Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:14]2[CH2:15][CH2:16][C@@H:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[N:27]=[CH:28][C:29]2[CH:34]=[C:33]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[N:32]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[C:30]=2[N:31]=1>>[CH:40]1([N:32]2[C:30]3[N:31]=[C:26]([NH:24][C:21]4[N:20]=[CH:19][C:18]([N:11]5[C:12](=[O:17])[CH2:13][C@H:14]6[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([CH2:16][CH2:15]6)[CH2:10]5)=[CH:23][CH:22]=4)[N:27]=[CH:28][C:29]=3[CH:34]=[C:33]2[C:35](=[O:36])[N:37]([CH3:38])[CH3:39])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)N(c1ccc(N)nc1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 88.3 %

Procedure:
Following general N—C coupling procedure 1, (1R,6S)-3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester (0.548 gm, 1.65 mmol) was combined with 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (483 mg, 1.65 mmol) which gave (1R,6S)-tert-butyl 3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (858 mg) in 88% yield.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12]1([O:17][CH2:16][CH2:15][O:14]1)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOCCBr)C(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(=NOCCBr)C1(C)OCCO1

Procedure:
A mixture of ethyl 2-(2-bromoethoxyimino)-3-oxobutyrate (syn isomer)(218.9 g), ethylene glycol (156 ml), and benzene (400 ml) was refluxed in the presence of p-toluenesulfonic acid monohydrate under an azeotropic dehydration condition for 3 days. The mixture was poured into a mixture of ethyl acetate and saturated aqueous solution of sodium bicarbonate under ice-cooling. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo to give a residue. The resiue was distilled at 2 mmHg at 144° to 149° C. to give ethyl 2-(2-bromoethoxyimino)3,3-ethylenedioxybutyrate (syn isomer)(333.3 g) as an oil.
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:9][C:10]1[CH:11]=[C:12]([SH:16])[CH:13]=[CH:14][CH:15]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:9][C:10]1[CH:11]=[C:12]([S:16][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(S)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Sc1cccc(N)c1
Reaction time: 8 h

Procedure:
At room temperature, 1.36 ml (10.5 mmol) of methyl 2-bromo-2-methylpropanoate were added slowly to a solution of 1.2 g (9.6 mmol) of 3-aminobenzenethiol and 1.046 g (12.5 mmol) of sodium bicarbonate in 6 ml of DMF, and the mixture was stirred overnight. After the reaction had ended, the reaction mixture was added to water. The reaction mixture was extracted three times with diethyl ether, and the combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the solvent was removed to dryness under reduced pressure. This gave 1.45 g (6.4 mmol, 67% of theory) of a colorless solid.
Reaction SMILES: [Cl:1][C:2](=[CH2:16])[CH2:3][N:4]([CH2:10][CH:11](OC)[O:12]C)[C:5](=[O:9])[O:6][CH2:7][CH3:8].C(O)=O.[Cl-].[Na+]>O>[Cl:1][C:2](=[CH2:16])[CH2:3][N:4]([CH2:10][CH:11]=[O:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: C=C(Cl)CN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: C=C(Cl)CN(CC=O)C(=O)OCC

Procedure:
151 g (0.6 mol) of ethyl N-(2-chloroallyl)-N-(2,2-dimethoxyethyl)-carbamate are heated under reflux for 3 hours with 60 ml of formic acid in 1.2 1 of water. The mixture is saturated with sodium chloride, and the aqueous phase is separated off and extracted twice with 300 ml of methylene chloride each time. The organic phases are washed with saturated sodium hydrogen carbonate solution until neutral, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21](Br)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])#[CH:32]>C(N(CC)CC)C.C1(C)C=CC=CC=1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[C:21]([C:32]#[C:31][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(C#C[Si](C)(C)C)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 94.8 %

