Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:30][C@H:25]1[O:26][C@@H:27]([CH3:29])[CH2:28][N:23]([C:20]2[CH:19]=[CH:18][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:31])=[O:3])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)=[CH:22][CH:21]=2)[CH2:24]1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2)C[C@H](C)O1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of 4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoic acid ethyl ester (2.46 g) and 1.0 mol/l sodium hydroxide solution (11.6 ml) in a mixed solvent of ethanol (50 ml) and tetrahydrofuran (125 ml) was refluxed for 33 hours, during which period additional 1.0 mol/l sodium hydroxide solution (24 ml) was added to the mixture. After cooling to ambient temperature, the reaction mixture was poured into cold water, and the mixture was adjusted to pH 2 with 1.0 mol/l hydrochloric acid. The resulting precipitates were filtered, washed with water and dried to give 4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoic acid (1.05 g).
Reaction SMILES: CN.C(CN)O.[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([N:23]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:19][CH2:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1>O>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](Oc2ccc3[nH]ncc3c2)CC1
Agent: CN
Solvent: O
Solvent: NCCO
Product: N[C@H]1CC[C@@H](Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 22 h
Yield: 56.2 %

Procedure:
A 30%-methylamine-ethanolamine solution (1.0 ml) was added to the cis-2-[4-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione (100 mg, 0.277 mmol) obtained in Example 380. After 22 hours, the mixture thus obtained was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol/(1%-aqueous ammonia)) to obtain cis-4-(1H-indazol-5-yloxy)cyclo-hexanamine (36 mg, 57%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[C:14]([Br:24])=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccnc(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Temperature: -18 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
A solution of crude (2-amino-pyridin-4-ylmethyl)-carbamic acid tertbutyl ester (17.55 g) in DMF (50 mL) was cooled to −18° C. (ice/MeOH bath), treated with NBS (12.6 g, 70.7 mmol), and stirred at −18° C. for 1 h. The reaction mixture was diluted in AcOEt (800 mL) and washed with water (2×100 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/DCM/TBME 100:10:1→TBME 100%) to yield the title compound (13.95 g, 46.2 mmol, 50% for 2 steps) as a pale yellow solid. MS: 303 [M+1]+ HPLC: AtRet=1.10; TLC: RF 0.18 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: C([Al:5]([CH2:10][CH:11]([CH3:13])[CH3:12])CC(C)C)C(C)C.[C:14]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])([CH3:16])[CH3:15]>CCCCC>[C:25]([C:20]1[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[O:29][Al:5]([O:29][C:19]1[C:20]([C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH:11]([CH3:12])[CH3:13])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: CCCCC
Product: Cc1cc(C(C)(C)C)c(O[Al](CC(C)C)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1

