Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.C(O)(=O)C.[O-:15][C:16]#[N:17].[K+]>O>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:17][C:16]1=[O:15]
Reactant: COC(=O)c1sccc1N
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
To a mixture of methyl 3-amino-thiophenecarboxylate 1 (850 g, 5.41 mol, 1.0 equiv.), acetic acid (6 L) and water (5 L), a solution of potassium cyanate (KOCN, 1316 g, 16.22 mole, 3.0 equiv.) in water (3.2 L) was added slowly over a period of 1 hour. The resulting mixture was stirred at the ambient temperature for 20 hour, filtered and rinsed with water (4 L). The cake was charged to a suitably sized reactor and 2 M aqueous sodium hydroxide solution (14 L) was added. The slurry was stirred for 2 hours and LCMS confirmed the formation of the desired product. The mixture was cooled to 10° C. and 3 M aqueous hydrochloric acid (˜11 L) was added until pH=5.0-6.0 (by pH paper). The slurry was filtered, rinsed with water (6 L), dried in vacuum oven at 50° C. for 24 hours to afford thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 2 as an off-white solid (834 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J=5.2 Hz, 1H), 8.10 (d, J=5.2 Hz, 1H), 5.40-5.55 (br s, 2H). LCMS (ESI pos) m/e 169 (M+1).
Reaction SMILES: [C-]#N.[K+].CC(C)(O)[C:6]#[N:7].[Cl:10][C:11]1[CH:12]=[C:13](/[C:18](/[C:41]([F:44])([F:43])[F:42])=[CH:19]\[C:20]([C:22]2[CH:39]=[CH:38][C:25]([C:26]([NH:28][CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:27])=[C:24]([CH3:40])[CH:23]=2)=[O:21])[CH:14]=[C:15]([Cl:17])[CH:16]=1.O>C1(C)C=CC=CC=1>[C:6]([C@@:18]([C:13]1[CH:12]=[C:11]([Cl:10])[CH:16]=[C:15]([Cl:17])[CH:14]=1)([C:41]([F:44])([F:42])[F:43])[CH2:19][C:20]([C:22]1[CH:39]=[CH:38][C:25]([C:26]([NH:28][CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:27])=[C:24]([CH3:40])[CH:23]=1)=[O:21])#[N:7]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Reaction time: 96 h
Yield: 31.7 %

Procedure:
Potassium cyanide (0.0082 g, 0.125 mmol) and acetone cyanohydrin (0.031 ml, 0.336 mmol) were added to a solution of 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (0.0600 g, 0.111 mmol) in toluene (3.0 ml). To this vigorously stirred suspension was added antracen-9-yl-methyl quininium chloride (0.0153 g, 0.028 mmol). The reaction mixture was stirred at 90 C for 4 days. After this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane) to afford 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (0.020 g, 32%) as a light yellow solid. Chiral HPLC analysis (Chiralpack AS-RH, acetonitrile:water:methanol=45:5:50, 1 ml/min, retention time 8.70 minutes (major enantiomer), 11.30 minutes (minor enantiomer) indicated that the reaction proceeded with 94% enantioselectivity.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH:15]([CH2:20][CH2:21]O)[C:14]=3[CH:13]=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:3][CH2:21][CH2:20][CH:15]1[CH2:16][CH2:17][CH2:18][C:19]2[N:11]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:12]=[CH:13][C:14]1=2
Reactant: OCCC1CCCc2c1cnn2-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: ClCCC1CCCc2c1cnn2-c1ccccc1
Temperature: 90 °C
Yield: 76 %

