Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[C:24]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[C:23]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:22]=1.BrC1C=C(C2C(=O)N(C)C(Cl)=NC=2C2C=CN=CC=2)C=CC=1>ClCCl>[CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[C:24]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[C:23]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:22]=1)([CH3:3])[CH3:2]
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reactant: CC(C)NC[C@H]1CCCN1
Agent: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (R)-isopropyl-pyrrolidin-2-ylmethyl-amine (0.186 g, 0.86 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 0.3 mL diisopropylethylamine (1.71 mmol) was added drop wise, and stirred for 10 min. 2-Chloro-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.2 g, 0.57 mmol) was added in one portion, and stirred at 0° C. to rt for 12 h. (This naphthyl chloro-intermediate was synthesized by a similar procedure as that of 5-(3-Bromo-phenyl)-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.) The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.21 g as pale yellow solid. MS (ES+): 454 (M+H)+; (ES−): 452 (M−H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[O:12])[CH2:4][CH2:3]1.C[N+]1([O-])CCOCC1>ClCCl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[N+:28]([C:25]1[CH:26]=[CH:27][C:9]([NH:8][CH:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)=[C:10]([CH:24]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1)=[O:12])([O-:30])=[O:29]
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg) in dichloromethane (3 mL) and acetonitrile (0.4 mL) were added tetrapropylammonium perruthenate (4.25 mg), 4-methylmorpholine N-oxide (42.5 mg) and molecular sieves (4 Å, 0.2 g). The resulting mixture was stirred for 2 hours at ambient temperature. The mixture was subjected to a silica gel chromatography eluting with ethyl acetate to give 5-nitro-2-(4-oxocyclohexylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (92 mg) as a solid substance.
Reaction SMILES: [NH4+:1].[OH-].[C:3]([C:5]1[CH:6]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)#[N:4]>C(#N)C>[C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH2:1])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: [NH4+]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NH4OH (22 mL, excess) can be added to a solution of 3-cyanobenzene-1-sulfonyl chloride (1.0 g, 4.97 mmol) in acetonitrile (22 mL) and the reaction stirred overnight at r.t. The reaction can be concentrated and the solid obtained washed with water to give 500 mg of product. The water phase can be extracted with AcOEt, dried with MgSO4 anh, filtered and evaporated to give 400 mg of product that can be combined with the solid obtained before (0.90 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: COCCN
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COCCNc1ccc(S(=O)(=O)Oc2ccc(N)c([N+](=O)[O-])c2)cc1
Temperature: 40 °C

Procedure:
15.6 g of 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene were combined with 35 ml methoxyethylamine in 100 ml dioxane in a round bottom flask. The reaction mixture was heated to reflux for 8 hours and then cooled to 40° C. and extracted two times with 250 ml water. Concentrate was solubilized with ethyl acetate and extracted with 2N aqueous HCl and water, the organic phase was then dried under reduced pressure, yielding 19.2 g of 2-amino-5-(4-[2-methoxyethyl]aminophenylsulfonyloxy)nitrobenzene (melting point 105° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)CC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][CH2:17][CH:12]([OH:11])[CH2:13][CH2:14]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCCO
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)nc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
To a suspension of 1.0 g (6.3 mmol) of 2-chloro-5-nitropyridine in 20 mL of n-propanol was added 1.9 g (18.9 mmol) of 4-hydroxypiperidine, and the mixture was stirred for 1.5 hours at 100° C. After cooling the reaction mixture, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to give 1.37 g (97%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[S:13])SC)=[N:7][CH:8]=1.[NH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[S:13])=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1ccc(NC(=S)SC)nc1
Product: COc1ccc(NC(=S)NCCCNC(=O)OC(C)(C)C)nc1
Yield: 100.1 %

Procedure:
Methyl 5-methoxy-2-pyridyldithiocarbamate (950 mg) and t-butyl 3-aminopropylcarbamate (772 mg) were treated in a similar manner to in Reference Example 58, and crystallized from n-hexane-ethanol to give the title compound (1.51 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]2[N:1]=[C:18]([C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]([F:14])([F:24])[F:25])[NH:11][C:10]=2[CH:9]=1
Reactant: COc1cc(N)c(N)c(C(=O)O)c1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)O)c2nc(-c3ccccc3C(F)(F)F)[nH]c2c1
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of 2,3-diamino-5-methoxybenzoic acid 86 (1.1 equiv) and 2-(trifluoromethyl)benzaldehyde 74 (1 equiv) and sodium metabisulfite (3 equiv) in DMF was stirred under reflux for 12 h. Upon cooling to room temperature, the reaction mixture was diluted with water. The resulting solids were collected by filtration and dried to afford 6-methoxy-2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 87 as dark yellow solid (40%).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[O:11][C:10](=[O:12])[CH:9]=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:23]([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36][C:9]1[C:10](=[O:12])[O:11][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)[CH2:7][C:8]=1[OH:13])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2cccc(O)c2)(C2CCCC2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccc(O)c3)(C3CCCC3)OC2=O)c(C(C)(C)C)cc1CO
Yield: 81 %

