Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](Cl)=[O:11]>>[CH3:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: CC(Cc1ccccc1)C(=O)Cl
Reactant: Oc1ccccc1
Product: CC(Cc1ccccc1)C(=O)Oc1ccccc1

Procedure:
The procedure as described in Example 4a) was repeated with phenol (30.5 mmol) and 2-methyl-3-phenylpropanoyl chloride (30.5 mmol). The crude product (5.51 g, 75%) was used without further purification in the next step.
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[N:9]=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=1>>[CH3:1][NH:2][C:4]1[N:9]=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: NS(=O)(=O)c1cccc(F)n1
Product: CNc1cccc(S(N)(=O)=O)n1

Procedure:
To 10 ml of condensed methylamine was added 1.86 g (10 mmol) of 6-fluoropyridine-2-sulfonamide. The mixture was allowed to reflux under a dry-ice condenser for 4 hr, then excess amine was allowed to evaporate overnight. The residue was crystallized with water to yield 1.64 g of tan solid, m.p. 124° C. to 26° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[CH2:14]([O:13][C:11]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCNCC1
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Scheme 1 illustrates an example of a route for the preparations of compounds of formula (VI) and (VII). 4-Piperidinecarboxylic acid of formula (II) is first reacted with benzyl chloroformate, in the presence of a base and in an aqueous medium, to obtain 1-(benzyloxy-carbonyl)-4-piperidinecarboxylic acid of formula (III). 1,2,3,4-tetrahydro-9-H-pyrido[3,4-b]indole is reacted with the acid chloride of the compound of formula (III), prepared in situ with a chlorinating agent, for example thionyl chloride, in an inert solvent, for example tetrahydrofuran, and in the presence of a base, for example triethylamine, at about room temperature, to obtain benzyl 4-[(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl)-carbonyl]-1-piperidinecarboxylate of formula (V). The compound of formula (V) is subjected to a catalytic reduction to obtain the compound of formula (VI).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:17]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ncc(Br)cc2C)c1
Yield: 23 %

Procedure:
Obtained (1.00 g, yield 23%) following the procedure described in Intermediate 27, starting with 2,5-dibromo-3-methylpyridine (15.94 mmol, 4.0 g), 3-methoxyphenylboronic acid (15.93 mmol, 2.42 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25](=[O:26])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with phenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (7.3 mg, 32%) having the following characteristics.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[CH3:20][N:21]=[C:22]=[S:23].C(Cl)(Cl)Cl.CO.N>CO>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:22]([NH:21][CH3:20])=[S:23])[N:11]=1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: CN=C=S
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNC(=S)NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 3 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.3 g.) and methyl isothiocyanate (0.18 g.) in methanol (6 ml.) was allowed to stand at room temperature for 3 hours. The residue obtained on evaporation of the solvent was subjected to preparative thin layer chromatography using chloroform/methanol/ammonia 90:10:0.5 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform 50:50 v/v (100 ml.). Evaporation of the solvent gave B 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-methylthioureido)butyl]thiazole as a straw-coloured gum. The n.m.r. spectrum d6 dimethylsulphoxide using tetramethylsilane as internal standard included the following resonances (ε): 2.75 (3H, doublet), 4.04 (2H, multiplet) and 6.34 (1H, singlet). On addition of D2O the multiplet at ε 4.04 collapsed to a quartet.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][C:12]([OH:14])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:27]([O:29][C:30]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:28]>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][C:12]([N:33]1[CH2:34][CH2:35][C:30]([O:29][CH2:27][CH3:28])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:31][CH2:32]1)=[O:14]
Reactant: CCOC1(c2ccccc2)CCNCC1
Reactant: O=C(O)CC1COc2ccccc2O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC1(c2ccccc2)CCN(C(=O)CC2COc3ccccc3O2)CC1

