Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:15]([O-])=[O:16].[Na+].[OH-].[Na+]>O.ClCCl>[N:15]([N:5]1[CH2:6][CH2:7][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4]1)=[O:16]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(N=O)CC1

Procedure:
In a 500 mL round-bottomed flask, 6N aqueous HCl (30 mL) was cooled to −10° C., and tert-butyl piperazine-1-carboxylate (10 g) was added. Sodium nitrite (4.5 g) dissolved in 35 ml water was added slowly. NaOH (10 g in 20 mL water) was used to neutralize the solution. Dichloromethane (3×50 mL) was used to extract the product. After drying over Na2SO4 and filtration, the solution was concentrated. The crude product was added to a silica gel column (Analogix, SF65-400 g,) and purified by eluting with 0-30% ethyl acetate in hexane.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.Br[C@@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][O:29][C:27](=[O:28])[C@@H:26]([N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)[C@@H](Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 65 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (300 mg, 0.905 mmol, 1 equiv), (S)-methyl 2-bromo-2-phenylacetate (207.4 mg, 0.905 mmol, 1 equiv) and potassium carbonate (312.7 mg, 2.26 mmol, 2.5 equiv) in N,N-dimethylformamide was stirred at 65° C. for 2 hours. The reaction mixture was cooled to ambient temperature and the mixture was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using a Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.4, gradient-2%-20% ethyl acetate/hexanes) to afford (S)-tert-butyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as an oil (183 mg, 42.3%); MS for C27H33N3O5 m/z 479.57 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[C:7](OC)=[CH:8][C:9]([F:13])=[C:10]([F:12])[CH:11]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:18]I.CN(C)[CH:22]=[O:23]>>[CH:1]1([NH:4][CH2:5][CH2:6][C:7]2[C:18]([O:23][CH3:22])=[CH:11][C:10]([F:12])=[C:9]([F:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(F)c(F)cc1CNC1CC1
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1cc(F)c(F)cc1CCNC1CC1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
2 g of cyclopropyl(4,5-difluoro-2-anisyl)amine and 0.48 g of sodium hydride are stirred in 10 ml of dimethylformamide for 20 min at ambient temperature, 1.25 ml of methyl iodide are subsequently added and the mixture is additionally stirred for 20 h at 40° C. After filtering and evaporating, the reaction mixture is taken up in diethyl ether and the organic phase is washed with water, dried with magnesium sulfate and evaporated to dryness. Cyclopropyl-(4,5-difluoro-2-anisyl)methylamine is thus obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(F)c(F)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3,4-difluoro-phenylboronic acid to give [1-(3,4-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[C:27]([NH2:35])=[N:28][C:29]([CH2:32][O:33][CH3:34])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:35])=[N:28][C:29]([CH2:32][O:33][CH3:34])=[CH:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(COC)nc1N
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(Cl)o2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCc1ccc(-c2cc(Cc3ccc(Cc4ccc(Cl)o4)cc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of (4-(5-chloro-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (25 mg, 0.088 mmol) described in Manufacturing Example 62-1-6 and tetrahydrofuran (1 mL) were added 3-ethynyl-6-methoxymethyl-pyridin-2-ylamine (11 mg, 0.069 mmol) described in Manufacturing Example 26-1-7 and triethylamine (19 μL, 0.014 mmol), which was stirred for 1 hour at 50° C. The reaction mixture was allowed to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound as a crude product. This product was then purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (7.5 mg, 27%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C1N2CN3CN(C2)CN1C3.CO.S(=O)(=O)(O)[OH:24]>C(O)(=O)C.O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(C=O)cc1
Yield: 45 %