Procedure:
To a mixture of [4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (example 1-7) (51 mg, 0.10 mmol) and ethynyl-trimethyl-silane (20 mg, 0.20 mmol) in triethylamine (0.5 mL) and toluene (0.5 mL), was added copper(I) iodide (0.6 mg, 0.003 mmol) and bis(triphenylphosphine)palladium(II) chloride (2.4 mg, 0.003 mmol). The mixture was heated in a microwave oven at 80° C., for 20 minutes. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-trifluoromethyl-5-trimethylsilanylethynyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (50 mg, 94.8%) as a brown oil. MS calcd. for C23H28F3N3O4SSi 527, obsd (ESI+) [(M+H)+] 528.
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH3:12])C.[Br:14][C:15]1[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[CH:19][CH:20]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CS(O)(=O)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]2[NH:21][C:4]([CH2:5][CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[CH3:12])=[N:22][C:17]=2[CH:16]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CCOC(=O)CCN1CCC[C@H]1C
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: C[C@@H]1CCCN1CCc1nc2cc(Br)ccc2[nH]1
Temperature: 110 °C
Yield: 40 %

Procedure:
In a round-bottom flask was charged 3-(2-(R)-methyl-pyrrolidin-1-yl)-propionic acid ethyl ester (5.6 g, 30 mmol), 4-bromo-benzene-1,2-diamine (5.6 g, 30 mmol) and 56 mL of 5% P2O5 in CH3SO3H (Eaton's reagent). After briefly stirring, the homogeneous solution was heated to 110° C. for approximately 24–48 h. The reaction mixture was quenched with ice (˜50 g) and then the pH slowly adjusted to pH >11 with 50% NaOH. The product was extracted with isopropyl acetate (100 mL). The organic layer was then extracted with 5% NaHCO3, H2O and then distilled to dryness. The crude product was purified by column chromatography to provide the title compound (3.7 g). 1H NMR (500 MHz, [(CD3)2SO] δ 1.00 (d, 3H), 1.27 (m, 1H), 1.63 (m, 2H), 1.85 (m, 1H), 2.11 (m, 1H), 2.31 (m, 1H), 2.45 (m, 1H), 2.91–2.99 (m, 2H), 3.09 (m, 1H), 3.19 (m, 1H), 7.24 (m, 1H), 7.43 (d, 1H), 7.66 (s, 1H), some protons were not readily identified due to exchange broadening. 13C NMR (500 MHz, [(CD3)2SO+2 drops DCI] δ 15.3, 21.0, 23.2, 31.0, 48.3, 52.3, 64.3, 115.9, 116.6, 117.9, 128.8, 130.2, 132.2, 151.1 (some 13C peaks were not readily identified due to exchange broadening at 25° C., but were observed under acidic conditions, 2 drops DCI). APPI-MS: (M+1)+ at 308 m/z.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[C:18]3=[N:23][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:19]3[CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(-c2cccnc2N)ccc1-c1ccccc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C2=CC=CN3CCS(=O)(=O)N=C23)ccc1-c1ccccc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 1.163 g) in THF (dry) (30 mL) was added 2-chloroethanesulfonyl chloride (1.22 ml.) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(2-methylbiphenyl-4-yl)pyridin-2-amine (1.51 g) in THF (dry) (50 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. carefully. Water and EtOAc were added and the precipitates were collected and washed with water and EtOAc, dried in vacuo to give the title compound (339 mg) as a white solid. A part of this was recrystallized from MeCN-THF/IPE.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:30][S:31](O)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Reactant: CS(=O)(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
A round bottom flask was charged with (R)-2-(3-(aminomethyl)-6-(5-cyclopropyl-1H-pyrazol -3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 8; 0.20 g, 0.50 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.50 mmol), DIEA (0.13 g, 1.00 mmol), DMAP (0.067 g, 0.067 mmol), and THF (10 ml). The resulting solution was shaken vigorously at 60° C. for 8 hrs. The reaction was filtered and the resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.075 g, 31%). 1H NMR (400 MHz, CD3OD) δ 7.50-7.41 (m, 2H), 7.15 (d, J=9.1 Hz, 1H), 7.04-7.00 (m, 2H), 6.09 (br s, 1H), 5.22-5.03 (m, 1H), 4.20-4.07 (m, 2H), 3.86-3.74 (m, 2H), 2.98 (s, 3H), 1.89-1.85 (m, 1H), 1.04-0.92 (m, 2H), 0.78-0.66 (m, 2H). MS: Calcd.: 478; Found: [M+H]+ 479.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25](B(O)O)=[CH:26][C:21]=2[CH2:20][CH2:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:2]3[C:10]4[N:9]5[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]5=[C:7]([CH3:16])[C:6]=4[CH:5]=[C:4]([F:17])[CH:3]=3)=[CH:26][C:21]=2[CH2:20][CH2:19]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc5c(c4)CCO5)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (70 mg, 83%), MS (ISP) m/z=337.5 [(M+H)+], mp 251° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2,3-dihydro-benzofuran-5-ylboronic acid (53.3 mg, 0.325 mmol).
Reaction SMILES: [SH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[F:26][C:27]([F:31])([F:30])[CH2:28]I>>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:14][C:10]1[CH:9]=[C:8]([C:2]2([S:1][CH2:28][C:27]([F:31])([F:30])[F:26])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)CI
Reactant: SC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1
Product: FC(F)(F)CSC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1
Yield: 61 %

