Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9]([NH2:11])=[NH:10])=[CH:5][CH:4]=1.[F:14][C:15]([F:24])([F:23])[C:16]#[C:17][C:18](OCC)=[O:19].[OH-].[K+]>C(O)C>[OH:19][C:18]1[CH:17]=[C:16]([C:15]([F:24])([F:23])[F:14])[N:11]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CCOC(=O)C#CC(F)(F)F
Reactant: N=C(N)c1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nc(-c2ccc(C(F)(F)F)nc2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
A mixture of 6-(trifluoromethyl)pyridine-3-amidine (1 g, 5.26 mmol) and ethyl 4,4,4-trifluoro-2-butynoate (1.1 ml, 7.89 mmol) in ethanol (100 ml) was stirred at 0° C. for 20 min. The temperature of the mixture was raised to 60° C. and was let to stir at this temperature for 30 min. Then aqueous KOH (0.86 g in 20 ml water) was added dropwise. The mixture was refluxed for 4 h. The mixture was cooled to room temperature, rotary evaporated and isolated as a white solid (1.5 g, 94%). 1H NMR (CDCl3): 9.72 (d, J=2.4 Hz, 1H), 8.87 (dd, J=2.1, 8.7 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.00 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>COCCOC>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 3-oxo-3-phenylpropionate (28.6 g, 145 mmol) in 1,2-dimethoxyethane (1.50 ml) was added sodium hydride (60% in oil, 5.65 g, 141 mmol) under ice-cooling and the mixture was stirred at room temperature for 1 hr. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (33.8 g, 141 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 2 hrs. The reaction solution was poured into water (500 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-oxo-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionate (45.4 g, 75%) as a yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:24][C:25]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:22][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)[OH:23])=[O:28]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 2,3-dichlorobenzoyl chloride (135 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) and recrystallized from ethyl acetate-hexane to give the title compound (161 mg, 77%).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][C:14]([NH2:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>>[CH3:13][C:14]([NH:21][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:20]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NC(C)(C)CC(C)(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1,1,3,3-tetramethylbutylamine as starting materials to give the aimed compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16]>C1COCC1>[C:11]([CH:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[C:13]([O:14][CH2:15][CH3:16])=[O:17])#[N:12]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium hydride (4.2 g, 177.7 mmol) in THF was added 4-fluoro phenyl acetonitrile (10 g, 74.0 mmol) at −10° C. The reaction mixture was stirred for 15 min at the same temperature. Diethyl carbonate (10.5 g, 88.0 mmol) was added to the reaction mixture and the reaction mixture was allowed to come to room temperature and heated to 40° C. (Caution: Reaction will start suddenly and exothermic). The heating path was removed immediately once the reaction was started and the reaction mixture was cooled under ice/acetone. The solution was allowed to come to room temperature and stirred for 1 h. The reaction mass was cooled to 0° C. and quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with water (50 mL), brine solution (50 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give ethyl 2-cyano-2-(4-fluorophenyl)acetate as crude compound as crude compound (10 g). The crude compound was taken to the next step without further purification. LC-MS (M−H)+=206.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.44 (2H, m), 7.11 (2H, m), 4.69 (1H, s), 4.27-4.22 (2H, q, J=7.2 Hz). 1.26 (3H, m)
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([NH2:44])[C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[C:39]([NH2:44])[C:40]([NH2:43])=[N:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(c2cnc(N)c(N)c2)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Product: Nc1cc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cnc1N
Yield: 54.3 %