Procedure:
3.9 g of p-cyanobenzylamine, 4.2 g of hexamethylenetetramine, 15 ml of methanol, 15 ml of water and 8 ml of acetic acid were mixed and after adjusting the pH of the solvent to 3 by sulfuric acid, the mixture was reacted at 70° C. for 5 hours while stirring. The reaction solution was concentrated to a half amount in an evaporator and 20 ml of water was added to precipitate crystals. The crystals precipitated were collected by filtration, washed with water and dried to obtain 1.8 g (yield: 45%) of p-cyanobenzaldehyde. The purity was 99.5% or more.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH:15]=[CH2:16].[K].[C:19]([CH:27]=[C:28](O)[CH3:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>C(O)C>[C:19]([CH:27]=[C:28]([NH:2][CH2:3][CH:4]([OH:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH:15]=[CH2:16])[CH3:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1
Reactant: C=CCOc1ccccc1OCC(O)CN
Reactant: CC(O)=CC(=O)c1cccnc1
Agent: Cl
Agent: [K]
Solvent: CCO
Product: C=CCOc1ccccc1OCC(O)CNC(C)=CC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5.1 g of 1-amino-3-(o-allyloxyphenoxy)-propan-2-ol hydrochloride ##STR30## are suspended in 50 ml of ethanol, 4 g of the potassium salt of 2-nicotinoyl-1-methyl-vinyl alcohol ##STR31## are then added and the mixture is stirred for 24 hours at room temperature. The suspension is filtered off and the residue is washed with ethanol. The filtrate, together with the wash alcohol is concentrated in vacuo. An oil is left, which solidifies after a short time. The oil which has solidified, together with the residue left on washing with alcohol, is repeatedly triturated with water and then recrystallised from ethanol. 1-(2-Nicotinoyl-1-methyl-vinylamino)-3-(o-allyloxyphenoxy)-propan-2-ol of the formula ##STR32## is thus obtained.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)#[CH:2].C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.Cl[Si](C)(C)C>[C:26]([N:5]1[C:4](=[O:18])[C:3]([C:1]#[CH:2])=[CH:16][N:7]([C@@H:8]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]2)[C:6]1=[O:17])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a stirred suspension of 2'deoxy-5-ethynyluridine (J. Med. Chem., 26(5), 661-6, (1983)) (0.3 g, 1.19 mmoles) in dry acetonitrile (8 ml) and chlorotrimethylsilane (0.5 ml) was added, with ice cooling, triethylamine (0.85 ml, 6.1 mmoles) and the whole was stirred at room temperature for 2 hrs. Benzoylchloride (0.18 ml, 1.54 mmoles) was then added and the mixture stirred for a further 1.5 hrs and filtered. The filtrate was concentrated, the residue dissolved in ethanol (10 ml) and glacial acetic acid (0.4 g) was added. After stirring for 0.5 hr, the solvents were evaporated and the residue purified by column chromatography on silica gel eluting with methylene chloride/methanol (19:1) to give the title compound 0.2 g (47% yield) melting at 156°-7° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH:17]([CH2:19][O:20][CH3:21])[O:16][C:15]3=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:20][CH2:19][CH:17]1[O:16][C:15](=[O:22])[N:14]([C:11]2[CH:10]=[CH:9][C:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:3][CH2:4]3)=[CH:13][CH:12]=2)[CH2:18]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCC1CN(c2ccc([C@H]3CC[C@H](O)CC3)cc2)C(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC1CN(c2ccc([C@H]3CC[C@H](OC(=O)c4ccccc4)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.5 g (1.639 mmol) of (RS)-3-[4-(trans-4-hydroxy-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one in 20 ml of methylene chloride and 5 ml of pyridine was treated dropwise with a solution of 0.95 ml (8.195 mmol) of benzoyl chloride in 10 ml of methylene chloride and stirred at room temperature for a further 3 hours. The reaction mixture was poured into ice-water, made acid with 3N hydrochloric acid and extracted with methylene chloride. The organic phase was washed with wate, dried over magnesium sulfate and the solvent was distilled off. The benzoate crystallized upon treatment with t-butyl methyl ether. There was obtained 0.52 g (77%) of benzoic acid (RS)-trans-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-cyclohexyl ester. M.p.: 104°-105°.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([NH:26][CH:27]1[CH2:30][N:29]([C:31]2[N:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][N:32]=2)[CH2:28]1)(=[O:25])=[O:24].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[O:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH:58]1[O:63][NH2:64]>C(Cl)Cl.C1COCC1>[O:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH:58]1[O:63][NH:64][C:37]([C:34]1[CH:33]=[N:32][C:31]([N:29]2[CH2:28][CH:27]([NH:26][S:23]([C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:13]=3)(=[O:25])=[O:24])[CH2:30]2)=[N:36][CH:35]=1)=[O:38]
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cnc(N2CC(NS(=O)(=O)c3ccc4ccccc4c3)C2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1cnc(N2CC(NS(=O)(=O)c3ccc4ccccc4c3)C2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
EDCl (90 mg, 0.47 mmol) was added to a solution of 2-{3-[(2-naphthylsulfonyl)amino]azetidin-1-yl}pyrimidine-5-carboxylic acid (150 mg, 0.39 mmol) in DCM (10 ml) and THF (10 ml) at r.t. under N2. Et3N (0.14 ml, 1.02 mmol), HOBt (63 mg, 0.47 mmol) and O-(tetrahydro-pyran-2-yl)-hydroxylamine (55 mg, 0.47 mmol) were added and the reaction stirred at r.t. overnight. The reaction mixture was concentrated in vacuo giving a colourless oil which was dissolved in DCM (20 ml), washed with water (3×20 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (162 mg, 86%). LCMS purity 93%, m/z 484 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=C(O)C=[CH:5][C:3]=1[OH:4].[C:10](Cl)(=[O:20])[C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13](Cl)=[O:14].[CH3:22][CH2:23][OH:24]>>[CH3:8][C:2]1[CH:1]=[C:23]([OH:24])[C:22]2[C:13](=[O:14])[C:12]3[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10](=[O:20])[C:5]=2[C:3]=1[OH:4]
Reactant: Cc1cc(O)ccc1O
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: CCO
Product: Cc1cc(O)c2c(c1O)C(=O)c1ccccc1C2=O
Yield: 62 %

