Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[CH:20]=[CH:19][C:18]([N+]([O-])=O)=[CH:17]C=3)=[N:9][C:8]=2[N:7]([CH2:24][CH2:25][CH3:26])[C:5]1=[O:6])[CH2:2][CH3:3].C(N1C(N)=C(N)C(=O)N(CCC)C1=O)CC.[N+:43](C1C=CC(C=O)=CC=1)([O-:45])=[O:44].C(O)(=O)C>C(O)C>[CH2:24]([N:7]1[C:8](=[N:9][C:10]2[CH:15]=[CH:20][C:19]([N+:43]([O-:45])=[O:44])=[CH:18][CH:17]=2)[CH:12]([NH2:11])[C:13](=[O:14])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:25][CH3:26]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2n(CCC)c1=O
Agent: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCN1C(=O)C(N)C(=Nc2ccc([N+](=O)[O-])cc2)N(CCC)C1=O

Procedure:
1,3-Dipropyl-8-(4-nitrophenyl)xanthine, was prepared by treatment of 1,3-dipropyl-5,6-diaminouracil (1.01 g, 4.5 mmol) with 4-nitrobenzaldehyde (0.85 g, 5.6 mmol) in absolute ethanol (50 ml) in the presence of acetic acid (0.6 ml) and heated at reflux for 1 hour to yield 1,3-dipropyl-5-amino-6-(4-nitrophenyl)iminouracil. Treatment of 1,3-dipropyl-5-amino-6-(4-nitrophenyl)iminouracil (1.2 g, 3.3 mmol) with diethyl azodicarboxylate (7 ml) at 90° C. in toluene (40 ml) gave after dilution with ethanol a precipitate. This precipitate was recrystallized from ethanol yielding 0.95 g of pure product (81%). IR (KBr) 3180 (N--H), 1710(C=O), 1650(C=O), 1520(C=C) cm-1 ; Anal. Calcd. for C17H19N5O4 : MW 357.38: C, 57.14; H, 5.36; N, 19.60. Found: C, 57.22; H, 5.42; N, 19.50.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]1([CH2:10][CH2:11][NH:12][C:13]([C:15]2[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=2)=[O:14])[CH2:9][CH2:8]1>C(#N)C.ClCCl>[CH:7]1([CH2:10][CH2:11][NH:12][C:13]([C:15]2[N:16]=[N:17][C:18]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:19][CH:20]=2)=[O:14])[CH2:9][CH2:8]1
Reactant: C1CNCCN1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Yield: 74.8 %

Procedure:
A mixture of piperazine (1.48 g, 17.2 mmol) and 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (1.29 g, 5.73 mmol) in acetonitrile (60 mL) was heated at reflux for 16 hours. After the reaction mixture was cooled, the gummy material was diluted with dichloromethane (50 mL), washed with water (2×20 mL), dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography eluting with dichloromethane (100%) then with methanol:dichloromethane (1:9) to obtain 1.18 g (75%) of the product as a solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc2c(-c3ccccc3)cccc2s1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(-c6ccccc6)cccc5s4)cc3CC[C@@H]12
Yield: 61.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-phenylbenzothiazole (113 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 110 mg (61%) of the title compound as an amorphous foam. FDMS: m/e=470. α[D]589 =+53.51 (c=0.66, chloroform).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:24])[CH3:23].C(OCC)(=O)C>CN(C)C(=O)C>[C:22]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[CH:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[CH:14]=1)=[O:19])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CSc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CSc1ccc(-n2cnc3ccc(C(=O)NNC(C)=O)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-[4-(methylthio)phenyl]-1H-benzimidazole-6-carbohydrazide (1.0 g, 3.35 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (262 μL, 3.69 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 1 hr. Ethyl acetate was added to the reaction mixture, the precipitate was collected by filtration and washed with ethyl acetate to give the title compound (1.14 g, yield 100%) as colorless crystals.
Reaction SMILES: N[C:2](N)=[S:3].[N+]([O-])([O-])=O.[NH4+].O1[CH2:27][CH:11]1[CH2:12][S:13][CH2:14][CH:15]1[CH2:20][S:19][CH:18]([CH2:21][S:22][CH2:23][CH:24]2OC2)[CH2:17][S:16]1.[S:28](=O)(=O)(O)O>C1(C)C=CC=CC=1.CO>[S:3]1[CH2:2][CH:24]1[CH2:23][S:22][CH2:21][CH:18]1[CH2:17][S:16][CH:15]([CH2:14][S:13][CH2:12][CH:11]2[S:28][CH2:27]2)[CH2:20][S:19]1
Reactant: C1OC1CSCC1CSC(CSCC2CO2)CS1
Reactant: NC(N)=S
Reactant: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C(SCC1CSC(CSCC2CS2)CS1)C1CS1
Yield: 83 %

