Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([NH:9][S:10]([C:13]1[CH:18]=[C:17](N)[CH:16]=[C:15](C)[C:14]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:12])=[O:11])([CH3:8])([CH3:7])[CH3:6].[CH2:25]([N:27](CC)CC)C>ClCCl>[C:5]([NH:9][S:10]([C:13]1[CH:18]=[C:17]([CH2:25][NH:27][C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][C:14]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:11])=[O:12])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1c(C)cc(N)cc1S(=O)(=O)NC(C)(C)C
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(C)=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
0.63 g (8 mmol) of acetyl chloride dissolved in 10 ml of dichloromethane is added dropwise to a solution, cooled to 0° C., of 2.01 g (6.7 mmol) of N-tert-butyl-5-amino-methyl-2-methoxycarbonylbenzenesulfonamide and 0.93 ml (6.7 mmol) of triethylamine in 30 ml of dichloromethane, and the mixture is then stirred at room temperature for 2 h. The reaction solution is washed with water, dried and evaporated to dryness i.v. 2.1 g (91%) of N-tert-butyl-5-acetamidomethyl-2-methoxycarbonylbenzenesulfonamide are obtained as a viscous oil.   1 ⁢ H ⁢   ⁢ NMR ⁢   ⁢ ( 100 ⁢   ⁢ MHz , CDCl 3 ) ⁢ : ⁢   ⁢ δ =   ⁢ 1.25 ⁢   ⁢ ( s , 9 ⁢ H , C ⁡ ( CH 3 ) 3 ) ,   ⁢ 2.05 ⁢   ⁢ ( s , 3 ⁢ H , COCH 3 ) ,   ⁢ 3.95 ⁢   ⁢ ( s , 3 ⁢ H , OCH 3 ) ,   ⁢ 4.50 ⁢   ⁢ ( s , 2 ⁢ H , Ar— ⁢ CH 2 ) ,   ⁢ 6.15 ⁢   ⁢ ( s , 1 ⁢ H , SO 2 ⁢ NH ) ,   ⁢ 6.38 ⁢   ⁢ ( bt , 1 ⁢ H , NH ) ,   ⁢ 7.47 ⁢   ⁢ ( dd , 1 ⁢ H , Ar ⁢ — ⁢ H ) ,   ⁢ 7.75 ⁢   ⁢ ( d , 1 ⁢ H , Ar ⁢ —H ) ,   ⁢ 7.95 ⁢   ⁢ ( dd , 1 ⁢ H , Ar ⁢ — ⁢ H ) .
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][OH:13]>ClCCl>[OH:13][CH2:12][CH2:11][NH:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCBr
Reactant: C[C@H](N)c1ccccc1
Solvent: ClCCl
Product: C[C@H](NCCO)c1ccccc1
Temperature: 51 °C
Reaction time: 52 h
Yield: 78683.9 %

Procedure:
108.23 g (0.903 mmole) of (S)-(−)-α-methylbenzylamine was dissolved in 140 ml of dichloromethane and 144.0 g (1.071 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 52 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 117.4 g of the title compound, which had a pale yellow color.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:29][NH:30][CH3:31]>C1COCC1.C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:17][CH:16]=4)[C:13]([N:30]([CH3:31])[CH3:29])=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CNC
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN(C)C1=CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCOCC2)cc1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (1.0 g, 2.65 mmol) and a saturated solution of dimethylamine in THF (13 ml) in toluene/DMF (2:1; 15 ml) according to method 8b described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[OH:37][CH2:36][C:35]([NH:34][S:31]([C:27]1[CH:26]=[C:25]([NH:24][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:23])[CH:30]=[CH:29][CH:28]=1)(=[O:33])=[O:32])([CH3:39])[CH3:38]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 566.2 [(M−H−]; mp 271° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1[OH:38])[CH2:26][CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:29]3[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:28]=3[CH2:25][CH2:26][CH3:27])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CCCc1ccc(C(F)(F)F)cc1O
Product: CCCc1ccc(C(F)(F)F)cc1Oc1nc(C(=O)NC(C)c2cc(F)c(NS(C)(=O)=O)c(F)c2)co1
Yield: 53.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with give 2-propyl-5-trifluoromethyl-phenol (54 mg, 0.26 mmol) to give the title compound (38 mg, 54%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[CH3:5][S:6]([C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([O:13]C)=[O:12])(=[O:8])=[O:7]>CCOCC>[CH3:5][S:6]([C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([O-:13])=[O:12])(=[O:8])=[O:7].[CH3:1][N+:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CN(C)C
Reactant: COC(=O)C(F)(F)C(F)(F)S(C)(=O)=O
Solvent: CCOCC
Product: CS(=O)(=O)C(F)(F)C(F)(F)C(=O)[O-]
Product: C[N+](C)(C)C
Reaction time: 8 h

