Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Clc1cnc2[nH]c(-c3ccc(Cn4cccn4)cc3)nc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.022 g, 0.06 mmol) and EtOH (2.5 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.015 g, 0.08 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.24 ml, 0.24 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 8%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.008 g, 27%); 1H-NMR (500 MHz, DMSO-d6) 2.62 (br s, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2pyridyl), 3.72 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.30 (t, J=2.0 Hz, 1H, pyrazole 4-H), 7.35 (d, J=8.3 Hz, 2H) and 8.13 (d, J=8.3 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.40 (d, J=5.8 Hz, 2H, pyridine 3-H, 5-H), 7.49 (d, J=1.5 Hz, 1H, pyrazole-H), 7.86 (d, J=1.8 Hz, 1H, pyrazole-H), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.9 Hz, 2H, pyridine 2-H, 6-H), 13.45 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.C([Li])CCC.CCCCCC.CN([CH:27]=[O:28])C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: COCCOCCn1ccnc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCOCCn1ccnc1C=O
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
1.30 g of (2) (0.008 mol) was dissolved in freshly distilled THF 35 mL under argon atmosphere, and the solution was cooled to −40° C. n-butyllithium 1.6M-hexane solution 5.6 mL (0.0088 mol) was added dropwise while the temperature was kept at −40° C. The mixture was then stirred at −40° C. for 30 min, after which dry DMF 1.28 mL (0.016 mol) was added. The contents were allowed to warm up to room temperature and stirred overnight. Sodium bicarbonate solution was added, then THF was dried (Rotavap), extracted by CHCl3, dried over Na2SO4, and dried (Rotavap) until a light yellow oil was left. The product was purified by silica gel flash column chromatography, CHCl3:CH3OH=50:1. 0.861 g product (3) (57% yield) was obtained as a light yellow oil. As an alternative to column chromatography, the product (3) is purified by vacuum distillation.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]2[O:5][CH2:4]1.[C:12]([O-:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].CS(C)=O>O>[C:12]([O:20][CH2:2][CH:3]1[CH2:4][O:5][C:6]2=[CH:11][S:10][CH:9]=[C:7]2[O:8]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C([O-])c1ccccc1
Reactant: BrCC1COc2cscc2O1
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCC1COc2cscc2O1)c1ccccc1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
In a 100 mL round bottom flask 9.00 g (0.0382 mol) 2-(bromomethyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine, 6.39 g (0.0459 mol) ammonium benzoate, and 55 g DMSO were combined. A reflux condenser was equipped and the reaction was heated to 100 C overnight. After cooling to room temperature, the reaction mixture was poured into water and the product was extracted with methylene chloride. The organic fractions were combined and the solvent removed under reduced pressure. Purification by column chromatography provided 7.5 g (71% yield) of a white solid whose structure was confirmed by 1H/13C NMR and LC-MS.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=O.[NH2:24][C@@H:25]1[C@@H:30]([OH:31])[CH2:29][CH2:28][O:27][CH2:26]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:10]2[CH:9]=[C:4]3[C:3]([CH2:1][N:24]([C@@H:25]4[C@@H:30]([OH:31])[CH2:29][CH2:28][O:27][CH2:26]4)[C:5]3=[O:6])=[C:12]([CH3:13])[C:11]=2[CH3:14])=[CH:21][CH:20]=1
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(C)c1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc3c(c(C)c2C)CN([C@H]2COCC[C@@H]2O)C3=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
To a solution of methyl 2-formyl-5-(4-methoxybenzyl)-3,4-dimethylbenzoate (13.5 g) in THF (270 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (5.06 g) and anhydrous magnesium sulfate (9.99 g), and the mixture was stirred at room temperature for 5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was diluted with methanol (220 mL)-THF (250 mL), sodium triacetoxyborohydride (18.3 g) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to give the crude title compound (6.4 g). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.85 g). The crude title compound and the title compound purified by column were combined, and recrystallized from ethanol to give the title compound (6.48 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.S(Cl)([Cl:17])(=O)=O>C(NCC(C)C)C(C)C.C1(C)C=CC=CC=1>[Cl:17][C:7]1[CH:6]=[C:5]([O:4][CH2:3][C:2]([F:12])([F:13])[F:1])[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccc(OCC(F)(F)F)cc1
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: Oc1ccc(OCC(F)(F)F)cc1Cl
Temperature: 70 °C
Yield: 106.1 %

