Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=[CH:16][N:15]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)CCOCCCc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCOCCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 94.7 %

Procedure:
A mixture of methyl thiosalicylate (7.4 g, 43.8 mmol), tert-butyl 3-[3-[2-cyano-4-pyridyl]propoxy]propanoate (14.0 g, 48.2 mmol), triethylamine (7.1 g, 70.2 mmol) and toluene (37 ml) was refluxed under nitrogen atmosphere for 24 hrs. The reaction mixture was concentrated under reduced pressure, subjected to a column chromatography and eluted with ethyl acetate-hexane (3:2, v/v) to give the titled compound (17.7 g, 86%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]1([N:17]2[C:21](=[O:22])[N:20]([C:23](OC3C=CC=CC=3)=[O:24])[N:19]=[C:18]2[O:32][CH2:33][CH3:34])[CH2:16][CH2:15]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:14]1([N:17]2[C:21](=[O:22])[N:20]([C:23]([NH:13][S:10]([C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[I:1])(=[O:12])=[O:11])=[O:24])[N:19]=[C:18]2[O:32][CH2:33][CH3:34])[CH2:15][CH2:16]1
Reactant: COc1cccc(I)c1S(N)(=O)=O
Reactant: CCOc1nn(C(=O)Oc2ccccc2)c(=O)n1C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOc1nn(C(=O)NS(=O)(=O)c2c(I)cccc2OC)c(=O)n1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 250 mg (0.80 mmol) of 2-iodo-6-methoxybenzenesulfonamide in 3 ml of acetonitrile is admixed at room temperature first with 254.08 mg (0.88 mmol) of 4-cyclopropyl-3-ethoxy-5-oxo-1-phenyloxycarbonyl-4,5-dihydro-1H-1,2,4-triazole and then slowly with 0.24 ml (1.60 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. After 60 min of stirring at room temperature the solution is adjusted slowly to a pH of 1 using 2 N salt solution. The precipitated solid is filtered off with suction, washed with diisopropyl ether and acetonitrile, and dried. This gives 267 mg (62% of theory) of 4-cyclopropyl-3-ethoxy-N-[(2-iodo-6-methoxyphenyl)sulfonyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:17]3[CH:16]=[CH:15][C:14]([CH:19]([CH3:22])[C:20]#[N:21])=[CH:13][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC(C#N)c1ccc2oc(Nc3ccc(Cl)cc3)nc2c1

Procedure:
4-chlorophenylisocyanate (3.1 g.) was slowly added to a stirred solution of 2-(3-amino-4-hydroxyphenyl propionitrile (3.3 g) in xylene (35 ml.) at room temperature. When the addition was complete p-toluenesulphonic acid (250 mg.) was added, and the solution was heated under reflux using a Dean and Stark apparatus. On cooling, the solution was washed with aqueous sodium bicarbonate solution and evaporated to dryness. The residue was recrystallised to give 2-[2-(4-chloroanilino)-5-benzoxazolyl] propionitrile as a creme solid which was characterised by n.m.r. spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]#[N:42]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:40][C:41]#[N:42])[C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)c2nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c(=O)n2CCN1CC#N
Temperature: 70 °C

Procedure:
A mixture of 3-(benzyloxy)-N-(4-fluorobenzyl)-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide (see Example 3, Step 1), K2CO3 (2 eq.) and bromoacetonitrile (2 eq.) in DMF was heated at 70° C. overnight and was then cooled to room temperature. The solvent was removed under reduced pressure and the residue was taken up in EtOAc, washed with brine, dried (Na2SO4) and concentrated to yield the crude nitrile which was used in the next step without further purification. 1H NMR (300 MHz, d6-DMSO) δ 8.9 (t, J=6.2 Hz, 1H), 7.26-7.41 (m, 7H), 7.06 (t, J=8.8 Hz, 2H), 5.06 (s, 2H), 4.41 (d, J=6.2 Hz, 2H), 3.96 (s, 2H), 3.89 (t, J=5.2 Hz, 2H), 3.15 (t, J=5.2 Hz, 2H), 1.53 (s, 6H); MS (ES) C26H26FN5O3 requires 475. Found: 476 (M+H+).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[Br:7].[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)=[O:12])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH2:8]([O:10][C:11](=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[Br:7])[CH:18]=1)[CH3:9]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: BrC1=C(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1cccc(C2=C(Br)CCC2)c1
Yield: 17.6 %

