Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:26]([OH:28])=O)[CH2:5][CH2:4]1)=[O:2].S(Cl)(Cl)=O.[CH3:33][N:34]([CH:36]=O)[CH3:35]>>[CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:26]([NH:3][C:9]2[CH:10]=[CH:11][C:12]([CH2:36][N:34]([CH3:33])[CH:35]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][CH:8]=2)=[O:28])[CH2:5][CH2:4]1)=[O:2]
Reactant: O=CN1CCC(C(=O)O)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3N(C=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (14 ml) was dissolved 1- formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.18 g). To the solution was added, under ice-cooling, thionyl chloride (0.1 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (50 ml). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.13 g) and triethylamine (0.33 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethanol/hexane to give 1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.16 g) as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([OH:14])(=O)=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([Cl:16])(=[O:14])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccc2cnccc12
Temperature: 120 °C
Yield: 96.6 %

Procedure:
A mixture of 5-isoquinolinesulfonic acid (4.18 g, 20 mmol), and phosphorus pentachloride (6.24 g, 30 mmol) in phosphorus oxychloride (20 mL) was heated at 120 ° C. for two days. The reaction mixture was cooled to room temperature and diluted with dry chloroform (60 mL). The white precipitate was collected, washed with dry chloroform, and dried under high vacuum to give the title compound as a white solid (4.40 g, 83%) which was used for next step without further purification. 1H-NMR (300 MHz, CDCl3)δ9.95 (s, 1H), 9.16 (d, J=6.8 Hz, 1H), 8.74 (d, J=6.8 Hz, 1H), 8.52 (t, J=7.0 Hz, 2H), 7.99 (t, J=7.3 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[C:8](=O)[NH:9][CH:10]=[N:11][C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][C:8]1[C:7]2[CH:6]=[C:5]3[O:1][CH2:2][O:3][C:4]3=[CH:13][C:12]=2[N:11]=[CH:10][N:9]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc3c(cc12)OCO3
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2cc3c(cc12)OCO3
Yield: 69 %

Procedure:
A mixture of 7H-[1,3]dioxolo[4,5-g]quinazolin-8-one (0.550 g, 2.78 mmol) and phosphorus pentachloride (0.800 g, 3.84 mmol) in 3 mL phosphorus oxychloride was heated to a gentle reflux for 2.5 hours. Solvent was removed in vacuo, and azeotroped with toluene. Residue was dissolved in ethyl acetate and washed with 5% sodium bicarbonate solution and then filtered, and then solvent was removed in vacuo to give 8-chloro-[1,3]dioxolo[4,5-g]quinazoline (0.400 g, 74%).
Reaction SMILES: [S:1]1(=[O:7])[CH:5]=[CH:4][C:3](=[O:6])[NH:2]1.[CH3:8][C:9]([C:11]([CH3:13])=[CH2:12])=[CH2:10].CCCCCC>C(Cl)CCl>[CH3:8][C:9]1[CH2:10][CH:4]2[C:3](=[O:6])[NH:2][S:1](=[O:7])[CH:5]2[CH2:12][C:11]=1[CH3:13]
Reactant: O=C1C=CS(=O)N1
Reactant: C=C(C)C(=C)C
Solvent: CCCCCC
Solvent: ClCCCl
Product: CC1=C(C)CC2C(C1)C(=O)NS2=O
Temperature: 60 °C

Procedure:
To a solution of 2.2 g (0.02 mole) of 4-isothiazolin-3-one 1-oxide in 50 ml of ethylene dichloride is added 2.0 g (0.024 mole) of 2,3-dimethyl-1,3-butadiene. The mixture is stirred and maintained at 60° C. overnight. Concentration of the mixture yields a thick oil, which affords a white solid on trituration with hexane. The solid is filtered and air dried to yield 3.4 g (90%) or product, m.p. 135°-137° C. which can be recrystallized from ethyl acetate-hexane.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N:4][N:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].[Cl-].[NH4+].C1C=CC2N(O)N=[N:20]C=2C=1.C(Cl)CCl.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:11])=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([NH2:20])=[O:8]
Reactant: On1nnc2ccccc21
Reactant: Cc1nn(C)c(C(=O)O)c1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1nn(C)c(C(N)=O)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-bromo-1,3-dimethyl-1H-pyrazole-5-carboxylic acid (0.3 g, 1.370 mmol) in DMF (5 mL) were added ammonium chloride (0.293 g, 5.48 mmol), HOBt (0.222 g, 1.644 mmol), and EDC (0.368 g, 1.917 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (1.193 mL, 6.85 mmol). The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was subsequently diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give the title compound, which was used without further purification (0.28 g).
Reaction SMILES: CO.[Cl:3][C:4]1[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[CH:15]=[O:16])=[N:6][CH:7]=[CH:8][CH:9]=1.[S-:17][C:18]#[N:19].[Na+].BrBr>[Br-].[Na+].CO>[Cl:3][C:4]1[C:5]([N:10]2[C:14]([S:17][C:18]#[N:19])=[CH:13][CH:12]=[C:11]2[CH:15]=[O:16])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccn1-c1ncccc1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: N#CSc1ccc(C=O)n1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.4 %

