Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:21])[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:23][NH2:24]>C(O)C>[CH3:6][C@@H:5]1[C:4](=[O:21])[NH:24][N:23]=[C:8]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[N:7]12
Reactant: CCOC(=O)[C@@H](C)N1C(=S)COc2ccc([N+](=O)[O-])cc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[C@@H]1C(=O)NN=C2COc3ccc([N+](=O)[O-])cc3N21
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of (R)-2-(6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (150.0 g, 483.0 mmol) in ethanol (1.5 L) was added hydrazine hydrate (98%, 48.4 g, 967.0 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was filtered and the filter cake was washed with EtOH (3×100 mL) to give (R)-1-methyl-9-nitro-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (100.0 g, 79%). SFC (Table 2, Method 4) Rt=3.19 min. 1H NMR (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.87 (dd, J=2.4, 8.8 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 4.98 (q, J=6.8 Hz, 1H), 4.83-4.74 (d, J=12.8 Hz, 2H), 1.36 (d, J=6.8 Hz, 3H). The crude (R)-1-methyl-9-nitro-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (33 g, 142 mmol, e.e. =77%) was dissolved in refluxing MeOH (2.1 L) and then cooled slowly to ambient temperature. The crystals were removed by filtration and the filtrate was concentrated in vacuo to give (R)-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (26 g, 79%) as a yellow solid. SFC (Table 2, Method 4) Rt=3.06 min, e.e. =98%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=2)=[S:27])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Sc2nc3ccccc3o2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4ccccc4o3)cc2)ccc1Cl
Yield: 33.3 %

Procedure:
2-(4-Aminophenylthio)benzoxazole (10.0 mmoles, 2.6 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (10.0 mmoles, 2.4 g) were reacted according to procedure A to yield of the title compound 1.6 g, 33%. Mass Spec (FD) 479. Calculated for C21H13ClF3 N3OS2 : C, 52.56; H, 2.73; N, 8.75. Found: C, 52.47; H, 2.70; N, 8.48.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[CH2:3][NH:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)[C:6]=1[CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:1][C@@H:2]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[CH2:3][NH:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)[C:6]=1[CH2:20][CH2:21][NH2:22]
Reactant: CC(C)(C)OC(=O)NCCc1c(-c2ccc3cnccc3c2)noc1NC[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1c(-c2ccc3cnccc3c2)noc1NC[C@@H](N)Cc1c[nH]c2ccccc12
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a 25 mL of round-bottom flask was added tert-butyl 2-(5-((S)-2-amino-3-(1H-indol-3-yl)propylamino)-3-(isoquinolin-6-yl)isoxazol-4-yl)ethylcarbamate (11 mg, 21 μmol). 2 mL of 50% TFA/DCM was added to the reaction mixture dropwise. After 10 minutes, LC-MS showed that the BOC group had been removed. The reaction mixture was concentrated under reduced pressure and purified by preparative LC to give N-((S)-2-amino-3-(1H-indol-3-yl)propyl)-4-(2-aminoethyl)-3-(isoquinolin-6-yl)isoxazol-5-amine (7 mg, 79% yield). MS m/z: 427 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.79 (s, 1H), 8.56-8.66 (m, 2H), 8.52 (s, 1H), 8.45 (s, 1H), 8.18 (d, J=8.22 Hz, 1H), 7.60 (d, J=7.83 Hz, 1H), 7.39 (d, J=8.02 Hz, 1H), 7.26 (s, 1H), 7.14 (t, J=7.53 Hz, 1H), 7.06 (t, J=7.43 Hz, 1H), 3.75-3.79 (m, 2H), 3.62-3.71 (m, 1H), 3.20 (td, J=14.48, 7.04 Hz, 2H), 2.99 (s, 2H), 2.88 (d, J=6.46 Hz, 2H).
