Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(F)cc3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([N:14]1[C@H:18]([C:19]([OH:21])=[O:20])[CH2:17][S:16][CH:15]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])=[O:13])(=O)C1C=CC=CC=1>N>[OH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:15]1[N:14]([C:12](=[O:13])[CH2:11][CH2:10][SH:9])[C@H:18]([C:19]([OH:21])=[O:20])[CH2:17][S:16]1
Reactant: O=C(SCCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O)c1ccccc1
Agent: N
Product: O=C(O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCS
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4.2 g of (4R)-3-(S-benzoyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 40 ml of conc. ammonia is added and this solution is stirred at room temperature for 1 hour. Excess ammonia is removed in vacuo and the by-product, benzamide, is extracted with ethyl acetate. The aqueous layer is acidified with dilute hydrochloric acid and the produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give the titled compound, yield 2.2 g (70%), mp. 146°-148° C. (ethyl acetate), [α]D26 +176° (c=1.0, methanol).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].O1CCCC1.[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:29]=[CH:30][CH:31]=1)#[CH:25]>[Cu]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(N(CC)CC)C>[C:14]([O:13][C:12]([NH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:25]#[C:24][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:29]=[CH:30][CH:31]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cc1I
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Into the reaction flask was added tert-butyl (2-iodo-4-nitrophenyl)carbamate (2.71 g, 7.44 mmol), copper(I) iodide (0.057 g, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (0.21 g, 0.30 mmol), tetrahydrofuran (20 mL), and triethylamine (1.1 mL). It was stirred under N2 bubbling for 5 min. tert-Butyl (3-ethynylphenyl)carbamate (1.62 g, 7.44 mmol) was then added. The reaction mixture was stirred at 65° C. for 3 h. After concentration, the residue was diluted with EtOAc and water. The aqueous layer was extracted again with fresh EtOAc. The organic layers were combined and dried over Na2SO4. After filtration and concentration, the crude was purified by silica gel column chromatography to give the desired product (2.7 g, 80%). LCMS for C24H28N3O6 (M+H)+: m/z=454.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[O-]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+].C(O)C.[OH-:24].[Ca+2].[OH-:26]>S(=O)(=O)(O)O.C(O)C.O1CCCC1>[CH3:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([OH:26])[N+:3]=1[O-:24]
Reactant: Cc1cncc(Cl)n1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cncc(O)[n+]1[O-]
Temperature: 0 °C
Reaction time: 24 h

Procedure:
156 mmol (20 g) 2-chloro-6-methylpyrazine were dissolved in 80 ml 96% sulfuric acid, 222 mmol (63 g) potassium peroxodisulfate were added portion wise at 10° C. and stirring was carried out for 2 days at 10° C. and 1 day at room temperature (see also C. E. Mixan, R. Garth, J. Org. Chem. 1977, 42, 1869-1871). The reaction mixture was poured on 200 g ice, under addition of ethanol neutralization was carried out with calcium hydroxide, then filtered off and washed with ethanol. The filtrate was evaporated until dryness, the obtained solid (20 g) were refluxed in 300 ml 20% KOH solution for 3 h and after cooling pH 3 was adjusted with 20% HCl. The solution was evaporated until dryness, the residue boiled with 0.2 l ethanol under reflux for 2 h, after cooling filtered and the filtrate evaporated until dryness. After recrystallization from ethanol/tetrahydrofuran from 7.4 g raw product 2.17 g (10% yield, 93% purity) of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH:33]1[C:45]2[N:44]([C@@H:46]([CH2:57][CH2:58][C:59]([O:61][CH2:62][CH2:63]O)=[O:60])[C:47]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:48])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]=2[CH:36]=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:33]1[C:45]2[N:44]([C@@H:46]([CH2:57][CH2:58][C:59]([O:61][CH2:62][CH2:63][O:17][C:16](=[O:18])[C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:20][CH:19]=3)=[O:60])[C:47]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:48])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]=2[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(CC[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCO
Reactant: O=C(Nc1ccc(C(=O)O)cc1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CC[C@@H](C(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21)OCCOC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 63.2 %

