Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH2:10][CH:11]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=2)[C:23]#[N:24])=[N:15][CH:14]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[S:17][C:13]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][CH2:11][N:30]4[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]4)[CH:7]=[CH:6][CH:5]=3)=[CH:14][N:15]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: CCc1c(CCC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1c(CCCN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A solution of 5-{5-[2-ethyl-3-(3-oxopropyl)phenyl]-1,3-thiazol-2-yl}-2-[(1-methyl ethyl)oxy]benzonitrile (D115) (150 mg, 0.371 mmol), 3-azetidinecarboxylic acid (75.0 mg, 0.742 mmol) and acetic acid (0.1 ml, 1.747 mmol) was stirred at room temperature for 15 min, then sodium triacetoxyborohydride (236 mg, 1.112 mmol) was added. The mixture was stirred at room temperature for 2 h. After concentration, the residue was partitioned between ethyl acetate and aqueous HCl (2M). The organic phase was concentrated and purified by Mass Directed AutoPrep to afford 1-{3-[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethyl phenyl]propyl}-3-azetidinecarboxylic acid (E93) (80 mg) as a TFA salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[NH:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:19]3[CH:23]=[CH:22][CH:21]=[CH:20]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: c1cc[nH]c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cccc2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (0.15 g, 0.5 mmol) and commercially available pyrrole (0.067 g, 1.0 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.12 g, 74%). MS (EI) 323.1 [(M)+]; mp 128.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][CH:21]=[C:22]1[CH:26]=[CH:25][O:24][CH2:23]1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([N:20]=[CH:21][C:22]4[CH:26]=[CH:25][O:24][CH:23]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: NC=C1C=COC1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(N=Cc2ccoc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-aminomethylenefurane were reacted to give N4-(3,4-ethylenedioxyphenyl)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 19.99 min.; purity: 88.4%; MS (m/e): 343.07 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:22][C:21]([F:24])([F:23])[CH2:20]2)=[C:15]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[N:14]=1)=[O:12])([CH2:8][CH3:9])[CH2:6][CH3:7])C.[OH-].[Na+]>>[CH:27]1([CH2:26][O:25][C:15]2[N:14]=[C:13]([C:11]([NH:10][C:5]([CH2:6][CH3:7])([CH2:8][CH3:9])[C:4]([OH:30])=[O:3])=[O:12])[CH:18]=[CH:17][C:16]=2[N:19]2[CH2:22][C:21]([F:23])([F:24])[CH2:20]2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCC(CC)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O

Procedure:
In analogy to the procedure described in Example 252 b), 2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester (Example 266) was treated with sodium hydroxide to give the title compound as colorless oil. MS: 396.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:18]4([CH2:19][CH2:20][O:16][CH2:17]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: O=C1CCOC1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC2(CCOC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 11.5 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), dihydro-3(2H)-furanone (0.215 g, 2.50 mmol), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 5 h at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol) to afford the title compound (0.0165 g, 11%) as a yellow solid:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][N:13]=1.C(OCC)(=O)C>O1CCCC1.O>[CH2:3]([O:10][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][N:13]=1)[C:18]#[N:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccnc(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
Sodium hydride (60% oil, 0.13 g, 3.3 mmol) was suspended in tetrahydrofuran (2 ml), Benzyl alcohol (0.30 g, 3.2 mmol) was added thereto and the mixture was stirred for 30 minutes. A solution of 2-chloro-4-cyanopyridine (0.40 g, 2.9 mmol) in tetrahydrofuran (1 ml) was added to the mixture and the mixture was refluxed for 6 hrs. The reaction mixture was combined with ethyl acetate and water and stirred. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel (30 g) column chromatography, eluted with hexane-ethyl acetate (4:1, v/v) to give the titled compound (0.37 g, 62%).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([CH3:30])=[CH:24][N:23]=1.[OH-].[Na+]>O>[CH3:29][O:28][C:26]1[C:25]([CH3:30])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[CH:27]=1
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Reactant: COc1cc(CCl)ncc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)ncc1C

