Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[C-:34]#[N:35].[Na+].CC(C)=O.[CH2:41]1[CH2:45]OC[CH2:42]1>O>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([C:41]([CH3:42])([CH3:45])[C:34]#[N:35])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: C1CCOC1
Reactant: [C-]#N
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(C)=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C#N)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (0.32 g, 0.6 mmol) was suspended in water (2.5 mL) and treated with sodium cyanide (50 mg, 0.6 mmol). A solution of acetone (60 mg, 0.9 mmol) in water (0.25 mL) was added followed by THF (˜2 mL) to aid dissolution. The reaction mixture was stirred at RT for 18 hours then extracted with DCM (×2). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile (0.26 g, quant.) LCMS: RT=4.66 min, [M+H]+=435
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)=O>C(O)(=O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)=[CH:15][CH:14]=[N:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1ccsc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccsc3)ccnc12

Procedure:
As for Example 2, 3.10 g. of 3-amino-4-carboethoxypyrazole is heated at reflux temperature for 10 hours with 3.62 g. of 3-dimethylamino-1-(3-thienyl)-2-propen-1-one in 25 ml. of glacial acetic acid to give 4.40 g. of the product of the example as tan crystals, m.p. 129°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:12]([CH:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[OH:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:12]([C:13](=[O:14])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(CCC(O)c2cccnc2Oc2ccc(F)cc2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1ccc(CCC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of 353 mg (1.00 mmol) 2-(4-Fluorophenoxy)-a-[2-(4-methoxyphenyl)ethyl]-3-pyridinemethanol in 5 mL of acetone was cooled to 0° C. and treated with 1.6 mL (2.00 mmol) of 1.25 M Jones Reagent solution. The mixture was allowed to warm to rt and then quenched by the addition of 5 mL of isopropanol. The precipitate was removed by filtration, and the filtrate was evaporated and partitioned between 50 mL of saturated aqueous sodium hydrogencarbonate solution and 100 mL of EtOAc. The separated organic layer was combined with a 100 mL EtOAc backwash of the aqueous layer, washed with brine (50 mL), dried (Na2SO4), and evaporated. Trituration of the residue in hexane gave 271 mg (77% yield) of the title compound, mp 73-74° C. 1H NMR (CDCl3) d 3.03 (2H, t, J=7 Hz), 3.43 (2H, t, J=7 Hz), 3.78 (3H, s), 6.75-7.18 (9H, m), 8.17 (1H, dd, J=2.8 Hz), ), 8.25 (1H, dd, J=2.4 Hz); Anal. Calcd for C21H18NO3F.0.25 H2O; C, 70.87; H, 5.10; N, 3.94. Found: C, 70.88; H, 4.79; N, 3.79.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4]C=1C.C([O:15][C:16](=[O:18])[CH3:17])(=O)C.S(=O)(=O)(O)[OH:20]>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C>[I:1]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:17]=1[C:16]([OH:15])=[O:18])=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1I
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=Ic1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 2-iodo-4-nitrotoluene (50 g, 0.19 mol) in a mixture of glacial acetic acid (380 ml), acetic anhydride (190 ml) and concentrated sulfuric acid (112 ml) was cooled in an ice bath. Chromium trioxide (97 g, 0.57 mol) was added portionwise over 30 minutes, during which time the internal temperature rose to ca. 90° C. The resultant thick suspension was cooled in an ice bath for 30 min, then poured over ice (2 kg). When the ice had melted, the precipitate was collected by filtration, washed with methanol (800 ml) and ether (200 ml), and dried in vacuo to afford 2-iodosyl-4-nitro-benzoic acid I-1a (54.9 a, 94%).
