Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](O)[CH2:36][CH3:37]>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH2:35][CH2:36][CH3:37])=[O:30])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: CCCO
Product: CCCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and n-propanol Rf value: 0.7 (silica gel, methylene chloride/methanol=5:1) C31H33N3O3
Reaction SMILES: [CH2:1]([N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:7][NH2:8])[CH2:2][CH2:3][CH3:4].[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[C:36](Cl)[N:35]=4)=[CH:30][CH:29]=3)[CH:22]=2)[NH:17][CH:16]=1)#[N:14]>>[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:1][CH2:2][CH2:3][CH3:4])[N:35]=4)=[CH:30][CH:29]=3)[CH:22]=2)[NH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CCCCN(CCN)CCCC
Product: CCCCN(CCCC)CCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 2-(dibutylamino)-ethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.Cl.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][CH2:32][NH2:33]>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:33][CH2:32][CH2:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:13])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: NCCC1CCCCO1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Agent: Cl
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCCC4CCCCO4)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.19 (m, 1H) 1.31-1.43 (m, 3H) 1.52 (d, J=12.9 Hz, 1H) 1.58 (q, J=7.1 Hz, 2H) 1.65-1.75 (m, 1H) 3.18-3.25 (m, 2H) 3.29-3.38 (m, 2H) 3.81 (m, J=2.0 Hz, 4H) 7.34 (br. s., 1H) 7.42 (d, J=5.1 Hz, 1H) 7.98 (d, J=5.6 Hz, 1H) 8.26-8.34 (m, 1H) 8.37 (br. s., 1H) 8.52 (br. s., 1H) 8.59 (t, J=5.4 Hz, 1H) 8.82 (s, 1H) 13.45 (br. s., 1H). MS m/z 424 [M+H]+.
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[CH:7][CH:6]=1.[ClH:20].[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(O)CC>[ClH:20].[OH:1][CH:2]([CH2:19][NH:24][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: CCCOC(=O)CCc1ccc(OCC2CO2)cc1
Agent: Cl
Solvent: CCCO
Product: CCCOC(=O)CCc1ccc(OCC(O)CNC(C)C)cc1
Yield: 56 %

Procedure:
A solution of 1.5 g (0.006 mole) of n-propyl 3-[4-(2,3-epoxypropoxy)phenyl]propionate in 10 mL of isopropylamine and 20 mL of n-propanol was heated to reflux for 4 hours. The reaction medium was then evaporated under reduced pressure to provide the crude free amine as an oil. The oil was dissolved in n-propanol and treated with ethereal HCl and provided 1.2 g (56%) of white crystals: mp 88°-92° C. The NMR spectrum of the product was consistent with the assigned structure and the elemental analysis data was consistent with the molecular formula C18H30NO4Cl.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[N:56]1[CH:61]=[C:60]([NH2:62])[CH:59]=[N:58][CH:57]=1>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:62][C:60]2[CH:61]=[N:56][CH:57]=[N:58][CH:59]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cncnc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cncnc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.33 h

Procedure:
A solution of chiral-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (39.4 mg, 84.3 mmol) in dichloromethane (3 ml) was reacted with DIPEA (44.5 mg, 0.343 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (49.7 mg, 0.210 mmol) and stirred for 20 min under argon. PYRIMIDIN-5-AMINE (8.3 mg, 0.0829 mmol, Ark Pharm) was added and stirred 2.5 hrs. The reaction mixture was diluted with dichloromethane, washed with water then with sat. NaHCO3, water, and sat. NaCl. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentyl-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide (35.7 mg., 77%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 544.14. found: 544.0.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH2:15][CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:8]2[N:9]=[C:20]1[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[S:17][CH2:14][CH2:15][CH3:16]
Reactant: CCCSc1ccccc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Yield: 13 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (0.96 g), 2-propylsulfanylbenzoic acid (1.08 g), WSC (0.78 g), and pyridine (10 ml) was stirred with heating at 120° C. for 1.5 hours. To the reaction mixture, HOBt (0.74 g) was added, and stirred with heating for 1.5 hours. WSC (0.38 g) was added thereto, and stirred with heating for further 2 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.23 g of 3-methyl-2-(2-propylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 7).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH3:2].[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:21][C:5]([S:17]([CH3:20])(=[O:19])=[O:18])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)C(C)(CCc1ccc(B(O)O)cc1)S(C)(=O)=O
Reactant: Oc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(CCc1ccc(Oc2ccccc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of {4-[4-ethoxy-3-methyl-3-(methylsulfonyl)-4-oxobutyl]phenyl}boronic acid (599 mg, 1.83 mmol) in methylene chloride (3 mL) was added phenol (86 mg, 0.91 mmol), pyridine (148 uL, 1.83 mmol) and copper (II) acetate (157 mg, 0.866 mmol). The mixture was stirred at ambient temperature under open atmosphere for 2 days. Silica gel was added and the mixture was concentrated to dryness and purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanoate as an oil. 312 mg. LCMS: (M+1) 377.2
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:22][CH:23]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC(=O)c1cc(-c2ccnc(Cl)c2)cc(C)n1
Product: Cc1cc(-c2ccnc(Cl)c2)cc(C(=O)Nc2ccc(Cl)cn2)n1

