Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(CC(N)C)C1C=CC=CC=1.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(N)=NC=2Cl)(=O)C.C(N(CC)CC)C.C(N(C(C)C)CC)(C)C.C([O:60][C@@H:61]1[C@H:65]([O:66]C(=O)C)[C@@H:64]([CH2:70][O:71]C(=O)C)[O:63][C@H:62]1[N:75]1[C:94]2[N:93]=[C:92]([NH2:95])[N:91]=[C:79]([NH:80][CH:81]([CH3:90])[CH2:82][O:83][C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)[C:78]=2[N:77]=[CH:76]1)(=O)C.N>O1CCOCC1>[NH2:95][C:92]1[N:91]=[C:79]([NH:80][CH:81]([CH3:90])[CH2:82][O:83][C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)[C:78]2[N:77]=[CH:76][N:75]([C:94]=2[N:93]=1)[C@@H:62]1[O:63][C@H:64]([CH2:70][OH:71])[C@@H:65]([OH:66])[C@H:61]1[OH:60]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC(C)COc4ccccc4)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(N)COc1ccccc1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(COc1ccccc1)Nc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
1-Phenoxy-2-propylamine (2.90 g, 19.2 mmol) and 9-(2,3,5-tri- O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloro-9H-purine (6.94 g, 16.2 mmol) were dissolved in dioxan (50 ml) and triethylamine (4.5 ml, 33.2 mmol) was introduced. After stirring the reaction mixture for 18 h at room temperature, diisopropylethylamine (2.08 g, 16.1 mmol) was added and the solution was heated at 80° C. for 100 h. Following column column chromatography, a 1.3 g sample of the resultant 2',3',5'-tri- O-acetyl-2-amino- N-(1-phenoxy-2-propyl)adenosine was deprotected using saturated methanolic ammonia (50 ml). The reaction mixture was evaporated, and the residue dissolved in in a mixture of ethyl acetate (150 ml) and water (150 ml). The phases were separated and the ethyl acetate phase was washed with water (2×150 ml). The ethyl acetate phase was then extracted with pH 2 dilute hydrochloric acid, and this acidic aqueous phase was washed with ethyl acetate (2×100 ml), and basified with sodium bicarbonate solution before extraction with ethyl acetate (100 ml). The ethyl acetate phase was was dried (MgSO4) and evaporated to give the title compound (0.43 g, 33%) a mixture of diastereoisomers as an amorphous foam, 1H NMR (DMSO-d6)δ 1.28 (3H, d, --CH3), 3.49-3.57 (1H, m, H-5'a), 3.61-3.68 (1H, m, H-5'b), 3.85-3.94 and 4.07-4.15 (4H, 2m, m, H-4', H-3' and --CH2 --), 4.50 (1H, q, H-2'), 4.68 (1H, br, --C HCH3), 5.11, 5.36 (2H, 2d, 2'- and 3'-OH), 5.40 (1H, t, 5'-OH) 5.73 (1H, d, H-1'), 5.83 (1H, br, --NH2), 6.88-6.96 (3H, m, Ar--H), 7.22-7.31 (2H, t, Ar--H), 7.95 (1H, s, H-8).
Reaction SMILES: C([O:3][P:4]1(=[O:45])[CH2:28][C:27]2[CH:29]=[CH:30][C:24](=[C:25]([O:31][CH3:32])[CH:26]=2)[NH:23][C:22]2=[N:33][C:18](=[C:19]([C:34]([F:37])([F:36])[F:35])[CH:20]=[N:21]2)[NH:17][C:16]2[CH:38]=[CH:39][C:13](=[N:14][C:15]=2[C:40]([NH:42][CH3:43])=[O:41])[C:12]2=[CH:44][N:9]([N:10]=[CH:11]2)[CH2:8][CH2:7][CH2:6][O:5]1)C>Cl>[OH:45][P:4]1(=[O:3])[CH2:28][C:27]2[CH:29]=[CH:30][C:24](=[C:25]([O:31][CH3:32])[CH:26]=2)[NH:23][C:22]2=[N:33][C:18](=[C:19]([C:34]([F:36])([F:35])[F:37])[CH:20]=[N:21]2)[NH:17][C:16]2[CH:38]=[CH:39][C:13](=[N:14][C:15]=2[C:40]([NH:42][CH3:43])=[O:41])[C:12]2=[CH:44][N:9]([N:10]=[CH:11]2)[CH2:8][CH2:7][CH2:6][O:5]1
Reactant: CCOP1(=O)Cc2ccc(c(OC)c2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCO1
Agent: Cl
Product: CNC(=O)c1nc2ccc1Nc1nc(ncc1C(F)(F)F)Nc1ccc(cc1OC)CP(=O)(O)OCCCn1cc-2cn1