Procedure:
To a solution of 4-(benzoyloxycarbonylamino)benzoic acid 10 (0.650 g, 2.40 mmol), EDC HCl (0.510 g, 2.65 mmol) and DMAP (0.044 g, 0.36 mmol) in CH2Cl2 (20 mL) was added (S)-1-benzyl 5-(2-hydroxyethyl) 2-(9H-carbazol-9-yl)pentanedioate 23 (0.800 g, 1.85 mmol). After the reaction mixture was refluxed for 6 h, the solution was extracted with CH2Cl2 (100 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using CH3OH:CH2Cl2 (1:99) as eluent to afford (S)-1-benzyl 5-(2-(4-(benzyloxycarbonylamino)benzoyloxy)-ethyl) 2-(9H-carbazol-9-yl)pentanedioate 24 (0.80 g, 63%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:5]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=O)[CH2:18][CH2:17]3)[CH:4]=1.[NH2:24][OH:25]>C(O)C>[OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[C:5]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[N:24][OH:25])[CH2:18][CH2:17]3)[CH:4]=1
Reactant: NO
Reactant: O=C1CCc2cc(-c3cc(CO)oc3-c3ccncc3)ccc21
Solvent: CCO
Product: OCc1cc(-c2ccc3c(c2)CCC3=NO)c(-c2ccncc2)o1
Yield: 81 %

Procedure:
The product of Step 3 (150 mg, (0.49 mmol) was heated at reflux in ethanol (10 ml) containing 50% aqueous hydroxylamine (1 ml) for 2 hours. The solution was concentrated in vacuo to an oil and purified by silica gel chromatography eluting with 1:9:90.880 ammonia:ethanol:dichloromethane to afford the title product (128 mg, 81%); MS(ES+) m/e 321 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[C:5]2[C:6](O)=[C:7]3[N:12]([C:13](=[O:14])[C:4]=2[CH:3]=1)[CH2:11][CH2:10][CH2:9][CH2:8]3.C(O)(C)(C)C>C(O)(=O)C>[OH:1][C:2]1[CH:17]=[C:16]([OH:18])[C:5]2[CH:6]=[C:7]3[N:12]([C:13](=[O:14])[C:4]=2[CH:3]=1)[CH2:11][CH2:10][CH2:9][CH2:8]3
Reactant: O=c1c2cc(O)cc(O)c2c(O)c2n1CCCC2
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=c1c2cc(O)cc(O)c2cc2n1CCCC2

Procedure:
Shake a 25° C. mixture of 1,2,3,4-tetrahydro-8,10,11-trihydroxy-6H-benzo[b]quinolizin-6-one (2.00 g), rodium-on-aluminum oxide (1.10 g), and tert.-butanol (220 ml) containing acetic acid (1 ml) under a hydrogen pressure of 60 psi. For continuous shaking of the pressurized mixture, use a Paar apparatus; and for complete reaction, shake the mixture for at least 72 hrs. Then open the vessel and filter the mixture, washing the collected catalyst with tert.-butanol. Combine and concentrate the filtrates, and partition the residue between ethyl acetate and IM sodium bicarbonate solution. Sequentially wash the separated organic layer with 0.1N hydrochloric acid solution, with water, and with brine. Filter the dried solution and concentrate it to obtain 1,2,3,4-tetrahydro-8,10-dihydroxy-6H-benzo[b]quinolizin-6-one, m.p.214°-215° C. (from EtOAc).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.O.NN>>[NH2:3][O:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(CON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CON)CC1
Yield: 85 %

