Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>CN(C)C=O>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:35])[C:9]([CH3:33])([CH3:34])[CH2:10]3)[C:18]=2[CH:31]=1
Reactant: COC(=O)CBr
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 25 °C
Yield: 48.4 %

Procedure:
5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.4 g, 0.814 mmol) was dissolved in dimethyl formamide (10 mL). Sodium hydride (0.029 g, 1.22 mmol, 1.5 equiv, 48 mg of a 60% suspension in mineral oil) was added at room temperature and gas evolution was visible. Methyl bromoacetate (0.187 g, 1.22 mmol, 116 uL) was added and the mixture was stirred at room temperature. After stirring overnight at room temperature, the reaction was quenched with water (10 mL). The resulting suspension was extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. The crude oil was purified by silica gel chromatography (methylene chloride to 10% methanol in methylene chloride gradient) to afford the title compound as a white solid (222 mg, 48%).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19].[H-].[K+]>C1COCC1>[I:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:18]#[N:19])=[C:7]2[O:4][CH2:3][CH:2]([CH3:5])[CH3:1]
Reactant: CC(C)CO
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)COc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from 2-methyl-propan-1-ol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 6-iodo-4-isobutoxy-quinoline-3-carbonitrile. LC-MS m/e 353(MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=[CH:3]1.C([Li])CCC.CN([CH:27]=[O:28])C>C1COCC1>[CH:27]([C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:4]=1)=[O:28]
Reactant: CN(C)C=O
Reactant: Cn1cnc(-c2ccccc2)c1-c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C=O)nc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-methyl-4-phenyl-5-[4-pyridinyl]imidazole (0.275 g, 1.17 mmol) in THF at −78° C. was added n-butyllithium (0.56 mL of 2.5 M solution, 1.40 mmol). The resulting red-orange solution was allowed to stir at −78° C. for 0.5 h when DMF (0.18 mL, 2.34 mmol) was added. The mixture was allowed to warm to rt and stir for 4 h, then quenched with ice water and partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4).The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with 50:1 CH2Cl2/MeOH. The title compound was obtained as a white solid (0.187 g, 61%): mp 167-168° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:8]=[N:9][C:10]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:11])[CH:7]=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22](/[C:23](=[CH:37]/[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=3)/[C:24](=[O:36])[N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si](C)(C)C)=[CH:21][CH:20]=1.CO>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:27]=[C:26]2[NH:25][C:24](=[O:36])[C:23]3([CH:37]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=4)[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:17])[C:22]2=[CH:21][CH:20]=1.[CH3:28][O:29][CH:30]([Si:13]([CH3:14])([CH3:15])[CH3:16])[CH3:31]
Reactant: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(C)[Si](C)(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 148 °C
Reaction time: 0.67 h
Yield: 49 %

Procedure:
To a solution of 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a in toluene (50 mL) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one prepared in example 55a (3.0 g, 7.14 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 148° C. for 40 min. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:Hexane=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as an off-white solid (Yield 2.1 g, 49%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=[O:22])[CH:12]([CH3:21])[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:5][CH:4]=1)#[N:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(O)(=O)=O.FC(F)(F)S(O)(=O)=O>C1(C)C(C)=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:12]([CH3:21])[C:11](=[O:22])[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C(=O)CC(=O)c1ccc(C#N)cc1)C(=O)c1ccccc1
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n(-c2ccccc2)c(-c2ccc(C#N)cc2)cc1=O
Yield: 20.1 %