Procedure:
To 10 ml of methanol were added 1.0 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine and 1.4 g of sodium thiocyanate. A solution of 1.0 g of bromine in 5 ml of saturated sodium bromide-methanol was added dropwise thereto at −20° C. The resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was added to 100 ml of ice water, and extracted with chloroform two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.6 g of 1-(3-chloro-2-pyridinyl)-5-thiocyanato-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([NH:40][CH2:41][CH3:42])=[O:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>O1CCOCC1.O.[Zn]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([NH:40][CH2:41][CH3:42])=[O:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc(N)cc2)on1
Temperature: 100 °C
Yield: 49.5 %

Procedure:
To a stirred solution of 5-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]-N-ethylisoxazole-3-carboxamide (1.45 g, 2.6 mmol) and ammonium chloride (1.4 g, 6.4 mmol, 10 eq.) in dioxane (18 mL) and water (3 mL) was added powered Zn (0.7 g, 10 mmol, 4 eq.). After heating at 100° C. for 2 hours, the solution was filtered and the filtrate was diluted with ethyl acetate and washed with 1 M NaHCO3 solution. After drying, the solvent was removed and the residue was chromatographed on silica gel eluting with hexane/ethyl acetate 3/1, to provide the title compound (0.69 g, 49% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6][S:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]([O-:15])=[O:14])=[C:2]1[C:16]([O:18]C)=[O:17].Cl>[OH-].[Na+].C(O)C>[S:1]1[CH:5]=[CH:4][C:3]([S:6][S:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]([OH:15])=[O:14])=[C:2]1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1sccc1SSc1ccsc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1sccc1SSc1ccsc1C(=O)O

Procedure:
(aaa) 38.9 g of methyl 3,3'-dithiobis-thiophene-2-carboxylate were suspended in 1500 ml of 1N sodium hydroxide solution and 700 ml of ethanol, whereupon the suspension was heated under reflux until the reaction finished. After cooling, in an ice-bath the mixture was acidified with 25 percent hydrochloric acid, whereby the product crystallized out. By recrystallization from water, there was obtained 3,3'-dithio-bis-thiophene-2-carboxylic acid as colorless crystals of m.p. 256°-257°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[CH2:24][C@H:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C(=O)[O:15][C@H:11]2[C@@H:10]([CH3:25])[CH2:9]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[N:39]=[C:38]([C:40](O)=[O:41])[CH:37]=[CH:36][C:35]=1[F:43].C(Cl)CCl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.CCO>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[N:39]=[C:38]([C:40]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@H:8]2[CH2:24][C@@H:12]([NH:13][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C@@H:11]([OH:15])[C@@H:10]([CH3:25])[CH2:9]2)=[O:41])[CH:37]=[CH:36][C:35]=1[F:43]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H]2[C@H]1OC(=O)N2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of (3aR,5R,7S,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv.) in DMF (0.2 M) was added 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.3 equiv.), aza-HOBt (1.3 equiv.) and EDC (1.3 equiv.). The mixture was stirred at rt for 16 hrs. The solution was diluted with EtOAc, washed with H2O, 1N NaOH, NaCl(sat.), dried over MgSO4, filtered and concentrated to yield crude protected amide. The material was dissolved in EtOH (0.45 M), Cs2CO3 (1.0 equiv.) was added and the solution was submerged in a 60° C. oil bath and stirred for 90 mins. The volatiles were removed in vacuo; the residue was partitioned between with EtOAc and H2O. The organic layer was washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and pumped on to yield tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate in 100% yield. LC/MS (m/z)=557.3 (MH+), Rt=0.83 min.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[NH2:13])=[CH:7][CH:6]=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([NH:13][C@@H:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH2:11][C:8]3[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=3)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccncc3)CC2)CC1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccncc3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(4-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and indole-6-carboxylic acid (50%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.ClC1C=CC=C(C(OO)=[O:20])C=1>CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:20])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cnccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Product: Cc1ccc2c[n+]([O-])ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
To a stirred solution of 6-methylisoquinoline (2.0 g, 14 mmol) in ether (80 mL) at 0° C. was added 3-chloroperbenzoic acid (57%, 4.3 g, 14 mmol). The mixture was warmed to room temperature, stirred for 3 h and filtered. The filter-cake was partitioned between chloroform (3×30 mL) and aqueous potassium carbonate solution (30 mL). The combined organic extracts were washed (brine), dried (sodium sulfate) and concentrated in vacuo to give the product as an off-white crystalline solid (1.2 g, 53%): mp 140-142° C.; IR νmax (Nujol)/cm−1 3047, 2925, 2855, 1606, 1562, 1466, 1377, 1328, 1270, 1217, 1182, 1133, 984, 920, 878, 858, 823, 803, 766, 600, 500 and 498; NMR δH (400 MHz, CDCl3) 2.53 (3H, s) 7.47 (1H, d, J 8.5 Hz) 7.59 (1H, d, .J 7.5 Hz) 7.64 (1H, d, J 8.5 Hz) 8.11 (1H, dd, J 2,7.5 Hz) 8.73 (1H, s).
Reaction SMILES: Br.[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:32][OH:33])[C:9]([NH:11][CH:12]2[C:30](=[O:31])[N:14]3[C:15]([C:27]([OH:29])=[O:28])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH3:26])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.C(=O)([O-])O.[Na+:38]>O>[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:32][OH:33])[C:9]([NH:11][CH:12]2[C:30](=[O:31])[N:14]3[C:15]([C:27]([O-:29])=[O:28])=[C:16]([CH2:19][S:20][C:21]4[N:25]([CH3:26])[N:24]=[N:23][N:22]=4)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.[Na+:38]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1

