Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C@@H:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=2[F:16])[C@@H:5]([CH3:17])[N:4]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:3]1=[O:23].[CH2:24]([C:30]([OH:32])=[O:31])[C@H:25]([OH:29])[C:26]([OH:28])=[O:27]>C1COCC1>[OH:29][C@@H:25]([CH2:24][C:30]([OH:32])=[O:31])[C:26]([OH:28])=[O:27].[NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=2[F:16])[C@@H:5]([CH3:17])[N:4]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:3]1=[O:23]
Reactant: C[C@@H]1[C@H](c2cc(F)cc(F)c2F)CC(N)C(=O)N1CC(F)(F)F
Agent: O=C(O)C[C@H](O)C(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2cc(F)cc(F)c2F)C[C@H](N)C(=O)N1CC(F)(F)F
Temperature: 58 °C
Yield: 73.2 %

Procedure:
To a solution of 48 (0.24 g, 0.72 mmol) in THF (3.7 mL) was added L-(−)-malic acid (0.10 g, 0.75 mmol). The homogeneous reaction was heated to 58° C. and aged for 3 h. After the reaction was complete, the slurry was cooled to 20-25° C. and aged for 16 h. The solids were filtered, washed twice with ice-cold THF, and dried to give product 49 (0.25 g, 73% yield) as crystals. 1H NMR (400 MHz, DMSO-d6): δ 7.50-7.54 (m, 1H), 7.01-7.06 (m, 1H), 4.68 (dq, J=15.3, 9.6 Hz, 1H), 4.05 (dd, J=11.6, 6.7 Hz, 1H), 3.91-3.92 (m, 2H), 3.84-3.87 (m, 2H), 2.51 (m, 1H), 2.45 (m, 1H), 2.33 (dd, J=15.6, 4.4 Hz, 1H), 2.15 (dd, J=12.3, 6.7 Hz, 1H), 0.97 (d, J=6.4 Hz, 3H); 13C NMR (100 MHz, DSMO-d6): δ 176.3, 172.0, 168.4, 157.4 (ddd, J=243, 11, 2 Hz), 150.0 (dt, J=248, 14 Hz), 144.7 (ddd, J=242, 13, 4 Hz), 130.4 (dd, J=13, 9 Hz), 124.8 (q, J=281 Hz), 110.9 (dt, J=26, 3 Hz), 105.1 (dd, J=28, 21 Hz), 66.1, 56.0, 49.6, 44.5 (q, J=33 Hz), 41.3, 35.1, 25.1, 13.8; 19F NMR (377 MHz, DMSO-d6): δ −69.3, −114.6 (d, J=14.9 Hz), −134.7 (d, J=21.8 Hz), −148.8 (dd, J=21.8, 14.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)[CH2:8]2)=[CH:4][CH:3]=1.O.NN.O1CCOCC1>C(O)C>[NH2:14][CH2:13][CH:9]1[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccc(Cl)cc2)CCO1
Agent: NN
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: NCC1CN(Cc2ccc(Cl)cc2)CCO1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a solution of 4-(p-chlorobenzyl)-2-phthalimidomethylmorpholine (20.28 g, 54.7 mmol) in ethanol (110 ml) was added hydrazine monohydrate (5.71 g, 0.114 mol) and the mixture was stirred at room temperature. 50 ml of dioxane was further added and the mixture was stirred at room temperature overnight. The crystal thus separated was filtered off and the filtrate was concentrated. The residue was dissolved in chloroform and the insolubles were filtered off. The filtrate was distilled off to give 9.31 g of the title compound as an oily substance. Yield=71%.
