Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][S:14][C:15]1[CH:28]=[CH:27][C:18]([CH:19]=[C:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Mg].Cl.C([O-])(O)=O.[Na+]>CO.O1CCOCC1.O>[CH3:1][N:2]([CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])=[CH:27][CH:28]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(CCSc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Mg]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CN(CCSc1ccc(CC2SC(=O)NC2=O)cc1)c1nc2ccccc2o1

Procedure:
5-(4-[2-(N-Methyl-N-(2-benzoxazolyl)amino)ethylthio]-benzylidene)-2,4-thiazolidinedione (2 g) was dissolved in a mixture of methanol (70 ml) and 1,4-dioxan (70 ml). Magnesium turnings (1.7 g) were added and the solution stirred until no more effervescence was observed. The mixture was added to water (300 ml), acidified (2M HCl) to form a solution, neutralised (saturated NaHCO3 solution) and extracted with dichloromethane (3×150 ml). The organic extracts were washed with brine
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+].[NH2:19][O:20][CH2:21][C:22]([NH2:24])=[O:23].Cl>O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:19][O:20][CH2:21][C:22](=[O:23])[NH2:24])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: NOCC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)glyoxylic acid (4.63 g.) and sodium bicarbonate (1.95 g.) in water (230 ml.) was added 2-aminooxyacetamide (2.5 g.) and the mixture was stirred at room temperature for 6 hours while keeping at pH 5. After adjusting the solution to pH 1.5 with 10% hydrochloric acid, the precipitates were collected by filtration, washed with water and dried to give 2-(2-formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetic acid (syn isomer, 3.6 g.), mp 195° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[CH:23]=[C:22]4[CH:27]=[CH:28][CH:29]=[CH:30][C:21]4=[CH:20][C:19]=3[C:18]2=[O:31])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:33][OH:34]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[CH:23]=[C:22]4[CH:27]=[CH:28][CH:29]=[CH:30][C:21]4=[CH:20][C:19]=3[C:18]2=[O:31])[CH2:13][C:14]([NH:33][OH:34])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cc4ccccc4cc3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cc4ccccc4cc3C2=O)ccc1OC
Yield: 77.2 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]-isoindol-2-yl)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propanoic acid (2.00 g, 4.77 mmol), N,N′-carbonyldiimidazole (889 mg, 5.48 mmol) and hydroxylamine hydrochloride (419 mg, 6.03 mmol) in tetrahydrofuran (8 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]-isoindol-2-yl)propionamide as an off-white solid (1.6 g, 77% yield): mp, 197.0–199.0° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=7.0 Hz, 3H, CH3), 3.11–3.28 (m, 2H, CH2), 3.73 (s, 3H, CH3), 4.00 (q, J=7.0 Hz, 2H, CH2), 5.79 (t, J=7.8 Hz, 1H, NCH), 6.87–7.09 (m, 2H, Ar), 7.10 (br s, 1H, Ar), 7.74–7.78 (m, 2H, Ar), 8.23–8.27 (m, 2H, Ar), 8.49 (br s, 1H, Ar), 8.85 (br s, 1H, OH), 10.66 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.69, 34.27, 50.42, 55.45, 63.73, 111.73, 112.45, 119.82, 124.50, 127.04, 129.28, 130.26, 131.20, 135.05, 147.69, 148.58, 166.07, 167.30; Anal Calcd for C24H22N2O6: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.22; H, 5.24; N, 6.08.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15].[Br:18][C:19]1[C:27]2[O:26][CH:25]=[CH:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.[NH4+].[Cl-]>C1COCC1.Cl>[Br:18][C:19]1[C:27]2[O:26][C:25]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cccc2ccoc12
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc2cccc(Br)c2o1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
A stirred solution of diisopropylamine (0.65 mL, 4.7 mmol) in THF (15 L) was cooled to 5° C. and n-BuLi (2.5 M in hexanes, 1.9 mL, 4.7 mmol) was added dropwise over 5 min. The mixture was stirred at 5° C. for 15 min and cooled to −70° C. Chlorotrimethylsilane (0.59 mL, 4.7 mmol) was added followed by a solution of 7-bromobenzofuran (0.46 g, 2.35 mmol) in THF (5 mL). The mixture was stirred at −70° C. for 1.5 h and poured into sat'd aq NH4Cl (80 mL). The mixture was diluted with 5% aq HCl (20 mL) and extracted with ether (2×80 mL). The combined ether extracts were washed with sat'd aq NaHCO3 (50 mL), dried over MgSO4 and concentrated to leave crude 7-bromo-2-(trimethylsilyl)benzofuran (0.62 g, 98%) as a yellow oil.
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:34]([NH2:36])=[O:35])=[N:13][N:14](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:5]=3[C:4]=2[N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:34]([NH2:36])=[O:35])=[N:13][NH:14][C:5]=3[C:4]=2[N:3]=1
Reactant: NC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CCc1cnc(I)nc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1n[nH]c2c1CCc1cnc(I)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
8-Iodo-1-trityl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (291 mg, 0.5 mmol) in DCM (10 mL) was treated with trifluoroacetic acid (0.5 mL). The resulting mixture was stirred at room temperature for 1 hour. DCM (40 mL) was added and the organic phase was washed with saturated solution of sodium hydrogen carbonate, then with brine, dried over sodium sulfate and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 143 mg of the title compound (84% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[N:11][N:12]=2)=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH:10]=[N:11][N:12]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(-c2nnco2)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nnco3)cc2)CC1

