Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([CH:26]2[CH2:28][CH2:27]2)[C:10]1=[O:29])C1C=CC=CC=1>CO.[H][H].[Pd]>[CH:26]1([N:11]2[C:12]3[N:19]=[C:18]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[C:17]([F:25])=[CH:16][C:13]=3[C:14](=[O:15])[N:9]([OH:8])[C:10]2=[O:29])[CH2:28][CH2:27]1
Reactant: [H][H]
Reactant: O=c1c2cc(F)c(N3CCCC3)nc2n(C2CC2)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(C2CC2)c(=O)n1O
Yield: 85.9 %

Procedure:
A suspension of 3-benzyloxy-1-cyclopropyl-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example K-2, 60 mg, 0.152 mmol) and 10% Pd/C (30 mg) in MeOH (3 mL) was stirred at room temperature in hydrogen atmosphere provided by a balloon for 30 minutes. Filtration and concentration of the filtrate gave a solid residue, which was further washed with 10% of dichloromethane/hexane to give 40 mg of the title compound as powder, mp 238° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[N:14]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[C:13](=[O:27])[NH:12][C:11]([CH2:28][O:29][CH3:30])=[C:10]2[C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH:43]=[C:42]([C:45]2[CH:46]=[C:47]([NH:51][C:52](=[O:54])[CH3:53])[CH:48]=[CH:49][CH:50]=2)[CH2:41][CH2:40]1>>[C:52]([NH:51][C:47]1[CH:46]=[C:45]([C:42]2[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][CH2:36][NH:35][C:15]([N:14]3[C@@H:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[C:10]([C:31]([O:33][CH3:34])=[O:32])=[C:11]([CH2:28][O:29][CH3:30])[NH:12][C:13]3=[O:27])=[O:16])[CH2:40][CH:41]=2)[CH:50]=[CH:49][CH:48]=1)(=[O:54])[CH3:53]
Reactant: CC(=O)Nc1cccc(C2=CCN(CCCN)CC2)c1
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCCN2CC=C(c3cccc(NC(C)=O)c3)CC2)C(=O)N1

Procedure:
Prepared from the reaction of 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate (describe in PCT Publication No. WO 00/37026, published Jun. 29, 2000) and N-{3-[1-(3-aminopropyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}acetamide: 1H NMR δ 8.90 (t, 1H, J=3.6 Hz), 7.75 (s, 1H), 7.50–7.00 (m, 8H), 6.68 (s, 1H), 6.03 (br s, 1H), 4.67 (s, 2H), 3.71 (s, 3H), 3.47 (s, 3H), 3.38 (ABm, 2H), 3.16 (m, 2H), 2.71 (t, 2H, J=5.4 Hz), 2.56 (m, 4H), 2.35–1.90 (br, 2H), 2.17 (s, 3H), 1.82 (p, 2H, J=7.2 Hz); ESMS, 612.25 (M+H)+.
Reaction SMILES: C(OCC([N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([OH:22])[C:12]=2[N:11]=[CH:10]1)(C)C)(=O)C>Cl>[NH:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([OH:22])[C:12]=2[N:11]=[CH:10]1
Reactant: CC(=O)OCC(C)(C)n1cnc2c(O)nc3ccccc3c21
Agent: Cl
Product: Oc1nc2ccccc2c2[nH]cnc12
Temperature: 20 °C

Procedure:
A solution of 18.1 g (0.0605 mole) of 1-(2-acetoxy-1,1-dimethylethyl)-1H-imidazo[4,5-c]quinolin-4-ol and 500 mL of 6N hydrochloric acid was heated at its reflux temperature for one day and cooled to about 20° C. The solid salt, 1H-imidazo[4,5-c]quinolin-4-ol hydrochloride, was separated by filtration. The salt was neutralized by slurring in saturated sodium bicarbonate solution. The solid was separated by filtration, dried, and further dried by twice repeated coevaporation with ethanol to provide tan solid 1H-imidazo[4,5-c]quinolin-4-ol. The structural assignment was supported by infrared and nuclear magnetic resonance spectral analyses and comparison with the spectra of the product from Example 17.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16]>CC(N(C)C)=O>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:16][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)c1ccncc1F
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccncc1NCc1cccc(F)c1
Temperature: 168 °C
Reaction time: 1.5 h
Yield: 33.2 %

