Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH2:39][CH3:40])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
130 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 130 mg of potassium carbonate were dissolved in 1.6 ml of water and 8 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.031 ml of ethyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=O)[CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[S:33])[CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1cc(N2CCOCC2)oc2c(-c3ccccc3)cccc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: S=c1cc(N2CCOCC2)oc2c(-c3ccccc3)cccc12
Temperature: 130 °C
Yield: 135.1 %

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) (150 mg, 488 μmol), Lawesson's reagent (118 mg, 293 μmol), and toluene (2 mL). The reaction mixture was sealed, and the reaction mixture was magnetically stirred and heated via microwave irradiation to 130° C. for 20 minutes. The final mixture was poured onto water (approximately 30 mL), extracted with dichloromethane (3×5 mL), the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Purification via column chromatography (silica gel; hexanes/ethyl acetate (1:1), then 100% ethyl acetate) afforded pure 2-morpholino-8-phenyl-4H-chromene-4-thione (68) (128 mg, 81% yield).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10].[OH-].[Na+]>O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1c(O)cccc1O

Procedure:
The RFL solution is produced by mixing together at room temperature the resorcinol, formaldehyde solution, sodium hydroxide and water to produce the resorcinol-formaldehyde component, separately mixing the Gen-Tac latex and the Pliolite Latex No. 2108, also at room temperature, to produce a latex mix and mixing the two pre-mixes together at room temperature. After mixing is completed the RFL product is aged 24 hours before use and is normally employed thereafter to pre-coat the polyester web within a period of seven days after manufacture, preferably within one or two days. During storage before use it is maintained at about room temperature, protected from heat and freezing.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:6]2[S:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.O>CN(C=O)C>[CH3:1][S:2][C:5]1[C:6]2[S:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: C[S-]
Reactant: Clc1ncnc2ccsc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncnc2ccsc12
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Sodium thiomethoxide (9.1 g) was added to a solution of 4-chlorothieno[3,2-d]pyrimidine (WO9849899, example 3A; WO9924440, example 1C) (17.0 g) in DMF (100 mL). After stirring for 90 minutes the mixture was poured into water (400 mL), extracted into EtOAc, washed with water, dried (MgSO4), and the solvent removed. Purification by flash chromatography on silica eluting with DCM:EtOAc (4:1) gave the title compound as a pale yellow solid (16.5 g, 69%);
Reaction SMILES: C([O:8][C:9]1[C:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:21]=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:11]2[CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:22]2[C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:11]3[CH:10]=[C:9]([OH:8])[C:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]3[N:21]=2)=[CH:29][CH:30]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(C)S(C)(=O)=O)c(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(C)S(C)(=O)=O)c(O)cc12
Yield: 94.5 %

Procedure:
A degassed solution of 5-(benzyloxy)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxamide (3.0 g, 6.2 mmol) in THF (50 mL) was charged with 10% palladium on carbon (0.3 g). The reaction mixture was hydrogenated at room temperature under H2 balloon for 4 hours. The reaction mixture was filtered, and washed with DMF twice. The filtrate concentrated in vacuo and dried to afford pure 2-(4-fluorophenyl)-5-hydroxy-N-methyl-6-(N-methylmethylsulfonamido) pyrazolo[1,5-a]pyridine-3-carboxamide (2.3 g, yield: 94%). MS (M+H)+: 393.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)=O)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12
Reactant: CN(C)CCN
Reactant: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 85.5 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (800 mg, 2.23 mmol) in DCM (45 mL) were added N,N-dimethylethylenediamine (0.36 mL, 3.23 mmol) and triethylamine (0.63 mL, 4.5 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (730 mg, 85%). LC-MS m/z 383 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[C:19]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20].C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[C:19]([N:24]1[CH2:29][CH2:28][N:27]([C:7]2[C:6]3[CH:18]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH:8]=2)[CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(Cl)ccc1S2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(C2=Cc3cc(C)ccc3Sc3ccc(Cl)cc32)CC1