Reaction SMILES: [CH:1](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([O:25][N:26]2[C:31](C)([CH3:32])[CH2:30]C(O)[CH2:28][C:27]2([CH3:36])[CH3:35])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH:1](=[C:8]([C:9]([O:11][CH:12]1[CH2:35][C:27]([CH3:36])([CH3:28])[N:26]([O:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:31]([CH3:32])([CH3:30])[CH2:13]1)=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
A mixture of 15.0 g (60.4 mmol) of diethyl benzalmalonate, 32.4 g (127 mmol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, and 150 ml of toluene is heated at reflux. Water is removed by fractional distillation. The reaction mixture is cooled to 80° C. and treated with 1.0 g of titanium tetrabutoxide. The mixture is heated at reflux for 7 hours while ethanol is removed by fractional distillation. The reaction mixture is diluted with ethyl acetate (400 ml). The organic solution is washed with 1N hydrochloric acid (200 ml) and saturated sodium bicarbonate solution (200 ml), dried over magnesium sulfate, and concentrated to an oil. Purification by flash chromatography on silica gel (19:1 heptane: ethyl acetate) affords 27.6 g (54% yield) of the title compound, a colorless syrup, which is a mixture of geometric isomers.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[O:14][CH2:15][CH2:16][OH:17])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl>O1CCCC1.O>[C:1]([O:17][CH2:16][CH2:15][O:14][C:13]1[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]([OH:21])=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:12]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(OCCO)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCOc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(3,5-ditert.butyl-4-hydroxyphenoxy)ethyl methacrylate was prepared by adding dropwise a solution of 3.1 grams of methacryloyl chloride in 15 milliliters of tetrahydrofuran to a solution of 7 grams of 2-(3,5-ditert.butyl-4-hydroxyphenoxy)ethanol and 11 grams of triethylamine in 50 milliliters of tetrahydrofuran. The addition was completed in 5 minutes and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then poured into a solution of 20 milliliters of concentrated hydrochloric acid in 400 milliliters of water and the oil which precipitated was separated by extraction with petroleum ether. The extract was allowed to evaporate and the solid residue was recrystallized from petroleum ether to yield 4 grams of product which melted at 68° C. to 70° C.
Reaction SMILES: Cl[C:2]1[N:10]2[C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH:40]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:10]4[C:2]([C:35]5[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=5)=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OC[C@@H]3c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
(4S)-2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (80 mg, 0.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.4 mmol) [Aldrich, cat. #CDS015890], and potassium phosphate (0.09 g, 0.4 mmol) [Aldrich, cat. #P5629] were suspended in 1,4-dioxane (3 mL) and water (0.70 mL). The resulting mixture was degassed with nitrogen for 10 min and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.008 g, 0.01 mmol) [Aldrich, cat. #741825] was added, followed by an additional 10 min of degassing. The reaction mixture was sealed and heated at 50° C. for 16 h. After cooling to room temperature, the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting ethyl acetate in hexanes (75-100%) to afford the desired product (98 mg, 