Procedure:
1,2-Dibromocyclopentene (Ex Aldrich, 27,732-0) (5 g, 0.0221 mol), (3-ethoxycarbonylphenyl) boronic acid (Ex Combiblocks inc. BB-2117-005) (4.26 g, 0.0221 mol), Pd(0)[PPh3]4 (0.5 g) and potassium carbonate (5 g) were stirred at 80° C. under nitrogen for 18 h in dimethoxyethane (30 mL). The reaction mixture was then filtered through Kieselguhr and evaporated down to an oil. Purification was carried out on a Biotage (90 g column) using isohexane containing a gradient of dichloromethane (0–30%) to give the required product (wt: 1.15 g i.e. 30% yield)
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>COC1C=C([Mg]Br)C=CC=1OC>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:26]3[CH:27]=[CH:26][C:30]([O:29][CH3:28])=[C:28]([O:29][CH3:30])[CH:27]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: C1CCOC1
Agent: COc1ccc([Mg]Br)cc1OC
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1OC

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 3,4-dimethoxyphenylmagnesium bromide. Yield: 55 mg of a white solid. LC-MSD, m/z for C24H19BrN2O4 [M+H]+=479.0, 481.0; HPLC retention time: 2.1 min.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[F:28][C:29]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:30]=1[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:29]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:30]=1[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:35][CH2:34]1
Reactant: Fc1ccc(CCN2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCN(CCc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, 1-(2,4-difluorophenethyl)piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(4-(2,4-difluorophenethyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=493.2). 1H NMR (CDCl3, 400 MHz) δ 2.55 (m, 10H), 2.78 (t, 4H, J=6.8 Hz), 4.28 (t, 2H, J=6.8 Hz), 5.67 (s, 2H), 6.58 (d, 1H, J=3.6 Hz), 6.73-6.80 (m, 3H), 6.97 (m, 1H), 7.15 (m, 1H), 7.24 (m, 1H), 7.61 (s, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[Cl:30])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:29].[NH2:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[Cl:30])=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2Cl)cc1
Reaction time: 2 h

Procedure:
To (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(2′,5′-dichlorobiphenyl-4-yl)butanoate (Intermediate 11: 1.09 g, 2.33 mmol) is added a solution of 4 M HCl in 1,4-dioxane (5.81 mL, 23.3 mmol) at room temperature. After stirring for 2 hours, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 3-amino-4-(2′,5′-dichlorobiphenyl-4-yl)butanoate hydrochloride. Next, a solution of the product, succinic anhydride (280 mg, 2.80 mmol) and DIPEA (0.489 mL, 2.80 mmol) in dichloromethane (15 mL) is allowed to stir for 2 hours. The reaction is quenched with 1 M aqueous HCl and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(2′,5′-dichlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (553 mg) as a white solid; HPLC retention time=1.02 minutes (condition B); MS (m+1)=452.14; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.2 Hz, 3 H) 2.47-2.67 (m, 6 H) 2.89 (A of ABX, Jab=13.7 Hz, Jax=7.8 Hz, 1 H) 3.00 (B of ABX, Jab=13.7 Hz, Jbx=6.7 Hz, 1 H) 4.12-4.24 (m, 2 H) 4.49-4.57 (m, 1 H) 6.53 (br d, J=8.8 Hz, 1 H) 7.23-7.26 (m, 3 H) 7.32-7.40 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:35])/[CH:19]=[C:20]3/[C:21](=[O:34])[N:22]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:23](=[O:25])[S:24]/3)[CH2:14][C@H:13]2[O:36][CH3:37])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].FC(F)(F)C(O)=O.ClCCl>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:35])/[CH:19]=[C:20]3/[C:21](=[O:34])[N:22]([CH2:26][C:27]([OH:29])=[O:28])[C:23](=[O:25])[S:24]/3)[CH2:14][C@H:13]2[O:36][CH3:37])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)/C=C3\SC(=O)N(CC(=O)OC(C)(C)C)C3=O)C[C@H]2OC)nc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)/C=C3\SC(=O)N(CC(=O)O)C3=O)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Yield: 39 %

