Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12](OCC)=O)[NH:6]2.[H-].C(N([Al](N(CC)CC)N(CC)CC)CC)C.[Na+].Cl.[NH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]1[NH:42][C:43]2[C:48]([C:49](=[O:51])[CH:50]=1)=[CH:47][CH:46]=[CH:45][CH:44]=2.C([BH3-])#N.[Na+]>C1COCC1.CO.CC(O)=O.C(OCC)C.O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:12][NH:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]1[NH:42][C:43]3[C:48]([C:49](=[O:51])[CH:50]=1)=[CH:47][CH:46]=[CH:45][CH:44]=3)[NH:6]2
Reactant: NCCCNc1cc(=O)c2ccccc2[nH]1
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Agent: CCN(CC)[Al](N(CC)CC)N(CC)CC
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=c1cc(NCCCNCc2cc3c(Cl)cc(Cl)cc3[nH]2)[nH]c2ccccc12
Reaction time: 0.33 h

Procedure:
To ethyl 4,6-dichloroindole-2-carboxylate (0.258 g, 1 mmol) in THF (1 ml) at −78° C. under argon was added 1 ml of a solution of sodium tris(diethylamino)aluminium hydride (prepared from NaAlH4 (1 M in THF, 6 ml) and diethylamine (1.86 ml, 18 mmol), 70 min/0° C.). After 20 min at −78° C. the reaction was allowed to warm to 0° C. over 1 h before addition of 5 M HCl (1.5 ml), water (10 ml) and diethyl ether (50 ml). The phases were separated and the organic layer washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure to give a pink solid (200 mg; comparison of NMR integrals indicated the presence of approx 40% aldehyde). To this material (132 mg) was added a solution of 0.125 M 2-(3-aminoprop-1-ylamino)-1H-quinolin-4-one in MeOH/HOAc (2 ml, prepared as in example 4a) and sodium cyanoborohydride (0.031 g, 0.5 mmol). After 2.5 h, the reaction mixture was applied to a Varian Bond Elute 1 g SCX cartridge which was flushed with MeOH then eluted with 0.2 M NH3 in MeOH. Product containing fractions were combined and purified by chromatography on silica gel eluting with 0-12% (9:1 MeOH/20 M NH3) in CH2Cl2 to give the title compound, isolated as a colourless solid, (0.050 g, 48%). δH (Methanol-D4) 8.1 (1H, dd, J=8.1, 1.3 Hz), 7.5 (1H, dt, J=1.3, 7.7), 7.2-7.3 (3H, m), 7.0 (1H, d, J=1.6 Hz), 6.5 (1H, s), 5.7 (1H, s), 3.95 (2H, s), (2H, t, J=6.7 Hz), 2.8 (2H, t, J=6.8 Hz), 1.9 (2H, m). MS (ES+) 415, 417 (35%, 25%, MH+), 218 (100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.CC#[N:16]>>[Cl:1][C:2]1[C:7]([C:8]([NH2:16])=[O:9])=[C:6]([F:11])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: COc1ccc(Cl)c(C(=O)O)c1F
Product: COc1ccc(Cl)c(C(N)=O)c1F
Yield: 85 %

Procedure:
Synthesised from commercially available 6-chloro-2-fluoro-3-methoxybenzenecarboxylic acid according to Method A, scheme 1. Yield 85%, mp 154-156° C., HPLC-MS (method 1): m/z 245 [M+H+CH3CN]+, Rt=2.37 min.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH:5]([CH3:25])[C:6]([C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:11]=[C:10]([CH2:21][CH3:22])[C:9]=1[C:23]#[N:24])=O.CN.Cl.O>CO.C(Cl)Cl>[CH2:21]([C:10]1[C:9]([C:23]#[N:24])=[C:8]([C:6]2[O:2][CH:3]=[CH:4][C:5]=2[CH3:25])[N:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:11]=1)[CH3:22]
Reactant: CCc1nn(-c2ccc(OC)cc2)c(C(=O)C(C)CC(OC)OC)c1C#N
Agent: CN
Agent: Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCc1nn(-c2ccc(OC)cc2)c(-c2occc2C)c1C#N
Temperature: 25 °C
Reaction time: 14 h
Yield: 40 %

