Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]1([CH2:21][C:22]2[NH:23][C:24](=O)[C:25]3[CH:30]=[N:29][N:28]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:26]=3[N:27]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH:15]1([CH2:21][C:22]2[NH:23][C:24](=[S:2])[C:25]3[CH:30]=[N:29][N:28]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:26]=3[N:27]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCC(CC)n1ncc2c(=O)[nH]c(CC3CCCCC3)nc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCC(CC)n1ncc2c(=S)[nH]c(CC3CCCCC3)nc21
Temperature: 0 °C

Procedure:
74 mg (0.33 mmol, 2 equiv.) of diphosphorus pentasulfide are added to a solution of 50 mg (0.17 mmol) of 6-(cyclohexylmethyl)-1-(1-ethylpropyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 3) in 1 ml of pyridine at room temperature, and the mixture is then stirred under reflux overnight. After cooling, the reaction solution is mixed with 20 ml of ice-cold 2.5% strength sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases are washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.[C:16]([Cu])#[N:17].Cl.C>CN1C(=O)CCC1.C(C(C)=O)C>[O:8]=[C:5]1[C:4]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:3]=2[C:2]([C:16]#[N:17])=[CH:7][NH:6]1
Reactant: O=c1[nH]cc(Br)c2sc3ccccc3c12
Reactant: N#C[Cu]
Agent: Cl
Solvent: CCC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1c[nH]c(=O)c2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-bromo[1]benzothieno[3,2-c]pyridin-1(2H)-one and CuCN (1.5 equiv) in NMP (0.41 M) was heated to reflux for 1.5 h. The mixture was cooled to room temperature and added to a stirring 2 N HCl solution. The mixture was stirred at room temperature for 1 h, filtered, washed with H2O and dried to give a dark grey solid. The crude product was heated to reflux with activated charcoal in methyl ethyl ketone (MEK) for 0.5 h and filtered through a short pad of silica gel, eluted with more MEK to give after concentration the title compound as a light brown solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([C:60]3[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=3)=[CH:57][CH:58]=2)[CH:53]=[CH:52]1>CN(C=O)C>[CH3:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([C:60]3[CH:61]=[C:62]([NH:66][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=3)=[CH:57][CH:58]=2)[CH:53]=[CH:52]1
Reactant: Cn1ccc2cc(-c3cccc(N)c3)ccc21
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(ccn5C)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 47.1 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-methyl-1H-indol-5-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.013 g of product in 46% yield: LCMS (ESI) m/z 425 (MH+).
Reaction SMILES: [C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:26]=C)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:43].[Na+]>CC(C)=O.O>[C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38][CH3:39])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:26]=[O:43])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1C=O)O2
Reaction time: 2 h

Procedure:
To a solution of the product from Step 1 (30 mg, 0.053 mmol) in acetone (1 ml) and water (1 mL) was added potassium osmate dehydrate (19.61 mg, 0.053 mmol). The reaction was stirred at room temperature for 10 minutes after which sodium periodate (114 mg, 0.532 mmol) was added. After stirring for 2 hours, an additional 15 mg of potassium osmate and 115 mg of sodium periodate were added. After stirring 16 hours, the reaction was filtered and the solid was washed with acetone. The filtrate was concentrated, diluted with EtOAc and washed with Na2S2O3 and NaHCO3 aq. soln. Purification by PTLC (30% EtOAc-hexane) provided the desired aldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:11][NH2:12])=[O:10])=[CH:4][CH:3]=1.[CH2:15]=[C:16]1[O:19][C:18](=[O:20])[CH2:17]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:11][NH:12][C:18](=[O:20])[CH2:17][C:16](=[O:19])[CH3:15])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C(=O)NN)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NNC(=O)C(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
2-(4-chlorophenyl)-2-methylpropanehydrazide (9.0 g, 42.5 mmol) was dissolved in dry tetrahydrofuran (100 ml), and 4-methyleneoxetan-2-one (3.9 ml, 51 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours, then solvent removed under rescued pressure, and ethyl acetate was added. The solution was passed through a 120 g silica gel column eluting with ethyl acetate, to provide clean N′-(2-(4-chlorophenyl)-2-methylpropanoyl)-3-oxobutanehydrazide (12.2 g, 97%) as a viscous golden oil. TLC Rf=0.47 using 100% ethyl acetate as eluent on a glass backed silica gel plate.
Reaction SMILES: [CH2:1]([C:12](C)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(O)(=[O:17])C>>[C:12]([OH:13])(=[O:17])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC(C)=O
Reactant: CC(=O)O
Product: CCCCCCCCCCCC(=O)O
Yield: 85 %