Procedure:
To a 30 ml toluene solution of 4-(2,2,2-trifluoroethoxy)phenol (1.02 g, 5.31 mmol) and diisobutylamine (0.074 ml, 0.42 mmol) was added sulfuryl chloride (0.38 ml, 4.7 mmol). This solution was heated to 70° C. for 2 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and sat. bicarb. solution. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 10% AcOEt/hexanes to give the title compound as a pale yellow oil 1.13 g (94%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:31]=[C:30](Br)[CH:29]=2)=[CH:20][C:19]=1[CH3:44]>CN(C=O)C.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:29]=[C:30]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][CH:4]=3)[CH:31]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:33]=2)=[CH:20][C:19]=1[CH3:44]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCCCC3)c2)cc1C
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCCCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-ethynyl-4-trifluoromethyl-benzene (300 mg, 1.77 mmol), (4-{3-[3-bromo-5-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (100 mg, 0.2 mmol, example 3), Pd(PPh3)4 (22 mg, 0.02 mmol), CuI (10 mg, 0.055 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 50 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using ethyl acetate/methanol mixtures to give (2-methyl-4-{3-[3-(3-piperidin-1-yl-prop-1-ynyl)-5-(4-trifluoromethyl-phenylethynyl)-phenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester in 30 mg (26%) yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:18])([F:17])[C:12](B(O)O)=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]([C:11]([F:18])([F:17])[F:10])=[CH2:13])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: C=C(B(O)O)C(F)(F)F
Reactant: Clc1cc(I)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)nc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Yield: 91.1 %

Procedure:
2,6-dichloro-4-iodopyridine (0.87 g), (3,3,3-trifluoroprop-1-en-2-yl)boronic acid (purity: 65%, 0.75 g) and potassium carbonate (0.96 g) were dissolved in the mixed solvent of THF and water, which was then degassed three times. To the solution was added dichlorobis(triphenylphosphine) palladium (II) (0.04 g), and the mixture was heated to reflux for 3 hours under argon atmosphere. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with hexane. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under reduced pressure, and the residue was then purified by silica gel chromatography to obtain 2,6-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (0.70 g) at a yield of 82%.
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5](Cl)[C:4]=1[Br:10].Cl.[CH3:12][OH:13]>>[NH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:13][CH3:12])[C:4]=1[Br:10]
Reactant: Nc1ccnc(Cl)c1Br
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COc1nccc(N)c1Br
Temperature: 0 °C

Procedure:
Methanol (350 mL) was charged in a two-neck round bottom flask equipped with a guard tube and septum and cooled to 0° C. Sodium metal (23 g) was added to it slowly in pieces. After all sodium metal had dissolved, 4-amino-3-bromo-2-chloro pyridine (23 g, 178 mmol) was added and the solution was heated at 180° C. in a pressure vessel for 5-6 h. The reaction mixture was then cooled to 0° C. and adjusted to pH 8 by addition of conc. HCl. Solvent was removed under reduced pressure and the residue was suspended in ethyl acetate. Undissolved impurities were removed by filtration and the filtrate was concentrated under reduced pressure to obtain pure product.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:20]=1[CH:21]=O>C1COCC1>[CH3:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:20]=1[CH:21]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(OC)c(OC)c1OC
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 245 mg) was suspended in THF (1 mL) under an argon atmosphere, to the suspension ethyl diethylphosphonoacetate (1.11 mL) was added dropwise under ice cooling, and the mixture was stirred for 30 minutes. After 2,3,4-trimethoxybenzaldehyde (1.0 g) was then added to the mixture, the reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was dissolved in chloroform, and the solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:17]([C:16]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:15]=1[Cl:14])=[O:18])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,4-dichlorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.90 (t, 3 H) 1.30-1.40 (m, 2 H) 1.58-1.65 (m, 2 H) 2.21 (s, 3 H) 2.23 (s, 3 H) 3.94-3.99 (m, 2 H) 6.11 (s, 1 H) 7.46 (dd, 1 H) 7.52-7.57 (m, 1 H) 7.62 (d, 1 H); MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[O:15][C:16]3[C:22]([C:23]4[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=4)=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:31]CN=C=NCCCN(C)C.Cl.C(O)=O>CN(C1C=CN=CC=1)C.ClCCl>[NH:29]1[C:26]2[CH:27]=[CH:28][C:23]([C:22]3[C:16]4[O:15][C:14]([NH:13][C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:18][C:17]=4[CH:19]=[CH:20][CH:21]=3)=[CH:24][C:25]=2[N:30]=[CH:31]1
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(N)c(N)c4)c3o2)cc(OC)c1OC
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Product: COc1cc(Nc2nc3cccc(-c4ccc5[nH]cnc5c4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.16 g (0.228 mmol) 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-benzene-1,2-diamine, 0.068 g (0.346 mmol) EDC-HCl, 0.043 g (0.345 mmol) DMAP, 0.012 g (0.27 mmol) formic acid), and 7 ml dichloromethane is stirred at room temperature for 20 h. Then the reaction mixture is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc:MeOH=9:1) to afford ca. the title compound. 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-benzene-1,2-diamine is prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene-1,2-diamine as described in Example 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:3]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CN1CCCC(c2nc3cccnc3[nH]2)C1
Product: CN1CCCC(c2nc3cccnc3n2Cc2ccccc2)C1

