Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[C:18]1(CCN)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1.C(OCC)(=O)C>CN(C)C=O>[C:18]1([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: NCCC1=CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCCC1=CCCCC1)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(1-cyclohexenyl)ethylamine (0.64 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.82 g (55%) of the titled product as yellow needles:
Reaction SMILES: CS(C1C=CC([N:11]2C(=O)C=CC(C([O-])=O)=N2)=CC=1)(=O)=O.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([O:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[C:30]([C:49]([O:51]C)=O)=[N:29]2)=[C:24]([F:53])[CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([O:35][CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[CH2:40][CH2:41]3)[C:30]([C:49](=[O:51])[NH2:11])=[N:29]2)=[C:24]([F:53])[CH:23]=1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)[O-])ccc2=O)cc1
Reactant: COC(=O)c1nn(-c2ccc(Br)cc2F)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Br)cc3F)nc2C(N)=O)CC1
Yield: 100 %

Procedure:
tert-Butyl 4-(1-(4-bromo-2-fluorophenyl)-3-carbamoyl-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was prepared in 100% yield according to procedures described in Example 31 (Step A) substituting methyl 441-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate for Methyl 1-(4-bromo-2-fluorophenyl)-4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-6-oxo-1,6-dihydropyridazine-3-carboxylate (Example 44). MS (ESI) 511 (M+H).
Reaction SMILES: Cl.[NH:2]=[C:3]([NH2:5])[CH3:4].[Cl:6][C:7]1[N:12]=[C:11]([C:13](Cl)(Cl)[S:14]Cl)[CH:10]=[CH:9][N:8]=1.[OH-].[Na+].O>C(Cl)Cl>[Cl:6][C:7]1[N:12]=[C:11]([C:13]2[S:14][N:5]=[C:3]([CH3:4])[N:2]=2)[CH:10]=[CH:9][N:8]=1
Reactant: ClSC(Cl)(Cl)c1ccnc(Cl)n1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1nsc(-c2ccnc(Cl)n2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
1-Imino-ethanamine hydrochloride (1:1) (0.08 mol) was added at 0° C. to a stirring mixture of intermediate 1 (0.07 mol) in DCM (300 ml). Sodium hydroxide (50%, 20 ml) was added dropwise at 0° C. The mixture was stirred at 5° C. for 1 hour. Water (300 ml) and DCM (300 ml) were added. The mixture was separated into its layers. The aqueous layer was washed twice with DCM. The combined organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: DCM). Two pure fractions were collected and their solvents were evaporated, yielding 3.5 g of 2-chloro-4-(3-methyl-1,2,4-thiadiazol-5-yl)pyrimidine (intermediate 2).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:25])[CH:9]=[C:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S)C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]1([NH:7][C:8](=[O:25])[CH2:9][CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C=C(Sc1ccccc1)Sc1ccccc1)Nc1ccccc1
Agent: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CC(Sc1ccccc1)Sc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 146.2 %

Procedure:
To N-phenyl-3,3-bis(phenylthio)acrylamide (2.04 g) were added thiophenol (8.21 mL) and triethylamine (1.12 mL), and the mixture was stirred at room temperature for 11 hours. To the reaction mixture was added ethyl acetate (50 mL), which was washed with a 1N aqueous sodium hydroxide solution, water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was isolated and purified by medium pressure preparative liquid chromatography (YAMAZEN SI-40C, hexane:ethyl acetate=85:15) to obtain N-phenyl-3,3-bis(phenylthio)propionamide (3.00 g) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:5]=[C:4]([CH2:16]O)[CH:3]=1.CN(C)C=O.P(Cl)(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:5]=[C:4]([CH2:16][Cl:25])[CH:3]=1
Reactant: N#Cc1cnc(Nc2cc(CO)cc(Cl)n2)s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cnc(Nc2cc(CCl)cc(Cl)n2)s1

