Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]([F:19])=[C:6]([B:8]2[O:15][C:14](=[O:16])[CH2:13][N:12]([CH3:17])[CH2:11][C:10](=[O:18])[O:9]2)[CH:7]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:21]1([C:2]2[CH:3]=[C:4]([CH3:20])[C:5]([F:19])=[C:6]([B:8]3[O:15][C:14](=[O:16])[CH2:13][N:12]([CH3:17])[CH2:11][C:10](=[O:18])[O:9]3)[CH:7]=2)[CH2:23][CH2:22]1
Reactant: OB(O)C1CC1
Reactant: Cc1cc(Br)cc(B2OC(=O)CN(C)CC(=O)O2)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Cc1cc(C2CC2)cc(B2OC(=O)CN(C)CC(=O)O2)c1F
Temperature: 120 °C
Yield: 60.8 %

Procedure:
In a microwave reaction vessel equipped with stir bar was charged 2-(5-bromo-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (300 mg, 0.9 mmol), cyclopropylboronic acid (220 mg, 2.6 mmol), palladium acetate (14 mg, 0.06 mmol), S-Phos (50 mg, 0.12 mmol) and potassium phosphate (560 mg, 2.6 mmol). Degassed toluene (15 mL) was added. The reaction was heated under microwave at 120° C. for 15 min. LCMS indicated completion of the reaction. The mixture was diluted with acetonitrile and filtered through a pad of Celite and washed with copious amount of acetonitrile. The filtrate was concentrated in vacuo and the residue was absorbed on Celite from an acetone solution. The resulting powder was subjected to Isco flash chromatography eluted with 0 to 70% acetonitrile in ether to give a light yellow oil, 2-(5-cyclopropyl-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (167 mg, 60%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>ClCCl>[C:14]1(=[O:19])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:17](=[O:18])[CH:16]=[CH:15]1
Reactant: O=C1C=CC(=O)O1
Reactant: CN(CCCCN)c1ccccc1
Solvent: ClCCl
Product: CN(CCCCN1C(=O)C=CC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
N-(4-Aminobutyl)-N-methylaniline (7.2 g) was dissolved in dichloromethane (70 ml) and maleic anhydride (4 g) was added thereto. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off and then acetic anhydride (10 ml) was added. The resulting mixture was stirred at 100° C. for 5 hours. After concentration, an aqueous sodium bicarbonate was added to the residue to neutralize it. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (2:1) to obtain the desired compound (2.0 g) as yellow needles.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3[CH2:16][CH2:17][CH2:18][CH2:19][C:12]=3[C:11]2=[O:20])=[CH:6][C:5]=1[OH:21])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:3][CH:2]1[CH2:1][C:4]2[CH:9]=[CH:8][C:7]([N:10]3[C:11](=[O:20])[C:12]4[CH2:19][CH2:18][CH2:17][CH2:16][C:13]=4[C:14]3=[O:15])=[CH:6][C:5]=2[O:21]1
Reactant: C=CCc1ccc(N2C(=O)C3=C(CCCC3)C2=O)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC1Cc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc2O1

