Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:47])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)=[CH:35][C:34]=3[CH3:46])[N:27]=2)[CH:12]=1.[C:48](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:47])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:45][CH2:44][N:43]([CH3:48])[CH2:42][CH2:41]4)=[CH:35][C:34]=3[CH3:46])[N:27]=2)[CH:12]=1
Reactant: CC(=O)O
Reactant: Cc1cc(OC2CCNCC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(OC2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 43.7 %

Procedure:
To N-(2,6-difluorophenyl)-3-[3-(2-{[2-methyl-4-(4-piperidinyloxy)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide (Example 6) (0.098 g, 0.16 mmol) in DCM (4 mL) and MeOH (2 mL) was added acetic acid (0.20 mL, 1M in DCM, 0.20 mmol) and formaldehyde (0.024 mL, 37% weight in H2O, 0.32 mmol). Sodium triacetoxyborohydride (0.053 g, 0.25 mmol) in one portion and the reaction was stirred at rt until complete by MS. Purification by flash chromatography, followed by preparative HPLC chromatography (prep-HPLC) provided the title compound (0.044 g, 0.070 mmol, 43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.67 (m, 2H), 1.88-1.95 (m, 2H), 2.11-2.21 (m, 8H), 2.55-2.65 (m, 2H), 4.33 (s, 1H), 6.45 (d, J=5.1 Hz, 1H), 6.81 (d, J=8.1 Hz, 2H), 6.87 (s, 2H), 7.17-7.26 (m, 3H), 7.36-7.47 (m, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.71 (d, J=9.1 Hz, 1H), 7.77-7.85 (m, 1H), 8.06 (d, J=9.5 Hz, 1H), 8.18 (d, J=5.3 Hz, 1H), 8.31 (s, 1H), 8.89 (s, 1H), 9.32 (br. s., 1H). MS (M+H, ES+) 646.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CCNCC1
Product: Brc1ccc(-c2nsc3cc(OCCCN4CCCCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Piperidine were converted to yield 3-(4-Bromo-phenyl)-6-(3-piperidin-1-yl-propoxy)-benzo[d]isothiazole as pink oil, MS: 431 (MH+,1Br).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.Cl.[C:14]([NH2:22])(=[NH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[K+]>O1CCCC1.O>[C:15]1([C:14]2[NH:21][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=3)[N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=C(N)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1Cl
Reaction time: 2 h

Procedure:
A solution of 68.0 g (0.254 mol) of the above-mentioned crude 2-bromo-3′,4′-dichloroacetophenone in 110 ml of tetrahydrofuran was added dropwise over 30 minutes, under reflux with heating, into a suspension of 39.8 g (0.254 mol) of benzamidine hydrochloride, 102.1 g (1.02 mol) of potassium bicarbonate in 400 ml of tetrahydrofuran and 100 ml of water. After the addition was complete, further refluxing with heating was carried out for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, to give a residual solid. This solid was successively washed with water and toluene, to give 45.5 g (62.0% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using acetonitrile, to give a purified white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]SCC(C)C(Cl)=S)=[CH:5][CH:4]=1.[SH:17][CH2:18][CH:19]([S:36][CH3:37])[C:20]([N:22]1[C@H:32]([C:33]([OH:35])=[O:34])[CH2:31][C:24]2(C(=O)CCC2=O)[CH2:23]1)=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][S:17][CH2:18][CH:19]([S:36][CH3:37])[C:20]([N:22]2[C@H:32]([C:33]([OH:35])=[O:34])[CH2:31][C:24]3([S:36][CH2:19][CH2:18][S:17]3)[CH2:23]2)=[O:21])=[CH:7][CH:8]=1
Reactant: CSC(CS)C(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O
Reactant: COc1ccc(CSCC(C)C(=S)Cl)cc1
Product: COc1ccc(CSCC(SC)C(=O)N2CC3(C[C@H]2C(=O)O)SCCS3)cc1