Procedure:
2-{[6-Chloro-4-(hydroxymethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile 11-7 (0.132 g, 0.49 mmol) was stirred in anhydrous CH2Cl2 (2 mL) under N2. N,N-Dimethylformamide (0.038 mL, 0.49 mmol) was added followed by the addition of phosphorous oxychloride (0.046 mL, 0.49 mmol). After 2.5 hours the reaction was concentrated and quenched by the addition of saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to afford 2-{[6-chloro-4-(chloromethyl)pyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile as a yellow solid. 1H NMR (DMSO-d6) δ 12.63 (bs, 1H), 8.34 (s, 1H), 7.24 (s, 1H), 7.17 (s, 1H), 4.82 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(O)(=O)C.[Cl-].[NH4+]>[NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[C:5]([Br:15])=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1cc([C@@H]2CNC(=O)C2)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Seven and one-half (7.5) g (35.71 mmol) of (4R)-4-(3-amino-4-chlorophenyl)-pyrrolidin-2-one was dissolved in 170 mL chloroform (0.25 M) and 3 mL of acetic acid. To this solution, 6.3 g of solid N-bromosuccinimide was added portion-wise. The reaction was stirred overnight at room temperature. The reaction mixture was diluted with saturated ammonium chloride aqueous solution (50 mL). The aqueous solution was extracted with dichloromethane (2×50 mL), dried over MgSO4 and the solvent evaporated to dryness. Water was added to the oil and the pH adjusted to 9 with 1N NaOH. The solid was filtered, washed consecutively with water, ether, and hexane and dried under a high vacuum to give 9.3 g of the title compound (88% yield).
Reaction SMILES: CC([N:5]([C@@H:9]1[C@H:13]([OH:14])[CH2:12][N:11]([CH2:15][CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=3)[N:20]=[CH:19][CH:18]=2)[CH2:10]1)C(=O)[O-])(C)C.Cl.O1CCOCC1>CO>[NH2:5][C@@H:9]1[CH2:10][N:11]([CH2:15][CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=3)[N:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:13]1[OH:14]
Reactant: COc1ccc2nccc(CCN3C[C@@H](O)[C@@H](N(C(=O)[O-])C(C)(C)C)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2nccc(CCN3C[C@@H](N)[C@@H](O)C3)c2n1
Reaction time: 12 h
Yield: 99.6 %

Procedure:
To a solution of 1,1-dimethylethyl((3S,4R)-4-hydroxy-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)carbamate (327 mg, 0.843 mmol) in MeOH (4 mL) at 25° C. was added dropwise a 4M HCl in dioxane solution (1.5 mL, 5.9 mmol). After 12 h, the solution was concentrated and the residue neutralized with excess MP carbonate resin in DCM to afford the title compound (242 mg, quant.) as a yellow oil: LCMS (ES) m/e 289 (M+H).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7]C(C)=C)=[O:6])=[N+:2]=[N-:3].[CH3:11][S:12](O)(=[O:14])=[O:13]>C(Cl)Cl>[CH3:11][S:12]([O:7][C:5](=[O:6])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:14])=[O:13]
Reactant: C=C(C)OC(=O)CN=[N+]=[N-]
Reactant: CS(=O)(=O)O
Solvent: ClCCl
Product: CS(=O)(=O)OC(=O)CN=[N+]=[N-]
Reaction time: 3 h

Procedure:
Isopropenyl azidoacetate (1.41 g, 0.01 mole) and anhydrous methanesulfonic acid (0.96 g, 0.01 mole) in 15 ml of methylene chloride is allowed to stand at room temperature for three hours. The solvent is removed in vacuo to give azidoacetyl methanesulfonate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20](Br)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.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:24])[N:7]([CH3:8])[CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Br)n3n2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(-c4ccncc4)n3n2)C1
Temperature: 150 °C
Yield: 25.7 %

Procedure:
A mixture of [1-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (100 mg, 0.25 mmol), 4-pyridinylboronic acid (40 mg, 0.33 mmol), K2CO3 (104 mg, 0.75 mmol) and dichlorobis(triphenylphosphine)palladium(II) (8.8 mg, 0.013 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the organic layer was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (25.3 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.50-1.55 (m, 9H) 2.22-2.32 (m, 2H) 2.89 (s, 3H) 3.46-3.57 (m, 2H) 3.72-3.80 (m, 2H) 4.91 (t, J=7.61 Hz, 1H) 6.95 (d, J=9.92 Hz, 1H) 7.77 (d, J=9.70 Hz, 1H) 8.11 (s, 1H) 8.23-8.27 (m, 2H) 8.53-8.58 (m, 2H). LRMS (ESI) m/z 395.2 [(M+H)]+, calc'd for C21H26N6O2: 394.48.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([CH3:17])([CH3:16])[CH2:8][C:9](=[O:15])[NH:10]2)C=C.CN(C)[C:20]1[CH:25]=CC=C[CH:21]=1>>[CH2:25]([C:14]1[C:5]([OH:4])=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:15])[CH2:8][C:7]2([CH3:16])[CH3:17])[CH:20]=[CH2:21]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cccc2c1C(C)(C)CC(=O)N2
Product: C=CCc1ccc2c(c1O)C(C)(C)CC(=O)N2
Yield: 86.9 %

