Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si](C)(C)C)[CH:2]=[CH2:3].[CH3:8][C:9]1([CH3:23])[CH2:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(O)[CH2:12][CH2:11][O:10]1.B(F)(F)F.O(CC)CC>C(Cl)Cl>[CH3:8][C:9]1([CH3:23])[CH2:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)([CH2:3][CH:2]=[CH2:1])[CH2:12][CH2:11][O:10]1
Reactant: C=CC[Si](C)(C)C
Reactant: Cc1ccc(C2(O)CCOC(C)(C)C2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCC1(c2ccc(C)cc2)CCOC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Allyltrimethylsilane (4.34 ml, 27.2 mmol) was added to a solution of 2,2-dimethyl-4-(4-methylphenyl)oxan-4-ol (3.0 g, 13.6 mmol) in dry CH2Cl2 (100 ml) at 0° C., followed by BF3—OEt2 (3.42 ml, 27.2 mmol). The resulting mix was stirred at 0° C. for 1 h. The reaction was quenched with H2O (10 ml) and diluted with CH2Cl2 (10 ml), and washed with sat. NaHCO3 (20 ml), brine (20 ml), dried and concentrated. Purified by normal phase SiO2 chromatography (5 to 40% EtOAc/hexanes) to give 2,2-dimethyl-4-(4-methylphenyl)-4-(prop-2-en-1-yl)oxane as a colorless oil, which was used crude (2.49 g, 75%).
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=O)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>>[O:9]=[C:7]1[CH:2]2[CH:1]([CH2:6][CH2:5][CH2:4][CH2:3]2)[C:10](=[O:11])[N:12]1[C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CC(C(=O)O)c1ccc(N)cc1
Reactant: O=C1OC(=O)C2CCCCC12
Product: CC(C(=O)O)c1ccc(N2C(=O)C3CCCCC3C2=O)cc1

Procedure:
Equimolar amounts of cyclohexane-1,2-dicarboxylic acid anhydride and α-(p-aminophenyl)propionic acid were treated as described in step (a) of Example 1, to yield quantitatively α-[4-(1,3-dioxo-hexahydro-2-isoindolinyl)phenyl]propionic acid, melting point 224°-226° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[N+:15]([O-])=O)=[C:4]([O:18][CH3:19])[CH:3]=1.NN>C(O)C.[Ru]>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[O:18][CH3:19])=[C:9]([NH2:15])[CH:10]=1
Reactant: COc1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Ru]
Agent: NN
Solvent: CCO
Product: COc1cc(Br)ccc1-c1ccc(Br)cc1N
Yield: 100 %