Procedure:
To a stirred solution of 5-(4,4-dimethoxy-2-methylbutanoyl)-3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (20 mg, 0.05 mmol) in MeOH (1.5 mL) were added methylamine (2.0 M solution in methanol, 0.20 mL, 0.4 mmol) and conc. HCl (0.1 mL) at ambient temperature in a closed microwave tube. The reaction mixture was stirred at ambient temperature for 14 h then additional methylamine (2.0 M solution in methanol, 2.70 mL, 5.4 mmol) and conc. HCl (0.3 mL) were added and the reaction was heated to 8° C. for 14 hours. Water and CH2Cl2 was added, the phases separated and the organic phase was concentrated under reduced pressure. Purification using a silica plug (heptane/CH2Cl2/Et2O-1:0:0-1:1:0-0:1:0-0:1:1) yielded 3-ethyl-1-(4-methoxyphenyl)-5-(3-methylfuran-2-yl)-1H-pyrazole-4-carbonitrile (5 mg, 0.02 mmol, 30%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:6]1[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(-c2cccc(F)c2)c(-c2ccncc2)c(=O)[nH]1
Product: Nc1nc(Cl)c(-c2ccncc2)c(-c2cccc(F)c2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A suspension of 2-amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone (1.0 g, 3.54 mmol) in phosphorus oxychloride (15 ml) was stirred at 100° C. for 30 minutes under an atmosphere of nitrogen gas. After cooling as it was, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and 2N sodium hydroxide. The organic layer was washed with an aqueous saturated sodium bicarbonate solution twice and brine, dried over anhydrous sodium sulfate and concentrated. To the residue was added diethyl ether, and the resulting precipitates were collected by filtration and washed with diethyl ether, to give the title compound (513 mg, 48%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1.Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCCCCC(=O)O)cc1
Agent: Br
Product: O=C(O)CCCCCCCCc1ccc(O)cc1

Procedure:
In step 1 of this synthetic sequence, the ether group of 9(4-methoxyphenyl)nonanoic acid is cleaved with hydrogen bromide to give the alcohol, 9(4-hydroxyphenyl)nonanoic acid. In step 2, this acid is converted to its methyl ester. In step 3, the 9(4-hydroxyphenyl)nonanoic acid, methyl ester is alkylated (with n-butyl or n-hexyl bromide) and then hydrolyzed to give 9(4-alkoxyphenyl)nonanoic acids. In step 4, the acid is converted to the acid chloride, using thionyl chloride. In step 5, the acid chloride is condensed with a substituted or unsubstituted hydroxylamine to give the final product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:10])[CH2:4]1)[CH3:2].C(CC1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)(=O)=O)(O)=O>>[CH2:1]([N:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:10])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@H](NC(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Agent: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CC(=O)O)ccc2c1OCC1CC21
Product: CCN1CC[C@@H](NC(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 80, starting from methyl (1aRS,7bSR)-5-(2-carboxymethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 83) and (R)-1-ethylpyrrolidin-3-ylamine ditrifluoroacetic acid salt (Intermediate 93) as a light brown foam.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([N+:17]#[C-])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:16])[CH:13]=2)[CH2:8]1)=[O:6])[CH3:3].C([O-])(O)=O.[Na+]>>[CH2:2]([O:4][C:5]([C:7]1([NH2:17])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:16])[CH:13]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: [C-]#[N+]C1(C(=O)OCC)Cc2ccc(F)cc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
Reaction time: 2 h

Procedure:
A methanolic solution of conc. HCl (35%) (9.3 mL in 110 mL of MeOH) is added dropwise to a methanolic solution of 5-fluoro-2-isocyano-indan-2-carboxilic acid ethyl ester E (17.6 g, 75.4 mmol) at RT and the mixture is stirred for 2 h. The mixture is then neutralized by saturated NaHCO3 solution and extracted with DCM (500 mL). The organic layer is washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure to obtain 16.0 g (94%) of F as yellowish semi solid.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.Cl.[CH3:40][NH:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46]>C(Cl)Cl>[C:2]([O:4][CH:5]1[C:14]2[C:15]3([CH3:30])[C:16]([C:17](=[CH:18][N:41]([CH3:40])[CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])[C:23](=[O:24])[O:25][CH:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CNCCCC(=O)O
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(C)CCCC(=O)O)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added 4-(methylamino)butyric acid hydrochloride (71 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 549 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][OH:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[N+:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)([O-:29])=[O:28]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18](=[CH:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=3)=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2cccc([N+](=O)[O-])c2)c1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2cccc([N+](=O)[O-])c2)c1