Procedure:
The title compound, was prepared from 2′-Chloro-6-methyl-[4,4′]bipyridinyl-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 2-amino-5chloropyridine instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=359.0, 361.1 (M+H)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:19]([CH3:29])[CH:18]=3)=[C:14]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]4[CH2:42]OC(=O)N4)=[CH:32][CH:31]=3)[S:13][C:12]=2[CH:44]=1.[CH:45]1(CCO)[CH2:49]C[CH2:47][CH2:46]1>C1COCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:19]([CH3:29])[CH:18]=3)=[C:14]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:49]4)=[CH:34][CH:35]=3)[S:13][C:12]=2[CH:44]=1
Reactant: Cc1cc(Cc2c(-c3ccc(OCC4COC(=O)N4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Reactant: OCCC1CCCC1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Cc2c(-c3ccc(OCCC4CCCC4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Yield: 58 %

Procedure:
By essentially following the conditions described in Example 2, Part A, the title compound was prepared from 6-benzyloxy-3-[3-methyl-4-[(1-pyrrolidinyl)methyl]benzyl]-2-(4-hydroxyphenyl)benzo[b]thiophene (Example 8; Part C) and 2-cyclopentylethanol in 58% yield following radial chromatography (SiO2; 5% THF and 2.5% TEA in hexanes).
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([OH:23])[CH3:22])[CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:25][NH:26][C:27](=O)OC(C)(C)C)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.Cl>C(O)C>[CH3:27][NH:26][CH2:25][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]([S:12]([C:15]2[CH:16]=[C:17]([C:21]([OH:23])([CH3:24])[CH3:22])[CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(C)(C)O)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(C)(C)O)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a solution of tert-butyl [1-(5-phenyl-1-{[3-(1-methyl-1-hydroxyethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]carbamate (334 mg) in ethanol (4 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (4.0 mL) and the mixture was stirred at room temperature for 3 hr. After the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give the title compound as a white solid (yield 203 mg, 76%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.Cl.[CH3:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].[OH-].[Na+]>C1COCC1.CO>[CH3:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:29]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Reactant: COCc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 3-methoxymethyl-aniline-hydrochloride in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:22])[C:17]#[C:18][CH2:19][CH2:20][CH3:21].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:22][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH3:21])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: CCCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 89.5 %

Procedure:
In 9 ml of N,N-dimethylformamide were dissolved 217 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 141 mg of 2-hexyn-1-ol, to which 58 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 7 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 247 mg of 4-(2,3-difluorophenyl)-6-(2-hexynyloxy)pyrimidine (the present compound (118)).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[C:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH:23]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]([F:10])([F:11])[F:12])[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CNc1ccccc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(c1ccccc1C(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.1 %

Procedure:
A mixture of 2-(methylamino)benzotrifluride (0.870 g, 5.000 mmol), 1-Boc-4-piperidone (1.500 g, 7.500 mmol)), acetic acid (1.5 mL, 17.5 mmol) and sodium triacetoxy borohydride (2.420 g, 11.000 mmol) in 1,2-dichloroethane (30 mL) was stirred at ambient temperature for 2 days. The reaction was quenched with water. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography to afford 4-[methyl-(2-trifluoromethylphenyl)amino]piperidine-1-carboxylic acid tert-butyl ester (0.360 g, 20%). 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, J=1.2, 7.8 Hz, 1H), 7.48-7.14 (m, 3H), 4.08-4.00 (m, 2H), 2.95-2.87 (m, 2H), 2.68-2.58 (m, 5H), 1.72-1:67 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][C:22]([N:31]1[CH:35]=[C:34]([NH2:36])[N:33]=[CH:32]1)([CH3:30])[CH2:23][NH:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[CH3:30][C:22]([N:31]1[CH:35]=[C:34]([NH:36][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:33]=[CH:32]1)([CH3:21])[CH2:23][NH:24][CH2:25][C:26]([F:27])([F:28])[F:29]
Reactant: CC(C)(CNCC(F)(F)F)n1cnc(N)c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CNCC(F)(F)F)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-[1,1-Dimethyl-2-(2,2,2-trifluoro-ethylamino)-ethyl]-1H-imidazol-4-ylamine to afford the title compound: C13 MR (100 MHz, CDCl3) 14.1, 19.5, 26.0, 28.2, 28.8, 29.8, 36.6, 38.8, 50.5, 50.8, 51.1, 51.4, 52.7, 58.6, 58.7, 60.8, 100.8, 101.0, 101.3, 104.3, 110.7, 110.8, 110.9, 118.0, 118.1, 124.2, 127.0, 131.2, 138.0, 139.8, 159.9, 172.6; MS m/z 502.2 (M+1).
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]([CH:19]([CH3:21])[CH3:20])=[C:11]2[S:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:22])C1C=CC=CC=1.B(Br)(Br)Br.CO>C1(C)C=CC=CC=1>[CH:19]([C:16]1[C:17](=[O:18])[NH:8][C:9](=[O:22])[N:10]2[CH2:15][CH2:14][CH2:13][S:12][C:11]=12)([CH3:21])[CH3:20]
Reactant: CC(C)c1c2n(c(=O)n(Cc3ccccc3)c1=O)CCCS2
Agent: BrB(Br)Br
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)c1c2n(c(=O)[nH]c1=O)CCCS2
Reaction time: 0.5 h