Procedure:
To a suspension of 4,4′-dibromo-2-methoxy-2′-nitro-biphenyl (3.76 g, 9.8 mmol) and 5% Ru/C (400 mg) in ethanol (37 ml) at 65-70° C. was added dropwise a solution of hydrazine (4.6 ml, 59 mmol) in ethanol (5 ml). The mixture was refluxed for 7 hours and filtered through a pad of CELITE. The CELITE pad was washed with ethanol. The combined solution was concentrated under reduced pressure. Coevaporation with ethanol, EtOAc and DCM gave 4,4′-dibromo-2′-methoxy-biphenyl-2-ylamine as yellow solid (3.5 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([NH:7]/[C:8](=[C:15]2\[C:16](=[O:28])[NH:17][C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>>[CH3:31][S:32]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7]/[C:8](=[C:15]2\[C:16](=[O:28])[NH:17][C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)/[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:29][CH:30]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN)cc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CNS(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-aminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and methanesulphonyl chloride/triethylamine Rf value: 0.7 (silica gel, methylene chloride/methanol=5:1) C25H23N3O5S
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@@H:14]1[C@@H:17]([CH2:18][CH:19]=[O:20])[N:16]([C:21](=[C:26]([CH3:28])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])[C:15]1=[O:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]1[C@@H:17]([CH2:18][CH2:19][OH:20])[N:16]([C:21](=[C:26]([CH3:27])[CH3:28])[C:22]([O:24][CH3:25])=[O:23])[C:15]1=[O:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](NC(=O)OCc2ccccc2)[C@H]1CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](NC(=O)OCc2ccccc2)[C@H]1CCO
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
Sodium borohydride (10 mg) was added to a solution of methyl 2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(2-oxoethyl)azetidin-1-yl]-3-methylbut-2-enoate (49 mg) in methanol (1 ml) at 0° C. The mixture was stirred at the same temperature for 20 minutes and quenched with acetic acid (~0.05 ml). The resulting solution was evaporated in vacuo. The residue was dissolved in dichloromethane and washed with brine containing sodium bicarbonate. The extract was dried over magnesium sulfate, evaporated, and chromatographed on silica gel (1.5 g, eluting with 5-10% acetone in dichloromethane) to give 39 mg of methyl 2-[(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)-2-oxoazetidin-1-yl]-3-methylbut-2-enoate.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[CH:20][C:15]=3[N:14]=[CH:13]2)=[CH:8][CH:7]=1)C>C(Cl)Cl.CO>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[CH:18]=[CH:17][C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:29])=[O:3])=[CH:7][CH:8]=4)[CH:13]=[N:14][C:15]=3[CH:20]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cc1ccc(-n2cnc3cc(-c4ccc(OC)cc4)ccc32)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2ccc3c(c2)ncn3-c2ccc(CC(=O)O)cc2)cc1

Procedure:
The title compound is prepared as described in Step 20.1 (Procedure B) but using {4-[5-(4-methoxy-phenyl)-benzoimidazol-1-yl]-phenyl}-acetic acid ethyl ester. The title compound: ES-MS: 359.3 [M+H]+; single peak at tR=3.60 min (System 1); Rf=0.26 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7](OCC)(=[O:10])[C:8]#[CH:9].C1(C)C=CC=CC=1>O1CCOCC1>[OH:10][C:7]1[CH:8]=[CH:9][N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=1
Reactant: Nc1cc[nH]n1
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Oc1ccn2nccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-aminopyrazole (11.5 g, 0.138 mol) in 65 mL of 1,4-dioxane was added ethyl propiolate (14.7 g, 15.2 mL, 0.150 mol) dropwise, and the resultant light yellow solution was warmed to reflux. After 4 h, the blood-red solution was cooled to room temperature and 100 mL of toluene was added with stirring. The resultant precipitate was collected with toluene and air-dried to afford the title compound as a tan solid. MS 136.0 (M+1)
Reaction SMILES: [CH2:1]([NH:3][C:4](=S)[NH:5][C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[N:7]=1)[CH3:2].[NH3:18]>>[CH2:1]([N:3]=[C:4]([NH2:18])[NH:5][C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[N:7]=1)[CH3:2]
Reactant: CCNC(=S)Nc1cnn(CCCCC#N)n1
Reactant: N
Product: CCN=C(N)Nc1cnn(CCCCC#N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-[4-(3-ethylthioureido)-1,2,3-triazol-2-yl]valeronitrile (2.2 g.) in methanolic ammonia (6M; 20 ml.) was treated with yellow mercuric oxide (2.08 g.) and the resulting suspension stirred at room temperature for 18 hours. The suspension was filtered through diatomaceous earth and the filtrate evaporated to give an oil which was purified by medium pressure chromatography using EtOAc then MeOH/EtOAc 1:1 v/v as eluants to give 5-[4-[2-ethylguanidino)-1,2,3-triazol-2-yl]valeronitrile (1.35 g.).
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:47])[NH:12][C:13]1([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[C:25]4[CH:30]=[CH:29][C:28](B5OC(C)(C)C(C)(C)O5)=[CH:27][N:26]4[C:40]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].[CH2:48]([O:55][C:56]1[C:61](Br)=[CH:60][CH:59]=[CH:58][N:57]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[C:6]([O:10][C:11](=[O:47])[NH:12][C:13]1([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[C:25]4[CH:30]=[CH:29][C:28]([C:61]5[C:56]([O:55][CH2:48][C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)=[N:57][CH:58]=[CH:59][CH:60]=5)=[CH:27][N:26]4[C:40]=3[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH2:16]1)([CH3:8])([CH3:7])[CH3:9]
Reactant: Brc1cccnc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(B5OC(C)(C)C(C)(C)O5)cn4c3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(-c5cccnc5OCc5ccccc5)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 110 °C