Procedure:
Trimethylamine (12.4 g, 0.21 mol) was distilled into a stirred solution of 47.8 g (0.20 mol) of methyl 3-methylsulfonyltetrafluoropropionate in 100 ml of ether. The mixture was stirred overnight, filtered under nitrogen, and the solid dried under vacuum. There was thus obtained 52.1 g (88%) of tetramethylammonium 3-methylsulfonyltetrafluoropropionate, mp 98° to 100°, as deliquescent crystals. NMR (DMSO-d6): 1H 3.40 (t, JHF 2 Hz, 3H, CH3SO2) and 3.17 ppm (s, 12H, (CH3)4N+); 19F-112.3 (t, JFF 3.0 Hz, 2F, CF2C=O) and -114.4 ppm (t, JFF 3.0 Hz, of m, 2F, CF2SO2). Anal. Calcd. for C8H15F4NO4S: C, 32.32; H, 5.09; N, 4.7. Found: C, 32.20; H, 5.17; N, 4.44.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.O=P(Cl)(Cl)[Cl:17].C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: COc1ccc2oc(=O)cc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: COc1ccc2oc(=O)cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A stirred mixture of 4-hydroxy-6-methoxycoumarin (116 g, 0.603 mole) and POCl3 (462.29 g, 3.015 mole) in toluene is treated dropwise with tri-n-butylamine (250 mL, 1.73 mole) at 25° C., heated at 100°-110° C. and monitored by HPLC analysis. When the reaction is complete, the mixture is cooled to room temperature, poured over ice, stirred mechanically for about 2 hours and filtered. The filtercake is washed with water and toluene, dissolved in methylene chloride and filtered through diatomaceous earth. The methylene chloride filtrate is concentrated and treated with a mixture of dimethylformamide and acetonitrile to afford crystallization. The mixture is filtered to give the title product, 81.7 g, (64% yield) identified by HPLC analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH2:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:25][CH:22]([CH3:24])[CH3:23])[N:15]=[C:14]([NH:19][CH2:20][CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: CCO
Product: CCNc1nc(NC(C)C)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Yield: 38 %

Procedure:
0.5 g (0.0015 mol) of 4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol and stirred with 13 ml (0.15 mol) of isopropylamine in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.20 g (37%) of 4-amino-N-(2-ethylamino-6-iso-propylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 258-259° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1>[Ru]>[CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2cnccc2c1
Agent: [Ru]
Product: C1CCC2CNCCC2C1

Procedure:
In this invention, when synthetic isoquinoline or refined coal tar isoquinoline or partially hydrogenated isoquinoline is used as the raw material, it is hydrogenated in its unmodified form in the presence of a ruthenium catalyst to produce decahydroisoquinoline.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([OH:12])=O.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:13]([CH2:20][CH2:21][NH:22][C:10]([C:2]1[NH:1][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCOc1ccccc1
Reactant: O=C(O)c1cc2ccncc2[nH]1
Product: O=C(NCCOc1ccccc1)c1cc2ccncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 15) and 2-phenoxyethylamine to give the title compound as a pale yellow solid. δH (CD3OD): 3.81 (2H, t), 4.18 (2H, t), 6.89-6.97 (3H, m), 7.14 (1H, s), 7.26 (2H, t), 7.65 (1H, d), 8.10 (1H, d), 8.78 (1H, s); m/z (ES+)=282 [M+H]+.
Reaction SMILES: BrC1C=C(N[C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])C=C2C=1COC2=O.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[O:37])[O:35][N:34]=[C:33]([CH3:38])[C:32]=2[CH:39]=1.C1(C2(CC(=O)C(O)=O)CC2)C=CC=CC=1>>[C:18]1([C:16]2([CH2:15][C:14](=[O:25])[C:13]([NH:27][C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[O:37])[O:35][N:34]=[C:33]([CH3:38])[C:32]=4[CH:39]=3)=[O:26])[CH2:17][CH2:24]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1noc(=O)c2ccc(N)cc12
Reactant: CC(C)(CC(=O)C(=O)Nc1cc(Br)c2c(c1)C(=O)OC2)c1ccccc1
Agent: O=C(O)C(=O)CC1(c2ccccc2)CC1
Product: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC3(c4ccccc4)CC3)cc12