Procedure:
305 g of thiourea, 3000 ml of methanol, 1500 ml of toluene, 10 g of ammonium nitrate, and 373 g of 2,5-bis(β-epoxypropylthiomethyl)-1,4-dithiane were mixed and reacted at 20° C. for 9 hours in a nitrogen atmosphere. During the reaction, no polymer was deposited. After the reaction, 3800 ml of toluene and 460 ml of 10% aqueous solution of sulfuric acid were put to the reaction vessel to extract the reaction product. Then, the extracted product was washed with 300 ml of water four times, and toluene was removed by distillation. As a result, 340 g of 2,5-bis(β-epithiopropylthiomethyl)-1,4-dithiane (in formula (6), p=1, q=1) was obtained. The yield was 83%. The results are shown in Table 4.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]2[O:7][C:8]([CH3:34])([CH3:33])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:31])[CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[CH:13][C:12]3=[O:32])[C:5]=2[CH:4]=1)#[N:2].[O:37]([C:44](Cl)=[S:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+]>C(#N)C.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:36]=[CH:35][C:6]2[O:7][C:8]([CH3:34])([CH3:33])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([O:31][C:44]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[S:45])[CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[CH:13][C:12]3=[O:32])[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc(COCCCC(O)c2ccn(C3=CC(C)(C)Oc4ccc(C#N)cc43)c(=O)c2)cc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(COCCCC(OC(=S)Oc2ccccc2)c2ccn(C3=CC(C)(C)Oc4ccc(C#N)cc43)c(=O)c2)cc1

Procedure:
In 30 ml of anhydrous acetonitrile, is dissolved 1.42 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-hydroxy-4-p-methoxybenzyloxybutyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 44. Then, 1.50 g of 4-dimethylaminopyridine and 0.81 ml of phenoxythiocarbonyl chloride are added to the solution at room temperature, and reacted at that temperature for 8 hours. After stopping the reaction by adding 0.1M aqueous solution of sodium hydrogen carbonate, the reaction mixture is extracted with ether. The organic layer is washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/2 mixture of ethyl acetate/n-hexane as a developing solvent. Thus, 1.61 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-phenoxythiocarbonyloxy-4-p-methoxybenzyloxybutyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: C([O:8][C@:9]([CH3:17])([CH2:15][OH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C@:9]([CH3:17])([CH2:15][OH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@](C)(CO)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@](C)(O)CO
Yield: 92.8 %

Procedure:
22 g of ethyl (R)-2-benzyloxy-3-hydroxy-2-methyl-propionate (manufactured in accordance with Example 1) in 150 ml of ethyl acetate were hydrogenated with hydrogen gas in the presence of 11 g of 5% by weight palladium/carbon catalyst up to the cessation of the hydrogen uptake. The catalyst was filtered off, washed with ethyl acetate (2×50 ml), the filtrate was concentrated in the vacuum and the residual oil was distilled at 56°-57°/0.1 mmHg. There were obtained 12.7 g of ethyl (R)-2,3-dihydroxy-2-methyl-propionate in the form of a colorless viscous liquid. [α]D =+0.339° (undiluted);=+11.6° (c=2.12 in chloroform).
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[N:10][CH:9]=1>O1CCCC1>[N:14]1([C:11]2[N:10]=[CH:9][C:8]([C:7](=[O:19])[CH3:1])=[CH:13][CH:12]=2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: CON(C)C(=O)c1ccc(-n2cccn2)nc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-n2cccn2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylmagnesium bromide (3 M in tetrahydrofuran) (3.16 mL, 9.5 mmol) was added to a −78° C. solution of N-methoxy-N-methyl-6-(1H-pyrazol-1-yl)nicotinamide (2.0 g, 8.6 mmol) in tetrahydrofuran (10 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with brine and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])=S.CN(C)C=O>C(#N)C>[C:2]([NH:3][C:7]([NH:6][CH3:5])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])#[N:1]
Reactant: CNC(=S)NCCSCc1[nH]cnc1C
Reactant: N#CN
Agent: [Pb]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 24 h

