Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][N:33]1[C:32]2[C:38]([CH3:40])=[CH:39][C:29]([NH:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:30][C:31]=2[O:35][C:34]1=[O:36]
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1)C(=O)N2
Temperature: 150 °C

Procedure:
90 mg (0.33 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90 mg (0.31 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.87 mmol) DIPEA were combined in 1.5 mL DMF and stirred at 150° C. After the reaction had ended the reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and dried.
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([O:24]CC)=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl.O>O1CCCC1.CO.O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([OH:24])=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccc3)nc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(C(=O)O)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
0.63 g (1.80 mmol) of ethyl 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were dissolved in 100 mL of a mixture tetrahydrofuran/methanol/water 8/1/1 and 0.19 g (4.53 mmol) of lithium hydroxide hydrate were added. The solution was stirred at 60° C. for 1.5 hours. The mixture was then cooled to room temperature and 1N HCl added until neutral pH. Water was added and the resulting precipitate collected by filtration (87% yield).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:26])[C@@H:11]([NH:22][C:23](=[O:25])[CH3:24])[CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35](O)=[O:36])=[CH:29][CH:28]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:2]([O:9][C:10](=[O:26])[C@@H:11]([NH:22][C:23](=[O:25])[CH3:24])[CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:35](=[O:36])[CH:34]=[CH:33][C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[CH2:17]1)=[O:15])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C=Cc1ccncc1
Reactant: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCNC1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)C=Cc2ccncc2)C1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of N-[(R)-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine benzyl ester hydrochloride (231 mg), 3-(4-pyridyl)-2-propenoic acid (82 mg) and 1-hydroxybenzotriazole (81 mg) in dimethylformamide (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.11 ml) at 0° C. The mixture was stirred for 2 hours at room temperature, then poured into ice water-ethyl acetate. The separated organic layer was washed with water, aqueous saturated NaHCO3, brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with CHCl3—MeOH (96:4) to give N-[(R)-1-[3-(4-pyridyl)-2-propenoyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine benzyl ester (263 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([Cl:23])[C:14]=1[N+:24]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.N>C(O)C>[NH2:24][C:14]1[C:15]([Cl:23])=[N:16][C:17]2[C:22]([C:13]=1[NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNc1c(N)c(Cl)nc2ccccc12
Yield: 61.1 %

Procedure:
0.27 g (0.70 mmol) of 4-[3-(tert-Butoxycarbonylamino)propylamino]-2-chloro-3-nitroquinoline was dissolved in 7 ml of ethanol. Tin chloride [II] dihydrate (0.55 g, 2.45 mmol) was added thereto and the mixture was refluxed under heating for 1 hour. After cooling, the reaction mixture was poured into 2N aqueous ammonia. The resulting solution was extracted twice with chloroform, thereafter the extract was washed (brine), and dried (Na2SO4). The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 (v/v)) to obtain 0.15 g (0.428 mmol) of 3-amino-4-[3-(tert-butoxycarbonylamino)propylamino]-2-chloro-quinoline shown below as pale yellow crystals. ##STR35## Its spectroscopic data are as follows: 1H-NMR (CDCl3) δ (ppm) : 1.49 (9H, s), 1.73 (2H, m), 3.29 (2H, t, J=6.2 Hz), 3.35 (2H, q, J=6.0 Hz), 4.28 (2H, br), 4.60 (1H, br), 4.75 (1H, br), 7.44 (2H, m), 7.87 (1H, d, J=7.6 Hz), 7.94 (1H, d, J=7.6 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Clc1cccc(-c2cncc(Br)c2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cccc(Cl)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-chloro-phenyl)-pyridine.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=O)[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1.[ClH:30]>ClCCl.O1CCOCC1>[ClH:30].[C:10]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=[CH:14][C:13]([CH:16]([CH2:22][C:21]2[NH:9][C:4]3[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: Nc1ccc(I)cc1N
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CC(Cc1nc2ccc(I)cc2[nH]1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-1,2-phenylenediamine (0.47 g) and 3-(biphenyl-4-yl)glutaric anhydride (0.53 g) were dissolved in dichloromethane (5 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.74 g) as light brown solid. This solid was dissolved in 1,4-dioxane (1 ml) with heating. 4M HCl in 1,4-dioxane (3 ml) was added and the solution was heated to reflux for 1 h. All volatiles were removed at the water aspirator and the amorphous residue is fractionally crystallised to provide 3-(biphenyl-4-yl)-4-(5-iodo-2-benzimidazolyl)butanoic acid HCl (0.43 g) as off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:31])[CH:11]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH:28]3[CH2:30][CH2:29]3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:7][CH:8]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>CN(C=O)C.O>[CH:28]1([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH:11]([O:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]4[N:32]=[N:33][NH:34][N:2]=4)=[CH:8][N:7]=3)=[O:31])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:30][CH2:29]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(NC(=O)C(OC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(-c2nn[nH]n2)cn1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 110 °C