Procedure:
The reaction of hydroxylamine 82 (0.71 g, 2 mmol) with 3-nitrobenzaldehyde (57) (0.302 g, 2 mmol) afforded, after workup, a light yellow solid. The crude product was recrystallized from ethyl acetate/petroleum ether to obtain 0.71 g (1.44 mmol. 72%) of 83 as a light yellow crystalline solid: mp 149°-151° C.; IR (CH2Cl2) 3440, 2980, 1700, 1622, 1552, 1535, 1475, 1355, 1300, 1215, 1100, 1018, 810 cm-1 ; 1H NMR (CDCl3) δ 1.14 (d, J=6.2 Hz, 3H), 1.25 (d, J=6.2 Hz, 3H), 2.30 (s, 6H), 3.64 (s, 3H), 4.97 (septet, J=6.2 Hz, 1H), 5.08 (s, 1H), 6.37 (s, 1H), 7.32-9.29 (m, 9H); 13C NMR (CDCl3) δ 19.78, 22.47, 22.70, 40.51, 51.58, 67.81, 103.27, 103.99, 119.82, 121.99, 123.79, 125.43, 129.16, 130.24, 131.05, 132.75, 132.94, 134.75, 145.57, 146.11, 148.91, 149.20, 150.56, 167.59, 168.60. Anal. Calcd for C26H27N3O7 : C, 63.28; H, 5.47. Found: C, 63.49; H, 5.47.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]([CH3:37])([CH3:36])[C:31]([O:33]CC)=[O:32])[N:29]=4)[N:26]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+:45]>C(O)C>[C:38]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]([CH3:37])([CH3:36])[C:31]([O-:33])=[O:32])[N:29]=4)[N:26]=3)[CH2:15][CH2:16]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Na+:45]
Reactant: CCOC(=O)C(C)(C)c1cn2nc(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)[O-])c1cn2nc(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1

Procedure:
631 mg of ethyl 2-[6-[4-[4-(diphenylmethoxy) piperidino]butyl]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate dihydrochloride was dissolved in 4 ml of ethanol; 5.5 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water and ajusted to pH 5.5 by the addition of 1 N hydrochloric acid. Acetone was added to cause crystallization; the crystal precipitated was washed with water-acetone (2:1) and dried to yield 345 mg of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCOc1ccc(N)cc1
Reactant: CSc1ccc(C#N)cc1
Product: CCOc1ccc(NC(=N)c2ccc(SC)cc2)cc1
Yield: 61 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (10.87 g, 73 mmol) and 4-ethoxyaniline (10 g, 73 mmol) by following the procedure described in preparation 10 (12.7 g, yield 61%, purity 96.27% by HPLC). 1H-NMR (CDCl3):δ 1.39-1.43 (t, 3H), 2.51 (s, 3H), 3.99-4.04 (q, 2H), 4.75 (bs, 2H, D2O exchangeable), 6.90 (s, 4H), 7.26-7.29 (m, 2H), 7.77-7.79 (d, 2H). MS m/z:287.2 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:44])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][C:40]([O:42]C)=[O:41]>>[C:40]([CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:44])=[O:17])([OH:42])=[O:41]
Reactant: COC(=O)CCc1c(CCCCCCOS(C)(=O)=O)cccc1OCC(=O)OC
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCCc2cccc(OCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-(2-methoxy-2-oxoethoxy)-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example, followed by saponification, in 64.4% overall yield. The product was an off-white solid, mp 127°-129° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Product: O=c1[nH]cnc2cc(N3CCOCC3)ccc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
20.0 g (0.122 mol) of 7-fluoro-3H-quinazolin-4-one were suspended in 80 ml of morpholine and stirred at an internal temperature of 90° C. for 16 h. Conventional work-up gave 14.1 g (Y=50%) of 7-morpholin-4-yl-3H-quinazolin-4-one (as described in Example 2.2, reaction step 1a).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:6]=[C:7]([S:10][CH3:11])[C:8]=1[OH:9].[N+](=[CH2:23])=[N-]>C(Cl)(Cl)Cl.CCOCC.C(O)(=O)C>[CH3:11][S:10][C:7]1[CH:6]=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:4]=[C:3]([S:2][CH3:1])[C:8]=1[O:9][CH3:23]
Reactant: CSc1cc(CCCCCCCCO)cc(SC)c1O
Reactant: C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1c(SC)cc(CCCCCCCCO)cc1SC
Temperature: 0 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
320 mg of compound 1 was dissolved in chloroform and 10 ml of a solution of diazomethane in ether (about 0.5M) was added thereto dropwise at 0° C. After stirring at 0° C. for 6 hours, several drops of acetic acid were added thereto. After the completion of the reaction, the mixture was extracted with ether. The extract was concentrated and subjected to column chyromatography (silica gel, ethyl acetate: hexane=1:5-1:4). As a result, 206 mg of the desired compound was obtained (yield: 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2[NH:8][C:9]3[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]([CH3:18])[C:10]=3[N:11]=2)=[CH:4][CH:3]=1.[BrH:21]>>[BrH:21].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2[NH:8][C:9]3[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([CH3:18])[C:10]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C)c2nc(Cc3ccc(Cl)cc3)[nH]c12
Agent: Br
Product: Cc1ccc(O)c2[nH]c(Cc3ccc(Cl)cc3)nc12

