Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([NH:16][NH2:17])=[O:15])[N:6]=1.[CH3:22][OH:23]>>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]2[O:15][C:22](=[O:23])[NH:17][N:16]=2)[N:6]=1
Reactant: CO
Reactant: NNC(=O)c1nc(Cc2ccccc2F)n2ccccc12
Product: O=c1[nH]nc(-c2nc(Cc3ccccc3F)n3ccccc23)o1

Procedure:
155 mg (0.55 mmol) of 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carbohydrazide from example 16A are dissolved in 3 ml of methanol. 106 mg (0.65 mmol) of N,N′-carbonyldiimidazole are added, and the mixture is heated to reflux for 2 h. It is then purified directly by preparative HPLC to result in 98 mg (58% of theory) of the desired compound as a pale beige solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O>[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:9][C:10]3[CH:19]=[CH:18][CH:13]=[CH:12][CH:11]=3)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccccc1
Temperature: 110 °C
Yield: 190 %

Procedure:
7-Benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.6 g, 4.7 mmol), (prepared as described for the starting material in Example 1), was then added and the reaction mixture heated at 110° C. for 2 hours. The mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were then washed with 2M sodium hydroxide solution, water and brine. Removal of the solvent under reduced pressure gave 7-benzyloxy-6-methoxy4-phenoxyquinazoline (1.6 g, 95%) as a yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]([NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=1.CN(C1C=CC=CN=1)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]([NH:16][C:23]([C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](N)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](NC(=O)c2ccncc2)C1
Temperature: 5 °C
Reaction time: 48 h

Procedure:
36.85 g of (3R,4S)-3-Amino-4-hydroxy-azepane-1-carboxylic acid tert-butyl ester, 19.70 g 4-pyridinecarboxylic acid, and 9.76 g dimethylaminopyridine were dissolved in 500 mL CH2Cl2 and cooled to 5° C. 33.01 g DCC was dissolved in 250 mL CH2Cl2 and added to the above mixture within 2 h. The reaction mixture was stirred for 48 h at rt. 200 mL water was added and the mixture is stirred for 2 h at rt. The precipitate was filtered off and the organic phase was extracted two times with 500 mL water. The organic solvent was evaporated in vacuo. The crude product was then submitted to column chromatography (SiO2, ethyl acetate/methanol 99:1) to give 46.2 g (86%) of 1 g as a white solid. MS (ESI): m/z (%): 334 (MH+), 336 ([M−H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]>>[Cl:9][C:10]1[CH:15]=[C:14]([O:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][CH:5]=2)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: Oc1cncc(Cl)c1
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)cc1Cl

