Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8](=[CH:11]Cl)[CH:9]=O.[NH2:13][C:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH:15]=1>C(Cl)Cl.CN(C)C=O.C([O-])(O)=O.[Na+]>[Cl:7][C:8]1[CH:9]=[N:13][C:14]2[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[C:15]=2[CH:11]=1
Reactant: NC1=CC(=O)CCC1
Reactant: O=CC(Cl)=CCl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCc2ncc(Cl)cc21
Temperature: 25 °C

Procedure:
Chloromalondialdehyde (19 grams, 0.178 mol) was suspended in methylene chloride (100 ml) with dry dimethylformamide (DMF) (2.5 ml). This was mechanically stirred under a nitrogen atmosphere while a solution of oxalyl chloride (23.7 grams/16.3 ml, 0.185 mol) in methylene chloride (50 ml) was added dropwise over 20 minutes. The reaction mixture at first started to warm from 22° to 28°, but as the evolution of gases increased the temperature fell to 18°. The reaction was stirred at room temperature and was followed by thin layer chromatography (ethyl acetate/hexanes, 1:1) until conversion to 2,3-dichloroacrolein was complete. A solution of 1-amino-cyclohexen-3-one (19.85 grams, 0.18 mol) in DMF (125 ml) was added dropwise and the reaction was heated to 70° C. overnight. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO3, and twice extracted with ethyl acetate (400 ml and 200 ml). The combined organic layers were washed with water (3×) and brine (1×). The organic solution was stirred with MgSO4 and decolorizing carbon (Darco (trademark)); then filtered through Super Cel (trademark)) and concentrated to a brown solid. Yield 21 grams (65%); mp 90°-91° C. NMR (CDCl3, 300 MHz) δ8.6 (d, 1), 8.24 (d, 1), 3.1 (t, 2), 2.7 (m, 2), 2.15 (m, 2).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:28]=1[CH:29]=[CH:30][C:31]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:32]
Reactant: O=C(O)C=Cc1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1c(F)cccc1F
Yield: 53 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (1.4 g), triethylamine (0,72 mL), 2,6-difluorocinnamic acid (1.0 g), WSC.HCl (1.0 g), and methylene chloride (50 mL), to give the captioned compound (1.1 g, 51%) as an oily product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C:11]([F:33])([F:32])[C@:12]([C@H:15]2[CH2:17][C@@H:16]2[C:18](=[O:31])[NH:19][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][C:26]([Cl:30])=[CH:25]3)([CH3:14])[N:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:30][C:26]1[CH:27]=[N:28][C:29]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[NH:19][C:18]([C@H:16]1[CH2:17][C@@H:15]1[C@:12]1([CH3:14])[C:11]([F:32])([F:33])[CH2:10][O:9][C:8]([NH2:7])=[N:13]1)=[O:31]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)([C@H]2C[C@@H]2C(=O)Nc2cccc3cc(Cl)cnc23)C(F)(F)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1([C@H]2C[C@@H]2C(=O)Nc2cccc3cc(Cl)cnc23)N=C(N)OCC1(F)F
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of {(R)-4-[(1S,2S)-rel-2-(3-chloro-quinolin-8-ylcarbamoyl)-cyclopropyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-carbamic acid tert-butyl ester (4.7 mg, 9.5 μmol) (intermediate J8.2) in dichloromethane (47 μl) was cooled to 0° C. Trifluoroacetic acid (11.0 mg, 7.4 μl, 95.0 μmol) was added and the solution was left to warm to room temperature. After 7 hours trifluoroacetic acid (33.1 mg, 22.3 μl, 285 μmol) was added again and the mixture stirred at room temperature for another hour. Thereafter, the solvent was removed at reduced pressure. The residue was dissolved in water, then the aqueous layer was basified with a solution of sodium carbonate (2M) and extracted 3 times with dichloromethane. The combined extracts were dried over sodium sulphate and evaporated. The (1S,2S)-rel-2-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid (3-chloro-quinolin-8-yl)-amide (3.7 mg, 99%) was obtained as a light brown solid. MS (ISP): m/z=395.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:24])[C@H:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](N(C1C=CC=CC=1C(F)(F)F)C(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:24])[C@H:15]([NH:23][C:25](=[O:27])[CH3:26])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@H](N)Cc1ccccc1
Reactant: CC(=O)N(C(C)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N[C@H](Cc1ccccc1)[C@H](O)[C@H]1CNCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Dissolve 2-(R)-(2-(R)-amino-1-(S)-hydroxy-3-phenyl-propyl)-piperazine-1-carboxylic acid tert-butyl ester (232 mg, 0.69 mmol) in 7 ml of dry CH2Cl2 and add N-acetyl-N-(2-trifluoromethyl-phenyl)-acetamide (Tetrahedron Letters, 38(21), 3751 (1997)) (162 mg, 0.66 mmol). Stir at room temperature overnight. Subject reaction mixture to silica gel chromatography, eluting ethyl acetate/triethylamine 98:2 to obtain 122 mg of the title compound (60% yield based on 79% conversion) and 50 mg of starting amine.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](OC)=O.N(CCO)CCO.C1CCCCCCCOC(=O)CCCCCCC1>>[OH:2][CH2:1][CH2:3][NH:4][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: NCCO
Reactant: COC(=O)CCCCCCCCCCCCCCCOC1CCCCO1
Agent: O=C1CCCCCCCCCCCCCCCO1
Solvent: OCCNCCO
Product: OCCNCCCCCCCCCCCCCCCCOC1CCCCO1