Procedure:
3-Fluoroisonicotinic acid (100 mg, 0.71 mmol) and 3-fluorobenzylamine (308 μL, 2.84 mmol) were combined in DMA (3 mL) and the solution was stirred at 168° C. in a microwave for 90 min. The solution was concentrated in vacuo and purified through a short plug of silica gel chromatography (20% MeOH/DCM). The semi-pure fractions were concentrated and then taken up in water to give a white precipitate, which was collected by filtration and dried under vacuum to give 58 mg (33%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.99 (br s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.31-7.41 (m, 2H), 7.15-7.23 (m, 2H), 4.62 (s, 2H). [M+H] calc'd for C13H11FN2O2, 247. Found 247.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[O:38][N:37]=[C:36]([C:39]2[N:40]=[C:41]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[S:42][CH:43]=2)[CH2:35]1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[O:38][N:37]=[C:36]([C:39]2[N:40]=[C:41]([CH:44]3[CH2:49][CH2:48][N:47]([C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:46][CH2:45]3)[S:42][CH:43]=2)[CH2:35]1
Reactant: Fc1ccccc1C1CC(c2csc(C3CCNCC3)n2)=NO1
Reactant: C#CCCC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4F)C3)cs2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 4-pentynoic acid (64 mg, 0.408 mmol) in dichloromethane (3 mL) was added 1-propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate, 0.5 mL). After stirring for 5 minutes, 4-[4-[5-(2-fluorophenyl)-4,5-dihydro-3-isoxazolyl)-2-thiazolyl]piperidine hydrochloride (i.e. the product of Step C, Example 6) (150 mg, 0.408 mmol), triethylamine (0.1 mL) and 4-dimethylaminopyridine (5 mg) were sequentially added. The reaction mixture was stirred for 3 h and then concentrated under reduced pressure. The resulting material was purified by column chromatography on silica gel to provide the title compound, a compound of the present invention, as an oil (142 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[N:18]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[C:19]=[O:20]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:3]=1[NH:4][C:19]([NH:18][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: O=C=Nc1ccncc1
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(NC(=O)Nc3ccncc3)c(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.7 %

Procedure:
A mixture of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (100 mg, 0.42 mmol) and 4-isocyanatopyridine (56 mg, 0.47 mmol) in tetrahydrofuran (2 ml) was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 193 mg (100% yield) of the title compound. This crude was used in the following step without any further purification. Purity 77%.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)[C:12](O)=[O:13])[N:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].[CH3:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][NH2:33])=[N:30][CH:31]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(#N)C>[CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)[C:12]([NH:33][CH2:32][C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[CH:31][N:30]=2)=[O:13])[N:7]=[CH:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3ncnc3C(C)C)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC#N
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(-n3ncnc3C(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.5 %

Procedure:
3-(5-Isopropyl-[1,2,4]triazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid (1.90 g, 6 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (0.73 g, 6 mmol), EDCI (1.69 g, 9 mmol), HOBt (1.20 g, 9 mmol) and NMM (3.2 mL) were added to 20 mL of acetonitrile. The reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere, then was partitioned between water and EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (IPA/DCM 1:4)) to give 1.63 g of 3-(5-isopropyl-[1,2,4]triazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=428.
Reaction SMILES: [P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[S:2].[CH3:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1>CO.C(Cl)Cl>[P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[N:30][NH:29][C:27](=[O:28])[C:26]2[CH:31]=[CH:32][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH:15]=1)([O:3][CH2:4][CH2:5][CH2:6][CH3:7])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[S:2]
Reactant: CCCCOP(=S)(OCCCC)Oc1cccc(C=O)c1
Reactant: Cc1ccc(C(=O)NN)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCOP(=S)(OCCCC)Oc1cccc(C=NNC(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of O,O-dibutyl O-(3-formylphenyl) thiophosphate (0.02 mole) in methanol (50 ml) and 4-methylbenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product O,O-dibutyl O-[3-(4-methylbenzoylhydrazonomethyl)phenyl] thiophosphate.
Reaction SMILES: N[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C.[CH2:27]([O:30][C:31](Cl)=[O:32])[CH:28]=[CH2:29]>C(Cl)Cl>[CH2:27]([O:30][C:31]([C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:32])[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC
Reaction time: 4 h
Yield: 60.4 %