Procedure:
5-Chloro-3-pyridinol (5 g, Aldrich) and 2,4-dichloronitrobenzene (7.4 g, Aldrich) were combined as described in Example 1. The title compound was isolated as the minor product using gravity chromatography on silica eluting with 10% ethyl acetate/hexanes.
Reaction SMILES: [I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([CH3:14])=[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:8]=[C:7]2SC.[I-].[CH3:24][C:25]1[S:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[N+:29]=1[CH3:30].C(N(CC)CC)C>CN(C)C=O>[I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[N:8][C:7]2=[CH:24][C:25]1[S:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[N+:29]=1[CH3:30]
Reactant: COc1ccc2c(c1)c(SC)nc(-c1ccccc1)[n+]2C
Reactant: Cc1sc2ccccc2[n+]1C
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(=Cc1sc3ccccc3[n+]1C)N=C(c1ccccc1)N2C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
600 mg (1.41 mmol) 6-Methoxy-1-methyl-4-methylsulfanyl-2-phenyl-quinazolin-1-ium iodide and 412 mg (1.41 mmol) 2,3-dimethyl-benzothiazol-3-ium iodide were dissolved in 2.0 ml dimethylformamide and 571 mg (0.79 ml, 5.64 mmol) triethylamine were added. The solution was stirred for 1 h at 80° C., filtrated and the residue was washed with water and methanol.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([F:31])=[C:26]([Cl:32])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:26]1[CH:25]=[C:24]([CH:19]([C:20]([F:21])([F:23])[F:22])/[CH:18]=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][CH2:9][CH2:10]3)[CH:29]=[C:28]([Cl:30])[C:27]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1c(Cl)cc(C(/C=C/c2ccc3c(c2)CCN3)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (E)-tert-butyl-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-carboxylate (0.2 g, 0.4 mmol) in CH2Cl2 (10.0 mL) was added TFA (0.6 mL) and the reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with CH2Cl2, washed with saturated aq NaHCO3, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a light brown gummy material which was used in the next step without further purification (0.12 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=6.4 Hz, 2H), 7.21 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.49 (d, J=15.6 Hz, 1H), 6.21 (dd, J=15.6, 8.4 Hz, 1H), 4.07 (m, 1H), 3.61 (t, J=8.4 Hz, 2H), 3.05 (t, J=8.4 Hz, 2H); ESIMS m/z 389.89 ([M+H]+); IR (thin film) 3385, 1112, 816 cm−1.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][C:23]1[CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[S:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:25]3[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1csc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1csc(C2=C(n3c4c(c5cc(C)ccc53)CN(C)CC4)CCC2)c1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 4-methylthiophene-2-boronic acid pinacol ester (129 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(4-methylthiophen-2-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.3 (s, 1H), 7.0 (m, 3H), 6.78 (s, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.37 (s, 3H), 3.03 (m, 2H), 2.83 (m, 2H), 2.61 (m, 2H), 2.4 (s, 3H), 2.2 (m, 2H), 2.17 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.O1CCCCC1[N:22]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C4CCCCO4)=[CH:34][CH:33]=3)[CH:27]=[C:28]2[NH2:31])=[N:23]1>C(Cl)Cl>[OH:38][C:35]1[CH:34]=[CH:33][C:32]([C:26]2[CH:25]=[C:24]3[C:29]([CH:30]=[N:22][NH:23]3)=[C:28]([NH:31][C:13]([CH:10]3[CH2:12][CH2:11]3)=[O:14])[CH:27]=2)=[CH:37][CH:36]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2ccc(OC3CCCCO3)cc2)cc2nn(C3CCCCO3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccc(O)cc2)cc2[nH]ncc12)C1CC1
Reaction time: 1 h

Procedure:
DIPEA (82 mg, 0.635 mmol) and cyclopropanecarbonyl chloride (15 mg, 0.14 mmol) were added to 2-(tetrahydro-2H-pyran-2-yl)-6-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazol-4-amine (50 mg, 0.127 mmol) in DCM (1 ml) and the reaction was stirred for 1 h. The solvent was removed under a stream of nitrogen. The residue was dissolved in MeOH (2 ml), 4 M HCl in 1,4-dioxane (2 ml) was added and the reaction was stirred for 1 h. The solvent was removed in vacuo. The residue was purified by MDAP (Method B), dried under a stream of nitrogen then freeze dried to give the title compound, 17 mg.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C:7]1=O)=[O:5])C.FC(F)(F)C([O-])=O.[CH2:28]([N+:30]([CH2:34][CH3:35])=[C:31]([NH2:33])[NH2:32])[CH3:29].[O-]CC.[Na+]>CCO.O>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C:6]2[C:4]([OH:5])=[N:32][C:31]([N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[N:33][C:7]=2[CH2:8]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC[N+](CC)=C(N)N
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1=O
Agent: CC[O-]
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(CC)c1nc(O)c2c(n1)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Yield: 0 %