Procedure:
Lead cyanamide (3.0 g.) was added to a so;ution of N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (2.44 g.) in acetonitrile (50 ml.). Dimethylformamide (20 ml.) was added subsequently and the suspension was heated under reflux, with stirring, for 24 hours. Filtration, followed by concentration under reduced pressure and purification of the product by chromatography on a column of silica gel with acetonitrile as eluant and recrystallisation from the same solvent afforded N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 139°- 141°. (Found: C, 47.3; H, 6.6; N, 33.4; S, 12.6. 12.6.C10N16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([SH:19])[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([S:19][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH3:24])[CH:27]=3)[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1
Reactant: COc1cccc(CBr)c1
Reactant: COc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CSc2nc(OC)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1

Procedure:
75 mg (0.229 mmol) of 4-[4-(2-hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile together with 36 μl (0.253 mmol) of 3-methoxybenzyl bromide and 52 mg (0.380 mmol) of potassium carbonate are stirred in 1 ml of DMF at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5, with 0.1% formic acid added). This gives 16 mg (56% of theory) of the target compound.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([C:12]2[S:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:20]([C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([CH3:32])[C:24]=1[NH2:25])(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([C:23]1[C:24]([NH:25][C:17]([C:15]2[N:16]=[C:12]([CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)[S:13][CH:14]=2)=[O:19])=[C:26]([CH3:32])[C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1csc(C2CCCCC2)n1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(C)=O)c(NC(=O)c2csc(C3CCCCC3)n2)c1C
Temperature: 25 °C
Yield: 98.3 %

Procedure:
POCl3 (1.4 mL, 14.9 mmol) was added drop wise at −35° C. over 5 min, to a stirred solution of 2-cyclohexylthiazole-4-carboxylic acid (117, 1.5 g, 7.1 mmol) and 2-acetyl-5-methoxy-6-methylaniline (1.27 g, 7.1 mmol) in dry pyridine (40 mL) After 1 h, the reaction mixture was successively warmed up to room temperature for 2.5 h, evaporated and neutralized with an aqueous solution of sodium bicarbonate. The precipitate was filtered, washed with water and dried to give 2.6 g (95%) of the title compound 118: m/z=373 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:27][CH2:26][CH2:25][C@H:14]1[C:15]([O:17]CC1C=CC=CC=1)=[O:16])=[O:12])[CH3:10])=[O:7])([OH:3])=[O:2]>C(O)C.[Pd]>[C:1]([CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:27][CH2:26][CH2:25][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH3:10])=[O:7])([OH:3])=[O:2]
Reactant: C[C@H](NC(=O)CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NC(=O)CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 19 h

Procedure:
A solution of the phenylmethyl ester product from part (a) (700 mg., 1.86 mmole) in 95% ethanol (100 ml.) containing 10% palladium on carbon catalyst (100 mg.) is hydrogenated at 25 psi in a Parr apparatus for 19 hours, after which it is filtered and concentrated to give 1-[N-(3-carboxy-1-oxopropyl)-L-alanyl]-L-proline as a colorless oil. This diacid product is dissolved in water, passed through a column of AG 50 W X8 (Li+) and lyophilized to give 1-[N-(3-carboxy-1-oxopropyl)-L-alanyl]-L-proline, dilithium salt as a stable, off white solid which is homogeneous by TLC (Rf 0.6, silica gel, 3:1:1 n-butanol:acetic acid: water). [α]D =-100° (1.5% water).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][OH:15])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][O:15][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO)CC(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CO[Si](C)(C)C(C)(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of DL-3-tert-butoxycarbonylamino-4-hydroxy-butyric acid in a mixture of DMF/DCM 1:5, 1.24 g of imidazole and 1.7 g of tert-butyldimethylsilyl chloride were added. The solution was left stirring at room temperature overnight. The solution was extracted three times with 5% aq. NaHSO4 and the aqueous phases were washed twice with DCM. The organic extracts were dried over anh. sodium sulfate and the solvent evaporated under vacuum to provide 2.1 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.ON1C2C=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=N1.CN(C)CCCN=C=NCC.N1CCCC1>C(Cl)(Cl)Cl.ClCCl>[N:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[C:9]([N:15]2[CH2:16][CH2:21][CH2:20][CH2:19]2)=[O:11])=[CH:5][CH:6]=1
Reactant: O=C(O)C=Cc1ccncc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCNC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccncc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a solution of 3-(4-pyridinyl)acrylic acid (1.01 g, 6.77 mmol) in CHCl3 (20 mL) in a 100 mL round bottom flask equipped with a magnetic stirrer and under nitrogen atmosphere was added 1-hydroxybenzotriazole (1.11 g, 8.21 mmol). The reaction mixture was stirred at RT for 10 min. Then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.56 g, 8.15 mmol) was added. The reaction mixture was stirred at 4° C. for 10 min. Then pyrrolidine (1.11 mL, 18.3 mmol) was added slowly and the reaction mixture was stirred for 15 h at +4° C. to RT. Dichloromethane (200 mL) was added and organic phase was washed with brine (100 mL), a solution of NaOH 0.5 N (100 mL) and brine (50 mL). The organic phase was dried over MgSO4, filtered, and evaporated to obtain (E)-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)prop-2-en-1-one (1.30 g, 94% yield). This free base (1.3 g, 6.40 mmol) was dissolved in MeOH (10 mL) at 4° C. and a solution of HCl 0.1 N in isopropanol (79 mL, 7.9 mmol) was added. After evaporation at 30° C. and drying, (E)-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)prop-2-en-1-one hydrochloride Compound 253 was obtained as a beige solid (1.40 g, 87% yield).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl.CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(I)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)cc1

