Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[C:9]3[S:25][CH:24]=[CH:23][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:15]=3F)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].CO.Cl.[O:32]1CCOC[CH2:33]1>C(Cl)(Cl)Cl.CO>[ClH:21].[N:1]1([C:8]2[C:9]3[S:25][CH:24]=[CH:23][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:15]=3[O:32][CH3:33])[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCO1
Reactant: Fc1cc(-c2nc(N3CCCCCC3)c3sccc3n2)c(F)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(Cl)c(F)cc1-c1nc(N2CCCCCC2)c2sccc2n1
Temperature: 120 °C
Reaction time: 120 h

Procedure:
A mixture of 514 mg of 4-azepane-1-yl-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine, 300 mg of sodium methoxide and 10 ml of MeOH was stirred in a sealed tube for 5 days at 120° C. After the reaction mixture was concentrated under reduced pressure, 40 ml of water was added to the obtained residue and extracted twice with 40 ml of chloroform. After the organic layer washed with a saturated saline solution and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to give a solid. After 0.6 ml of 4M HCl-dioxane solution was added to 10 ml of chloroform-MeOH with this solid, the resultant was concentrated under reduced pressure to give a solid. After the obtained solid was recrystallized three times from EtOAc and EtOH, the crystal generated was filtered and washed with EtOAc to give 223 mg of 4-azepane-1-yl-2-(4-chloro-5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine hydrochloride.
Reaction SMILES: [CH:1]1([NH2:16])[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[C:24]([NH:16][CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(=O)Cl
Reactant: Nc1c2c(nc3ccccc13)CCCC2N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(=O)NC1CCCc2nc3ccccc3c(N)c21
Reaction time: 0.08 h

Procedure:
To a chilled solution of 1,2,3,4-tetrahydro-1,9-acridinediamine (4.96 g) and triethylamine (3.6 ml) in 100 ml of tetrahydrofuran was added hexanoylchloride (3.6 ml). This was stirred for five minutes, then quenched into adilute NaOH solution. The aqueous phase was extracted with ethyl acetate (3x) and dried (MgSO4). The organics were concentrated to a semi-solid which was triturated with ethyl ether to give 3.32 g of a pale yellow powder, m.p. 205°-211° C. (dec.). This was recrystallized from methanol/water to give 2.54 g of a pale yellow powder,m.p. 214°-217° (dec.).
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:19]([CH3:20])[C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13](B(O)O)=[CH:14][C:15]=3[C:6]=2[N:5]1[C:21]1[CH:22]=[N:23][C:24]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:25][CH:26]=1)#[N:2].Br[C:33]1[C:34]([CH3:43])=[CH:35][C:36]([NH:39][C:40](=[O:42])[CH3:41])=[N:37][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:1]([N:3]=[C:4]1[N:19]([CH3:20])[C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([C:33]4[C:34]([CH3:43])=[CH:35][C:36]([NH:39][C:40](=[O:42])[CH3:41])=[N:37][CH:38]=4)=[CH:14][C:15]=3[C:6]=2[N:5]1[C:21]1[CH:22]=[N:23][C:24]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:25][CH:26]=1)#[N:2]
Reactant: CC(=O)Nc1cc(C)c(Br)cn1
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)nc2)c2c3cc(B(O)O)ccc3ncc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C)c(-c2ccc3ncc4c(c3c2)n(-c2ccc(C(C)(C)C#N)nc2)c(=NC#N)n4C)cn1
Temperature: 111 °C

