Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[CH:14]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][O-:28].[K+].O1CCOCCOCCOCCOCCOCC1>CN(C)C=O>[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:21])[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCC[O-]
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ncccc3F)no2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCCOc1cccnc1-c1noc(-c2cc(F)cc(C#N)c2)n1

Procedure:
Alternatively, treatment of 3-(3-fluoropyrid-2-yl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole with potassium 4-dimethylaminobutoxide in N,N-dimethylformamide with a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) and heating at 110° C. affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recystallization, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(4-dimethylaminobutoxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:41]=[CH:40][C:11]([CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:25]=4)=[CH:23][C:18]=3[CH:17]=[C:16]([C:37](O)=[O:38])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH3:36])=[CH:28][CH:29]=4)=[CH:23][C:18]=3[CH:17]=[C:16]([C:37]([NH:13][C:19]3[CH:20]=[CH:21][C:22]([CH2:4][N:2]([CH3:1])[CH:3]4[CH2:32][CH2:31][O:30][CH2:27][CH2:26]4)=[CH:23][CH:18]=3)=[O:38])[CH2:15][CH2:14]2)=[CH:40][CH:41]=1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccc(OC)cc2)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccc(OC)cc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(4-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (110 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (96 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (71 mg) and triethylamine (328 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(4-methoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 55) (86 mg) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:13][Br:14])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cc(Cl)nc1C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1c(C)cc(Cl)nc1CBr

Procedure:
To a solution of 710 mg, (3.6 mmol) 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester in CCl4 (16 ml) were added 688 mg (3.90 mmol) N-bromosuccinimide, 59 mg (0.36 mmol) AlBN and 210 μl (3.72 mmol) acetic acid. The reaction mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. The mixture was then filtered through celite, washed with CCl4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue a mixture of 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester, 4-(bromomethyl)-6-chloro-2-methyl-pyridine-3-carboxylic acid methylester and 2-(bromomethyl)-6-chloro-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This mixture was dissolved in dioxane (10 ml) and added at 0° C. to a solution prepared by dissolving 594 mg (25.8 mmol) sodium in MeOH (11 ml) at 0° C. This reaction mixture was stirred at RT for 3 h. Then the reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue again a mixture of 6-chloro-4-(methoxymethyl)-2-methyl-pyridine-3-carboxylic acid methylester and 6-chloro-2-(methoxymethyl)-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This material was dissolved in NMP (7.8 ml) and 860 μl (9.85 mmol) morpholine and 1.36 g (9.85 mmol) K2CO3 were added followed by heating at 100° C. for 5 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 90 mg (0.32 mmol, 9%) 2-(methoxymethyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)=[CH:8][CH:7]=1>CCO>[CH3:1][N:2]([CH3:4])[N:3]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([Br:5])=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1Cc1ccc(Br)cc1
Reactant: CN(C)N
Solvent: CCO
Product: CN(C)N=C1CCCCC1Cc1ccc(Br)cc1

Procedure:
Anhydrous N,N-dimethylhydrazine (17 ml) (3,7 eq.) was quickly poured in a solution of 2-[(4-bromophenyl)methyl]-cyclohexanone (16 g) (0.06 mol) in EtOH (200 ml). The reaction mixture was refluxed for 10 h, then concentrated to dryness. The residue was partitioned between tBuOMe and water, the organic phase washed twice with water, dried over magnesium sulfate and concentrated to yield 2-[(4-bromophenyl)methyl]-cyclohexanone dimethylhydrazone (16 g) as a yellow oil. 1H NMR (CDCl3): 7.35 (2H, d), 7.05 (2H, d), 3.05 (1H, dd), 2.4 (6H,s), 2.7-2.2 (4H, m), 1.8-1.3 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[C:23]1([CH2:29][CH2:30][CH2:31]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: BrCCCc1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCCc3ccccc3)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with 3-phenylpropyl bromide and sodium carbonate in dimethylformamide there is obtained 3-[4-chloro-2-fluoro-5-(3-phenylpropoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 1H-NMR (CDCl3, 400 MHZ): 7.15°-7.34 ppm (m,6H), 6.71 ppm (d,1H), 6.36 ppm (s,1H), 3.96 ppm (t,2H), 3.55 ppm (d,3H), 2.83 ppm (t,2H), 2.10°-2.20 ppm (m,2H):
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(OCCO)C>[NH:10]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: Cc1ccnc(F)c1
Reactant: NN
Solvent: O
Solvent: CCOCCO
Product: Cc1ccnc(NN)c1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
3.33 g (30.0 mmol) 2-fluoro-4-methylpyridine are initially introduced into 40 ml 2-ethoxyethanol, 14.6 ml (15.0 g, 300 mmol) hydrazine hydrate are added to the solution and the mixture is stirred at the boiling point (150° C. bath temperature) for 16 h. Thereafter, the reaction solution is concentrated on a rotary evaporator, the residue is added to 100 ml water and the mixture is extracted with ethyl acetate (three times with 100 ml each time). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is dried in vacuo.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[C:12](Br)[CH:11]=[C:10]([F:15])[C:9]=1[F:16])(=[O:3])[CH3:2].[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([C:32]2[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=2)[CH:11]=[C:10]([F:15])[C:9]=1[F:16])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cc(F)c1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2ccncc2)cc(F)c1F
Yield: 81 %

Procedure:
By carrying out the operation analogously to example 3, starting from 5-bromo-2,3-difluorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 4-pyridineboronic acid, the expected product is obtained in the form of a white powder with a yield of 81%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH3:16])[CH:8]=[O:9])[CH2:2][CH3:3].CO.[BH4-].[Na+]>O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH3:16])[CH2:8][OH:9])[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1OCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOc1ccc(CO)cc1OCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a mixture of 3,4-dipropoxybenzaldehyde (6.65 g) and methanol (90 ml) was added sodium borohydride (1.13 g) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3,4-dipropoxybenzyl alcohol (6.22 g) as a yellow oily substance.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:8])=[O:7].ClC([O:19][CH2:20][CH2:21]Cl)=O.Cl>COCCOC.O>[OH:19][CH2:20][CH2:21][NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=C(Cl)OCCCl
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccccc1NCCO
Temperature: 80 °C

Procedure:
60.1 g of calcium carbonate are added to a solution of 138.1 g of 2-nitroaniline in 360 g of monoethylene glycol dimethylether and 60 g of water. 150.0 g of 2-chloroethyl chloroformate are then metered in at 80° C. and the reaction is brought to completion by subsequent stirring at 80° C. 100 g of water and 8.7 g of 35% strength hydrochloric acid are then added, up to a pH of 1, and the lower aqueous phase is separated off. The upper organic phase is diluted with 90 g of monoethylene glycol dimethylether, and 370.6 g of a 50% strength potassium hydroxide solution are added at 15° C. The reaction mixture is then heated to 85° C. and subsequently stirred at 85° C. for 4 hours. Thereafter, 250 g of water are added and the lower salt-containing aqueous phase is separated off. First 500 g of water and then 9 g of 10% strength sulphuric acid are added to the yellow-red organic phase, up to a pH of 8.5. After the monoethylene glycol dimethyl ether has been distilled off and the residue has been cooled to 10° C., the product is obtained in the form of yellow-red crystals.
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C([NH:27][OH:28])=O)(=O)=O)CC3)=NC=2)=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[N:42][C:43]([N:46]3[CH2:51][CH2:50][N:49]([S:52]([CH2:55][C@H:56]([CH:60]([CH3:62])[CH3:61])[C:57](O)=[O:58])(=[O:54])=[O:53])[CH2:48][CH2:47]3)=[N:44][CH:45]=2)[CH:36]=[CH:37][C:38]=1[Cl:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[N:42][C:43]([N:46]3[CH2:47][CH2:48][N:49]([S:52]([CH2:55][C@H:56]([CH:60]([CH3:61])[CH3:62])[C:57]([NH:27][OH:28])=[O:58])(=[O:53])=[O:54])[CH2:50][CH2:51]3)=[N:44][CH:45]=2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)NO
Yield: 29 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 2-(R)-{4-[5-(3,4-dichlorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid (0.270 g), to yield the title compound as a white solid (0.080 g, 29%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11][NH:12][C:13]1[CH:18]=[C:17](Cl)[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C>[CH3:11][NH:12][C:13]1[CH:18]=[C:17]([CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])[O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(Oc2ccc(N)cc2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a mixture of NaH (60% oily, 440 mg, 11.0 mmol) in DMF (30 mL) was added a solution of 4-aminophenol (1.20 g, 11.0 mmol) in DMF (15 mL) followed by N-methyl-5-chloro-2-nitroaniline (Intermediate 8D-2.02 g, 10.0 mmol) in DMF (20 mL). The mixture was stirred at 90° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (2.44 g, 94%): MS m/e 260 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:34]>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:50][CH2:49][CH:48]([NH:47][C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:53][CH2:52]2)([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccncc3)C2)cc(OC)c1OC