Procedure:
To a solution of 3-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.67 g, 2.3 mmol) in EtOH (10 mL) was added diethyl guanidinium trifluoroacetate (0.54 g, 2.3 mmol) and sodium ethoxide (21 wt % in EtOH, 2.3 mL). The reaction was heated at reflux for 16 h then cooled to room temperature (rt). The reaction mixture was diluted with H2O and extracted with CH2Cl2 (2×). The combined organic extracts were dried and concentrated. The resulting material was triturated with hexanes/Et2O (9:1) to give the title compound (0.334 mg, 43%) as a light brown solid. MS (ESI): mass calcd. for C17H28N4O3, 336.4; m/z found, 337.4 [M+H]+. 1H NMR (CDCl3): 4.34-4.25 (m, 2H), 3.62-3.46 (m, 6H), 2.66-2.58 (m, 2H), 1.88-1.77 (m, 2H), 1.50-1.36 (m, 9H), 1.21-1.14 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:15][C:16]([F:41])([F:40])[CH2:17][NH:18][C:19]([C:21]1([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:28][C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]>>[F:41][C:16]([F:15])([F:40])[CH2:17][NH:18][C:19]([C:21]1([CH2:35][CH2:36][CH2:37][CH2:38][N:12]2[CH2:13][CH2:14][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=3)[CH2:10][CH2:11]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[O:28][C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:20]
Reactant: COc1cccc(N2CCNCC2)n1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: COc1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methoxy-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]3[C:11]([SH:14])=[N:12][N:13]=[C:6]3[C:5]=2[CH:4]=[N:3]1.[K].[CH3:16]I>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]3[C:11]([S:14][CH3:16])=[N:12][N:13]=[C:6]3[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1ncn1c(S)nnc21
Reactant: CI
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1nnc2c3cnn(C)c3ncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3 g. of 7-methyl-3-mercapto-7H-pyrazolo[4,3-e][1,2,4]-triazolo[4,3-c]pyrimidine, potassium salt, in 25 ml. of dimethylformamide, 2.1 g. of methyl iodide are added and the mixture is stirred for 1 hour at room temperature. The reaction mixture is then poured into 200 ml. of water and the product, 7-methyl-3-methylthio-7H-pyrazolo[4,3-e][1,2,4]triazolo [4,3-c]-pyrimidine, is filtered under suction, crystallized from dimethylformamide and obtained as yellowish crystals, m.p. 204°-206°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:17][CH3:18])([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:9]#[N:10])=[CH:4][CH:3]=1.[OH-:19].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)([CH2:17][CH3:18])[C:9]([NH2:10])=[O:19])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 91.6 %

Procedure:
To a 500 mL flask was charged 100.0 g (0.38 mole) of alpha-(4-chlorophenyl)-alpha-ethyl-1H-1,2,4-triazole-1-propanenitrile and 100 mL of dimethyl sulfoxide. To the stirring solution was added 100 g (1.25 mole) of 50% sodium hydroxide. The reaction mixture was heated at 100° C. for 1 hour after which GLC indicated the starting material was consumed. The reaction was poured into water and extracted with ethyl acetate. After washing with brine, the organic phase was dried over magnesium sulfate and concentrated under vacuum without heating. Removal of the solvent gave a foamy glassy solid which was triturated with hexane, filtered and gave 97 g (91% yield) of a white solid, melting point 139°-140° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH2:23]C)[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)C.[CH3:28][C:29]([CH3:31])=O>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH3:23])[C:15]2[C:20]([NH:21][CH:29]([CH3:31])[CH3:28])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)=O
Agent: CC=O
Product: CCN(c1ncccc1NC(C)C)C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure of EXAMPLE 115 and making non-critical variations but substituting 1-benzyl-4-[N-ethyl-N-(3-amino-2-pyridinyl)amino]piperidine (PREPARATION 4) for 1-benzyl-4-[N-propyl-N-(3-amino-2-pyridinyl)amino]piperidine and acetone for acetaldehyde, the title compound is obtained, NMR (CDCl3) 7.71, 7.30, 7.25, 6.80, 4.72, 3.55, 3.50, 3.11, 3.00, 2.88, 2.00, 1.74, 1.66, 1.20 and 0.86δ.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13]O)=[CH:12][C:7]=2[N:6]=[C:5]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH3:3].[Cl:21]CCl.CS(Cl)(=O)=O>C(N(CC)CC)C>[Cl:21][CH2:13][C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:6][C:7]=2[CH:12]=1
Reactant: ClCCl
Reactant: CCCn1c(-c2cccnc2)nc2cc(CO)ccc21
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCn1c(-c2cccnc2)nc2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66 %