Procedure:
7.8 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one were suspended in 200 ml of alcohol and the suspension was treated while cooling with ice with 6.3 g of 2-chloromethyl-4-methoxy-5-methylpyridine hydrochloride. Thereafter, 2.4 g of sodium hydroxide in 100 ml of water were added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 500 ml of methylene chloride. The solution was washed firstly with 250 ml of 1.5N sodium hydroxide solution and then with 3×250 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 150 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 5,7-dihydro-2-[[(4-methoxy-5-methyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 204°-205°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][OH:12])[CH:10]=1)[N:7]([CH3:13])[CH:6]=[CH:5]2>CC(C)=O.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=1)[N:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cn1ccc2cc(Br)cc(CO)c21
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: Cn1ccc2cc(Br)cc(C=O)c21
Reaction time: 3 h
Yield: 80.8 %

Procedure:
To a solution of (5-Bromo-1-methyl-1H-indol-7-yl)-methanol (220 mg, 0.92 mmol) in acetone (20 mL) was added MnO2 (239 mg, 2.7 mmol) at room temperature. The mixture was stirred at the same temperature for 3 hours. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 5-Bromo-1-methyl-1H-indole-7-carbaldehyde (177 mg, 81%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-])=O>C(O)C.[Ni]>[NH2:13][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:7]=1[NH:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: O=[N+]([O-])c1cnccc1NCCCCO
Agent: [Ni]
Solvent: CCO
Product: Nc1cnccc1NCCCCO
Reaction time: 3 h
Yield: 106.8 %

Procedure:
4-(4-Hyrdoxybutylamino)-3-nitropyridine (6 g) was dissolved in ethanol (60 cm3) containing Raney Ni catalyst (0.5 g) and then hydrogenated at room temperature for 3 hours under pressure (30 p.s.i.=206.8 kPa). The mixture was filtered under nitrogen and the filtrate was evaporated under vacuum to yield the crude product (5.5 g) which was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][NH:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[NH:11][N:10]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:33]O>>[ClH:25].[Cl:25][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([NH:8][CH2:7][C:6]4[CH:26]=[CH:27][CH:28]=[C:4]([C:1]([O:3][CH3:33])=[O:2])[CH:5]=4)[C:17]=23)[CH:24]=[CH:23][CH:22]=1
Reactant: CO
Reactant: O=C(O)c1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Product: Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Preferably, the same compound is obtained as follows: To 70 mg (0.177 mmol) of 3-(3-carboxy-benzyl-amino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (cf. Example 21) and 2 ml of methanol are added 0.1 ml of thionylchloride. The mixture is stirred in a sealed vessel for 3 h at 70° C., and then cooled to room temperature. Filtration and washing with methanol affords 4-(3-chloro-phenylamino)-3-(3-methoxycarbonyl-benzylamino)-1H-pyrazolo[3,4-d]pyrimidine-hydrochloride; (C20H17N6ClO2 ×HCl×0.28H2O), calc. C 53.34, H 4.15, N 18.66, Cl 15.74, H2O 1.12, found C 53.35, H 4.13, N 18.82, Cl 15.87, H2O 1.12.
Reaction SMILES: O[CH:2]([C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(S(Cl)(=O)=O)C=CC=CC=1>N1C=CC=CC=1>[C:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[C:13]3([CH2:14][CH2:15][CH2:16][CH2:17]3)[C:18](=[O:19])[O:20]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C1(C(O)CCCCc2ccccc2)CCCC1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C1OC(CCCCc2ccccc2)C12CCCC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
1-(1-Hydroxy-5-phenylpentyl)cyclopentane carboxylic acid (11.3 g, 40.9 mmol) is dissolved in pyridine (90 mL) and cooled to 0° C. Benzenesulfonyl chloride (10.4 mL, 81 mmol) is added over 1 minute and the reaction is kept at 0° C. overnight. The reaction is poured into ice (100 mL) and the product extracted into ether (2×100 mL). The ether layer is washed with NaHCO3 (100 mL), 1 N HCl (100 mL) and water (2×100 mL). The solution is dried over MgSO4 and the solvent removed in vacuo (without heat). The crude product is purified by column chromatography (silica, 15% ether in petroleum ether) to yield 3-(4-phenylbutyl)-2-oxaspiro[3,4]octan-1-one (5.6 g, 54%): 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.20-7.15 (m, 3H), 4.31-4.26 (m, 1H), 2.63 (t, J=7.6 Hz, 2H), 2.22-2.13 (m, 1H), 1.99-1.26 (m, 13H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([CH2:36][C:37](O)=[O:38])#[N:35]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:37](=[O:38])[CH2:36][C:34]#[N:35])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#CCC(=O)O
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)CC#N)cc2)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and cyanoacetic acid, as a pale yellow oil (96%). M− (ESI): 507.4; M+ (ESI): 509.4. HPLC, Rt: 5.22 min (Purity: 86.2%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:7]=1.[CH2:12]([O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16])[CH3:13]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH:11][C:18]([NH:17][C:15]([O:14][CH2:12][CH3:13])=[O:16])=[S:19])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:7]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ncc(C2CC2)cc1Br
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ncc(C2CC2)cc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-bromo-5-cyclopropyl-pyridin-2-ylamine (1.0 g, 4.69 mmol) in dry 1,4-dioxane (20 mL) was added ethoxy carbonyl isothiocyanate (0.55 mL, 5.16 mmol) under an argon atmosphere and stirred at room temperature for 6 hours. The solvent was evaporated and the title compound was obtained as light yellow oil (1.5 g, 98%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH2:5]1.Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>C(N(CC)CC)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]2[N:18]([CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][CH:6]([CH3:9])[CH2:5]3)[C:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][C:23]=3[C:14]=2[CH:13]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Reactant: CC1CCN(CCBr)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1CCN(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-3-methylpyrrolidine, 4-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Br:19])[NH:11][C:10](=[S:20])[NH:9]1.[CH3:21][I:22]>CCO>[IH:22].[Br:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C@H:12]1[C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[NH:9][C:10]([S:20][CH3:21])=[N:11]1
Reactant: S=C1N[C@H](c2ccccc2Br)[C@H](c2ccccc2Br)N1
Reactant: CI
Solvent: CCO
Product: CSC1=N[C@@H](c2ccccc2Br)[C@@H](c2ccccc2Br)N1
Product: I
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A solution of cis-4,5-bis-(2-bromophenyl)imidazolidine-2-thione (35) (0.51 g, 1.36 mmol) and methyl iodide (0.178 mL, 2.1 mmol) in abs. EtOH (20 mL) is heated at 90° C. overnight. The reaction mixture is cooled to rt, concentrated in vacuo, and the residue suspended in Et2O. The insoluble material is filtered to give 0.51 g of the product 52.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[CH3:18].[H-].[Na+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:16]=[CH:17][C:2]([O:1][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:3]([CH3:18])[CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)c2ccc(O)c(C)c2)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)c2ccc(OC)cc2)cc1C
Reaction time: 8 h