Procedure:
A mixture of 0.20 g of 1C, 100 mg of p-toluenesulfonic acid (PTSA), and 10 mL of xylene was refluxed for 24 hours, then cooled and poured into a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate, and the extract was washed with succession with sodium bicarbonate solution, water and brine, dried (Na2SO4) and filtered. The solvent was evaporated and the residue was chromatographed on a Chromatotron™ plate, starting with a 3:17 v:v mixture of ethyl acetate and hexane as eluent and gradually increasing the ethyl acetate content in the eluent, to give the title compound, as yellow crystals, m.p.: 114°-118° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7]([C:10](=O)[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:4])=[O:3].[CH3:14][C:15]([S@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C1COCC1.C(OCC)C.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][S:2]([C:5]1[S:6][C:7](/[C:10](=[N:20]\[S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])/[CH2:11][CH3:12])=[CH:8][N:9]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCC(=O)c1cnc(S(C)(=O)=O)s1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC/C(=N/S(=O)C(C)(C)C)c1cnc(S(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(2-methanesulfonyl-thiazol-5-yl)-propan-1-one (110 mg, 0.50 mmol), (R)-2-methyl-2-propanesulfinamide (70 mg, 0.6 mmol) and titanium (IV) isopropoxide (0.29 mL, 1.0 mmol) in THF (10 mL) was warmed at reflux for 18 hours. The mixture was cooled to room temperature and diluted with diethyl ether (100 mL) and water (6 mL). After 10 minutes with stirring, the solution was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in hexanes to afford 2-methyl-propane-2-sulfinic acid [1-(2-methanesulfonyl-thiazol-5-yl)-prop-(Z)-ylidene]-amide.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)[CH:6]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[NH:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.Cl.CCOCC>>[Cl:18][C:12]1[CH:11]=[C:10]([C:7]2[CH:6]=[C:5]([CH2:4][CH2:3][NH:2][C:30]([C:27]3[CH:26]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[NH:29][N:28]=3)=[O:31])[O:9][N:8]=2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: O=C(O)c1cc(-c2cccnc2)[nH]n1
Reactant: N#Cc1ccc(-c2cc(CCN)on2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2cc(CCNC(=O)c3cc(-c4cccnc4)[nH]n3)on2)cc1Cl
Yield: 47.4 %

Procedure:
The title compound was prepared from 4-(5-(2-aminoethyl)isoxazol-3-yl)-2-chlorobenzonitrile hydrochloride (0.080 g, 0.282 mmol), 5-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (0.053 g, 0.282 mmol), DIPEA (0.196 ml, 1.126 mmol 1), HOBt hydrate (0.065 g, 0.422 mmol) and EDCI (0.081 g, 0.422 mmol) using the method of Example 274. The title compound was converted to HCl salt by treatment of 1 M HCl ether solution for 2 h affording 0.056 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): 3.15 (t, 2H), 3.66 (m, 2H), 7.16 (s, 1H), 7.42 (bs, 1H), 7.90 (m, 1H), 8.02 (d, 1H), 8.13 (d, 1H), 8.21 (s, 1H), 8.63 (d, 1H), 8.75 (d, 1H), 8.83 (bs, 1H), 9.19 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17](Cl)=[O:18]>O>[CH3:15][O:16][C:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:18]
Reactant: COC(=O)Cl
Reactant: NCCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)NCCCCCCO
Yield: 91 %

Procedure:
To a stirred solution of 6-aminohexanol in 50 ml of water basified with 11 g of K2CO3, was added 4.03 g of methylchloroformate at room temperature. After one night the resulting aqueous solution was extracted with 3×50 ml of dichloromethane. The organic phases were combined, evaporated to dryness and the residue was filtered over silica gel. This furnished 1.36 g (yield 91%) of N-methoxycarbonyl-6-aminohexanol as a white solid. Then, to a solution of N-methoxycarbonyl-6-aminohexanol (200 mg) in dichloromethane (5 ml) was added 361 mg of triphenylphosphine and 832 mg of tetrabromomethane.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])(=[O:4])=[O:3].[OH-].[Na+]>C(O)C>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CCOC(=O)CCCS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of Intermediate 36 (0.130 g) in ethanol (2 ml), was added 2N aqueous sodium hydroxide (0.75 ml). The mixture was stirred at room temperature under nitrogen overnight. The solution was evaporated in vacuo to remove the ethanol, and applied to a solid phase extraction cartridge (Isolute SCX sulphonic acid column, 2 g). The cartridge was eluted with methanol (15 ml) and the solvent concentrated in vacuo to give the title compound as a clear oil (0.110 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[O:13])=[N:4][CH:3]=1.[CH3:25][C:26]1[C:31]([O:32][CH3:33])=[C:30]([CH3:34])[C:29]([CH2:35][S:36]([C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[O:37])=[N:28][CH:27]=1.O.O.O.[Mg+2:52]>CO>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:13])[C:14]2[N-:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[N:15]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[CH:27]=[N:28][C:29]([CH2:35][S+:36]([O-:37])[C:38]2[N-:42][C:41]3[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:40]=3[N:39]=2)=[C:30]([CH3:34])[C:31]=1[O:32][CH3:33].[Mg+2:52]
Reactant: COc1ccc2[n-]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Mg+2]
Solvent: O
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1