Procedure:
Thionyl chloride (4 mL) is slowly added at room temperature over a solution of 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)ethanol (516 mg, 2.13 mmol) in 25 mL of toluene. The reaction mixture is heated at 90° C. during 2 hours. The solvent is eliminated at reduced pressure. The crude is diluted in ethyl acetate and washed twice with a NaHCO3 solution. The solvent is next evaporated at reduced pressure, to obtain 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazole (423 mg, 1.62 mmol, 76%, oil).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16])=[C:6]=[O:7]>C1(C)C=CC=CC=1>[CH2:13]([NH:14][C:15]([N:3]1[CH2:4][CH:2]1[CH3:1])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:5][C:6]([N:3]1[CH2:4][CH:2]1[CH3:1])=[O:7]
Reactant: O=C=NCCCCCCN=C=O
Reactant: CC1CN1
Solvent: Cc1ccccc1
Product: CC1CN1C(=O)NCCCCCCNC(=O)N1CC1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methyl aziridine (15.05 grams, 0.26 moles) was added drop wise over one hour to a solution of 1,6-diisocyanatohexane (20.00 grams, 0.12 moles, Aldrich) in toluene (40 mL) while cooling in an ice bath. After stirring for a total of 24 hours at room temperature, a potion of the solvent was removed under vacuum to give N,N′-(hexane-1,6-diyl)bis-(2-methylaziridine-1-carboxamide)
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:12]=1>C1(C)C=CC=CC=1>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][C:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:31][C:26]([O:25][CH2:24][CH3:23])=[O:27])[CH:12]=1
Reactant: O=C(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(CCCCOC1CCCCO1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 5.74 mL 93.33 mmol) of 0.58 M potassium hexamethyldisilazane in toluene is added dropwise 0.66 mL triethyl phosphonoacetate resulting in a yellow gelatinous mixture. This reaction mixture is stirred at room temperature for 25 minutes, a solution of 0.5 g (1.66 mmol) 1-(3-pyridyl)-4-oxo-8-(2-tetrahydropyranyloxy)-octane in 3 mL toluene is added and the mixture is refluxed for 15 hours. The reaction mixture is cooled to room temperature, quenched with 5 mL saturated aqueous ammonium chloride solution and extracted with ethyl acetate twice. The combined organic phase is washed with water and brine, dried, filtered and concentrated to give a brown oil which is purified by chromatography using 1:1 ethyl acetate, hexane to yield ethyl 3-[3-(3-pyridyl)propyl]-7-(2-tetra- hydropyranyloxy)-hept-2-enoate as a mixture of cis and trans isomers; NMR (CDCl3): delta 5.7 (s,1H), 4.2 (q,2H), 1.3 (t,3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:14][NH2:15])=[N:4][N:3]=1
Reactant: NN
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CCO
Solvent: O
Product: NNc1nnc(Cl)c2ccccc12
Temperature: 25 °C

Procedure:
10 g commercially available dichlorophthalazine are added portionwise at 90° C. to a solution of 50 ml ethanol and 20 ml hydrazine hydrate. After 10 min the reaction mixture is cooled to ambient temperature, the precipitate is filtered with suction and rinsed with ethanol to yield 8.4 g of the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)O1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:30])[C:26]=1[CH:27]([OH:29])[CH3:28]>>[F:30][C:25]1[C:26]([CH:27]([OH:29])[CH3:28])=[C:21]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)[CH:22]=[N:23][CH:24]=1
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: CC(O)c1c(F)cncc1Br
Product: CC(O)c1c(F)cncc1-c1ccc2c(c1)COC2=O

Procedure:
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-isobenzofuran-1-one and 1-(3-bromo-5-fluoro-pyridin-4-yl)-ethanol were reacted according to the procedure described in Example 35.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[N:23]=[C:22]4[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[N:25][N:26]([CH3:27])[C:21]4=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[N:23]=[C:22]4[C:24]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[N:25][N:26]([CH3:27])[C:21]4=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(n3)c(N3CCN(C)CC3)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(n3)c(N3CCN(C)CC3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 45 °C