Procedure:
To the crude DMF solution of the boronate from Step 1 was added 2-benzyloxy-3-bromopyridine (0.25 g), aqueous sodium carbonate solution (2M, 2.8 mL) and dioxane (4 mL) and the mixture placed under argon. [1,1-bis-(diphenylphosphino)-ferrocene]-dichloropalladium-dichlormethane-complex (0.070 mg) was added and the mixture heated at 110° C. under microwave irradiation for 30 minutes. On cooling the mixture was partitioned between DCM and water and extracted. The organic portion was washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound (138 mg).
Reaction SMILES: [N:1]([C:4]1([CH2:21][OH:22])[C:17]2[CH:16]=[C:15]([Cl:18])[N:14]=[C:13]([F:19])[C:12]=2[O:11][C:10]2[C:5]1=[CH:6][C:7]([Br:20])=[CH:8][CH:9]=2)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:4]1([CH2:21][OH:22])[C:17]2[CH:16]=[C:15]([Cl:18])[N:14]=[C:13]([F:19])[C:12]=2[O:11][C:10]2[C:5]1=[CH:6][C:7]([Br:20])=[CH:8][CH:9]=2
Reactant: [N-]=[N+]=NC1(CO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1(CO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
A solution of (5-azido-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (25.1 g, 65.1 mmol) in THF (500 mL) was cooled to −10° C. and a solution of LAH (1.0 M in THF; 65.1 mL, 65.1 mmol) was added drop wise via an addition funnel over a time period of 1.5 hours. Upon complete addition, the reaction mixture was stirred additional 20 min at −10° C. The reaction mixture was quenched with the drop wise addition of saturated aqueous potassium sodium tartarate solution (60 mL). The reaction was diluted with water and EtOAc. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford (5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (21.74 g, 60.5 mmol, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:24][N:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3.[CH3:30][O:31][CH2:32]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[CH:22][N:23]([CH2:30][O:31][CH3:32])[N:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: COCBr
Product: COCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 36 above, using 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-5-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one from Example 39 above and bromomethyl methyl ether.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=2C)=[O:18])[CH:12]=1>O1CCCC1>[CH:1]1([O:7][C:11]2[N:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[O:18])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1)c1cc(OC2CCCCC2)ncn1
Reaction time: 0.17 h

Procedure:
Cyclohexanol (Fluka, 4.00 mL; 37.8 mmol) was treated with sodium hydride (35.0 mg; 0.80 mmol) and stirred during 10 minutes. Tetrahydrofuran (3 mL) was added, followed by 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide. Intermediate 7 (50.0 mg; 0.20 mmol). After 2 hours the solvents were removed in vacuo, the crude was redissolved in EtOAc. The organic phase was washed with sat. ammonium chloride and brine, dried over magnesium sulfate, filtered and evaporated in vacuo to give a residue, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=2)[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCN1CCNCC1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)cc3ccccc23)CC1
Yield: 89 %

Procedure:
A mixture of 1-chloro-3-(4-methoxyphenyl)isoquinoline (0.89 g), N-ethylpiperazine (0.86 g) and potassium carbonate (1.10 g) was heated in dimethylformamide (20 ml) at 90° C. for 12 hr. The reaction mixture was evaporated, water was added to the resulting residue, and then it was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried over magnesium sulfate, and then the solvent was removed. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the tilte compound as a pale brown oil (1.02 g, yield; 88%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:19])[C:5]([O:7][CH3:8])=[O:6].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[O:19][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[F:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccc2ccccc2c1O
Reactant: Fc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CON=C(C(=O)OC)c1ccc2ccccc2c1OCc1ccccc1F
Temperature: 25 °C
Yield: 71.6 %