Procedure:
The title compound was prepared as described in General Method 9 using 6-cyclopentyl-4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (0.26 g, 0.9 mmol) from Example AAAAA, toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 0.35 g, 1.0 mmol), 0.54 g (3.9 mmol) of K2CO3 in DMF (10 mL). The product was purified by column chromatography on silica gel eluting with EtOAc:hexane:CH2Cl2 (1:1:1) to afford the product in 81% yield as a white solid (m.p. 172-174° C.). 1H-NMR (DMSO-d6) δ 1.47 (s, 9 H), 1.4-1.7 (m, 8 H, 1.9 (s, 3 H), 1.95-2.1 (m, 2 H), 2.35 (t, 1 H), 2.5-2.6 (m, 2 H, partially obscured by DMSO), 2.7 (q, 2 H), 4.35 (s, 2 H), 4.95 (bs, 1 H), 6.55 (t, 3 H), 6.65 (s, 1 H), 7.05 (t, 1 H), 7.25 (s, 1 H), 9.25 (s, 1 H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.C[C:15]1[CH:16]=[C:17]([N:22]2CC[NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:20]3[CH:19]=[C:18]4[C:17](=[CH:16][CH:15]=3)[NH:22][CH2:23][CH2:24][NH:25]4)[CH2:11][CH2:12]2)[CH:2]=1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: Cc1cccc(N2CCNCC2)c1
Product: Cc1cccc(N2CCN(Cc3ccc4c(c3)NCCN4)CC2)c1

Procedure:
Example 9 was prepared according to Example 2 except that in Step A 1-(m-tolyl)piperazine is substituted for 1-(3,4-dimethylphenyl)piperazine; mp 135°-136° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C)C=O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:10]=[CH:11][C:12]([C:15](=[O:17])/[CH:16]=[CH:22]/[N:23]([CH3:25])[CH3:24])=[CH:13][CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(-c2nc3cc(Br)ccc3[nH]2)cc1
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)c1ccc(-c2nc3cc(Br)ccc3[nH]2)cc1
Temperature: 100 °C

Procedure:
Subsequently, 1-[4-(5-bromo-1H-benz[d]imidazol-2-yl)phenyl]-1-ethanone (592 mg) and N,N-dimethylformamide dimethyl acetal (468 μL) were dissolved in N,N-dimethylformamide (10 mL), followed by heating at 100° C. for 2 hours. The reaction mixture was concentrated, and the residue was subjected to flash chromatography. Fraction eluted by dichloromethane-methanol (15:1) were concentrated under reduced pressure, followed by recovering the solid through filtration by use of isopropyl ether, to thereby yield a 1:1 mixture (116 mg) of (E)-1-[4-(5-bromo-1H-benz[d]imidazol-2-yl)phenyl]-3-dimethylamino-2-propen-1-one and (E)-1-[4-(6-bromo-1H-benz[d]imidazol-2-yl)phenyl]-3-dimethylamino-2-propen-1-one.
Reaction SMILES: C(SC1N=CNN=1)C.C(Cl)(Cl)=O.[C:13](N1C=NC(SCC)=N1)([N:15]1[CH:19]=[N:18][C:17]([S:20][CH2:21][CH3:22])=[N:16]1)=[O:14].[CH2:31]([NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]>O1CCCC1.N1C=CC=CC=1>[CH2:31]([N:34]([CH2:35][CH2:36][CH3:37])[C:13]([N:15]1[CH:19]=[N:18][C:17]([S:20][CH2:21][CH3:22])=[N:16]1)=[O:14])[CH2:32][CH3:33]
Reactant: CCSc1ncn(C(=O)n2cnc(SCC)n2)n1
Reactant: CCCNCCC
Agent: CCSc1nc[nH]n1
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCN(CCC)C(=O)n1cnc(SCC)n1
Reaction time: 0.5 h