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate (11 mg, 0.017 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was added 2N NaOH (174 μL). The reaction mixture was heated at 45° C. overnight. The reaction mixture was concentrated, the residue was dissolved in DMF and MeOH, filtered and purified by reverse phase HPLC (10-100% ACN/H2O+0.1% TFA) to give the product. 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=4.4 Hz, 1H), 7.97 (d, J=4.4 Hz, 1H), 7.85 (s, 1H), 7.70-7.57 (m, 4H), 5.22 (s, 1H), 4.75-4.74 (m, 2H), 3.92 (s, 3H), 3.61-3.59 (m, 2H), 3.36-3.34 (m, 4H), 2.94 (s, 3H), 2.61 (s, 3H), 0.96 (s, 9H). .LCMS-ESI+: calc'd for C32H35ClN6O3S: 619.2 (M+H+); Found: 619.3 (M+H+).
Reaction SMILES: O[C:2]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:16])[C:3]=1[CH3:17].P(Cl)(Cl)([Cl:20])=O.CN(C)C1C=CC=CC=1>>[Cl:20][C:2]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:16])[C:3]=1[CH3:17]
Reactant: CCOC(=O)c1c(O)c(C)c(=O)n2c1CCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n2c1CCC2
Reaction time: 16 h
Yield: 62.9 %

Procedure:
Compound 8b (659 mg, 2.8 mmol) was stirred in phosphorous oxychloride (1.5 mL, 15.8 mmol) at RT. Dimethylaniline (0.07 mL, 0.56 mmol) was added and the reaction stirred for 16 h. The solution was concentrated in vacuo, quenched with ice, and made basic with sat. NaHCO3 solution. The aqueous solution was concentrated in vacuo. The residue was taken up in a 20% MeOH/CH2Cl2 and insoluble inorganic salts were removed by filtration. Organics were concentrated and purified by silica gel chromatography (75% EtOAc/CH2Cl2) to give 450 mg (63%) of compound 8c as a white solid. MS (ES) [m+H] calc'd for C12H14ClNO3, 256. found 256.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15]>Cl.C(O)C>[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:15]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: CN(N)c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Agent: Cl
Solvent: CCO
Product: CN(N=Cc1ccc2ccccc2c1)c1ccccc1

Procedure:
3.1 g of 2-naphthaldehyde and 2.4 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude 2-naphthaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethyl acetate. The yield was 3.5 g (67.3%) of white needle-like crystals which melt at 172.5°-174.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH2:27][CH3:28])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].CN(C1C=CC=CN=1)C.[CH2:38]([NH:40][CH2:41][CH2:42][OH:43])[CH3:39]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:40]([CH2:38][CH3:39])[CH2:41][CH2:42][OH:43])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH2:27][CH3:28])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCNCCO
Reactant: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N(CC)CCO)ccc3OCC)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
0.64 g (1.5 mmol) of 4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 20 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of dimethylaminopyridine, 0.40 g (4.50 mmol) of 2-(ethylamino)-ethanol are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Chromatography (dichloromethane/methanol=95:5) gives 0.454 g (63%) of a colourless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[NH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1.[CH3:23][N:24](C=O)C>O>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[NH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1)#[N:24]
Reactant: O=c1[nH]cc2c(c1-c1ccc(Br)cc1)Nc1ccccc1S2
Reactant: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2c3c(c[nH]c2=O)Sc2ccccc2N3)cc1