Procedure:
111.4 G. of 8-chloro-2-methyl-dibenzo[b,f]thiepin-10(11H)-one in 1 l. of absolute benzene are mixed together with 268 ml. of carbethoxypiperazine and within 1 hour at 20°-25° with a solution of 65 ml. of titanium tetrachloride in 500 ml. of absolute benzene. The resulting reaction mixture thereafter is heated under reflux conditions over a period of 20 hours. The reaction mixture is then poured over a mixture of 500 ml. of saturated aqueous sodium bicarbonate solution and 700 ml. of water with strong stirring, subsequently filtered, and washed again with chloroform. After an equilibrium is reached between both phases, the organic phase is dried and evaporated, whereby there is obtained 1-carbethoxy-4-(8-chloro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine as a dark brown viscous oil.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4]O.[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>>[CH2:1]([N:11]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: OCCCCO
Product: CCCCN1CCCC1
Yield: 96 %

Procedure:
11.7 kg of butane-1,4-diol were reacted with 7.3 kg of n-butylamine similarly to Example 1. N-(n-butyl)-pyrrolidine was obtained in 96% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[C:22]([Cl:23])[CH:21]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(Cl)c(Cl)c1

Procedure:
The title compound, MS: m/e=363.7 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,4-dichlorobenzene boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[N:14]([C:15]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[N:17]=1)[CH:13]=[CH:12][O:11]2.Cl>O1CCOCC1.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[N:14]([C:15]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:17]=1)[CH:13]=[CH:12][O:11]2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nccc(-c3c(-c4ccccc4Cl)nc4occn34)n2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Clc1ccccc1-c1nc2occn2c1-c1ccnc(NC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 167.4 %

Procedure:
The tert-butyl 4-({4-[6-(2-chlorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (1.8 g, 3.6 mmol) is dissolved in 20 ml of dioxane and treated with 40 ml of anhydrous a four molar HCl in dioxane at room temperature (RT). The reaction mixture is stirred at room temperature for three hours. The mixture is then diluted with 100 ml of ether and stirred until product separates as a solid. Solid product is filtered and washed with ether. The product is dried at high vacuum to yield 1.3 g of pale yellow solid (94%).
Reaction SMILES: Br[C:2]([C:7]1[C:8]([C:31](Br)([C:34]#[N:35])[C:32]#[N:33])=[C:9]2[C:28](=[CH:29][CH:30]=1)[C:27]1[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=1)C1C(=CC=CC=1)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1)([C:5]#[N:6])[C:3]#[N:4].C([Sn](CCCC)(CCCC)[C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:43]1[CH:44]=[CH:45][CH:46]=[C:42]1[C:7]1([CH:2]([C:3]#[N:4])[C:5]#[N:6])[CH:30]=[CH:29][C:28]2[C:27]3[C:22](=[C:23]([C:44]4[S:43][CH:42]=[CH:46][CH:45]=4)[CH:24]=[CH:25][CH:26]=3)[C:8]3[C:7](=[CH:30][CH:29]=[CH:28][CH:9]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]1[CH:31]([C:32]#[N:33])[C:34]#[N:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: N#CC(Br)(C#N)c1ccc2c(c1C(Br)(C#N)C#N)-c1ccccc1-c1ccccc1-c1ccccc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#CC(C#N)C1C2=C(C=CC1(c1cccs1)C(C#N)C#N)c1cccc(-c3cccs3)c1-c1ccccc1-c1ccccc12
Temperature: 25 °C
Yield: 203.6 %

