Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].CN1CCOCC1.Cl.[CH3:20][O:21][C:22](=[O:26])[CH2:23][CH2:24][NH2:25].O>ClCCl>[CH3:20][O:21][C:22](=[O:26])[CH2:23][CH2:24][NH:25][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)CCN
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-formyl-benzoic acid (20 g, 133 mmol), CDMT (24 g, 137 mmol), and 4-methyl-morpholine (15.4 mL, 140 mmol) are combined in anhydrous dichloromethane (DCM) (300 mL) under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. Beta-alanine methyl ester hydrochloride (20.4 g, (147 mmol) is then added to the reaction mixture, followed by 4-methylmorpholine (15.4 mL, 140 mmol), and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction is diluted with DCM. The reaction is diluted with water and extracted with 1N HCl. The organic layer is washed with water and brine, followed by drying over anhydrous sodium sulfate. The solution is filtered and concentrated and further purified using flash column chromatography (30 g, 128 mmol).
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[C:41]([C:45]#[CH:46])([CH3:44])([CH3:43])[CH3:42]>[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[CH3:42][C:41]([CH3:44])([CH3:43])[C:45]#[C:46]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: C#CC(C)(C)C
Reactant: CCCN(C/C=C/Cl)Cc1cccc(O)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCCN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
To 12.5 ml of tetrahydrofuran were added 2.00 g (8.34 mmol) of (E)-N-(3-chloro-2-propenyl)-N-propyl-3-hydroxybenzylamine, 79.4 mg (0.417 mmol) of copper (I) iodide, 37.4 mg (0.167 mmol) of palladium acetate and 87.5 mg (0.334 mmol) of triphenylphosphine, and further, 1.65 mi (16.7 mmol) of n-butylamine and 1.23 ml (10.0 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 20 hours at room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate =19/1→9/1). The desired fractions were put together and concentrated under reduced pressure to oil. The oil was cooled to crystallize and the crystals were suspended in cooled n-hexane. The crystals were collected by filtration and then dried to obtain 2.13 g (yield: 89%) of the above identified compound as slightly yellow crystalline powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:18])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[O:18][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture of 3-(benzyloxy)-4-nitrophenol (31.4 g), 2-bromo-5-(methylsulfonyl)pyridine (30.3 g), cesium carbonate (83.6 g) and N,N-dimethylformamide (300 mL) was stirred at 100° C. for 3 h. The mixture was concentrated under reduced pressure. Water was added to the residue and the resulting brown suspension was filtered to give the title compound (45.6 g, 89%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl.[CH3:16]O>>[CH3:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([O:14][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c2cccnc12
Agent: Cl
Product: COC(=O)c1ccc(C)c2ncccc12
Reaction time: 15 h

Procedure:
The compound obtained in Example 87-2 (1 g) was dissolved in methanol (25 ml). The solution was stirred for 15 hours while blowing hydrochloric acid gas, and the solvent was removed by distillation. The obtained residue was dissolved in water and 1 mol/l sodium hydroxide aqueous solution was added to cause a solid substance to precipitate. The solid was collected by filtration and the filtrate was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation to obtain a solid. The solid was combined with the previously collected solid and purified by silica gel column chromatography (20 g, chloroform) to obtain the title compound (0.7337 g) as a white solid.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:8][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3].Cl.Br[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:15][CH2:16][N:17]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:18][CH2:19]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3]
Reactant: CCc1nn(-c2ccccc2)c2nc(C3CCNCC3)[nH]c(=O)c12
Reactant: Brc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nn(-c2ccccc2)c2nc(C3CCN(c4ccncc4)CC3)nc(O)c12
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-ethyl-1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (200 mg, 0.56 mmol, 1.00 equiv) in N,N-dimethylformamide (40 mL) at room temperature. To the resulting mixture was then added 4-bromopyridine hydrochloride (131 mg, 0.68 mmol, 1.10 equiv), in portions at room temperature, followed by triethylamine (188 mg, 1.86 mmol, 3.00 equiv), in portions at room temperature. The resulting solution was stirred overnight at 130° C. The resulting mixture was concentrated under vacuum. The resulting residue (150 mg) was purified by Prep-HPLC with the following conditions (Gilson Pre-HPLC): Column, SHISEIDO, CAPCELL PAK C18, 20 mm ID*250 mm, 5 u; mobile phase, methanol/H2O; Detector, UV 254 nm, to yield 3-ethyl-1-phenyl-6-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol as a white solid.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1.CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)(=O)=O.O>CO.C(OC)(C)(C)C>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[CH2:14][S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1
Reactant: CS(=O)(=O)OCC1CCCCO1
Reactant: Sc1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CO
Product: c1nc(SCC2CCCCO2)n[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9.7 g (173 mmol) of potassium hydroxide and 17.5 g (173 mmol) of 3-mercapto-1,2,4-triazole were dissolved in 200 ml of methanol and heated under reflux for one hour. After the solvent had been distilled off under reduced pressure, the residue was dried by azeotropic distillation with toluene and then taken up in 300 ml of methanol. 33.6 g (173 mmol) of tetrahydropyran-2-ylmethyl methanesulfonate (step a) were then added and the mixture was stirred at room temperature for 24 hours. 200 ml of water and 200 ml of methyl tert-butyl ether were then added to the reaction mixture and the organic phase was separated off, washed with water and dried. The mixture was concentrated and the residue was chromatographed over silica gel, yielding 18.2 g (53% of theory) of a yellow oil. (1H-NMR (CDCl3; δ in ppm): 8.05 (s,1H); 4.15 (d,1H); 3.65 (m,1H); 3.50 (m,1H); 3.25-3.10 (m,2H); 1.85 (m,1H); 1.75-1.25 (m,6H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[CH2:35]Br>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([OH:37])=[O:25])=[C:28]([CH2:35][N:21]2[CH2:22][CH2:23][CH:18]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH2:12][C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[CH:7]=3)[CH2:19][CH2:20]2)[CH:29]=1
Reactant: COC(=O)c1ccc(OC)cc1CBr
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1cccs1
Product: COc1ccc(C(=O)O)c(CN2CCC(c3cn(Cc4cccs4)c4ccc(OC)cc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.06 g (0.19 mmol) of 5-methoxy-3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole (example 89, part B) and 0.064 g (0.23 mmol) of 2-bromomethyl-4-methoxy-benzoic acid methyl ester. After standard work-up and purification by chromatography using a C18 column, 0.018 g (19% of yield) of the expected acid were obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:21]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38].O>CN(C=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:33][C:34]4[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=4)[C:37]([O:39][CH3:40])=[O:38])[CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:21]=1)[CH3:2]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCOCc1nc2c(c3cc(O)ccc3n3nnnc23)n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1nc2c(c3cc(OCc4cccc(C(=O)OC)c4)ccc3n3nnnc23)n1CC(C)C
Reaction time: 8 h

Procedure:
5-(Ethoxymethyl)-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinolin-8-ol, 4.0 g, 11.75 mmol was dissolved in 100 mL of DMF and stirred with potassium carbonate (3.3 g, 23.5 mmol) for 30 minutes. To this mixture was added methyl 3-(bromomethyl)benzoate (2.8 g, 12.33 mmol) and the reaction was stirred overnight. The reaction was poured into 10 volumes of water and the precipitate was sequentially filtered, dissolved in dichloromethane, dried over magnesium sulfate, filtered, and concentrated to give 6.1 g of methyl 3-{[(5-ethoxymethyl-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinolin-8-yl)oxy]methyl}benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: Nc1ccncc1
Reactant: O=c1[nH]c(-c2cc(Cl)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Cl)cc1-c1nc(Nc2ccncc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-chloro-2-fluorophenyl)-pteridin-4-one with 4-aminopyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)[N:9]=1.[I-].[Na+].Br[CH:40]1[CH2:43][O:42][CH2:41]1>CN(C=O)C.O>[CH3:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:40]3[CH2:43][O:42][CH2:41]3)[CH:15]=2)[N:11]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)[N:22]=2)[N:9]=1
Reactant: BrC1COC1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(OC2COC2)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of K2CO3 (19.8 mg, 0.144 mmol), 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenol (Example 59; 30.0 mg, 0.072 mmol), sodium iodide (21.6 mg, 0.144 mmol) and 3-bromooxetane (22 uL, 0.288 mmol) in DMF (0.36 mL) was stirred at 50° C. for 48 h. The crude mixture was diluted with H2O and extracted with 4:1 CHCl3:i-PrOH. The organic layer was dried over MgSO4, concentrated under reduced pressure, and the residue was purified using Prep-HPLC to furnish the title compound; MS (ES+) C22H18F3N5O4 requires: 473. found 474 [M+H]+; 1H-NMR (600 MHz, CD3OD) δ ppm 8.28 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.28 (m, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.64 (m, 2H), 5.42 (s, 2H), 5.18 (m, 1H), 4.95 (m, 2H), 4.74 (m, 2H), 2.54 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:26]([C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1)[CH2:27][CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:30][CH2:29][CH2:28][CH2:27][N:26]([CH:20]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=1)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:38](=[O:46])[C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCN)C(C(=O)N(C)C)c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl](4-methylbenzoyl)amino]propylcarbamate (500 mg), was added 20% solution of trifluoroacetic acid in methylene chloride at room temperature. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography to give N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-methylbenzanide (336 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: N#CC1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: N#C[C@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O

Procedure:
1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (23 g) obtained in Step D of Example 103 was resolved by HPLC (column: CHIRALPAK IC, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=200/800) to give the title compound (11 g: a longer retention time).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[OH:15])=[CH:10][CH:9]=1
Reactant: O=C(c1ccc(F)cc1)c1cccs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(F)cc1)c1cccs1
Reaction time: 8 h
Yield: 99 %

Procedure:
Lithium aluminium hydride (3.68 g, 97 mmol) was added portionwise to a stirred solution of (4-fluorophenyl)-(2-thienyl)ketone (10.0 g, 48.5 mmol) in dry THF (160 ml) at room temperature under argon. The mixture was stirred overnight and water (3.7 ml) added dropwise with caution. After 0.5 h 15% aqueous sodium hydroxide (3.7 ml) was added and the mixture stirred for 0.5 h, finally water (11 ml) was added and the mixture stirred for 0.5 h. The precipitate was removed by filtration through celite and the flitrate was concentrated under reduced pressure to give (4-fluorophenyl)-(2-thienyl)methanol (10.0 g, 99%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11](OC)=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1.[Si:21]([O:28][CH2:29][CH2:30][C@H:31]([NH2:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:39][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])[CH2:30][CH2:29][O:28][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: COC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1F
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.7 %

Procedure:
A solution of 188 mg of 5-(3-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 157 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamine in 2 ml of methylene chloride was stirred at room temperature for 3 hours and the conversion was checked by LCMS. Since no reaction had taken place yet, the solvent was concentrated by rotary evaporation and the residue with addition of 0.25 ml of methylene chloride was stirred at room temperature for 17 hours. Subsequently, the reaction mixture was stirred at 50° C. for 4 hours. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (206 mg) with a molecular weight of 613.7 g/mol (C27H38BrFN2O4SSi); MS (ESI): m/e=614 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)=[O:33])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1cccc(N=C=O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(NC(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 40 °C
Yield: 6.1 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 3-methoxyphenylisocyanate (0.45 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The residue was triturated in Et2O (50 mL) for 3 h at rt, then refluxed in acetone (50 mL) for 1 h. The product was isolated by filtration and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(3-methoxy-phenyl)-urea as a white solid (0.08 g, 6% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 8.01 min (99.44%); mp: 323-325° C.; 1H NMR (DMSO-d6) δ 2.03-2.09 (m, 1H, CHH), 2.49-2.63 (m, 2H, CHH, CHH), 2.85-2.91 (m, 1H, CHH), 3.70 (s, 3H, CH3), 4.47 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 13.5 Hz, 1H, CH), 6.47-6.50 (m, 1H, Ar or NH), 6.82-6.91 (m, 2H, Ar or NH), 7.09-7.15 (m, 2H, Ar or NH), 7.78-7.91 (m, 3H, Ar or NH), 8.74 (s, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.98, 30.90, 42.57, 48.96, 54.81, 103.52, 106.72, 110.14, 121.63, 123.47, 129.36, 129.65, 131.57, 133.17, 141.49, 143.07, 148.75, 155.16, 159.60, 167.02, 167.18, 169.80, 172.72; LCMS: MH=437; Anal Calcd for C22H20N4O6: C, 58.38; H, 4.85; N, 12.38. Found: C, 58.36; H, 4.45; N, 11.98.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[O-:29][C:30]#[N:31].[Na+].C(O)(=O)C.CN(C=O)C>O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:30]([NH2:31])=[O:29])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(N)=O)c1
Reaction time: 1 h

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.202 g, 0.51 mmol) and sodium cyanate (0.052 g, 0.77 mmol) were combined in H2O (2 mL). Acetic acid (0.04 mL, 0.77 mmol) was added, and the reaction was stirred for 1 hour. DMF (1 mL) was added to facilitate stirring, and the reaction was stirred for 1.5 hours. The solution was extracted with EtOAc, and the combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2([NH:69][C:70](=[O:75])[C:71]([F:74])([F:73])[F:72])[CH2:68][CH2:67][CH2:66]2)=[CH:61][C:60]=1[O:76][CH3:77]>>[F:72][C:71]([F:73])([F:74])[C:70]([NH:69][C:65]1([C:62]2[CH:63]=[CH:64][C:59]([NH:58][C:2]3[N:7]=[CH:6][C:5]4=[CH:8][CH:9]=[C:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[N:17]([S:18]([CH3:21])(=[O:20])=[O:19])[CH3:22])[N:4]4[N:3]=3)=[C:60]([O:76][CH3:77])[CH:61]=2)[CH2:66][CH2:67][CH2:68]1)=[O:75]
Reactant: COc1cc(C2(NC(=O)C(F)(F)F)CCC2)ccc1N
Reactant: CN(c1ccccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2(NC(=O)C(F)(F)F)CCC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
Into a 8-dram vial, N-[2-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (176 mg, 0.552 mmol), N,N-Dimethylformamide (2.00 mL, 25.8 mmol), N,N-Diisopropylethylamine (0.211 mL, 1.21 mmol), and N-Phenylbis(trifluoromethanesulphonimide) (0.236 g, 0.662 mmol) were added. The reaction was stirred at room temperature for 30 minutes. N-[1-(4-Amino-3-methoxy-phenyl)-cyclobutyl]-2,2,2-trifluoro-acetamide (0.350 g, 1.21 mmol) was then added. The reaction mixture was heated at 120° C. for 4 hours. The solvent was removed under vacuum overnight. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid. The solid was partitioned with NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2,2,2-Trifluoro-N-[1-(4-{7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-cyclobutyl]-acetamide as a yellow solid (180 mg, 55%). LCMS (E/I+) 589.23 (M+H). NMR 1H (DMSO-d6)-9.98 (s, 1H), 8.96 (s, 1H), 7.93-8.00 (m, 1H), 7.90 (d, 1H, J=8.35 Hz), 7.77 (s, 1H), 7.60-7.68 (m, 1H), 7.48-7.56 (m, 2H), 7.04 (s, 1H), 7.02 (d, 1H, J=4.74 Hz), 6.95 (d, 1H, J=4.74 Hz), 6.87 (d, 1H, J=8.51 Hz), 3.84 (s, 3H), 3.03 (s, 3H), 2.09 (s, 3H), 2.54 (t, 4H, J=7.44 Hz), 1.70-2.00 (m, 2H).