Procedure:
The starting material is prepared as follows: To the solution of 3.3 g of 1,4-benzodioxan-2-yl-acetic acid in 30 ml of tetrahydrofuran, 3.1 g of 1,1'-carbonyldiimidazole are added while stirring followed, after 30 minutes, by 3.5 g of 4-ethoxy-4-phenylpiperidine in 30 ml of tetrahydrofuran. The mixture is stirred for 18 hours at room temperature, evaporated and the residue taken up in ethyl acetate. The solution is washed with water, N hydrochloric acid and saturated aqueous sodium chloride, dried and evaporated, to yield the 1-(1,4-benzodioxan-2-yl-acetyl)-4-ethoxy-4-phenylpiperidine.
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].COC1C=CC=C[N:17]=1>>[C:8]1([C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][N:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccccn1
Reactant: CCCCCCCCCCCCC
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
In a reaction flask was placed NiCl2(PCy3)2 (58.5 mg, 0.0847 mmol), tridecane (345 mg, 1.875 mmol, as an internal standard), and 2-methoxypyridine (343 mg, 3.146 mmol). The Grignard reagent (1 M in THF, 6.2 mmol) was added to the above catalyst mixture under a nitrogen atmosphere at 0° C. The resulting solution was stirred for several minutes and warmed to room temperature for 15 hours. The reaction mixture was quenched with an aqueous sodium citrate solution (1 M). The resulting aqueous solution was extracted with MTBE (4×25 mL). The combined organic layer was washed with an aqueous HCl solution (2.5 M, 4×15 mL). The aqueous layer was then extracted with MTBE (1×25 mL). This solution was cooled to 0° C. and a dilute aqueous KOH solution was added until pH 8. The aqueous layer was extracted with MTBE (4×25 mL) and dried over MgSO4. The resulting solution was filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (eluted with MTBE) to afford 2-phenylpyridine (368 mg, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:24]([O:28][C:29]([NH:31][CH:32]([CH2:36][S:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:41]([O:40][C:38](=[O:39])[S:37][CH2:36][CH:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[C:33]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC(CSC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)C(CSC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
Using General Procedure G: To a solution of COMPOUND 249 (0.1233 g, 0.40 mmol) in DMF (5 mL) were added 2-tert-butoxycarbonylamino-3-tert-butoxycarbonylsulfanyl-propionic acid (0.1414 g, 0.44 mmol), DIPEA (0.14 mL, 0.80 mmol), EDCI (0.0920 g, 0.48 mmol), and HOBT (0.0649 g, 0.48 mmol), and stirred at room temperature for 16 hours. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1652 g (67%) of thiocarbonic acid S-(3-{4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-2-tert-butoxycarbonylamino-3-oxo-propyl) ester O-tert-butyl ester as a white solid. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.47 (s, 9H), 1.67 (s, 5H), 2.08 (d, 6H, J=6.0 Hz), 2.39-2.43 (m, 1H), 2.75-3.14 (m, 3H), 3.80-3.83 (m, 4H), 4.13 (d, 1H, J=15.0 Hz), 4.65 (d, 1H, J=15.0 Hz), 4.88-4.89 (m, 1H), 5.52-5.55 (m, 1H), 7.07-7.11 (m, 2H), 7.37 (d, 2H, J=6.0 Hz), 8.34 (d, 2H, J=3.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[CH2:22][CH2:21]3)[N:15]=2)[CH:3]=1.[NH3:23]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:23])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[CH2:22][CH2:21]3)[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C2CC2)n1
Product: NC(=O)c1nnc(Cl)cc1Nc1cccc(C2CC2)n1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
Ethyl 6-chloro-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxylate (140 mg, 439 μmol) and ammonia (7M in methanol, 9.44 g, 12 mL, 84.0 mmol) were heated at 50° C. in a sealed tube for 21 h. After cooling to room temperature, concentration in vacuo gave 6-chloro-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxamide (112 mg, 88%) as a yellow solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 11.51 (br. s., 1H) 9.16 (s, 1H) 8.16 (br. s., 1H) 7.52 (t, J=7.74 Hz, 1H) 6.86-6.96 (m, 1H) 6.68 (d, J=7.93 Hz, 1H) 5.65 (br. s., 1H) 1.99-2.10 (m, 1H) 1.06-1.12 (m, 4H). LCMS (EI/CI) m/z: 290 [M+H]. The crude product was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([OH:21])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.I[CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([O:21][CH3:30])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CI
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1O
Product: COc1cc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)ccc1CS(C)(=O)=O
Yield: 23.2 %

Procedure:
N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide (50 mg, 0.12 mmol) was treated with iodomethane (7.5 μl, 0.12 mmol) via procedure U to yield 12 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-methoxy-4-(methylsulfonylmethyl)benzamide. MS (Q1) 431 (M)+.
Reaction SMILES: [N:1]1[C:9]2[C:8](=O)[C:7](=[N:11]O)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)(=O)C.[Pd]>[N:1]1[C:9]2[CH2:8][CH:7]([NH:11][C:13](=[O:15])[CH3:14])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=NO)Cc2cccnc21
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)NC1Cc2cccnc2C1

