Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH2:8])(=[NH:7])[CH2:3][CH2:4][CH2:5][CH3:6].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([C:22]([CH3:24])=O)[C:17](OCC)=[O:18].[Cl-].[NH4+]>CN(C=O)C.[Cl-].[Na+].O.C[O-].[Na+]>[CH2:3]([C:2]1[NH:8][C:17](=[O:18])[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[C:22]([CH3:24])[N:7]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1Cl
Reactant: CCCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)c(-c2ccccc2Cl)c(=O)[nH]1
Temperature: 25 °C
Yield: 18.4 %

Procedure:
A solution of 4.5 g valeramidine hydrochloride, 1.9 mg sodium methoxide, and 1.0 g ethyl 2-(2-chlorophenyl)acetoacetate in 20 mL DMF was heated to 150° C. for 20 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of brine and saturated ammonium chloride solutions then was extracted three times with ether. The combined organic material was dried over MgSO4, stripped of solvent in vacuo, and MPLC'd in 40% ethyl acetate/hexane to give 212 mg of the title compound as a white solid, 37% yield. Rf 0.17 in 40% ethyl acetate/hexane; 1H NMR (300 MHz, CDCl3) δ7.55 (m, 1H), 7.38 (m, 2H), 7.26 (m, 1H), 4.64 (br s, 1H), 2.74 (3 line m, 2H), 2.11 (s, 3H), 1.79 (m, 2H), 1.42 (6 line m, 2H), 0.96 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:12]#[CH:13])([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1CCCCC1.[H][H]>[Ni].O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.CO>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([CH:12]=[CH2:13])([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: C#CC(O)(c1ccccc1)c1ccccc1F
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Solvent: C1CCNCC1
Product: C=CC(O)(c1ccccc1)c1ccccc1F

Procedure:
22.6 g. 2-fluoro-α-ethynyl-benzhydrol and 0.74 g. of zinc acetate dihydrate are dissolved in a mixture of 260 ml. of methanol and 10 ml. of piperidine, and 4.4 g. of Raney-nickel catalyst are added to the mixture. The reaction mixture is hydrogenated at room temperature under atmospheric pressure until the uptake of the calculated amount of hydrogen. Thereafter the catalyst is filtered off, and the solvent is evaporated in vacuo. The residue is dissolved in benzene, and the solution is washed with water in order to remove zinc acetate. The benzene phase is dried over anhydrous magnesium sulfate, filtered, and evaporated. The residual oil is distilled at 0.05 mmHg. 21.4 g. of colorless, oily 2-fluoro-α-vinyl-benzhydrol are obtained; b.p.: 91°-93° C/0.05 mmHg.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C.O1CCCC1.CN(C=O)C>[CH3:1][C:2]1[C:3]([C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]4[C:33]5[C:38]([CH:39]=[CH:40][C:25]3=4)=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:20][CH:19]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1ncccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 77.9 %

Procedure:
2-Methylnicotinic acid (55 mg, 0.4 mmol) was suspended in dry dichloromethane (4 mL), the suspension was added with DMF (0.08 mL) and oxalyl dichloride (0.05 mL, 0.6 mmol), and the mixture was stirred at room temperature for 21 hours. The solvent was evaporated under reduced pressure, and the residue was concentrated twice from dry dichloromethane (1 mL) under reduced pressure. The resultant was added with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63 mg, 0.2 mmol) obtained in Example 1, (3), dry tetrahydrofuran (4 mL), and triethylamine (0.11 mL), and the mixture was stirred at room temperature for 24 hours. This reaction mixture was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform=1/20) to give 5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (68 mg, yield 80%) as white crystals.
Reaction SMILES: O.[NH2:2]N.C[N:5](C)/[CH:6]=[CH:7]/[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][N:19]3[CH:25]=2)=[CH:12][CH:11]=1)=O>C(O)C>[I:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:25]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([C:8]4[CH:7]=[CH:6][NH:5][N:2]=4)=[CH:11][CH:12]=3)[N:17]=2)[CH:20]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Ic1ccc2nc(-c3ccc(-c4cc[nH]n4)cc3)cn2c1

