Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(CNC)=CC=1.[CH3:11][O:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][CH2:19][NH:20][CH3:21])=[CH:15][CH:14]=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][NH:30][C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[N:42][CH:41]=[C:40](I)[N:39]=3)=[N:35][C:34]=2[CH3:45])=[O:32])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][NH:30][C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[N:42][CH:41]=[C:40]([N:20]([CH2:19][CH2:18][O:17][C:16]4[CH:22]=[CH:23][C:13]([O:12][CH3:11])=[CH:14][CH:15]=4)[CH3:21])[N:39]=3)=[N:35][C:34]=2[CH3:45])=[O:32])=[CH:27][CH:26]=1
Reactant: CNCCOc1ccc(OC)cc1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Agent: CNCc1ccc(F)cc1
Product: COc1ccc(OCCN(C)c2cncc(-c3nc(C)c(C(=O)NCc4ccc(F)cc4)s3)n2)cc1
Yield: 80 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with [2-(4-methoxy-phenoxy)-ethyl]-methyl-amine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide, the title compound was obtained in 80% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.50 (s, 1H), 8.04 (s, 1H), 7.31-7.38 (m, 2H), 7.02-7.09 (m, 2H), 6.72-6.82 (m, 4H), 6.25 (bs, 1H), 4.55-4.59 (m, 2H), 4.18-4.23 (m, 2H), 4.01-4.08 (m, 2H), 3.69 (s, 3H), 3.31 (s, 3H), 2.71 (s, 3H); MS (ES+) m/z 508.2 (M+1), Rt=1.57 min.
Reaction SMILES: [CH3:1][C:2]([OH:17])([CH2:15][CH3:16])[C:3]#[C:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[OH:6].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[OH:17][C:2]([CH3:1])([CH2:15][CH3:16])[C:3]#[C:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([S:13][CH3:14])=[CH:11][CH:12]=1)=[O:6]
Reactant: CCC(C)(O)C#CC(O)c1ccc(SC)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(C)(O)C#CC(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To 9.9 g of 4-methyl-1-{4-(methylthio)phenyl}-2-hexyn-1,4-diol dissolved in 200 ml dichloromethane, were added 15 g of pyridinium dichromate (PDC) and 15 g of celite. The suspension was stirred overnight at room temperature, and then the insoluble material was filtered off through Florisil. The filtrate was purified by column chromatography (hexane/ethylactate=4:1) to give 5.34 g of 4-hydroxy-4-methyl-1-{4-(methylthio)phenyl}-2-hexyn-1-one. NMR: δ1.13 (t, J=7.5 Hz, 3H), 1.62 (s, 3H), 1.85 (q, J=7.8 Hz, 2H), 2.54 (s, 3H), 7.28 (d, J=8.7 Hz, 2H), 8.01 (d, J=8.7 Hz, 2H). IR (cm−1): 3427, 2974, 1588, 1095, 914, 745.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[F:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][C:47]([F:48])=[C:26]([NH:25][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[O:3][C:4]=5[C:10]([F:13])([F:12])[F:11])=[O:9])[CH:27]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2F)c(C(F)(F)F)o1
Yield: 89.6 %

Procedure:
In the same manner as in Example 18-4 and using 2-methyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic acid (238 mg, 1.22 mmol), tetrahydrofuran (7 mL), oxalyl chloride (160 μL, 1.83 mmol), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (276 mg, 90%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]([C:15](=[O:17])[CH3:16])[CH:6]2[CH3:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]([C:15](=[O:17])[CH3:16])[CH:6]2[CH3:18])[C:19]([CH3:20])=[O:21]
Reactant: CC(=O)N1c2ccccc2-c2c(N)cnn2C1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cnn2c1-c1ccccc1N(C(C)=O)C2C
Reaction time: 10 h
Yield: 90 %