Procedure:
There is also reported, in Japanese Patent Application (Laid-Open) No. 175951/1989, a process for production of ketone from higher aliphatic carboxylic acid and lower aliphatic carboxylic acid using cerium oxide-on-alumina catalyst. According to the literature, methyl n-undecyl ketone, for example, is produced from lauric acid and acetic acid and the yield is 85%. In the process, however, GHSV (gas phase space velocity) is as low as 171 hr-1 ; consequently, the productivity is low and a large reactor is necessary, which are not advantageous industrially.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)Cl>[Br:29][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3
Reactant: COCCOCCn1c2ccccc2c2cc(F)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COCCOCCn1c2ccc(F)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 3-fluoro-9-(2-(2-methoxyethoxy)ethyl)-9H-carbazole (1.06 g, 3.71 mmol) in chloroform (20 ml) was added NBS (0.66 g, 3.71 mmol) batch-wise in an ice-water bath. After complete addition, the reaction mixture was allowed to warm to room temperature slowly and stirred overnight. The reaction mixture was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give compound 6 in 84% yield. 1H NMR (400 MHz, CDCl3) δ 8.09-8.06 (m, 1H), 7.63-7.60 (m, 1H), 7.52-7.50 (m, 1H), 7.36-7.26 (m, 2H), 7.21-7.16 (m, 1H), 4.40 (d, J=5.6 Hz, 2H), 3.82-3.80 (m, 2H), 3.49-3.46 (m, 2H), 3.40-3.38 (m, 2H), 3.29 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.7, 156.3, 140.1, 137.4, 128.9, 124.2, 124.2, 123.2, 122.3, 122.2, 114.4, 114.1, 111.8, 110.8, 110.0, 109.9, 106.2, 106.0. HRMS (MALDI-TOF) m/z Calcd for C17H17BrFNO2 366.0499. Found 366.0502[M]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=[O:12])C.O.[NH2:15][NH2:16]>C(O)CCC>[O:12]=[C:7]1[CH2:8][O:9][CH2:10][CH2:11][N:6]1[CH2:5][C:4]([NH:15][NH2:16])=[O:3]
Reactant: NN
Reactant: CCOC(=O)CN1CCOCC1=O
Solvent: CCCCO
Solvent: O
Product: NNC(=O)CN1CCOCC1=O
Yield: 56 %

Procedure:
As described for example 112a, (3-oxo-morpholin-4-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate at 100° C. for 6 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 56%). MS: m/e=174.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[S:11][C:10]([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:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(Cl)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:4]#[N:5]
Reactant: Nc1ccccc1
Reactant: N#Cc1c(F)cccc1F
Agent: Cl
Product: N#Cc1c(F)cccc1Nc1ccccc1

Procedure:
A mixture of 2.8 g (20 mmol) of 2,6-difluorobenzonitrile in 20 ml of aniline is refluxed for 6 hrs. The mixture is poured into diluted HCl and the acid is extracted with methylene chloride. Evaporation gives the crude product which is chromatographed on silica gel (50% hexane--CH2Cl2) to give the title compound, m.p. 97°-99° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([CH:8]3[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]3[CH3:12])(=[O:15])=[O:14])=[CH:21][CH:20]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CCN(C)C(S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(C(=O)O)CC1S(=O)(=O)c1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
[4-(4-Chloro-benzyloxy)-benzenesulfonyl-1-methylpiperidine-4-carboxylic acid was prepared starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75: 75 ml) and 10N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.9 g (50%); off white solid; MS: 426.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:14][OH:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:5][CH:14]([OH:15])[CH2:7][CH2:8]1
Reactant: CO
Reactant: O=c1ccc2ccc(Br)cc2[nH]1
Agent: Cl
Product: O=C1CCc2cc(N3CCC(O)CC3)c(Br)cc2N1