Procedure:
Hydrazine monohydrate (100 μL) was added to a solution (30 mL) of (E)-3-(dimethylamino)-1-[4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-2-propen-1-one (344 mg) in ethanol, and the mixture was refluxed for 3 hours. The reaction mixture was left to cool, and the precipitated matter was recovered through filtration and dried, to thereby yield the title compound (290 mg).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][NH:13][NH2:14].C(OCC)(=O)C.O>C(O)(=O)C>[CH2:6]([O:5][C:3]([C:2]1[CH:8]=[C:9]([CH3:10])[N:13]([CH3:12])[N:14]=1)=[O:4])[CH3:7]
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(C)n(C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 2,4-dioxovalerate (5.6 ml, 40 mM) was dissolved in glacial acetic acid (35 ml) before cooling the reaction temperature to 8°-10° C. Methylhydrazine (2.0 ml, 38 mM) was added dropwise so that the reaction temperature did not rise above 15° C. After stirring at room temperature for 90 minutes the reaction was poured into ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate solution, water and brine before drying (MgSO4). Purification was accomplished was by chromatography on silica gel (10×4.5 cm) loading in dichloromethane and eluting with 50% ethyl acetate in hexane. Evaporation of solvent gave the title compound as a coloured oil which crystallised on standing (4.69 g); νmax (CH2Cl2) 1717 and 1223 cm-1 ; δH (CDCl3) 1.39 (3H, t, J 7.13 Hz), 2.30 (3H, s), 3.85 (3H, s), 4.39 (2H, q, J 7.21 Hz), 6.57 (1H, s); E.I m/e 168 (25% ).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:21][C:22]([CH3:29])=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:24]2[CH:23]=[C:22]([CH3:29])[O:21][C:20]=2[CH3:19])(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: Cc1cc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)c(C)o1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 2,5-dimethylfuran-3-sulfonyl chloride (0.5 mmol) to obtain N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2,5-dimethylfuran-3-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 2.2 (s, 3H), 2.3 (s, 3H), 5.8 (s, 1H), 6.0 (dt, 1H), 6.8 (s, 1H), 7.0 (q, 1H), 7.2 (d, 1H), 7.3 (m, 2H), 7.4 (dd, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][NH:4][C:3]1=[O:8].[H-].[Na+].[CH2:11]([CH:13]1[O:15][CH2:14]1)Br.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]([CH2:11][CH:13]2[CH2:14][O:15]2)[C:3]1=[O:8]
Reactant: BrCC1CO1
Reactant: Cc1n[nH]c(=O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn(CC2CO2)c(=O)n1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
After dissolving 4,5-dimethyl-2,4-dihydro[1,2,4]triazol-3-one (CAS 54770-19-3) (560 mg) in N,N-dimethylformamide (5 ml), sodium hydride (60% in oil) (238 mg) and epibromohydrin (0.85 ml) were added and the mixture was stirred at room temperature for one day. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (390 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[OH:33])[C:28]#[N:29]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:32]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=4[F:24])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: N#Cc1ccc(O)c(F)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C#N)cc4F)ncnc32)CC1

Procedure:
4-[4-(4-Cyano-2-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-fluoro-4-hydroxybenzonitrile (available from Alfa Aesar, Ward Hill, Mass., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.98-2.07 (m, 4H), 2.99-3.07 (m, 2H), 4.07-4.12 (m, 2H), 5.00-5.05 (m, 1H), 7.76-7.80 (m, 1H), 7.88-7.90 (m, 1H), 8.16-8.19 (m, 1H), 8.50 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=439.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23].S(Cl)(Cl)=O.[CH3:32][C:33]1[S:37][C:36]([NH2:38])=[N:35][N:34]=1>COCCOC.ClCCl>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:38][C:36]1[S:37][C:33]([CH3:32])=[N:34][N:35]=1)=[O:23]
Reactant: Cc1nnc(N)s1
Reactant: O=C(O)c1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1nnc(NC(=O)c2cccc(-c3c(O)ccc4cc(-c5cccc(O)c5)ccc34)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To 3-(2-hydroxy-6-(3-hydroxyphenyl)naphthalene-1-yl)benzoic acid (220 mg, 0.62 mmol, 1 eq), which is dissolved under a nitrogen atmosphere in 5 ml of dry DME, thionyl chloride (600 μl) is added, and the mixture is stirred at RT for 2 h. After the excess thionyl chloride has been removed in vacuum on a rotary evaporator, the residue is dissolved in dry THF and added dropwise to a suspension of 5-methyl-1,3,4-thiadiazole-2-amine (42.6 mg, 0.74 mmol, 1.2 eq) in dry dichloromethane cooled at 0° C. The reaction mixture is stirred at RT over night, followed by removing the solvent on a rotary evaporator. Purification of the raw product by column chromatography with dichloromethane/methanol 95/5 as the eluent yielded the desired compound in a yield of 47%, 132 mg.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1.CCOCC>[NH2:1][C@@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 2.04 g (4.83 mmol) 3α-azido-5α-cholestane in 50 ml THF, 16 ml (16 mmol) of a 1M solution of LiAlH4 in ether are carefully added dropwise. The mixture is heated for 4 h under reflow, cooled to RT, followed by cautious addition of 5 ml of a saturated NH4Cl solution. After filtration and washing of the residual filtrate twice with ether, the ether phase is dried over Na2SO4 and concentrated. The amine is obtained as white solid and directly processed further. Yield 96%, F=95-97° C. C27H49N (387.7), calc. C, 83.65; H, 12.74; N, 3.61. found: C, 83.30; H, 12.42; N, 3.65.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:2]1=[O:15].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:25]1([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:12]3[CH2:11][CH2:10][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][C:2]4=[O:15])[CH2:14][CH2:13]3)[CH:18]=2)=[O:24])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2ccccc21
Reactant: O=C1Nc2ncccc2C12CCNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC3(CC2)C(=O)Nc2ncccc23)ncn1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
43 mg (0.21 mmol) spiro[piperidine-4,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one were added to 50 mg (0.19 mmol) (6-chloro-pyrimidin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 52 μL (0.58 mmol) DIPEA in 5 mL DMF. The reaction mixture was stirred for 2 h at RT. The reaction mixture was evaporated down using the rotary evaporator and the residue was mixed with 20 mL water and stirred for 30 min at RT. The product precipitated was suction filtered, stirred with diisopropylether and isopropanol, suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH3:14])[C:4]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC.C1COCC1>[CH3:1][O:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH3:14])[CH2:4]1
Reactant: COC1C(=O)N(C)CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC1CN(C)CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 1028.5 %