Procedure:
The title compound was prepared from t-butyl 4-((1,3-dioxoisoindolin-2-yloxy)methyl)-piperidine-1-carboxylate and hydrazine monohydrate in 85% yield using the same procedure as described in the synthesis of intermediate B.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:15][C:16]([F:19])([F:18])[O-:17].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[C:3]1([CH:2]([O:17][C:16]([F:19])([F:18])[F:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [O-]C(F)(F)F
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: O
Solvent: CC#N
Product: FC(F)(F)OC(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
Bromodiphenylmethane, 20.7 g (0.084 mol), was added portionwise at 25° to a stirred solution of 0.093 mole of tris(dimethylamino)sulfonium trifluoromethoxide (prepared as in Example 1) in 75 mL of acetonitrile. The reaction mixture was stirred for 18 h and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and then distilled to give 8.34 g of trifluoromethyl diphenylmethyl ether as a colorless oil: bp 83.3° (0.7 mm); 1H NMR (CDCl3) δ6.17 ppm (s, 1H), 7.27 ppm (m, 10H); 19F NMR (CDCl3) δ-58.4 ppm (s). Anal. Calcd. for C14H11F3O: C, 66.66; H, 4.40; F, 22.60. Found: C, 66.82; H, 4.57; F, 22.39.
Reaction SMILES: C1(C)C=CC(S([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:29])(=O)=O)=CC=1.[C:31]([NH:34][CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)(=[O:33])[CH3:32].C(N(CC)CC)C>C(O)C>[C:31]([NH:34][CH:35]1[CH2:39][CH2:38][N:37]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:21][CH2:22]3)=[CH:12][C:11]=2[F:29])[CH2:36]1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(S(=O)(=O)c3ccc(C)cc3)c(F)cc2c1=O
Reactant: CC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 80.2 %

Procedure:
A mixture of ethyl 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (800 mg), 3-acetylaminopyrrolidine (300 mg), triethylamine (236 mg), and ethanol (25 ml) was refluxed for 2 hours. After evaporation of the solvent under reduced pressure, the residual crude crystals were recrystallized from ethanol-isopropyl ether to give ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (600 mg), m.p. 246°-248° C.
Reaction SMILES: [CH3:1][C:2]1[NH:19][C:18]2[C:20]3[C:3]=1[CH2:4][C@@H:5]1[C:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:12][C@@H:8]([C:9](=[O:11])[OH:10])[CH2:7][N:6]1[CH3:21].Cl.CO.[CH3:25]COCC.CCCCCC>CO>[CH3:25][O:11][C:9]([C@@H:8]1[CH:12]=[C:13]2[C@@H:5]([CH2:4][C:3]3[C:20]4[C:18](=[CH:17][CH:16]=[CH:15][C:14]2=4)[NH:19][C:2]=3[CH3:1])[N:6]([CH3:21])[CH2:7]1)=[O:10]
Reactant: Cc1[nH]c2cccc3c2c1C[C@@H]1C3=C[C@@H](C(=O)O)CN1C
Reactant: CCOCC
Agent: Cl
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 25 g 2-methyl-lysergic acid in 500 ml CH3OH are added 253 ml 3.5N HCl/CH3OH. The reaction mixture is then stirred at room temperature for 15 hours, then diluted with 500 ml CH3OH and stirred 2 days. The mixture is evaporated and partitioned between ethyl acetate and 5% K2CO3 solution. After drying and evaporating the heading compound is obtained as crystals, which are then rubbed with ether/hexane (1:1), m.p. 154° (sintering 150°).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:6]=[C:7]([CH2:9][O:10][Si](C(C)(C)C)(C)C)[N:8]=1)(=[O:3])[CH3:2].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:4]1[N:5]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nc(CO[Si](C)(C)C(C)(C)C)cn1COC(=O)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)c1nc(CO)cn1COC(=O)C(C)(C)C
Reaction time: 4 h
Yield: 106.3 %