Procedure:
Prepared in analogy to example 4.4(a) from 2-(4-Bromo-phenyl)-[1,3,4]oxadiazole and N-BOC-piperazine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N.[Ni]>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(CC#N)cccc1OCc1ccccc1
Agent: [Ni]
Agent: N
Product: COc1c(CCN)cccc1OCc1ccccc1

Procedure:
7.7 g (34 mmol) (3-Benzyloxy-2-methoxy-phenyl)-acetonitrile (example XI) in 100 mL methanolic ammonia (c=7 mol/L) are hydrogenated (3 bar, r.t.) using 250 mg Raney-nickel. The reaction mixture is filtered and the solvent is removed in vacuo.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([C:23]([OH:25])=O)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1C2N=NNC=2C=CC=1.[NH2:36][N:37]1[CH2:42][CH2:41][NH:40][C:39](=[O:43])[C:38]1=[O:44].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[O:44]=[C:38]1[C:39](=[O:43])[NH:40][CH2:41][CH2:42][N:37]1[NH:36][C:23]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][N:12]=1)=[O:25]
Reactant: NN1CCNC(=O)C1=O
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C1NCCN(NC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)cn2)C1=O
Yield: 82.1 %

Procedure:
To a suspension of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid (7.1 g, 21.17 mmol), hydroxybenzotriazole (0.29 g, 2.12 mmol) and N-aminopiperazine-2,3-dione (2.73 g, 21.17 mmol) in 140 ml of dry dimethylformamide was added, after 15 minutes of stirring, 4.80 g (23.3 mmol) of dicyclohexylcarbodiimide. After stirring for 21 hours at room temperature, dicyclohexylurea was filtered off (4.0 g ) and the solvent was evaporated in vacuo. The solid residue was triturated for 40 minutes with 240 ml of tetrahydrofuran, filtered, washed with tetrahyrofuran and dried in vacuo to yield 7.76 g of the title compound, melting point 231.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])[CH:35]=[CH2:36]>CO.ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:36][CH2:35][C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCN1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 70 °C