Procedure:
Esomeprazole magnesium trihydrate (100 g) was dissolved in methanol (1000 ml) at 25-30° C. Any undissolved material was filtered off. The clear solution thus obtained was spray dried with an inlet temperature of 65-68° C. and an outlet temperature of 22-42° C. The solid was further dried under vacuum at 60-65° C. for 14 to 15 hours to yield 55g of esomeprazole magnesium of amorphous form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.N1C=CC=CC=1.ClC(OC)=O>C(Cl)Cl>[CH3:1][O:5][C:6](=[O:33])[N:7]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])[CH3:8]
Reactant: CN(CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)N(C)CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{2-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-ethyl}-methyl-carbamic acid tert-butyl ester (25 mg, 0.055 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 1 h. Solvent and excess TFA were removed in vacuo. To the residue were added CH2Cl2 (2 mL), pyridine (0.072 mL, 0.88 mmol), and methyl chloroformate (0.034 mL, 0.44 mmol), and the resulting mixture was stirred for 16 h. The mixture was diluted with CH2Cl2 and washed with 1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was dissolved in 5 mL of 0.5 M NaOMe solution and refluxed for 1 h. After cooling to r.t., the mixture was acidified to pH about 2 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (0-5% MeOH/CH2Cl2) to give the desired product and an impurity. The crude product was then treated with a mixture of 1 M NaOH and MeOH (1:1 v/v) for 16 h at r.t. The mixture was acidified to pH about 2 and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated, and the crude product was purified by chromatography (0-5% MeOH/CH2Cl2) to give 6.3 mg of the title compound. MS: (+) m/z 411.25 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:14][CH:11]1[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: O=Cc1cccc(Cl)c1Cl
Product: Clc1cccc(CNC2CC2)c1Cl

Procedure:
Synthesized according to typical procedure J from 2,3-dichlorobenzaldehyde and cyclopropylamine.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:13]=1[CH2:14][NH:15][C:16]1[C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1)(OC(C)(C)C)=O.C(Cl)Cl>FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:13]=1[CH2:14][NH:15][C:16]1[C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC(C)c1ccc(CNc2ncccc2C(=O)Nc2ccc(Cl)cc2)c(OCCNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(CNc2ncccc2C(=O)Nc2ccc(Cl)cc2)c(OCCN)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
2-[2-(N-Boc-Aminoethoxy)-4-isopropylbenzylamino]-N-(4-chlorophenyl)pyridine-3-carboxamide (0.02 g, 0.04 mmol) was dissolved in 2 mL of a 1:3 mixture of trifluoroacetic aicd:methylene chloride. The reaction mixture was stirred at room temperature for 30 min. The solvent was removed, and the material was purified by ion exchange chromatography to afford the title compound (0.014 g, 88%) as the free base.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28](O)=[O:29])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:65]([O:69][C:70]([N:72]1[CH2:77][CH2:76][N:75]([C:78](=[O:83])[C@@H:79]([NH2:82])[CH2:80][F:81])[CH2:74][CH2:73]1)=[O:71])[CH2:66][CH2:67][CH3:68]>CN(C=O)C>[CH2:65]([O:69][C:70]([N:72]1[CH2:73][CH2:74][N:75]([C:78](=[O:83])[C@@H:79]([NH:82][C:28]([C:19]2[CH:18]=[C:17]([O:16][CH2:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[O:31])[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=2)=[O:29])[CH2:80][F:81])[CH2:76][CH2:77]1)=[O:71])[CH2:66][CH2:67][CH3:68]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CF)CC1
Reactant: Cc1ccc2c(OCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc(C(=O)O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)c2cc(OCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c3ccc(C)cc3n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 452 mg 4-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 15 ml DMF were added 0.54 ml DIPEA and 400 mg HATU. After 5 minutes 410 mg 4-((R)-2-Amino-3-fluoro-propionyl)-piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate were added and the mixture stirred for 24 h. The mixture was concentrated, diluted with DCM and washed with aqueous LiCl (4%), saturated aqueous NaHCO3 and 0.1 M HCl. The crude product thus obtained after evaporation of the solvent was used in the next step without further purification. Yield: 1.28 g.
Reaction SMILES: C=C(O[C:5](=[O:27])[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:24])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=3)[C:10]([CH3:25])=[CH:9][C:8]=1[F:26])C.Cl.[F:29][C:30]([F:35])([F:34])[CH2:31][CH2:32][NH2:33].CN1CCCC1.O>C1COCC1>[Cl:23][C:18]1[CH:17]=[C:16]2[C:21]([CH:22]=[C:13]([C:11]3[C:10]([CH3:25])=[CH:9][C:8]([F:26])=[C:7]([NH:6][C:5]([NH:33][CH2:32][CH2:31][C:30]([F:35])([F:34])[F:29])=[O:27])[CH:12]=3)[C:14]([CH3:24])=[N:15]2)=[CH:20][N:19]=1
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(Cl)cc3nc2C)c(C)cc1F
Reactant: NCCC(F)(F)F
Agent: CN1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c(NC(=O)NCCC(F)(F)F)cc1-c1cc2cnc(Cl)cc2nc1C
Temperature: 25 °C
Yield: 96.3 %

Procedure:
Heat a mixture of prop-1-en-2-yl(5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamate (0.20 g, 0.518 mmol), 3,3,3-trifluoropropylamine hydrochloride (0.093 g, 0.622 mmol) and 1-methylpyrrolidine (0.068 mL, 0.648 mmol) in THF (5 mL) at 55° C. overnight. Cool to RT, add H2O, extract with EtOAc (2×), wash the combined organics with brine (2×), dry over MgSO4 and concentrate to dryness to afford the title compound (220 mg, 96%). 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 6.75 (t, J=5.9 Hz, 1H), 3.58-3.02 (m, 2H), 2.42 (m, 2H), 2.41 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:6]=[C:7]([C:12]([OH:14])=O)[S:8][C:9]=1[CH:10]=[O:11])[CH3:4].C([O:17][C:18](=[O:34])[CH2:19][CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([C:28](=[NH:31])[NH:29]O)=[CH:23][C:22]=1[CH2:32][CH3:33])C>CO>[CH2:32]([C:22]1[CH:23]=[C:24]([C:28]2[N:29]=[C:12]([C:7]3[S:8][C:9]([CH:10]=[O:11])=[C:5]([CH2:3][CH3:4])[CH:6]=3)[O:14][N:31]=2)[CH:25]=[C:26]([CH3:27])[C:21]=1[CH2:20][CH2:19][C:18]([OH:34])=[O:17])[CH3:33]
Reactant: CCOC(=O)CCc1c(C)cc(C(=N)NO)cc1CC
Reactant: CCc1cc(C(=O)O)sc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(C)c(CCC(=O)O)c(CC)c3)no2)sc1C=O