Procedure:
In 400 ml of xylene were dissolved 10.0 g (0.033 mole) of 5-(4-cyanophenyl)-2-methyl-1-phenyl-1,3,5-pentanetrione, 25.0 g (0.26 mole) of aniline and 7.0 g (0.073 mole) of methanesulfonic acid. The solution obtained was heated under reflux for 30 minutes in a reactor fitted with a Dean-Stark apparatus. After cooling, 6.5 g (0.043) of trifluoromethanesulfonic acid was added further to the reaction mixture and the resultant mixture was similarly heated under reflux for 30 minutes. After cooling, solid matter was removed from the reaction mixture, followed by concentration under pressure. The concentrate was extracted with dichloromethane. The organic layer was washed successively with 100 ml of 10% hydrochloric acid, 100 ml of a 10% aqueous solution of sodium hydroxide and water. The organic layer was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). The resultant crystals were washed with acetone to afford 2.4 g of 6-(4-cyanophenyl)-3-methyl-1,2-diphenyl-4(1H)-pyridinone having a melting point of 229°-233° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (R)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 75.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.81 min, m/z=473.1-474.1 [M+H]+, m/z=472.2-471.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.52-1.61 (m, 1H) 1.78-1.87 (m, 1H) 2.17-2.26 (m, 1H) 2.53 (s, 3H) 2.99 (dd, J=11.00, 6.85 Hz, 1H) 3.11-3.20 (m, 2H) 3.21-3.29 (m, 2H) 3.33-3.37 (m, 1H) 4.60 (t, J=5.14 Hz, 1H) 7.34 (dd, J=8.44, 3.06 Hz, 2H) 7.69 (dd, J=7.82, 2.20 Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 7.98 (d, J=2.20 Hz, 1H) 8.49 (d, J=1.96 Hz, 1H) 8.74 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [OH:1][C:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH2:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C(C)=CC=CC=1C.[C:27]([O:30][CH2:31]C)(=O)C.O>COC(OC)O>[OH:1][C:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH2:8][O:9][CH2:27][O:30][CH3:31])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)(CO)Cc1ccc(OC)cc1
Reactant: CCOC(C)=O
Agent: COC(O)OC
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)C(O)(COCOC)Cc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
A solution of 1.06 g of ethyl 2,3-dihydroxy-2-(4-methoxybenzyl)propanoate in 20 ml of dimethoxymethanol was cooled to 0° C. under an atmosphere of nitrogen gas. 0.94 g of 2,6-lutidine and 1.59 ml of 1,1,1-trimethylsilyl tri-fluoromethanesulfonate were sequentially added, and the mixture was stirred for 1 hour. 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography, to give 1.00 g of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[CH:7][S:8](=O)[C:4]=2[CH:3]=1.[OH-].[Na+].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[SH:22].[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:28](Cl)=[O:29])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:7]1[S:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:11]=[CH:10][C:5]=2[N:6]=1)[CH3:24].[CH2:23]([O:25][C:26]([C:27]1[S:22][C:16]2[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:15]=2[NH:14][C:28]=1[OH:29])=[O:31])[CH3:24]
Reactant: Nc1ccc(Br)cc1S
Reactant: O=S1C=Nc2ccc(Br)cc21
Reactant: CCOC(=O)CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C1=C(O)Nc2ccc(Br)cc2S1
Product: CCOC(=O)Cc1nc2ccc(Br)cc2s1

Procedure:
Compounds of formula (22) can be prepared from 6-bromobenzothiazolone as shown in Scheme 3. 6-Bromobenzothiazolone is heated in the presence of NaOH base to provide a mixture of 2-amino-5-bromothiophenol (15) and its disulfide (16). The mixture is treated with chlorocarbonyl-acetic acid ethyl ester to provide 6-bromo-benzothiazol-2-yl-acetic acid ethyl ester (17) and 7-bromo-3-hydroxy-4H-benzo[1,4]thiazine-2-carboxylic acid ethyl ester (18), which can undergo rearrangement by treatment with zinc and ethyl acetate to provide compound (17). Compound (17) is reduced with NaBH4 to provide 2-(6-bromo-benzothiazol-2-yl)-ethanol (19). Compound (19) is treated with mesyl chloride in the presence of triethyl amine to afford the corresponding methanesulfonic acid 2-(6-bromo-benzothiazol-2-yl)-ethyl ester (20), which is treated with an amine of formula HNRaRb, wherein Ra and Rb each is as defined for R4 and R5, to provide compounds of formula (21). Compounds of formula (21) can be treated with a boronic acid, wherein Rc is aryl or heteroaryl, to provide compounds of formula (22).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][C:10]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]([CH2:21][CH3:22])[C:11]=3[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([O-:32])=[O:31]>CN(C)C=O>[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:8]=[CH:9][C:10]4[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]([CH2:21][CH3:22])[C:11]=4[N:12]=3)[CH2:6][CH2:5]2)=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)nc21
Temperature: 90 °C
Yield: 69.9 %