Procedure:
A round bottom flask was charged with 4-iodobenzoic acid (3.0 g, 12.1 mmol) in chloroform (100 mL). To the solution was added thionyl chloride (5.0 mL) in chloroform (10 mL) and 2-3 drops of dimethylformamide (DMF). The slurry was heated at reflux for 2 hours. while monitoring the reaction through an oil bubbler. A clear solution of 4-iodobenzoyl chloride was obtained. The volatiles were removed and a colorless oil was obtained which solidified upon cooling.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:19][S:20]([NH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:31])[CH2:29]Br)=[CH:26][CH:25]=1)(=[O:22])=[O:21].C(N(CC)CC)C.CO>ClCCl>[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:29][C:28]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:33][CH:32]=3)=[O:31])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Nc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(C(=O)CN2CCN(c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(4-Methanesulphonamidophenyl)piperazine hydrochloride (1.18 g), 4-methanesulphonamidophenacyl bromide (1.16 g), [see J. Med. Chem, 9, 88 (1966)], triethylamine (0.82 g), methanol (10 ml) and dichloromethane (10 ml) were warmed briefly to attain homogeneity, then stirred at ambient temperature for 4 hours, evaporated to dryness, the residue triturated and washed with water, and then crystallized from methanol/acetone. The yield of the title compound was 0.88 g, m.p. 222°-5° (dec.).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)=O>C1(C)C(C)=CC=CC=1>[ClH:15].[Cl:15][CH2:16][C:17]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH2:28][CH3:29])[CH:26]=2)[CH2:21][CH2:20][N:19]=1
Reactant: CCc1ccc(CCNC(=O)CCl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: CCc1ccc2c(c1)C(CCl)=NCC2
Product: Cl
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 199.7 %

Procedure:
Phosphorus pentoxide (15.85 g) was added to a solution of 2-chloro-N-[2-(4-ethylphenyl)ethyl]acetamide (7.87 g) in xylene (140 mL) under stirring at 90° C. over 5 minutes. The reaction mixture was heated at 120° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature. The supernatant was removed and the residue was washed sequentially with toluene and ether. Crushed ice (150 g) was added to the residue, followed by stirring. A 20% aqueous sodium hydroxide solution was further added to the mixture to be a pH of 10 or higher, and the mixture was extracted with chloroform. The organic layer was collected, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. To the organic layer was added a 4 M HCl/EtOAc solution (15 mL), and the mixture was concentrated under reduced pressure to obtain 1-(chloromethyl)-7-ethyl-3,4-dihydroisoquinoline hydrochloride (8.5 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[C:34]([CH3:39])[N:35]=[C:36]([CH3:38])[CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M304) (0.38 g, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (203 mg, 67%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][CH2:8]Cl)=[CH:2]1.[NH2:10][C:11]1[S:12][C:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]=2[N:20]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(C)C>C(Cl)(Cl)Cl>[NH2:10][C:11]1[S:12][C:13]2[CH2:14][CH2:15][N:16]([CH2:8][CH:7]=[CH:6][C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH2:17][CH2:18][C:19]=2[N:20]=1
Reactant: ClCC=Cc1ccsc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Nc1nc2c(s1)CCN(CC=Cc1ccsc1)CC2
Yield: 8 %

Procedure:
Prepared from 3-(3-thienyl)allyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform in the presence of I equivalent of potassium carbonate. Yield: 8% of theory, Melting point: 128°-132° C. (isopropanol).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[CH2:11][CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:11][CH:12]=[O:13]
Reactant: Cc1cccc(C)c1N
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Dimethylaniline (60 grams), the dimethyl acetal of 2-chloroacetaldehyde (25 grams) and sodium carbonate )21.2 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at 150°C for a period of about 30 hours. After this time the mixture was filtered and the filtrate was distilled to yield the desired product the dimethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde having a boiling point of 105°C at 1 mm of Hg pressure.