90%). LCMS for C29H32O4N5 (M+H)+: calculated m/z=514.2. found 514.2; 1H NMR (300 MHz, CD3OD) δ 8.54 (d, J=4.7 Hz, 1H), 7.72 (m, 2H), 7.44-7.27 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.14 (s, 1H), 6.07 (d, J=2.8 Hz, 1H), 4.78 (dd, J=11.6, 2.9 Hz, 1H), 4.59 (dd, J=11.6, 3.1 Hz, 1H), 4.11-3.72 (m, 2H), 3.51 (d, J=16.0 Hz, 2H), 2.60 (s, 2H), 2.25 (s, 3H), 2.10 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:37]=[CH:36][C:27]2[O:28][C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:30]=3[C:26]=2[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:35][C:32]1[CH:33]=[CH:34][C:29]2[O:28][C:27]3[CH:36]=[CH:37][C:24]([C:16]4[CH:17]=[CH:18][C:19]5[N:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[C:8]6[C:13]([C:14]=5[CH:15]=4)=[CH:12][CH:11]=[CH:10][CH:9]=6)=[CH:25][C:26]=3[C:30]=2[CH:31]=1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: Brc1ccc2oc3ccc(Br)cc3c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc2oc3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3c2c1
Temperature: 80 °C
Reaction time: 16.5 h
Yield: 64.7 %

Procedure:
A mixture of (9-phenyl-9H-carbazol-3-yl)boronic acid (1.50 g, 5.22 mmol), 2,8-dibromodibenzo[b,d]furan (2.98 g, 9.14 mmol), tetrakis(triphenylphosphine) palladium(0) (0.30 g, 0.26 mmol), potassium carbonate (2.17 g, 15.67 mmol), 1,4-dioxane (50.00 mL), and water (10.00 mL) was degassed with bubbling argon for 30 min. The reaction mixture was then heated to 80° C. and was stirred overnight (16.5 hours), maintaining an argon atmosphere. Consumption of the starting material was confirmed by thin-layer chromatography and the reaction was cooled to room temperature. The product was extracted with dichloromethane, dried, and purified by silica gel column chromatography with dichloromethane in hexanes as the eluent. The product fractions were then dried and the product was collected to yield Compound 17 (1.65 g, 65%). Confirmed by LCMS (APCI): calculated for C30H18BrNO (M+H): 488. Found: 488.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[N:24][CH:25]=1.O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:26][C:22]1[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[CH:21]=1)[CH3:2]
Reactant: Oc1cncc(Cl)c1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1Oc1cncc(Cl)c1
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of 2-Chloro-nicotinic acid ethyl ester (2.07 grams, 11.2 mmole), Cesium carbonate (7.27 grams, 22.3 mmole) and 5-chloro-3-pyridinol (1.45 grams, 11.2 mmole) in dry dimethylformamide (40 ml) was stirred at 90° C. overnight. The suspension was cooled to room temperature, poured into water and extracted with diethyl ether. The combined organics were washed with water and brine, dried over MgSO4, and concentrated to a tan solid. Recrystalization from hexane gave a yellow solid (1.0 g). M.P. 65-69° C.; Anal. calcd. for C13H11ClN2O3: C, 56.03; H, 3.98; N, 10.05. Found: C, 56.14; H, 4.04; N, 10.16.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][S:14]([CH3:13])(=[O:16])=[O:15])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1sc(N)nc1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(NS(C)(=O)=O)nc1C
Yield: 86.6 %

Procedure:
A stirred solution of ethyl-2-amino-4-methyl-thiazole-5-carboxylate (558 mg, 3 mmol) in dichloromethane (15 mL) and pyridine (5 mL) was treated with methanesulfonyl chloride (687 mg, 6 mmol) at rt overnight. The solution was diluted with dichloromethane (50 mL) and washed with 2N aq. HCl solution (15 mL, 3×), dried (MgSO4), filtered and concentrated. The crude residue was diluted with ether (25 mL) and the solid was filtered, washed with 1:1 ether:hexane mixture (10 mL, 3×), and dried in vacuo to obtain the title compound (687 mg, 87%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[H-].[Na+].[CH2:16]1COCC1>[NH4+].[Cl-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:16])[CH2:7][CH2:6]2
