Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=CC=1C(N[C@H:10]([C:18]([NH:20][C@H:21]([C:29](O)=O)[CH2:22]C1C=CC=CC=1)=O)CC1C=CC=CC=1)=O.[CH:32]1[CH:33]=CC2N(O)N=NC=2[CH:37]=1.Cl.C(N=C=NCCCN(C)C)C>C1COCC1>[CH:32]([N:20]([CH2:18][CH3:10])[CH:21]([CH3:22])[CH3:29])([CH3:33])[CH3:37]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCN(C(C)C)C(C)C
Yield: 200 %

Procedure:
N-pyrazineformyl-L-phenylalanyl-L-phenylalanine (0.42 g, 1 mmol) of Preparation example 5 was dissolved in 7 ml of THF, HOBt (0.16 g, 1.2 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.5 mmol) were added at −20° C., then reacted for 30 min followed by addition of LeuBdiol-NH2 (0.3 g, 1 mmol) obtained in Preparation example 42 and N,N-diisopropylethylamine (0.26 g, 2 mmol), the mixture was stirred overnight at −20° C. TLC monitored the reaction, the after the reaction was completed, insoluble substance was removed by filtration, and solvent was evaporated under reduced pressure, the residue was dissolved with 20 ml of ethyl acetate, washed with 10% citric acid solution, 5% sodium bicarbonate solution, saturated table salt solution (3×15 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and the residue was separated by column chromatography to give 0.54 g of compound 4a as a white solid with a yield of 82%. m.p.: 78-80° C.; 1H-NMR (CDCl3, 500 MHz): δ 9.31-9.26 (m, 1H), 8.82-8.77 (m, 1H), 8.58-8.54 (m, 1H), 8.23-8.19 (m, 1H), 7.32-6.99 (m, 10H), 6.48-6.42 (m, 1H), 5.72-5.67 (m, 1H), 4.80-4.77 (m, 1H), 4.59-4.55 (m, 1H), 4.36-4.33 (m, 1H), 3.19-3.09 (m, 4H), 2.90-2.88 (m, 1H), 2.36-2.22 (m, 2H), 2.08-2.03 (m, 1H), 1.94-1.86 (m, 2H), 1.47-1.39 (m, 3H), 1.30-1.28 (m, 3H), 1.29-1.21 (m, 3H), 0.90-0.83 (m, 9H); 13C-NMR (CDCl3, 125 MHz): 169.86, 169.77, 163.21, 147.63, 144.33, 143.52, 142.69, 136.25, 135.94, 129.22, 129.13, 128.81, 128.45, 127.28, 126.72, 84.72, 54.73, 54.27, 51.50, 39.41, 39.37, 38.37, 38.03, 37.84, 37.64, 35.68, 28.53, 28.44, 27.05, 26.36, 26.32, 25.58, 23.96, 22.36; MS (EI): m/z 665.6 (M)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-:21].[Ca+2]>C(#N)C.O.C(OCC)(=O)C>[OH:21][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccc(CO)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 80.9 %

Procedure:
4-bromomethyl-4′-nitrobenzophenone (3.20 g, 10.0 mmol, 1 eq) was dissolved in a 2:1 acetonitrile/water mixture (300 mL) and calcium carbonate (3.00 g, 30.0 mmol, 3 eq) was added. The turbid mixture was stirred under reflux for 60 hr. After this time the reaction mixture was allowed to cool and the solid calcium carbonate was filtered off. The solid was washed with ethyl acetate (10 mL) and the filtrate was concentrated under reduced pressure to give an off-white solid. The solid was dissolved in ethyl acetate and washed with concentrated hydrochloric acid. The organic solution was then neutralised with sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure to give 4-hydroxymethyl-4′-nitrobenzophenone (2.08 g, 81%) as a beige solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([O:22][C@@H:23]([C@H:25]2[CH2:29][O:28]C(C)(C)[O:26]2)[CH3:24])[N:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH:14]=[C:13]([O:22][C@H:23]([CH3:24])[C@H:25]([OH:26])[CH2:29][OH:28])[N:12]=1
Reactant: C[C@@H](Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-methanesulfonamide (the product of step i) (0.23 g) in DCM (5 mL) was added iron (III) chloride hexahydrate (0.25 g). The reaction mixture was stirred at ambient temperature for 2 h then saturated aqueous sodium bicarbonate (2 mL) was added. The layers were separated and the aqueous material extracted with DCM (×3) and ethyl acetate (×3). The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residual yellow solid was precipitated from 10% DCM in Et2O, filtered and the resulting material washed with minimal Et2O (2×1 mL) to afford the title compound as a white powder. Yield: 24 mg.
Reaction SMILES: C(O)C.CC(O)C.[Br:8][C:9]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C@H:12]([N+:23]([O-:25])=[O:24])[CH2:11][C:10]=1[CH:26]=[O:27].[BH4-].[Na+].[NH4+].[Cl-]>C(OCC)(=O)C>[Br:8][C:9]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C@H:12]([N+:23]([O-:25])=[O:24])[CH2:11][C:10]=1[CH2:26][OH:27]
Reactant: O=CC1=C(Br)C[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])[C@@H]1CC(CO)=C(Br)C[C@H]1c1ccc(Cl)cc1Cl
Yield: 84.2 %