Procedure:
A reaction was conducted in the same manner as in Preparation Example 37 except that ethanolamine and methyl 16-(2-tetrahydropyranyloxy)hexadecanate were used in place of diethanolamine and cyclohexadecanolide, respectively, in Preparation Example 37, thereby obtaining the title compound (IId-4).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=O.CO[C:19]1C2C(=CC=CC=2)C(OC)=C[C:20]=1/[CH:31]=[C:32](\C)/[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CCOCC>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1/[CH:15]=[C:32](\[CH2:31][CH2:20][CH3:19])/[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: COc1cc(C=O)c(OC)c2ccccc12
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Solvent: CCOCC
Product: CCC/C(=C\c1cc(OC)c2ccccc2c1OC)C(=O)OCC

Procedure:
Compound 28b was prepared from 27 (0.495 g, 2.29 mmol) as described above for 28a to give 0.443 g (1.35 mmol, 59%) of the product as a white solid following flash chromatography (1:19 Et2O:hexanes) and recrystallization from Et2O/hexanes.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([CH3:6])[CH2:4][OH:5].F[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)=[N:11][CH:12]=[N:13]2>>[CH3:26][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[CH:17][C:8]=3[O:5][CH2:4][C@H:3]([NH:2][CH3:1])[CH3:6])[N:13]=[CH:12][N:11]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: CN[C@H](C)CO
Reactant: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Product: CN[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Yield: 80 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using (2R)-2-(methylamino)propan-1-ol (obtained as described in Becker et al., J. Chem. Soc. 1957, 858) and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 2-methyl-4-[(5-{[(2R)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol as a brown solid in 80% yield; NMR spectrum (DMSO-d6) 1.16 (d, 3H), 2.14 (s, 3H), 2.34 (s, 3H), 3.04 (m, 1H), 3.24 (bs, 1H), 4.08 (dd, 1H), 4.25 (dd, 1H), 6.76 (d, 1H), 7.06 (d, 1H), 7.26 (d, 1H), 7.47 (d, 1H), 7.53 (dd, 1H), 7.65 (t, 1H), 8.39 (s, 1H), 9.17 (s, 1H), 10.37 (s, 1H); Mass spectrum MH+ 339.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]([NH:9][C:10](=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])SC)#[N:8]>C(O)C>[C:7]([NH:9][C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])#[N:8]
Reactant: NCCCCO
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CCO
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCCCO
Yield: 38.6 %

