Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH2:41])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH:41][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CS(=O)(=O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
2-(Methylsulfonyl)acetic acid (601 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 (50 mL) was added. The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)acetamide (503 mg, 66.1% yield) was obtained as a solid.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[N:5]([O:14]COC)[C:4](=[O:18])[C:3]=1[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=1[CH3:27].Br[Si](C)(C)C.O>ClCCl>[OH:14][N:5]1[C:6]2([CH2:7][CH2:8][N:9]([O:12][CH3:13])[CH2:10][CH2:11]2)[C:2]([OH:1])=[C:3]([C:19]2[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])[C:4]1=[O:18]
Reactant: COCON1C(=O)C(c2c(C)cc(C)cc2C)=C(O)C12CCN(OC)CC2
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-8-methoxy-1-methoxymethoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2ii.6 obtained in analogy to preparation example 11, step 5) (500 mg, 1.33 mmol) in dichloromethane (10 ml) under argon atmosphere at 0° C. was added 3 {acute over (Å)} molecular sieves (0.5 g), followed by bromotrimethylsilane (1.72 ml, 2.03 g, 13.28 mmol) dropewise and the reaction mixture was stirred at 0° C. for one hour and at room temperature for 48 hours. The mixture was poured on cold water, the water layer saturated with sodium chloride and thoroughly extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate). Yield: 40 mg of 1,4-dihydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2ii.4) as a white solid, mp 152-154° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[C:13]([N:17]3[CH:22]=[C:21]([O:23]CC4C=CC(OC)=CC=4)[C:20](=[O:33])[CH:19]=[C:18]3[CH:34]([OH:36])[CH3:35])[CH:14]=[CH:15][CH:16]=2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[C:13]([N:17]3[CH:22]=[C:21]([OH:23])[C:20](=[O:33])[CH:19]=[C:18]3[CH:34]([OH:36])[CH3:35])[CH:14]=[CH:15][CH:16]=2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(COc2cn(-c3cccc(-c4c(Cl)cnc5[nH]ccc45)c3)c(C(C)O)cc2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1cc(=O)c(O)cn1-c1cccc(-c2c(Cl)cnc3[nH]ccc23)c1

Procedure:
To a 100 mL round-bottom flask containing 2.34 g (4.66 mmol) 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]-2-(1-hydroxyethyl)-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one was added 25 mL 1:1 (v/v) dichloromethane:trifluoroacetic acid and the solution stirred at room temperature for 30 min. Concentration in vacuo, purification by reversed phase HPLC (2 cm×5 cm C18, acetonitrile-water gradient, 0.05% TFA added), and elution from an SCX column (50 g, sulfonic acid, rinsed with MeOH, eluted with 1 N NH3 in MeOH) afforded 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]-5-hydroxy-2-(1-hydroxyethyl)pyridin-4(1H)-one. 1H NMR (600 MHz, DMSO, 50° C.): δ 11.96 (s, 1 H); 8.35 (s, 1 H); 7.75 (dd, J=7.9, 7.7 Hz, 1 H); 7.70 (d, J=7.8 Hz, 1 H); 7.60-7.55 (m, 3 H); 7.34 (s, 1 H); 6.46 (s, 1 H); 6.29 (s, 1 H); 4.41 (q, J=6.4 Hz, 1 H); 1.20 (d, J=6.4 Hz, 3 H). HRMS (FT/ICR) Calc (M+H)+ 382.0953 found 382.0955.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][OH:15])=[CH:6][CH:5]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:15][CH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH:2]([F:16])[F:1])=[CH:5][CH:6]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(OC(F)F)c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(OC(F)F)c2ccccc12