Procedure:
A mixture of 2.0 g of 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid, 1.34 g of triethylamine, 2.14 g of p-nitrobenzyl bromide, and 50 ml of dimethylformamide was heated at 90° C. for 14 hours with stirring and concentrated to dryness under reduced pressure. Addition of 50 ml of water to the residue resulted in the separation of a solid, which was collected and recrystallized from dimethylformamide to give the product (2.02 g), m.p. 259°-261° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([C:8]2[CH:9]=[C:10]3[N:19]([CH3:20])[CH:18]=[CH:17][C:11]3=[N:12][C:13]=2[C@@H:14]([NH2:16])[CH3:15])=[C:6]([CH3:21])[NH:5][N:4]=1.[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25](Cl)[N:24]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([C:30]#[N:31])=[C:25]([NH:16][C@H:14]([C:13]2[N:12]=[C:11]3[CH:17]=[CH:18][N:19]([CH3:20])[C:10]3=[CH:9][C:8]=2[C:7]2[C:6]([CH3:21])=[N:5][NH:4][C:3]=2[CH3:2])[CH3:15])[N:24]=1
Reactant: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Reactant: N#Cc1c(N)nc(N)nc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)Nc1nc(N)nc(N)c1C#N
Temperature: 120 °C
Yield: 54.9 %

Procedure:
(1S)-1-(6-(3,5-Dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (123 mg, 0.403 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (82 mg, 0.484 mmol), and N-ethyl-N-isopropylpropan-2-amine (211 μL, 1.21 mmol) were combined in acetonitrile (4030 μL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated in vacuo. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 30% ACN in water. The fractions containing the desired product were combined, concentrated, and lyophilized to give the title compound as an off-white solid (89 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (d, J=6.35 Hz, 3 H), 1.92 (br s, 3 H), 2.06 (br s, 3 H), 3.82 (s, 3H), 5.20 (br s, 1 H), 6.43 (br s, 2 H), 6.53-6.60 (m, 3 H), 6.96 (br s, 1 H), 7.62-7.69 (m, 2H), 12.36 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C26H22N10, 403; found 403.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:29]=1.[CH3:30]I>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]([CH3:30])[C:11](=[O:13])[N:10]([CH2:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([C:21]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:29]=1
Reactant: CI
Reactant: COc1ccc2[nH]c(=O)n(C[C@H]3CC[C@H](C(=O)N4CCOCC4)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCOCC3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
NaH (60% in mineral oil, 12 mg, 0.3 mmol) was added to a solution of 6-Methoxy-1-[trans-4-(morpholine-4-carbonyl)-cyclohexylmethyl]-1,3-dihydro-benzoimidazol-2-one (56 mg, 0.15 mmol) in DMF (1.5 ml). MeI (19 μL, 0.3 mmol) was added and the mixture was stirred at room temperature for six hours. The solvent was evaporated, the crude was dissolved in 2 ml of DCM and the solution was washed with H2O. The organic layer was separated and the solvent was removed under reduced pressure. The crude material was purified by column chromatography with EtAc/MeOH (9/1) as eluent. 45 mg (yield 78%) of the title compound were isolated.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][N+:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.BrCC(C1C=CC(F)=CC=1)=O.CC1C=C2C([CH:39]=[CH:40][CH:41]=[N:42]2)=CC=1>>[C:41]([C:40]1[CH:39]=[C:10]([C:9](=[O:22])[C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH:14]=[CH:13][C:12]=12)#[N:42]
Reactant: Cc1ccc2ccc[n+](CC(=O)c3ccc(F)cc3)c2c1
Reactant: Cc1ccc2cccnc2c1
Agent: O=C(CBr)c1ccc(F)cc1
Agent: [Br-]
Product: Cc1ccc2ccc3c(C#N)cc(C(=O)c4ccc(F)cc4)n3c2c1

Procedure:
1-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-7-methyl-quinolinium bromide: The title compound was prepared from 2-bromo-(4-fluoro-phenyl) ethanone (0.352 g, 2.46 mmol) and 7-methyl-quinoline (0.71 g, 3.27 mmol), by a method similar to that described for the preparation of Example 1a, and yielded 0.741 g (84%). 1H NMR (DMSO-d6): 9.42 (dd, J=16.2, 5.7 Hz, 2H), 8.44 (d, J=8.4 Hz, 1H), 8.35 (s, 1H), 8.24 (m, 3H), 7.92 (d, J=8.4 Hz, 1H), 7.56 (m, 2H), 6.95 (s, 2H), 2.60 (s, 3H).
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:48][CH3:49])=[C:31]([C:36]([CH2:39][S:40]([N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>>[O:25]1[CH:26]=[CH:27][C:23]([C:29]2[C:30]([O:48][CH3:49])=[C:31]([C:36]([CH2:39][S:40]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)(=[O:42])=[O:41])=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:24]1
Reactant: COC(=O)c1c(CS(=O)(=O)N2CCCC2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)N2CCCC2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-2-methoxy-6-(pyrrolidin-1-ylsulphonylmethyl)benzoate (Intermediate 150) as a colourless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][N:15]=[C:16]=[S:17]>>[CH3:11][N:12]([CH3:18])[CH2:13][CH2:14][NH:15][C:16]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][N:2]=1)=[S:17]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1ccsn1
Product: CN(C)CCNC(=S)NCCNCc1ccsn1