Procedure:
Dissolve methoxy-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one (375 g, 183 mmol, 1.0 eq) in THF (2.5 L) and add the solution via an addition funnel over 1 hour to slurry of lithium aluminium hydride (LAH) (175 g, 457 mmol, 2.5 eq) in ether/THF (4.5 L/2 L) in a 22 L reaction vessel under nitrogen while cooled in an ice/acetone bath. Add the starting amide at a rate to maintain the reaction temperature below 30° C. Stir the resulting mixture for 3 hours at room temperature under nitrogen. The reaction is determined to be complete by TLC. Cool the reaction mixture in an ice/acetone bath and quench slowly over 2 hours (off-gassing, exothermic) with water (175 mL) and 5.0 N NaOH solution (350 mL) added in succession. Filter the slurry and wash the solids with THF. Add sodium sulfate to the filtrate to remove any excess water, and then filter. Concentrate the filtrate down under vacuum to a dark oil to obtain the product methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (360 g, quantitative yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10](O)=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]1[N:14]=[C:15]([N:19]([CH:23]([CH:30]2[CH2:32][CH2:31]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][CH3:22])[S:16][C:17]=1[CH3:18])(O)=[O:2].B.C(=O)([O-])[O-].[K+].[K+].CO>O1CCCC1.O>[OH:2][CH2:1][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:13]1[N:14]=[C:15]([N:19]([CH:23]([CH:30]2[CH2:31][CH2:32]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][CH3:22])[S:16][C:17]=1[CH3:18]
Reactant: CCCN(c1nc(-c2ccc(C(=O)O)cc2C(=O)O)c(C)s1)C(c1ccccc1)C1CC1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(c1nc(-c2ccc(CO)cc2CO)c(C)s1)C(c1ccccc1)C1CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1 g of the compound obtained in Step A is dissolved in 20 ml of anhydrous tetrahydrofuran, followed, at -7° C., by addition of 5 ml of 1M borane solution in tetrahydrofuran, and the mixture is stirred overnight. 0.5 g of potassium carbonate and 10 ml of a mixture of methanol and water (1:1 v/v) are then added. The mixture is maintained at 60° C. for 2 hours and then cooled and evaporated under vacuum. The residue is taken up in water and extracted with ethyl ether, and the organic phase is washed with water, then with saturated aqueous sodium chloride and dried over anhydrous sodium sulphate. It is evaporated to dryness and the residue is taken up in pentane. The expected product is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.Cl[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](CC)([O-])=O>[O:15]=[S:14]1(=[O:16])[C:3]2[CH:4]=[C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:7][C:2]=2[NH:1][C:18](=[O:19])[NH:17]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC[N+](=O)[O-]
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of N-(4-amino-phenyl)-methanesulfonamide (Example 3b′, 90.7 g, 0.49 mol) in nitroethane (900 mL) was added dropwise over 1.5 h to a mechanically stirred solution of chlorosulfonylisocyanate (50.6 mL, 0.54 mol) in nitroethane (150 mL) at −20° C. The resulting suspension was stirred at −20° C. for 30 min, then aluminum chloride (77.9 g, 0.58 mol) was added in one portion over 1 min. The resulting brown solution was warmed to 25° C., and then was heated at 110° C. for 1 h (considerable gas evolution was noted during this time). After cooling to −5° C., water (300 mL) was added dropwise via addition funnel over 15 min, followed by the rapid addition of more water (700 mL). The resulting suspension was allowed to warm to 25° C. and vigorously stirred for 30 min, and then was filtered through medium paper using a Büchner funnel. The collected solid was washed with water (1×300 mL) and was air-dried to afford the desired product, N-(1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazin-7-yl)-methanesulfonamide (115.2 g, 0.40 mmol, 81% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 3.00 (3H, s), 7.22 (1H, d, J=8.5 Hz), 7.46 (1H, dd, J1=8.8 Hz, J2=2.7 Hz), 7.51 (1H, d, J=2.4 Hz), 9.92 (1H, s), 11.20 (1H, s).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:13]=[N:14][C:15]1(Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]>CCOCC>[C:9]([N:13]=[N:14][C:15]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Solvent: CCOCC