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: COc1ccc2c(c1)CCN(C)C2=O
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 6-(methyloxy)-3,4-dihydro-1(2H)-isoquinolinone (5 g, 28.2 mmol) in THF (300 mL) was added NaH (1.35 g, 34.1 mmol) and the mixture was stirred for 30 min, then Mel (4.82 g, 33.87 mmol) was added. Stirring was maintained for 3 hours and then the solution was diluted with sat. NH4Cl (aq) and extracted with dichloromethane. The combined organic layer was concentrated under reduced pressure to afford 6-methoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one(6.3 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:6]=1[C:7](OCC)=[O:8].Cl.Cl[C:21]([NH2:23])=[NH:22].CS(C)(=O)=O.N>O>[NH2:23][C:21]1[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:6]=2[C:7](=[O:8])[N:22]=1
Reactant: N=C(N)Cl
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)csc1N
Agent: CS(C)(=O)=O
Agent: Cl
Agent: N
Solvent: O
Product: Nc1nc(=O)c2c(-c3ccc(F)cc3)csc2[nH]1
Temperature: 135 °C
Yield: 111.5 %

Procedure:
A mixture of ethyl 2-amino-4-(4-fluorophenyl)thiophene-3-carboxylate (400 mg, 1.51 mmol), chloroformamidine hydrochloride (434 mg, 3.78 mmol) and dimethylsulfone (710 mg, 7.55 mmol) was heated at 135° C. for 45 minutes. Water was added and the mixture was cooled down to room temperature. An aqueous ammonia solution was added to adjust the solution to pH 9. The precipitate was filtered off, yielding the title compound (440 mg) as a white powder. δH (300 MHz, DMSO-d6) 10.85 (1H, NH, D2O exchangeable), 7.53 (2H, t), 7.17 (2H, t), 6.92 (1H, s), 6.58 (2H, NH2, D2O exchangeable).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:7]([CH3:21])[C:6]=1[CH3:22])=[O:4].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CC(O)C>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:11]([C:8]1[N:7]([CH3:21])[C:6]([CH3:22])=[C:5]([C:3](=[O:4])[CH2:2][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:9]=1[CH3:10])=[O:20]
Reactant: C1CCNCC1
Reactant: Cc1c(C(=O)CCl)c(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: CC(C)O
Product: Cc1c(C(=O)CN2CCCCC2)c(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 66.6 %

Procedure:
A solution of 8.0 g (0.022 mole) of 2-chloro-1-[5-(2,4-dichlorobenzoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl]-ethanone (6) and 4.64 mL (0.066 mole) of piperidine in 130 mL of 2-propanol was heated under reflux for 1.5 h. The reaction was cooled and the solvent evaporated in vacuo. The residue was partitioned between diethyl ether and water and the organic solution was extracted twice with 1N HCl. A solid was removed by filtration and the filtrate was made basic with sodium bicarbonate. The mixture was extracted with diethyl ether and the ether solution was washed with water, brine and dried (MgSO4). The solvent was evaporated in vacuo. The product was converted to the hydrochloride salt and recrystallized from 2-propanol to give 5.97 g of product: mp 177-179° C.; mass spectrum (Cl—CH4) m/z=393 (m+1); NMR 300 MHz (Me2SO-d6) d 7.85 (s,1H); 7.6-7.5 (m, 2 H); 4.7 (s, 2 H); 3.8 (s, 3 H); 3.6-3.4 (m, 2 H); 3.2-3.0 (m, 2 H); 2.6 (s, 3H); 2.0 (br s, 4 H); 1.8 (s 3 H). Anal Calcd for C20H22Cl2N2O2: C, 55.22; H, 5.87; N, 6.05. Found: C, 55.06; H, 5.89; N, 6.05.