Procedure:
Compound 2b (1.00 g, 2.30 mmol, as prepared in Example 2, Step B) was subjected to Suzuki coupling conditions with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2,3-diamine (1.62 g, 6.91 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 6b (580 mg, 51% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C26H24N8O: 465.2 (M+H). Found 465.3.
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][C@H:63]1[CH2:68][CH2:67][C@H:66]([OH:69])[CH2:65][CH2:64]1>CN(C=O)C>[CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@H:21]([O:28][CH3:29])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:8]([NH:62][CH:63]2[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65][CH2:64]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H](c1ccccc1)c1nc2cc(F)ccc2n1C(C(=O)NC1CCC(O)CC1)C1CCCCC1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a solution of cyclohexyl-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetic acid (100 mg, 0.25 mmol, 1.0 equiv) in DMF (1.5 mL) was added triethylamine (51.1 mg, 70.0 μL, 0.50 mmol, 2.0 equiv) and HATU (124.7 mg, 0.33 mmol, 1.3 equiv) and the mixture stirred at 40° C. After 15 min, trans-4-amino-cyclohexanol hydrochloride (50.03 mg, 0.33 mmol, 1.3 equiv; [CAS RN 50910-54-8]) was added and stirring continued at 50° C. for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 50 mg (40%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][N:6]=1.[NH4+:11].[OH-]>CCN(CC)CC>[Cl:1][C:2]1[S:3][C:4]([S:7]([NH2:11])(=[O:9])=[O:8])=[CH:5][N:6]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1cnc(Cl)s1
Agent: [OH-]
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cnc(Cl)s1
Yield: 61.4 %

Procedure:
Prepared by general procedure III from 2-Chloro-thiazole-5-sulfonyl chloride (1.1 g, 5 mmol) and NH4OH (0.42 mL, 6 mmol) with Et3N (0.77 mL, 6 mmol to give the title compound as a light-brown solid (610 mg, 61%). MS (ISN) 197 [(M−H)−].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16](=S)[CH2:17][C:18](=O)[CH3:19])[C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:12]1)(=[O:10])=[O:9].FC(F)(F)C(O)=O.[S:33]1[CH2:38][CH2:37][CH:36]([NH:39][NH2:40])[CH2:35][CH2:34]1>>[CH3:25][O:24][C:22]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH2:15][N:14]1[C:16]1[N:39]([CH:36]2[CH2:37][CH2:38][S:33][CH2:34][CH2:35]2)[N:40]=[C:18]([CH3:19])[CH:17]=1)=[O:23]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: NNC1CCSCC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCSCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with (tetrahydro-2H-thiopyran-4-yl)hydrazine 2,2,2-trifluoroacetate (CAS Reg. No. 693287-87-5) to give the title compound as yellow foam. MS (ESI): m/z=484.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>O>[CH:2]([S:4][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])([CH3:3])[CH3:1]
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(SC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of propane-2-thiol (3.30 mL), potassium carbonate (6.60 g) and DMF (40 mL), 1-fluoro-4-methyl-2-nitrobenzene (4.85 g) was added and stirred at room temperature for 5 hours. After addition of water, the reaction liquid was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 1-(isopropylsulfanyl)-4-methyl-2-nitrobenzene (6.60 g) as a yellow oil.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:34]([NH2:36])[CH3:35].[OH-].[Na+]>>[CH2:34]([NH:36][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:35]
Reactant: CCN
Reactant: Oc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: CCNc1cccc2ccccc12
Yield: 90 %

