Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1(OC)O[C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)=[CH:15][C:14]=2[CH3:26])(OC)[CH:4]=[CH:3]1.CO.C(O)(=O)C.O.[NH2:36][NH2:37]>O>[CH3:1][C:2]1[N:36]=[N:37][C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)=[CH:15][C:14]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC1(C)C=CC(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)(OC)O1
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)nn1
Temperature: 25 °C
Yield: 29 %

Procedure:
Under nitrogen with stirring 5-methyl-2-[3-[2,6-dimethyl-4(2-methyl-tetrazol-5-yl)-phenoxy]-propyl]-2,5-dimethoxy-2,5dihydrofuran (820 mg, 1.8 mmol), 0.8 mL of methanol, and 1.5 mL of 1% aqueous acetic acid solution were combined at room temperature, refluxed for 10 min, and then cooled to room temperature. To the above solution was added hydrazine hydrate (0.26 mL) over a 2 min period, and the mixture was allowed to reflux for 1 h, and cooled to room temperature. The mixture was diluted with water, the aqueous layer was extracted with methylene chloride, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford 180 mg (29%) of 3-methyl-6-[3-[2,6-dimethyl-4-(2-methyl-tetrazol-5-yl)-phenoxy]-propyl]-pyridazine (Formula I; R1, R2 =3,5-dimethyl, R3 =6-methyl, R4 =hydrogen, R5 =2-methyltetrazol-5-yl), m.p. 114°-115° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH:17](Br)([CH3:19])[CH3:18]>CN(C)C=O.CC(C)=O>[CH:17]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A solution of 2-nitrophenol (10 g, 71.9 mmol) and potassium carbonate (21.85 g, 158.1 mmol) in N,N-dimethylformamide:acetone (1:2, 150 mL) was heated under reflux and isopropyl bromide (14.8 mL, 158 mmol) was added dropwise (in 30 minutes) during reflux and stirred overnight. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% ethyl acetate:hexanes) to provide the title compound as a golden yellow oil (11.5 g, 88%). 1H NMR (300 MHz, CDCl3) δ 1.4 (d, 6H, J=6 Hz), 4.7 (septet, 1H, J=6 Hz), 6.98 (m, 1H), 7.09 (d, 1H, J=9 Hz), 7.45 (m, 1H), 7.78 (dd, 1H, 3 Hz); MS (DCI/NH3) m/e 182 (M+H)+.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[N:13][C:14]1[CH:19]=[C:18]([C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:21])[CH:17]=[CH:16][C:15]=1[OH:28])([O-])=O.C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.C=O.S(=O)(=O)(O)O>O.CO>[OH:28][C:15]1[CH:16]=[CH:17][C:18]([C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:21])=[CH:19][C:14]=1[N:13]1[N:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:3]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: C=O
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 80.9 %

