Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH2:17][CH3:18])([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+]>CO>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH2:17][CH3:18])([C:13]([OH:15])=[O:14])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CC[C@]1(C(=O)OC)C=C[C@@H](n2c(C)ccc2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@]1(C(=O)O)C=C[C@@H](n2c(C)ccc2C)C1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-ethylcyclopent-2-ene-1-carboxylate (12.94 g, 52.3 mmol) in methanol (100 ml) was treated with 2.5N NaOH (30 ml, 75.0 mmol) and stirred at room temperature. After 15 hours more 2.5N NaOH (10 ml, 25.0 mmol) was added and the reaction was stirred for an additional four days. The methanol was removed under reduced pressure and the residue partitioned between diethyl ether and water. The layers were separated and the aqueous was acidified with 4N HCl, extracted twice with ethyl acetate, washed with brine, dried over MgSO4, and concentrated under reduced pressure to give (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-ethylcyclopent-2-ene-1-carboxylic acid as a brown oil (11.83 g, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 5.98-5.96 (2H), 5.73 (2H), 5.30-5.26 (1H), 2.47-2.35 (2H), 2.20 (6H), 1.82-1.77 (2H), 0.96-0.92 (3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:18][CH:19]1[O:23][B:22]([OH:24])[C:21]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:20]1=2>>[Cl:1][C:2]1[C:3]([O:29][C:27]2[CH:26]=[CH:25][C:21]3[B:22]([OH:24])[O:23][CH:19]([CH3:18])[C:20]=3[CH:28]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(C)OCCOc1nc(Cl)c(Cl)cc1C#N
Reactant: CC1OB(O)c2ccc(O)cc21
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)C(C)OB3O)c(Cl)cc1C#N

Procedure:
This compound was prepared from 5,6-dichloro-2-(2-isopropoxyethoxy)nicotinonitrile and 3-methylbenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.0 (d, J=4.5 Hz, 6H), 1.40 (d, J=4.8 Hz, 3H), 3.4-3.47 (m, 3H), 4.07-4.1 (m, 2H), 5.2-5.22 (m, 1H), 7.23 (dd, J=6.0, 1.5 Hz, 1H), 7.36 (s, 1H), 7.75 (d, J=6.0 Hz, 1H), 8.59 (s, 1H), 9.18 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=1>>[NH2:17][C:18]1[N:23]=[C:22]([C:24]([NH:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=2)[CH3:13])=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCC(F)(F)F)nc1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (98 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (92 mg, 0.36 mmol, Amine-1, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (50 mg, 0.36 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].O>C1COCC1>[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: Oc1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Phenol (2.00 g, 12.3 mmol) was dissolved in THF (40 mL), 55% sodium hydride (1.02 g, 23.4 mmol) was added thereto at 0° C., followed by stirring at 0° C. for 30 minutes. A solution (10 mL) of 2-methylbenzoyl chloride (4.16 mL) in THF was added dropwise to the reaction mixture, followed by stirring overnight at room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=9:1) to afford phenyl 2-methylbenzoate (2.88 g, 64%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:23]=[CH:22][C:15]3[N:16]=[C:17](S(C)=O)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:23]=[CH:22][C:15]3[N:16]=[C:17]([NH:31][CH2:30][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: NCC1CCCCC1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(NCC4CCCCC4)sc3c2)ccn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To the solution of 4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (25 mg, 0.072 mmol, 1.0 eq) in DMF (500 μL), was added cyclohexylmethylamine (18.7 μL, 0.144 mmol, 2.0 eq) and reaction was stirred at 70° C. overnight. The neat reaction mixture was purified on reverse phase preparatory HPLC. Pure fractions were lyophilized as TFA salts. M+H=397.1
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[CH:18][N:17]=1.O>CN(C)C=O>[C:3]([O:7][C:8]([C:10]1[CH:14]=[CH:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[CH:18][N:17]=2)[CH:11]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)c1cc[nH]c1
Reactant: FC(F)c1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccn(-c2ccc(C(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
Sodium hydride (230 mg) was added to a solution of 1H-pyrrole-3-carboxylic acid tert-butyl ester (804 mg) in N,N-dimethylformamide (9.6 ml) at room temperature and stirred at the same temperature for 0.5 hour. 2-Bromo-5-(difluoromethyl)pyridine (1.0 g) was added and stirred at 60° C. for an hour. After completion of the reaction, the reaction solution was cooled to room temperature, water was added and the precipitated solid was filtered. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[5-(difluoromethyl)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid tert-butyl ester (1.01 g) as a white solid.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]=[C:27]1[CH:33]=[CH:32][C:31]2[CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=[CH:37][C:30]=2[O:29][CH2:28]1>CO>[CH2:26]=[C:27]1[CH:33]=[CH:32][C:31]2[CH:34]=[C:35]([C:38]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:39])[CH:36]=[CH:37][C:30]=2[O:29][CH2:28]1
Reactant: Nc1ccccc1
Reactant: C=C1C=Cc2cc(C(=O)O)ccc2OC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: C=C1C=Cc2cc(C(=O)Nc3ccccc3)ccc2OC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
1.12 g (4.07 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride and then 0.379 g (4.07 mmol) of aniline are successively added to 0.75 g (3.7 mmol) of 3-methylene-2,3-dihydro-1-benzoxepin-7-carboxylic acid, prepared according to example 40, in solution in 25 ml of methanol. The medium is stirred at ambient temperature for 24 h. After evaporating the methanol, the crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 40/60) to give 185 mg (49%) of 3-methylene-N-phenyl-2,3-dihydro-1-benzoxepin-7-carboxamide in the form of a pink solid; M.p.=139° C.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][O:29][CH3:30]>CN(C=O)C>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:27][CH2:28][O:29][CH3:30])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Yield: 46.7 %