Procedure:
A solution of 51.6 g. 3-ethylthio-1,2,4-triazole and 31.6 g. dry pyridine in 100 ml. dry tetrahydrofuran was added dropwise to 200 ml. of a 10% w/v solution of phosgene in dry tetrahydrofuran (20 g. phosgene, 0.5 molecular proportion) with stirring and cooling to maintain the reaction temperature at 25° - 30° C. The mixture was stirred at 25° - 30° C. for a further period of 0.5 hour, and was then filtered to remove pyridine hydrochloride formed in the reaction. To the resulting solution 1,1'-carbonylbis(3-ethylthio-1,2,4-triazole) was added dropwise with stirring a solution of 20.2 g. dipropylamine in 50 ml. dry tetrahydrofuran. The mixture was stirred for a further period of 0.5 hour, and was then evaporated under reduced pressure to remove solvent. The residual oil was dissolved in methylene dichloride and the resulting solution was washed successively with 0.5N sodium hydroxide solution, water, and finally 0.5N hydrochloric acid. The washed solution was distilled under reduced pressure to give 1-dipropylcarbamoyl-3-ethylthio-1,2,4-triazole, b.p. 130° - 132° C./0.5 mm. Elemental analysis satisfactory.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[N:6]2[CH:25]=1.[N-:26]=[N+:27]=[N-:28].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[NH:26]1[C:23]([C:20]2[N:21]=[CH:22][C:17]([C:7]3[N:6]4[CH:25]=[C:3]([CH2:2][OH:1])[N:4]=[C:5]4[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:9][CH:8]=3)=[CH:18][CH:19]=2)=[N:24][N:28]=[N:27]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CO)cn23)cn1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCc1cn2c(-c3ccc(-c4nnn[nH]4)nc3)cnc(N3CCOCC3)c2n1
Temperature: 105 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of compound 1g (220 mg, 0.650 mmol) in DMF (15 mL) was added NaN3 (440 mg, 6.77 mmol) and triethylamine hydrochloride (440 mg, 3.21 mmol). The reaction mixture was stirred at 105° C. for 1 h. The resulting mixture was concentrated, and diluted with H2O (30 mL). The solids were collected by filtration and washed with Et2O to obtain compound 1h as a yellow solid (189 mg, 76% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C17H17N9O2: 380.2 (M+H). Found 380.2.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]Br)=[CH:3][CH:2]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[C:4]1([CH2:7][CH2:8][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: C1CNCCN1
Product: c1ccc(CCN2CCNCC2)cc1
Yield: 92 %

Procedure:
Using β-phenethyl bromide and piperzine, the procedure of Reference Example 16 was otherwise repeated to provide the title compound. Yield 92%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9](=[O:23])(=[O:22])[NH:10][CH:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH3:13])[C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1.[CH2:31]([OH:34])[CH2:32][OH:33]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH:33][CH2:32][CH2:31][O:34][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9](=[O:23])(=[O:22])[NH:10][CH:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH3:13])[C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1
Reactant: OCCO
Reactant: CCC(NS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(Br)cc1)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CCC(NS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(Br)cc1)OCc1ccccc1
Temperature: 87.5 °C
Reaction time: 48 h

Procedure:
To as suspension of 1-benzyloxypropanesulfamic acid[6-chloro-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (524 mg, 1.02 mmol) in ethylene glycol (10 mL) is added potassium tert. butylate (1.15 g, 10.2 mmol). The resulting clear solution is stirred at 85-90° C. for 48 h before it is cooled to rt, diluted with 10% aq. citric acid solution (75 mL) and extracted with EA (2×75 mL). The organic extracts are washed with water (2×75 mL) and the solvent is removed in vacuo. The remaining residue is purified by column chromatography on silica gel eluting with heptane/EA 1:1 to give 1-benzyloxypropanesulfamic acid[6-(2-hydroxyethoxy)-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (517 mg) as a colourless foam. LC-MS: tR=0.97 min, [M+H]+=536.99; 1H NMR (CDCl3): δ 8.34 (s, 1H), 7.65-7.60 (m, 2H), 7.38-7.29 (m, 5H), 7.20-7.15 (m, 2H), 6.86 (s br, 1H), 5.98 (t br, J=5.9 Hz, 1H), 4.51-4.45 (m, 4H), 3.86-3.82 (m, 2H), 3.56 (t, J=5.9 Hz, 2H), 3.17 (q, J=6.4 Hz, 2H), 2.54 (s br, 1H), 1.93-1.84 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].N1C2C(=CC=CC=2)[C:23]2([CH2:33][O:32][C:31]3[CH:34]=C4C(=C[C:30]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:34][C@H:31]1[CH2:30][CH2:23][CH2:33][O:32]1)[C:10]3=[O:18]
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: COc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless liquid: 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.32-7.25 (m, 1H), 7.16-6.99 (m, 3H), 6.61 (d, J=8.1 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 6.36 (dd, J=8.1, 2.1 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.32-4.22 (m, 1H), 4.00-3.66 (m, 4H), 3.77 (s, 3H), 2.10-1.66 (m, 4H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.0, 177.9, 162.0, 161.4, 142.9, 142.8, 132.4, 132.3, 128.7, 128.6, 123.6, 123.5 (2C), 123.4, 123.2, 121.0, 120.9, 109.6, 109.3, 107.4 (2C), 96.5, 80.5, 80.4, 76.8, 76.7, 68.2, 68.1, 57.5, 55.5, 44.5 (2C), 29.2, 28.9, 25.6, 25.5; MS (ES+) m/z 352.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Ni].C(O)C(C)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[O:9])=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)c(C)c1
Agent: [Ni]
Solvent: CC(C)CO
Product: Cc1ccc(C(=O)c2ccc(N)cc2)c(C)c1