Procedure:
The 3-[[(4-methoxy)phenylmethyl]thio]-2-methylthiopropionyl chloride from part (a) is reacted with 4,4-ethylenedithio-L-proline according to the procedure of Example 9 (d) to yield [8S]-7-[3-[[(4-methoxy)phenylmethyl]thio]-2-methylthio-1-oxopropyl]-7-aza-1,4-dithiaspiro[4.4]nonane-8-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:41])[C:16]2[CH:21]=[CH:20][C:19]([C@@H:22]([N:30]3[CH2:35][C@@H:34]([CH3:36])[N:33]([CH2:37][CH:38]=[CH2:39])[CH2:32][C@@H:31]3[CH3:40])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)C.Cl>C1COCC1.[OH-].[Na+]>[CH2:37]([N:33]1[C@H:34]([CH3:36])[CH2:35][N:30]([C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[C:19]2[CH:18]=[CH:17][C:16]([C:15]([N:11]3[CH2:12][CH2:13][CH2:14][N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:42])=[O:3])[CH2:9][CH2:10]3)=[O:41])=[CH:21][CH:20]=2)[C@@H:31]([CH3:40])[CH2:32]1)[CH:38]=[CH2:39]
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N3CCCN(CCCC(=O)OCC)CC3)cc2)c2cccc(O)c2)C[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N3CCCN(CCCC(=O)O)CC3)cc2)c2cccc(O)c2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To the compound of Example 117 (330 mg) in THF (5 mL) was added IN NaOH solution (3 mL). The reaction was stirred at room temperature overnight. The reaction solution was neutralized by the addition of 1 N HCl solution (3 mL). The organic solvent was removed under vacuum. The remaining water layer was diluted by water (4 mL). The water layer was extracted by n-butanol (10 mL×3). The combined n-butanol layer was washed by water (10 mL×2) and concentrated to give crude product (245 mg), which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% CH2Cl2 to 30% MeOH in CH2Cl2) to give 4-(4-{4-[(R)-((2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxy-phenyl)methyl]benzoyl}[1,4]diazepan-1-yl)butyric acid (180 mg; 57%). 1H NMR (300 MHz, DMSO-d6) δ 9.36 (bs, 1H), 8.31 (s, 1H), 7.40 (d, 2H, J=7.5 Hz), 7.30 (d, 2H, J=7.5 Hz), 7.12 (dd, 1H, J=8.0, 8.0 Hz), 6.66 (m, 3H), 5.78 (m, 1H), 5.20-4.97 (m, 3H), 3.59 (m, 2H), 3.47-3.34 (m, 2H), 3.18 (m, 1H), 2.86 (m, 1H), 2.73 (m, 2H), 2.60-2.49 (m, 7H), 2.42 (m, 1H), 2.21 (m, 2H), 2.10 (m, 1H), 1.83 (m, 2H), 1.69-1.55 (m, 3H), 1.06 (d, 3H, J=6.0 Hz), 0.94 (d, 3H, J=5.5 Hz).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10].[C:12](OC)(=[O:16])[C:13]([CH3:15])=[CH2:14].O.COC1C=CC(O)=CC=1>CO>[C:12]([O:11][CH:8]([CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCCCCC(O)CC
Agent: COc1ccc(O)cc1
Solvent: CO
Solvent: O
Product: C=C(C)C(=O)OC(CC)CCCCCCC

Procedure:
In the same reactor as used in Example 1, 760 kg (5 kmoles) of tricyclo[5.2.1.02,6 ]deca-8-yl alcohol and 1500 kg (15 kmole) of methyl methacrylate were placed and well mixed with stirring. The water content of the resulting mixture was 2500 ppm. To the mixture, 550 g of hydroquinone monomethyl ether was added and heated while introducing thereinto dried air at a rate of 4 m3/ hr and reluxing methyl methacrylate through the distillation column to remove water by azeotropic distillation. After 1 hour from the beginning of the reflux of methyl methacrylate, the water content in the reactor became 630 ppm. Then, 3 kg of anhydrous lithium hydroxide was charged into the reactor to carry out the reaction. While removing methanol by-produced by the reaction from the reaction system by distillation, the reaction was continued until almost no methanol was distilled (about 7 hours), followed by removal of unreacted methyl methacrylate under reduced pressure. After cooling, the mixture was filtered under pressure (2 kg/cm2) using a filter paper (pore size 0.1 mm, area 5 m2) placing thereon 10 kg of diatomaceous earth to yield 990 kg of tricyclo[5.2.1.02,6 ]deca-8-yl methacrylate with the filtrating time of 2 hours.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:34].CCOCC>>[ClH:34].[CH2:25]([O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][S:16][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:23][CH:22]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(OCc3ccccc3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(SCc1ccc(OCc2ccccc2)cc1)N1CCNCC1