Procedure:
20.5 g (0.08 mole) of 1-amino-5-methyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline are dissolved in 400 ml of pyridine. 100 ml of acetic anhydride are added and the solution is left to stand at room temperature for 10 hours. A portion of the product separates as a crystalline substance, the remaining portion is separated by evaporating the mother liquor. 21.1 g (90%) of 1-acetamino-5-methyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 218°-220° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]1[NH:24][C:23](=[O:25])[N:22]2[C:26]([CH3:32])=[N:27][C:28]([CH2:29][CH2:30][CH3:31])=[C:21]2[N:20]=1)[CH3:7]>ClCCl>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]1[NH:24][C:23](=[O:25])[N:22]2[C:26]([CH3:32])=[N:27][C:28]([CH2:29][CH2:30][CH3:31])=[C:21]2[N:20]=1)[CH3:7]
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Reactant: COCCN
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)NCCOC)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
55 mg (0.73 mmol) of 2-methoxyethylamine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5) and stirring up with diethyl ether, 64 mg (57%) of 4-ethoxy-N-(2-methoxy-ethyl)-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α][1,3,5]triazin-2-yl)-benzenesulfonamide are obtained.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[C:20]1[S:24][C:23]([NH2:25])=[N:22][N:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:18][C:3]([F:2])([F:17])[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:20]2[S:24][C:23]([NH2:25])=[N:22][N:21]=2)[CH2:9][CH2:8]1
Reactant: Nc1nnc(Br)s1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(trifluoromethyl)phenoxy]piperidine hydrochloride (5.5 g, 2.2 mmol) in DMF (50 mL) was added 5-bromo-1,3,4-thiadiazol-2-amine (3.3 g, 2.2 mmol) and K2CO3 (9.1 g, 6.6 mmol). The reaction was heated at 80° C. with stirring overnight. After cooling, the salt was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with EtOAc to afford the title compound.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=2)[CH:18]=[C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[N:12][CH:13]=1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[NH:56]1[CH2:60][CH2:59][CH2:58][CH2:57]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:56]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=3)[CH:18]=[C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:12][CH:13]=2)[CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(Br)cn3)c2)CC1
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(N4CCCC4)cn3)c2)CC1
Temperature: 0 °C
Yield: 36 %

Procedure:
To a mixture of sodium-tert-butoxide (0.18 g, 1.87 mmol) in toluene (2 mL) cooled to 0° C. was added tert-butyl 4-(3-(5-bromopyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.6 g, 1.34 mmol). The mixture was degassed for 20 min. Palladium acetate (0.02 g, 0.089 mmol) and (2-biphenyl)di-tert-butylphosphine (0.06 g, 0.2 mmol) was added and the mixture was degassed for 10 min. Pyrrolidine (0.114 g, 1.6 mmol) was added and the mixture was heated at 85° C. for 15 h. The reaction was cooled and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to give the title compound (0.21 g, 35.8%). 1H NMR (500 MHz, DMSO-d6): δ 7.61 (s, 1H), 7.28 (s, 1H), 6.99 (m, 1H), 6.91 (d, J=7.25 Hz, 1H), 6.83 (m, 3H), 6.31 (s, 1H), 3.48 (m, 2H), 3.38 (m, 2H), 3.28 (m, 4H), 2.44 (m, 2H), 2.29 (m, 2H), 2.04 (m, 4H), 1.47 (s, 9H); m/z (436.2, MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][NH2:11])[CH:3]=1.[CH3:12][S-:13].[Na+]>CO>[CH3:9][S:8][C:6]1[NH:5][C:4]([S:13][CH3:12])([NH:10][NH2:11])[CH:3]=[CH:2][N:7]=1
Reactant: C[S-]
Reactant: CSc1nc(Cl)cc(NN)n1
Agent: [Na+]
Solvent: CO
Product: CSC1=NC=CC(NN)(SC)N1
Temperature: 20 °C
Yield: 65.1 %