Procedure:
6-(tert-Butylsulfonyl)-4-chloroquinolin-7-ol (0.81 g, 2.70 mmol), K2CO3 (1.143 g, 8.11 mmol), and 1-bromo-2-methoxyethane (0.508 ml, 5.40 mmol) in DMF (8.50 ml) were heated at 70° C. The reaction mixture cooled and partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc twice and the combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The residue was purified via Biotage (SNAP Cartridge KP Sil 25 g, 10-50% EtOAc/Hexane) to yield 6-(tert-butylsulfonyl)-4-chloro-7-(2-methoxyethoxy)quinoline (0.461 g, 1.262 mmol, 46.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.93 (d, J=4.55 Hz, 1H), 8.66 (s, 1H), 7.73-7.79 (m, 2H), 4.40 (dd, J=3.54, 5.31 Hz, 2H), 3.76 (dd, J=3.66, 5.18 Hz, 2H), 3.34 (s, 3H), 1.33 (s, 9H), MS: m/z: 358.1 [M+H]+.
Reaction SMILES: CC([C:5]1([C:20]([O-:22])=[O:21])[CH2:9][N:8]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7](=[O:18])[N:6]1[CH3:19])(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24].C(Cl)Cl>>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[CH3:19][N:6]1[CH:5]([C:20]([OH:22])=[O:21])[CH2:9][N:8]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:7]1=[O:18]
Reactant: CN1C(=O)N(CCN2CCOCC2)CC1(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(CCN2CCOCC2)CC1C(=O)O

Procedure:
To a stirred solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (1.0 g, 5 mmol) (prepared as described in step (iii) of Example 13) in N,N-dimethylformamide (20 ml) at 0° C. was added sodium hydride (60% dispersion in oil) (220 mg, 5.5 mmol). After 10 minutes a solution of 4-(2-chloroethyl)morpholine (898 mg, 6 mmol) in N,N-dimethylformamide (2 ml) and potassium iodide (166 mg, 1 mmol) was added and the mixture was heated at 70° C. for 2 hours. After cooling to room temperature water was added and the mixture was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organic extracts were separated, washed with water and brine, dried and evaporated. The residue was purified by silcia gel chromatography eluting with 5-10% 2M ammonia in methanol and dichloromethane to give 1,1-dimethylethyl-3-methyl-1-[2-(4-morpholinyl)ethyl]-2-oxo-4-imidazolidinecarboxylate (740 mg, 47%) as an oil. LC/MS [M+H]+=314. (ii) A solution of 1,1-dimethylethyl-3-methyl-1-[2-(4-morpholinyl)ethyl]-2-oxo-4-imidazolidinecarboxylate (740 mg, 2.361 mmol) in TFA/DCM (1:2, 6 ml) was stirred at room temperature for 5 hours. The solution was evaporated and the residue was co-evaporated with DCM and dried to give crude 3-methyl-1-[2-(4-morpholinyl)ethyl]-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜2.3 mmol) which was used in the next step. LC/MS [M+H]+=258.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([N+:23]([O-])=O)[C:14]([N+:20]([O-])=O)=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:19][CH:17]([C:16]3[CH:15]=[C:14]([NH2:20])[C:13]([NH2:23])=[CH:12][C:11]=32)[CH2:18]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC(C1)c1cc(N)c(N)cc12