Reaction SMILES: C(OC([NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=1)=O)(C)(C)C.[ClH:24].O1CCOCC1>C(Cl)Cl>[ClH:24].[NH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=1
Reactant: CCOC(=O)Cn1cc(NC(=O)OC(C)(C)C)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(N)c2ccccc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of ethyl 2-(3-(tert-butoxycarbonylamino)-1H-indol-1-yl)acetate (275 mg, 0.864 mmol) in dry DCM (8 ml), cooled at 0° C. and under nitrogen, 4N HCl in dioxane (2.159 ml, 8.64 mmol) was added, and the mixture was stirred at room temperature for 36 hours. The solvent was removed under reduced pressure without heating to give ethyl 2-(3-amino-1H-indol-1-yl)acetate hydrochloride (220 mg, 0.864 mmol, quantitative yield). MS/ESI+ 219.1 [MH]+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](=[O:39])[NH:37][OH:38])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.C(Cl)[Cl:42]>>[ClH:42].[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH:8]([NH2:7])[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([NH:37][OH:38])=[O:39])=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH2:12][CH2:13]1)(=[O:19])[CH3:18]
Reactant: ClCCl
Reactant: CC(=O)N1CCN(C(=O)C(Cc2ccc(Oc3ccc(CCC(=O)NO)cc3)cc2)NC(=O)OC(C)(C)C)CC1
Product: CC(=O)N1CCN(C(=O)C(N)Cc2ccc(Oc3ccc(CCC(=O)NO)cc3)cc2)CC1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
The acid compound 21 (0.8 g) was dissolved in CH2Cl2 (30 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×25 mL), decanted, and dried to yield the desired compound 22 as a white amorphous solid (0.82 g, 85%). 1H NMR (CD3OD): 7.26 (overlapped d, J=8.8 Hz, 1H), 7.25 (overlapped d, J=8.8 Hz, 1H), 7.20 (d, J=8.8 Hz, 2H), 6.97 (overlapped d, J=8.4 Hz, 1H), 6.95 (overlapped d, J=8.4 Hz, 1H), 6.89 (overlapped d, J=8.4 Hz, 1H), 6.88 (overlapped d, J=8.4 Hz, 1H), 4.65 (m, 1H), 3.3-3.6 (m, 6H), 3.0-2.8 (m, 4H), 2.91 (t, J=7.6 Hz, 2H), 2.39 (t, J=7.6 Hz, 2H), 2.10(d, J=11.2 Hz, 3H). LCMS: Obsd. 455.0, Calcd. 454.52
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:44]=[S:41]1(=[O:45])[CH2:42][CH2:43][N:38]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:39][CH2:40]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1)c1ccccc1

Procedure:
200 mg (0.39 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 4.3 ml of DMF, and 158 mg (1.17 mmol) of thiomorpholine 1,1-dioxide and 54 mg (0.39 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([C:33](O)=[O:34])[C:29](=[O:36])[N:28]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl.C(OCC)(=O)C>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:33]([C:30]2[C:29](=[O:36])[N:28]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:27]([CH3:26])[C:31]=2[CH3:32])=[O:34])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([OH:21])([CH3:22])[CH3:20])=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1
Reactant: CC(C)(O)COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC(C)(C)O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 41 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a solution of 1-((4-(4-amino-2-fluorophenoxy)quinolin-7-yl)oxy)-2-methylpropan-2-ol (5 g, 14.6 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (3.46 g, 14.9 mmol) and HOAT (0.39 g, 2.9 mmol) in dichloromethane (30 mL) was added EDCI (3.35 g, 17.5 mmol). The mixture was stirred at 41° C. for 6 hours, cooled to room temperature and diluted with ethyl acetate (30 mL). The resulted suspension was filtered, and the solid was washed with 95% ethanol (50 mL×2). The solid was collected through filtration and dried in vacuo at 45° C. for 6 hours to give the title compound as a white solid (6.35 g, 78%).