Procedure:
To the stirred solution 2-(cyanoimino)-1-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-ylboronic acid (0.390 mmol) in dry DMF (5 mL) was added N-(5-bromo-4-methylpyridin-2-yl)acetamide (0.390 mmol) followed by catalyst palladium dichlorobis triphenylphosphine (0.039 mmol). Saturated solution of sodium carbonate (0.780 mmol) was added to it and the resulting solution was heated to 111° C. for 8 minutes in microwave. Solvent was evaporated and the crude material was extracted in EtOAc, washed with brine several times and dried over anhydrous Na2SO4. The solvent was evaporated and the crude solid was purified (silica gel column, CHCl3/MeOH as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.46 (s, 1H), 9.26 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.35 (dd, J=2.4, 8.4 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.91 (m, 3H), 7.70 (dd, J=1.8, 8.7 Hz, 1H), 6.60 (s, 1H), 3.90 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.70 (s, 6H); MS (m/z): 516 (M+1)+.
Reaction SMILES: [OH:1][C@H:2]([CH:18]([CH3:20])[CH3:19])[C:3]([NH:5][C@H:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH3:7])=[O:4].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:19][CH:18]([CH3:20])[C@@H:2]([O:1][S:29]([CH3:28])(=[O:31])=[O:30])[C:3]([NH:5][C@H:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH3:7])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](O)C(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OS(C)(=O)=O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of methyl 4-[(1S)-1-[[(2R)-2-hydroxy-3-methyl-butanoyl]amino]ethyl]benzoate (40 g; 143 mmol), and triethylamine (22.0 mL, 157 mmol) in CH2Cl2 (400 mL) is cooled to 0° C. A solution of methanesulfonyl chloride (11.1 mL, 143 mmol) in CH2Cl2 (200 mL) is added dropwise over 45 min, and the mixture is stirred to room temperature for 1 h. The mixture is washed sequentially with 1N HCl (100 mL) and aq. NaHCO3 (200 mL). The organic layer is dried over MgSO4, filtered, and concentrated. The crude material is slurried in methyl t-butyl ether (200 mL) and hexane (600 mL) for 30 min, filtered, and dried under vacuum to provide the title compound as a white solid (50 g, 98%). MS (m/z): 358.2 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:13]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OP([CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])(OCC)=O)C.[H-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])/[CH:13]=[CH:28]/[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)CC[C@H](C=O)CCCO[Si](C)(C)C(C)(C)C
Reactant: CCOP(=O)(CC(=O)OCc1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)CC[C@H](/C=C/C(=O)OCc1ccccc1)CCCO[Si](C)(C)C(C)(C)C

Procedure:
A solution of Example 8H (2.61 g, 9.16 mmol), benzyl diethylphosphonoacetate (2.83 g, 9.90 mmol), and sodium hydride (0.24 g, 10 mmol) in benzene (40 mL) at room temperature was stirred 2 hours, diluted with ethyl acetate, washed sequentially with saturated aqueous NH4Cl and pH 7 buffer, dried (MgSO4), filtered, and concentrated. Flash column chromatography (silica gel, 2:1 hexanes/CH2Cl2) provided the desired product. MS (ESI) m/e 419 (M+H)+.
Reaction SMILES: CCO.[C:4]1([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([O:20]CC3C=CC=CC=3)[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>[C].[Pd].C1COCC1>[O:20]=[C:12]1[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=[C:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:11]1
Reactant: [H][H]
Reactant: COC(=O)c1cc(OCc2ccccc2)nc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1