Procedure:
2,2-Dimethylpropionic acid [2-acetyl-4-(tert-butyldimethylsilyloxymethyl)imidazol-1-yl]methylester (1.50 g) was dissolved in THF (50 mL), and at room temperature acetic acid (1 mL) and TBAF (1.0 M THF solution, 4.97 mL) were added, followed by stirring for 4 hours. The reaction solution was concentrated, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=100%→100%) using silica gel column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation) to afford the title compound (1.10 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:18][C:19]1[C:24]2[B:25]([OH:28])[O:26][CH2:27][C:23]=2[CH:22]=[C:21]([OH:29])[CH:20]=1>>[Cl:1][C:2]1[C:3]([O:29][C:21]2[CH:20]=[C:19]([CH3:18])[C:24]3[B:25]([OH:28])[O:26][CH2:27][C:23]=3[CH:22]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1cc(O)cc2c1B(O)OC2
Reactant: CC(=O)CCCOc1nc(Cl)c(Cl)cc1C#N
Product: CC(=O)CCCOc1nc(Oc2cc(C)c3c(c2)COB3O)c(Cl)cc1C#N

Procedure:
This compound was prepared from 5,6-dichloro-2-(4-oxopentyloxy)nicotinonitrile and 7-methylbenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.67-1.71 (m, 2H), 2.02 (s, 3H), 2.33 (t, J=5.4 Hz, 2H), 2.44 (s, 3H), 4.01 (t, J=5.3 Hz, 2H), 4.95 (s, 2H), 7.0 (s, 1H), 7.07 (s, 1H), 8.56 (s, 1H), 9.0 (s, 1H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.Cl.[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2[CH:52]([CH2:53][NH2:54])[CH2:51][O:50][N:49]=2)[CH:44]=[CH:45][C:46]=1[Cl:47].[OH-].[Na+]>CN(C=O)C.O>[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2[CH:52]([CH2:53][NH:54][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH2:51][O:50][N:49]=2)[CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: O=C(O)c1cccnc1
Reactant: NCC1CON=C1c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCC1CON=C1c1ccc(Cl)c(Cl)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of nicotinic acid (1 eq) in DMF (13 vol) was added HOBt (1.2 eq) and EDC.HCl (1.2 eq) at room temperature. To this mixture was added the free-based (using triethylamine (1.1 eq)) salt of C-[3-(3,4-dichloro-phenyl)-4,5-dihydro-isoxazol-4-yl]-methylamine hydrochloride (1 eq) in DMF (10 vol) and the reaction was stirred at room temperature for 18 hours. Water (100 vol) was added and the pH adjusted to 12 using 2N NaOH. The oily precipitation was extracted with EtOAc (2×67 vol). The organic phases were combined and washed with water (3×67 vol), brine (1×67 vol), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash column chromatography (eluent: EtOAc:heptane) to yield N-[3-(3,4-Dichloro-phenyl)-4,5-dihydro-isoxazol-4-ylmethyl]-nicotinamide.
Reaction SMILES: [Br-].Br[CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH:32]=O.O>C1COCC1>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[C:32]#[CH:3]
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(F)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of (bromomethyl)triphenylphosphonium bromide (3.3 g, 7.6 mmol) in THF at 0° C. was added potassium tert-butoxide (2.12 g, 18.9 mmol). The reaction was stirred for 30 minutes and a solution of 2-chloro-6-fluorobenzaldehyde (1 g, 6.31 mmol) in THF was added. The reaction was allowed to warm to room temperature overnight and water was added. The solution was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to give 1-chloro-2-ethynyl-3-fluorobenzene (41).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([C:20]5[CH:24]=[CH:23][NH:22][N:21]=5)=[CH:18][C:17]([C:25]([O:27]C)=[O:26])=[N:16][N:15]4[C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].O.Cl>CO>[NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([C:20]5[CH:24]=[CH:23][NH:22][N:21]=5)=[CH:18][C:17]([C:25]([OH:27])=[O:26])=[N:16][N:15]4[C:29]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(-c2cc[nH]n2)c2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC1(c2ccc(-c3nc4c(-c5cc[nH]n5)cc(C(=O)O)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 6 %