Reaction SMILES: [F:1][C:2]1([F:35])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[CH:25][C:26](=[O:33])[N:27]([CH2:29][C:30]([OH:32])=O)[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[N:36]#[C:37][NH2:38].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH:38]([C:30](=[O:32])[CH2:29][N:27]1[C:26](=[O:33])[CH:25]=[CH:24][C:23]([C:21]2[N:22]=[C:17]([NH:16][C:14]([C:11]3([C:9]4[CH:8]=[CH:7][C:5]5[O:6][C:2]([F:35])([F:1])[O:3][C:4]=5[CH:10]=4)[CH2:13][CH2:12]3)=[O:15])[CH:18]=[CH:19][C:20]=2[CH3:34])=[CH:28]1)[C:37]#[N:36]
Reactant: N#CN
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CC(=O)NC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To 2-(5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)acetic acid (0.13 g, 0.27 mmol), cyanamide (27 μL, 0.32 mmol), and triethylamine (75 μL, 0.54 mmol) in N,N-dimethylformamide (3 mL) was added 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.12 g, 0.33 mmol) and the reaction mixture was stirred at room temperature for 1 hour. At this point the reaction mixture was filtered and purified by reverse-phase HPLC. The resulting trifluoroacetic acid salt was dissolved in dichloromethane and washed with a saturated sodium bicarbonate solution and 1N Hydrochloric acid. The organics were dried over sodium sulfate and evaporated to dryness to give the product (45 mg, 31%). ESI-MS m/z calc. 507.14. found 508.4 (M+1)+ Retention time 1.63 minutes.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]1([C:5]([N:8]2[CH2:13][CH2:12][C:11]3([CH2:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[O:14]3)[CH2:10][CH2:9]2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Reactant: O=C(Cl)C1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(C1CCC1)N1CCC2(CC1)Cc1ccccc1O2

Procedure:
A mixture of 4.2 g of cyclobutylcarbonyl chloride in 10 ml of chloroform is added dropwise to a stirred mixture of 6.0 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 7, and 20.0 g of potassium carbonate in 75 ml of chloroform. After total addition, the reaction mixture is successively refluxed for 24 hours, cooled, filtered and poured into water. The biphasic mixture is sequentially washed with 3 N hydrochloric acid, 3 N sodium hydroxide, a saturated sodium chloride solution, dried and the solvent is removed, leaving a solid residue. The residue is recrystallized twice from a benzene-hexane mixture to give the product, 2,3-dihydro-1'-cyclobutylcarbonylspiro[benzofuran-2,4'-piperidine], mp 91°-93° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17](F)[CH:18]=1)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:1][C:2]2[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=2)[CH:18]=1)[C:14]#[N:15]
Reactant: Cc1cc(O)cc(=O)[nH]1
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2cc(Cl)cc(C#N)c2)cc(=O)[nH]1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine (3-2; 20.1 g; 161 mmol) in NMP (1.6 L) was added 3-chloro-5-fluorobenzonitrile (3-1; 25 g; 161 mmol) and potassium carbonate (44.4 g; 321 mmol). The resulting solution stirred at 120° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with 4 L of ice-water. The aqueous layer was acidified to pH 5 to precipitate out the product. The precipitate was collected via filtration, washed with water, and air dried. The crude solid product was triturated in 5% methanol/dichloromethane and filtered to give a solid. The solid was triturated with 1:1 ethyl acetate:hexane, stirred, and filtered to afford the title product as a tan solid. MS M+1=261.0.
Reaction SMILES: N1C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:16])=CC=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](=O)[N:32]([CH3:37])[N:31]=1.C(Cl)(Cl)Cl>CO>[NH2:29][C:30]1[CH:35]=[CH:34][C:33](=[S:16])[N:32]([CH3:37])[N:31]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1nc(N)ccc1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cn1nc(N)ccc1=S
Yield: 64.3 %

Procedure:
Pyridine (5 ml) and a Lawesson's reagent (970 mg, 2.4 mmol) were added to 3-amino-1-methyl-1,6-dihydropyridazin-6-one (500 mg, 4 mmol) as described in Journal of Medicinal Chemistry, 34 (10), 3074 (1991), and the mixture was refluxed under heating for 5 hours. The reaction mixture was concentrated and the residue obtained was subjected to silica gel column chromatography (chloroform:methanol=100:1) to give 218 mg of 3-amino-1-methyl-1,6-dihydropyridazine-6-thione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:28]=[C:29]1[NH:34][CH2:33][CH2:32][CH2:31][N:30]1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([N:30]3[CH2:31][CH2:32][CH2:33][NH:34][C:29]3=[O:28])[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2c(cccc2C(F)(F)F)C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: CN1C(=O)c2c(cccc2C(F)(F)F)C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 109.7 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(4-trifluoromethyl-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.416 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.183 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the hydrochloride salt to afford the title compound (0.34 g); mp 190°-205° C. (d); MS: m/z=583(M+1); NMR(CD3SOCD3): 1.66 (m,2), 2.11 (m,1), 3.05 (s,3), 4.37 (m,1), 4.96 (m,1), 6.31 (m,1), 6.75 (m,1), 6.90 (s,1), 7.34 (m,1), 7.82 (s,1), 8.22 (m,1). Analysis for C28H31Cl2N4O2 F3.1.0 H2O.1.0 HCl: Calculated: C, 52.71; H, 5.37, N, 8.78; Found: C, 52.48; H, 5.22; N, 8.46.