Product: CC(C)(C)N=NC1(c2ccccc2)CCCCC1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a clean, dry 250 ml. round bottom 4 neck flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel, which was being purged with nitrogen, was added an ether solution containing 0.06 moles of phenyl-magnesium bromide. The solution was cooled to 5° C. and a solution of 8.7 g. (0.043 moles) of 1-t-butylazo-1-chlorocyclohexane in 50 ml. of ether was added dropwise over 1/2 hour. After the addition was complete, the reaction was stirred for 15 minutes at room temperature and the excess phenylmagnesium bromide destroyed by the addition of wet ether. The reaction mixture was poured into 200 ml. of cold water and the ether layer separated, washed with 5% HCl, saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the ether removed on a rotating evaporator leaving 9.75 g. (93%) of a yellow liquid. The infrared spectrum of the product was in agreement with the structure of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[CH:8]=[C:9]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2C)[CH:10]=[N:11][C:12]=1[Cl:13].[CH3:24][C:25]1[S:26][C:27]([C:31](O)=[O:32])=[C:28]([CH3:30])[N:29]=1>C(#N)C>[C:20]([NH:19][C:17]1[S:18][C:14]([C:9]2[CH:8]=[C:7]([NH:6][C:31]([C:27]3[S:26][C:25]([CH3:24])=[N:29][C:28]=3[CH3:30])=[O:32])[C:12]([Cl:13])=[N:11][CH:10]=2)=[CH:15][N:16]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Reactant: Cc1nc(C)c(C(=O)O)s1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1ncc(-c2cnc(Cl)c(NC(=O)c3sc(C)nc3C)c2)s1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
Phosphorus oxychloride (296 mg) was added to a stirred mixture of N-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (180 mg), 2,4-dimethylthiazole-5-carboxylic acid (J. Med. Chem., 1999, 42, 5064; 109 mg) and acetonitrile (10 mL) that had been heated to reflux. The resultant mixture was stirred and heated to reflux for 1 hour. The mixture was cooled to room temperature and the precipitate was collected by filtration, washed with acetonitrile and dried under vacuum. There was thus obtained the title compound (172 mg); 1H NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 2.39 (s, 3H), 2.62 (s, 3H), 2.68 (s, 3H), 8.21 (s, 1H), 8.40 (s, 1H); Mass Spectrum: M+H+ 422.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][C:8]=2[C:9](OCC)=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][C:8]=2[C:9]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(OCC)c2nnn(CC)c12
Reactant: CCCCN
Product: CCCCNc1nc(C)c(C(=O)OCC)c2c1nnn2CC
Yield: 78 %

Procedure:
2.8 g. of 4-ethoxy-1-ethyl-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester is treated for 14 hours with 10 ml. of n-butylamine at reflux temperature. The excess butylamine is distilled off and the residue of 4-butylamino-1-ethyl-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester is recrystallized from petroleum ether, yield 78%, m.p. 85°-87°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.ClCCl.[CH3:25][N:26](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].C(OCC)(=O)C>[C:25]([C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1)#[N:26]
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(Cl)nc1
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(C#N)nc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of methyl 3-(6-chloropyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.11 g, 0.38 mmol), zinc cyanide (45 mg, 0.38 mmol), zinc (5 mg, 0.08 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (14 mg, 0.019 mmol), and N,N-dimethylacetamide (0.5 mL) was stirred at 120° C. under argon for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (10 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (0-100% ethyl acetate in hexanes) gave methyl 3-(6-cyanopyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (70 mg, 0.24 mmol, 63% yield) as a colorless solid. MS found: (M+H)+=295.27.