Procedure:
A solution of 86 mg (0.19 mmol) 4-(4-benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carboxylic acid tert-butyl ester in 2.2 ml 1.5M HCl/Et2O and 0.45 ml abs. MeOH was stirred at rt for 4 h. Evaporation of the reaction mixture provided 64 mg product as colourless powder. 1H-NMR(d6-DMSO): 3.03–3.17 m, 4H and 3.58–3.73 m, 4H; 4.09 s, 2H; 5.08 s, 2H; 6.95 d, J=7.5 Hz, 2H and 7.26 d, J=7.5 Hz, 2H (AB-system) and 7.30–7.50 m, 5H; 9.2 br, 2H. MS (ISP): 343.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[NH:4][CH:3]=1.[Si:12]([O:19][C@@H:20]1[CH2:25][CH2:24][C@H:23](O)[CH2:22][CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(C=P(C)(C)C)#N>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[N:4]([C@H:23]2[CH2:24][CH2:25][C@H:20]([O:19][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[CH2:21][CH2:22]2)[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](O)CC1
Reactant: Clc1ncc2c(Br)c[nH]c2n1
Agent: CP(C)(C)=CC#N
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(Br)c3cnc(Cl)nc32)CC1

Procedure:
To a suspension of 5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.13 g, 0.50 mmol) and cis-4-(tert-butyldimethylsilyloxy)cyclohexanol (0.23 g, 1.0 mmol) in toluene (8 mL) was added (cyanomethylene)trimethylphosphorane (CMMP; prepared according to Chem. Pharm. Bull. 2003, 51(4), 474-476.) (6.3 mL, 0.16 M in THF, 1.0 mmol). The resulting clear solution was refluxed for 16 h. The reaction mixture was washed with brine, and extracted with EtOAc (3×). The combined organic layer was dried (Na2SO4) and concentrated. The residue was purified on ISCO to provide the desired product (0.16 g, 72%). 1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 7.27 (s, 1H), 4.70 (tt, J=12.2, 3.9 Hz, 1H), 3.69 (tt, J=10.5, 4.2 Hz, 1H), 2.09-1.99 (m, 3H), 1.86-1.71 (m, 2H), 1.66-1.54 (m, 3H), 0.90 (s, 9H), 0.08 (s, 6H). MS m/z 444.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[I:13]I.N(OC(C)(C)C)=O.O>C(#N)C.[Cu]I>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([I:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1N
Reactant: II
Agent: [Cu]I
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: O
Product: Cc1cc(F)cc([N+](=O)[O-])c1I
Yield: 46.5 %