Procedure:
5 g (19 mmol) of methyl 1-hydroxy-2-naphthylglyoxylate O-methyloxime, 2.7 g (19 mmol) of 2-fluorobenzyl chloride and 2.6 g (19 mmol) of potassium carbonate in 65 ml of methanol are stirred under reflux for 8 h. The mixture is cooled to room temperature and the solids are removed by filtration. The filtrate is concentrated, and dilute sodium hydroxide solution is added. The mixture is then extracted by shaking several times with ether; the combined ether phases are washed with H2O, dried over sodium sulfate and concentrated. 5 g (13.6 mmol) of methyl 1-(2-fluorobenzyloxy)-2-naphthylglyoxylate O-methyloxime (yield 71%) are obtained (compound no. 2, Table 1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:11]1([CH2:17][CH2:18][CH2:19][OH:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:20][CH2:19][CH2:18][CH2:17][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: OCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCCCN2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Chloro-4-fluorobenzonitrile (5.0 g) and 3-(1-piperidinyl)-1-propanol (3.4 g) were stirred in DMSO (70 ml) at rt under argon. Sodium hydride (60% wt in mineral oil, 1.976 g) was then added and the reaction stirred at rt for 5 h. The reaction mixture was diluted with ethyl acetate (200 ml), washed with saturated sodium hydrogen carbonate (100 ml), water (3×100 ml), brine (100 ml), dried (MgSO4) and evaporated. The crude product was then purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)] and fractions containing pure product were combined and evaporated to give the title compound (D26) as a white solid (6.29 g). MS electrospray (+ion) 279/281 (MH+).
Reaction SMILES: NC1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.CI.C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]([CH3:33])[CH:31]=O>O>[CH3:29][N:30]([CH3:33])[C:31]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2cc(-c3ccc(N)cc3)oc12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc2cc(-c3ccc(N(C)C)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.6 g of methyl 2-(4-aminophenyl)benzofuran-7-carboxylate, 1.52 ml of methyl iodide, 6.72 g of potassium carbonate and 25 ml of dimethylformamide is stirred at room temperature for 1 hour. 2.2 ml of methyl iodide are added to the mixture and the mixture is stirred for 2 hours. The reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:4) to give 2.0 g of methyl 2-(4-dimethylaminophenyl)benzofuran-7-carboxylate as orange needles.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:7]([O:6][P:4]([CH:9]([CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: BrCc1cscn1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(Cc1cscn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35 %

Procedure:
To a solution of tert-butyl diethylphosphonoacetate (15.6 g, 62 mmol) in dimethylformamide (50 mL) was added sodiumhydride (60% dispersion in mineral oil, 2.48 g, 62 mmol) at 0° C. under nitrogen atmosphere. After 45 min, to the mixture was added a solution of 4-(bromomethyl)-1,3-thiazole in toluene (27 g). The mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with toluene/ethyl acetate (1/3). The combined organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1/2 to 100% ethyl acetate) to afford 7.17 g (35%) of the title compound as a colorless oil:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Br-]>CN(C=O)C>[N:24]([CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=1)[CH:20]([CH3:22])[CH3:21])=[N+:25]=[N-:26]
Reactant: Cc1nsc2nc(C(Br)C(C)C)n(Cc3ccccc3)c(=O)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nsc2nc(C(N=[N+]=[N-])C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of 5-benzyl-6-(1-bromo-2-methyl-propyl)-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 28) (0.6 g, 1.52 mmol) in anhydrous DMF (20 mL), sodium azide (0.65 g, 10 mmol) was added and the mixture was stirred at room temperature for 1 hour. The TLC of the RM showed the complete disappearance of the starting bromide. The reaction mixture was poured into ice water (300 mL) and extracted with EtOAc (3×100 mL). The organic layer was washed with water (100 mL), brine (100 mL) and dried (Na2SO4). Concentration of the organic layer provided the crude product which was purified by column (silica gel) chromatography using 30% EtOAc in hexanes as eluent to isolate 6-(1-azido-2-methyl-propyl)-5-benzyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (0.506 g, 94%) as a low melting solid. m/z 355 (MH+), 1H NMR (300 MHz) δ 0.57 (d, 3H), 1.07 (d, 3H), 2.50-2.74 (m, 1H), 2.98 (s, 3H), 3.71 (d, 1H), 5.05 (d, 1H), 5.78 (d, 1H), 7.12-7.40 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[N:21]([C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1)=[C:22]=[S:23]>>[CH2:31]([O:30][P:29]([CH2:28][C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22]([NH:18][C:16]2[CH:17]=[C:12]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=4)[CH:13]=[CH:14][C:15]=2[O:19][CH3:20])=[S:23])=[CH:38][CH:37]=1)(=[O:36])[O:33][CH2:34][CH3:35])[CH3:32]
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: CCOP(=O)(Cc1ccc(N=C=S)cc1)OCC
Product: CCOP(=O)(Cc1ccc(NC(=S)Nc2cc(-c3cc4cc(F)c(F)cc4[nH]3)ccc2OC)cc1)OCC