Procedure:
To a solution of 4.75 g (15 mmol) of 7-benzyl-9-isopropyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione in 120 ml of toluene, 7.52 g (30 mmol) of boron tribromide was added under ice cooling conditions, followed by refluxing for 16 hours. After the reaction mixture was cooled, 50 ml of methanol was added, followed by stirring for 30 minutes. After this mixture was concentrated to dryness, methanol-diethyl ether was added to the residue. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to yield 1.95 g (57.4%, light white powder) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[S:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([OH:19])=[O:18])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([CH3:20])[S:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][C@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:39])[F:40])=[C:33]([O:41][CH2:42][CH:43]2[CH2:44][CH2:45]2)[CH:32]=1)[CH2:28][C:27]1[C:26]([Cl:46])=[CH:25][N+:24]([O-:47])=[CH:23][C:22]=1[Cl:21])=[O:18])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccsc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)S(=O)(=O)c1ccsc1C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 68.1 %

Procedure:
To a solution of 3-(N-(tert-butoxycarbonyl)-N-methylsulfamoyl)-thiophene-2-carboxylic acid (Int. 34) (150 mg, 0.467 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (196 mg, 0.467 mmol), EDC (268 mg, 1.400 mmol) and DMAP (28.5 mg, 0.233 mmol) were added and the mixture was reacted at RT overnight. The solvent was removed and the crude was purified by flash chromatography on silica gel (DCM/MeOH=95/5) affording (S)-4-(2-(3-(N-(tert-butoxycarbonyl)-N-methylsulfamoyl)thiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) phenyl)ethyl)-3,5-dichloropyridine 1-oxide (Int. 35) (230 mg, 0.318 mmol, MS/ESI+722.8 [MH]+).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: O=Cc1ccc(B(O)O)s1
Product: O=Cc1ccc(-c2ccc(Cn3ccnc3)cn2)s1

Procedure:
Synthesized using 5-formyl-2-thiophenylboronic acid (197 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 78 mg, 0.28 mmol, 46%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.18 (s, 2H), 6.92 (t, J=1.3 Hz, 1H), 7.13 (t, J=1.3 Hz, 1H), 7.47 (dd, J=8.2, 2.2 Hz, 1H), 7.56 (brs, 1H), 7.66 (d, J=4.1 Hz, 1H), 7.71 (dd, J=8.2, 0.6 Hz, 1H), 7.76 (d, J=4.1 Hz, 1H), 8.52 (dd, J=2.2, 0.6 Hz, 1H), 9.93 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 119.0, 119.8, 125.5, 130.5, 131.7, 135.8, 136.7, 137.3, 144.6, 148.7, 151.4, 152.8, 183.0; MS (ESI): m/z=270.22 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.[CH:19]1[C:32]2[CH:31]([C:33]([Cl:35])=[O:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.Cl>CC(C)=O>[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:33]([CH:31]2[C:32]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:34])[CH2:13][CH2:14]1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(CCCOC(=O)C2c3ccccc3Oc3ccccc32)CC1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A solution of 3.8 g of 3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-hydroxy-propane in 40 ml of acetone is added dropwise at 20° C. to a stirred solution of 4.9 g of xanthene-9-carbonyl chloride in 30 ml of acetone. The reaction mixture is refluxed for 30 minutes, allowed to cool to 60° C., and then ethanolic hydrochloric acid is added to the mixture until no more crystalline substance separates. The reaction mixture is cooled to 0° C., the separated crude substance is filtered off, and the crude substance is recrystallized from 20 ml of a 1:2 mixture of water and ethanol. 5.3 g (73%) of 3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-(xanthene-9-carbonyloxy)-propane hydrochloride are obtained; m.p.: 193°-195° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Br:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[N:3]=1
Reactant: Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1ccc(CNc2nc(N)nc(-c3ccc(Br)o3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-[(5-methyl-pyridin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile and N-bromosuccinimide in DMF. ES-MS m/e (%): 387 (M{81Br}+H+, 100), 385 (M{79Br}+H+, 85).