Procedure:
In a nitrogen atmosphere, 10% palladium-carbon (3.2 g) was added to an EtOH (50 mL)-THF (5 mL) mixed solution of methyl 2-phenyl-6-benzyloxypyridine-4-carboxylate (5.3 g), and in a hydrogen atmosphere, this was stirred at room temperature for 9 hours. The reaction liquid was filtered through Celite, concentrated under reduced pressure, and a mixed solution of hexane/ethyl acetate=2/1 was added thereto. The precipitate was taken out through filtration, washed with that solution, and dried to obtain the title compound as a white powder. The filtrate was concentrated, and the residue was purified through silica gel column chromatography (from hexane/ethyl acetate to chloroform/methanol), and combined with the previous powder to obtain the title compound as a white powder.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[C:15]([C:21]([O:23]C)=O)=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])=O)=[CH:7][C:6]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]1)=[O:26]>C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:14]3[C:15](=[C:16]([CH3:20])[NH:17][C:18]=3[CH3:19])[C:21](=[O:23])[NH:2][N:3]=2)=[CH:7][C:6]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]1)=[O:26]
Reactant: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)[nH]c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
Hydrazine hydrate (0.021 mL, 0.28 mmol) was added to methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (57) (0.108 g, 0.25 mmol) in acetic acid (4 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 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 afford the desired material (0.033 g, 31.9% yield). 1H NMR (399.902 MHz, DMSO) δ 1.30 (1H, m), 1.44 (1H, m), 1.72 (1H, m), 1.87 (1H, m), 2.27 (3H, s), 2.51 (3H, s), 3.05 (1H, m), 3.26 (3H, s), 3.32 (2H, m), 3.42 (1H, m), 3.92 (1H, m), 4.08 (2H, s), 7.14-7.30 (3H, m), 11.08 (1H, s), 11.94 (1H, s); m/z (LC-MS, ESI+), RT=1.44 min (M+H=413.36).
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)N(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (610 mg) in methylene chloride (30 ml) is added triethylamine (0.22 ml), and further thereto is added dimethylcarbamoyl chloride (0.15 ml) under ice-cooling. The mixture is stirred at room temperature for 5 hours. The reaction mixture is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent; chloroform) to give the desired compound (720 mg) as white amorphous.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.Br[CH2:19][CH2:20][CH3:21].CC(C)([O-])C.[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:17][CH2:19][CH2:20][CH3:21])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2
Reactant: CCCBr
Reactant: COC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(Br)ccc2c1CC[C@H](C)N2C(=O)OC
Temperature: 100 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
A mixture of (S)-methyl 6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.110 g, 0.366 mmol), 1-bromopropane (0.166 mL, 1.832 mmol), and potassium tert-butoxide (0.103 g, 0.916 mmol) in DMF (3.0 mL) was heated in a sealed tube at 100° C. After 24 h, additional 1-bromopropane (0.166 mL, 1.832 mmol) and potassium tert-butoxide (0.103 g, 0.916 mmol) were added and the mixture was heated in a sealed tube at 100° C. for 24 h. The reaction mixture was cooled to rt and water was added. The mixture was extracted with dichloromethane and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-methyl 6-bromo-2-methyl-5-propoxy-3,4-dihydroquinoline-1 (2H)-carboxylate (0.120 g, 96%) as a colorless oil. MS (ESI, pos. ion) m/z 342, 344 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][C@H:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]1)[CH:8]=[CH:7]2)([O-])=O>C(O)C.O.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][C@H:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: O=[Pt]
Solvent: O
Solvent: CCO
Product: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(6-Nitro-quinolin-2-yl)-(R)-indan-1-yl-amine (0.37 g, 1.2 mmol) was dissolved in ethanol (15 mL). Platinum oxide hydrate (9 mg) was added and the mixture stirred for 4 h at ambient temperature under an atmosphere of hydrogen. The reaction mixture was filtered and evaporated and the residue was subjected to column chromatography (silica gel, heptane, ethyl acetate 1:0=>6:4). (6-Amino-quinolin-2-yl)-(R)-indan-1-yl-amine was isolated as a yellow foam (0.22 g, 66%); MS 276.5 [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:42]([O:43][CH3:44])=[CH:41][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:42]([O:43][CH3:44])=[CH:41][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CC(=O)N1CCOCC1)CC2
Yield: 60 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone. Product was isolated as a white foam (65 mg, 60%). mp: 100° C., MS (ESI+): 629.6 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.53 (s, 1H), 8.57 (d, J=9 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.95 (d, J=8 Hz, 1H), 7.62 (t, J=8 Hz, 1H), 7.52 (s, 1H), 6.67 (s, 1H), 3.90 (s, 3H), 3.74 (s, 8H), 3.67 (d, 2H), 3.30 (m, 3H), 2.87 (m, 2H), 2.74-2.66 (m, 6H), 1.33 (d, J=7 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][C:11]([CH3:15])=[C:12]([O:13][CH3:14])[C:3]=12.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:15][C:11]1[N:10]=[CH:9][C:4]2=[C:5]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:6]=[N:7][C:2]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:3]2[C:12]=1[O:13][CH3:14]
Reactant: C1COCCN1
Reactant: COc1c(C)ncc2c(Cl)nnc(Cl)c12
Product: COc1c(C)ncc2c(N3CCOCC3)nnc(N3CCOCC3)c12

Procedure:
0.5 part by weight of 1,4-dichloro-7-methyl-8-methoxypyrido[3,4-d]pyridazine and 3.6 parts by weight of morpholine are heated together at 80°C for 1.5 hour and, then, the excess morpholine is distilled off. To the residue is added water, whereupon an oily precipitate is obtained. This oil is triturated with a small amount of methanol to obtain crystals of 7-methyl-8-methoxy-1,4-dimorpholinopyrido[3,4-d]pyridazine. Recrystallization from a mixture of methanol and water (1:3) yields crystals melting at 145°-146°C. Yield 0.5 part by weight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1.ClCCl>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7])(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N#Cc1ccc(N)cc1C#N
Reactant: CCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc(C#N)c(C#N)c1
Reaction time: 2 h
Yield: 70.9 %

Procedure:
4-Aminophthalonitrile (3.60 g, 25.2 2.mmole) was dissolved in 8.6 mL of pyridine. Hexanoyl chloride (8.6 10, 61.5 mmole) was added and the mixture was stirred under N2 for 2 hours. The pyridine was distilled under vacuum until a yellow-orange residue was obtained. This residue was dissolved in dichloromethane and washed with 0.1 M HCl (5×15 mL) and then neutralized with aqueous sodium bicarbonate (3×50 mL). The organic solution was separated and dried over magnesium sulfate. Purification by column chromatography (silica, dichloromethane: methanol 5%) afforded 4.3 g (71% yield) of 4-hexanamidophthalonitrile as a light yellow compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[S:4](=[O:15])[CH2:3][CH2:2]1.C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:19][N:20]([CH:22]=[C:3]1[CH2:2][CH2:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[S:4]1=[O:15])[CH3:21]
Reactant: CCOC(OCC)N(C)C
Reactant: O=S1CCCc2c1ccc1ccccc21
Product: CN(C)C=C1CCc2c(ccc3ccccc23)S1=O