Procedure:
18 g (0.11 mol) of the compound of step c were dissolved in 500 ml of acetic acid and 500 ml of acetic acid anhydride and hydrogenated for 20 h at a pressure of 2 bar over 5 g of palladium on barium sulfate. The reaction mixture was filtered and evaporated. The residue was dissolved in 1000 ml of ethanol, treated with 10.8 ml of perchloric acid and hydrogenated for 10 h at 50° C. and a pressure of 3.5 bar over 5 g of palladium on charcoal (10%). The resulting mixture was evaporated, the residue taken up in dilute NaOH solution and extracted with ethyl acetate. Evaporation of the combined organic phases and subsequent chromatography of the residue yielded racemic N-(6,7-dihydro-5H-[1]pyrindin-6-yl)acetamide.
Reaction SMILES: [OH-].[K+:2].[S:3]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[N:4]1>O.C(O)C>[S:3]1[C:7]([C:8]([O-:10])=[O:9])=[CH:6][N:5]=[N:4]1.[K+:2]
Reactant: CCOC(=O)c1cnns1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])c1cnns1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of potassium hydroxide (3.30 g.) in water (7 ml.) was added to a solution of ethyl 1,2,3-thiadiazole-5-carboxylate (8.00 g.) in ethanol (25 ml.). The mixture was stirred at 23° C. for 2 hours, and then was worked up to yield potassium 1,2,3-thiadiazole-5-carboxylate. A suspension of this salt (3.00 g.) in toluene (25 ml.) was treated at 0° C. with oxalyl chloride (1.6 ml.), stirred at 0° C. for 1 hour, and then was worked up to yield 1,2,3-thiadiazole-5-carbonyl chloride.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([CH3:12])=[N:8][O:9][C:10]=1[CH3:11])=[O:5].[CH3:14][Mg]Br.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCOCC.Cl>[CH3:12][C:7]1[C:6]([C:4](=[O:5])[CH3:14])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1c(C)noc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1c(C)noc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A solution of 580 mg (3.15 mmol) of N-methoxy-N-methyl-3,5-dimethylisoxazole-4-carboxamide in 20 mL of THF is cooled to 0° C. A solution of 1.57 mL (4.72 mmol) of 3 M methylmagnesium bromide in ether is added. After stirring for 4 hours at room temperature, the reaction medium is taken up in 10 mL of 1 N HCl and stirred for a further 1 hour at room temperature. The mixture is then basified with K2CO3 and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 420 mg of 1-(3,5-dimethylisoxazol-4-yl)ethanone, corresponding to the following characteristics:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[Br:12])C=C.[C:13]1(C)[CH:18]=C(C)C=C(C)[CH:14]=1>>[CH2:18]([C:10]1[CH:9]=[C:8]([F:11])[CH:7]=[C:6]([Br:12])[C:5]=1[OH:4])[CH:13]=[CH2:14]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1ccc(F)cc1Br
Product: C=CCc1cc(F)cc(Br)c1O
Yield: 99 %

Procedure:
Treatment of 1-(allyloxy)-2-bromo-4-fluorobenzene (23.90 g, 0.103 mol) in refluxing mesitylene (50 mL) generally according to the procedure described for Intermediate 8 provided 23.44 g (99%) 2-allyl-6-bromo-4-fluorophenol as a brown oil. Rf=0.64 (silica, ethyl acetate:hexanes 1:19); Anal. calcd. for C9H8BrFO: C, 46.78; H, 3.49. Found: C, 49.19; H, 3.59.
Reaction SMILES: O[CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.CC1C=CC(S([Cl:26])(=O)=O)=CC=1>N1C=CC=CC=1>[Cl:26][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC#Cc1ccc(-c2cccs2)s1
Solvent: c1ccncc1
Product: ClCCC#Cc1ccc(-c2cccs2)s1
Reaction time: 8 h
Yield: 16.2 %

Procedure:
8.48 g of 5-(4-hydroxy-1-butynyl)-2,2'-bithiophene was dissolved in 100 ml of pyridine. 16 g of p-tosyl chloride was added in under nitrogen gas atmosphere. After stirred overnight, the pyridine was evaporated under reduced pressure. The reside was extracted with ethyl acetate (100 ml) twice, filtered, washed with water (100 ml) twice, HCl solution twice (5%, 100 ml) and water (100 ml) twice again. The organic layer dried over anhydrous magnesium sulfate was filtered and the solvent thereof was evaporated. The residual solid was further purified by rapid silica gel column chromatography. From the eluate of ethyl acetate/n-hexane (1/6). 6.25 g of 5-(4-tosyloxy-1-butynyl)-2,2,'-bithiophene and 1.48 g of 5-(4-chloro-1-butynyl)-2,2'-bithiophene were respectively obtained and the yield thereof was 44% and 16%.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCOc1cc(Cl)nc2ccccc12
Agent: Cl
Product: CCOc1cc(NCCCOc2cccc(CN3CCCCC3)c2)nc2ccccc12
Yield: 94.5 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (9.93 g) and 2-chloro-4-ethoxyquinoline (4.15 g) were fused at 160° C. for 41/4 hours. The reaction mixture was cooled, dissolved in dilute hydrochloric acid to pH 6 and washed with diethyl ether (2×). The solution was taken to pH 5 and extracted continuously into chloroform. The chloroform extract was evaporated under reduced pressure, dissolved in water, taken to pH 9 with aqueous sodium hydroxide and extracted into diethyl ether (7×) and chloroform (2×). The ether and chloroform extracts were dried (MgSO4) and evaporated to give the title compound as an oil (7.92 g). This was treated with maleic acid in ethanol to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-4-ethoxyquinoline dimaleate (8.24 g), m.p. 145.5°-147.5° C. (recrystallised from ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1([CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: NCC(c1ccccn1)N1CCOCC1
Product: Cc1ccccc1C(=O)NCC(c1ccccn1)N1CCOCC1