Procedure:
This 7-bromocarbostyril was dissolved in 2.5 ml of hydrogen chloride-methanol solution, and mixture was refluxed for 1 hr. The reaction mixture was concentrated and purified by a silica gel column chromatography to give 56 mg of 7-bromo-6-(4-hydroxypiperidino)-3,4-dihydrocarbostyril.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:34][CH:31]5[CH2:33][CH2:32]5)=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: NC1CC1
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: O=C(NC1CC1)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 13.4 mg (0.23 mmol) of cyclopropylamine are reacted together by general method E. 20 mg (32.2% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](=[O:32])[N:17]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:18]3=[O:23])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](=[O:32])[N:17]([CH2:24][C:25]([OH:27])=[O:26])[C:18]3=[O:23])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N(CCN3CCOCC3)S(C)(=O)=O)c2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(CCN1CCOCC1)c1cccc2c1C(=O)N(CC(=O)O)C2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl 2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (256 mg, 0.548 mmol) and TFA (844 μl, 10.95 mmol) in DCM (5 ml) was stirred at room temperature for 48 hours. The mixture was evaporated and so obtained crude of 2-(4-(N-(2-morpholinoethyl)-methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid 2,2,2-trifluoroacetic acid salt (MS/ESI+ 412 [MH]+) was used as such in the following reaction.
Reaction SMILES: [C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([Br:15])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].IC>CN(C)C=O>[C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([Br:15])[CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1c[nH]c2c(Br)cccc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)c1cn(C)c2c(Br)cccc2c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of 3-acetyl-8-bromoquinolin-4(1H)-one (5.35 g, 20.11 mmol) and K2CO3 (9.17 g, 66.3 mmol) in dry N,N-dimethylformamide (100 mL) was heated at 90° C. for 30 min. After cooling to room temperature, iodomethane (3.77 mL, 60.3 mmol) was added and the mixture was stirred again at 90° C. for 2 h. Then the reaction mixture was concentrated and diluted with water (50 mL), extracted with dichloromethane (4×50 mL), dried over sodium sulfate and absorbed onto silica gel. Purification by automatic silica gel column chromatography (Combiflash RF) eluting with ethyl acetate/hexanes (10-100%) afforded 3-acetyl-8-bromo-1-methylquinolin-4(1H)-one (3.4 g, 12.14 mmol, 60.4% yield) as a brown solid. LCMS: (M+H)+: 279.9.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([O:25][CH2:26][CH3:27])[CH3:24].[ClH:28]>CN(C=O)C.CO>[ClH:28].[O:25]([C:26]1[CH:2]=[CH:3][CH:4]=[CH:5][C:27]=1/[CH:12]=[CH:13]\[CH2:14][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:3][CH2:2]1)[C:23]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:24]=1
Reactant: CCOCC
Reactant: O=C1c2ccccc2CN1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CN1C1CCN(C/C=C\c2ccccc2Oc2ccccc2)CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of Part E compound (600 mg, 2.45 mmol) in DMF (20 mL) was added Example 2 Part A compound (2-(4-piperidinyl)-2,3-dihydro-1H-isoindol-1-one) (530 mg, 2.45 mmol) followed by anhydrous potassium carbonate (372 mg, 2.69 mmol). The reaction was stirred at 55° C. overnight. The reaction was cooled to RT. Ethyl ether (200 mL) was added to dilute the reaction, and the organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over MgSO4. Evaporation gave a crude oil. Purification was performed by flash chromatography on 100 g of silica gel, loaded and eluted with 2% methanol in dichloromethane. Pure fractions were combined and evaporated to give a colorless oil. The resulting oil was dissolved in methanol (2 mL) and HCl in ethyl ether solution (1.0 M, 3.0 mL, 3.0 mmol) was added. The HCl salt precipitated from the solution. The salt was filtered and dried at 60° C. under vacuum to give title compound (490 mg, 80%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][C:12]2[N:16]3[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[C:9]([F:24])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:25].[NH2:26][O:27][CH2:28][CH2:29][OH:30]>CO.C(Cl)Cl>[OH:30][CH2:29][CH2:28][O:27]/[N:26]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:24])[N:6]([CH3:25])[N:5]=[CH:4]4)=[CH:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: CC(=O)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Reactant: NOCCO
Solvent: CO
Solvent: ClCCl
Product: C/C(=N\OCCO)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Yield: 58.8 %