Procedure:
The method was the same as in Example 1 but using 12.4 g (0.1 mols) of 2-methyl hydroquinone and 20.2 g (0.1 mols) of phthalic acid dichloride. The product was 15.7 g (62% yield) of 2-methyl-1,4-dihydroxy-9,10-anthraquinone (3), m.p.=177°-178° C. (literature 178°-179° C. EtOH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].O[NH3+:20].C([O-])(=O)C.[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:20])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
A mixture of 4-benzyloxy-3-hydroxybenzaldehyde (19.0 g), hydroxylammonium chloride (8.6 g), sodium acetate (13.7 g), water (30 mL) and ethanol (150 mL) was stirred at 80° C. for 8 hours. Water (100 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and then pyridine (20 mL) was added. Trifluoroacetic anhydride (35.3 mL) was added dropwise under ice-cooling, and the resulting mixture was stirred at room temperature for 6 hours. Two mol/L hydrochloric acid was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/10) to give the title compound (1.0 g).
Reaction SMILES: Cl[CH2:2][N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH2:15]([OH:18])[CH2:16][OH:17].C(N(CC)CC)C>C(OCC)(=O)C>[OH:17][CH2:16][CH2:15][O:18][CH2:2][N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: OCCO
Reactant: CN(C)C(=O)N(CCl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(COCCO)c1ccccc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
212 g (1 mole) of 1-chloromethyl-1-phenyl-3,3-dimethylurea were dissolved in 100 ml of anhydrous ethyl acetate and 63 g (1.0 mole) of ethylen glycol and 60 g (1.0 mole) of triethylamine were added dropwise whilst cooling with ice. After stirring for 2 hours at 10° to 15°C, the triethylamine hydrochloride used was filtered off and the solvent was distilled off. 238 g of 1-β-hydroxyethoxymethyl-1-phenyl-3,3-dimethylurea were obtained as an oil, in quantitative yield.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18]>CO>[BrH:1].[NH2:19][C:17](=[NH:16])[S:18][CH2:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: NC(N)=S
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Solvent: CO
Product: Br
Product: COC(=O)c1cccc([N+](=O)[O-])c1CSC(=N)N

Procedure:
A solution of 18.8 g of the product from Example 1 and 5.2 g thiourea in 150 ml methanol was stirred at reflux temperature overnight. Removal of the solvent in vacuo yielded a viscous oil which slowly crystallized. The crude product was washed well with ethyl acetate, filtered and dried. The yield of 2-[[(amino)(imino)methyl]thiomethyl]-3-nitrobenzoic acid, methyl ester hydrobromide, m.p. 178°-180° (dec.), was 22.6 g; NMR (CDCl3 /DMSO-d6): δ 4.0 (3H, s, CO2CH3), 4.85 (2H, s, --CH2 --), 7.6-8.35 (3H, m), 9.05 (4H, br s, NH).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][CH:12]=2)=[CH:7][CH:6]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(O)(C)(C)C>[C:17]([NH:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: c1cc(-c2cnns2)ccc1OCC1CO1
Reactant: CC(C)(C)N
Solvent: CC(C)(C)O
Product: CC(C)(C)NCC(O)COc1ccc(-c2cnns2)cc1