Procedure:
50 g of 4-hydroxy-3-methyl-4'-methoxybenzophenone (R. Martin et al. Monatsh. Chemie 110, 1057-1066 (1979)) are dissolved in 200 ml of dry DMF and, under N2, 9 g of a 55% dispersion of sodium hydride in mineral oil are cautiously added. Then, while stirring, 19.5 ml of methyl bromoacetate are added dropwise, and the mixture is left to stand at room temperature overnight. The precipitated salt is filtered off with suction, and the filtrate is concentrated in vacuo. The residue is taken up in ethyl acetate, and the solution is washed with sodium bicarbonate solution and water. The organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo. The residue is triturated with ether, filtered off with suction and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:22]3[S:23][CH:24]=[CH:25][C:26]=3[Cl:27])[CH2:9]2)=[CH:4][CH:3]=1.N(C1C=CC(C(O)=O)=CC=1)N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=3)[N:11]=[C:10]([C:22]3[S:23][CH:24]=[CH:25][C:26]=3[Cl:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(N2N=C(c3sccc3Cl)CC2c2ccc(Cl)cc2)cc1
Agent: NNc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(-n2nc(-c3sccc3Cl)cc2-c2ccc(Cl)cc2)cc1

Procedure:
5-(4-Chloro-phenyl)-3-(3-chloro-thiophen-2-yl)-1-(4-carboxy-phenyl)-4,5-dihydro-pyrazole: The title compound was prepared from 3-(4-chloro-phenyl)-1-(3-chloro-thiophen-2-yl)-propenone and 4-hydrazinobenzoic acid by a procedure similar to that of Example 105a as a yellowish oil (166 mg, 74%). 1H NMR (CDCl3): 9.02 (s, 1H), 7.92-6.80 (m, 10H), 5.72 (m, 1H), 4.20 (m, 1H), 4.01 (t, 1H), 3.41 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[CH3:29][CH2:30][N:31](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:31][CH2:30][CH3:29])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2-n2c(C)nnc21
Reaction time: 48 h
Yield: 47 %