Procedure:
A solution of 1-(3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (62 mg, 0.136 mmol) and 2-(aminooxy)ethanol (intermediate S) (77 mg, 0.681 mmol) in 3 mL of MeOH and 2 mL of DCM was stirred at rt for 2 days. Solvent was evaporated to give a residue, which was purified by chromatography (DCM:MeOH 10:1) and recrystallized from MeOH to give the title compound as a white solid (32 mg, 59%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.16 (s, 1H), 8.04 (d, 1H), 7.62 (t, 2H), 7.48 (d, 1H), 4.44 (s, 2H), 4.24 (t, 2H), 4.00 (s, 3H), 3.68 (m, 2H), 2.29 (s, 3H). LCMS (method E): [MH]+=401.1, tR=5.591 min.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH2:10]([O:18][C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)=[N:23][CH:24]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:10]([O:18][C:19]1[CH:24]=[N:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])=[CH:27][CH:26]=2)=[N:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: C[Si](C)(C)CCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCC[Si](C)(C)C)cc2)nc1

Procedure:
439 mg (3 mmol) of 4-(Trimethylsilyl)butan-1-ol and 901 mg (3 mmol) of 4-(5-n-octyloxypyrimidin-2-yl)phenol are added to the solution of 0.46 ml (3 mmol) of diethyl azodicarboxylate and 790 mg (3 mmol) of triphenylphosphine in 15 ml of dry tetrahydrofuran. After a reaction time of 15 h, the solvent is distilled off and the residue is purified chromatographically (SiO2 /CH2Cl2). After recrystallization from n-hexane, 790 mg of colorless crystals are obtained.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[SH-:16].[Na+]>CO>[SH:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1
Reactant: [SH-]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1C
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(S)cc1C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of methyl 4-chloro-2-methyl-5-nitrobenzoate (1.21 g) in methanol (20 ml) was added sodium hydrosulfide (561 mg), and the mixture was refluxed with stirring for 2 hours. After the reaction was complete, the reaction solution was concentrated, and methanol was concentrated under reduced pressure. Then, to the resultant were added water and 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (1.17 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:22][CH:21]([OH:23])[CH:20]([NH2:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:25][CH2:26][C:27]#[N:28])[CH:7]=1)=[O:5])[CH3:2].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:22][CH:21]([OH:23])[CH:20]([NH:24][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:25][CH2:26][C:27]#[N:28])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(N)C(O)C3)c(F)cc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(O)C(NCc4ccccc4)C3)c(F)cc2c1=O
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 199A (0.12 g) and benzaldehyde (0.063 mL) in methanol (10 mL) and acetic acid (2 drops) was stirred for 30 minutes at 25° C., treated with sodium triacetoxyborohydride (0.196 g), stirred for 18 hours, and concentrated; and the concentrate chromatographed on silica gel with 5% methanol/dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.[H-].[Na+].Br[CH2:29][CH2:30][F:31]>CN(C=O)C>[F:31][CH2:30][CH2:29][N:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:25]=[CH:24][C:6]=3[N:7]=2)=[CH:15][N:14]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: FCCBr
Reactant: COc1ccc2nc(-c3ccc(NC(=O)OC(C)(C)C)nc3)oc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(N(CCF)C(=O)OC(C)(C)C)nc3)oc2c1
Temperature: 25 °C

Procedure:
tert-Butyl [5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-yl]carbamate (0.65 mmol) and sodium hydride (0.78 mmol) were dissolved in dry DMF (20 mL) at 0° C. After 5 min 1-bromo-2-fluoroethane (0.72 mmol) was added and the reaction was allowed to warm to r.t. After 2 h additional sodium hydride and 1-bromo-2-fluoroethane was added and the reaction mixture was stirred over night. The solvent was removed under reduced pressure and redissolved in EtOAc. Water was added and the layers separated. The aqueous layer was extracted with EtOAc (2×), dried (Na2SO4) and evaporated to give 253 mg as brown oil. The crude product was taken to the next step without further purification. MS m/z 388 (M+H).