Procedure:
To a solution of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (200 mg) in methanol (0.3 mL) and dichloromethane (0.3 mL) was added a solution of t-butyl acrylate (1.80 mL; 1.57 g) in methanol (0.8 mL) and dichloromethane (0.4 mL) in 1 min. The reaction was heated to 70° C. for 24 hr. The reaction was cooled to room temperature and concentrated. The resulting residue was purified by silica column (ISCO) (5% MeOH/CH2Cl2) to yield tert-butyl 3-(4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)propanoate.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([CH2:19][CH2:18][CH2:17][NH:16][C:2]2[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=23)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NCCCN1CCOCC1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Product: Cc1nnc(NCCCN2CCOCC2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 4-(3-aminopropyl)morpholine gave the title compound as the free base which was converted to the dihydrochloride salt, mp. 295°-296° C. (after recrystallization from ethanol).
Reaction SMILES: [CH3:1][N+]1([O-])CCOCC1.[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH2:22][CH:23]=[O:24])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[Mg]Cl>CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH2:22][CH:23]([OH:24])[CH3:1])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=CC[C@H]1CN(Cc2ccccc2)CCN1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[Mg]Cl
Product: CC(O)C[C@H]1CN(Cc2ccccc2)CCN1

Procedure:
Briefly (and essentially as described in PCT International Publication Numbers WO 98/20001 and WO 99/65922), (Nα-(t-butyloxycarbonyl)-β-(benzyl ester)-L-aspartic acid) is reacted with N-benzylglycine in the presence of DCC and HOBt to produce the corresponding N-benzylglycine amide, which is further reacted with TFA to remove the BOC protecting group, yielding ((S)-4-benzyl-3,6-dioxo-piperazin-2-yl)-acetic acid ethyl ester. This is reduced to 2-((S)-4-benzyl-piperazin-2-yl)-ethanol by reaction with LiAlH4 in THF. Essentially as described in PCT International Publication Number WO 02/094799, the free amine is reacted with (BOC)2O to produce the corresponding carbamate, and the primary alcohol is oxidized with catalytic TPAP in the presence of NMO to the corresponding aldehyde, ((S)-4-benzyl-piperazin-2-yl)-acetaldehyde. This is reacted with MeMgCl under Grignard reaction conditions to produce the secondary alcohol, 1-((S)-4-benzyl-piperazin-2-yl)-propan-2-ol, as a mixture of diastereoisomers, which is oxidized to the corresponding methylketone, 1-((S)-4-benzyl-piperazin-2-yl)-propan-2-one, by reaction with catalytic TPAP and NMO. The methylketone undergoes a tandem aldol condensation/Michael conjugated addition by reaction with 1-(4-methoxy-2,3-dimethylphenyl)-ethanone in the presence of LiCl and DBU as a base in THF as the solvent, yielding bicyclic (6R,9aS)-2-benzyl-6-(4-methoxy-2,3-dimethyl-phenyl)-octahydro-pyrido[1,2-a]pyrazin-8-one. This is deoxygenated to (6R,9aS)-2-benzyl-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazine by conversion to the corresponding tosylhydrazone and subsequent reduction with NaBH3CN in the presence of zinc triflate. The benzyl group is removed by catalytic transfer hydrogenation reaction promoted by Pd(OH)2 in the presence of excess ammonium formate in MeOH. Finally, (6R,9aS)-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrido[1,2-a]pyrazine is converted to the desired heteroaroyl analog by reaction with the corresponding acid chloride under Schotten-Bauman reaction conditions.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[NH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1O>CN(C)C=O>[N+:11]([C:9]1[CH:10]=[CH:5][C:2]([C:1]2[O:3][C:6]3[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=3[N:4]=2)=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1