Procedure:
A mixture of the known compound 6-chloro-4-hydrazinyl-2-methylthiopyrimidine (15 g, 0.079 mole) and 21 g (0.1 mole) of sodium methyl mercaptide in 250 ml of methanol was heated at reflux for about 16 hours, and was then allowed to cool to about 20° C. The solid precipitate was separated by filtration, washed with methanol and water and dried. The filtrate was evaporated to provide a solid residue. This residue was then washed thoroughly with water and combined with the precipitate. The solids were dissolved in 500 ml of acetic acid, and the solution was treated with decolorizing charcoal, and filtered. The filtrate was cooled and treated with ammonium hydroxide until it was slightly basic. The precipitate was collected by filtration, providing 10.5 g (65%) of 2,6-bis(methylthio)-6-hydrazinylpyrimidine, m.p. 120°-125° C.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1.C(Cl)[Cl:32]>S(Cl)(Cl)=O>[Cl:32][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1
Reactant: O=C1CC(c2cccc(-c3nc(CO)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CC(c2cccc(-c3nc(CCl)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-[3-(4-hydroxymethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 26) (1.0 g) in CH2Cl2 (15 mL) and thionyl chloride (0.27 mL) was heated with stirring to 40° C. for 0.5 h and subsequently cooled in the ice bath. The solid was isolated by filtration and washed with CH2Cl2 to give 4-[3-(4-chloromethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (1.0 g) as yellow crystals.
Reaction SMILES: [C:1]1([S:7]([CH3:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20][N:19]=1.O>O1CCCC1.O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C>[C:1]1([S:7]([CH2:9][CH:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[N:19][NH:20]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1ccccc1
Reactant: c1ccc2cnncc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=S(CC1NN=Cc2ccccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A solution of 1 g of methyl phenyl sulphoxide in 14 ml of tetrahydrofuran is added dropwise at 78° C. within 10 min. to 3.93 ml of 2M solution of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene in 20 ml of tetrahydrofuran. The reaction mixture is stirred for a further 30 min. A solution of 0.928 g of phthalazine in 14 ml of tetrahydrofuran is added dropwise within 10 min. The mixture is stirred at -78° C. for 1 hr., treated with 100 ml of water and extracted 3 times with 50 ml of chloroform. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is concentrated. 1.9 g of crude (RS)-1-benzenesulphinylmethyl-1,2-dihydro-phthalazine are isolated as a yellowish oil, MS(ISP): 271.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[Li]CCCC.[C:19]([S:23]([N:25]=[CH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:24])([CH3:22])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:21][C:19]([CH3:22])([S:23]([NH:25][CH:26]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13])[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:24])[CH3:20]
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Reactant: COc1ccc2ccccc2c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ccc2ccccc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 1-bromo-2-methoxynaphthalene (0.839 g; 2.14 mmol) in anh. THF (20 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.35 ml; 2.16 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (0.500 g; 2.14 mmol) in anh. THF (2 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 30 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (35 ml), Et2O (75 ml) and water (20 ml). The separated organic layer was then washed with brine (30 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=15/1) afforded methyl 5-(1,1-dimethylethylsulfinamido)-5-(2-methoxynaphthalen-1-yl)pentanoate as a yellow oil. LC-MS (conditions A): tR=0.83 min. and [M+H]+: 391.93 g/mol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:30]([NH2:34])[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)N(C)CCC1.O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:34][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CN(S(=O)(=O)c2ccc(F)cc2)C1
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CCCCNc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)C(=O)OC(C)(C)C)C2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 97.1 %

Procedure:
To a solution of Benzyl-[1-(4-fluoro-benzenesulfonyl)-azetidin-3-yl]-carbamicacid tert-butyl ester (0.21 g, 0.5 mmol) in N,N′-dimethylpropyleneurea (0.5 ml) was added butylamine (0.15 g, 2 mmol) and potassium carbonate (0.07 g, 0.5 mmol), and the mixture was stirred at 50° C. for 2 days. It was then cooled to room temperature and diluted with water (20 ml). The aqueous phase was removed, and the residue dissolved in ether (20 ml). The ether solution was washed with 0.5 N HCl, saturated sodium bicarbonate solution, and brine, and dried over anhydrous sodium sulfate. It was then filtered through a pad of silica gel. The filtrate was evaporated, and the residue was triturated with hexanes to give 0.23 g of a white solid; m.p. 115-116° C.; MS (ES) m/z 474.1 (MH+); HRMS (El) Calcd. for C25H35N3O4S (M+): 473.2348, Found: 473.2338.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](S(CC3C=CC=CC=3)(=O)=O)[C@@H:16]([CH3:30])[CH2:15]2)[CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39](Cl)=[O:40])=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:39](=[O:40])[CH2:38][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[C@@H:16]([CH3:30])[CH2:15]2)[CH:3]=1
Reactant: C[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)Cc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: C[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)Cc1ccc(Cl)cc1