Procedure:
Using a similar procedure to that described in Example 1, 4-mercapto-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran was reacted with 2,2,2-trifluoroethyl iodide to give 4-[3-(naphth-2ylmethoxy)phenyl]-4-(2,2,2-trifluoroethylthio)tetrahydropyran in 61% yield, m.p. 76°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:20][C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(Cl)cc1
Product: Clc1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
4-Chlorobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](N)[CH2:22][NH2:23]>C(=S)=S.O>[F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]1[NH:23][CH2:22][CH2:21][N:16]=1)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Reactant: NCCN
Solvent: O
Solvent: S=C=S
Product: FC(F)(c1ccccc1)C(F)(F)c1ccccc1C1=NCCN1

Procedure:
2-(α,α,β,β-Tetrafluorophenethyl)benzonitrile, 2.06 g. (0.0074 mole), together with 1.2 g. (0.02 mole) of ethylenediamine and 3 drops of carbon disulfide, is heated in a sealed tube at 160°-165° C. for 18 hours. After cooling in an ice-bath, the tube is opened and the contents are poured into water. The orange gum that separates is washed with water by decantation and then dissolved in ethyl acetate. The ethyl acetate solution is extracted with 3N hydrochloric acid. The combined, ice-cold, acid extracts are rendered strongly alkaline with 40% aqueous sodium hydroxide and the oily base is extracted into ethyl acetate. The washed and dried ethyl acetate extract is concentrated under reduced pressure to a volume of about 25 ml. and 0.6 ml. of 8N ethanolic hydrogen chloride is added. Dilution with an equal volume of absolute ether precipitates the white crystalline hydrochloride salt of the product, m.p. 263°-266° C., sintering at 258° C. Recrystallization from acetone gives a purified sample, m.p. 266°-267° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:19](=[O:21])[CH3:20])[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(C2CCCN2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCCC1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 132 %