Reaction SMILES: [C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([OH:11])=[O:10])[C@@H:5]1[CH2:4][CH:3]=[CH:2]2.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])[C@@H:5]1[CH2:4][CH:3]=[CH:2]2
Reactant: CCO
Reactant: O=C(O)C=C1C[C@H]2C=CC[C@@H]12
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=C1C[C@H]2C=CC[C@@H]12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
The compound of Example 2 was dissolved in ethanol (20 ml) and concentrated sulfuric acid was added. The reaction was heated to 80° C. and stirred for 18 hours. The solvent was removed in vacuo to yield the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH3:14])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)(O)=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:31][N:32]([CH3:41])[C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:9]1[C:8]2[CH:23]=[C:4]([C:1](=[O:2])[NH:38][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([N:32]([CH3:41])[CH3:31])=[CH:34][CH:35]=3)[CH:5]=[CH:6][C:7]=2[N:11]=[C:10]1[CH2:12][CH2:13][CH3:14]
Reactant: CN(C)c1ccc(CN)cc1
Reactant: CCCc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2ccc(C(=O)NCc3ccc(N(C)C)cc3)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
Four-hundred milligrams of 6-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole were dissolved in 3 ml of methylene chloride containing 1 drop of N,N-dimethylformamide. Oxalyl chloride (28 mg) was added to this solution at 5° C. The thus-obtained solution was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure. The residue was dissolved in 3 ml of methylene chloride, and the mixture was added to a mixed solution prepared by adding 271 mg of 4-dimethylaminobenzylamine hydrochloride and 1 ml of triethylamine to 10 ml of methylene chloride at room temperature. The resulting reaction mixture was stirred at the same temperature for 1 hour, washed with water, dried and then concentrated under reduced pressure. The residue was developed and purified through thin-layer chromatography to give 215 mg of 1-(2-chlorobenzyl)-6-(4-dimethylaminophenylmethylcarbamoyl)-2-n-propylbenzimidazole (61).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][S:8][C:9]1[NH:13][C:12]2[CH:14]=[C:15]([Cl:19])[C:16](I)=[CH:17][C:11]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)#[CH:22]>CN(C=O)C.CO.CCOC(C)=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:20])[CH2:7][S:8][C:9]1[NH:13][C:12]2[CH:14]=[C:15]([Cl:19])[C:16]([C:22]#[C:21][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[CH:17][C:11]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(I)c(Cl)cc2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)CSc1nc2cc(C#Cc3ccc(Oc4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 120 °C

Procedure:
A 2 mL Biotage™ microwave vial equipped with a stirring bar was charged with copper iodide (1.1 mg, 10 mol %), and Pd(PPh3)2Cl2 (2.1 mg, 5 mol %). A solution of (6-chloro-5-iodo-1H-benzoimidazol-2-ylsulfanyl)-acetic acid tert-butyl ester (Intermediate 4, 25.0 mg, 0.059 mmol) in DMF (0.5 mL) was added to the vial, followed by a solution of 1-ethynyl-4-phenoxy-benzene (15.0 mg, 0.118 mmol) in DMF (250 uL) and TEA (57 uL, 0.41 mmol). The resulting suspension was heated in a microwave synthesizer (Biotage Initiator™) at 120° C. for 5 min. The solvent was removed in vacuo to give dark brown oil which was re-dissolved in a 1:1 MeOH/EtOAc mixture (3 mL) and passed through a Thiol StratoSphere™ SPE cartridge (Polymer Labs). The resulting solution was evaporated to dryness in vacuo to give the crude product as brown solid. LR-MS (API-ES): calculated for C27H23ClN2O3S 490.1, observed m/e 491.0 (M+H)+ (Rt 3.74 min). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2([OH:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2([OH:17])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[CH:8][C:9]=1[N:10]=[CH:20][N:23]([CH3:25])[CH3:24])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(C2(O)CCOCC2)cc1N