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>C(O)C.O>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Oc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium borohydride (1.52 g) was added to a stirred solution of 3-hydroxybenzaldehyde (4.9 g) and piperidine (6.8 g) in ethanol (25 ml) cooled in an ice-water bath. The mixture was stirred at ambient temperature for 16 hours and then poured into water (250 ml) and the resulting mixture acidified with 2N hydrochloric acid. The acidified mixture was extracted with ethyl acetate and the aqueous phase was made alkaline by the addition of aqueous ammonia solution (S.G. 0.880) to yield N-3-hydroxybenzylpiperidine (m.p. 135°-139° C.) as a colourless solid.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[N:22]=[C:23]([CH3:26])[S:24][CH:25]=3)[N:13]=[C:12]2[CH3:27])[CH:5]=1.[OH-].[Na+].[C:31](N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:44][N:45](C)[OH:46].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([N:45]([O:46][CH3:31])[CH3:44])=[O:28])[C:12]([CH3:27])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([CH3:26])[S:24][CH:25]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Cl)c2=O)c1
Reactant: CN(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of 3-[5-chloro-2-methyl-4-(2-methyl-thiazol-4-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step A (125 mg, 0.30 mmol) in tetrahydrofuran (1 mL) was added 1N sodium hydroxide (1 mL) and the solution stirred at ambient temperature for eighteen hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to an orange oil used without any additional purification. To a solution of the crude acid in tetrahydrofuran (2 mL) was added 1,1′-carbonyldiimidazole (72 mg, 0.45 mmol). After stifling at ambient temperature for one hour, N,N-dimethylhydroxylamine HCl (44 mg, 0.45 mmol) and triethylamine (0.08 mL, 0.60 mmol) were added. The solution continued to stir for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the amide as a light brown oil (93 mg, 71%). MS (M+H): 449
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:13]4[S:18][C:17]([CH:19]=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.ClCCl.C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:13]4[S:18][C:17]([CH2:19][N:31]5[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
To a mixture of 2-(1H-Indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (91 mg, 0.26 mmol), 1-methylpiperazine (34 mg, 0.36 mmol) and acetic acid (15 uL) in 1,2-dichloroethane (2 mL) was added sodium triacetoxyborohydride (60 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight and then basified (NaHCO3, saturated), diluted with dichloromethane, washed with brine. Organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified using flash chromatography to give the title compound (33 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:6][C:5]=1N.N([O-])=O.[Na+].[IH:24].C(=O)(O)[O-].[Na+]>CS(C)=O>[I:24][C:5]1[CH:6]=[C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:19])([F:18])[F:1]
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(N)c2)CC1
Reactant: I
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(OC(F)(F)F)c(I)c2)CC1
Temperature: 35 °C
Reaction time: 5 h
Yield: 34.5 %

Procedure:
To a solution of 2-trifluoromethoxy-5-(4-methyl-piperazin-1-yl)-phenylamine (5.0 g, 0.018 mol), sodium nitrite (5.1 g, 0.0734 mol) in dimethyl sulfoxide (180 mL) a solution of 57% hydroiodic acid (9.6. mL, 0.0427 mol) in dimethyl sulfoxide were added dropwise at room temperature in 20 minutes. The reaction was stirred for 5 hours at 35° C., then cooled in a ice bath and sodium bicarbonate in small portion was added until basic pH. The aqueous layer was extracted with dichoromethane (3×500 mL), the organic phases washed with 10% solution of sodium bisulphite (2×500 mL) then water (1×300 mL). The organic phase was dried over anhydrous Na2SO4, the solvent evaporated under vacuum to yield the intermediate (2.4 g, 34%) as a orange solid which was used as such in the next step.