Procedure:
A solution of 259A (900 mg, 3.3 mmol) in CH2Cl2 (20 mL) was treated with triethylamine (0.64 mL, 4.62 mmol) and allylchloroformate (0.35 mL, 3.96 mmol) at room temperature. The mixture was stirred for four hours, then washed with 0.1 N HCl (2×10 mL), 1N NaOH (2×10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 680 mg (yield: 58%) of Compound 259B as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(#N)C.ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CC#N
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNS(=O)(=O)c1ccc(F)cc1
Temperature: 4 °C
Yield: 40.9 %

Procedure:
1-(4-Aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) was dissolved in anhydrous acetonitrile (35 mL) and the solution was cooled to 4° C. A solution of 4-fluorobenzenesulfonyl chloride (0.194 g, 1.0 mmol) in anhydrous dichloromethane (10 mL) was slowly added. The reaction was allowed to slowly warm to ambient temperature over the weekend. The reaction was quenched by the addition of aqueous saturated sodium bicarbonate solution. The layers were separated and the organic layer was concentrated to provide a pale yellow solid. This material was recrystallized from isopropyl alcohol and then further purified by flash chromatography (silica gel eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated. The residue was recrystallized from isopropyl alcohol to provide 0.2 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-fluoro-1-benzenesulfonamide as a pale yellow solid, m.p. 214-216° C. Analysis: Calculated for C26H24FN5O2S: % C, 63.79; % H, 4.94; % N, 14.30; Found: % C, 63.19; % H, 4.85; % N, 13.90. Mass spec M+1=490.2
Reaction SMILES: [N:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][C:26]1[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH2:6][CH2:5]1)#[N:33]
Reactant: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1O2
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1CN1CCN(C2=Nc3ccccc3Oc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine (2.79 g, 10.0 mmol) (prepared from 10,11-dihydrodebenz[b,f][1,4]oxazepine-11-one, Aldrich and piperazine, as in example 1) in DMF (25 mL) was added sodium hydride (0.56 g, 60% in oil, 14 mmol) at 0° C. under argon. The mixture was stirred at 0° C. for 10 minutes at room temperature for 20 minutes, and then treated with α-bromo-o-tolunitrile (2.35 g, 12.0 mmol, Aldrich). The resulting mixture was stirred at room temperature overnight and quenched with saturated ammonium chloride solution (25 mL). The mixture was separated and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate:hexane (1:2) as the eluent. The title compound was obtained as a white solid (2.34 g, 59%), m.p. 136°-138° C.; MS 395 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:37]([C:34]5[CH:35]=[CH:36][N:31]=[N:32][CH:33]=5)=[O:38])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: O=C(O)c1ccnnc1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(NC(=O)c3ccnnc3)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 37) has been coupled with pyridazine-4-carboxylic acid to yield the title compound as light brown amorphous solid. MS: 534.1 (MH+, 1Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:37]=4[CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)c1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A mixture of 0.79 g of 5-(3-methoxy-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.40 g of N,N-diisopropylethylamine and 0.55 g of 2-methyl-5-fluorobenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to the filtrate to give 1.05 g of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@H:13]([N:17]2[CH2:20][C:19]4([CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)[CH2:18]2)[CH2:12][CH2:11]3)[CH:3]=1.[ClH:33]>CO.O1CCOCC1>[ClH:33].[ClH:33].[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@H:13]([N:17]2[CH2:20][C:19]4([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH2:18]2)[CH2:12][CH2:11]3)[CH:3]=1
Reactant: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)ncn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)ncn1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
(R)-tert-butyl 2-(5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (72.6 g, 167 mmol) was suspended in methanol (363 mL) and 4M HCl in 1,4-dioxane (251 mL) was added. After stirring for 2 hours, the slurry was concentrated to dryness. The crude material was re-suspended in MeOH (500 mL) and concentrated (3×). The resulting solids were further dried under vacuum at 45° C. to afford the title compound (74.1 g, 99.9%). MS (ES+) 335.2 (M+H)+. 1H NMR (CD3OD) δ 2.16-2.23 (m, 5H), 2.59 (br s, 1H), 2.78-2.80 (m, 3H), 3.12 (br s, 1H), 3.19-3.24 (m, 4H), 3.37-3.49 (m, 1H), 4.14-4.23 (m, 3H), 4.49 (br s, 1H), 5.11 (br s, 1H), 7.84 (d, 1H), 8.30-8.34 (m, 2H), 8.46 (s, 1H), 9.36 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
7 g (30.56 mmol) of ethyl 4-bromobenzoate are dissolved in 60 ml of 1,2-dimethoxyethane and, under argon, 6.96 g (36.67 mmol) of 4-trifluoromethylphenylboronic acid, 271 mg of bis(triphenylphosphine)palladium(II) chloride and 40.7 ml of a 2 M sodium carbonate solution in water are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 1 g of Extrelute, washed with dichloromethane and concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/dichloromethane 2:1). 6.31 g (21.4 mmol, 70% of theory) of a colorless solid are obtained.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6].[Br:28][CH2:29][C:30](Br)=[O:31].O>ClCCl>[Br:28][CH2:29][C:30]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[C:9]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=3[N:19]=2)[CH:10]=1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)CBr)ccc3OCC)nc12
Reaction time: 18 h
Yield: 78.4 %