Procedure:
Example 11 of U.S. Pat. No. 4,780,541 is duplicated. This is an example of the use of an aldehyde reducing agent and the aromatic ketone 9-fluorenone as a catalyst. Methanol (110 ml), water (20 ml), 97% sodium hydroxide (12.4 g), and 2-nitro-2'-hydroxy-5'-t-octylazobenzene (17.8 g) are mixed and stirred. After adding 9-fluorenone (2.4 g) to the resultant mixture at 65° to 70° C., 80% paraformaldehyde (6 g) is added to the mixture for 4 hours, and then the reaction liquor is further stirred at the boiling point (73° C. ) for 6 hours, thus the reduction reaction having completed. Thereafter, water (50 ml) is added to the reaction liquor, and the reaction liquor is neutralized to pH 8 with 62% sulfuric acid (16 g) to precipitate a crystal. The crystal thus obtained is filtered by suction to separate the crystal, and the separated crystal is fully washed with water and further with methanol. The washed crystal is then dried, thus producing 13.1 g of 2-(2-hydroxy-5-t-octylphenyl)benzotriazole having a melting point of 103° to 105° C. at the yield of 81.0%. One can see that the reaction takes over 10 hours to complete.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH2:29]([N:31]=[C:32]=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CNC>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([N:31]([CH3:32])[CH3:29])=[O:26])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (97 mg, 0.504 mmol), and 1-Hydroxybenzotriazole (68 mg, 0.504 mmol) were dissolved in 3.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (88 μL, 0.504 mmol) and dimethylamine (2M in THF, 126 μL, 0.252 mmol) were added. The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with saturated citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified in silica gel using the gradient 100% DCM to 5% 7M NH3 in methanol diluted with 95% DCM. After purification, pure white solid was obtained. Yield: 73 mg (White solid)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][OH:28]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:8]([CH2:25][CH2:26][CH2:27][OH:28])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: OCCCCl
Reactant: CCOC(=O)c1c[nH]c(=O)c2cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCCO)c(=O)c2cc(Cl)ccc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
25 g of 7-chloro-4-ethoxycarbonyl-1(2H)-isoquinolone was dissolved in 100 ml of dimethylformamide while warming, and 27 g of anhydrous potassium carbonate was added to the solution, followed by stirring for 2 hours at 110° C. Then, 14 g of 3-chloropropanol was added thereto and the stirring was continued for 5 hours at 110° C.The solvent was distilled off and the residue was dissolved in dichloromethane. The solution was washed with water, dried and the solvent was distilled off. The resulting crystals were recrystallized from a mixture of ethanol and petroleum ether to obtain 20.1 g of 7-chloro-4-ethoxycarbonyl-2-(3-hydroxypropyl)-1-(2H)-isoquinolone having a melting point of 193° C. as colorless prisms.
Reaction SMILES: [F:1][CH:2]([F:11])[N:3]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[N:4]1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:9][C:8]([C:5]1[CH:6]=[CH:7][N:3]([CH:2]([F:1])[F:11])[N:4]=1)=[O:10]
Reactant: CO
Reactant: O=C(O)c1ccn(C(F)F)n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccn(C(F)F)n1

Procedure:
A solution of 1-difluoromethyl-1H-pyrazole-3-carboxylic acid (CAS 925179-02-8) (500 mg, 3.1 mmol) in methanol (18 ml) was cooled to 0° C. and treated with sulphuric acid (98%, 0.2 ml, 3.1 mmol). The mixture was heated to reflux for 2 hours. For the workup, the solution was cooled and concentrated at reduced pressure. The residue was partitioned between ethyl acetate (25 ml) and water (30 ml). The organic layer was separated, washed with water until the water phase showed a neutral pH. After drying over sodium sulphate, the organic layer was evaporated at reduced pressure. The 1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester was obtained as a colorless liquid (535 mg, 99% of theory) pure enough to be engaged in the next step without further purification. MS (ISP): m/z=177.1 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4].Cl.[NH2:25][CH2:26][CH2:27][N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30].C[O-].[Na+]>CCO>[CH3:32][S:29]([N:28]([CH3:33])[CH2:27][CH2:26][NH:25][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4])(=[O:31])=[O:30]
Reactant: CN(CCN)S(C)(=O)=O
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 54.5 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (25 mg, 0.081 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (61 mg, 0.32 mmol), and NaOMe (17 mg, 0.32 mmol) in EtOH (3 mL) was heated at 140° C. for 6 h in a microwave reactor. The mixture was concentrated to dryness, and the residue was partitioned between EtOAc and 0.1 M HCl. The organic layer was dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 19 mg of the title compound as a white solid. MS: (+) m/z 431.34 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].Cl[CH2:18][C:19](=[O:21])[CH3:20]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[CH3:7][O:8][CH2:9][C:10](=[O:16])[CH:11]([CH2:18][C:19]([CH3:20])=[O:21])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COCC(=O)CC(=O)OC
Reactant: CC(=O)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: COCC(=O)C(CC(C)=O)C(=O)OC
Temperature: 0 °C
Yield: 102 %

Procedure:
165.8 g (1.2 mol) of potassium carbonate and 4.6 g (0.02 mol) of benzyltriethylammonium chloride are suspended in 500 ml of acetonitrile. While stirring there are added thereto 146.1 g (1 mol) of methyl 4-methoxy-acetoacetate and there are added dropwise thereto within 10 minutes 138.8 g (1.5 mol) of chloroacetone. The mixture is stirred at 20°-25° C. for a further 7 hours. The reaction mixture is poured on to 1 liter of 10% NaH2PO4 solution/ice (pH value=5) and extracted 3 times with 500 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator to give 206.30 g (100%) of methyl 4-methoxy-2-acetonylacetoacetate, content: 84.3%; b.p. 104°-105° C./0.06 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]([F:36])[F:35])(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([F:36])[F:35])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cn(C(CC(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
150 mg (388 μmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 125 mg (582 μmol) of 2,2-difluoroethyl trifluoromethanesulphonate and 427 μl (427 μmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 3 ml of THF were reacted according to General Method 7B. Purification by column chromatography (24 g silica cartridge, flow rate: 35 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 122 mg (71% of theory)
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:1]1=[O:14]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2c1[nH]c1ccccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2c([nH]c3ccccc23)C1=O
Yield: 1.3 %