Procedure:
A suspension of 2-(4-chlorobenzyl)-4-methoxy-7-methylbenzimidazole (4.0 g) in 48% aqueous hydrobromic acid (400 ml) under nitrogen was heated at 130° for 5 h, then evaporated to dryness in vacuo. The residue was recrystallized from ethanol-ether to afford the title compound (3.95 g), m.p. 275°-277° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:22][C:21]3[NH:20][CH:19]=[C:18]4[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=34)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2cc(Br)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-Bromo-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]=1[N:6]2[CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(#N)C.C(OCC)C>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][CH2:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:31](=[O:32])[O:33][CH2:34][CH3:35])[CH:10]=[CH:9][CH:8]=2)[C:4]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]1=2
Reactant: CCOC(=O)Cl
Reactant: CN(C)CCCn1c2c(c3c(N)cccc31)CCCCCC2
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cccc2c1c1c(n2CCCN(C)C)CCCCCC1
Reaction time: 18 h

Procedure:
To a solution of 1-amino-5-(3-dimethylaminopropyl)-6,7,8,9,10,11-hexahydro-5H-cyclooct[b]indole (5 g, 0.024 mol) and 5 mL of triethylamine in 80 mL dry acetonitrile (under nitrogen), stirred and kept below 20° C., was added 5 mL ethyl chloroformate. The reaction mixture was stirred at 25°-28° C. for 18 hours. The mixture was diluted with diethyl ether and the precipitate (Et3N.HCl) was filtered off and washed with diethyl ether. The filtrate was dried over sodium sulfate, filtered and the filtrate treated with dry hydrogen chloride. On standing a blueish solid separated. This was filtered, washed with diethyl ether, and dried in a vacuum pistol. There was obtained 1.15 g of the title compound as the hydrochloride.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.Cl.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-BOC-L-alanine (150 mmol) in DMF (250 mL) at 0° C., is added proline methyl ester.HCl (150 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0.164 mmol), ethyl-3-(3-dimethylamino)propyl carbodiimide.HCl (31.4 g, 0.164 mmol) and 4-methylmorpholine (22.6 g, 0.224 mmol). The reaction mixture is stirred for 12 h while allowing the reaction to warm to room temperature. The reaction mixture is poured in water (750 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts are washed as follows: KHSO4 (0.25 M, 2×50 mL), water (1×50 mL), saturated aqueous NaHCO3 (2×50 mL) and saturated NaCl (1×50 mL). The organic layer is dried over MgSO4, filtered and the solvent removed in vacuo to give title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=[O:6].C1(C)C=CC(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:25]=[N:24][CH:23]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Fc1cc(-c2cnco2)ccc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 3-fluoro-4-(trifluoromethyl)benzaldehyde (1.40 g, 7.07 mmol) and p-toluenesulfonylmethyl isocyanide (1.53 g, 7.68 mmol; TosMIC) in MeOH (100 mL) was treated with potassium carbonate (1.97 g, 14.14 mmol) and the suspension heated to reflux for 14 h. After being cooled to room temperature, the solvent was removed under reduced pressure and the crude product triturated with water at 0° C. (2×25 mL). The slightly orange precipitate was collected by filtration and dried under vacuum (4.46 g, 92%). MS: 232.0 (M+H)+.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[Cl:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]([N:10]2[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:24]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Clc1cc(-n2c(/C=C/c3ccccc3)nc3ccccc32)ncn1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 4,6-dichloropyrimidine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.