Procedure:
Using a 250 ml balloon flask disposed in an argon atmosphere and provided with a magnetic stirrer rod, a solution of 0.493 g of triisobutylaluminium in 20 ml of pentane is introduced, and then a solution of 1.095 g of 2,6-di-t-butyl-4-methylphenol in 30 ml of pentane is introduced dropwise with agitation and at ambient temperature. After about 30 hours of reaction the pentane is evaporated under vacuum and analysis of the white solid remaining indicates that it is formed essentially by bis-(2,6-di-t-butyl-4-methylphenoxy)-isobutylaluminium. That compound is put back into solution in 5 ml of heptane.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[N:10]([C:11](=[O:33])[C@@H:12]([NH:22][C:23](OCC2C=CC=CC=2)=[O:24])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9][CH2:8][N:7]([CH2:34][C:35]([OH:37])=[O:36])[C:6]1=[O:38].C(=O)([O-])O.[Na+].O=C1N(O[C:55](=[O:66])[C:56]2[CH:61]=[CH:60][C:59]([NH:62][C:63]([NH2:65])=[NH:64])=[CH:58][CH:57]=2)C(=O)C2C1C1CC2C=C1.[ClH:69]>CO.[H][H].O1CCOCC1.O>[ClH:69].[NH:62]([C:59]1[CH:60]=[CH:61][C:56]([C:23]([NH:22][C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:11]([N:10]2[CH2:9][CH2:8][N:7]([CH2:34][C:35]([OH:37])=[O:36])[C:6](=[O:38])[C@@H:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:55](=[O:66])[C:56]2[CH:57]=[CH:58][C:59]([NH:62][C:63]([NH2:65])=[NH:64])=[CH:60][CH:61]=2)=[O:33])=[O:24])=[CH:57][CH:58]=1)[C:63]([NH2:65])=[NH:64]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCN)cc1
Reactant: [H][H]
Reactant: N=C(N)Nc1ccc(C(=O)ON2C(=O)C3C4C=CC(C4)C3C2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(C[C@H](NC(=O)c2ccc(NC(=N)N)cc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCNC(=O)c2ccc(NC(=N)N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 ml of methanol was dissolved 250 mg of (S,S)-3-(3-aminopropyl)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-2-oxopiperazine-1-acetic acid produced in Reference Example 36. To the solution was added 100 mg of 10% Pd--C, and the mixture was stirred for one hour at room temperature in hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to leave an oily substance. The oily substance was dissolved in a mixture of 10 ml of dioxane and 10 ml of water. To the solution were added 210 mg of sodium hydrogencarbonate and 450 mg of 4-guanidinobenzoic acid 3,5-dioxo-4-azatricyclo[5,2,1,0 2,6]deca-8-en-4-ylester. The mixture was stirred for one hour at room temperature. The pH of the reaction mixture was adjusted to 3 with 1N HCl, then dioxane was distilled off under reduced pressure. The remaining aqueous solution was subjected to a CHP-20 column. The fraction eluted with 10% acetonitrile/water was freeze-dried to afford 130 mg of the title compound as an amorphous powdery product.
Reaction SMILES: [CH3:1][N:2]1C[CH2:6][CH2:5][CH2:4][C:3]1=O.Cl.[C:10](=[O:13])([O-])[O-:11].[Na+].[Na+].[Br:16][C:17]1[C:18](F)=[CH:19][CH:20]=[C:21]([CH:24]=1)[CH:22]=[O:23]>[OH-].[Na+].CS(C)=O.C(OC(C)C)(C)C>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([N:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:10]([OH:11])=[O:13])[CH3:1])=[C:21]([CH:22]=[O:23])[CH:24]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C([O-])[O-]
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(C)OC(C)C
Product: CN(CCCCC(=O)O)c1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 57.4 %

Procedure:
A suspension of 1-methyl-2-piperidone (5.0 g) in 4N sodium hydroxide (22.1 ml) was heated and stirred for 8.5 hours under reflux. After the suspension was cooled to room temperature, conc. hydrochloric acid (7.4 ml) was added. A solution of sodium carbonate (9.4 g) and 5-bromo-4-fluorobenzaldehyde (4.5 g) in DMSO (74 ml) was added, and the resulting mixture was stirred for 1.5 hours under reflux. The mixture was allowed to cool to room temperature, and adjusted to pH of about 3.3 with 6N hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The precipitated crystal obtained was redissolved in isopropylether [IPE] (20 ml) under heating, and the solution was allowed to cool to room temperature, and stirred for 1 hour at 0° C. The crystal obtained was filtered and washed with IPE. Drying under reduced pressure (40° C., 1 hour) gave yellow crystal of 5-(4-bromo-2-formyl-N-methylanilino)pentanoic acid (4.0 g, yield 57%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:16])[CH2:10]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH3:16])[CH2:10][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(CN1CCOCC1)NC(=O)OC(C)(C)C
Yield: 62 %