Procedure:
To a solution of [(4S)-6-(4-Chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid (for a preparation see Intermediate 1) (16.0 g, 40 mmol) in THF at RT was added DIEA (14 mL, 80 mmol) followed by HATU (30.4 g, 80 mmol). The reaction mixture was stirred for 3 h at this temperature and ethylamine (40 mL, 2M in THF, 80 mmol) was added. The mixture was stirred for 48 h before being concentrated under reduced pressure. The crude material was suspended in water and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude solid was purified by chromatography on SiO2 (DCM/MeOH 95/5) and the resulting solid recrystallised in MeCN. The solid was then dissolved in DCM and precipitated with i-Pr2O to give the title compound (8 g, 47% yield) as a white solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH3:6][O:7][C:8]1[C:9]([CH3:27])=[C:10]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]=[O:26])=[CH:17][N:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1>>[CH3:6][O:7][C:8]1[C:9]([CH3:27])=[C:10]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]([OH:26])[CH2:1][CH2:2][CH3:3])=[CH:17][N:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: COc1ccc(C)c(-c2ncc(C=O)c3ccccc23)c1C
Reactant: CCC[Mg]Cl
Product: CCCC(O)c1cnc(-c2c(C)ccc(OC)c2C)c2ccccc12
Temperature: 25 °C
Yield: 66.6 %

Procedure:
n-PrMgCl (4.7 ml of 2M solution in THF, 9.36 mmol) is added to a solution of 1-(3-methoxy-2,6-dimethyl-phenyl)-isoquinoline-4-carbaldehyde (2.48 g, 8.51 mmol) dropwise at −78 C and the mixture is allowed to warm to room temperature. After quenching with saturated NH4Cl, the mixture is extracted with EtOAc. The combined extracts are washed with saturated brine, dried over Na2SO4, and concentrated. The residue is chromatographed on silica gel to give 1.9 g of 1-[1-(3-methoxy-2,6-dimethyl-phenyl)-isoquinolin-4-yl]-butan-1-ol as a white foam.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29]Br)[CH:22]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][O:39][C:36]2[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=2)[CH:22]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCBr)c2)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCOc3ccc(Cl)cc3)c2)c1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To a stirred solution of 3-{5-amino-4-[3-(2-bromoethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide (24 mg, 0.05 mmol) and 4-chlorophenol (128 mg, 1 mmol) in DMF (1 mL), was added K2CO3 (138 mg, 1 mmol) and the mixture was stirred at 100° C. for 2 h. The mixture was cooled and the solids were filtered off. The filtrated was concentrated and purified by preparatory HPLC, to provide the product as a beige solid (10 mg, 38%). HPLC (4 minute 10-90 gradient) tR 2.77 min; MS m/z 531.21 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[N:19][C:9]=23)[CH2:3][CH2:2]1.Cl[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.CCOC(C)=O.C(=O)([O-])O.[Na+]>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]4[NH:17][CH:18]=[N:19][C:9]=34)[CH2:3][CH2:2]2)=[N:22][CH:23]=1)#[N:26]
Reactant: NC(=O)c1cnc2[nH]cnc2c1NC1CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N2CCC(Nc3c(C(N)=O)cnc4[nH]cnc34)CC2)nc1
Temperature: 90 °C
Yield: 10.9 %

Procedure:
A mixture of 7-(4-piperidinylamino)-3H-imidazo[4,5-b]pyridine-6-carboxamide (46 mg), 6-chloronicotinonitrile (37 mg) and N,N-diisopropylethylamine (46 uL) in NMP (0.5 mL) was heated in the microwave reactor (90° C., 10 minutes). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (20 mL) and half-saturated aqueous sodium hydrogencarbonate (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the product by column chromatography (silica gel, gradient elution, chloroform:methanol=20:1 to 10:1) provided (7 mg) 7-{[1-(5-cyano-2-pyridinyl)-4-piperidinyl]amino}-3H-imidazo[4,5-b]pyridine-6-carboxamide as a white solid.