Procedure:
(b-1) To a stirred solution of 4.01 parts of 1-propyl-2-(3-pyridinyl)-1H-benzimidazole-5-methanol in 65 parts of dichloromethane and 3 parts of N,N-diethylethanamine were added 2.23 parts of methanesulfonyl chloride. The whole was stirred for 45 minutes at room temperature. The mixture was poured into crushed ice and the dichloromethane layer was separated, dried, filtered and evaporated. The residue was dissolved in methylbenzene. The precipitate was filtered off and the filtrate was evaporated, yielding 2.3 parts (66%) of 5-(chloromethyl)-1-propyl-2-(3-pyridinyl)-1H-benzimidazole as a residue (int. 16).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.O=[CH:10][CH2:11][NH:12][C:13]([C:15]1[S:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)=[O:14].O>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[S:16][C:15]3[C:13](=[O:14])[NH:12][CH:11]=[CH:10][C:19]=3[CH:18]=2)=[CH:21][CH:22]=1
Reactant: O=CCNC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Add trifluoromethane sulfonic acid (3 mL, 0.03 mol) and 5-(4-chlorophenyl)-thiophene-2-carboxylic acid (2-oxoethyl) amide (1 g, 0.004 mol) to a 25 mL three-necked round bottom flask equipped with a stir bar, Dean-Stark trap, nitrogen inlet/outlet, and thermocouple. Heat the reaction mixture to 95° C. for 2 h, then cool to 40° C., and pour onto cold water (20 mL, 1.11 mol). Stir the mixture for 10 min. Filter the resulting slurry and rinse the solids with water (100 mL). Dry to afford crude 2-(4-chlorophenyl)-6H-thieno[2,3-c]pyridine-7-one (0.95 g, 0.004 mol) as a brown solid. LC-MS/ES m/z (35Cl) 262 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1)=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc(Cl)cn1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ncc(Cl)cn1
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 2-methylthio-5-chloropyrimidine (13 mmol) in chloroform (85 ml) was cooled to -20° C. and m-chloroperbenzoic acid (17 mmol) added with stirring. The mixture was stirred for 40 min at -20° C. and for 4 h at 0° C. and left at this temperature overnight. The chloroform solution was then washed with 1 M potassium carbonate (3×10 ml) and the dried (MgSO4) solution evaporated. The residual oily material crystallized on standing; yield 80% m.p. 48° C. (n-heptane). 1H NMR (CDCl3): δ2.93 (Me), 8.83 (2H-4,6).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30]([OH:38])(=O)[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[N:34]1[CH:33]=[CH:32][C:31]([C:30]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:38])=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccncc1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1ccncc1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with isonicotinic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(4-pyridylcarbonyl)-N-methyl-(D)phenylalanyl-(L)-tryptophan; FAB-MS m/e 471 (M+H)+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.[CH3:12][CH2:13][O:14]C(C)=O.[NH4+].[OH-]>C(Cl)Cl.CO>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]([NH:11][C:13](=[O:14])[CH3:12])[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: NC1CCOc2cccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@@H]1CCOc2cccnc21
Reaction time: 2 h