Procedure:
In a solution of 0.168 g of sodium hydrogen carbonate in 4 ml of water was dissolved 0.578 g of 7-[2-(2-imino-4-thiazolin-4-yl)-2-hydroxyimino-acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrobromide. The solution was subjected to column chromatography on dextran gel (Sephadex LH-20, Pharmacia), development being carried out with water. The fractions including the desired product were pooled and lyophilized. By the above procedure there was obtained 0.267 g of the captioned compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:13]=3[CH:14]=[N:15][CH:16]=2)=[O:10])=[CH:5][N:6]=1.[CH3:27][NH2:28].C1COCC1.C([O-])([O-])=O.[K+].[K+]>[Cl-].[NH4+].CCOC(C)=O>[CH3:27][NH:28][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:13]=3[CH:14]=[N:15][CH:16]=2)=[O:10])=[CH:5][N:6]=1
Reactant: CN
Reactant: O=C(NCc1cnc(Br)s1)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1ncc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)s1
Temperature: 100 °C

Procedure:
1-(4-Fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (2-bromo-thiazol-5-ylmethyl)-amide (50 mg, 0.10 mmol) was treated with a 2 M solution of methylamine in THF (2.0 mL, 4.0 mmol) in a microwave tube. To this solution was added solid K2CO3 (19 mg, 0.14 mmol), and the microwave tube was sealed and heated at 100° C. for 1 hour in a microwave. The mixture was then heated at 160° C. in a microwave for 4 hours, and the mixture was diluted with saturated aqueous ammonium chloride (40 mL) and EtOAc (20 mL). The layers were separated and the organics layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[O:31][N:30]=1.CC#N>CCOC(C)=O>[F:20][C:2]([F:1])([F:19])[CH2:3][C:4]1[N:5]([CH2:28][C:29]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=3)[O:31][N:30]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2
Reactant: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc2c(cc(CC(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
A mixture of 2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 374A) (0.080 g, 0.27 mmol), K2CO3 (0.042 g, 0.30 mmol), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.143 g, 0.54 mmol) and CH3CN (5 mL) was stirred at 60° C. for 6 h. The mixture was diluted with EtOAc (25 mL) and washed with water (15 mL) and brine (15 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 0-30% EtOAc in hexanes) to afford the title compound (0.031 g, 22%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.69-7.63 (m, 2H), 6.94 (s, 1H), 5.56 (s, 2H), 3.96 (q, 2H); MS m/z 517 (M−H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][C:13]#[CH:14])([CH3:4])([CH3:3])[CH3:2].[Cl:15]N1C(=O)CCC1=O>CC(C)=O.C([O-])(=O)C.[Ag+]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][C:13]#[C:14][Cl:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCOc1ccccc1C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccccc1OCC#CCl
Yield: 102.4 %