Reaction SMILES: O.C(=O)(O)[O-].[Na+].[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1.[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[CH2:19]([O:18][C:16]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Water (75 ml), followed by sodium bicarbonate (30.8 g), was added to piperidine-4-carboxylic acid (25 g) in THF (75 ml). The mixture was cooled to 0° C., and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was then stirred for 5 h at room temperature (TLC monitoring). When the conversion was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml) and washed with ethyl acetate (2×150 ml). The aqueous phase was acidified with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated in vacuo. Yield: 48.5 g (96%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]1([CH:30]([NH2:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][NH:37][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(CNC(c3ccccc3)c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A suspension (12 mL) of 1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (1.2 g), diphenylmethylamine (1.35 g) and powder molecular sieves 4A (5.0 g) in dichloromethane was stirred at room temperature for 6 hr, sodium triacetoxyborohydride (1.56 g) was added, and the mixture was further stirred at room temperature for 3 hr. The reaction mixture was filtered through celite, and the filtrate was partitioned using an ethyl acetate-saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1). The obtained oil was left standing in a freezer (temperature: −20° C.) to give the title compound as a colorless solid (yield 1.61 g, 89%).
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][NH2:4].C1CCN2C(=NCCC2)CC1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCOCC1>[CH:17]1([NH:23][C:24]([NH:4][CH2:3][C:2]([CH3:1])=[CH2:5])=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=NC1CCCCC1
Reactant: C=C(C)CN
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: C=C(C)CNC(=O)NC1CCCCC1
Temperature: 60 °C
Yield: 86.7 %

Procedure:
A solution of 2-methylallylamine (0.156 g, 2.197 mmol) in dioxane (5 mL) was treated with DBU (0.030 mL, 0.200 mmol) and cyclohexyl isocyanate (0.25 g, 1.997 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, treated with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-cyclohexyl-3-(2-methylallyl)urea (340 mg, 87%). 1H NMR (400 MHz, DMSO-d6): δ 5.80 (m, 1 H), 5.72 (d, J=8.0 Hz, 1 H), 4.72 (m, 1 H), 4.68 (m, 1 H), 3.50 (d, J=5.3 Hz, 2 H), 3.30 (m, 1 H), 1.70 (m, 2 H), 1.61 (s, 3 H), 1.60 (m, 1 H), 1.48 (m, 1 H), 1.27 (m, 2 H), 1.13 (m, 4 H); MS (ESI) m/z: 197.2 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH3:17][O:18][CH2:19][CH2:20]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:17][O:18][CH2:19][CH2:20][O:1][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: O=c1[nH]c2c([nH]c1=O)C(O)c1ccccc1-2
Reactant: COCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCCOC1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 60 %

Procedure:
A suspension of 9-hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione. 1H2O (0.50 g, 2.13 mmol) in benzene (20 ml), 2-methoxyethanol (10 ml) and p-toluensulfonic acid (20 mg) was refluxed with water separation for 20 hours. The reaction mixture was evaporated in vacuo to dryness, the residue was suspended in ethanol (10 ml) and the precipitate was filtered off and washed with ethanol and dried to give 0.48 g of the crude product, which was recrystallized from ethanol to yield 0.35 g (60%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 3.22 (s, 3H), 3.27-3.51 (m, 4H), 5.24 (s, 1H), 7.18 (t, 1H), 7.33 (t, 1H), 7.42 (d, 1H), 7.5 (d, 1H), 2.06 (s, 1H), 12.29 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.O=[C:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:26][CH:28]2[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=C1CC(C(=O)O)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1CC(Nc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (183 mg, 0.506 mmol) and 3-oxocyclobutanecarboxylic acid (63.5 mg, 0.557 mmol) in DCM (2.5 mL) and triethylamine (212 μl, 1.519 mmol) was added titanium(IV) chloride in DCM (0.759 ml, 0.759 mmol) at ambient temperature. The reaction mixture was concentrated, suspended in water, filtered, washed with water, and dried in a vacuum oven to give 3-((3-fluoro-4-(5-(1-phenyl-cyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)cyclobutanecarboxylic acid as yellow solid. MS (ESI) m/z: Calculated: 459.1; Observed: 460.4 (M++H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.O>CC(N(C)C)=O>[NH2:19][C:20]1[N:21]=[C:22]([Cl:27])[CH:23]=[C:24]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:25]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(Cl)cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 90 °C