Procedure:
Dibromotetraphenylenedimalononitrile 10 (180 mg, 0.187 mmol), 2-tributylstannylthiophene (168 mg, 0.449 mmol), and Pd(PPh3)4 (15 mg) in anhydrous toluene (8.0 mL) were heated overnight at 110° C. under nitrogen. The reaction mixture was cooled to room temperature and concentrated to dryness. The crude product was purified by column chromatography on silica gel (CHCl3/hexanes (7:3)) to give 2,8-dithien-2-yl-tetraphenylenedimalononitrile (10B) as a yellow solid (0.114 g, 70% yield). 1H NMR (CDCl3): δ 0.88-1.66 (m, 46H), 2.10 (t, 4H), 7.13 (t, 2H) 7.35 (d, 2H, J=4.5 Hz), 7.44 (d, 2H, J=3.5 Hz), 7.51 (s, 2H), 7.75 (d, 2H, J=8.0 Hz), 8.69 (s, 2H), 8.78 (s, 2H) ppm; m.p: 280-281° C.; MS(MALDI-TOF) m/z (M+): 870.8; and Elemental Analysis: C, 79.80; H, 7.74.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH:30]([NH:33][CH2:34][CH2:35]O)([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][CH2:34][NH:33][CH:30]([CH3:32])[CH3:31])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)NCCO
Product: CC(C)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{2-[(1-methylethyl)amino]ethyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(isopropylamino)ethanol following General Procedure K.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8].[NH:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:12][CH2:11]1.C(=O)([O-])O.[Na+]>C(O)C>[O:25]=[C:17]1[N:16]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:2][CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH2:15][CH2:14]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18]1
Reactant: CCOC(=O)NCCBr
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 12.94 parts of ethyl (2-bromoethyl)carbamate, 13.51 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 10.1 parts of sodium hydrogen carbonate and 160 parts of ethanol is stirred and refluxed overnight. The reaction mixture is cooled, filtered over hyflo and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane, 10% of methanol and one drop of ammonium hydroxide, as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4.4 parts of ethyl 2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethylcarbamate as a residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]=[C:5]2[CH3:22].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH:6]=[C:5]2[CH2:22][Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c(=O)c2ccc(Br)cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=c1c2ccc(Br)cc2c(CBr)cn1S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
A solution of 6-bromo-4-methyl-2-(phenylsulfonyl)isoquinolin-1(2H)-one (Example 11c, 4.55 g) in benzene (40 mL) was treated with N-bromosuccinimide (3.00 g) and benzoyl peroxide (0.291 g) under nitrogen. The resulting solution was heated at 80° C. for 3 h. The cooled reaction mixture was evaporated to dryness. Purification (SiO2 chromatography, elution with 60% DCM in isohexane) afforded the subtitle compound (3.40 g) as a white solid.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:8](=[O:10])[CH3:9])\[C:5]([OH:7])=[O:6].[BrH:11].BrBr>C(O)(=O)C.ClCCl>[Br:11][CH2:9][C:8](=[O:10])/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([OH:7])=[O:6]
Reactant: CO/N=C(/C(C)=O)C(=O)O
Reactant: Br
Agent: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CO/N=C(\C(=O)O)C(=O)CBr

Procedure:
145 g of (Z)-2-methoxyimino-3-oxo-butyric acid are dissolved in 1000 ml of alcohol-free anhydrous dichloromethane. 10 ml of 30% hydrobromic acid in glacial acetic acid are added to this solution. Then, a solution of 37.5 ml of bromine in 112.5 ml of dichloromethane are added dropwise during about 2 hours, the temperature of the mixture being held at 20°-25° C. by means of slight cooling. Now, in order to remove hydrogen bromide from the mixture, nitrogen is vigorously blown through. Subsequently, 250 g of ice, 250 ml of water and 2 l of ether are successively added. The aqueous phase is separated and discarded. The organic phase is washed with 250 ml of water and 250 ml of saturated sodium chloride solution, dried with sodium sulphate and evaporated in vacuo. There remains a brown oil which is crystallized from carbon tetrachloride. There is obtained almost colourless (Z)-4-bromo-2-methoxyimino-3-oxo-butyric acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][B:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[O:4][C:3]1([CH3:17])[CH3:16].[NH2:19][C@@H:20]([CH:28]([CH3:30])[CH3:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][CH:28]([CH3:30])[C@H:20]([NH:19][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([B:5]2[O:4][C:3]([CH3:17])([CH3:16])[C:2]([CH3:1])([CH3:18])[O:6]2)=[CH:15][CH:14]=1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.0 g, 8.1 mmol) and (S)-tert-butyl 2-amino-3-methylbutanoate (2.0 g, 9.5 mmol) in DMF (10 mL) were added HATU (6.1 g, 16 mmol) and DIEA (4.2 g, 33 mmol). The reaction mixture was stirred at rt overnight. The reaction was then quenched with water (100 mL). The resulting mixture was extracted with DCM (2×100 mL), and the organic layer was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:50)) to obtain compound 43a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H34BNO5: 404.3 (M+H). Found 404.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11]NCC)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O[C:24]([C:26]1C(C)=NC(NNCCCC)=[C:30]([N+]([O-])=O)[C:31]=1Cl)=O)C>>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]([CH3:15])=[N:5][C:6]=1[NH:11][CH2:24][CH2:26][CH2:31][CH3:30]
Reactant: CCCCNNc1nc(C)c(C(=O)OCC)c(Cl)c1[N+](=O)[O-]
Reactant: CCNNc1nc(C)c(C(=O)OCC)c(Cl)c1[N+](=O)[O-]
Product: CCCCNc1nc(C)c(C(=O)OCC)c(Cl)c1N
Yield: 72 %