Procedure:
A solution 10-ethoxy-14-methoxy-N-methyl-20-(trifluoromethyl)-9-oxa-4,5,16,18,22,25,28-heptaaza-10-phosphapentacyclo[21.2.2.212,15.12,5.117,21]hentriaconta-1(25),2(31),3,12,14,17(28),18,20,23,26,29-undecaene-24-carboxamide 10-oxide (Example 6, 30.0 mg, 0.0464 mmol) in concentrated HCl (6.0 mL) was stirred at 50° C. for 72 hours. The reaction mixture was concentrated under reduced pressure to a yellow foam. The material was purified on a Teledyne ISCO Combiflash® Rf system using a reverse phase column with Water/MeOH (100:0→0:100) as eluent to afford the title compound as 7.5 mg of a white solid (26%). 1H NMR (400 MHz, CD3OD): δ=8.41 (br. s., 1H), 8.31 (s, 1H), 8.27 (br. s., 1H), 7.87 (d, J=6.6 Hz, 1H), 7.59 (d, J=6.6 Hz, 1H), 7.45 (d, J=6.6 Hz, 1H), 6.70 (br. s., 1H), 6.27 (d, J=4.8 Hz, 1H), 4.42 (br. s., 2H), 3.83 (br. s., 3H), 3.52 (br. s., 2H), 2.93 (s, 3H), 2.80 (d, J=17.4 Hz, 2H), 2.16 (br. s., 2H). MS (ESI): m/z 619.17 [M+H]+. UPLC: tR=0.80 min (polar—2 min).
Reaction SMILES: F[C:2]1[C:7]2[C:8](=[O:17])[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:6]=2[C:5](F)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:21][CH2:20][CH2:19][NH:22][C:2]1[C:7]2[C:8](=[O:17])[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:6]=2[C:5]([NH:21][CH2:20][CH2:19][NH2:22])=[CH:4][CH:3]=1
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Reactant: NCCN
Product: NCCNc1ccc(NCCN)c2c1C(=O)c1ccncc1C2=O

Procedure:
The reported synthetic procedures use, as a key intermediate, 6,9-difluorobenzo[g]isoquinoline-5,10-dione. This compound is reacted with ethylene-diamine which produces the desired 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 120 %

Procedure:
To a −78° C. solution of 2.8 mL (20.0 mmol) of diisopropylamine in 40 mL of dry tetrahydrofuran was added 13.75 mL (22 mmol) of 1.6 M n-butyllithium in hexanes. The reaction was let warm to 0° C. and then cooled to −78° C. A solution of 2.7 mL (20 mmol) of ethyl cyclobutanecarboxylate in 10 mL of tetrahydrofuran was added dropwise and the reaction let warm to 0° C. The reaction was stirred for 15 min before being cooled to −78° C. To the solution was added 3.1 mL (26 mmol) of benzyl bromide dropwise and the reaction stirred for 15 min before being let warm to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated ammonium chloride, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 5.24 g of crude ethyl 1-benzylcyclobutanecarboxylate. The crude product was dissolved in 100 mL of tetrahydrofuran and cooled to 0° C. To this solution was added dropwise 14.1 mL (14.1 mmol) of 1M lithium aluminum hydride in tetrahydrofuran. The reaction was stirred for 1 h before being carefully quenched with brine. The mixture was filtered through a celite plug and the filter cake washed with ethyl acetate. The filtrate was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 1.6 g (45%) of ethyl (1-benzylcyclobutyl)methanol. 1H NMR (300 MHz, DMSO-d6) δ 7.18-7.34 (m, 5H), 4.63 (t, J=5 Hz, 1H), 3.24-3.25 (d, J=5H, 2H), 2.71 (s, 2H), 1.66-1.79 (m, 6H).
Reaction SMILES: [NH2:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[ClH:27].C(OCC)(=O)C>C(O)C.CCCCCC>[ClH:17].[ClH:27].[C:5]1([CH:3]([OH:4])[CH:2]([NH:1][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCCCN1CCCCC1
Reactant: CCCCCCC(N)C(O)c1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCC(NCCCN1CCCCC1)C(O)c1ccccc1
Yield: 59 %

Procedure:
A mixture of (1RS,2RS)-2-amino-1-phenyloctan-1-ol (1.77 g, 8 mmol) and 1-(3-chloropropyl)piperidine (1.29 g, 8 mmol) was melted at 70° C. in a nitrogen atmosphere. The mixture was then heated at 110° to 120° C. for 3 hours. The reaction mixture was dissolved with heating in ethanol, followed by addition of concentrated hydrochloric acid (0.67 ml). Ethyl acetate was added and the resulting mixture was allowed to stand. Precipitated crystals were collected by filtration and washed with ethyl acetate and then with hexane to obtain 1.96 g of the title compound as white crystals (yield: 59%).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.ClCCO.[OH-].[K+].[CH3:10][CH:11]([NH2:15])[CH:12]([CH3:14])[NH2:13]>CO>[OH:3][CH2:1][CH2:2][NH:13][CH:12]([CH3:14])[CH:11]([CH3:10])[NH2:15]
Reactant: C1CO1
Reactant: CC(N)C(C)N
Agent: OCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(N)C(C)NCCO

Procedure:
Ethylene oxide generated from 2-chloroethanol (36 g) and potassium hydroxide pellets (20 g) in methanol (60 ml) was reacted with 1,2-dimethylethylenediamine (22.6 g) in methanol (50 ml) at -15° C. to give N-(2-hydroxyethyl)-1,2-dimethylethylenediamine as a colourless liquid (b.p. 89°-91° C. at 1 mmHg).
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[C:11](Cl)([CH3:14])([CH3:13])[CH3:12].[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Cl
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
In a 200 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.05 g (0.0005 mol (corresponding to 1% by mol)) of copper(I) chloride and 20 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 6.0 g (0.065. mol) of tert-butyl chloride and 1.9 g (0.078 mol) of metallic magnesium in 50 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 20° C. to 25° C. After the dropwise addition was completed, stirring was conducted at a temperature of 35° C. to 40° C. for 3 hours. Then, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 20 ml of toluene and 20 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 111° C. to 113° C. under reduced pressure of 15 Torr were collected. As a result, 9.2 g (purity: 99.0%) of the aimed tri-tert-butylphosphine was obtained as an oily substance. The yield was 90.2%.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][C:52]=1[F:53])[C:48]#[N:49]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:46]=[C:47]([CH:50]=[CH:51][C:52]=3[F:53])[C:48]#[N:49])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(F)c(N)c1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cc(C#N)ccc3F)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 3-amino-4-fluoro-benzonitrile according to procedure B followed by deprotection yielded the title compound as a pale yellow solid. MS (ESI): m/z=398.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH:38]12[O:45][CH:42]([CH2:43][CH2:44]1)[CH2:41][NH:40][CH2:39]2.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:40]3[CH2:39][C@@H:38]4[O:45][C@@H:42]([CH2:43][CH2:44]4)[CH2:41]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1CC2CNCC1O2
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2C[C@H]3CC[C@@H](C2)O3)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 18.7 %

Procedure:
A mixture of 0.15 g (0.28 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.13 g (0.84 mmol) 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride and 0.20 g (1.4 mmol) potassium carbonate in 1 ml dimethyl sulfoxide was heated at 150° C. under microwave irradiation in a sealed tube for 30 min. Another portion of 0.06 g (0.4 mmol) 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride was added and the reaction mixture was heated at 150° C. under microwave irradiation in a sealed tube for 30 more minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with four portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate and concentrated. Flash column chromatography gave 32 mg (18%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[C:11]([N+:27]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.[OH-].[Na+]>C(#N)C>[NH2:27][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:24]([O:25][CH3:26])=[CH:23][C:12]=1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: COc1cc(C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)OCc2ccccc2)c(N)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (77 g) was dissolved in acetonitrile (882 ml). Sodium dithionite (160.5 g) was added to the solution and the temperature adjusted to 25° C. Water (588 ml) was then added, maintaining the temperature at 25° C. The pH was maintained at 6 using 8.8 M sodium hydroxide during the reduction. The slurry was then heated to 65° C. and the lower aqueous phase was removed. Concentrated hydrochloric acid (35% w/w, 7.25 ml) was then added. The slurry was allowed to cool to 40° C. and then to 20° C. Sodium hydroxide solution (47% w/w, 12.4 ml) was added and the slurry cooled to 0° C. The product (benzyl 2-amino-4-(benzyloxy)-5-methoxybenzoate) was isolated by filtration, washed with water (2×196 ml) and then dried at 40° C. under vacuum. Yield: 66.2 g, 92.4%; NMR Spectrum (CDCl3) 3.8 (s, 3H), 5.1 (s, 2H), 5.3 (s, 2H), 6.2 (s, 1H), 7.3-7.4 (m, 10H); Mass Spectrum (M+H)+=364.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][S:10]([O:12][Na])=[O:11].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.O>[CH3:9][S:10]([C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:12])=[O:11]
Reactant: CS(=O)O[Na]
Reactant: Oc1ccc(Cl)nc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(O)cn1
Temperature: 140 °C
Yield: 44.9 %

Procedure:
A mixture of 6-chloropyridin-3-ol (2.00 g, 15.44 mmol), MeSO2Na (2.36 g, 23.16 mmol), CuI (882.16 mg, 4.63 mmol), L-proline (533.28 mg, 4.63 mmol), and K2CO3 (640.19 mg, 4.63 mmol) in DMSO (20 mL) were charged into a microwave tube. The sealed tube was heated at 140° C. for 3 hrs under microwave. After cooling to room temperature, water (100 mL) was added. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (1.2 g, 44.8%) as a yellow solid. 1H NMR (Methanol-d4, 400 MHz) δ 8.24 (d, J=2.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.37 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 3.15 (s, 3H).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.C[O-].[Na+].C1(C)C=CC(S(O[CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=2)[C:23]#[N:24])(=O)=O)=CC=1.O>CO>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([S:7][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=2)[C:23]#[N:24])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Reactant: Cc1ccc(S)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(SC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.17 h
Yield: 100.7 %

Procedure:
p-Toluenethiol (5.00 g) was dissolved in 6 ml of methanol, and 1.60 ml of a 2.5 M methanol solution of sodium methoxide was added to the solution at room temperature in a stream of argon. The mixture was stirred under ice cooling. Then, 1.516 g of O-(p-toluenesulfonyl)-m-phenoxymandelonitrile was added, and the mixture was stirred for 30 minutes under ice cooling and then for 10 minutes at room temperature. Water (20 ml) was added, and the mixture was extracted with 30 ml of methylene chloride three times. The extract was washed with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene) to afford 1.334 g (yield 100%) of alpha-(p-tolylthio)(m-phenoxyphenyl)acetonitrile as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:8])[NH:5][CH2:4][NH:3]1.[H][H]>[Ni]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:8])[N:5]=[CH:4][NH:3]1
Reactant: CC1CC(C)(C)NCN1
Reactant: [H][H]
Agent: [Ni]
Product: CC1CC(C)(C)NC=N1