Procedure:
4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (1.9 g, 5.44 mmol) was hydrogenated in MeOH under a H2 atmosphere (45 psi) over 10% Pd/C (100 mg) for 1.5 hours then filtered through a Celite pad and concentrated to white solids (1.57 g, 100%). (TLC 5% MeOH/CH2Cl2 (NH3) Rf 0.14).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:14][C:13](=O)[C:12]3[CH:16]=[CH:17][S:18][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[C:12]2[CH:16]=[CH:17][S:18][C:11]=2[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1
Reactant: COc1ccc(-c2cc3sccc3c(=O)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3sccc3c(Cl)n2)cc1
Temperature: 120 °C
Yield: 73 %

Procedure:
6(4-methoxyphenyl)-5H-thieno[3,2-c]pyridin-4-one (9.1) g) was added to phosphorus oxychloride (90 g), and the mixture was heated at 120° C. for 3 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The organic layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporate, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a white powder (6.6 g, yield; 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (44 mg, 39%). MS (ISP) 449.3 [(M+H)+]; mp 236–237° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:20]([NH:25][C:26](=O)[O:27]C1C=CC=CC=1)[CH2:21][CH2:22][CH2:23][CH3:24]>CN(C)C=O>[CH2:20]([NH:25][C:26]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:27])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCNC(=O)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
4-(1H-5-Indolyloxy)-2-pyridinamine (5.0 g, 22 mmol, CAS No. 417722-11-3) which was described in WO 02/32872 was dissolved in N,N-dimethylformamide (60 ml); sodium hydride (1.06 g, 27 mmol) was added thereto at room temperature; and the reaction mixture was stirred for 30 minutes. Phenyl N-n-pentylcarbamate (5.06 g, 24 mmol) while stirring at room temperature; and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate (insoluble portions were perfectly dissolved by adding a small amount of methanol); and the organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH; hexane:ethyl acetate=1:1, ethyl acetate, ethyl acetate:methanol=95:5 in this order). The obtained crystals were suspended in hexane:ethanol=10:1, filtered off, washed with hexane, and dried under aeration to yield the title compound as colorless crystals (1.55 g, 4.58 mmol, 21%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12](N)[CH:13]=[CH2:14].CCOCC>ClCCl>[CH2:14]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH:13]=[CH2:12]
Reactant: C=CCN
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCNS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 4-bromobenzenesulfonamide (6.80 g 26.6 mmol) in dichloromethane (50 mL) was added allylamine (5.0 mL, 66.5 mmol) at 0° C. The clear, colorless solution was stirred at room temperature for 1 h. The reaction mixture was poured into ether (100 mL) and washed with 10% aq HCl (50 ML), water (2×50 mL), and saturated aq NaHCO3 (50 mL). The organic phase was dried (MgS04) and concentrated. The residue crystallized upon treatment with hexane to provide 7.03 g (96% yield) of the desired product as fine, white crystals. Mp: 63-65° C. (lit. 64-65° C. See Keasling, H. H.; Schumann, E. L.; Veldkamp, W. J. Med. Chem. 1965, 8, 548). 1H NMR (400 MHz, CDCl3): δ 7.77-7.72 (m, 2H), 7.69-7.64 (m, 2H), 5.71 (ddt, J=17.1, 10.2, 6.0 Hz, 1H), 5.18 (dq, J=17.1, 1.5 Hz, 1H), 5.12 (dq, J=10.2, 1.5 Hz, 1H), 4.67 (t, J=6.0 Hz, 1H), 3.61 (tt, J=6.0, 1.5 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 139.0, 132.6, 132.4, 128.6, 127.6, 118.0, 45.7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9]O)=[C:4]([F:12])[CH:3]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])=[C:4]([F:12])[CH:3]=1
Reactant: C[C@H](CO)c1ccc(Br)cc1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CN1C(=O)c2ccccc2C1=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a solution of (S)-2-(4-bromo-2-fluorophenyl)propan-1-ol (800 mg, 3.43 mmol), phthalimide (554 mg, 3.77 mmol), and triphenylphosphine (1.34 g, 5.14 mmol) in THF (2 mL) was added DIAD (1 mL, 5.14 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 h and evaporated under vacuum. Flash chromatography of the residue afforded the desired product (1 g, 81%) as a white solid ESI MS m/z 363 [C17H13BrFNO2+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1)=[O:29].[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[O:35])[CH2:31][CH2:32]1)=[O:29]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Reactant: CN1CCC(N)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)C2(C(=O)Nc3ccc(Oc4ccnc(NC(=O)N(C)C5CCN(C)CC5)c4)cc3F)CC2)CC1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added 4-amino-1-methylpiperidine (18.8 mg), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 8 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (20.0 mg, 42%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12](O)=[O:13])[CH:8]=[CH:9][CH:10]=1)(O)=[O:2].CSC.B>C1COCC1>[OH:2][CH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCc1cccc(CCO)c1
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a stirred solution of (3-carboxymethylphenyl)acetic acid (1.0 g, 5.15 mmol) in THF (100 mL) was added slowly borane dimethyl sulfide (2.3 mL, 30.9 mmol). The resulting solution was stirred overnight (˜18 hours) and then quenched by slowly adding 1N HCl (100 mL). The mixture was then extracted using EtOAc (3×100 mL) and the combined organic layers were washed with saturated NaCl (100 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to provide 750 mg of the title intermediate (87% yield), which was used without further purification.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9]2[S:10][CH:11]=[C:12]([CH3:13])[C:8]=2[S:7](=[O:15])(=[O:14])[N:6]=[CH:5]1.Cl>C(O)(C)C.O>[CH3:3][N:4]1[C:9]2[S:10][CH:11]=[C:12]([CH3:13])[C:8]=2[S:7](=[O:15])(=[O:14])[NH:6][CH2:5]1
Reactant: Cc1csc2c1S(=O)(=O)N=CN2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1csc2c1S(=O)(=O)NCN2C
Temperature: 50 °C