Procedure:
To a solution of 3-bromo-5-(2-pyrrolidinyl)pyridine (200 mg, 0.881 mmol) and pyridine (0.2 mL, 1.96 mmol) in DCM (1 mL) in a 8-mL vial is added acetic anhydride (0.093 mL, 0.969 mmol) dropwise. The mixture is stirred at room temperature for 2.5 h. The mixture is concentrated. The resulting crude product is purified by normal phase chromatography using 0-4.5% MeOH in DCM as the gradient to afford 1-[2-(5-bromo-pyridin-3-yl)-pyrrolidin-1-yl]-ethanone (313 mg, 83% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[CH3:25][S:22]([O:1][CH2:2][CH2:3][C:4]1([NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])[CH2:5][CH2:6]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(CCO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(CCOS(C)(=O)=O)CC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 6.472 g (32.16 mmol) of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate in 61 ml of anhydrous dichloromethane was added 12.79 ml (91 mmol) of anhydrous triethylamine. The resulting mixture is cooled at −20° C. Then 3.54 ml (45.66 mmol) of mesyl chloride in 11 ml of anhydrous dichloromethane was added. The resulting mixture was stirred at room temperature for 2 h. The mixture was poured into ice-water and the organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The crude product was triturated with petroleum ether and filtered to give 7.82 g of pure product as an orange solid. Mp: 88-89° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3OC)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1COc1ccc(-c2c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c2N2CCC(C)(C)CC2)cc1
Yield: 72.1 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((2-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.036 g, 0.061 mmol) and LiOH (0.015 g, 0.611 mmol) in 9:1 EtOH/H2O (2 mL0 was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((2-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0247 g, 0.044 mmol, 72.0% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.50 (dd, J=1.5, 7.5 Hz, 1H), 7.34 (dt, J=1.7, 7.8 Hz, 1H), 7.14-7.17 (m, 1H), 7.06-7.10 (m, 3H), 7.01 (dt, J=1.0, 7.5 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 5.94 (br. s., 1H), 5.17-5.24 (m, 2H), 3.91 (s, 3H), 3.61 (br. s., 1H), 2.90 (br. s., 1H), 2.66 (s, 3H), 2.24 (s, 3H), 1.24 (s, 9H), 0.88 (br.s., 3H), 0.68 (br.s., 3H). 6H of piperidine were not resolved. LCMS (M+H)=561.4.
Reaction SMILES: CC1O[C:5]([CH:7]=O)=[CH:4][CH:3]=1.C(N(CCC)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1)CC.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:37]([OH:39])[CH3:38]>>[CH2:16]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:7][CH2:5][CH2:4][CH2:3][CH:23]([NH2:24])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]=[CH:16][C:15]2[O:39][C:37]([CH3:38])=[CH:13][CH:14]=2)=[CH:26][CH:25]=1)[CH2:15][CH3:14]
Reactant: CCCN(CCC)CCCCNCc1ccc(CN)cc1
Reactant: CCO
Reactant: Cc1ccc(C=O)o1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCCN(CCC)CCCCC(N)c1ccc(CN=Cc2ccc(C)o2)cc1
Yield: 100 %

Procedure:
Under a nitrogen stream 415 mg (3.77 mmol, 1.1 equivalents) of 5-methyl-2-furaldehyde, 10 ml of ethanol, 1.0 g (3.43 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzylamine (5a), and 3 g of anhydrous sodium sulfate were charged in a 50 ml recovery flask and reacted at 25° C. for 20 hours. After completion of the reaction, the reaction solution was filtered, and concentrated, thereby obtaining 1.32 g of {(4-dipropylaminobutyl)-[4-(5-methylfuran-2-ylmethylidene)aminomethylbenzyl]}amine (26) as a reddish brown oily substance (yield: 100%). [HPLC: 95.7% (HPLC measurement conditions C)]
Reaction SMILES: [CH2:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:10][N:11]([CH3:23])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)=[O:13].C(Cl)[Cl:25]>>[CH3:23][N:11]([S:10][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[Cl:25])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)=[O:13]
Reactant: ClCCl
Reactant: CN(SCl)C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: C1CCCCCCC1
Product: CN(SC1CCCCCCC1Cl)C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
An 11.0-g (0.1 mol) sample of cyclooctane was added dropwise at 0°C. to a solution of 0.1 mol N-chlorothio-N-methyl-N'-(3,4-dichlorophenyl) urea, prepared by a procedure similar to that of Example 3, in methylene dichloride. After the addition was completed, the reaction mixture was washed successively with water, aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to give a solid residue. The solid was recrystallized from isopropyl alcohol and washed with hexane to give 15 g of product, m.p. 90°-91°C. Elemental analysis for C16H21Cl3N2OS showed: %S, calc. 8.1, found 8.2; %Cl, calc. 26.9, found 27.4.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]3)[N:11]=[C:7]2[CH:6]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 28 mg (0.14 mmol) of 6-[(2-aminoethyl)-amino]pyridine-3-carbonitrile dihydrochloride (Example 2A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 48 mg (74% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[O:11])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][CH2:25]OS(C)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:25][CH2:24][C:14]1[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:17][C:13]=1[CH3:12])[CH:10]=[O:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Product: COc1cc(C=O)ccc1OCCc1nc(-c2ccccc2)oc1C

Procedure:
In analogy to the procedures described in examples 114 b], c] and d], vanilline was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] to give 3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde. Treatment of 3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde with (benzyloxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride then gave 2(Z,E)-methoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid benzyl ester, which was hydrogenated to yield [rac]-2-methoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid.