Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([O:19]C)=[O:18].[OH-].[Na+]>CO>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:14])[F:15])[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1c(-c2ccccc2C(F)(F)F)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Temperature: 30 °C
Reaction time: 7 h
Yield: 95.7 %

Procedure:
methyl 5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylate (6.0 g, 21.03 mmol) was dissolved in methanol (60 mL), added with 3% sodium hydroxide aqueous solution (60 mL), stirred at 30° C. for 7 hours, and vacuum-evaporated so as to remove methanol. The remaining solution was washed with ethyl acetate (20 mL), and the aqueous layer was neutralized by a hydrochloric acid aqueous solution. Then, the produced crystal was filtered, washed with purified water (50 mL), and dried so as to provide a white solid required compound (5.48 g, 20.12 mmol, 96%).
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH:9]([CH2:18][OH:19])[N:8]3[CH:7]=1)=O.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:22]1>>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30]2[C:31](=[O:32])[NH:33][C:3](=[O:20])[C:4]=2[C:6]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=[CH:15]3)[CH2:11][CH2:10][CH:9]([CH2:18][OH:19])[N:8]4[CH:7]=2)=[CH:22]1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2CO
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3CO)=C1c1c[nH]c2ccccc12

Procedure:
Beginning with (4-hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester and (1H-indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[C:16]([Cl:21])[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:53].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[I:20])[CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[NH:50][CH2:51][C:52](=[O:53])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Cl)c1)C(=O)O
Reactant: NCC(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Cl)c1)C(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(3-chloro-4-iodophenyl)propanoic acid (4.16 g, 9.77 mmol) in DMF (80 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (4.6 g, 10.0 mmol). After 10 minutes at rt the solution was treated with a solution of 2-amino-1-phenylethanone hydrochloride (2.52 g, 14.6 mmol) and N,N-diisopropylethylamine (8.5 mL, 49.0 mmol). The solution was stirred at rt for 2 h. The solution was diluted with ethyl acetate (250 mL) and washed with saturated aqueous sodium bicarbonate solution (200 mL). The organic phase was dried over sodium sulfate. Purification by silica gel chromatography (5–25% ethyl acetate:hexanes) afforded product as a white solid (3.1 g, 58%). LCMS found for C22H25ClIN2NaO4 (M+Na)+: m/z=565.
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[C:7](=[C:8]([C:13]#[N:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH2:4]1)=C.[O:15]=[O+][O-].S(C)C>C(Cl)Cl>[CH:1]([CH:3]1[C:12]2[C:7](=[C:8]([C:13]#[N:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH2:4]1)=[O:15]
Reactant: C=CC1COCc2c(C#N)cccc21
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: N#Cc1cccc2c1COCC2C=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-ethenyl-3,4-dihydro-1H-isochromene-8-carbonitrile (62 mg, 0.334 mmol) in DCM (10 mL) was bubbled with O3 for 10 mins at −78° C. until the blue color appeared. Then Me2S (1 mL) was added and the mixture was stirred at r.t. for 5 hours. Then the mixture was concentrated in vacuo to give the desired product 4-formyl-3,4-dihydro-1H-isochromene-8-carbonitrile, which can be used for next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[NH:14][C:13]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=4)=[N:12][C:11]=3[N:10]([CH3:30])[C:9]2=[O:31])=[CH:5][CH:4]=1.Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[C:13]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:29])[F:28])[CH:20]=4)=[N:12][C:11]=3[N:10]([CH3:30])[C:9]2=[O:31])=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2c(=O)c3[nH]c(Cc4cccc(OC(F)(F)F)c4)nc3n(C)c2=O)cc1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(nc(Cc4cccc(OC(F)(F)F)c4)n3Cc3ccccn3)n(C)c2=O)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (136 mg, 0.295 mmol) in DMF (2 mL) was added 2-(bromomethyl)pyridine hydrobromide (112 mg, 0.442 mmol) followed by potassium carbonate (102 mg, 0.738 mmol). The reaction was stirred at 65° C. for 2 h. The mixture partitioned between ethyl acetate and brine. The organic layer was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/methanol (45:1) to give 1-(4-methoxybenzyl)-3-methyl-7-(pyridin-2-ylmethyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (96 mg, 59% yield) as a white solid. LCMS retention time 1.791 min; LCMS MH+ 552.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].I[CH:17]([CH3:19])[CH3:18]>>[CH:17]([O:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1C
Product: COC(=O)c1cc(OC(C)C)cc([N+](=O)[O-])c1C

Procedure:
reacting methyl 5-hydroxy-2-methyl-3-nitrobenzoate with 2-iodopropane in the presence of a base to form methyl 5-isopropoxy-2-methyl-3-nitrobenzoate;
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](NC(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C:14]23[O:21][CH:18]([CH2:19]C2)[CH:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:15]3)[N:6]=1.[F:40][C@@H]1[C@H](NC(=O)OC(C)(C)C)CC[C@@H](C2N(C)N=CC=2[N+]([O-])=O)OC1.BrC1SC=C(C(O)=O)N=1>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@H:14]2[O:21][CH2:19][C@H:18]([F:40])[C@H:17]([NH:22][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][CH2:15]2)=[O:31])[N:6]=1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Agent: O=C(O)c1csc(Br)n1
Product: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1

Procedure:
Following the procedure for Intermediate 65, starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24) and replacing 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid with 2-bromothiazole-4-carboxylic acid (commercial) gave tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate.
Reaction SMILES: C([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][C:20](=[O:22])[NH2:21])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[H][H]>CO.O.[C].[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][C:20](=[O:22])[NH2:21])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Into a 200 ml three-necked flask was charged 5.0 g (14.2 mmol) of Z-L-Ala-L-Gln, and the peptide was dissolved in 100 ml of a mixture of methanol and water (methanol:water =7:3) and stirred with a magnetic stirrer. After the air in the flask had been replaced with nitrogen, 0.8 g of 2% by weight of palladium-carbon was added thereto, and the protective group was eliminated in a stream of hydrogen. After 2 hours, the completion of the reaction was confirmed by thin layer chromatography, and then the palladium-carbon was filtered off. The filtrate was concentrated to 20 ml under reduced pressure, and 40 ml of isopropyl alcohol was added thereto. The resulting mixture was stirred for 30 minutes, during which time crystals precipitated. The crystals were collected by filtration, washed with isopropyl alcohol and then dried under reduced pressure to give 2.8 g (12.9 mmol) (90%) of L-Ala-L-Gln.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[CH:21]=[CH:20][C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12](=[O:22])[C:11]=2[C:23]=1[F:24])(=O)=O.[O:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[CH2:33][N:34]([CH3:39])[S:35]([NH2:38])(=[O:37])=[O:36].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12](=[O:22])[C:11]3[C:23]([F:24])=[C:7]([NH:38][S:35]([N:34]([CH2:33][CH:28]4[CH2:29][O:30][CH2:31][CH2:32][O:27]4)[CH3:39])(=[O:36])=[O:37])[CH:8]=[CH:9][C:10]=3[CH:21]=[CH:20][C:14]2=[N:15][CH:16]=1
Reactant: O=c1c2cc(Cl)cnc2ccc2ccc(OS(=O)(=O)C(F)(F)F)c(F)c12
Reactant: CN(CC1COCCO1)S(N)(=O)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(CC1COCCO1)S(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1F
Temperature: 110 °C

Procedure:
To a stirred solution of 3-chloro-6-fluoro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl trifluoromethanesulfonate (200 mg, 0.49 mmol) in 1,4-dioxane (7 mL) were added N-(1,4-dioxan-2-ylmethyl)-N-methylsulfamide (200 mg, 0.98 mmol), Pd2(dba)3 (68 mg, 0.074 mmol), Xantphos (85 mg, 0.15 mmol), and K3PO4 (280 mg, 1.3 mmol). The reaction mixture was purged with N2 for 5 min, heated to 110° C. 8 h, cooled to room temperature, diluted with water, and extracted with CH2C12 (×3). The combined organics were dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.78 (d, 1H); 8.24 (d, 1H); 7.99 (d, 1H); 7.93 (t, 1H); 7.36 (d, 1H); 7.21 (br s, 2H); 3.64-4.00 (series of m, 7H); 3.36 (dd, 1H); 3.08 (dd, 1H); 2.99 (s, 3H). LRMS (ESI) calc'd for (C20H19ClFN3O5S) [M+H]+, 468.1; found 468.0.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[CH2:17]([NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)[CH3:18].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH2:17]([NH:19][C:20](=[O:33])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:28][CH2:29][N:30]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:31][CH2:32]2)=[CH:25][CH:26]=1)[CH3:18]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (50.00 mg, 0.232 mmol), N-ethyl-4-(piperazin-1-yl)benzamide (67.8 mg, 0.290 mmol) and (cyanomethyl)trimethylphosphonium iodide (90 mg, 0.372 mmol) in propiononitrile (Volume: 1.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.202 mL, 1.162 mmol) at 23° C. The reaction was stirred at 95° C. for 3 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×2 mL) and dried in vacuo to provide N-ethyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0595 g, 0.138 mmol, 59.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3 H) 2.51-2.60 (m, 4 H) 3.18-3.31 (m, 6 H) 3.62 (s, 2 H) 6.71-6.77 (m, 1 H) 6.94 (m, J=9.09 Hz, 2H) 7.08 (dd, J=3.54, 1.52 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.68 (dd, J=3.03, 1.52 Hz, 1 H) 7.71 (m, J=8.84 Hz, 2 H) 8.17 (t, J=5.56 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.62 (br. s., 1H). ESI-MS: m/z 431.4 (M+H)+. mp=251.7-259.6° C.
Reaction SMILES: [C:1](=[S:3])=[S:2].OS(O[CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11]1)(=O)=O.[OH-].[Na+].Cl>O>[CH2:9]1[CH:10]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19]2)[C:1](=[S:3])[S:2]1
Reactant: O=S(=O)(O)OCC1Cc2ccccc2CN1
Reactant: S=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: S=C1SCC2Cc3ccccc3CN12
Temperature: 20 °C
Reaction time: 24 h
Yield: 77.9 %

Procedure:
Carbon disulphide (63 g) is added dropwise, at 20° C. and whilst stirring vigorously, to a solution of (RS)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (151 g) and sodium hydroxide pellets (63 g) in water (5000 cc). A cream precipitate is immediately formed. The very thick mixture is stirred at a temperature of about 20° C. for 24 hours. The reaction mixture is then neutralised by adding 4 N hydrochloric acid (130 cc). The solid is filtered off and then washed copiously with water. After drying, (RS)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (107 g) is obtained in the form of white crystals which melt at 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[CH2:20][S:21][CH2:22][C:23]=2[C:24]([O:26]C)=O)=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:24](=[O:26])[C:23]3[CH2:22][S:21][CH2:20][C:19]=3[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)CSC1
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CSC3)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[4-(methoxycarbonyl)-2,5-dihydrothien-3-yl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-{1,2,5,7-tetrahydro-2,4-dioxothieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate, m.p. 180°-183° C.,
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:4][CH2:3]1.C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[O:32]=[S:28]1(=[O:31])[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][NH:10][CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:33])[CH2:7][CH2:6]2)[CH2:26][CH2:27]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCN1CCS(=O)(=O)CC1)CCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=S1(=O)CCN(CCNCCN2CCS(=O)(=O)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
N,N-bis(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.85 g, 1.13 mmol) and thiophenol (0.373 g, 3.39 mmol) were combined in dry acetonitrile (10 mL). Potassium carbonate (0.936 g, 6.78 mmol) was added and the mixture was stirred at rt for 18 h. The mixture was diluted with ethyl acetate and filtered to remove unwanted solids. The crude filtrate was concentrated in vacuo, redissolved in methanol, and loaded onto a strong cation exchange resin cartridge to capture the desired product. Undesired materials were eluted from the cartridge with methanol, and then the desired material was released from the resin by elution with 2M ammonia in methanol. Concentration in vacuo gave a sticky yellow oil (0.381 g, 100% yield). No further purification was performed and the mixture was carried forward to the next step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)O)[CH:5]=[CH:4][CH:3]=1.CC1C=CC=C(C#CC=C2CCNCC2)N=1.Cl[C:35]1[C:40]([C:41]#[N:42])=[N:39][CH:38]=[CH:37][N:36]=1>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]=[C:12]2[CH2:17][CH2:16][N:15]([C:35]3[C:40]([C:41]#[N:42])=[N:39][CH:38]=[CH:37][N:36]=3)[CH2:14][CH2:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C#CC(O)C2CCNCC2)n1
Reactant: N#Cc1nccnc1Cl
Agent: Cc1cccc(C#CC=C2CCNCC2)n1
Product: Cc1cccc(C#CC=C2CCN(c3nccnc3C#N)CC2)n1
Yield: 81 %

Procedure:
The title compound was prepared as reported for the compound of Example 237 but starting from the compound of Example 3 instead of Compound 237a and using 2-chloro-3-cyanopyrazine instead of 2-bromo-3-nitropyridine After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from 7:3 affording the title product. Yellowish solid. Yield: 81%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17](Cl)[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:29])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:33]2[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=[C:32]2[CH2:30][CH3:31])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 120 °C
Yield: 62.3 %

Procedure:
A mixture of 3-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene)azetidine-1-carboxylic acid tert-butyl ester (1.4 g, 3.33 mmol), 2-ethylbenzimidazole (584 mg, 3.99 mmol), tris(dibenzylideneacetone)dipalladium (152 mg, 0.17 mmol), XPhos (317 mg, 0.66 mmol) and Cs2CO3 (2.17 g, 6.65 mmol) in dioxane (15 mL) was purged with argon then heated at 120° C. for 16 h in a sealed tube. The reaction mixture was filtered through Celite®, washing with EtOAc, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-100%) affording the title compound as a cream solid (1.1 g, 62%). LCMS (method H): RT 3.20 min [M+H]+ 531.4
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([Cl:12])[CH:3]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>C(O)C.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: OCc1ccc(Br)cc1Cl
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
Methyl 4-bromo-2-chlorobenzoate (477 g) of Reference Example 11 was dissolved in a mixed solution of ethanol (3000 mL) and water (680 mL), calcium chloride (212.2 g) was added at 10° C., and the mixture was stirred for 30 min. To the solution was added sodium borohydride (144.7 g) by portions so that the inside temperature would not exceed 25° C., and the mixture was stirred at room temperature for 5 hr. 1M Hydrochloric acid (5100 mL) was added dropwise to the reaction mixture, and the reaction solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue. After partitioning and extraction, the organic layer was washed with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (399 g) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:19]C(C)([O-])C.[K+].CI>C1COCC1>[CH3:19][N:7]1[C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:14]=2[C:13]2[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1cccc2c1c1c(n2C)CCCC1=O
Reaction time: 0.5 h
Yield: 178.8 %

Procedure:
To a solution of methyl 4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate (0.27 g, 1 mmol) in THF (5 ml) at 0° C. under N2 was added potassium t-butoxide (0.12 g, 1.05 mmol). The reaction mixture was stirred for 30 minutes followed by the addition of methyl iodide (0.76 g, 5.0 mmol). After 3 hours, the reaction mixture was concentrated to a residue and partitioned between EtOAc (40 ml) and 1N HCl (5 ml). The layers were shaken and separated. The organic layer was washed with 1N HCl (2×80 ml) and brine (2×10 ml), dried over Na2SO4, filtered, and concentrated to give a solid (0.46 g). The solid was used in the next step without further purified. 1H NMR (DMSO-d6) δ 7.35-7.39 (m, 2H), 7.29 (t, 1H, J=7.2 Hz), 4.01 (s, 3H), 3.72 (s, 3H), 2.93-2.95 (m, 2H), 2.54-2.56 (m, 2H), and 2.23-2.26 (m, 2H). MS (ESI) m/e [M+1]+ 258.0
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:7]=1.[CH3:28][C:29]([CH3:34])([CH3:33])[C:30]([NH2:32])=[O:31]>>[F:27][C:5]1[CH:4]=[CH:3][C:2]([NH:32][C:30](=[O:31])[C:29]([CH3:34])([CH3:33])[CH3:28])=[CH:7][C:6]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[CH2:12][CH2:11]1
Reactant: Cc1ccc2c(N3CCN(CCc4cc(Br)ccc4F)CC3)cccc2n1
Reactant: CC(C)(C)C(N)=O
Product: Cc1ccc2c(N3CCN(CCc4cc(NC(=O)C(C)(C)C)ccc4F)CC3)cccc2n1
Yield: 52 %

Procedure:
The title compound was prepared in 52% yield according to the general procedure for the preparation of amides, ureas and carbamates (Method A) starting from 5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and 2,2-dimethylpropanamide.