Procedure:
240 mg of sodium borohydride are added to 120 mg of the compound obtained in Step B above dissolved in 6 ml of isopropanol. The mixture is heated at 50° C. for 10 minutes. The solvent is removed under reduced pressure, then the residue that is obtained is taken up in 5 ml of water. The pH of the solution is adjusted to 4 by addition of 6N hydrochloric acid. The precipitate is collected by filtration, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH2:29][C@H:28]([C:30]([NH2:32])=[O:31])[O:27][C:26]2=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][O:16]CC2C=CC=CC=2)[CH2:10][CH2:9]1.[H][H]>CO.CCO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH2:29][C@H:28]([C:30]([NH2:32])=[O:31])[O:27][C:26]2=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:24])[CH2:15][OH:16])[CH2:12][CH2:13]1
Reactant: NC(=O)[C@H]1CN(c2ccc(N3CCN(C(=O)COCc4ccccc4)CC3)c(F)c2)C(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: NC(=O)[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1

Procedure:
A mixture of (5R)-3-[3-fluoro-4-[4-[(phenylmethoxy)acetyl]-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinecarboxamide (Step 2, 260 mg, 0.570 mmol) and 10% palladium-on-carbon (61 mg, 0.0570 mmol) in a mixture of methanol (5 mL) and EtOH (23 mL) is shaken under a 40 psi hydrogen atmosphere on a Parr apparatus for 22 h. The catalyst is then removed by filtration through a pad of Celite, rinsing with tetrahydrofuran (200 mL), and the filtrate is concentrated under reduced pressure and triturated with methanol/diethyl ether. Filtration then provides the title compound, mp 232-235° C. (dec.); MS (ESI+) for C16H19FN4O5 m/z 367 (M+H)+; [α]25D=−20 (c 0.98, DMSO).