Procedure:
4-Aminobutanol (2.7 g) and N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (4.05 g) were refluxed in ethanol (30 ml) for 4 hours. The reaction mixture was evaporated to yield an oil which was chromatographed on a silica gel column and eluted with chloroform and chloroform/methanol (20:1) to give the title compound as a colourless oil (1.8 g).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:28][C@H:29]1[NH:34][C@@H:33]([CH3:35])[CH2:32][N:31]([C:36]2[S:37][C:38]3[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=3[N:40]=2)[CH2:30]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:34]2[C@H:33]([CH3:35])[CH2:32][N:31]([C:36]3[S:37][C:38]4[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=3)[CH2:30][C@@H:29]2[CH3:28])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: C[C@@H]1CN(c2nc3ccccc3s2)C[C@H](C)N1
Product: C[C@@H]1CN(c2nc3ccccc3s2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-benzothiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[N:15]=[C:14](F)[CH:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH3:20]>C(O)C>[NH2:20][C:14]1[CH:13]=[CH:12][C:8]2[N:9]=[CH:10][N:11]=[C:6]([NH:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=3)[C:7]=2[N:15]=1
Reactant: N
Reactant: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Solvent: CCO
Product: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Yield: 72 %

Procedure:
Reaction of 4-(3-bromoanilino)-6-fluoropyrido [3,2-d) pyrimidine (0.12 g, 0.38 mmol) (described in a previous experimental) with a saturated solution of ammonia in ethanol in a pressure vessel at 100° C. for 18 h gives 6-amino-4-(3-bromoanilino)pyrido[3,2-d]pyrimidine, (87 mg, 72%). 1H NMR (CDCl3) δ 8.76 (1H, brs), 8.64 (1H, s), 8.23 (1H, brs), 7.93 (1H, d, J=9.0 Hz), 7.81 (1H, dt, Jd =7.7 Hz, Jt =1.8 Hz), 7.28-7.22 (2H, m), 7.00 (1H, d, J=9.0 Hz), 4.90 (2H, brs).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)(C)C>[C:5]([NH:18][C@H:19]([C:25]([O:27][CH:9]([CH3:10])[CH3:8])=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH:6]([CH3:7])[CH3:5])=[O:23])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O
Solvent: CC(C)O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)OC(C)C)C(=O)OC(C)C
Yield: 195.3 %

Procedure:
7.24 g of thionyl chloride was gradually and dropwise added to 73.32 g of isopropyl alcohol, then 10.0 g of N-lauroylglutamic acid was added, and reacted at room temperature for 1 day. The reaction liquid was concentrated under reduced pressure to obtain 12.26 g of a white crystal of diisopropyl N-lauroylglutamate.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a mixture of (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (150 mg, 0.31 mmol) in 10 ml DCM was added TFA (10 ml). The reaction mixture was stirred at RT for 2 h. Solvent was removed and sat. NaHCO3 (10 mL) was added. The resulting mixture was extracted with DCM. The organic layer was dried and concentrated to afford (R)-5-(4-phenoxyphenyl)-7-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 83% in yield), which was subjected to the next step without any further purification.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8][CH2:9][CH3:10])([OH:7])[CH2:5][CH2:4][NH:3]1.F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:7][C@@:6]1([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:4][N:3]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]([F:21])([F:23])[F:22])[C@H:2]1[CH3:1]
Reactant: CCC[C@]1(O)CCN[C@H]1C
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCC[C@]1(O)CCN(c2ccc(C#N)cc2C(F)(F)F)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-methyl-3-propylpyrrolidin-3-ol 0.5 oxalate (250 mg), 4-fluoro-3-(trifluoromethyl)benzonitrile (499 mg) and lithium carbonate (195 mg), the title compound was obtained as colorless oil (yield: 383 mg, yield: 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:19])=[O:11].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:19])(=[O:28])=[O:11]
Reactant: Cc1ccc[n+]([O-])c1S(=O)Cc1c(Cl)cccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc[n+]([O-])c1S(=O)(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.1 %