Procedure:
To a solution of methyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Example 56 (0.19 g, 0.41 mmol) in MeOH (5 mL) was added an aqueous NaOH solution (10% 0.65 mL, 1.64 mmol, 4.0 equiv). The resulting mixture was stirred at room temperature for 48 h. Water 10 mL) was added to the resulting mixture and the pH was adjusted to pH 4 using an aqueous 2N HCl solution. The resulting precipate was collected by filtration, and recrystallized from dimethyl sulfoxide to give 2-[4-(1-aminocyclobutyl)phenyl]-3-phenyl-8-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6-carboxylic acid (0.012 g, 6%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][OH:26])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25]=[O:26])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
Oxalyl chloride (2.2 mL, 25 mmol) was added to 75 mL of anhydrous CH2Cl2 at −78° C. DMSO (3.5 mL, 50 mmol) was then added dropwise over 5 min, and the resulting mixture was stirred for 15 min. 1-t-Butyloxycarbonyl-4-(2-hydroxyethyl)piperidine (2.29 g, 10 mmol, step A) was dissolved in 5 mL of anhydrous CH2Cl2 and added over 10 min to the above mixture. After stirring 30 min, DIEA (17.4 mL, 100 mmol) was added over 10 min. The mixture was then warmed to 0° C. and maintained at that temperature for 1 hr. After quenching with water, the reaction mixture was diluted with 75 mL of CH2Cl2 and the layers were separated. The organic phase was washed with 3×50 mL of water and dried over anhydrous magnesium sulfate. Solvent removal gave an oil, which was purified on silica gel using 20% EtOAc in hexane to give 2.05 g of the desired aldehyde which hardened overnight into an oily solid. NMR: 1.2 (m, 2H),1.5˜1.7 (m, 3H), 2.15 (d, 2H, J=3), 2.75 (m, 2H), 4.1 (m, 2H) 9.8(s, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]1[C:24]([C:25]#N)=[C:23]([CH3:27])[CH:22]=[C:21]([CH3:28])[N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.[O:30]1CCCC1>>[CH2:11]([O:18][C:19]1[C:24]([CH:25]=[O:30])=[C:23]([CH3:27])[CH:22]=[C:21]([CH3:28])[N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCOC1
Reactant: Cc1cc(C)c(C#N)c(OCc2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Product: Cc1cc(C)c(C=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3-cyano-4,6-dimethyl-1H-pyridin-2-one (4.6 g) in dichloromethane (150 mL) were added benzyl bromide (5.6 mL) and silver carbonate (26 g), and the mixture was stirred under shading for 3 hours at 50° C. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=7/1) to give 2-benzyloxy-3-cyano-4,6-dimethylpyridine (7.1 g). To diisobutylaluminum hydride (1.5 mol/L solution in toluene, 8.7 mL) was added a solution of 2-benzyloxy-3-cyano-4,6-dimethylpyridine (2.4 g) in tetrahydrofuran (4.3 mL) at 0° C., and the mixture was stirred for 4 hours at 0° C. The reaction mixture was poured into 1 mol/L hydrochloric acid solution (40 mL), and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=50/1-20/1-10/1) to give 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.90 g). To a solution of 4-ethylbromobenzene (0.044 g) in tetrahydrofuran (1.2 mL) was added tert-butyllithium (1.5 mol/L solution in hexane, 0.17 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. A solution of 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.048 g) in tetrahydrofuran (1.3 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes for 0° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethylether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=5/1) to give 2-benzyloxy-4,6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.066 g). To a solution of the obtained 2-benzyloxy-4,6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.061 g) in ethanol (3.5 mL) was added 10% palladium carbon powder (0.037 g), and the mixture was stirred for 12 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloro-methane/methanol=10/1) to give 3-(4-ethylbenzyl)-4,6-dimethyl-1H-pyridin-2-one (0.039 g).