Procedure:
Prepared by reacting (4-difluoromethoxy-naphthalen-1-yl)-methanol with methanesulphonic acid chloride in methylene chloride in the presence of triethylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7](O)[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1.O.O.[Sn](Cl)Cl.Cl>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:2]=1
Reactant: OC(c1cccnc1)c1cccs1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: c1cncc(Cc2cccs2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
To a solution of 2-(3-pyridylhydroxymethyl)thiophene (8.82 g, 46.2 mmol), prepared as in step 1, in acetic acid (50 mL) was added tin(II)chloride dihydrate (22.9 g, 101 mmol) and HCl gas was bubbled through the reaction mixture for about 10 min. The reaction mixture was stirred for 1.5 hours at ambient temperature, and the liquid was decanted, concentrated in vacuo to a volume of about 10 mL, and poured into H2O. The aqueous solution was made basic by the slow addition of saturated aqueous NaHCO3 and extracted with ethyl acetate/ether. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (5% methanol/CHCl3) gave 2-(3-pyridylmethyl)thiophene (2.63 g).
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:16]([F:27])=[C:15]2[C:10]=1[C:11](=[O:34])[C:12]([C:31]([OH:33])=[O:32])=[CH:13][N:14]2[CH:28]1[CH2:30][CH2:29]1)C1C=CC=CC=1.C(O)(=O)C>[C].[Pd].C(O)C>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[C:16]([F:27])=[C:15]2[C:10]=1[C:11](=[O:34])[C:12]([C:31]([OH:33])=[O:32])=[CH:13][N:14]2[CH:28]1[CH2:30][CH2:29]1
Reactant: CN1CCN(c2c(F)c(NCc3ccccc3)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A mixture of 5-benzylamino-1-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (700 mg), 5% palladium-carbon (0.2 g), acetic acid (10 ml), and ethanol (15 ml) was stirred at room temperature for 30 minutes under a hydrogen stream. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. After addition of water to the residue, the mixture was adjusted to pH 8 with aqueous ammonia. The resulting crystals were filtered to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (510 mg), m.p. 254°-255° C.
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:20][NH:21][C:22]([CH2:27][S:28][CH3:29])([CH2:25][OH:26])[CH2:23][OH:24])=[CH:11]1)C1C=CC=CC=1.Cl.[NH2:31]N.ClCCl>N.[Pd]>[NH2:31][C:17]1[C:18]2[NH:10][CH:11]=[C:12]([CH2:20][NH:21][C:22]([CH2:27][S:28][CH3:29])([CH2:25][OH:26])[CH2:23][OH:24])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CSCC(CO)(CO)NCc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Reactant: NN
Agent: [Pd]
Agent: Cl
Agent: N
Solvent: ClCCl
Product: CSCC(CO)(CO)NCc1c[nH]c2c(N)ncnc12
Yield: 36.4 %

Procedure:
To a suspension of 2-((5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-2-(methylthiomethyl)propane-1,3-diol (9.0 mg, 0.037 mmol) and palladium-black (10 mg) in 7 M methanolic ammonia (2 mL) was added hydrazine hydrochloride (0.250 mL, 6.87 mmol) dropwise. After 1 h at ambient temperature the reaction was virtually complete by TLC (dichloromethane:7 M methanolic ammonia, 3:1, visualised with UV and Erlichs). The supernatant solution was filtered through a small pad of celite and the palladium was washed twice with methanol and also filtered through celite. The combined filtrates were concentrated under reduced pressure and the resulting residue triturated with chloroform and dichloromethane. Lyophilization of the residue gave 2-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-2-(methylthiomethyl)propane-1,3-diol (4 mg, 63%) as a white solid. 1H NMR (D2O) δ 8.16 (s, 1H), 7.58 (s, 1H), 4.12 (s, 2H), 3.79-3.70 (m, 4H), 2.85 (s, 2H), 2.15 (s, 3H). +ESMS Found 298.1346 (M+H+) C12H20N5O2S requires 298.1338.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][C:11]1([CH3:21])[CH3:20]>CO>[CH3:20][C:11]1([CH3:21])[CH:10]([CH2:9][CH2:8][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1
Reactant: CC1(C)Oc2ccccc2CC1CCN
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CCC1Cc2ccccc2OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.74 g (55 mmol) of acrylic acid methyl ester are added at room temperature to a solution of 5.13 g (25 mmol) of 3-(2-aminoethyl)-2,2-dimethylchroman in 50 ml of methanol. The mixture is stirred for 16 hours at room temperature and then concentrated by evaporation in vacuo, yielding 9.43 g (100% of the theorectical yield) of N-[2-(2,2-dimethylchroman-3-yl)-ethyl]-N,N-bis(2-methoxycarbonylethyl)-amine in the form of a light-yellow oil which is further used in that form.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[F:23][CH:24]([F:32])[O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:23][CH:24]([F:32])[O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:5])[CH2:28][CH2:27]1
Reactant: FC(F)OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC(F)F)CC1
Reaction time: 2 h