Procedure:
To a solution of methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester (23 mmol) in CH3CN (20 mL) was added morpholine (28 mmol) and K2CO3 (23 mmol) at room temperature. The reaction mixture was brought to 50° C. and kept at the same temperature overnight. The reaction mixture was cooled and solvent was removed under reduced pressure, and the residue was treated with CH2Cl2 (50 mL) and H2O (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4. Solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate) to afford (1-methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-butyl ester as viscous liquid, yield: 62%. MS (M+H)=245.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH3:10])[N:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[N:20]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[N:24][C:19]2=[N:18][CH:17]=1)CCC>>[CH2:9]([O:8][C:4]1[N:3]=[C:2]([C:16]2[N:20]3[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[N:24][C:19]3=[N:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:10]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: CCOc1cccc(Br)n1
Product: CCOc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 25.8 %

Procedure:
2-Bromo-6-ethoxypyridine (0.30 g, 1.48 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-40%) and trituration with isohexane gave 3-(6-ethoxypyridin-2-yl)-7-(trifluoromethyl)imidazo[1,2-α]pyrimidine (90 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 1.50 (3H, t, J 7), 4.45 (2H, quartet, J 7), 6.73 (1H, d, J 8), 7.34 (1H, d, J 7), 7.41 (1H, d, J 7), 7.71 (1H, dd, J 8 and 7), 8.46 (1H, s), 10.31 (1H, d, J 7); m/z (ES+) 309 (M++H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:28])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:11][C:10]2([CH3:27])[CH3:26])=[O:4].Cl>CO.O1CCCC1.[OH-].[Na+].O>[F:28][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:16]=1)[CH2:11][C:10]2([CH3:27])[CH3:26]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCCC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)O)cc(F)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 93.8 %

Procedure:
A mixture of afford 6-fluoro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.32 g, 0.81 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-fluoro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.28 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=369.3.
Reaction SMILES: C[O:2]/[CH:3]=[CH:4]/[C:5]([CH3:14])([CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].C(O)=O.OC1C2NC(=O)SC=2C([C@@H](O)CNCCC(C)(C)CCCCCCN2CCC3(OCCN(C(C4N=C(C(C)C)SC=4)=O)C3)CC2)=CC=1.C(N(CC)CC)C.[CH3:72][S:73](Cl)(=[O:75])=[O:74]>ClCCl>[CH3:72][S:73]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:14])([CH3:13])[CH2:4][CH:3]=[O:2])(=[O:75])=[O:74]
Reactant: CS(=O)(=O)Cl
Reactant: CO/C=C/C(C)(C)CCCCCCO
Agent: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCC(C)(C)CCNC[C@H](O)c4ccc(O)c5[nH]c(=O)sc45)CC3)C2)cs1
Solvent: O=CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC=O)CCCCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of (E)-9-methoxy-7,7-dimethylnon-8-en-1-ol and (Z)-9-methoxy-7,7-dimethylnon-8-en-1-ol (example 279, step d) (1.6 g) was dissolved in dichloromethane (15 mL) and triethylamine (1.33 mL) was added then the mixture was cooled to 0° C. in an ice bath under argon. Methanesulfonyl chloride (0.68 mL) was added dropwise over 5 minutes and the reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 1 hour. The reaction mixture was washed with brine (2×30 mL), dried over magnesium sulfate, filtered and evaporated under vacuum to give the crude product. Purification was by silica gel chromatography, eluting with 0-100% ethyl acetate in cyclohexane to afford the subtitled compound as a colourless oil. Yield 1.2 g.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:13])O[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14]1[C@@H:17](C(O)=O)[NH:16][CH2:15]1>CN(C)C=O.C(O)(=O)C>[F:1][C:2]1[C:7]2[C:8](=[O:13])[N:16]3[CH2:17][CH2:14][C@H:15]3[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1Nc2cccc(F)c2C(=O)N2CC[C@@H]12
Yield: 49.4 %

