Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:38])([CH3:37])[C:3]([NH:5][C@H:6]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[C:14]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:11]1=[O:32])=[O:8])=[O:4].[O:39]=C1O[C@H]([C@H](CO)O)C(O)=C1O.O=O>C(O)(=O)C.O>[NH2:1][C:2]([CH3:37])([CH3:38])[C:3]([NH:5][C@H:6]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[C:14]([N:20]3[C:24](=[O:39])[CH2:23][CH2:22][CH:21]3[OH:25])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:11]1=[O:32])=[O:8])=[O:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: O=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C[C@@H](NC(=O)C(C)(C)N)C(=O)NC1Cc2cccc(N3C(=O)CCC3O)c2N(Cc2ccsc2)C1=O

Procedure:
(2R)-2-(2-Amino-2-methylpropanamido)-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (1.08 g) was dissolved in acetic acid (30 mL), and a solution of L-(+)-ascorbic acid (3.52 g) and Cu(ClO4)2.6H2O (741 mg) in water (40 mL) was added thereto, followed by stirring at room temperature for 15 minutes while oxygen gas was bubbled into the mixture. Saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was washed with ethyl acetate twice. Sodium bicarbonate (88.2 g) was added to the aqueous layer, and the mixture was extracted with chloroform twice. The organic layer was concentrated under reduced pressure, and the thus-recovered residue was purified through chromatography, whereby the title compound (0.5 mg) was yielded.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[C:25]([O:29][C:30](=[O:37])[C:31]([CH2:35][NH2:36])([CH3:34])[CH2:32][CH3:33])([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([O:29][C:30](=[O:37])[C:31]([CH2:35][NH:36][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:11]=2)=[O:22])([CH3:34])[CH2:32][CH3:33])([CH3:26])([CH3:27])[CH3:28]
Reactant: CCC(C)(CN)C(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CO
Product: CCC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (55 mg, 0.17 mmol) and 2-aminomethyl-2-methyl-butyric acid tert-butyl ester (88 mg of the crude, 0.47 mmol) in MeOH (3 mL) were heated at 140° C. in a microwave for 1 hour. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 60 mg. MS: (−) m/z 474.24 (M−1).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH:2]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:5][CH:6]=1)#[N:9]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(C(=O)C=Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Acetylbenzonitrile (14.5 g, 0.1 mol) and 4-fluorobenzaldehyde (12.1 g, 0.1 mol) are dissolved in methanol (150 ml) and solid sodium hydroxide is added to make the solution alkaline. The mixture is stirred in room temperature for 6 hours. The product is filtered off and washed with methanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:36]1[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33]([N:36]3[CH2:37][CH2:38][S:39](=[O:42])(=[O:43])[CH2:40][CH2:41]3)(=[O:34])=[O:35])=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Reactant: O=S1(=O)CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccccc2S(=O)(=O)N2CCS(=O)(=O)CC2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 4-((2-bromophenyl)sulfonyl)thiomorpholine 1,1-dioxide. MS (ESI): mass calcd. for C21H18FN5O4S2, 487.08; m/z found, 488.1 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.26 (s, 1H), 8.08 (dd, J=8.0, 1.3, 1H), 7.83-7.77 (m, 1H), 7.73-7.68 (m, 1H), 7.68-7.63 (m, 1H), 7.51 (dd, J=7.6, 1.3, 1H), 7.44 (dd, J=10.9, 1.7, 1H), 7.40 (s, 2H), 7.35 (dd, J=7.9, 1.6, 1H), 3.31-3.23 (m, 4H), 3.11-3.04 (m, 4H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][C:25]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:25]=3[Br:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1cccc(C(=O)O)c1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3cccc(C)c3Br)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg) with 2-bromo-3-methylbenzoic acid (19 mg) under the agency of HATU (68 mg) and N,N-diisopropylethylamine (32 μl) in dichloromethane (4 ml) was performed according to the method described in example 11.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH2:8]([N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1)[CH2:9][CH3:10].Br[C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C(#N)C>[CH2:8]([N:11]1[CH:15]=[C:14]([C:26]2[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=2)[CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH:13]=[N:12]1)[CH2:9][CH3:10]
Reactant: CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)cn1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 105.6 %