Product: COC(=O)c1sc(C2(O)CCOCC2)cc1N=CN(C)C

Procedure:
3-Amino-5-(4-hydroxytetrahydropyran-4-yl)thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 312.39 (C14H20N2O4S) was obtained in this way; MS (ESI): 313 (+H+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[O:24][C:23]([NH2:25])=[N:22][N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[O:24][C:23]([NH2:25])=[N:22][N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(NC(C)C)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Nc1ccnc(-c2c[nH]c3ccc(-c4nnc(N)o4)cc23)n1
Temperature: 100 °C

Procedure:
To a solution of 5-(3-(4-(isopropylamino)pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (400 mg, 0.817 mmol) in p-dioxane (4 mL) was added aq. 10% NaOH (2 mL). The mixture was heated at 100° C. for 2 h. The reaction was quenched with ice cold H2O and the resulting precipitate was filtered, washed with ice cold H2O and dried. The residue was purified with RP-HPLC to 5-(3-(4-(isopropylamino)pyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (60 mg, 22%) as an off-yellow solid. MS (ESI, pos. ion) m/z: 335.9 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 11.77 (d, J=2 Hz, 1H), 9.02 (s, 1H), 8.14-8.07 (m, 2H), 7.65 (dd, J=2, 8.8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.11-7.06 (m, 3H), 6.24 (d, J=8 Hz, 1H), 4.33 (brs, 1H), 1.26 (d, J=6.8 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH2:10])=[NH:9])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:15]=1[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19]>>[NH2:21][CH2:20][C:17]1[C:18]([NH2:19])=[N:9][C:8]([CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)=[N:10][C:16]=1[C:15]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:14]=1[Cl:13]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)COc1ccc(F)cc1
Product: NCc1c(N)nc(COc2ccc(F)cc2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=392.8 (M+H+), was prepared from 2-(4-fluoro-phenoxy)-acetamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cccnc1-c1ccc(CCl)nn1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(-c2ncccc2F)nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine. A solution of 3-(3-fluoropyridin-2-yl)-6-methylpyridazine (200 mg, 1.05 mmol) in 5 mL of DCE was treated with trichloroisocyanuric acid (98 mg, 0.42 mmol). The mixture was heated at 90° C. for 1 h. The mixture was cooled to RT and the precipitate was filtered off with a fritted funnel and rinsed with 2×20 mL of DCM. The brown solid was discarded. The filtrate was washed with 2×5 mL of 0.5 M NaOH (aq.) followed by brine (5 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (55-75% EtOAc in hexanes) to give 3-(chloromethyl)-6-(3-fluoropyridin-2-yl)pyridazine as a brown crystalline solid. MS (ESI, pos. ion) m/z: 224.0 (M+1). A solution of the 3-(chloromethyl)-6-(3-fluoropyridin-2-yl)pyridazine in 1 mL of DMF at RT was treated with NaN3 (69 mg, 1.05 mmol) and stirred at RT for 5 h. The mixture was filtered through a fritted funnel and the collected solid was rinsed with 2×5 mL of EtOAc. The solid was discarded and the filtrate was concentrated and the crude material was purified by silica gel chromatography (35-75% EtOAc in hexanes) to give 3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine (100 mg, 41% yield) as an off white amorphous solid. MS (ESI, pos. ion) m/z: 231.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (1 H, m), 8.27 (1 H, d, J=8.8 Hz), 8.00 (1 H, m), 7.94 (1 H, m), 7.69 (1 H, dt, J=8.4, 4.2 Hz), 4.89 (2 H, s). 19F NMR (376 MHz, DMSO-d6) δ ppm-121.47.