Procedure:
The mixture of N-(5-cyano-2-pyridyl)-2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetamide (0.1 g, 0.22 mmol), sodium azide (0.03 g, 0.453 mmol) and ammonium chloride (0.024 g, 0.453 mmol) in DMF (8 mL) was heated at 110° C. for 16 h. After completion, reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (2×50 mL), combined organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Crude compound was purified by LCMS purification to afford title compound. (0.020 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=CCCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCC(O)c1ccccc1

Procedure:
By the general method described in Step 7 of Example 1, 6-(3-nitroquinolin-4-ylamino)hexanal (9.9 g, 34.5 mmol) was reacted with phenylmagnesium bromide (36.2 mL of a 1 M solution in THF, 36.2 mmol) to provide 6-(3-nitroquinolin-4-ylamino)-1-phenylhexan-1-ol (4.4 g) as a bright yellow solid after chromatography on silica gel (elution with ethyl acetate and hexane, 1:1, volume:volume).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].C(O)(=[O:12])C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([OH:12])[CH2:4][O:5][CH2:6][CH2:7][OH:8]
Reactant: COCCOCCO
Reactant: C=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(O)COCCO

Procedure:
682 grams Methyl Carbitol (diethylene glycol monomethyl ether, Union Carbide) were azeotropically esterified with 598.9 grams acrylic acid in 272 grams toluene in the presence of 22.8 grams p-toluenesulfonic acid and inhibitors until no more water was collected. Conditions were 95°-98° C., nitrogen sparge in vacuo. On completion, the product was washed and neutralized with sodium carbonate. 1,300 ppm p-methoxyphenol were added and solvent removed at 80° C. at maximum vacuum with an air sparge. Filter aid was added and the product filtered to clarity at 50° C. The final product was a clear, light yellow liquid, viscosity 6 cps with a Gardner 1 color.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:34]([NH2:36])=[O:35])[CH:24]=[C:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:40][CH2:39]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: CN1CCN(CCCS(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)CC1
Yield: 71.9 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (65 mg, 0.14 mmol) and 1-methylpiperazine (70.5 mg, 0.7 mmol) were allowed to react in the presence of K2CO3 (77.3 mg, 0.56 mmol) and NaI (Cat. 2.13 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (52.7 mg, 71%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([O:34]C(=O)C)[CH2:21][NH:22][CH:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:34])[CH2:21][NH:22][CH:23]([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(C)NCC(OC(C)=O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(CC(C)NCC(O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Yield: 79.7 %