Procedure:
A solution of 10 g (55.2 mmol) of 5-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione and 5.66 g (55.2 mmol) of L-azetidine-2-carboxylic acid in 75 ml of dimethylformamide and 15 ml of acetic acid was stirred at 120° for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 6 g (42%) of (S)-5-fluoro-1,2,4,9,10,10a-hexahydroazeto[2,1-c][1,4]benzodiazepine-4,10-dione as beige needles of m.p. 232°-233.5°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12)[NH2:5].[C:19]1([CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:29]([NH:28][C:26](=[O:27])[CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[S:30])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (0.105 g, 0.403 mmol) in THF (1 mL) was added 2-phenylethanoyl isothiocyanate (0.257 g, 1.45 mmol; prepared according to the procedure described by J. Org. Chem. 1964, 29, 1115-1119). The reaction was stirred for 4 hours at room temperature. The reaction mixture was partially purified by Biotage Flash 40 silica gel chromatography, eluting with a gradient of 10-50% EtOAc in hexanes. The product was further purified by preparative TLC (10% MeOH in CH2Cl2). Yield: 18 mg (9%). 1H NMR (400 MHz, CDCl3) δ 12.55 (s, 1H), 9.00 (s, 1H), 8.53 (d, J=5 Hz, 1H), 7.94 (m, 1H), 7.75 (d, J=5 Hz, 1H), 7.58 (d, J=5 Hz, 1H), 7.08-7.50 (m, 7H), 6.54 (d, J=5 Hz, 1H), 3.75 (s, 2H). LRMS (APCI neg) m/e 436 (M−1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:25])=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=2)[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][C:11](F)=[CH:10][C:9]=1[F:16].[CH3:26][O-:27].[Na+].[O:29]1[CH2:33]CCC1>O>[F:16][C:9]1[CH:10]=[C:11]([O:27][CH3:26])[CH:12]=[C:13]([F:14])[C:8]=1[C:7]1[C:6]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=2)=[C:5]([CH3:25])[N:4]=[N:3][C:2]=1[O:29][CH3:33]
Reactant: C[O-]
Reactant: C#Cc1ccc(-c2c(C)nnc(Cl)c2-c2c(F)cc(F)cc2F)cc1
Reactant: C1CCOC1
Agent: [Na+]
Solvent: O
Product: C#Cc1ccc(-c2c(C)nnc(OC)c2-c2c(F)cc(OC)cc2F)cc1
Temperature: 55 °C

Procedure:
A mixture of 3-chloro-5-(4-ethynylphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (Compound No. 2, 1.0 g), sodium methoxide (30% solution in methanol, 1.78 g) and 20 ml of tetrahydrofuran is heated to 55° C. for 2 h. Subsequently the reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The combined organic layer is washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by chromatography on silica gel, using a mixture of heptane/ethyl acetate 2:1 as eluent to obtain 4-(2,6-difluoro-4-methoxyphenyl)-5-(4-ethynylphenyl)-3-methoxy-6-methylpyridazine (Compound No. 4) as colourless crystals, m.p. 192-193° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[CH:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH3:33])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[C:29]([F:31])[C:26]([C:27]#[N:28])=[C:25]([Cl:32])[CH:24]=2)=[N:19]1.CN(C=O)C>C(Cl)Cl>[Cl:32][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[CH:10]=[CH:11][N:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:8]=3)=[O:14])[CH3:33])[N:19]=2)[CH:30]=[C:29]([F:31])[C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cn1cc(-n2ccc(C(=O)O)n2)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2cnn(C)c2)n1
Yield: 41.2 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1′-methyl-1′H-[1,4′-bipyrazole]-3-carboxylic acid (0.861 mmol, 165 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.718 mmol, 200 mg) and using DMF (2 ml) as the solvent. DCM was added and the reaction mixture was evaporated. The residue was purified by flash chromatography. The purified product was dissolved in DCM and washed three times with 1 M NaHCO3. The combined organics were evaporated. 134 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.15 (d, 3H), 3.88 (s, 3H), 4.28-4.42 (m, 2H), 4.42-4.52 (m, 1H), 6.75 (d, 1H), 7.01 (d, 1H), 7.81-7.88 (m, 3H), 7.94 (s, 1H), 8.13-8.17 (m, 2H), 8.18 (s, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:25][C:26](=[O:28])[CH3:27])[C:7](=[O:24])[NH:8][C:9]1[C:14]([I:15])=[C:13]([C:16](Cl)=[O:17])[C:12]([I:19])=[C:11]([C:20]([Cl:22])=[O:21])[C:10]=1[I:23])(=[O:3])[CH3:2].[CH3:29][C:30]1([CH3:40])[O:34][CH:33]([CH2:35][NH:36][CH2:37][CH2:38][OH:39])[CH2:32][O:31]1.C(N(CC)CC)C>CC(N(C)C)=O>[C:1]([O:4][CH2:5][CH:6]([O:25][C:26](=[O:28])[CH3:27])[C:7](=[O:24])[NH:8][C:9]1[C:14]([I:15])=[C:13]([C:16](=[O:17])[N:36]([CH2:35][CH:33]2[CH2:32][O:31][C:30]([CH3:40])([CH3:29])[O:34]2)[CH2:37][CH2:38][OH:39])[C:12]([I:19])=[C:11]([C:20]([Cl:22])=[O:21])[C:10]=1[I:23])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(OC(C)=O)C(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: CC1(C)OCC(CNCCO)O1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(OC(C)=O)C(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)N(CCO)CC2COC(C)(C)O2)c1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.5 %