Procedure:
To 8.0 g (0.03 mole) of 2[(2,6-dichlorophenyl)methylsulfinyl]-3-methyl-pyridine-N-oxide (See Example 29 above) in 150 ml of chloroform were added 10 g (0.05 mole) of metachloroperbenzoic acid. The mixture was stirred at room temperature for 24 hours, and then was washed with 20% K2CO3, and then with aqueous NaHSO3 until no peroxides were present. The chloroform layer was dried with Na2SO4 and then the mixture was filtered and the solvent removed on a steam bath. The residue was taken up in ether and filtered to give 2 g of solid, having a melting point of 215-218° C. The elemental analysis for C,H,N; the infrared, and the NMR all supported the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(O)(=O)C.S(Cl)([Cl:22])(=O)=O>O>[Cl:22][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([C:11]([F:12])([F:13])[F:14])[C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Cl)c(O)c(C(F)(F)F)c1
Temperature: 40 °C

Procedure:
A mixture of 11.7 g (57 mmol) 4-hydroxy-3-trifluoromethyl-benzoic acid and 40 ml acetic acid was combined dropwise with 5.15 ml (63 mmol) sulphurylchloride, with stirring at a bath temperature of 40° C., and stirred for 2 hours at 40° C. Then another 2.5 ml (31 mmol) sulphurylchloride were added and the mixture was stirred for 4 hours at 60° C. The reaction mixture was poured onto 300 ml of water and extracted with 200 ml EtOAc. The organic phase washed twice with 500 ml of water, dried and evaporated down under reduced pressure. The residue was stirred with 80 ml petroleum ether, the precipitate was suction filtered, washed with 20 ml petroleum ether and dried.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Cc1cc2c(cc1-c1ccc(N)nc1)CCO2
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1-c1ccc(NC(=O)c3c(F)cccc3F)nc1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a solution of 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (161) (13 mg, 0.06 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (22 μl, 3 eq) followed by addition of DIEA (94 μl). The resulting solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/brine. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (162) (13.9 mg, yield: 63.9%, purity>95%) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.I[CH3:19].[OH-].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:17][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(Cc1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(Cc1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 193 %

Procedure:
A mixture of 1,2-di(p-bromophenyl)-hydroxyethane (40 g, 0.056 mol), iodomethane (150 g) and powdered potassium hydroxide (30 g) was stirred at room temperature of 3 days. The reaction mixture was transferred into a 500 mL separatory funnel and water (200 mL) was added. The resulting mixture was extracted with chloroform (150 mL×2). The combined organic phases were dried through sodium sulfate and concentrated to provide an oil which was distilled under vacuum to give the title compound (40 g, 85%). This oil solidified upon standing and was recrystallized from methanol to provide fine crystals (mp: 53-54° C.), which showed the expected proton NMR spectrum.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:61][CH3:62])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@@H:4]([CH2:3][C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[CH:41]([CH3:40])[CH2:61][CH3:62])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A solution containing the product from Example 23S (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 36E (0.020 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate, to give the title compound (0.025 g, 64% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.57 (d, J=6.62 Hz, 3 H), 0.71 (t, J=7.17 Hz, 3 H), 0.82 (m, 12 H), 1.26 (m, 1 H), 1.54 (m, 2 H), 1.73 (m, 1 H), 2.33 (m, 4 H), 2.76 (m, 3 H), 3.51 (s, 3 H), 3.59 (m, 1 H), 3.82 (d, J=18.38 Hz, 1 H), 4.01 (m, 2 H), 4.18 (s, 1 H), 4.67 (m, 2 H), 4.87 (d, J=5.15 Hz, 1 H), 6.82 (d, J=9.56 Hz, 1 H), 7.02 (m, 6 H), 7.12 (d, J=7.72 Hz, 1 H), 7.30 (d, J=8.46 Hz, 3 H), 7.64 (m, 2 H), 7.87 (m, 4 H), 8.09 (d, J=9.19 Hz, 1 H), 8.63 (d, J=4.04 Hz, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[CH3:34]>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:33][CH3:34])[CH2:22]3)=[O:20])[CH2:17][CH2:18]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCBr
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CCCNC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-4-(piperidin-3-ylcarbonyl)piperazine-1-carboxamide hydrochloride (200 mg) in dimethylformamide (10 mL) was added potassium carbonate (138 mg) and ethyl bromide (0.035 mL). The reaction mixture was stirred overnight. The reaction mixture was partitioned between dichloromethane and water and the organic layer was washed with brine. The organic extract was dried over sodium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (94 mg, 48%).