Procedure:
0.5 g of 8-benzyloxy-5-{1-acetoxy-2-[N-(2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril (α-isomer) hydrochloride.methanol is dissolved in a mixture of 10 ml of methanol and 2 ml of water, and 180 mg of triethylamine are added thereto. The mixture is refluxed for 5 hours under stirring. The mixture is concentrated under reduced pressure to remove solvent. The residue is extracted with chloroform, and the extract is washed with 5% hydrochloric acid. The chloroform solution is dried and concentrated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of isopropanol and ether. 365 mg of 8-benzyloxy-5-{1-hydroxy-2-[N-(2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril (α-isomer) hydrochloride are obtained. Yield: 86.1%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=O)[CH2:11][CH2:12][OH:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: O=C(CCO)Nc1cc(F)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCNc1cc(F)ccc1F

Procedure:
A solution of 0.185 g of N-(2,5-difluorophenyl)-3-hydroxypropionamide in 3 ml of tetrahydrofuran is added dropwise at room temperature to a suspension of 0.074 g of lithium aluminium hydride in 6 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred at room temperature over 12 hours and subsequently hydrolysed with 0.13 ml of water followed by 0.13 ml of 1M NaOH. The mixture is filtered through Hyflo and the filtrate is washed with 10 ml of brine. The organic phase is dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow liquid from the residue by means of flash chromatography (SiO2 60F). Rf=0.28 (1:1 EtOAc-heptane); Rt=3.39.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH2:7][CH2:6]1)C.[CH2:15]([S:22][C:23](=[NH:25])[NH2:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([S:22][C:23]1[N:24]=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[C:10]=2[N:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC1=CCCC(=CN(C)C)C1=O
Reactant: N=C(N)SCc1ccccc1
Solvent: CN(C)C=O
Product: CCOC1=CCCc2cnc(SCc3ccccc3)nc21
Temperature: 95 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of 2.0 g (0.01 mol) of 6-[(dimethylamino)methylene]-2-ethoxycyclohex-2-en-1-one in 20 mL of dimethylformamide 2.6 g of S-benzylisothiourea (2 eq. mol.) were added. The reaction mixture was stirred at 95° C. for 4 hours. The solvent was then evaporated under reduced pressure and the crude purified by chromatography on a silica gel column (eluant dichloromethane/methanol 9/1) leading 1.5 g (50% yield) of the title compound.
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8](SC)=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.CN(C)C([C:36](OCC)=[O:37])=CC=[N+](C)C.CC[O-].[Na+].COCC(C1C=CC=CC=1)=O>C(O)C>[CH3:18][N:17]([CH3:19])[C:11](=[CH:10][CH:9]=[C:8]([O:37][CH3:36])[C:7](=[O:22])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Agent: CC[O-]
Agent: COCC(=O)c1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(OC)C(=O)c1ccccc1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino2,4-hexadienoate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (11.4 g), a 2M ethanolic solution of sodium ethylate (20 cc) and α-methoxyacetophenone (6 g) in ethanol (50 cc). After purification by chromatography on a silica column with a mixture of dicholoromethane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-5-methoxy-6-oxo-6-phenyl-2,4-hexadienoate (8.1 g) is obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(OCC)(=O)C.CO>C(O)C>[N:27]1([CH2:26][C@@H:22]2[CH2:23][CH2:24][CH2:25][N:21]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: C1CN[C@H](CN2CCOCC2)C1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1Nc2cccnc2N(C(=O)CN2CCC[C@H]2CN2CCOCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 31 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (S)-4-[(2-pyrrolidinyl)methyl]morpholine to give colorless crystals, mp. 202-203° C. (ethyl acetate/methanol 1:1 v/v); [α]D20 =-2.93° C. (ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2].Cl.[NH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(O)C>[OH:21][NH:20][C:1](=[NH:2])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCn1ncc2c(C#N)cccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1ncc2c(C(=N)NO)cccc21
Yield: 70.4 %