Procedure:
tert-Butyl cis(±)-{(5Z)-5-[2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-oxoethylidene]-2,4-dioxo-1,3-thiazolidin-3-yl}acetate obtained in Example (163a) (20.4 mg, 0.04 mmol) was dissolved in methanol (4 mL). A 20% trifluoroacetic acid-dichloromethane solution (5 ml) was added, and the mixture was stirred at room temperature. The organic solvent was evaporated under reduced pressure, and then the residue was washed with ether. The solid was collected by filtration to obtain 7.79 mg of the title compound as a white solid (43%).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>ClCCl.[OH-].[Na+]>[F:1][CH:2]([F:10])[C:3]1[C:4]([CH3:9])=[N+:5]([O-:19])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ncccc1C(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(C(F)F)ccc[n+]1[O-]
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of 3-(difluoromethyl)-2-methylpyridine (2.56 g, 17.9 mmol) in dichloromethane was added 3-chloroperbenzoic acid (6.01 g, 26.8 mmol) at ambient temperature. After stirring for 2 h, the mixture was diluted with a 1 M aqueous sodium hydroxide (50 mL) and extracted with dichloromethane (4×50 mL). The organic phase was washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-(difluoromethyl)-2-methylpyridine-1-oxide as a yellow oil (2.22 g, 78%): 1H NMR (300 MHz, CDCl3) δ8.36 (d, J=6.5 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.23 (m, 1H), 6.80-6.70 (m, 1H), 2.57 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 88 %

Procedure:
To a suspension of 5-chlorosalicylic acid (500 g) in ethanol (2 L) was added concentrated sulphuric acid (40 ml) with stirring at room temperature. After the reaction mixture was refluxed for 12 hours, the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% NaCl solution and 4% sodium hydrogen carbonate solution, and then evaporated under reduced pressure, dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure to give the title compound (514 g, 88%) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]2[C:30](=[O:31])[N:12]3[CH:13]=[CH:14][C:15]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]3=[N:10]2)=[CH:6][CH:5]=[C:4]([C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH3:36][NH:37][CH3:38].ClC1C=CC(C2C=CN3C(=O)N(CC4C(NC)=NC(C(F)(F)F)=CC=4)N=C3C=2C2C=CN=CC=2)=CC=1>O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]2[CH:14]=[CH:13][N:12]3[C:30](=[O:31])[N:9]([CH2:8][C:7]4[C:2]([N:37]([CH3:38])[CH3:36])=[N:3][C:4]([C:32]([F:35])([F:33])[F:34])=[CH:5][CH:6]=4)[N:10]=[C:11]3[C:16]=2[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:28][CH:27]=1
Reactant: CNC
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2Cl)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: CNc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Solvent: O
Product: CN(C)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Yield: 46 %

