. nD 1.5320.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:27])[C:15](=[O:26])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[F:25])=[CH:17][C:7]2=1)(=[O:3])[CH3:2].CC(O[CH:33](N(C)C)[N:34]([CH3:36])[CH3:35])(C)C>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[C:15](=[O:26])[N:14]([CH3:27])[C:8]3[N:9]([CH3:13])[C:10]4[C:6]([C:7]=3[CH:17]=2)=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:33][N:34]([CH3:36])[CH3:35])=[CH:12][CH:11]=4)=[C:19]([F:25])[CH:20]=1
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3F)c(=O)n(C)c1n2C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3F)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in preparation 1.9C above, with compound B 6-acetyl-3-(4-chloro-2-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and Bredereck's reagent.