Procedure:
A mixture of 1.5 g. of 5-[4(2,3-epoxypropoxy) phenyl]-1,2,3-thiadiazole, 45 ml. of t-butylamine and 5 ml. of t-butanol is stirred at room temperature for 96 hours. It is then evaporated to dryness under reduced pressure and the residue crystallized from methanol-ether to afford the pure 5-[4(3-t-butylamino-2-hydroxypropoxy)phenyl]-1,2,3-thiadiazole, m.p. 133°-134° C; λmax 225-226, 314 nm (ε 760, 12300) ir 3390, 3210, 1655, 1615 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]=1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:4])([CH3:3])[CH3:2].Cl[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:27]([O:26][C:24](=[O:25])[NH:23][C:9]1[CH:10]=[C:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([C:42]([F:43])([F:44])[F:45])(=[O:40])=[O:41])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2S(=O)(=O)C(F)(F)F)cc1NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 74.8 %

Procedure:
A mixture of [2-tert-butoxycarbonylamino-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester (0.213 g, 0.490 mmol), 1-chloro-2-trifluoromethanesulfonyl-benzene (0.100 g, 0.409 mmol), sodium carbonate (0.260 g, 2.45 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.027 g, 0.0409 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the title compound as a yellow solid (0.158 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][C:15]=2[C:22](=[O:33])[NH:23][C:24]2[CH:32]=[CH:31][C:27]3[N:28]=[CH:29][S:30][C:26]=3[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]([C:37]1[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=1)=[C:35]=S>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:22](=[O:33])[NH:23][C:24]3[CH:32]=[CH:31][C:27]4[N:28]=[CH:29][S:30][C:26]=4[CH:25]=3)=[CH:16][C:17]3[N:21]=[C:35]([NH:34][C:37]4[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=4)[NH:20][C:18]=3[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccnc1N=C=S
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c(N)cc2C(=O)Nc2ccc3ncsc3c2)CC1
Solvent: ClCCCl
Product: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4ncsc4c3)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2[nH]1

Procedure:
4-[4,5-diamino-2-(benzothiazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylic acid tert-butyl ester (see Example 163; 0.3 mmol) was reacted with 2-isothiocyanato-3-methylpyridine (0.3 mmol; prepared from 2-amino-3-methylpyridine and thiophosgene employing procedure described in Example 115) followed by cyclization in situ using EDC as described in general procedure B to provide 4-[6-(Benzothiazol-6-ylcarbamoyl)-2-(3-methyl-pyridin-2-ylamino)-3H-benzoimidazol-5-yl]piperazine-1-carboxylic acid tert-butyl ester. MS: m/z 585 (M+H)+.
Reaction SMILES: O1CCCC1.C([NH:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19](=[O:24])[C:18]=2[CH:25]=1)C1C=CC=CC=1>[C].[Pd].CO>[NH2:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][C:20]([CH3:22])([CH3:23])[C:19](=[O:24])[C:18]=2[CH:25]=1
Reactant: Cc1c(NCc2ccccc2)cc2c(c1C)OC(C)(C)C2=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(N)cc2c(c1C)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 100 %

Procedure:
5% palladium carbon (50% water content, 9.50 g) was added to a mixed solution of tetrahydrofuran (100 mL) and methanol (100 mL) containing 5-(benzylamino)-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (9.48 g, 32.1 mmol) synthesized in Reference Example 19, and the mixture was stirred under hydrogen atmosphere at room temperature for 22 hours. Palladium carbon was removed by filtration, and then the solvent was removed under reduced pressure to give 6.59 g of the title compound (yield: 100%).
Reaction SMILES: [O:1]=[C:2]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[CH:7][CH:6]=1.[OH-:23].[Na+].C(O)C.Cl.[OH2:29]>>[O:1]=[C:2]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([OH:29])=[O:23])=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: CCCCC(=O)C(Cc1ccc(C#N)cc1)c1ccccc1
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCC(=O)C(Cc1ccc(C(=O)O)cc1)c1ccccc1

Procedure:
3.5 g of product of Step A with 20 ml of N sodium hydroxide solution and 50 ml of ethanol were stirred for 15 hours at reflux and the reaction medium was poured into ice-cooled water and acidified with concentrated hydrochloric acid. After separating, the residue was washed with water and dried. The crude product was impasted in 100 ml of isopropyl ether to obtain 3.27 g of the desired compound melting at 140° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:38][CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[C:34]([Cl:33])[CH:35]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of 4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (from Example 13 supra) (230 mg, 0.50 mmol) and 3-chlorobenzylamine (283 mg, 2.0 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 7 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford 4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-piperidine-1-carboxylic acid tert-butyl ester. (Yield 80 mg, 30.0%).