Procedure:
356 mg (1.52 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and 73.1 mg (3.1 mmol) NaH is added. 250 mg-(1.54 mmol) 2-amino-4,6-dichloropyrimidine is then added and the solution stirred at 90° C. over night. 1 mL water is added carefully to quench all excess NaH and the mixture poured into 50 mL 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate:cyclohexane from 1:1 to 3:1). Yield: 254 mg (46%). ESI-MS m/z 361.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][CH3:9])[C:6]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:5]=2[N:4]=1.C(OC([N:23]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)=[N:24]1)=O)(C)(C)C>>[CH2:8]([N:7]1[C:6]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:5]=2[N:4]=[C:3]1[CH2:2][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[C:25]1[CH:26]=[CH:27][NH:23][N:24]=1)[CH3:9]
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ncc[nH]2)n1
Reactant: CCn1c(CCl)nc2cc(C#N)ccc21
Product: CCn1c(Cn2ccnc2-c2cc[nH]n2)nc2cc(C#N)ccc21

Procedure:
As described previously, nucleophilic displacement of 2-Chloromethyl-1-ethyl-1H-benzoimidazole-5-carbonitrile with 3-(1H-Imidazol-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester followed by usual work-up provides 1-Ethyl-2-[2-(1H-pyrazol-3-yl)-imidazol-1-ylmethyl]-1H-benzoimidazole-5-carbonitrile; 1H NMR (CD3OD) δ 7.97 (s, 1H), 7.53 (brs, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=6.3 Hz, 2H), 6.79 (br s, 1H), 6.10 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 0.88 (t, J=7.2 Hz, 3H); m/z 318 [M+l]
Reaction SMILES: C(CCCCC1C=C(/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76])[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:59])[CH3:58])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:34])=[O:33])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][S:43]([O-:46])(=[O:45])=[O:44])C=CC=1)(O)=O.[Na+:79].[Na+].[Na+].[Na+].[Na+].B([C:87]1[CH:88]=[C:89]([CH:95]=[C:96]([F:98])[CH:97]=1)[O:90][CH2:91][C:92]([OH:94])=[O:93])(O)O>>[C:92]([CH2:91][O:90][C:89]1[CH:88]=[C:87](/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76])[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:69])=[O:70])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:59])[CH3:58])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:26])([CH3:27])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:37])=[O:38])[CH:30]=[C:31]([S:32]([O-:35])(=[O:33])=[O:34])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][S:43]([O-:46])(=[O:44])=[O:45])[CH:97]=[C:96]([F:98])[CH:95]=1)([OH:94])=[O:93].[Na+:79].[Na+:79].[Na+:79].[Na+:79].[Na+:79]
Reactant: O=C(O)COc1cc(F)cc(B(O)O)c1
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cc(F)cc(OCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 36 was prepared analogously to compound 8 (Example 8), except that 2-(3-borono-5-fluorophenoxy)acetic acid is used as a starting material.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2ccsc2)c1F)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2ccsc2)c1F
Reaction time: 8 h
Yield: 38.1 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[(3-thienylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.7045 g, 1.272 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). The reaction mixture was stirred overnight. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(3-thienylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.2284 g, 38%). LCMS: (M+H)+=471.0.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[CH3:14][S:15]([O:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]2[NH:1][N:2]=[N:3][N:4]=2)[CH:7]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(-c2nnn[nH]2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
50 mg (0.28 mmol) of the compound from Example 49A are dissolved in 5 ml of dry dichloromethane, and 33 μl (0.43 mmol) of methanesulfonyl chloride and 0.06 ml (0.43 mmol) of triethylamine are added. The reaction mixture is stirred at RT for 10 h. The reaction mixture is then diluted with 10 ml of dichloromethane and washed in each case once with in each case 5 ml of water, 1 N hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate. Removal of the solvent on a rotary evaporator gives a solid which is used in the next reaction without further purification.