Procedure:
Pd-118 (51.7 mg) was dissolved in acetonitrile (8 mL) and stirred for 5 min before addition of potassium carbonate (1.1 g), water (8 mL) and a solution of 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (750 mg) in MeCN (1 mL). The mixture was stirred for a further 5 min then a solution of tert-butyl 3-(3-bromophenethoxy)propanoate (870 mg, prepared as in Preparation 3, Step i)) was added and the reaction was heated at the heating block (80° C.) for 30 min. The mixture was cooled and extracted into DCM. Organic was separated using a phase separator cartridge, solvents evaporated to give a brown oil. The crude product was purified by flash silica chromatography using elution gradient 0 to 100% ethyl acetate in isohexane to afford the subtitled compound (1 g) as a gum. MS [M+H-C4H9]+=303 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.63 (s, 1H), 7.34-7.30 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 7.09-7.05 (m, 1H), 4.11 (t, J=7.2 Hz, 2H), 3.70 (t, J=6.5 Hz, 2H), 3.68 (t, J=7.2 Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.49 (t, J=6.4 Hz, 2H), 1.93 (sextet, J=7.2 Hz, 2H), 1.43 (s, 9H), 0.95 (t, J=7.3 Hz, 3H)
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.O.[OH-].[Na+]>C(O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCCCCOc1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCOc1ccc(I)cc1
Yield: 93 %

Procedure:
Ethyl 6-(4-iodophenoxy)hexanoate (3.62 g, 10 mmol), in ethanol (30 ml), water (30 ml) was treated with sodium hydroxide (1 g, 25 mmol) and the reaction was stirred under reflux for 3 h. The reaction was then allowed to cool and concentrated in vacuum to a solid. The solid was then treated cautiously with ethyl acetate (100 ml) and 1N hydrochloric acid (100 ml) and the reaction stirred at room temperature for 10 min. The ethyl acetate layer was separated dried over sodium sulfate and concentrated in vacuum to give a pale yellow solid (3.11 g, 9.3 mmol, 93%), δH (CDCl3) 1.48-1.82 (6H, m, 3,4,5-CH2), 2.40 (2H, t, 2-CH2), 3.91 (2H, t, 6-CH2O), 6.67 (2H, dd, 2,6-ArH), 7.53 (2H, dd, 3,5-ArH), δc (CDCl3) 24.31, 25.50, 38.75, 33.89, 82.54, 116.87, 138.14, 158.83 and 179.97
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11](=[O:38])[N:12]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[N:18]=[C:17]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:40]1[C:41]2[CH2:48][C:47](=[O:49])[NH:46][C:42]=2[N:43]=[CH:44][N:45]=1>CN(C=O)C>[CH2:3]([O:10][C:11](=[O:38])[N:12]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[N:18]=[C:17]1[CH:32]1[CH2:33][CH2:34][N:35]([C:40]2[C:41]3[CH2:48][C:47](=[O:49])[NH:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:36][CH2:37]1)[CH3:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1)C(=O)OCc1ccccc1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3c2CC(=O)N3)CC1)C(=O)OCc1ccccc1
Yield: 79.4 %

Procedure:
Combine {2-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-methyl-carbamic acid benzyl ester dihydrochloride (277 μmol; 160 mg); 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1.30 equiv; 360 μmol; 61.1 mg); DMF (3 mL); TEA (7 equiv; 1.94 mmol; 270 μL) and heat to 160° C. in microwave for 45 min. Evaporate, dissolve the residue in DCM, wash with saturated sodium bicarbonate and evaporate the organic layer. Purify the residue on 40 g silica gel with 3% MeOH/DCM to provide the title compound (138.2 mg; 0.22 mmol; 78%). MS (ES+): m/z=638 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4](/[CH:9]=[CH:10]/[C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([CH3:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11](/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[N:16]=1
Reactant: Cc1cc(O)nc(/C=C/c2ccc(F)c(Cl)c2F)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(/C=C/c2ccc(F)c(Cl)c2)n1
Yield: 83.3 %