Procedure:
To 10 parts of 4-(4-bromophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one suspended in 300 parts of DMF is added 4 parts of cuprous cyanide and the reaction mixture is refluxed for 2 to 12 hours. After cooling, water is added and the solution extracted with ethyl acetate. The combined extracts are washed with saturated NaCl solution and dried. Solvent removal gives a residue which upon recrystallization from aqueous DMF gives 4-(4-cyanophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one, which melts above 290° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][CH3:24])[N:15]=[C:14]([NH:25][CH3:26])[N:13]=2)[CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7])[CH3:2].CCN(C(C)C)C(C)C.[NH2:37][NH2:38]>CCO>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][CH3:24])[N:15]=[C:14]([NH:25][CH3:26])[N:13]=2)[CH:9]=[C:8]2[C:5]=1[C:6]([NH2:7])=[N:37][NH:38]2)[CH3:2]
Reactant: CCOc1cc(-c2cc(N3CCC[C@H]3CC)nc(NC)n2)cc(F)c1C#N
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(-c2cc(N3CCC[C@H]3CC)nc(NC)n2)cc2[nH]nc(N)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
In a microwave tube, 2-(ethyloxy)-4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-6-fluorobenzonitrile (137 mg, 0.371 mmol), 5 mL of EtOH, Hunig's base (0.065 mL, 0.371 mmol), and hydrazine anhydrous (0.070 mL, 2.225 mmol) were added. The yellow suspension mixture was heated to 100° C. in an oil bath overnight. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature, then the white solid was filtered from the yellow solution, washed by CH3CN (2 mL), and dried under reduced pressure to afford the title compound (120 mg) as a white solid. LC-MS (ES) m/z=382 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, J=7.3 Hz, 3H), 1.35 (m, 1H), 1.44 (t, J=7.0 Hz, 3H), 1.80 (m, 2H), 1.93 (m, 3H), 2.82 (d, J=4.6 Hz, 3H), 3.39 (m, 1H), 3.40-3.45 (m, 1H), 3.48-3.62 (m, 1H), 4.05 (m, 1H), 4.13-4.25 (q, J=7.0 Hz, 2H), 4.99 (s, 2H), 6.17 (s, 1H), 6.40 (s, 1H), 6.92 (s, 1H), 7.44 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([NH:22][NH2:23])[CH:14]=[C:15]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[C:29]1([CH3:37])[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=1>C(O)C>[CH3:37][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=1)[CH:35]=[N:23][NH:22][C:13]1[CH:14]=[C:15]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:24]=[C:11]2[N:12]=1
Reactant: Cc1cccc(C=O)c1
Reactant: Cc1ccc(-c2cc3nc(NN)cc(N4CCOCC4)n3n2)cn1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccc(C)nc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
There was suspended, in ethanol (3 mL), [2-(6-methyl-pyridin-3-yl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl]-hydrazine (70 mg, 0.22 mM) prepared in the preceding step 2, then acetic acid (6.3 μL, 0.11 mM) and metatolualdehyde (28 μL, 0.24 mM) were added to the suspension and the mixture was stirred at room temperature for 16 hours. The precipitated solid was recovered through filtration and then washed with diethyl ether to thus give the title compound (50.2 mg, yield: 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Reactant: COC(=O)CC(=O)CCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)Cc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 33.2 %

Procedure:
Following the method of Example 2, Step C, 1-(3-(benzyloxy)pyridin-2-yl)thiourea (2.00 g, 7.71 mmol), methyl 4-chloro-3-oxo-butanoate (1.63 g, 10.8 mmol), and triethylamine (1.83 mL, 13.1 mmol) were reacted in methanol (40 mL) to provide methyl 2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)acetate (910 mg, 33%) as a yellow oil. 1H NMR (d6-DMSO) δ 10.10 (s, 1H), 7.86 (d, 1H), 7.58 (d, 2H), 7.30-7.42 (m, 4H), 6.90 (d, 1H), 6.80 (s, 1H), 5.25 (s, 2H), 3.62 (s, 3H). Mass spectrum (apci) m/z=356 (100) (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](I)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[C:20]([C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:14]=[C:13]([CH3:15])[N:12]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(I)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-2-iodo-6-methyl-pyridine (example A.52) (5.5 g, ca. 60% pure, ca. 9 mmol) and commercially available 3-bromo-benzene-boronic acid (1.82 g, 9.1 mmol) according to the general procedure IVb. Obtained as a white solid (1.3 g, 36%). MS (ISP) 391.9 [(M+H)+], 394.0 [(M+2+H)+], 396.0 [(M+4+H)+] and 398.0 [(M+6+H)+].
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11](=[O:34])[CH:12]([CH2:29][S:30][C:31](=[O:33])[CH3:32])[CH:13]([C:15]1[CH:16]=[N:17][C:18]([NH:21]C(OC(C)(C)C)=O)=[CH:19][CH:20]=1)[CH3:14])[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:34])[CH:12]([CH2:29][S:30][C:31](=[O:33])[CH3:32])[CH:13]([C:15]1[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=1)[CH3:14])[CH3:9]
Reactant: CCOC(=O)C(CSC(C)=O)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CSC(C)=O)C(C)c1ccc(N)nc1
Reaction time: 1 h
Yield: 132.3 %