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 4-(difluoromethoxy)piperidine (18) (0.101 g, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.381 g, 1.01 mmol) were added to N,N-dimethylformamide (30 mL). To this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and the reaction was stirred for 2 hours before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.266 g, 92%); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.45 (1H, m), 1.65-1.56 (1H, m), 1.83-1.74 (1H, m), 1.98-1.92 (1H, m), 3.15-3.09 (1H, m), 3.40-3.26 (2H, m), 4.01-3.91 (1H, m), 4.33 (2H, s), 4.41-4.35 (1H, m), 6.75 (1H, t), 7.22 (1H, t), 7.38-7.36 (1H, m), 7.44-7.40 (1H, m), 7.83 (1H, t), 7.88 (1H, t), 7.97 (1H, d), 8.27 (1H, d), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 432).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)([O-:5])=[O:4].[O-][Cl:16].[Na+].Cl>O>[Cl:16][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=2)[NH:11][N:10]=1
Reactant: [O-]Cl
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]nc(Cl)c2c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
A mixture of NaOH (5.00 g, 125 mmol) in H2O (150 mL) was added 5-nitroindazole (5.00 g, 30.7 mmol), and the mixture was heated until a red solution formed. The mixture was cooled in an ice-water bath for 15 minutes, NaClO (60.0 mL, 5.25%, 45.0 mmol) was added and the mixture stirred at 0° C. for 5 hour after which the pH was adjusted to 7 with diluted HCl. The mixture was extracted with ethyl acetate, and the combined organic layer washed with H2O and concentrated under reduced pressure. The residue was purified by flash chromatography to provide the title compound (5.5 g, 92%). 1H NMR (300 MHz, DMSO-d6) ppm 7.78 (m, 1H), 8.28 (m, 1H), 8.61 (m, 1H), MS (DCI/NH3) m/Z 197[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([O:12][CH3:13])[N:3]=1.[Li+].[BH4-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:12][CH3:13])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)cc(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of methyl (2-chloro-6-methoxypyridin-4-yl)carboxylate (15-1, 2.0 g, 9.92 mmole) in dry THF (40 mL) was added LiBH4 (7.4 mL, 2 M in THF, 14.88 mmole) then the mixture was heated to reflux. After 18 hr the mixture was cooled to RT and quenched by slow addition of H2O. The layers were separated and the aqueous layer extracted with EtOAc (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the titled compound a white solid which was sufficiently pure for use in the next step. 1H-NMR (500 MHz, CDCl3) δ 6.90 (s, 1 H), 6.65 (s, 1 H), 4.67 (m, 2 H), 3.94 (s, 3 H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH2:20][S:21][CH3:22])[N:16]=[N:15][C:14]=12.[OH:23]OS([O-])=O.[K+]>CN(C=O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH2:20][S:21]([CH3:22])=[O:23])[N:16]=[N:15][C:14]=12
Reactant: CSCn1nnc2c(-c3nc4ccccc4s3)ncn2c1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)Cn1nnc2c(-c3nc4ccccc4s3)ncn2c1=O
Temperature: 0 °C
Yield: 98 %

Procedure:
To a 0° C. solution of 8-(benzo[d]thiazol-2-yl)-3-(methylthiomethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (0.23 mmol, 75 mg, 1 eq.) in DMF (4.5 mL) was added slowly drop wise Oxone™ (0.25 mmol, 77 mg, 1.1 eq.) dissolved in water (0.75 mL). The formed suspension was stirred at 0° C. and stepwise additions of Oxone™ in water were made until reaction completion. The reaction mixture was filtered and the obtained solid washed with water, acetonitrile, ethyl acetate and ether, and dried under vacuum to give the title compound. Yield: 98%. δH (DMSO-d6) 9.07 (1H, s), 8.22 (1H, m), 8.16 (1H, m), 7.60 (1H, m), 7.52 (1H, m), 5.63 (1H, d, J=13.2), 5.50 (1H, d, J=13.2), 2.79 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CC(O)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1ccc(Cl)nn1
Solvent: CC(C)O
Product: CN1CCN(c2ccc(C(N)=O)nn2)CC1
Temperature: 130 °C
Yield: 75.3 %