Procedure:
was obtained analogously to the process that is described for 4-bromo-6-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 6-amino-4-methyl-2,3-benzoxazin-1-one and 3-(1-phenyl-cyclopropyl)-2-oxo-propionic acid, melting point 197-200° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([NH:13][C:14](=[O:21])[CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18]Br)=[CH:11][C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:37]1([C:44](=[O:46])[CH3:45])[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]([NH:13][C:14](=[O:21])[CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][N:40]2[CH2:41][CH2:42][CH2:43][N:37]([C:44](=[O:46])[CH3:45])[CH2:38][CH2:39]2)=[CH:11][C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cc(NC(=O)C(C)CCCBr)n(C(=O)OC(C)(C)C)n2)cc1
Reactant: CC(=O)N1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2cc(NC(=O)C(C)CCCN3CCCN(C(C)=O)CC3)n(C(=O)OC(C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
5-(5-Bromo-2-methyl-pentanoylamino)-3-(4-methoxy-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (280.0 mg, 0.6 mmol, 1.0 eq) was dissolved in DCM (3 mL). Triethylamine (80 μL, 0.6 mmol, 1.0 eq) and 1-[1,4]-diazepan-1-yl-ethanone (158 μL, 170.0 mg, 1.2 mmol, 2.0 eq) were added and the mixture was stirred at room temperature for 24 hours, then at 50° C. for 16 hours. NaHCO3 saturated solution was added and the organic layer separated and collected. Evaporation of the solvent gave a crude product purified using SiO2 column (elution DCM, DCM:MeOH 99:1 to 96:4) obtaining the title product (181.3 mg, yield 54%).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[NH:8][CH:9]=[CH:10][C:11]=1[NH2:12])=[O:6])C.[CH:13]([C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)=O.[BH3-]C#N.[Na+].CCN(CC)CC.C([N:39]=[C:40]=[S:41])(=O)C1C=CC=CC=1>CO>[NH:16]1[C:15]([CH2:13][N:12]2[C:11]3[CH:10]=[CH:9][NH:8][C:7]=3[C:5](=[O:6])[NH:39][C:40]2=[S:41])=[CH:19][N:18]=[CH:17]1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=Cc1c[nH]cn1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=S)n(Cc2cnc[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
3-Amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (0.10 g, 0.52 mmol) was dissolved in methanol (4 mL) and 4-formylimidazole (0.060 g, 0.63 mmol), NaCNBH3 (0.033 g, 0.52 mmol) and Et3N (0.073 g, 0.52 mmol) were added. The resulting mixture was stirred at r.t. overnight. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (3 mL) and methanol (1 mL). Benzoyl isothiocyanate (0.078 mL, 0.58 mmol) was added and after stirring at r.t. for 30 minutes the mixture was concentrated in vacuo. The residue was dissolved in ammonia (7N in methanol, 3 mL) and heated at 80° C. for 1 h. The precipitated product was filtered and washed with methanol, followed by diethyl ether. The crude product was purified by preparative HPLC, obtaining 0.017 g (13%) of the title compound as a solid. OC 710/07
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[O-]CC.[Na+].[F:13][C:14]1[CH:26]=[CH:25][C:17]([CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1>C(O)C>[C:1]([CH:3]([CH:18]([C:17]1[CH:16]=[CH:15][C:14]([F:13])=[CH:26][CH:25]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)C=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(F)cc1)C(C#N)C(=O)OCC
Yield: 47.4 %

Procedure:
To 12 g of ethyl cyanoacetate dissolved in 20 mL of ethanol, 8 g of sodium ethoxide and 40 mL of ethanol were added under cooling with ice, and then 20 g of ethyl p-fluorocinnamate and 40 mL of ethanol were added. The reaction mixture was heated under reflux for 20 hours and then filtered. The filtrate was poured into a mixture of 200 g of ice and 10 mL of concentrated hydrochloric acid and extracted with chloroform. The extract was concentrated and separated by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 15 g of diethyl 2-cyano-3-(p-fluorophenyl)glutarate as a diastereomer mixture.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][C:7](=[NH:14])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13].CC(C)=O.O.[C:20]([O:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30])(=[O:24])[C:21]([CH3:23])=[CH2:22].[OH-].[Na+:32]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:32].[C:20]([O:25][CH2:26][CH2:27][NH:28][C:29]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:7]([NH2:6])=[NH2+:14])=[O:30])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: N=C(N)NCCCCN
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCNC(=O)NCCCCNC(N)=[NH2+]
Product: O=S(=O)([O-])[O-]
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
Agmatine sulfate (100 g, 397 mmol) was dissolved in 400 mL of aqueous 1.00 N NaOH. Acetone (200 mL) was then added and the stirred mixture was cooled to about 10° C. in a cold water bath. An additional 80 mL of H2O was added to keep the agmatine sulfate in solution. 2-isocyanatoethyl methacrylate (58.0 mL, 411 mmol) was then added to the reaction mixture, via an addition funnel, over a period of 30 min. After stirring an additional 45 min, the reaction mixture was placed on a rotary evaporator at ambient temperature. After pulling off most of the acetone, the reaction mixture was transferred to a separatory funnel and washed with ethyl acetate (2×250 mL) and methylene chloride (2×200 mL). The remaining aqueous solution was adjusted to pH 7 by addition of a small amount of dilute sulfuric acid and then placed on a rotary evaporator at ambient temperature to draw off any remaining volatiles. Lyophilization yielded the title compound (162 g) as a white powder. 1H NMR (500 MHz, D2O) δ 6.14 (s, 1H), 5.73 (s, 1H), 4.23 (t, J=5.2 Hz, 2H), 3.45 (t, J=5.4 Hz, 2H), 3.18 (t, J=7.0 Hz, 2H), 3.12 (t, J=6.4 Hz, 2H), 1.22 (s, 3H), 1.61-1.48 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl

Procedure:
106.6 g of 2,4-dichloro-5-fluoro-3-nitro-benzoic acid are heated at the boiling point under reflux with 250 ml of thionyl chloride for 2 hours. The excess thionyl chloride is then distilled off under normal pressure and the residue is fractionated under a fine vacuum. 104.7 g of 2,4-dichloro-5-fluoro-3-nitro-benzoyl chloride pass over at 110°-115° C./0.08-0.09 mbar. On standing, crystals of melting point 35°-37° C. form.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.C([Mg]Cl)(C)C.[B:17](OC)([O:20]C)[O:18]C>>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([B:17]([OH:20])[OH:18])=[CH:6][CH:5]=1
Reactant: COB(OC)OC
Reactant: FC(F)Oc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Product: OB(O)c1ccc(OC(F)F)cc1

Procedure:
In a departure from the procedure described above the compound is prepared from 4-difluoromethoxy-1-iodo-benzene using iPrMgCl to generate the arylmetal compound and trapping this intermediate with trimethyl borate.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:37]=[C:38]=O)(=O)=O.CN(C)C=O.Cl>ClCCl>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:38]#[N:37])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2)c1Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
NMR (CDCl3, δ): 1.06 (9H, s), 4.98 (2H, s), 6.32 (2H, d, J=4 Hz), 6.83 (2H, d, J=4 Hz), 7.22 (1H, d, J=10 Hz), 7.32-7.48 (7H), 7.74 (4H, d, J=8 Hz) (2) To a solution of 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (1.20 g) in anhydrous dichloromethane (12 ml) was added a solution of chlorosulfonyl isocyanate (0.28 ml) in anhydrous dichloromethane (2.8 ml) dropwise in a dry ice-carbon tetrachloride bath. The mixture was stirred at the same temperature for 30 minutes and then at ambient temperature for additional 1 hour. Anhydrous dimethylformamide (0.4 ml) was added to this mixture dropwise in a dry ice-carbon tetrachloride bath. After stirring at the same temperature for 30 minutes and at ambient temperature for additional 1 hour, the reaction mixture was treated with 4N-hydrochloric acid under ice-water cooling for 30 minutes. The organic layer was isolated and the aqueous layer was extracted with chloroform twice. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluted with n-hexane--ethyl acetate to give 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]-2-cyanopyrrole (930 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:18]2)=[O:14])=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O.O>C(O)C>[NH2:1][C:2]1[N:7]2[C:8]([Cl:27])=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22]2)=[O:14])=[CH:4][CH:3]=1
Reactant: CCCCN1CCC(CNC(=O)c2ccc(N)n3cc(CC)nc23)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCO
Solvent: O
Product: CCCCN1CCC(CNC(=O)c2ccc(N)n3c(Cl)c(CC)nc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of 5-amino-N-[(1-butylpiperidin-4-yl)methyl]-2-ethylimidazo[1,2-a]pyridine-8-carboxamide (EXAMPLE 10, Step 4, 170 mg, 0.48 mmol) in ethanol (4 mL) was added N-chlorosuccinimide (76 mg, 0.57 mmol) at room temperature. After stirring at room temperature for 1 h, water (50 mL) was added to the mixture. The aqueous layer was extracted with dichloromethane (60 mL×3). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was suspended in diethyl ether and the insoluble solid was collected by filtration to give 71 mg (38%) of the title compound as a gray solid.
Reaction SMILES: [CH:1]1([Sn:7](C2CCCCC2)([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[Sn](Cl)(Cl)(Cl)[Cl:34].O>CCCCCC>[CH:1]1([Sn:7]([Cl:34])([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: C1CCC([Sn](C2CCCCC2)(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cl[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Yield: 79.4 %

Procedure:
55.1 g of tetracyclohexyltin (122 mmol) and 50 ml of toluene were mixed together in a 200 ml eggplant type flask, and containing a stirrer. Then, 18.1 ml of tin tetrachloride (155 mmol) was added, and the mixture was refluxed for 3 hours. Upon completion of the reaction, the mixture was cooled to 0° C., and 30 ml of water and 50 ml of hexane were added. After the hexane layer was separated, the solid precipitate, which had been precipitated by removing the solvent under reduced pressure, was washed with 20 ml of acetonitrile, and dried under a vacuum, to yield 39.1 g of the final product (yield=59.5%).