Procedure:
By replacing 4-chloro-6-(1-ethyl)hydrazino-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester in Example 1 c with 6-(1-butyl)hydrazino-4-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester, 5-amino-6-butylamino-4-chloro-2-methylpyridine-3-carboxylic acid, ethyl ester is obtained. Yield 72%, b.p. 200°-210°/0.01.
Reaction SMILES: C([Mg]Br)C.[O:5]([CH2:12][C:13]#[CH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[O:5]([CH2:12][C:13]#[C:14][CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCOc1ccccc1
Reactant: C#CCC#CCBr
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC#CCC#CCOc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.81 ml (1.92 g, 14.4 mmol) of a 3N solution of ethylmagnesium bromide in ether was added dropwise under argon to a solution of 2 g (15.15 mmol) of 3-phenoxy-1-propyne (G. Pourcelot, et al., Bull. Soc. Chim., France, (1966), pp 3016-24, in 15 ml of anhydrous tetrahydrofuran. The rate of addition was adjusted to maintain the temperature at 0° C. Thereafter, the reaction mixture was stirred for 1 hour further at 0°-5° C. Then, 77 mg of cuprous cyanide was added. After stirring 20 minutes more, a solution of 1.13 g (7.22 mmol) of 1-bromo-2,5-hexadiyne in 10 ml of anhydrous tetrahydrofuran was added dropwise. The temperature was maintained at between 0°-5° C.The resulting mixture was stirred at room temperature for 3 additional hours, then poured into 60 ml of 1N sulfuric acid and ice, and the resulting solution extracted with ether (3×100 ml). The combined organic extracts were concentrated in vacuo to a small volume, and washed several times with EDTA and water, dried over sodium sulfate and evaporated. The crude material was purified by TLC using hexane:methylene chloride (80:20) as the eluant, and the product crystallized from methylene chloride-hexane, to yield 9-phenoxy-1,4,7-nonatriyne, as an oil.The product was stored in dry ice.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([CH:19]=1)[NH2:18].N1C=CC=CC=1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C(#N)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([NH:18][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH:19]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)c(Br)n2n1
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)c(Br)n2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
A solution of 5-(3-bromo-6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.165 g, 0.495 mmol) in acetonitrile (25 mL) containing pyridine (1.48 mmol) is added trimethylacetylchloride (0.495 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford 0.200 g (97%) of the title compound as a white solid: Rf 0.41 (1:1 EtOAc:hexanes); LCMS (m/z)=417.3, 419.3 [M+H]+, tR=2.76 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:10](=[O:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: COC(CN)OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cccc(CC(=O)NCC(OC)OC)c1

Procedure:
A mixture of 3-methoxyphenylacetic acid (47.7 g, 0.287 m), thionyl chloride (50 ml) and N,N-dimethylformamide (6 drops) in toluene (500 ml) was stirred for 16 hours at 25° and concentrated in vacuo to afford 3-methoxyphenylacetyl chloride. The acetyl chloride was dissolved in chloroform (100 ml) and added to a solution of aminoacetaldehyde dimethyl acetal (32.1 g, 0.306 m) and triethylamine (32.4 g, 0.320 m) in chloroform (500 ml) stirred at 5°. The mixture was stirred at 25° for 16 hours, washed with water, 1.5 N hydrochloric acid and water, dried with magnesium sulfate and concentrated in vacuo to give N-(2,2-dimethoxyethyl)-3-methoxybenzeneacetamide.