Procedure:
The 4-nitro-2',4'-dimethylbenzophenone obtained in b) was mixed with 900 ml of isobutanol and 3.5 g of activated nickel powder and hydrogenated under a slight superatmospheric pressure (1.25 bar) of hydrogen at 50°-60° C. to give 4-amino-2',4'-dimethylbenzophenone. The catalyst was filtered off and then the organic solvent was distilled off to recover it, and water at 95° C. was added to the residue at 100°-110° C. and the mixture was stirred until room temperature was reached. 4-Amino-2',4'-dimethylbenzophenone crystallized out at 90° C. The crystalline product was filtered off with suction, washed with water and dried. 215 g of amino compound (melting point 121° C.) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[OH-].[Na+].[CH2:20]([NH2:23])[CH2:21][CH3:22]>ClCCl>[CH2:20]([NH:23][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:21][CH3:22]
Reactant: CCCN
Reactant: COc1ccc(CCC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCNC(=O)CCc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
3-(4-methoxyphenyl)-propionic acid (8.8 g, 49 mmol) was refluxed in dichloromethane (200 mL) with thionyl-chloride (6.6 mL, 90 mmol) for 1 h. The volatiles were evaporated and the resulting oil was dissolved in dichloromethane (100 mL). This was added to a vigorously stirred mixture of 5% aqueous NaOH (200 mL), dichloromethane (100 mL) and n-propylamine (3.0 mL, 71 mmol). After stirring for 1 h the layers were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and was dried over MgSO4. Evaporation of the solvent gave the amide in quantitative yield (10.7 g, 49 mmol, 100%). IR (neat) cm−3300, 2961; 1734, 1642; MS (EI) m/z 221 (M+) Analyses were in agreement with literature data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.[NH2:30][CH2:31][C@@H:32]([OH:35])[CH2:33][OH:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:30][CH2:31][C@@H:32]([OH:35])[CH2:33][OH:34])=[O:26])=[CH:27][CH:28]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: NC[C@@H](O)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid (example 332, step 2) was coupled with (R)-3-aminopropane-1,2-diol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=483.2 [M+H]+.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: Cc1ccc(CN)cc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: Cc1ccc(CN=C(NC#N)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Isopropyl N cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (5 ml), and 4-methylbenzylamine (0.35 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.60 g, 2.4 mmol, yield: 91%) as colorless powder.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C@H:6]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[C:7]([O:9][CH3:10])=[O:8].Cl.[CH3:26][C:27]1[CH:36]=[C:35]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1>>[CH3:26][C:27]1[CH:36]=[C:35]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH:4][CH2:5][C@H:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[CH2:15][CH2:16]3)[C:7]([O:9][CH3:10])=[O:8])(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1
Reactant: COC(=O)[C@H](CN)N1CCN(Cc2ccc(C)cc2)CC1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(Cc2ccc(C)cc2)CC1

Procedure:
In a manner analogous to example 3.6, using 1.0 g (2.5 mmol) of methyl (S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate trihydrochloride and 1.3 g (3.5 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride (prepared as described in example 17.2), 950 mg (63%) of methyl (S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-methylbenzyl)piperazin-1-yl]propenoate are obtained in the form of a white solid.