Procedure:
Operation is carried out similarly to the description of Example 5 with the difference that 2-(1-methylpiperidin-3-yl)3H-imidazo [4,5-b] pyridine is reacted with benzylchloride to obtain 3-benzyl-2-(1-methylpiperidin-3-yl)-3H-imidazo [4,5-b] pyridine as an oil, after purification by chromatography on silicagel column (CHCl3 -CH3OH 9:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[N:18]1([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:29][CH2:28]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1>>[N:18]1([CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:31][CH2:32]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1CCC(n2nnc3ccccc32)CC1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCC(n2nnc3ccccc32)CC1

Procedure:
Batch size: 3.1 g (22.5 mmol) 3-(3-pyridyl)-acrylic acid, 5.4 ml (45 mmol) oxalyl chloride and 5.6 g (20.5 mmol) 4-(4-benzotriazol-1-yl-piperidin-1-yl)-butylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11](O)=[O:12])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1.[CH3:26][CH2:27][N:28]=[C:29]=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.CNCC>CN(C=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([N:28]([CH2:27][CH3:26])[CH3:29])=[O:12])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Agent: CCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid (297 mg, 0.70 mmol) in DMF (2 ml) was added EDC.HCl (148 mg, 0.77 mmol), HOBT.H2O (104 mg, 0.77 mmol), and N-methylethanamine (0.30 ml, 3.5 mmol). The reaction was stirred at room temperature for 16 hours, diluted with 1M HCl, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-40% EtOAc in hexane) to yield the title compound (269 mg, 83%) as a mixture of amide bond cis-trans isomers.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:15][CH2:14]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)(C(F)(F)F)=O>>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Yield: 74.1 %

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 2) (0.70 g, 2.5 mmol, 1 eq), 4-amino-3-methoxybenzoic acid (1.25 g, 7.5 mmol, 3 eq) and TFA (1.43 g, 12.5 mmol, 5 eq) were heated to reflux in TFE (25 mL) for 18 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with MeOH to give 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (0.81 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[CH3:15][C:12]1[N:13]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=1
Reactant: Clc1ncccn1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#Cc2cn(-c3ncccn3)c(C)n2)ccn1

Procedure:
2-Methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (II-1) (87 mg, 0.44 mmol) dissolved in 3 mL dimethyl formamide. Potassium carbonate (122 mg, 0.88 mmol) and 2-chloro-pyrimidine (76 mg, 0.66 mmol) were added and the reaction mixture was refluxed overnight. The reaction mixture was poured into 60 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was treated with ethyl acetate (2 mL) and diisopropyl ether (2 mL). The solid was filtered off and washed with little diisoppropyl ether. The desired compound was as an off-white solid (49 mg, 50%), mp=164–165° C., MS: m/e=276.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:15][S:16]C.[Na]>>[CH2:13]([N:3]1[C:2]([S:16][CH3:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:14]
Reactant: CCn1c(Cl)cc2ccccc2c1=O
Reactant: CSC
Agent: [Na]
Product: CCn1c(SC)cc2ccccc2c1=O

Procedure:
By following the same procedure as in Example 1 using 0.6 g. of 3-chloro-2-ethyl-1-oxo-1,2-dihydroisoquinoline and 0.8 g. of an aqueous solution of 20% sodium methylsulfide, 0.31 g. of 2-ethyl-3-methylthio-1-oxo-1,2-dihydroisoquinoline was obtained (recrystallized from cyclohexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[N:17]=[CH:16]2)[C@@H:9]([NH2:11])[CH3:10].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[N:17]=[CH:16]2)[C@@H:9]([NH:11][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1Cl
Product: C[C@H](NC(=O)C(C)(C)C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1Cl

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-(2-chlorophenyl)-1-(1-(4-fluorophenyl) 1H-indazol-5-yloxy)propan-2-amine (300a, 18 mg, 0.05 mmol) and Pivaloyl chloride (17 μl, 0.14 mmol). Yield 22 mg (100%).