Procedure:
To a solution of Example 100A (22.2 g, 118 mmol) in acetone (300 mL) was added N-chlorosuccinimide (18.8 g, 141 mmol) and silver acetate (1.96 g, 11.7 mmol). The reaction was heated to reflux for 24 h, cooled, and the solvent removed by evaporation. The residue was taken up in a mixture of water (125 mL) and diethyl ether (125 mL), and filtered to remove the undissolved silver salts. The filtrate was extracted with diethyl ether (150 mL), and the combined organic layers washed with brine (75 mL) and concentrated to produce 26.9 g of the crude title compound which was used without further purification. MS (DCI/NH3) m/z 240 (M+NH4)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([O:22][CH:23]([O:32][CH2:33][CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[O:31])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:13][C:14]1[C:19]([CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]([O:22][CH2:20][CH3:21])[O:32][CH2:33][CH3:34])[OH:31])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Fc1ccccn1
Reactant: CCOC(OCC)c1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(OCC)c1ccccc1C(O)c1cccnc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2.5 ml of diisopropylamine in 20 ml of dry tetrahydrofuran at −78° C. was added 11 ml of a 1.6 M solution of butyllithium in hexanes. The solution was stirred for 20 min. then a solution of 1.15 g of 2-fluoropyridine in 3 ml of tetrahydrofuran was added. The solution was stirred at −78° C. for 30 min then a solution of 2-formylbenzaldehyde diethylacetal in 3 ml of tetrahydrofuran was added dropwise. This solution was stirred for 1 h then warmed to room temperature overnight. The reaction was poured into a 5% solution of sodium carbonate and extracted with two 300 ml portions of ether. The combined organic layers were washed with 300 ml of water then the same volume of brine and dried over sodium sulfate. Evaporation of the solvent afforded (2-fluoropyridin-3-yl)-2-(diethoxymethyl)-phenylmethanol as a viscous oil; 1H-NMR (200 MHz, CDCl3) d 5.60 (CHOEt).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7](=[O:21])[N:8](CC3C=CC(OC)=CC=3)[CH2:9][C:10]=2[N:11]=1.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7](=[O:21])[NH:8][CH2:9][C:10]=2[N:11]=1
Reactant: COc1ccc(CN2Cc3nc(F)ccc3N(c3ccccc3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2nc(F)ccc2N1c1ccccc1
Yield: 59.4 %

Procedure:
6-Fluoro-3-(4-methoxy-benzyl)-1-phenyl-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one (300 mg, 0.83 mmol) was deprotected according to the method of General procedure 1 (TFA deprotection). The free base was isolated and purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-100%) to afford 6-fluoro-1-phenyl-3,4-dihydro-1H-pyrido[3,2-d]pyrimidin-2-one (120 mg). MS: [M+H]+=244.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.C(O)(=O)C>O>[CH3:1][N:2]1[C:8](=[O:9])[CH2:7][CH2:6][N:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:3]1=[O:4]
Reactant: CNC(=O)N(CCC(=O)O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)CCN(c2ccc(C(F)(F)F)cc2)C1=O
Yield: 88.7 %

Procedure:
At first, 4 g (0.014 moles) of N-(methylcarbamoyl)-N-(4-trifluoromethylphenyl)-β-alanine was added to a solution consisting of 45 ml of 6N-hydrochloric acid and 15 ml of acetic acid, and the mixture was refluxed with heating for 2 hours. After completion of the reaction, 50 ml of water was added thereto. The deposited crystals were recovered by filtration with suction and recrystallized from ethyl acetate-n-hexane, 3.38 g of the desired compound was obtained as colorless needle crystals having a melting point of 115°-117° C. (yield: 90.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=O)[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][O:25][NH2:26].Cl>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=[N:26][O:25][CH3:24])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CON
Reactant: O=C1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=C1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of the Compound of Example 83 (0.14 g, 0.44 mmol) in 1.5 mL of pyridine was added O-methylhydroxylamine (0.04 g, 0.48 mmol). After 4 hours stirring at r.t., the reaction was checked by TLC and considered to completion. It was diluted with water, acidified by 1N HCl and extracted with EtOAc. After drying on Na2SO4 and evaporation to dryness, the residue from evaporation was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 1:1) to give the title compound as a colorless oil. Yield: 75.4%