Procedure:
The title compound is prepared according to Method E followed by treating the corresponding propionic ester derivative for 1 h at rt with 1 N aq. NaOH in methanol starting from 4-ethyl-5-formyl-thiophene-2-carboxylic acid and 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid ethyl ester; LC-MS: tR=0.87 min; [M+1]+=399.20.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:31]#[C:30][CH2:29][OH:32])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(I)cc1Cl
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: OCC#Cc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-4-fluoroiodobenzene (5.00 g), copper(I) iodide (74.3 mg), triphenylphosphine (256 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (404 mg), propargyl alcohol (1.27 ml), diisopropylethylamine (13.6 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 8 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.20 g) as a brown oil.
Reaction SMILES: C([O:8][CH2:9][C@:10]1([CH2:16][O:17][C:18](=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[C:18]([O:17][CH2:16][C@@:10]1([CH2:9][OH:8])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)(=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCC(=O)OC[C@]1(COCc2ccccc2)CCC(=O)O1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)OC[C@]1(CO)CCC(=O)O1
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
A solution of 2.15 (0.036 g, 0.08 mmol) in CH2Cl2 (4 mL) was cooled to -78° C., treated with boron trichloride (1.0M in dichloromethane, 0.24 mL, 0.24 mmol), and stirred at that temperature for 1.5 h. The reaction mixture was quenched by the slow addition of a saturated NaHCO3 solution (0.3 mL) at -78° C., and immediately partitioned between ice-cold ether and a pH 7 buffer solution. The organic layer was washed five times with the pH 7 buffer solution, dried (Na2SO4), and concentrated to give a white solid. This solid was washed with cold hexane several times to give a pure sample of 2.2 (24 mg, 84%) as a solid; mp 65°-66° C.; [α]22D +1.43° (c 4.2, CHCl3). The IR, 1H NMR, and 13C NMR were identical to those reported for the racemate (3e, Example 1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])[CH3:14]
Reactant: CC(C)=O
Reactant: O=Cc1ccc(F)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1ccc(F)cc1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 500 mL recovery flask was added 2-bromo-4-fluorobenzaldehyde (1A, 10.0 g, 49.3 mmol, 1.0 eq.) and acetone (22.9 g, 394 mmol, 8.0 eq.). The mixture was cooled to 0° C. in an ice bath. H2O (200 mL) was added and the mixture became a thick suspension. Solid NaOH (2.16 g, 54.2 mmol, 1.1 eq.) was added and the reaction was gradually warmed to room temperature and stirred overnight. The reaction was acidified with 1N HCl and extracted with EtOAc (3×100 mL). The organic phases were combined and washed with saturated aqueous NaCl. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a dark yellow oil that was carried on to the next step without further purification (11.9 g, 99%). ESI-MS: m/z 243.2 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[Si:5]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(N)cc1
Reaction time: 72 h
Yield: 95 %

Procedure:
The compound (1.65 g, 5.86 mmol) prepared in step 1 was dissolved in ethyl acetate (20 ml), added with 10%-palladium (Pd) (165 mg) at room temperature. The reaction mixture was stirred for 3 days under hydrogen gas. 10%-palladium (Pd) was removed by using celite-filter and the filtrate was concentrated under reduced pressure. The residue was then purified by flash column chromatography (ethylacetate:hexane=1:4) to obtain the title compound (1.4 g, yield: 95%, colorless oil).
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=1)O)=[O:4].[NH2:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.CN1C(N)=CC(C)=N1.ClC(N(C)C)=C(C)C>CCOC(C)=O.CCN(CC)CC>[Br:10][C:8]1[N:7]([CH:11]([CH3:12])[CH3:13])[C:6]2[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=3)[N:24]([C:25]3[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=3)[C:3](=[O:4])[C:5]=2[CH:9]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)c(F)c1
Agent: CC(C)=C(Cl)N(C)C
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cc1cc(N)n(C)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)c(F)c1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate AW but in the step corresponding to Step AW2, 5-bromo-2-[(4-chloro-3-fluoro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step AZ1) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 2,5-dimethyl-2H-pyrazol-3-ylamine respectively. Moreover, in this step, the procedures described for Steps H3 and H2 using 1-chloro-N,N,2-trimethylpropenylamine and Et3N were used. The title compound (containing some of the corresponding 2-chloro analog) was obtained as a white foam. tR: 1.18 min (HPLC 3); ESI-MS: tR=1.10 min, [M+H]+ 512/514/516 (LC-MS 1); TLC: Rf=0.19 (EtOAc).