Procedure:
5-Allyloxy-4,4-dimethyl-3,4-dihydrocarbostyril (817 mg, 3.73 mmol) was dissolved in dimethylaniline (15 ml), and the resultant solution was stirred in a bath at 205° C. for 5 hours. The reaction solution was condensed under reduced pressure, followed by extracting with chloroform and 2N-aqueous caustic soda solution. The aqueous phase was neutralized with conc. HCl. Subsequently, the neutralized phase was extracted with a mixture of chloroform-methanol (10:1), dried, and condensed under reduced pressure. Recrystallization from a mixture of chloroform-methanol-ether yielded 710 mg of the title compound as pale yellow needles (86.9%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: c1cnc2ccc(Cc3nnc4ccc(-c5cn[nH]c5)nn34)cc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)n1cc(-c2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of 6-[6-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-quinoline as prepared in Example 3 (10 mg, 0.03 mmol) and DIEA (9 μL, 0.05 mmol) in DCM (2 mL) was added methane sulfonylchloride (4 μL, 0.05 mmol). The reaction was stirred at rt overnight. The reaction was concentrated in vacuo followed by purification by HPLC (5-65% CH3CN over 35 min) resulting in the title compound (3.1 mg, 31%) as a white solid. 1H-NMR (CD3OD): δ 9.06-9.00 (2H, q, J=5.3, 7.0 Hz), 8.89 (1H, s), 8.44 (1H, s), 8.29-8.10 (4H, m), 7.96-7.92 (1H, q, J=5.3, 3.0), 7.75-7.73 (1H, d, J=9.8 Hz), 4.87 (2H, s), 3.42 (3H, s). ESI-MS (m/z): Calcd. For C19H15N7O2S: 405.10; found: 406.1 (M+H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)=O>>[CH3:39][C:33]1[C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)=[CH:37][CH:36]=[C:35]([CH3:38])[N:34]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: Cc1ccc(C(=O)CBr)c(C)n1
Product: Cc1ccc(-c2csc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)c(C)n1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 83 mg (0.269 mmol) of 2-bromo-1-(2,6-dimethylpyridin-3-yl)ethanone were reacted according to the General Method 3. Yield: 13 mg (10% of theory)
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[C:15]([Cl:28])[N:14]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:17]3[CH:16]=[C:15]([Cl:28])[N:14]=[C:13]([Cl:12])[CH:18]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Clc1ccn2c(Br)cnc2c1
Reactant: CC1(C)OB(c2cc(Cl)nc(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccn2c(-c3cc(Cl)nc(Cl)c3)cnc2c1