Procedure:
In analogy to example 12c), by heating (E)-2-[2-(3-chloro-4-fluorofluoro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (1.85 g, 7 mmol) in POCl3 (12.83 ml, 0.14 mol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-6-methyl-pyrimidine (1.65 g, 83%) as a yellow solid. EI mass spectrum, m/e: 282 (M+1 calculated for C13H9Cl2FN2: 282).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][CH:8]=[CH:7]2.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>ClCCl>[Br:1][C:2]1[C:10]2[CH2:9][CH:8]3[O:20][CH:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc2c(c1Br)CC=C2
Solvent: ClCCl
Product: Fc1ccc2c(c1Br)CC1OC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A solution of Example 25C (500 mg, 2.347 mmol) in dichloromethane (30 mL) was cooled to 0° C. and a solution of mCPBA (631 mg, 2.82 mmol) in dichloromethane (5 mL) was added. The mixture was warmed to ambient temperature and stirred for 2 hours. The mixture was diluted with dichloromethane (50 mL), quenched with a saturated solution of Na2S2O3 and partitioned. The organic portion was dried (MgSO4), filtered, concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution with 10% EtOAc/hexanes) to provide the title product (316 mg, 1.38 mmol, 59%). MS (DCI) m/z 230 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30](Cl)=[O:31]>>[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30]([NH:5][C@H:4]([C:3]([OH:26])=[O:2])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][C:18]=2[CH3:19])=[CH:11][CH:12]=1)=[O:31]
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl)-L-phenylalanine was prepared from 4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester and 2-chloro-6-methylbenzoyl chloride using the general procedures described in example 44. ES-LRMS m/z 507.1 (M+H), 529.1 (M+Na).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.O[C:24]1[CH:25]=[CH:26][C:27]([N+:34]([O-:36])=[O:35])=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1>>[CH:20]([O:19][C:10]1[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:9]=1[C:7]([N:4]1[CH2:5][CH2:6][CH:2]([O:1][C:24]2[CH:25]=[CH:26][C:27]([N+:34]([O-:36])=[O:35])=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:29]=2)[CH2:3]1)=[O:8])([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1
Yield: 56 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and 5-hydroxy-2-nitrobenzotrifluoride. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 56%). MS (m/e): 517.5 (M+H+, 100%).
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[NH:8][CH2:7]2)[O:5][CH2:4]1.[Cl:19][CH2:20][CH2:21][CH2:22]Cl>CN(C=O)C>[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[N:8]([CH2:22][CH2:21][CH2:20][Cl:19])[CH2:7]2)[O:5][CH2:4]1
Reactant: O=S1(=O)NCC2(OCCO2)c2ccccc21
Reactant: ClCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2C2(CN1CCCCl)OCCO2
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a suspension of 2.20 g (50 mmol) of 60% sodium hydride in 100 ml of DMF, a solution of 12.06 g (50 mmol) of 3,4-dihydro-2H-1,2-benzothiazin-4-one 1,1-dioxide ethylene acetal in 50 ml of DMF was added under ice cooling and stirring. The reaction mixture was stirred for 30 minutes at 0° C. and then for further one hour at room temperature. Under ice cooling, a solution of 16.95 g (150 mmol) of 1,3-dichloropropane in 50 ml of DMF was added to the reaction mixture, followed by stirring for 17 hours at room temperature. The post-treatment and purification were conducted as in Example 10, whereby 13.41 g of the title compound were obtained (yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:9]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=C1NCCN1c1ccc(Cl)cc1
Reactant: COc1ccc(OCCCOCCCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCOCCCCCN2CCN(c3ccc(Cl)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-chlorophenyl)-2-imidazolidinone (0.10 g, 0.53 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 27.3 mg, 0.80 mmol). The mixture was stirred at room temperature for 30 min and then cooled in ice bath. 1-{3-[(5-Bromopentyl)oxy]propoxy}-4-methoxybenzene (0.18 g, 0.53 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvents were pumped off. 5 mL saturated aqueous NH4Cl solution and 10 mL dichloromethane were successively added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 6) as a white solid (0.16 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]([F:20])[C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:17]=[C:2]([F:1])[C:3]([O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=2)=[C:14]([F:20])[CH:15]=1
Reactant: NC(=O)c1ccc(Oc2c(F)cc(C=O)cc2F)nc1
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)CCNCc1cc(F)c(Oc2ccc(C(N)=O)cn2)c(F)c1
Yield: 80.4 %