Reaction SMILES: [CH3:1][NH2:2].C1COCC1.[C:8]([C:11]1[C:12]([C:32]([F:35])([F:34])[F:33])=[N:13][N:14]([CH2:16][C:17]([NH:19][C:20]2[S:24][C:23]3[CH2:25][CH2:26][CH2:27][CH2:28][C:22]=3[C:21]=2[C:29]([NH2:31])=[O:30])=[O:18])[CH:15]=1)(=O)[CH3:9].[Na]>C(O)(=O)C.CO>[CH3:1][NH:2][CH:8]([C:11]1[C:12]([C:32]([F:34])([F:35])[F:33])=[N:13][N:14]([CH2:16][C:17]([NH:19][C:20]2[S:24][C:23]3[CH2:25][CH2:26][CH2:27][CH2:28][C:22]=3[C:21]=2[C:29]([NH2:31])=[O:30])=[O:18])[CH:15]=1)[CH3:9]
Reactant: CN
Reactant: CC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNC(C)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Yield: 14 %

Procedure:
To MeOH (1.5 mL) was added 2M methylamine in THF (0.724 mL, 1.448 mmol). Acetic acid was added to the mixture to adjust the pH to 4-5. 2-(2-(4-acetyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.121 mmol) and sodium cyanoborohyde (7.58 mg, 0.121 mmol) were added before heating the reaction to 100° C. for 30 min by microwave irradiation. The reaction mixture was quenched with water before purification by preparative reverse phase HPLC. The product fractions were acidified to pH 3 with acetic acid before applying to a strong cation exchange cartridge (500 mg). The cartridge was washed with DCM/MeOH (1:1) before eluting the product with 2M NH3 in MeOH. The solvent was removed in vacuo to give the title compound (7.1 mg, 0.017 mmol, 14%).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[CH:8][N:7]=2)=[N:4][N:3]=[N:2]1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[CH:23]=1>>[NH:4]1[C:5]([C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:29]([NH:28][C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=4)=[O:30])=[CH:17][CH:18]=3)[CH:9]=[CH:8][N:7]=2)=[N:1][N:2]=[N:3]1
Reactant: Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-[2-(1H-tetrazol-5-yl)-pyridin-4-yloxy]-phenylamine and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 4 h. The crude product Is washed with a solution of CH2Cl2/MeOH (95/5) and dried In vacuo to afford the title compound as a beige solid: ES-MS: 441.9 [M+H]+; single peak at tR=7.93 min (System 2); Rf=0.36 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31](F)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:13]=1)=[O:6].[NH:34]1[CH2:38][CH:37]=[CH:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([N:34]2[CH2:38][CH:37]=[CH:36][CH2:35]2)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=2)[CH:13]=1)=[O:6]
Reactant: C1=CCNC1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(F)c3)ccc2C)cc1
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(N4CC=CC4)c3)ccc2C)cc1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 67 except that the reaction mixture was heated to 100° C. for 16 hours rather than for 6 days, N-[5-(3,5-difluorobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide was reacted with 3-pyrroline. There was thus obtained the title compound in 58% yield; NMR Spectrum: (DMSOd6) 1.0 (t, 6H), 2.2 (s, 3H), 2.5 (m, 4H), 3.6 (s, 2H), 4.15 (s, 4H), 6.05 (m, 1H), 6.45-6.55 (m, 1H), 6.9 (s, 1H), 6.97 (m, 1H), 7.22 (m, 1H), 7.45 (d, 2H), 7.57 (m, 1H), 7.8 (m, 1H), 7.95 (d, 2H), 9.8 (s, 1H), 10.12 (broad s, 1H); Mass Spectrum: M+H+ 501.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:14]([O:23][CH3:24])=[N:15][CH:16]=[N:17][C:18]=1[C:19]([F:22])([F:21])[F:20].[CH:25](OCC)=[O:26]>O1CCCC1.O>[CH3:24][O:23][C:14]1[C:13]([CH:25]=[O:26])=[C:18]([C:19]([F:22])([F:21])[F:20])[N:17]=[CH:16][N:15]=1
Reactant: CCOC=O
Reactant: COc1ncnc(C(F)(F)F)c1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ncnc(C(F)(F)F)c1C=O
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
30.0 ml of n-butyllithium (a 1.6 moles/liter n-hexane solution, 48.0 mmoles) was gradually added, at −65 to −60° C., to a solution of 10.3 g (40.0 mmoles) of 5-bromo-4-methoxy-6-trifluoromethylpyrimidine dissolved in 100 ml of tetrahydrofuran. The mixture was stirred for 30 minutes. Thereto was added 3.6 g (48.0 mmoles) of ethyl formate at the same temperature. The resulting mixture was stirred at the same temperature for 3 hours to give rise to a reaction. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.3 g (yield: 15.8%) of 4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.