Product: CCOCCn1c(NC2CCN(CCC3(c4ccncc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [CH2:1]1[CH2:10][C:8](=O)[C:4]2[CH:5]=[CH:6][S:7][C:3]=2[CH2:2]1.C[Si]([C:15]#[N:16])(C)C>C(#N)C.[I-].[Zn+2].[I-]>[C:15]([C:8]1[C:4]2[CH:5]=[CH:6][S:7][C:3]=2[CH2:2][CH2:1][CH:10]=1)#[N:16]
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCCc2sccc21
Agent: [I-]
Agent: [Zn+2]
Solvent: CC#N
Product: N#CC1=CCCc2sccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of zinc iodide (6.2 g) in acetonitrile (200 ml) were added 4-keto-4,5,6,7-tetrahydrothianaphthene (20 g) and trimethylsilylcyanide (18 ml) successively. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated. The residue was dissolved in pyridine (65 ml), followed by adding phosphryl chloride (15 ml) dropwise at room temperature. The mixture was refluxed for 30 minutes. The reaction mixture was cooled with ice and thereto was added dropwise isopropanol. The reaction mixture was poured onto ice water and extracted with ethyl acetate. The extract was washed by hydrochloric acid, water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated to give the title compound (17 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:34][CH:18]([C:19]1[S:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)[CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:3]([O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7])=[C:2]([Cl:1])[C:14]=1[Cl:15])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(Oc1ccc(CCC(OCc2ccccc2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(4-(3-(Benzyloxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2,3-di-chlorophenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 2.2 equivalents of sodium hydride and 2.2 equivalents of benzyl bromide according to general procedure H.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][CH:12]1[CH:19]2[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2)=[O:10]>>[CH:19]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][CH:13]([CH2:14]3)[CH:12]1[O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])[CH2:18]2
Reactant: COP(OC)OC
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Product: COP(=O)(OC)C(=O)OC1C2CC3CC(C2)CC1C3

Procedure:
From 1.5 g (12 mmole) of trimethylphosphite and 2.0 g (9.3 mmole) of 2-adamantyl chloroformate. (100°-110° C., 2 hrs). Yield 1.0 g (37%). Bp0.3 160° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[N+]=[N-])=[CH:3][CH:2]=1.[CH2:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([CH:12]1[CH2:11][N:7]1[C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Reactant: C=CCCCCCCCC
Product: CCCCCCCCC1CN1c1ccc(C)cc1

Procedure:
0.1% catalyst loading: p-Tolyl azide (0.240 g, 1.81 mmol), 1-decene (7.410 g, 52.8 mmol), and [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (0.0025 g, 0.0018 mmol) were used in the General Catalytic Reaction described above yielding 0.312 g, 70.4%. 1% catalyst loading: p-Tolyl azide (0.103 g, 0.773 mmol), 1-decene (2.223 g, 15.8 mmol), and [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (0.0107 g, 0.0077 mmol) were used in the General Catalytic Reaction described above yielding 0.156 g, 82.1%. 1H NMR (CDCl3, 499.74 MHz): δ 7.03 (d, J=7.5 Hz, 2H), 6.89 (d, J=7.0 Hz, 2H), 2.28 (s, 3H), 2.03 (m, 3H), 1.59 (m, 4H), 1.40 (m, 2H), 1.31 (m, 8H), 0.91 (t, J=6.0 Hz, 3H). 13C NMR (CDCl3, 125.66 MHz): δ 152.77, 131.45, 129.51, 120.65, 40.33, 34.17, 33.41, 32.02, 29.74, 29.69, 29.42, 27.85, 22.80, 20.78, 14.24. GC/MS (m/z): 245.2. DART HR MS (m/z): [M+H]+246.2211 (found). C17H28N, 246.2222 (calcd).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:23]=1[CH3:39].Cl.O1CCOCC1.CN1C(=O)CCC1>>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:20][C:10]3[C:11]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[N:12][CH:13]=[C:8]([N:6]4[CH2:5][CH2:4][O:3][C@@H:2]([CH3:1])[CH2:7]4)[CH:9]=3)=[C:23]([CH3:39])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: C[C@H]1CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCO[C@@H](C)C2)cnc1N1CCOCC1
Temperature: 165 °C