Procedure:
TFA (2 mL) was added to a solution of 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-butyric acid ethyl ester (178 mg, 0.449 mmol) in methylene chloride (2 mL). The mixture was stirred for 60 min and concentrated under reduced pressure. Flash chromatography (toluene/EtOAc, 1:6) gave unpure 2-acetylsulfanylmethyl-3-(6-amino-pyridin-3-yl)-butyric acid ethyl ester (176 mg, 95%). Further purification by HPLC (10→70% acetonitrile in water, 0.1% TFA) gave 2-acetylsulfanylmethyl-3-(6-amino-pyridin-3-yl)-butyric acid ethyl ester (104 mg, 56%) as the TFA salt.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17](OC)[C:18]([CH:20]=2)=[O:19])[C:13]2[C:12]([O:24][CH3:25])=[C:11]([O:26][CH3:27])[C:10]([O:28][CH3:29])=[CH:9][C:8]=2[CH2:7][CH2:6]1)=[O:3].[CH3:30][S-:31].[Na+]>O>[CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([S:31][CH3:30])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](NC(C)=O)CC2
Reaction time: 24 h

Procedure:
Colchicine (1.25 mmole) was dissolved in 10.0 mL of water to which was added sodium methanethiolate (7.13 mmol). The yellow solution was stirred for 24 hours, then extracted 3× with ETOH:Chloroform (1:1), then evaporated to yield the desired compound as yellow crystals.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][OH:44])[CH2:38][CH2:37]1>>[OH:44][CH2:43][CH2:42][N:39]1[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:37][CH2:38]1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: NCCCCN1CCN(CCO)CC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCN(CCO)CC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[4-(4-amino-butyl)-piperazin-1-yl]-ethanol by the procedure analogous to Example 1. MS (APCl, m/z): 545 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C>[Cl:9][C:6]1[CH:5]=[C:4]([F:10])[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:2]([N:1]=[C:32]=[O:34])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N=C=O

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methylphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1.0 g, 2.9 mmol) and triethylamine (0.58 g, 5.7 mmol) were dissolved in ethyl acetate (15 ml) and the solution was slowly added to a solution of triphosgene (0.85 g, 2.9 mmol) in ethyl acetate (15 ml). Solution was heated under reflux for 2 hr and filtered. Solvent was evaporated to afford the title compound as a residue which was used for the next step.
Reaction SMILES: Cl.S(OS([O-])(=O)=O)([O-])(=O)=[O:3].[NH2:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](N)=[N:18][C:16]=2[N:17]=1>O>[NH2:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([OH:3])=[N:18][C:16]=2[N:17]=1
Reactant: O=S(=O)([O-])OS(=O)(=O)[O-]
Reactant: Nc1ncc2cc(-c3ccccc3)c(N)nc2n1
Agent: Cl
Solvent: O
Product: Nc1ncc2cc(-c3ccccc3)c(O)nc2n1
Reaction time: 8 h

Procedure:
To a solution of 2 L of concentrated HCl and 1 L of water is added 300 g of the disulfate salt of 2,7-diamino-6-phenylpyrido[2,3-d]pyrimidine and the resulting mixture refluxed with stirring overnight The reaction mixture is cooled in an ice bath, filtered, and the insoluble product washed with water, followed by ethanol to give 149 g of the title compound 2-amino-6-phenyl-pyrido[2,3-d]pyrimidin-7-ol, mp 390-395° C. (darkens slowly above 350° C.).