Procedure:
6-Chloropyridazine-3-carboxamide (0.315 g, 2 mmol) and 1-methylpiperazine (0.555 ml, 5.00 mmol) were suspended in 2-propanol (2.000 ml) and sealed into a microwave tube. The reaction was heated to 130° C. for 30 mins in the microwave reactor and cooled to ambient temperature. The resulting precipitate was collected by filtration, washed with 2-propanol (10 mL) and dried under vacuum to afford 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (0.333 g, 75%) as a white solid, which was used without further purification. A sample (100 mg) of the crude product was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (54 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[Cu][C:16]#[N:17].C(N)CN>CN(C=O)C.[Cu]I>[OH:13][CH2:12][CH2:11][C@H:10]1[C:5]2[CH:4]=[CH:3][C:2]([C:16]#[N:17])=[CH:14][C:6]=2[CH2:7][CH2:8][O:9]1
Reactant: N#C[Cu]
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Agent: [Cu]I
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CCO[C@H]2CCO
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A suspension of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (300 g, 1.17 mol), copper(I) cyanide (209 g, 2.34 mol), and copper(I) iodide (33.3 g, 0.18 mol) in dry DMF (1.16 L), under an atmosphere of nitrogen, was heated to 140° C. After 8 h at this temperature, HPLC analysis of an aliquot indicated that the reaction was complete. The reaction mixture was cooled to room temperature and poured into an aqueous solution of ethylenediamine (3 L, v/v 3/1) then extracted into toluene. The combined organic layers were washed with water and concentrated in vacuo to give the crude title compound. This material is used without further purification in the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:43]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(CCNC(=O)OC(C)(C)C)CCCC1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)C1(CCNC(=O)OC(C)(C)C)CCCC1
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To a solution of N-[[1-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (1.00 g, 2.16 mmol) in toluene/dioxane (1:1, 10 mL) was added Lawesson's reagent (0.524 g, 1.29 mmol). The resultant mixture was warmed to 50° C. and was stirred for 24 h. The reaction mixture was filtered through a sintered glass funnel and the filtrate was concentrated in vacuo. Purification of the crude product by silica gel flash column chromatography (hexane-ethyl acetate, 6:1 then 4:1), afforded N-[[1-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (460 mg, 44%; 65% based on recovered starting material) as a light yellow oil. HR MS: Obs. mass, 478.2014. Calcd. mass, 478.2012 (M−H).
Reaction SMILES: [CH2:1]1[C@@:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[C:17]2=[O:27])=[CH:12][CH:11]=1.Br[CH2:29][CH2:30][CH2:31][F:32]>>[F:32][CH2:31][CH2:30][CH2:29][N:7]1[CH2:8][CH2:9][C@@:5]2([CH2:1][N:2]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=5)[C:17]4=[O:27])=[CH:12][CH:11]=3)[CH2:3][CH2:4]2)[CH2:6]1
Reactant: FCCCBr
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@]3(CCNC3)C2)cc1
Product: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@]3(CCN(CCCF)C3)C2)cc1

Procedure:
According to Method X, 2-[(S)-4-(2,7-diaza-spiro[4.4]non-2-yl)-phenyl]-6-hydroxy-2H-isoquinolin-1-one was reacted with 1-bromo-3-fluoro-propane. In this way the product was obtained with molecular weight 421.52 (C25H28FN3O2); MS (ESI): 422 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH:5]([S:16][CH3:17])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].[C:18](NC(OCC)C(NCC1C=CC=CC=1)=O)(=O)C.CCS>>[C:1]([NH:4][CH:5]([S:16][CH2:17][CH3:18])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Reactant: CSC(NC(C)=O)C(=O)NCc1ccccc1
Solvent: CCS
Product: CCSC(NC(C)=O)C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
Using the procedure described for the synthesis of 2-acetamido-N-benzyl-2-(methylmercapto)acetamide, 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol) and EtSH (0.65 g, 10.4 mmol) were converted to 0.80 g (38%) of the desired product. The compound was further purified by recrystallization from chloroform/hexane to give a beige solid.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][CH2:24][F:25])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[F:25][CH2:24][O:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1
Reactant: NNc1nc2ccc(OCF)cc2s1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: O=C(NNc1nc2ccc(OCF)cc2s1)c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4f was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (430 mg, 1 mmol) and 2-hydrazino-6-fluoromethoxybenzothiazole (274 mg, 1.5 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 242 mg, 75%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Cl.[CH3:16][C:17]1([CH3:24])[CH2:22][NH:21][C:20]([NH2:23])=[N:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:16][C:17]1([CH3:24])[CH2:22][N:21]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:23]=[C:20]2[NH:19][CH2:18]1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CC1(C)CN=C(N)NC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(C)CNc2nc(-c3ccncn3)cc(=O)n2C1

Procedure:
A mixture containing 5.15 g (26.52 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate, (prepared by analogy to the method described in patent DE 2705582), 4.34 g (26.52 mmol) of 5,5-dimethyl-1,4,5,6-tetrahydro-2-pyrimidinamine monohydrochloride (prepared by analogy to U.S. Pat. No. 4,262,122) and 3.66 g (26.5 mmol) of potassium carbonate in 60 ml of methanol were heated at reflux temperature during 18 h.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])[CH:7]=[CH:8][CH:9]=1.[CH2:20]([O:22][C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Cl)[CH3:21]>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[C:11]1=[O:19])[CH3:21]
Reactant: O=c1[nH]c2ccccc2n1-c1cccc(Cl)c1
Reactant: CCOC(=O)CCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(=O)n(-c2cccc(Cl)c2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 1.2 g. of NaH (80% suspension in mineral oil), 9.8 g. of 1-(3-chlorophenyl)-benzimidazolin-2-one (produced in usual manners by subjecting N-(3-chlorophenyl)-o-phenylene diamine to reaction of phosgene), 80 cc. of DMF, 7.7 g. of 7-chloroenanthic acid ethyl ester and 1.2 g. of NaJ.