Procedure:
Prepared by the method of example 62 part (e) using the product from example 62 part (d) and 4-chlorobenzeneacetyl chloride to give the title compound.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[C:21]([OH:29])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][CH2:4][C@@H:2]2[CH2:3][O:1]2)[CH:20]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(=O)Nc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Cl)cc1OC[C@@H]1CO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
To a mixture of (2S)-oxiran-2ylmethyl3-nitrobenzenesulfonate (3.37 g, 13.25 mmol), N-(4-chloro-2-hydroxyphenyl)acetamide (2.46 g, 17.23 mmol) and Cs2CO3 (6.48 g, 19.88 mmol) was added DMF (20 mL) at 0° C. and the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (hexane:ethyl acetate 3:2) to give the subtitled compound (2.36 g).
Reaction SMILES: C(OC(N[C@H:9]([CH2:15]C1C=CC=CC=1)[CH:10](O)[C:11](O)=[O:12])=O)(C)(C)C.[CH2:22]([O:29][C:30](=[O:34])[C@H:31]([CH3:33])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:34])[C@H:31]([CH3:33])[NH:32][C:11](=[O:12])[CH2:10][CH2:9][CH3:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(O)C(=O)O
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Product: CCCC(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
The product of example 20A and L-alanine benzyl ester were processed as in examples 1E to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine benzyl ester. 0.5 g of the above product was hydrogenated in 2 mL of isopropyl alcohol in the presence of 20 mg of 10%-palladium on charcoal to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine (0.4 g).
Reaction SMILES: [CH3:1][O:2][N:3]([CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](N2C=CN=C2)=[O:13])[S:9][CH:10]=1)[CH3:4].[C:19]([OH:23])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][N:3]([O:2][CH3:1])[CH3:4])[N:7]=1)=[O:13])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)O
Reactant: CON(C)Cc1csc(NC(=O)n2ccnc2)n1
Product: CON(C)Cc1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.33 h
Yield: 90 %

Procedure:
A mixture of Intermediate 28: 2-(N-imidazocarbonylamino)-4-(N-methoxy-N-methyl-aminomethyl)thiazole (23.3 g, 87.2 mmol) and anhydrous tert-butanol (140 mL) was stirred under an inert atmosphere and heated to 80 C. After 20 minutes, a clear solution was obtained. tert-Butanol was evaporated at reduced pressure and the oily residue was dissolved in hexane (200 mL) and washed with water (2×100 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound as a colorless oil which crystallized on standing (21.4 g, 90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=O)=[CH:4][CH:3]=1.[CH:21]1([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:31]([C:30]3[CH:32]=[CH:33][C:27]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:28][CH:29]=3)[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccc(C2CCCCC2)cc1
Product: Brc1ccc(-c2ccc(-c3ccc(Br)cc3)n2-c2ccc(C3CCCCC3)cc2)cc1
Yield: 91 %

Procedure:
The product from Example 26E and 4-cyclohexylaniline (Alfa) were processed using the method described in Example 26F to provide 1.23 g (91%) of the title compound. 1H NMR (400 MHz, benzene-D6) δ 1.09 (s, 5H) 1.60 (s, 5H) 2.14 (s, 1H) 6.52 (s, 2H) 6.67 (s, 4H) 6.84 (s, 4H) 7.11 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].[N+:11]([CH3:14])([O-:13])=[O:12].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]([OH:9])[CH2:14][N+:11]([O-:13])=[O:12]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])CC(O)c1c(Cl)cncc1Cl
Reaction time: 1 h

Procedure:
To a solution of 3,5-dichloro-4-pyridinecarboxaldehyde (2.3 g, 13.3 mmol) in MeOH (25 mL) were added nitromethane (2.2 mL, 39.9 mmol) and sodium methoxide (861 mg, 15.9 mmol). After addition, the mixture was stirred for 1 h. The reaction mixture was quenched by adding 2 M aqueous HCl (7 mL) and extracted with EtOAc. The organic layer washed with brine×2 and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound A1-1 (2.8 g, 90%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:36][CH2:37][C@@H:38]2[CH2:43][O:42][CH2:41][CH2:40][N:39]2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[C:34]=1[Cl:35])[C:30]#[N:31].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.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:35][C:34]1[C:33]([O:36][CH2:37][C@@H:38]2[CH2:43][O:42][CH2:41][CH2:40][N:39]2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:19][CH2:20]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: COc1ccc(CN2CCOC[C@H]2COc2cc(C#N)cc(N)c2Cl)c(OC)c1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC[C@@H]4COCCN4Cc4ccc(OC)cc4OC)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (47.2 mg, 0.133 mmol), (S)-3-amino-4-chloro-5-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)benzonitrile (53 mg, 0.127 mmol), palladium(ii) acetate (7.55 mg, 0.034 mmol), Xantphos (7.34 mg, 0.013 mmol), DPPF (7.03 mg, 0.013 mmol) and cesium carbonate (107 mg, 0.330 mmol) in dioxane (1 ml) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 10 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated. the crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-40% ethyl acetate/hexanes) to give (S)-2-((2-chloro-5-cyano-3-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg) as a light yellow solid.