Procedure:
Following the general procedure, 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine (243 mg, 1.62 mmol), CALB (73 mg) and EtOAc (6.0 mL) were stirred for 2 hours. The conversion determined from 1H NMR by integration of the peaks at 7.93 ppm and 8.16 ppm was 50% (CHNH2 and CHNHAc signals were not distinct). Flash chromatography of the material on silica gel using 1:10 MeOH:CH2Cl2 followed by 1:1:10 NH4OH:MeOH:CH2Cl2 furnished the (R)-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)acetamide ((145 mg, 47%) in 98% ee (chiral GC method: 140° C. for 16 min, ramp rate 5° C./min to 160° C., hold at 160° C. for 50 min, (S)-enantiomorrt=41.5 min, (R)-enantiomerrt=40.9 min); [α]D=−69° (c 1.45, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.91-2.00 (m, 1H), 1.97 (s, 3H), 2.47-2.57 (m, 1H), 4.18-4.22 (m, 2H), 4.85-4.92 (m, 1H), 6.97 (m, 2H), 7.24 (br s, 1H), 7.93-7.95 (dd, 1H, J=1.8, 3.9 Hz); 13C NMR (CDCl3) δ 23.3, 28.9,47.2, 64.4, 124.3, 124.7, 141.3, 141.7, 152.0, 170.9; MS m/z: 215 (M+Na+). The unreacted (S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine (was isolated in 43% yield (104 mg) and 99% ee ((S)-enantiomerrt=14.7 min, (R)-enantiomerrt=15.6 min); [α]D=−13° (c 0.72, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 1.84 (br s, 2H), 1.90-2.01 (m, 1H), 2.24-2.34 (m, 1H), 4.12 (dd, 1H, J=5.7, 6.9 Hz), 4.18-4.26 (m, 1H), 4.28-4.36 (m, 1H), 7.06-7.13 (m, 2H), 8.15 (dd, 1H, J=1.8, 3.6 Hz); 13C NMR (CDCl3) δ 31.5, 47.8, 64.2, 123.8, 124.5, 142.1, 147.0, 151.1; MS m/z: 151.0 (M+H+), 134.0 (M−NH2); Anal. Calc. for C8H10N2O.0.1H2O: C; 63.22; H, 6.76; N, 18.43. Found: C, 62.99; H, 6.81; N, 18.22.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][CH2:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2sc(-c3ccccc3)nc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: BrCc1cccc2sc(-c3ccccc3)nc12
Reaction time: 8 h

Procedure:
42.8 g (190 mmol) of 4-methyl-2-phenyl-benzothiazole [compare Perregaard, Lawesson, Acta Chem. Scand. Ser. B, 31, 203 (1977)] were dissolved in 1 l of carbon tetrachloride, and catalytic amounts of 2,2'-azoisobutyronitrile were added. 40.6 g (0.228 mol) of N-bromosuccinimide (NBS) were added under reflux in portions and the mixture was boiled overnight. A further 40.6 g of NBS were added and the mixture was boiled for 2 h. After cooling, the mixture was diluted with methylene chloride, washed with water, dried and concentrated, and the residue was crystallized using petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11](O)[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:20][CH:11]1[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[CH2:8][O:7][C:6]2[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]1=2
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccccc2COc2cc(F)ccc21
Solvent: ClCCl
Product: Fc1ccc2c(c1)OCc1ccccc1C2Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 1.5 g of 3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-ol in 20 ml of methylene chloride is added dropwise a solution of 1.6 g of thionyl chloride in 10 ml of methylene chloride under ice cooling over 30 minutes and then the mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated at room temperature under reduced pressure to give 1.5 g of 11-chloro-3-fluoro-6,11-dihydrodibenz[b,e]oxepin (oil). Mass spectrum m/z: 248(M+)
Reaction SMILES: C1(P(C2C=CC=CC=2)(S)=[S:8])C=CC=CC=1.[NH2:16][C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[CH3:28])=[CH:23][CH:22]=1)=[CH:18][C:19]#[N:20]>CC(O)C.CCOC(C)=O>[NH2:16][C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[CH3:28])=[CH:23][CH:22]=1)=[CH:18][C:19]([NH2:20])=[S:8]
Reactant: S=P(S)(c1ccccc1)c1ccccc1
Reactant: CC(F)(F)c1ccc(C(N)=CC#N)cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(F)(F)c1ccc(C(N)=CC(N)=S)cc1
Temperature: 45 °C
Yield: 67.2 %

Procedure:
Add diphenylphosphinodithioic acid (13.2 g, 52.9 mmol) to a solution of 3-amino-3-[4-(1,1-difluoroethyl)phenyl]acrylonitrile (5.50 g, 26.4 mmol) in propan-2-ol (264 mL). Heat to 45° C. for 4 h. Dilute with EtOAc (400 mL), wash with brine 3× (100 mL), and evaporate. Crystallize from EtOAc/hexane to afford 3-amino-3-[4-(1,1-difluoroethyl)-phenyl]thioacrylamide. Yield: 67.2%. ES-MS: m/e 243.0 (m+1).