Procedure:
3-Bromo-7-chloro-imidazo[1,2-a]pyridine (1 eq, 3.02 mmol, 700 mg) and 2,6-dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.1 eq, 3.32 mmol, 1.01 g) are dissolved in DME (4 ml) and water (1 ml) and Na2CO3 (1.5 eq, 5.53 mmol, 562 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.3 mmol, 212 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 15 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 7-chloro-3-(2,6-dichloro-pyridin-4-yl)-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=299
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46]Br)=[CH:40][CH:39]=1>CN(C=O)C>[CH3:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:24])[CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (3.20 g, 9.21 mmol) in DMF (30 mL) at 0° C. was added NaHMDS (1M in THF, 11.5 mL, 11.5 mmol). After 1 h, 4-(3-bromo-propyl)-benzoic acid methyl ester (2.84 g, 11.0 mmol) was added and the reaction mixture was stirred at 70° C. for 18 h. The DMF was removed in vacuo and the residue was dissolved in EtOAc. The organic solution was washed with water, dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography (30% EtOAc in hexanes) to yield 3.39 g of 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester. 1H NMR (CDCl3) (selected peaks) δ 7.92 (m, 2H), 7.25-7.09 (m, 7H), 3.86 (s, 3H), 3.80 (m, 1H), 3.61 (m, 1H), 3.46 (m, 1H), 2.90 (m, 1H), 2.78-2.57 (m, 4H), 2.38-2.18 (m, 2H), 0.83 (s, 9H); MS 524.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH2:26][NH:27][CH2:28][CH2:29][CH:30]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:27]1[CH2:28][CH2:29][CH:30]=[C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH2:26]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C1=C(c2ccccn2)CNCC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H](N1CCC=C(c2ccccn2)C1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.9 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.83 g, 3.3 mmol) and 1′,2′,5′,6′-tetrahydro-2,3′-bipyridine (3.51 g, 21.9 mmol) were dissolved in acetonitrile (50 ml), and lithiumperchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.87 g of the intended substance (yield 61.9%).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:10]=[N:11][C:12]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=CC=1.OS(O)(=O)=O>>[F:18][C:15]([F:16])([F:17])[C:14]1[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[N:11]=[N:10][C:9]=1[NH2:8]
Reactant: COc1ccc(CNc2nnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: Nc1nnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
(4-Methoxy-benzyl)-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridazin-3-yl]-amine (example C.26 step 8) (6.48 g, 15 mmol) was added portionwise at 5° C. to conc. H2SO4 (d 1.83, 17.0 mL, 303 mmol). The deep purple solution was stirred for 5 min at 5° C. then the cooling bath was removed and stirring was continued for further 60 min at 23° C. The mixture was poured onto ice, made alkaline with 32% NaOH-sol., saturated with solid NaCl and extracted with THF and TBME, dried the organic layer over MgSO4. Removal of the solvent in vacuum left the title compound as a light yellow solid (4.44 g, 95%), which was used without further purification. MS (ISP) 308.1 [(M+H)+]; mp 186-190° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH:22]1([N:26]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@@H:12]1[C:17]([N:29]1[CH2:30][CH2:31][CH2:32][N:26]([CH:22]2[CH2:23][CH2:24][CH2:25]2)[CH2:27][CH2:28]1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CC(O)CN1C(=O)OCc1ccccc1
Reactant: C1CC(N2CCCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C([C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1)N1CCCN(C2CCC2)CC1
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A solution of cis-D-hydroxyproline (221.1 mg, 1.687 mmol) in CH2Cl2 (15 mL) was treated with diisopropylethylamine (0.60 mL) and chlorotrimethylsilane (0.60 mL). The mixture was stirred for 2 hours, cooled to 0° C. and treated with benzyl chloroformate (0.250 mL). The reaction was stirred for 15 h at rt and then extracted with 1 N NaOH/Et2O. The aqueous layer was acidified with 1 N HCl and extracted with EtOAc. The organic layer was dried and concentrated to give 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.270 g), which was used directly in the next step. A solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.2377 g) in acetonitrile (20 mL) was treated with cyclobutyl-[1,4]diazepane dihydrochloride (0.2411 g), triethylamine (0.400 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.4780 g). After 3 h, the reaction mixture was extracted with 1 N NaOH/CH2Cl2, and the organic layer was dried and concentrated. Purification by FCC provided the desired product (0.1628 g, 24% over two steps). MS (ESI): mass calcd. for C22H31N3O4, 401.50; m/z found, 402.3 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[K+].[OH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[N:15]=NC1C=CC(S([O-])(=O)=O)=CC=1.[Na+]>O>[C:1]([C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH2:15])=[C:5]([OH:4])[CH:14]=1)#[N:2]
Reactant: [C-]#N
Reactant: O=S(=O)([O-])c1ccc(N=Nc2c(O)ccc3ccccc23)cc1
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(O)c(N)c2ccccc12
Reaction time: 48 h
Yield: 55.2 %

Procedure:
30 g (0.46 mol) of potassium cyanide are added to a solution of sodium 4-(2-hydroxy-1-naphthylazo)benzenesulfonate (10 g, 28.5 mmol) in 120 ml of water. After 2 days at 90° C., the mixture is filtered and the filtrate is saturated with carbon dioxide. The yellow precipitate is filtered off to give 2.9 g (55%) of 4-cyano-2-hydroxynaphthylamine (V).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([O:20][CH3:21])=[O:19])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1sccc1N
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A mixture of 4-cyanobenzoyl chloride (1.0500 g, 6.4 mmol), methyl 3-aminothiophenecarboxylate (1.0000 g, 6.4 mmol), and triethylamine (1 mL, 7.0 mmol) in dichloromethane was stirred at room temperature for 18 hours. The mixture was poured into a separatory funnel and washed by 1 N HCl. The organic layers were combined, dried over MgSO4, concentrated in vacuo, and chromatographed through a silica gel column to give the title compound 1.6588 g (91%). ES-MS 287 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:19][CH2:20][C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[OH:26][C:21]1([CH2:20][NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: NCC1(O)CCCC1
Agent: Cl
Product: O=C(NCC1(O)CCCC1)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 54, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 1-(aminomethyl)cyclopentanol hydrochloride (CAN 76066-27-8) as starting materials and isolated (71 mg, 63%) as a white solid; MS (ESI, m/z): 331.0 (M+H+).