Procedure:
288 parts of α-naphthol, 10 parts of triphenyl phosphite and 100 parts of ethylamine gas are heated for 20 hours at 240° C, whilst stirring. After the mixture has cooled, it is next stirred for 20 minutes at 70° C with 1,000 parts of 2.5 percent strength by weight aqueous sodium hydroxide solution. The organic phase is separated off, washed with 2,000 parts of water at 30° C, again separated off and distilled. 308 parts of N-ethyl-α-naphthylamine boiling at 119° - 120° C/0.1 mm Hg are obtained, corresponding to a yield of 90% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C@@H:10]2[NH:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C@@H:10]2[N:15]([CH3:33])[CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(Cl)c2)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
Combine 10-((S)-3-[2-(3-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (608.3 mg, 1.53 mmol), formaldehyde (124.3 μL, 1.53 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (442.5 mg, 2.09 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 502.3 mg (80%) of the title compound as a brown foam: mp 69°, dec; mass spectrum (ion spray): m/z=451.2 (M+1).
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[O:16]([C:18]#[N:19])[K]>O>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH:15][C:18]([NH2:19])=[O:16])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: CCC(N)C1CCC2(CC1)OCCO2
Reactant: N#CO[K]
Agent: Cl
Solvent: O
Product: CCC(NC(N)=O)C1CCC2(CC1)OCCO2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round-bottom flask were placed a solution of 1-1,4-dioxaspiro[4.5]decan-8-ylpropan-1-amine hydrochloride (as prepared in Example 104 Step B) (100 mg, 0.42 mmol, 1.00 equiv) in water (3 mL) and KOCN (38 mg, 0.47 mmol, 1.10 equiv). The resulting solution was stirred overnight at 70° C. The resulting solution was cooled and extracted with 3×10 mL of dichloromethane. The organic layers were combined, dried and concentrated under vacuum to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[F:36].O>CN(C=O)C>[F:36][C:30]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:3]1[C:4]2[CH:10]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: Cc1cccc(CBr)c1F
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C)c1F
Temperature: 80 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
A mixture of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 26, step d (500 mg, 1.82 mmol), K2CO3 (502 mg, 3.64 mmol) and 1-(bromomethyl)-2-fluoro-3-methylbenzene (389 mg, 1.91 mmol) in DMF (25 mL) was stirred at 80° C. for 18 h. The reaction mixture was cooled, poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc:MeOH=100:1 to give the desired product (350 mg, 48%) as a red solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.24 (d, 3H, J=1.8 Hz), 2.47 (s, 3H), 3.09 (t, 4H, J=4.8 Hz), 3.75 (t, 4H, J=4.8 Hz), 3.86 (s, 3H), 5.51 (s, 2H), 6.62 (t, 1H, J=7.5 Hz),7.00 (t, 1H, J=7.5 Hz), 7.22 (t, 1H, J=7.5 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.36 (d, 1H, J=2.4 Hz); LC-MS: m/e=398 [M+1]+
Reaction SMILES: N[C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1.N([O-])=[O:19].[Na+]>C(O)(=O)C.Cl>[OH:19][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1nc(-c2ccccc2)cnc1N
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1nc(-c2ccccc2)cnc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of acetic acid/hydrochloric acid (1:1, 20 mL) at 0° C. was added methyl 3-amino-6-phenylpyrazine-2-carboxylate (1.02 g, 4.50 mmol). Aqueous solution of sodium nitrite (0.77 g, 11.2 mmol) was added drop wise. During the addition, the temperature of the reaction was controlled at 0-5° C. The reaction was slowly warmed to room temperature and stirred overnight. The reaction mixture was extracted with ethyl acetate (2×50 mL). The organic layer was washed with water (30 mL), saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford the crude methyl 3-hydroxy-6-phenylpyrazine-2-carboxylate which was used in the next step with out any purification. The crude product was treated with phosphorus oxychloride (30 mL) and heated to 90° C. for 2 h. The reaction was cooled to room temperature and poured into ice-water mixture and extracted with ethyl acetate (3×40 mL). The organic layer was washed with water (30 mL), saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate, filtered, and concentrated to give crude product. Column purification on silica (8:2 hexanes/ethyl acetate) afforded methyl 3-chloro-6-phenylpyrazine-2-carboxylate (0.22 g, 20% yield) as yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.90 (s, 1H), 8.02 (t, 2H), 7.40 (t, 1H), 7.20 (br s, 2H), 3.90 (s, 3H): MS (EI) for C12H9N2O2Cl: 249 (MH+).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].S(=O)(=O)(O)O>O>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(COc2ccccc2)cc1
Reactant: CC(C)(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(Oc1ccc(COc2ccccc2)cc1)C(=O)O