Procedure:
To a ice cooled solution of acetic acid 2-acetoxy-1-(3,5-bis-chlorocarbonyl-2,4,6-triiodo-phenylcarbamoyl)-ethyl ester (20 g, 0.026 mol) in anhydrous DMAC (20 ml) were added dropwise a solution of 2-[(2,2-Dimethyl-[1,3]dioxolan-4-yl-methyl)-amino]-ethanol (4.6 g, 0.026 mol) in DMAC (20 mL) followed by triethylamine (˜3 g). The mixture was stirred at room temperature for 24 h and then poured over icewater (0.75 liter). A white precipitate formed. This was collected and washed with cold water. The filter cake was then dissolved in ethyl acetate and washed with brine. The organics were collected, dried over MgSO4, filtered and evaporated to dryness. The product was purified by silica column chromatography eluting with Petroleum ether/ethyl acetate. Two peaks closely eluting at 80% ethyl acetate were analysed by NMR and mass spec, and show to both contain the desired material. These were combined post analysis to give the desired product (10 mmol, Yield=38%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.Cl.[O-:12][Mn](=O)(=O)=O.[K+].[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>>[CH2:18]([N:20]1[C:21](=[O:22])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:9](=[O:12])[S:10]1)[CH3:19]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(N=C=S)cc1
Reactant: CCN=C=O
Agent: Cl
Agent: [K+]
Product: CCn1sc(=O)n(-c2ccc(C)cc2)c1=O

Procedure:
Reagents: 4-Methylphenyl isothiocyanate (0.88 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), ethyl isocyanate (0.51 ml, 6.5 mmol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[C:13]3[C:9]([CH2:10][C:11](=[O:15])[NH:12]3)=[CH:8][CH:7]=2)=[CH:2]1.[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.N1CCCCC1>C(O)C>[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:7][CH:8]=2)[NH:12][C:11]1=[O:15]
Reactant: O=Cc1ccccc1O
Reactant: O=C1Cc2ccc(-c3ccsc3)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(-c3ccsc3)ccc2C1=Cc1ccccc1O
Yield: 68.9 %

Procedure:
A mixture of 6-thiophen-3-yl-1,3-dihydroindol-2-one (100 mg, 0.5 mmol), 2-hyroxy-benzaldehyde (60 mg, 0.5 mmol) and piperidine (0.23 mL) in ethanol (4 mL) was stirred at reflux overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 110 mg (69%) of 3-(2-hydroxybenzylidene)-6-thiophen-3-yl-1,3-dihydroindol-2-one as yellow-red crystals.