Procedure:
About 60 grams (0.3 mole) of the 4-nitro-phenylchloroxime is mixed with 340 milliliters of ethanol, 60 grams (0.39 moles) of 2-amino-4-nitrophenol and 60 milliliters of dimethylformamide. The mixture is heated to reflux for about 6.5 hours, filtered, washed with methanol and air dried. Approximately 55 grams of 2-(p-nitrophenyl)-5-nitrobenzoxazole are obtained.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.[CH2:8]([Mg]Br)[CH3:9].B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CCOCC.C1(C)C=CC=CC=1>[S:1]1[CH:5]=[C:4]([C:6]2([NH2:7])[CH2:9][CH2:8]2)[N:3]=[CH:2]1
Reactant: CC[Mg]Br
Reactant: N#Cc1cscn1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: NC1(c2cscn2)CC1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
Thiazole-4-carbonitrile (1035 mg, 9397 μmol) was azeotroped with toluene. Et2O was added, and the clear solution was cooled to −70° C., followed by addition of titanium tetraisopropoxide (3025 μl, 10337 μmol), and ethylmagnesium bromide (6265 μl, 18795 μmol). The reaction mixture turned yellow. It remained yellow until about 15 min. The reaction was raised to RT, the solution changed into black. After 1 h., boron trifluoride diethyl etherate (2361 μl, 18795 μmol) was added and stirred for 1.5 hr. Then 1N HCl 27 mL was added, followed by 100 mL ether, 95 mL 10% NaOH. The reaction was extracted with Et2O×2 and 30% IPA/CHCl3×1. The organic layer was concentrated and purified with silica gel chromatography using 0-10% MeOH/DCM. 650 mg of product 14.2.B was obtained in 49% yield.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccccc1
Product: C=CCn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 63.2 %

Procedure:
The title compound was prepared as a white powder in 63.2% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:9]1(=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:7]#[N:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CCc1cccs1
Reactant: O=C1CCCCC1
Product: N#CC(=C1CCCCC1)c1cccs1

Procedure:
The expected intermediate is obtained in the manner described in General Protocol A starting from 2-thienylacetonitrile and cyclohexanone.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:27]=[CH:26][S:25][C:4]=2[N:5]([CH:22]([CH3:24])[CH3:23])[C:6](=[O:21])[C:7]=1[C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17](C)[CH2:16][CH2:15]1)=[O:9].[CH2:28]([Li])CCC.CI>C1COCC1>[CH:22]([N:5]1[C:6](=[O:21])[C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:9])=[C:2]([O:1][CH3:28])[C:3]2[CH:27]=[CH:26][S:25][C:4]1=2)([CH3:24])[CH3:23]
Reactant: [Li]CCCC
Reactant: CC1CCN(CCCNC(=O)c2c(O)c3ccsc3n(C(C)C)c2=O)CC1
Solvent: C1CCOC1
Solvent: CI
Product: COc1c(C(=O)NCCCN2CCCCC2)c(=O)n(C(C)C)c2sccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
To a solution of 6,7-dihydro-4-hydroxy-7-isopropyl-N-(3-(4-methylpiperidin-1-yl)propyl)-6-oxothieno[2,3-b]pyridine-5-carboxamide (0.075 g, 0.20 mmol) in THF (2.5 mL) at −78° C. was added n-butyllithium (0.087 mL, 2.5 M in hexanes, 0.22 mmol). The reaction mixture was warmed to 0° C. for 30 min and re-cooled to −78° C.; then methyl iodide (0.037 mL, 0.40 mmol) was added. The mixture was warmed to room temperature, stirred for 4 h and concentrated. The residue was dissolved in dichloromethane; the resulting solution was washed with water, dried over anhydrous sodium sulfate and concentrated to afford the title compound as an off-white solid (0.077 g, 99%). 1H NMR (400 MHz, CD3OD): δ 7.35 (d, 1H), 7.20 (d, 1H), 3.55 (t, 2H), 3.49-3.45 (m, 2H), 3.40 (t, 4H), 3.09 (s, 3H), 2.17-2.09 (m, 2H), 1.91 (m, 4H), 1.76-1.62 (m, 2H), 1.64 (d, 6H); MS: m/e 392 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[C:18]([F:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:26])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[F:25][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[NH:16][C:15](=[O:26])[N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:23]2=[O:24]
Reactant: O=c1[nH]c2c(F)cccc2c(=O)n1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2c(F)cccc2c(=O)n1C1CCNCC1
Reaction time: 8 h