Procedure:
Ethyl 3-(4-cyano-1H-indazol-1-yl)propanoate (D96) (0.95 g, 3.91 mmol), hydroxylamine hydrochloride (1.086 g, 15.62 mmol), and sodium bicarbonate (3.28 g, 39.1 mmol), were heated in ethanol (20 ml) at 50° C. for 3 hours. The mixture was filtered and evaporated to give the title compound (760 mg) as a white powder. MS (ES): C13H16N4O3 requires 276; found (MH+) 277.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[C:8]([C:15]([OH:17])=O)=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:20])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[C:8]([C:15]([NH:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:17])=[CH:9][N:10]([CH3:14])[C:11](=[O:13])[CH:12]=2)=[C:4]([F:20])[CH:3]=1
Reactant: NCCCO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(Br)cc2F)cc1=O
Yield: 71 %

Procedure:
4-(4-Bromo-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in a mixture of anhydrous THF and anhydrous DMF and treated with 3-amino-1-propanol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2) to give 4-(4-bromo-2-fluoroanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (71%) as a cream solid; m.p. (EtOAc/Hexane) 167-170° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.10 (br s, 1H), 8.40 (t, J=5.3 Hz, 1H), 8.24 (s, 1H), 7.69-7.64 (m, 1H), 7.48-7.40 (m, 2H), 5.56 (s, 1H), 4.48 (t, J=5.1 Hz, 1H), 3.47 (dd, J=11.5, 6.2 Hz, 2H), 3.37 (s, 3H), 3.27 (dd, J=12.7, 6.9 Hz, 2H), 1.67 (p, J=6.7 Hz, 2H). LCMS (ACPI−) 398 (85%), 396 (100%). Anal. Calcd for C16H17BrFN3O3: C, 48.3; H, 4.3; N, 10.6. Found C, 48.2; H, 4.2; N, 10.5.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1)(=O)=O.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC([O-])(C)C.[Na+].O>CS(C)=O.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>[CH:23]1([NH:22][C:18]2[N:17]=[C:16]([C:15]3[CH:14]=[N:13][N:11]4[C:10]=3[CH:9]=[CH:8][C:7]([S:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:12]4)[CH:21]=[CH:20][N:19]=2)[CH2:24][CH2:25]1
Reactant: Sc1ccccc1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(Sc2ccc3c(-c4ccnc(NC5CC5)n4)cnn3n2)cc1
Temperature: 100 °C
Yield: 35.5 %

Procedure:
To a solution of 3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yl trifluoromethanesulfonate (250 mg, 0.625 mmol) in DMSO (8 mL) was added Pd(PPh3)4 (29 mg, 0.025 mmol), benzene thiol (0.064 mL, 0.625 mmol), and NaOtBu (120 mg, 1.31 mmol). The reaction mixture was heated at an oil bath temperature of 100° C. for about 2 hours. The mixture was cooled to RT and water (40 mL) was added. The aqueous layer was washed with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo and purified by silica-gel column chromatography (gradient 50-100% EtOAc in hexanes) to give the title compound as a yellow solid (80 mg, 36%). 1H-NMR (400 MHz, CDCl3) δ 8.90 (d, 1H, J=9.1 Hz), 8.34 (s, 1H), 8.29 (bs, 1H), 7.67 (m, 2H), 7.47 (m, 3H), 6.92 (d, 1H, J=5.3 Hz), 6.88 (d, 1H, J=9.4 Hz), 5.38 (s, 1H), 2.82 (m, 1H), 0.85 (m, 2H), 0.61 (m, 2H); MS (ESI) (M+H)+ 361.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=1.IC.O>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]([CH3:1])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=1
Reactant: Brc1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(Br)cc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
Potassium tert-butoxide (1.23 g) was added to a solution of 2-(4-bromophenyl)indole (2.72 g) in dimethylformamide (40 ml). Iodomethane (1.25 ml) was added and the reaction mixture stirred at ambient temperature for 18 hours. The reaction mixture was added to water. This solid was collected by filtration and purified by vacuum chromatography on silica gel (Merck Art. 7736) using 5% ethyl acetate/hexane as eluent to give 2-(4-bromophenyl)-1-methylindole (1.625 g) as a solid, m.p. 114°-115° C.