Procedure:
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (I-61e: 250 mg, 1.34 mmol) was reacted with 3-iodo-4-methylpyridine (294.3 mg, 1.34 mmol), 1,4-dioxane (10 mL), copper iodide (25.6 mg, 0.134 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (59.8 mg, 0.402 mmol) and potassium phosphate (710 mg, 3.35 mmol) at 120° C. overnight to afford the crude product. Purification by column chromatography on silica gel (40% ethyl acetate in hexane), followed by preparative HPLC afforded 5 mg of the product (2% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:5]([C:7]1[CH:8]=[CH:9][C:10](F)=[C:11]([CH:14]=1)[C:12]#[N:13])=[O:6].O.[NH2:21][NH2:22].Cl>O1CCCC1>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:7]([C:5]([C:4]3[CH:3]=[C:2]([F:1])[CH:18]=[C:17]([F:19])[CH:16]=3)=[O:6])[CH:14]=2)[NH:22][N:21]=1
Reactant: NN
Reactant: N#Cc1cc(C(=O)c2cc(F)cc(F)c2)ccc1F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1n[nH]c2ccc(C(=O)c3cc(F)cc(F)c3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(3,5-difluoro-benzoyl)-2-fluoro-benzonitrile (2.05 g, 7.84 mmol) and hydrazine hydrate (0.73 mL, 15.7 mmol) in dry tetrahydrofuran (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was treated with 37% hydrochloric acid (1.3 mL, 15.7 mmol) for 30 min and then the volatiles were partially evaporated. The reaction mixture was then diluted with water (100 mL) and aqueous NH3 was added to reach neutral pH. The resulting solid was filtered, washed thoroughly with water and dried under vacuum at 60° C. The title compound was obtained as yellow solid (1.75 g, 80% yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.C(O)CCC.O>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[O:10])=[CH:8][C:2]=1[F:1]
Reactant: Oc1ccccn1
Reactant: Nc1ccc(I)cc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCCCO
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 130 °C
Yield: 89.8 %

Procedure:
A mixture of 2-fluoro-4-iodoaniline (3.00 g, 12.6 mmol), 2-hydroxypyridine 1-7 (1.20 g, 12.6 mmol), 8-hydroxyquinoline (0.184 , g, 1.26 mmol) and K2CO3 (3.49 g, 25.3 mmol) in DMSO (20 mL) was degassed with Ar before being charged with CuI (0.241 g, 1.27 mmol). The mixture in a sealed tube was heated at 130° C. overnight. After being cooled down to room temperature, H2O and nBuOH were added. The organic phase was separated, concentrated in vacuo to give 1-(4-amino-3-fluorophenyl)pyridin-2(1H)-one as a solid (2.31 g).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[N:11]1[CH2:12][CH:9]([O:8][C:3]2[C:2]([C:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10]1
Reactant: Clc1nccnc1OC1CN(c2ccc3ccccc3n2)C1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 2-(3-((3-chloropyrazin-2-yl)oxy)azetidin-1-yl)quinoline (see PREPARATION P2.6; 624 mg, 2.0 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (618 mg, 2.0 mmol) and K3PO4 (848 mg, 4.0 mmol) in 1,4-dioxane (20 mL) and H2O (4 mL) was added Pd(dppf)Cl2 (146 mg, 0.2 mmol) then the reaction mixture was stirred at 110° C. under N2 atmosphere overnight. The reaction mixture was filtered through CELITE® and washed with CH2Cl2 (50 mL). The filtrate was concentrated and the crude product was purified by silica gel column to give tert-butyl 4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (600 mg, 1.3 mmol, yield 65%). ESI-MS (M+1): 460 calc. for C26H29N5O 459.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:21]C)[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(OC)cc(Cl)c2OC1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(O)cc(Cl)c2OC1C(F)(F)F
Temperature: -78 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of ethyl 8-chloro-6-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Step 2 (1.41 g, 4.19 mmole) in anhydrous CH2Cl2 (80 mL) was cooled to −78° C. and a solution of BBr3 in CH2C2 (42 mL-1.0 M, 42.0 mmole) was added dropwise under a dry N2 atmosphere. The dry ice bath was removed and the mixture was allowed to warm to room temperature. After 3 h, the mixture was cooled to −78° C. and quenched by the addition of anhydrous MeOH (20 mL). The solvent was removed in vacuo and the residue extracted with EtOAc (200 mL). The extract was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a light brown solid. Purification by silica chromatography (98:2 CH2Cl2—MeOH gave 1.10 g (82% yield) of the product a as dark yellow solid: EIHRMS m/z 322.0215 (M+, C13Hn10ClF3O4, Calc'd 322.0220). 1H NMR (dmso-d6/300 MHz) 9.79 (s, 1H), 7.89 (s, 1H), 6.78-6.91 (m, 2H), 5.99 (q, 1H, J=7.3 Hz), 4.17-4.32 (m, 2H), 1.26 (t, 3H, J=7.05 Hz);
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:8][S:9]([N:12]=C=O)(=[O:11])=[O:10]>C1C=CC=CC=1>[C:1]([NH:12][S:9]([Cl:8])(=[O:11])=[O:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCCC(=O)O
Solvent: c1ccccc1
Product: CCCCC(=O)NS(=O)(=O)Cl
Yield: 100.2 %