Procedure:
Aluminium trichloride (12.8 g, 0.096 mol) was added portionwise over 1 hour to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (10.0 g, 0.032 mol) and bromoacetyl bromide (5.6 ml, 0.064 mol) in dichloromethane (150 ml) at 0° C. After 18 hours at room temperature, the reaction mixture was poured into ice and water (400 g) and the resulting mixture stirred vigorously. The organic phase was separated and the aqueous phase further extracted with dichloromethane (2×100 ml). The organic solutions were combined, dried (Na2SO4) and evaporated under vacuum to give an off-white solid, trituration of which from ether gave the title compound as a white solid (10.87 g, 78%), m.p. 159°-160° C. Found: C,52.54; H,4.88; N,12.78. C19H21BrN4O3 requires C,52.67; H,4,88; N,12.93%.
Reaction SMILES: [C:1](=[O:43])([O:14][CH2:15]/[C:16](/[C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1)=[C:17](/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)\[CH2:18][O:19][Si](C(C)(C)C)(C)C)[O:2][CH2:3][CH:4]([O:10][N+:11]([O-:13])=[O:12])[CH2:5][O:6][N+:7]([O-:9])=[O:8]>CC#N.C1(C)C=CC=CC=1>[C:1](=[O:43])([O:14][CH2:15]/[C:16](/[C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:35][CH:34]=1)=[C:17](/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)\[CH2:18][OH:19])[O:2][CH2:3][CH:4]([O:10][N+:11]([O-:13])=[O:12])[CH2:5][O:6][N+:7]([O-:9])=[O:8]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.1 %

Procedure:
To a 0° C. solution of 3.73 g of 2,3-bis(nitrooxy)propyl (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate in 150 mL of MeCN was added 5 mL of 70% PyHF. The resultant mixture was allowed to warm to rt and stirred for an additional 4 h. The reaction mixture was diluted with 600 mL of toluene and filtered through a plug of silica gel, eluting with EtOAc. The filtrate was concentrated and the resulting residue was further purified by flash chromatography over silica gel (10-50% EtOAc/hexane) to afford 3.1 g of the title compound along with a 20% impurity. 1H NMR of major compound (500 MHz, acetone-d6): δ 7.72 (d, 2H), 7.37 (d, 2H), 7.17-7.11 (m, 5H), 5.79-5.73 (m, 1H), 5.38 (s, 2H), 5.05 (dd, 1H), 4.87 (dd, 1H), 4.68-4.65 (m, 3H), 4.49 (dd, 1H), 4.15 (t, 1H), 3.05 (s, 3H).
Reaction SMILES: O.[SH:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=O>C1(C)C(C)=CC=CC=1>[SH:2][CH2:3][CH2:4][N:5]1[C:6](=[O:12])[CH2:7][CH2:8][C:9]1=[O:11]
Reactant: O=C(O)CCC(=O)NCCS
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CCC(=O)N1CCS
Temperature: 140 °C
Yield: 100.2 %

Procedure:
In a 100 cm3 reactor fitted with a water separator (Dean Stark) there is heated to a temperature of 140° C. a mixture, stirred under an inert atmosphere, of 20 g of N-(2-mercapto ethyl) succinamic acid in 50 cm3 of xylene. After about 5 hours of reaction, the theoretical amount of water (2 cm3) is removed. The xylene is then distilled under reduced pressure. The crude product is dried and 18 g of a pasty product are obtained which slowly crystallizes at ambient temperature, its characteristics being the same as those of the product prepared following the procedures in section (a) immediately above.