Procedure:
A mixture of 4.4 grams (0.026 mole) of 4-fluoro-2-nitro-6-methylaniline, 13.2 grams (0.052 mole) of iodine, and 5.5 grams (0.029 mole) of copper(I) iodide in 125 mL of acetonitrile was stirred, and a solution of 4.6 mL (0.039 mole) of tert-butyl nitrite in 25 mL of acetonitrile was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 16 hours. After this time the reaction mixture was poured into 300 mL of water. Excess iodine was destroyed using sodium meta-bisulfite. The mixture was then extracted with two 250 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:3 methylene chloride: petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.4 grams of 4-fluoro-2-nitro-6-methylphenyl iodide. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain more product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=[CH:7][C:3]=1C(O)=O.[N-:18]=[N+]=[N-].[Na+]>OS(O)(=O)=O>[NH2:18][C:3]1[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=1[Cl:1])[CH2:11][NH:12][C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14]
Reactant: O=C(O)c1cc(CNC(=O)C2CC2)ccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1cc(CNC(=O)C2CC2)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoic acid (5.0 g, 19 mmol) in conc.H2SO4 (30 mL) was added NaN3 (1.4 g, 21 mmol) lotwise at 50° C. The reaction mixture was stirred at 50° C. for 18 h. The reaction mass was quenched with ammonia and ice water. The solid obtained was filtered and suck dried to afford 3.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.66 (m, 4H), 1.56 (m, 1H), 4.12 (d, J=6.0 Hz, 2H), 5.27 (s, 2H), 6.41 (d, J=6.9 Hz, 1H), 6.61 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 8.48 (m, 1H); MS (m/z): 225.22 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=3[O:27][CH3:28])=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O>[F:26][C:22]1[C:23]([F:25])=[CH:24][C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=3)=[CH:18][CH:17]=2)=[C:20]([O:27][CH3:28])[CH:21]=1
Reactant: CCOC(=O)c1csc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2nc(C(=O)O)cs2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 2-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid ethyl ester (2.38 g, 5.870 mmol) in THF (40 mL) was treated with a solution of lithium hydroxide monohydrate (2.6 g, 61.96 mmol) in water (40 mL) at room temperature and stirred at 60° C. for 2 h. The mixture was cooled, diluted with water (75 mL), acidified with aq. 3N HCl and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (100 mL), dried (MgSO4), filtered and concentrated to 2-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid (2.13 g, 96.1%) as a pale yellow solid. LC-MS (ES) calculated for C18H13F2NO4S, 377.37; found m/z 378 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]2[C:3]([N:4]=1)=[C:2]([N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CCS(C)(=O)=O)c2n1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCS(C)(=O)=O)c2n1
Yield: 76.4 %

Procedure:
Heat a solution of 6-chloro-8-(2-chlorophenyl)-2-methyl-9-(2-methylsulfonylethyl)purine (0.3 g, 0.0007 mol), N-methylpiperazine (0.08 g, 0.0008 mol) and triethylamine (0.08 g, 0.0008 mol) in ethanol (15 mL) at 90° C. for 16 h. Cool and concentrate the reaction mixture under reduced pressure. Dissolve the residue in dry dichloromethane and wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column using dichloromethane:methanol (96:4) as eluent to afford a 8-(2-chlorophenyl)-6-(4-methylpiperazin-1-yl)-2-methyl-9-(2-methylsulfonylethyl)purine (0.24 g). ES/MS m/z 449 (M+1).
Reaction SMILES: [C:1]([N:3]([CH2:14][C:15]#[CH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)#[N:2].C(N(CC)CC)C.[SH2:24]>CO>[NH:2]=[C:1]1[N:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)[CH2:14][C:15](=[CH2:16])[S:24]1
Reactant: C#CCN(C#N)c1cccc(C(F)(F)F)c1
Reactant: S
Solvent: CCN(CC)CC
Solvent: CO
Product: C=C1CN(c2cccc(C(F)(F)F)c2)C(=N)S1

Procedure:
To a solution of N-cyano-3-trifluoromethylaniline (5.0 g) in acetone (100 ml), potassium carbonate (7.4 g) and propargyl bromide (3.5 g) were added, and the resultant mixture was stirred at room temperature for 10 hours, followed by filtration of the reaction mixture. The solvent was removed from the filtrate by distillation under reduced pressure, and the residue was subjected to column chromatography to give N-cyano-N-propargyl-3-trifluoromethylaniline (3.8 g). The thus obtained N-cyano-N-propargyl-3-trifluoromethylaniline (1 g) and a catalytic amount of triethylamine were dissolved in methanol (30 ml), and the resultant mixture was cooled to 0° C. Hydrogen sulfide was gradually introduced into the mixture for 20 minutes while keeping the temperature at 0° C., followed by introduction of nitrogen gas to remove hydrogen sulfide. The solvent was removed by distillation, and the residue was subjected to column chromatography to give 0.2 g of 2-imino-3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (Compound (ix)).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7]([O:16][C:17](=O)[CH3:18])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1([O-])[CH:26]=CC=[CH:23][CH:22]=1.[Na+].C1(O)C=CC=CC=1.C[O-].[Na+]>O1CCOCC1>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:26][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: [O-]c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: C1COCCO1
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)Oc1ccccc1