Procedure:
Anal. Calc.ed for C7H16N2 : N, 21.85. Found: N, 21.6 Nuclear magnetic resonance spectrum, solvent CDCl3, δ in ppm; 3.82 s, 2H; 2.87 m, 1H; 1.42 & 1.65, 2d's, 2H; 1.02 d, 3H; 1.08 & 1.13 2s's, 6H; 1.67 s, 2H exchangeable with D2O. A sample of 12.8 grams of 4,4,6-trimethylhexahydropyrimidine and 0.5 grams of 60% nickel catalyst on kieselguhr was heated for 8 hrs. at 185°-187° C. During this time the theoretical amount of hydrogen gas was evolved.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1.O.[NH2:31][NH2:32]>CN(C=O)C>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:32][N:31]=1
Reactant: NN
Reactant: COc1cccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Yield: 82.5 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(3-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (50 mg, 0.13 mmol, prepared in Synthetic Example 14) in DMF (1 ml) was added hydrazine monohydrate (80%, 20 μl, 0.50 mmol, 3.8 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(3-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (41 mg, 83%).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br-].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 145 °C
Reaction time: 7 h

Procedure:
In 24 L of dimethyl sulfoxide were suspended 14.5 kg (44.68 mol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine, 8.0 kg (29.88 mol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate, 6.3 kg (59.43 mol) of sodium carbonate and 300 g (2.92 mol) of sodium bromide, which were then heated to 145±5° C. under a nitrogen atmosphere and stirred for 7 hours. After cooling to room temperature, 80 L of ethyl acetate and 80 L of water were added, followed by separation into two layers. The organic layer was washed with 40 L of water twice and concentrated under reduced pressure. To the residue was added 60 L of ethanol and concentrated until the total volume became 40 L under reduced pressure to yield a solution of crude ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate in ethanol. To the ethanol solution was added 2.4 kg of sodium hydroxide dissolved in 8 L of water. The reaction mixture was heated to 60±5° C. and stirred for 1 hour. The reaction mixture was cooled to 30±5° C. and adjusted to pH 10 or lower by the addition of 13 L of 3N hydrochloric acid, followed by the addition of 56 L of ethyl acetate. The mixture was adjusted to pH 6-7 by the addition of 13 L of 3N hydrochloric acid and 6 L of water was added thereto. The crystals formed were collected by filtration, washed with 40 L of a mixed solvent of water:ethanol:ethyl acetate (1:1:1), and dried to yield 13.5 kg of the title compound. HPLC purity area percentage 98.0%, Yield 80.1%.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: C1CCN(CCCCC2CCCCN2)CC1
Product: O=C1Nc2cccnc2N(C(=O)N2CCCCC2CCCCN2CCCCC2)c2ccccc21
Yield: 41 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-(1-piperidinyl)butyl]piperidine in a yield of 41% of theory. Colourless crystals, m.p. 199°-201° C. (after being recrystallised twice from ethanol using animal charcoal).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]#[N:5].[F:6][C:7]1([F:23])[CH2:10][CH:9]([C:11](OCC2C=CC(OC)=CC=2)=[O:12])[CH2:8]1.O>O1CCOCC1>[F:6][C:7]1([F:23])[CH2:10][CH:9]([C:11](=[O:12])[CH2:3][C:4]#[N:5])[CH2:8]1
Reactant: CC#N
Reactant: COc1ccc(COC(=O)C2CC(F)(F)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCC(=O)C1CC(F)(F)C1
Reaction time: 0.33 h
Yield: 155.1 %

Procedure:
To a solution of NaH (2.85 g, 71.1 mmol) in dioxane (200 mL) was added MeCN (2.92 g. 71.1 mmol). The mixture was stirred for 20 min, then the solution of 4-methoxybenzyl 3,3-difluorocyclobutanecarboxylate (14.0 g, 54.7 mmol) in dioxane (100 mL) was added dropwise. After the mixture was heated at reflux for 4 h, the reaction mixture was poured into water (400 mL) and extracted with EtOAc (200 mL). The pH of the aqueous layer adjusted to 7 with 3N HCl and extracted with EtOAc. The organic layer was washed with brine (200 mL), dried (Na2SO4), filtered and concentrated to afford 13.5 g crude 3-(3,3-difluorocyclobutyl)-3-oxopropanenitrile which was used in the next step without purification.