Procedure:
From 3-dimethylaminomethylenebenzo[f]thiochroman-4-one (400 mg, 1.26 mmol) and 4-(2-dimethylaminoethoxy)phenylguanidinium dinitrate (438 mg, 1.26 mmol) to afford the title compound (155 mg) as a canary yellow solid m.p. 165-167°. δH (CDCl3) 9.08 (1H, d, J 8.3 Hz), 8.38 (1H, s), 7.77 (2H, m), 7.55-7.46 (5H, m), 7.05 (1H, br s), 6.88 (2H, m), 4.05 (2H, t, J 5.8 Hz), 3.78 (2H, s), 2.73 (2H, t, J 5.8 Hz) and 2.34 (6H, s). MS (ES+) 429 (MH+). 3-Dimethylaminomethylenebenzo[f]thiochroman-4-one was prepared from benzo[f]thiochroman-4-one (1.50 g, 7.01 mmol) and N,N-dimethyl-formamide diethylacetal to give the compound as a yellow solid (1.67 g) m.p. 163-1650. MS(EI) 269 (M+, 49.8%), 82 (100%).
Reaction SMILES: C([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7]C1(C)C)(=O)CC.Cl.[OH-].[Na+]>C(Cl)Cl.O>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([C@@H:8]([OH:7])[C@H:9]([NH2:5])[CH2:10][F:11])=[CH:17][CH:16]=1)(=[O:20])=[O:19]
Reactant: CCC(=O)N1[C@H](CF)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Temperature: 95 °C

Procedure:
Methylene chloride (450 mL) distills from a solution of (4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound IX: R1 is methylsulfonyl, R2 and R3 are methyl and R4 is ethyl) (50.0 g, 0.1456 moles) after addition of water (300 mL) containing 20% hydrochloric acid and heating to 90-100° C. for 2-4 hours. Adjusting the pH to greater than 12 by addition of sodium hydroxide and extraction with methylene chloride (350 mL) yields a solution of (1R,2S)-1-[4-(methylsulfonyl)phenyl]-2-amino-3-fluoro-1-propanol (Compound Xa). Methanol (150 mL) replaces methylene chloride which distills off. Addition of methyl dichloroacetate (52.0 g, 0.3640 moles) and triethylamine (11.0 g, 0.1092 moles) with agitation for 12-16 hours at 20-25° C. then addition of water (150 mL) and toluene (100 mL) precipitates the crude product. Filtration, washing with water (75 mL) and toluene (125 mL) then dissolution in water (50 mL) and isopropanol (100 mL) at reflux, cooling to 20-25° C., filtration of the solids, washing with 1 to 1 water/isopropanol (50 mL) then drying gives pure (1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol (Florfenicol).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:38])=[CH:35][CH:34]=1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(Cl)cc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 4-chlorobenzoyl chloride (0.5 g, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched with MeOH (1 mL). The suspension was then filtered, and the solid was rinsed with CH2Cl2 (10 mL) to afford 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a white solid (0.5 g, 52%): mp, 233-235° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.7 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.84-2.93 (m, 1H), 4.95 (d, J=5.8 Hz, 2H), 5.15-5.20 (dd, J=5, 12 Hz, 1H), 7.56-7.59 (dd, J=1.7, 6.8 Hz, 2H), 7.72-7.83 (m, 3H), 7.93-7.96 (dd, J=1.8, 6.8 Hz, 2H), 9.23 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.38, 48.86, 121.90, 127.15, 128.45, 129.25, 131.53, 132.65, 133.09, 134.80, 136.28, 139.08, 165.57, 166.94, 167.51, 169.81, 172.74. Anal Calcd for C21H16ClN3O5: C, 59.23; H, 3.79; N, 9.87; Cl, 8.33. Found: C, 59.27; H, 3.42; N, 9.75; Cl, 8.57.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].Cl[CH:26]([F:28])[F:27].Cl>CO>[F:27][CH:26]([F:28])[O:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:19])[CH3:20])([CH3:17])[N:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: FC(F)Cl
Reactant: COC(=O)c1cc(O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(OC(F)F)cnc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 5 °C

Procedure:
Into a solution containing 1.25 g methyl 5-hydroxy-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate and 1.40 g sodium methoxide in 50 mL absolute methanol at 50° C. is passed through a dispersion tube, chlorodifluoromethane for one hour. The mixture is cooled to 5° C. and the pH adjusted to 5 with 2N methanolic HCl. The solution is filtered and the filtrate concentrated in vacuo. The residue is extracted with 2×100 mL ether, the extracts combined, dried and concentrated. The residue is chromatographed on silica gel using ether as the eluant to give the product, analytically pure methyl 5-difluoromethoxy-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate as a white crystalline solid, mp 104°-105° C.