Procedure:
To 2.9 g. (0.01 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester in 10 ml. of dioxane was added a solution of sodium phenolate prepared from 0.94 g. of phenol and 0.54 g. of sodium methoxide in 15 ml. of dioxane. After refluxing for 2 hours, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with cold 10% aqueous sodium hydroxide, dried (MgSO4) and concentrated to yield the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18](=[O:48])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:21]([NH:36][C:37](=[O:44])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:20]=3[N+:45]([O-])=O)[N:10]=[N:9]2)=[CH:5][CH:4]=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:45][C:20]1[C:21]([NH:36][C:37](=[O:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=[CH:24][C:19]=1[C:18]([C:11]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:50][CH:49]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:48]
Reactant: CCOC(=O)c1c(C(=O)c2ccc(OCCCCc3ccccc3)c(NC(=O)c3ccccc3)c2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C(=O)c2ccc(OCCCCc3ccccc3)c(NC(=O)c3ccccc3)c2N)nnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.9 %

Procedure:
Ethyl 1-(4-methoxybenzyl)-4-(2-nitro-4-phenylbutoxybenzoylaminobenzoyl)-1,2,3-triazole-5-carboxylate (b-1) (529.5mg, 0.78 mmol) prepared in the step (b) was dissolved in ethanol (8 ml) and ethyl acetate (2 ml), 10% palladium on carbon (53 mg) was added to the solution, and the mixture was stirred at room temperature under a hydrogen atmosphere for two days. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resultant precipitate was collected by filtration to give ethyl 4-(2-amino-4-phenylbutoxybenzoylaminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (c-1) as a yellow oil (484.4 mg, 96%).
Reaction SMILES: CS[C:3]1[NH:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH2:27][NH2:28]>CC(O)(C)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[CH2:27][NH:28][C:3]1[NH:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)c1ccc2c(c1)N=C(SC)NC2
Solvent: CC(C)(C)O
Product: COC(=O)c1ccc2c(c1)N=C(NCc1ccc(OC)cc1OC)NC2
Yield: 67 %

Procedure:
Methyl 2-(methylthio)-3,4-dihydroquinazoline-7-carboxylate (1.30 g, 4.2 mmol) was dissolved in tBuOH (10 mL) and (2,4-dimethoxyphenyl)methanamine (2.8 g, 16.8 mmol) was added. The reaction mixture was heated at reflux overnight. After cooling, the solid was filtrated to afford methyl 2-(2,4-dimethoxybenzylamino)-3,4-dihydroquinazoline-7-carboxylate (1.0 g) as brown solid.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=O.[NH:13]1[CH2:20][CH2:19][CH2:18][C@@H:14]1C(O)=O>>[CH2:19]1[C@@H:20]2[C:5](=[O:12])[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:4])[N:13]2[CH2:14][CH2:18]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=C(O)[C@H]1CCCN1
Product: O=C1Nc2ccccc2C(=O)N2CCC[C@H]12
Yield: 78.9 %

Procedure:
The same procedures used in the method B in Reference Example 19 were repeated except for the use of isatoic anhydride and D-proline to form the title compound. Yield 78.9%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][S:23](Cl)(=[O:25])=[O:24])=[C:17]([O:27][CH3:28])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[S:23]([NH:1][C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=2[S:10]([NH2:13])(=[O:11])=[O:12])(=[O:24])=[O:25])=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: N#Cc1ccc(S(N)(=O)=O)c(N)c1
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Product: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1cc(C#N)ccc1S(N)(=O)=O
Yield: 36 %

Procedure:
The title compound was synthesized as described for Example 178 in 36% yield, starting from 2-amino-4-cyanobenzenesulfonamide and 2-(4-chloro-2-methoxy-phenyl)-ethenesulfonyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].CN(C)C(=O)C.Cl[C:18]([O:20][CH3:21])=[O:19].C(=O)(O)[O-].[Na+]>O>[CH3:21][O:20][C:18]([NH:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][CH:8]=1)=[O:19]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 93 %

Procedure:
A mixture of 10 g of 3-nitroaniline and 100 ml of N,N-dimethylacetamide was stirred under ice cooling and 8.2 g of methyl chloroformate was added dropwise to the mixture. After stirring the mixture for 30 minutes, 300 ml of water was added to the reaction mixture and then the reaction mixture was neutralized by the addition of sodium bicarbonate to deposit crystals, which were recovered by filtration, washed with water, and dried. The amount of the product was 13.1 g (yield: 93%).