Procedure:
Prepared according to Procedure K, method 2 using (S)-5-(2-methylmorpholino)-2-morpholinopyridin-3-amine (85 mg, 0.305 mmol; described herein), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (83 mg, 0.305 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (80 μL, 0.31 mmol), and NMP (350 μL, 3.7 mmol), and heating in a microwave at 165° C. for 3 h. Purification afforded 7-fluoro-3-methyl-N-(5-((2S)-2-methyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine as a yellow solid (absolute configuration of stereocenter not determined) 1H NMR (500 MHz, chloroform-d) δ ppm 8.70-8.76 (1H, m), 7.85-7.94 (2H, m), 7.75-7.85 (2H, m), 7.59 (1H, d, J=2.7 Hz), 7.39 (1H, ddd, J=7.1, 5.0, 1.6 Hz), 7.25-7.33 (1H, m), 6.77 (1H, s), 6.23 (1H, d, J=2.7 Hz), 3.84-3.99 (5H, m), 3.56-3.71 (2H, m), 3.23 (4H, br. s.), 3.15 (1H, dt, J=11.7, 2.2 Hz), 3.02-3.11 (1H, m), 2.63-2.74 (1H, m), 2.31-2.43 (4H, m), 1.16 (3H, d, J=6.4 Hz). Mass Spectrum (ESI) m/e=515.2 (M+1).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[C:12]2[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[O:19])=[CH:16][C:11]=2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:9]=1.C(O)C(N)(CO)CO.C([SiH](CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[C:23]1([C@H:21]([NH:20][C:18](=[O:19])[NH:17][C:15]2[N:14]=[CH:13][C:12]3[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:9][NH:10][C:11]=3[CH:16]=2)[CH3:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CCS(=O)(=O)Cl
Agent: CC[SiH](CC)CC
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an 8 mL vial charged with ethanesulfonyl chloride (10.53 μL, 0.111 mmol) was added (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 47, Step 1; 20 mg, 0.037 mmol) in DCM (1 mL) and pyridine (0.1 mL). The reaction mixture was stirred at room temperature for 2 h. Excess sulfonyl chloride was quenched by shaking with MP-Trisamine (91 mg, 0.186 mmol) for 3 h. The resin was filtered, the volatiles removed in vacuo, and the resulting residue dissolved in TFA (1 mL) and stirred at room temperature for 1 h. Triethylsilane (5.93 μL, 0.037 mmol) was added and the reaction mixture was stirred for an additional 5 min. The reaction mixture was concentrated in vacuo, the resulting crude residue dissolved in DMSO (1.5 mL), filtered, and purified by mass-triggered reverse phase HPLC to afford (R)—N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)ethanesulfonamide. MS ESI calc'd. For C17H20N6O3S [M+1]+ 389. found 389. 1H NMR (500 MHz, DMSO-d6) δ 12.74 (1H, s), 10.63 (1H, s), 9.20 (1H, s), 8.76 (1H, s), 7.70 (1H, s), 7.50 (1H, s), 7.31 (4H, d, J=4.4 Hz), 7.20-7.21 (1H, m), 4.84 (1H, t, J=7.2 Hz), 3.30 (2H, q, J=7.4 Hz), 1.38 (3H, d, J=7.0 Hz), 1.23 (3H, t, J=7.4 Hz).