Procedure:
The title compound (12 mg, 46% yield) as a yellow powder was prepared from 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (26 mg, 0.05 mmol) and 40 wt. % dimethylamine in water (0.5 mL) according to the procedures described for 7-(4-chlorophenyl)-2-((2-(methylamino)-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. HPLC/MS: retention time=3.25 min, [M+H]+=525.2.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][CH2:16][CH3:17])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.O>CN(C)C=O>[C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([CH2:15][CH2:16][CH3:17])[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: CCCc1csc(NCCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1csc(N(CCc2ccccc2)Cc2ccc(COc3ccc(CCC(=O)OC)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of N-(2-phenylethyl)-4-propyl-1,3-thiazole-2-amine (246 mg) in N,N-dimethylformamide (2 mL) was added sodium hydride (40 mg), and the mixture was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]-oxy}phenyl)propanoate (318 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) to give the title compound (380 mg) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[S:11][CH2:12][CH2:13][C:14]([OH:16])=O>C(Cl)(Cl)Cl>[O:16]=[C:14]1[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[S:11][CH2:12][CH2:13]1
Reactant: Cn1c(SCCC(=O)O)cc2ccccc21
Solvent: ClC(Cl)Cl
Product: Cn1c2c(c3ccccc31)C(=O)CCS2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
88.2 G (0.375 mol) of 3-(1-methyl-2-indolylthio)propionic acid obtained in stage B, and 300 g of polyphosphate ester, prepared according to W. POLLMANN and G. SCHRAMM (Biochem. Biophysica Acta, 80, 1 (1963)), are placed in 3.5 1 of chloroform. The mixture is stirred at room temperature and under a nitrogen atmosphere for 16 hours. After hydrolysis with 3 liters of ice-cold water, the organic phase is separated after settling has occurred and the aqueous phase is extracted twice with chloroform. The organic phases are combined, washed with 10% strength sodium bicarbonate solution and then with water and dried, and the organic medium is evaporated off on a water bath under vacuum. The residue is recrystallized in acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N.[CH:36]([O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43]O)=[CH2:37]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH:36]=[CH2:37])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: C=COCCOCCO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=COCCOCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In toluene (30 ml) was dissolved the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (520 mg, 1.72 mmol) obtained in Example 5. After addition of 2,2-(2-vinyloxyethoxy)ethanol (0.270 ml, 2.10 mmol) and cyanomethylenetri-n-butylphosphorane (500 mg, 2.07 mmol), the mixture was heated under reflux for 24 hours under an argon atmosphere. The reaction mixture was then allowed to cool down. After addition of 2-(2-vinyloxyethoxy)-ethanol (0.170 ml, 1.25 mmol) and cyanomethylenetri-n-butylphosphorane (300 mg, 1.24 mmol), the mixture was heated under reflux for 12 hours under an argon atmosphere. The reaction mixture was allowed to cool down and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=7:1) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (140 mg, 20%) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:32][CH3:33])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:30]=O)=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:20])[CH3:13]>>[CH2:32]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:30]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:20])[CH3:33]
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)c2c1CCCC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c2c1CCCC2
Yield: 67.3 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (20 mg, 0.1 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (3-diethylaminopropyl)amide (30 mg) to give 33 mg (46%) of the title compound as an orange solid.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[C:10]([NH2:11])=[C:9]([OH:12])[N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:6]=1>O>[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:7]1[N:8]=[C:9]([OH:12])[C:10]2[C:5](=[N:4][C:15]([CH3:14])=[C:16]([CH3:17])[N:11]=2)[N:6]=1)([OH:21])=[O:20]
Reactant: Nc1nc(NCCCCCC(=O)O)nc(O)c1N
Agent: Cl
Solvent: O
Product: Cc1nc2nc(NCCCCCC(=O)O)nc(O)c2nc1C
Yield: 163.5 %

Procedure:
4.3 g of 4,5-diamino-2-(5-carboxypentylamino)-6-hydroxypyrimidine dihydrochloride monohydrate and 2.5 g of diacetyl were dissolved in 100 ml of water and, after adjusting the pH to 2 to 3, the solution was heated under reflux for 1 hour. After cooling, the precipitate was crystallized from 50% (v/v) methanol, and 3.1 g of 2-(5-carboxypentylamino)-4-hydroxy-6,7-dimethylpteridine was obtained as yellow needles having an m.p. 215°-219° C. (dec.).
Reaction SMILES: C([O:8][C:9](=[O:28])[C@H:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]([N:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH3:15])=[O:13])C1C=CC=CC=1>CO.[Pd]>[CH3:15][N:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[C:12]([CH2:11][C@@H:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([OH:28])=[O:8])=[O:13]
Reactant: CN(CC(O)CO)C(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(CC(O)CO)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Yield: 95.8 %

Procedure:
The resultant compound from Example 144 (200 mg, 0.523 mmol) and 10% Pd on carbon (200 mg) in methanol (10 ml) were stirred under a hydrogen atmosphere for 3 h. The reaction was filtered and evaporated to afford 148 mg (97%) of the desired product as an oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[CH:8]([N:6]1[CH2:7][CH:4]([NH2:1])[CH2:5]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 10 (5.7 g, 21.6 mmol), triphenylphosphine (11.3 g, 43 mmol) and water (5 ml) was heated to reflux for 24 hours. After cooling to room temperature the solvent was removed in vacuo and the residue purified by chromatography on silica gel (90:9:1 CHCl3:MeOH:NH4OH).