Procedure:
By the procedure of Example 40(a)(ii), N-(3-isothiazolylmethyl)ethylenediamine is reacted with 2-dimethylaminoethyl isothiocyanate to give N-(2-dimethylaminoethyl)-N'-[2-(3-isothiazolylmethylamino)ethyl]thiourea. Reacting with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5]([O:12][C:13](=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:22]=[N:23][C:24]3N[CH2:26][CH2:27][CH2:28][C:29]=3[CH:30]=2)[CH:20]=1)[C:6]1C=CC=CC=1>>[CH2:5]([O:12][C:13](=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:22]=[N:23][C:24]3[N:1]([C:2](=[O:3])[NH2:4])[CH2:26][CH2:27][CH2:28][C:29]=3[CH:30]=2)[CH:20]=1)[CH3:6]
Reactant: O=C(Cc1cncc(-c2cnc3c(c2)CCCN3)c1)OCc1ccccc1
Reactant: NC(N)=O
Product: CCOC(=O)Cc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1

Procedure:
[5-(8-Carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-acetic acid ethyl ester is synthesized according to the procedure of Urea Formation Method I using [5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-acetic acid benzyl ester.
Reaction SMILES: NC(C(N)=S)=S.CO.C(N)C1C=CC=CC=1.C([NH:24][C:25]([C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[S:28])=[S:26])C1C=CC=CC=1>O>[CH2:30]([NH:29][C:27]([C:25]([NH2:24])=[S:26])=[S:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: S=C(NCc1ccccc1)C(=S)NCc1ccccc1
Agent: NC(=S)C(N)=S
Solvent: NCc1ccccc1
Solvent: CO
Solvent: O
Product: NC(=S)C(=S)NCc1ccccc1
Reaction time: 0.33 h

Procedure:
Into a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, and reflux condenser were placed 212 g (1.77 mol) of dithiooxamide (DTO), 2,200 g of methanol, and 224 g of deionized water. The reaction mixture was stirred and heated to reflux. At that point, 126 g (1.18 mol) of benzylamine, i.e., the reactive amine, was added. The progress of the reaction was monitored by thin layer chromatography (TLC) to detect the initial formation of N,N'-dibenzyldithiooxamide. After about 20 minutes, formation of the disubstituted product was detected and the reaction was quenched by the addition of 100 g of concentrated HCl.
Reaction SMILES: O=[C:2]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.[NH2:18][OH:19].Cl>CCO>[OH:19][N:18]=[C:2]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2COCC1CC(=NO)C2

Procedure:
A solution of tert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (482 mg, 2 mmol, 1.0 eq) and NH2OH.HCl (462 mg, 3 mmol, 3.0 eq) in EtOH (10 mL) was refluxed for 2 h. The reaction mixture was concentrated to give tert-butyl 7-hydroxyimino-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 104b as a white solid, which was used in next step without further purification. MS: calc'd (MH+) 267, measured (MH+) 267.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.ClCCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:11][CH:17]2[CH2:16][CH2:15][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([N:13]([CH3:27])[CH3:12])[CH2:19][CH2:18]2)=[CH:2]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(NCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
970 mg C-(1H-Indol-3-yl)methylamine and 1.44 mg 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in dry tetrahydrofuran (15 ml) and 1,2-dichloroethane (50 ml) under argon. Glacial acetic acid (13.2 mmol) and 1.82 g sodium triacetoxyborohydride were added to this mixture and the mixture was stirred for 72 hours at RT. For working up, the reaction mixture was concentrated, water (20 ml) and ether (30 ml) were added to the residue and the mixture was stirred vigorously. The aqueous phase was separated off, washed with ether (2×15 ml), adjusted to pH 11 with five molar sodium hydroxide solution and extracted with ethyl acetate (4×25 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product (2.11 g) was chromatographed over silica gel with methanol/triethylamine (199:1). 465 mg of the nonpolar diastereomer of N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained (m.p. 182-184° C.), from which the corresponding dihydrochloride was precipitated with chlorotrimethylsilane (443 μl) in 2-butanone/acetone (20 ml/50 ml) (498 mg; m.p. 164-168° C.).