Procedure:
From 2-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=[O:27])[C:20]4=[N:19][C:18]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:29][Mg+].[Br-]>C1COCC1>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]([OH:27])[CH3:29])[C:20]4=[N:19][C:18]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C=O)cccn34)c(C)nc12
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(C)O)cccn34)c(C)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A solution of 3-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-imidazo[1,2-a]pyridine-8-carboxaldehyde (1.07 g, 2.84 mmol) in THF (30 mL) is cooled at 0° C., treated with 3.0 M CH3MgBr (1.1 mL, 3.41 mmol). The reaction is stirred at 0° C. for 30 min. It is then quenched with sat. NH4Cl (15 mL), diluted with H2O (15 mL), extracted with EtOAc (2×30 mL). The combined organic layers is dried with Na2SO4, filtered and concentrated. Purification of the crude material by silica gel chromatography gives the title compound (0.93 g, 2.38 mmol, 83). 1H NMR (CDCl3): δ 0.91 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.1 Hz, 3H), 1.75 (d, J=6.6 Hz, 3H), 1.79-1.94 (m, 4H), 2.41 (s, 6H), 2.45 (s, 3H), 3.32-3.42 (m, 1H), 5.17 (m, 1H), 5.39 (m, 1H), 6.72 (t, J=7.0 Hz, 1H), 6.73 (s, 1H), 7.13 (d, J=7.1 Hz, 1H), 7.43 (d, J=7.1 Hz, 1H) ppm. ES-MS (m/z): calcd for C23H29N5O (M+H)+: 392.5. found: 392.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([NH2:16])[C:13]([N+:17]([O-])=O)=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.[C:20](OCC)(=[O:26])[C:21](OCC)=[O:22]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9]3=[CH:15][C:14]4[NH:16][C:20](=[O:26])[C:21](=[O:22])[NH:17][C:13]=4[CH:12]=[C:10]3[N:11]=2)=[CH:3][CH:2]=1
Reactant: Nc1cc2[nH]c(-c3ccncc3)nc2cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc3nc(-c4ccncc4)[nH]c3cc2[nH]c1=O
Yield: 45 %

Procedure:
Analogously to Example 3, from 2-(4-pyridyl)-5-amino-6-nitrobenzimidazole, by hydrogenation and reaction with diethyl oxalate, there was obtained, in a yield of 45% of theory, the title compound; m.p. above 300° C.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][C:34](=[O:44])[N:35](C1C=CC(N)=CC=1)[CH3:36]>>[CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:35]([CH3:36])[C:34](=[O:44])[O:33][CH3:32])=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Reactant: COC(=O)N(C)c1ccc(N)cc1
Product: COC(=O)N(C)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, methyl-4-aminophenyl(methyl)carbamate and 2-Chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave methyl 4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl(methyl)carbamate (MS calcd for C19H22N6O2 366.2, found [MH] 368.0; UV 209.8, 271.2, 304.5 nm).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[N:7][C:8]([S:12]([CH2:15][C:16]3C=C[CH:19]=[C:18](F)[C:17]=3F)(=O)=O)=[N:9]2)=[N:4][CH:3]=1.[S:29]1C=CC=C1S.CC(C)([O-])C.[K+]>CS(C)=O.C1COCC1>[NH2:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[N:7][C:8]([S:12][CH2:15][C:16]3[S:29][CH:19]=[CH:18][CH:17]=3)=[N:9]2)=[N:4][CH:3]=1
Reactant: Sc1cccs1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2nc(N)cnc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C[C@H](CO)Nc1nc(SCc2cccs2)nc2nc(N)cnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Example 10, step (a) (0.18 g) and 2-thienylmercaptan (70 mg) in anhydrous DMSO (3 ml) was treated with potassium t-butoxide solution in THF (1.0 M, 0.44 ml) and stirred at room temperature for 1 hour. The solution was purified directly by preparative reversed phase HPLC on a Waters 19×50 mm Symmetry C8 silica column eluted with 0.1% aqueous ammonium acetate:acetonitrile (70:30) to give an off-white solid that was dried under reduced pressure at 40° (20 mg).