Procedure:
n-Pentanoic acid (1.02 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was taken up in benzene (10 mL) and the mixture concentrated in vacuo to provide the title compound(2.0 g, quantitative) as a crystalline, hygroscopic solid.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=[O:11].[Na+]>OS(O)(=O)=O.O>[OH:11][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 24 h
Yield: 28203.2 %

Procedure:
To a stirred solution of L-Leu-OH (5.0 g, 38.2 mmol) in 1 N H2SO4 (50 mL) at 0° C. was slowly added over 11/2 h a solution of sodium nitrite (NaNO2 ) (7.5 g, 0.11 mmol) in water (20 mL) while maintaining the temperature at 0° C. The reaction mixture was gradually warmed to R.T., stirred for 24 h, and concentrated to give a white solid. The solid was extracted with ether (5×50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give (2S)-2-hydroxy-4-methylpentanoic acid as an oil (4.1 g, 81.2%): 1H NMR (CDCl3, 300 MHz) δ 0.98 (d, 6H, J=12.0 Hz), 1.57-1.67 (m, 2H), 1.82-1.93 (m, 1H), 4.36 (t, 1H, J=6.0 Hz) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(N)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.532 g (4.5 mmol) 4-aminobenzonitrile is heated for 1.5 h at 90° C. The reaction mixture is then distributed between dichloromethane and 20% aqueous potassium carbonate solution. The organic phase washed with water and dried over sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (50:1 and ). 25:1). Title compound is obtained after crystallization of the product-containing fractions from dichloromethane and drying under HV (8 h, 90° C.); m.p. 228-230° C.; ESI-MS: (M+H)+=338.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[C:5]([Br:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2cc(=O)c3c(N)cccc3o2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(=O)c3c(N)ccc(Br)c3o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
2.50 g (11.9 mmol) of 5-amino-2-(4-aminophenyl)-4H-1-benzopyran-4-one (EP-A-374789) was dissolved in 75 ml of dioxane, 1.86 g (13.1 mmol) of N-bromosuccinimide was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with a mixed solution of chloroform and methanol. The extract was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/acetone=40:1) to give 767 mg (20%) of Compound 5.
Reaction SMILES: S(O[CH2:6][CH2:7][O:8][S:9](=[O:12])(=[O:11])[NH2:10])(=O)(=O)N.[CH2:13]([OH:17])CCO>>[S:9]([O:17][CH2:13][CH2:6][CH2:7][O:8][S:9](=[O:11])(=[O:12])[NH2:10])(=[O:11])(=[O:8])[NH2:10]
Reactant: OCCCO
Reactant: NS(=O)(=O)OCCOS(N)(=O)=O
Product: NS(=O)(=O)OCCCOS(N)(=O)=O

Procedure:
1,3-Bis-O-sulfamyl-1,3-propanediol is prepared in the same manner as 1,2-bis-O-sulfamyl-1,2-ethanediol in Example 1 except that 1,3-propanediol (29.2 g., 0.385 mol.) is employed as the alkanediol.