Procedure:
A flask containing a solution of 3-(1-benzylpiperidin-4-yl)-8-fluoroquinazoline-2,4(1H,3H)-dione (75.0 mg, 0.21 mmol) and palladium on charcoal (8.00 mg, 0.035 equiv) in methanol (3.00 mL) was flushed first with nitrogen, then hydrogen. The reaction was stirred under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated to give 53 mg (95%) as a white solid which was used without purification. Mass spec.: 264.25 (MH)+.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:15][C:10]=2[N:9]=[CH:8]1.[I:22]N1C(=O)CCC1=O>CCCCCC.C1COCC1>[I:22][C:8]1[N:7]([CH3:6])[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:15][C:10]=2[N:9]=1
Reactant: Cn1cnc2cc(CN3CCCC3)ccc21
Reactant: O=C1CCC(=O)N1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1c(I)nc2cc(CN3CCCC3)ccc21
Reaction time: 0.17 h

Procedure:
0.80 mL (1.28 mmol) 1.6 M n-butyllithium solution in hexane are added to a solution, cooled to −75° C., of 250 mg (1.16 mmol) 1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole in 8 mL THF. The reaction mixture is stirred for 10 min at this temperature and then 288 mg (1.28 mmol) N-iodosuccinimide in 5 mL THF are added. The cooling bath is removed and the reaction stirred for 1 h at RT. 12 mL 0.1 M HCl are added and the aqueous phase is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH/NH3 9:1:0.1).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][CH2:26]Cl)=[O:23])=[CH:17][C:16]=2[CH2:28][S:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH:7]=1)C.[O-]CC.[Na+]>CCO>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:3])=[O:35])=[CH:7][C:8]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][C:22]2=[O:23])=[CH:17][C:16]=1[CH2:28][S:29][CH2:30][C:31]([F:34])([F:32])[F:33]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)OCCCl)cc2CSCC(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(N2CCOC2=O)cc1CSCC(F)(F)F
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To {3-[4-(2-chloro-ethoxycarbonylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.100 g, 0.19 mmol) in EtOH (5 mL) was added sodium ethoxide (21 wt % in EtOH; 4.61 mL, 0.37 mmol), and the reaction was stirred at 65° C. overnight. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:27]2[CH:26]=[CH:25][N:24]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:23](=[O:34])[C:22]=2[C:21]([CH3:35])=[C:20]1[C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>N1C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:27]2[CH:26]=[CH:25][N:24]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:23](=[O:34])[C:22]=2[C:21]([CH3:35])=[C:20]1[C:36]1[CH:37]=[CH:38][C:39]([O:42][S:5]([CH2:4][CH2:3][C:2]([F:10])([F:9])[F:1])(=[O:7])=[O:6])=[CH:40][CH:41]=1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: Cc1c(-c2ccc(O)cc2)n(-c2ccc(Cl)cc2Cl)c2ccn(N3CCCCC3)c(=O)c12
Solvent: c1ccncc1
Product: Cc1c(-c2ccc(OS(=O)(=O)CCC(F)(F)F)cc2)n(-c2ccc(Cl)cc2Cl)c2ccn(N3CCCCC3)c(=O)c12
Reaction time: 0.25 h

Procedure:
3,3,3-Trifluoro-propane-1-sulfonyl chloride (100 mg, 0.509 mmol) was added to 1-(2,4-dichlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (74 mg, 0.158 mmol) dissolved in pyridine (5 ml) at 0° C. The reaction was continued at 0° C. for 1 h and 15 min and then at rt. After 15 min at rt more 3,3,3-trifluoro-propane-1-sulfonyl chloride (260 mg, 1.323 mmol) was added. After 15 min the solvent was evaporated. Purified by flash chromatography (20-100% EtOAc in toluene) to yield the title compound as a white solid after evaporation (24 mg, 24%).