Procedure:
A mixture of 20 g. of 4-phenoxymethylphenol and 13.2 g. of the ethyl ester of 2-hydroxyisobutyric acid is combined with 15 g. of sulfuric acid, and the reaction mixture is agitated for 2 hours at 50°-60°. After cooling, the mixture is combined with water and worked up as usual, obtaining the ethyl ester of 2-(4-phenoxymethylphenoxy)-2-methyl-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:7]([OH:27])[C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=23)[S:5][CH:6]=1.[F:28]C1C=C(C2NC(C=O)=C3C=2C(=O)N(C)C(=O)N3C)C=CC=1.C(C1C=C(C2N(CCC(N(OC)C)=O)C=C3C=2C(=O)N(C)C(=O)N3C)C=CC=1)#N>>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]([OH:27])[C:8]2[NH:9][C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)=[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=23)[S:5][CH:6]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C(O)c3nc(Cl)cs3)c2n(C)c1=O
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C=O)c2n(C)c1=O
Agent: CON(C)C(=O)CCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(O)c3nc(Cl)cs3)c2n(C)c1=O

Procedure:
The title compound was prepared by an analogous method to 7-((4-chlorothiazol-2-yl)(hydroxy)methyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Example 21 Step 1) from 5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-7-carbaldehyde (Intermediate Nc) and 2-bromo-4-chlorothiazole (Intermediate Q, step 2);
Reaction SMILES: [OH-].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N+:9]3[C:15]([OH:16])=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)S[C:10]=32)=[CH:5][CH:4]=1.[C:23]([O:27][CH3:28])(=[O:26])[C:24]#[CH:25]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]3[C:10](=[C:24]([C:23]([O:27][CH3:28])=[O:26])[CH:25]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]3=[O:16])[C:11]=2[CH:12]=1
Reactant: C#CC(=O)OC
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccc(Cl)cc1-2
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2

Procedure:
ba) 4.2 g of 9-chloro -2-phenyl-5,6-dihydro-3-hydroxythia-zolo[2,3-a]isoquinolinium hydroxide (internal salt) were heated under reflux for 4 hours in 100 ml of toluene together with 1.32 ml of methyl propiolate. After concentration in vacuo, the residue was chromatographed on silica gel with toluene/acetone (9:1). There was obtained methyl 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate of m.p. 139°-141° (from ethyl acetate).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:18][C:13]1[CH:14]=[C:15]([CH3:17])[N:10]=[C:8]([C:7]2[CH:11]=[CH:12][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:9]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(C(=N)N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2nc(C)cc(O)n2)cc1
Reaction time: 7 h

Procedure:
To the mixture of 10 g of 4-methoxybenzamidine hydrochloride, 7.7 g of ethyl acetoacetate and 16.3 g of potassium carbonate were added 120 ml of ethanol, and the mixture was heat-refluxed with stirring for 7 hours. The reaction mixture was cooled and filtered to remove insoluble substances. The filtrate was evaporated. Water was added to the residue to dissolve and then the resulting solution was neutralized with acetic acid. The precipitated crystals were filtered off, washed with water and dried. Whereby 10.9 g of the desired substance was obtained as white crystals. Melting point is 202° to 203° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]=[N:2]1.[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:13][CH2:6][C:4]1[N:3]=[N:2][S:1][CH:5]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=Cc1csnn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(CNCc2csnn2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2,3-thiadiazole-4-carboxaldehyde (750 mg, 6.57 mmol) and 2,4-dimethoxybenzylamine (1086 μl, 7.23 mmol) in 1,2-dichloroethane (13.1 mL) at 0° C. was added molecular sieves (powdered, 4 A) (2.50 g, 6.57 mmol) followed by sodium triacetoxyborohydride (1950 mg, 9.20 mmol). The reaction was allowed to warm to room temperature with stirring overnight. Then, the resulting suspension was poured into dichloromethane (75 mL) and aqueous sodium hydrogen carbonate (saturated, 75 mL). The layers were mixed and then filtered through celite. The aqueous layer was then extracted with dichloromethane (3×50 mL) and the combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes+1% triethylamine gradient) to afford the title compound as a pale yellow liquid. LRMS (APCI) calculated for C12H16N3O2S [M+H]+, 266.1. found 266.1.