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.137 g, 0.5 mmol) was reacted with the product from Example 23, Step A (0.156 g, 0.54 mmol) according to the procedure for Example 23, Step B to give the product (0.172 g), mp 180-182° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([NH:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[CH:15][N:14]=1)=O.O>O1CCOCC1>[CH:1]([NH:4][C:11]([C:13]1[CH:18]=[N:17][C:16]([NH:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[CH:15][N:14]=1)=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccccc2)c1CNc1cnc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of isopropylamine (0.69 mL, 8 mmol) in dioxane (5 mL) was added dropwise trimethylaluminum solution (2M solution in hexane, 4 mL, 8 mmol). After stirring for 1 h at room temperature a suspension of 5-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyrazine-2-carboxylic acid methyl ester (650 mg, 2 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred at 90° C. for 90 min, cooled to room temperature and poured into water. Extraction with ethyl acetate and washing with saturated aqueous Seignette salt solution was followed by drying of the organic phase over sodium sulfate and evaporation which afforded an oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 20:80) afforded the title compound (600 mg, 85%) as a white solid MS: m/e=352.3 [M+H]+.
Reaction SMILES: [CH:1]([N:4]([S:20]([C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([Cl:30])=[CH:25][C:24]=1[CH3:31])(=[O:22])=[O:21])[CH2:5][CH2:6]OS(C1C=C(C)C(Cl)=CC=1C)(=O)=O)([CH3:3])[CH3:2].[F:32][C:33]1[CH:47]=[CH:46][C:36]2[NH:37][C:38]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[N:39][C:35]=2[CH:34]=1>>[Cl:30][C:26]1[C:27]([CH3:29])=[CH:28][C:23]([S:20]([N:4]([CH2:5][CH2:6][N:43]2[CH2:42][CH2:41][CH:40]([C:38]3[NH:37][C:36]4[CH:46]=[CH:47][C:33]([F:32])=[CH:34][C:35]=4[N:39]=3)[CH2:45][CH2:44]2)[CH:1]([CH3:2])[CH3:3])(=[O:21])=[O:22])=[C:24]([CH3:31])[CH:25]=1
Reactant: Cc1cc(S(=O)(=O)OCCN(C(C)C)S(=O)(=O)c2cc(C)c(Cl)cc2C)c(C)cc1Cl
Reactant: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Product: Cc1cc(S(=O)(=O)N(CCN2CCC(c3nc4cc(F)ccc4[nH]3)CC2)C(C)C)c(C)cc1Cl

Procedure:
The title compound was prepared using the procedure described in Example 1 using D8 and 4-(5-fluoro-1H-benzimidazol-2-yl)piperidine (D17). MH+ 507/509.