Procedure:
Using a method similar to Example 710, Step 4, using 6-(2,6-difluoro-4-formyl-phenoxy)-nicotinamide (278 mg, 1.00 mmol), 3,3-dimethylbutylamine (105 mg, 1.20 mmol), and NaBH4 (57 mg, 1.50 mmol) gave the title compound (292 mg) as a white solid. Mass spectrum (ion spray): m/z=364 (M+1); 1HNMR (DMSO-d6): 8.54 (s, 1H), 8.30 (d, 1H), 8.04 (s, 1H), 7.51 (s, 1H), 7.29 (d, 1H), 7.22 (d, 2H), 3.71 (s, 2H), 2.49 (t, 2H), 1.36 (m, 2H), 0.86 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:28]([NH:30][C:31](=[N:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH:45]=1)OC1C=CC=CC=1)#[N:29]>>[C:28]([NH:30][C:31]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:25])=[N:39][CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:51]2[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]2)[CH:45]=1)#[N:29]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: COc1ccc(CN(CCN(C)CCCCCCN)c2ccccn2)cc1
Product: COc1ccc(CN(CCN(C)CCCCCCNC(=NCCCOc2cccc(CN3CCCCC3)c2)NC#N)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.56 g (1.52 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=669 ([M+H]+, 5), 121 (100); IR (KBr): 2163 cm-1 (C≡N). For analytical purposes a sample is converted into the tartaric acid salt in an ether/ethanol solvent mixture; m.p.: 79° C. (ether/ethanol).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([OH:20])=[O:19])[C:9]2=[O:21])[CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=[O:26])[C:23](Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([O:20][C:2]3[CH2:3][CH2:4][CH2:23][C:22](=[O:26])[CH:1]=3)=[O:19])[C:9]2=[O:21])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-n2c(=O)c(C(=O)O)nc3ccccc32)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-n2c(=O)c(C(=O)OC3=CC(=O)CCC3)nc3ccccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 185.2 %

Procedure:
23.3 g of 1-(6-methyl-2-pyridyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid was dissolved in chloroform (100 mL), and 21.0 g of oxalyl chloride was added thereto. The mixture was stirred for one hour at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 mL of chloroform. 10.2 g of 1,3-cyclohexadione and 10.1 g of triethylamine were added, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, to obtain 28.8 g of 3-oxo-1-cyclohexenyl 1-(6-methyl-2-pyridyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[C:16](Cl)(=[O:18])[CH3:17].O>C1(C)C=CC=CC=1>[C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:15][CH:14]=2)(=[O:18])[CH3:17]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A 1.0 M solution of SnCl4 (10 mL, 10.0 mmol) was added to a stirred solution of 5-bromoindole (ab) (980 mg, 5.0 mmol) and acetyl chloride (0.714 mL, 785 mg, 10.0 mmol) in 20 mL of dry toluene at 0° C. The resulting mixture was stirred at room temperature during 4 hours, and then 50 ml, of water was added. The mixture was extracted with EtOAc (3×20 mL) and the collected organic layers were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum. Column chromatography using EtOAc-pentane (from 5/95 to 80/20) yielded pure acetylindole (jb) (1.0 g, 4.2 mmol) as a white solid. Yield: 84%.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:12]([N:17]([CH3:25])[C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@:28]1([CH3:35])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@:28]1([CH3:35])[C:29]([NH:20][C@H:19]([C:18]([N:17]([C@@H:12]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:25])=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:30]
Reactant: CN1CCC[C@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Yield: 106.2 %

Procedure:
According to the general procedure D, from #6 (7.75 g, 21.6 mmol, 1 eq.), #152 (3.88 g, 21.6 mmol, 1 eq.), dichloromethane (100 mL), HATU (9.8 g, 25.9 mmol, 1.2 eq.), and diisopropylethylamine (11.1 g, 86.4 mmol, 4 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 20 to 55% ethyl acetate in petroleum ether) to afford #195 (11.1 g, quantitative yield) as a yellow oil.