Procedure:
To a cold (0° C.) ethanol/2-propanol (3 mL/3 mL) solution of Example 7B (758 mg, 2 mmol) under N2 flow, NaBH4 (80 mg, 2.1 mmol) was added. The reaction mixture was stirred and the temperature was allowed to increase from 0° C. to room temperature over two hours. The solution was treated with saturated NH4Cl, and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and then purified by flash chromatography with 30% ethyl acetate/hexane to provide the title compound (642 mg, 84%). 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.51 (m, 1H), 7.26-7.32 (m, 1H), 7.11-7.22 (m, 1H), 5.04-5.20 (m, 1H), 4.31-4.45 (m, 2H), 4.14-4.27 (m, 1H), 2.59-3.32 (m, 4H). MS (DCI) m/z 399 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:20](=[O:22])[CH3:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[C:5]([C:20](=[O:22])[CH3:21])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(C)=O)c3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 200 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 122 (0.37 g, 1.3 mmol) and Pyridine HCl (10 g) was heated to 200° C. After 1 hr, the reaction was cooled, diluted with water and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated and the product was purified by column chromatography (50% EtOAc/Hex) to give 123 as a solid (0.25 g, 74%): Mp=274-276° C.;
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6](N)[C:5]=2[CH:4]=1.C(=O)([O-])[O-:19].[K+].[K+]>O.C(O)C>[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=[O:19])[C:5]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1NC2=O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Combine 2-methyl-4H-3-thia-4,9-diazabenzo[f]azulene-10-ylamine hydrochloride (U.S. Pat. No. 5,229,382) (50 g, 0.19 mol) and solid potassium carbonate (182 g, 1.32 mol) in a mixture of water (1 L) and ethanol (450 mL) and heat at 85° C. for 48 h. Cool to room temperature, and place in ice bath for 2 h. The desired material precipitates out as a yellow solid. Collect solid by filtration, wash with cold water, air-dry for a few minutes and place in the vacuum oven at 45° C. for 48 h to obtain 41.9 g of the title compound, which can be used directly on the next step without further purification: mass spectrum (APCI): m/z=231.0 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:46])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:42])[NH:32][C:33]5[S:34][C:35]([C:38]([F:41])([F:40])[F:39])=[N:36][N:37]=5)=[CH:27][C:26]=4[N+:43]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].C(O)C.O1CCCC1>O.C(OCC)(=O)C.[Fe]>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:46])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:42])[NH:32][C:33]5[S:34][C:35]([C:38]([F:39])([F:41])[F:40])=[N:36][N:37]=5)=[CH:27][C:26]=4[NH2:43])=[CH:22][CH:23]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3nnc(C(F)(F)F)s3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)Nc2nnc(C(F)(F)F)s2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 90 °C

Procedure:
The product of Example 154A (307 mg, 0.463 mmol), ammonium chloride (162 mg, 3.03 mmol), and iron powder (159 mg, 2.845 mmol) in a mixture of water (3 mL), ethanol (6 mL) and tetrahydrofuran (6 mL) was heated at 90° C. under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (3×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to give the product as a light yellow solid (224 mg, 76
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[C:14]([CH2:19]O)[N:15]([CH3:18])[N:16]=2)[CH:12]=[CH:11][CH:10]=1.[NH3:21].CC(O)C.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[C:14]([C:19]#[N:21])[N:15]([CH3:18])[N:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1CO
Reactant: N
Agent: O=[Mn]=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1C#N
Reaction time: 48 h
Yield: 39 %

Procedure:
To a solution of [7-(2,4-dichloro-phenyl)-2-methyl-2H-indazol-3-yl]-methanol from step 2 (0.153 g) in 2 mL of THF was added a 2 M ammonia in IPA solution (1.0 mL, 2.0 mmol), MgSO4 (0.910 g, 7.56 mmol), and 85% activated MnO2 (0.771 g, 7.54 mmol). The dark mixture was stirred for 2 d, then filtered thru CELITE® 521 (rinsing with dichloromethane) and concentrated to a yellow solid. Column chromatography (0→10% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carbonitrile (20: R3=2,4-dichlorophenyl; 0.058 g; 39%; m.p. 137-139) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([NH:29][C:30]([CH3:35])([CH3:34])[C:31]([NH2:33])=[O:32])[CH:26]([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:30]([CH3:35])([CH3:34])[C:31](=[O:32])[N:33]=3)[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: CC(C)CNC(C)(C)C(N)=O
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: Cc1c(C2=NC(=O)C(C)(C)N2CC(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 12 was synthesized from 4a (248 mg, 0.66 mmol) and 5g (160 mg, 1.01 mmol) as a white solid (110 mg, 33%) in a manner similar to that described in Example 36. 1H NMR (600 MHz, CDCl3) δ 7.46 (d, 1H), 7.29-7.24 (m, 3H), 7.11 (d, 1H), 7.06 (d, 2H), 3.78-3.75 (m, 2H), 2.34 (s, 3H), 2.03-2.01 (m, 1H), 1.44 (s, 6H), 0.85-0.82 (d, 6H); ESMS m/z: 503.1 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(O)[CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:21]>>[ClH:21].[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCCNC1
Agent: Cl
Product: c1ccc(C(=C2CCCNC2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(diphenylhydroxymethyl)piperidine (801 mg, 3.0 mmol) and 2M hydrochloric acid (12 ml) was stirred at 100° C. for 2 hours and evaporated. The residue was triturated with toluene and recrystallised from methanol to give the title compound (730 mg) as a colourless solid, m.p. 236°-237° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:22])([F:21])[CH:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[O:9]1>C(OCC)C>[Cl:1][S:2]([C:18]1[CH:19]=[CH:20][C:10]2[O:9][CH:8]([C:7]([F:22])([F:21])[F:6])[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[CH:17]=1)(=[O:5])=[O:3]
Reactant: O=C(O)C1=Cc2ccccc2OC1C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: CCOCC
Product: O=C(O)C1=Cc2cc(S(=O)(=O)Cl)ccc2OC1C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To chlorosulfonic acid (50.0 mL) chilled to −15° C. was added 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 10) (4.0 g, 16.7 mmol). After stirring at −15° C. for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. The resulting solution was added dropwise over ice (100 mL) with two diethyl ether(2×75 mL) extractions. The diethyl ether layers were combined, washed with water (2×75 mL), and brine (2×75 mL, dried over sodium sulfate and concentrated in vacuo. The resulting solids were triturated with hexane-ethyl acetate (9:1, 100 mL). The 6-chlorosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid was isolated as a white solid: mp 169-174. 1H NMR (CD3OD/300 MHz) 8.18 (d, 1H, J=2.7 Hz), 8.06 (dd, 1H, J=8.7, 2.7 Hz), 7.93 (s, 1H), 7.28 (d, 1H, J=8.7 Hz), 6.00 (q, 1H, J=6.6 Hz). EIHRMS m/z 324.9977 (M+, Calcd 324.9994).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C@@:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH2:13][C@H:12]2[C:14]([OH:16])=O)=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C.CCOC(C)=O.CCCCCCC>C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C@@:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH2:13][C@H:12]2[C:14]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=2)=[O:16])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cn1
Reactant: Cc1ncc(OC[C@@]2(c3cccc(F)c3)C[C@H]2C(=O)O)c(C)n1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(OC[C@@]2(c3cccc(F)c3)C[C@H]2C(=O)Nc2ccc(F)cn2)c(C)n1
Temperature: 2.5 °C
Reaction time: 0.42 h

Procedure:
(1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-cyclopropanecarboxylic acid (13, 12.80 g, 0.040 mol, 1.0 equiv.), and 2-amino-5-fluoropyridine (4.76 g, 0.0425 mol, 1.05 equiv.) were dissolved in ethyl acetate (102.4 mL), under nitrogen. The solution was cooled to 0-5° C., and N,N-diisopropylethylamine (14.10 mL, 0.081 mol, 2.0 equiv.) was added to the reaction mixture while maintaining the internal temperature at 0-15° C. The reaction mixture was stirred at 0-10° C. for 20-30 minutes. n-Propylphosphonic anhydride (T3P; 50% w/w solution in ethyl acetate, 36.1 g, 1.4 equiv.) was added to the reaction mixture while maintaining the internal temperature at 0-15° C., The reaction was stirred at 20-25° C. for at least 20-24 hour and monitored by HPLC and TLC (EtOAc/Heptane=1/1), Upon completion of the reaction, the reaction mixture was cooled to 0-5° C. and then was quenched with water (64.0 mL) while maintaining the internal temperature below 10-15° C. The aqueous layer was back extracted once with MTBE (76.8 mL). The organic layers were combined and washed once with saturated aqueous NaHCO3 solution (38.4 mL) and once with water (38.4 mL). The organic layer was polish filtered and the filter rinsed with MTBE (12.8 mL). The organic layer was then concentrated under reduced pressure to a minimum stirrable volume. Ethyl acetate (60.8 mL) was added to the reaction mixture and the mixture was heated to no more than 50° C. to achieve a clear solution. n-Heptane (86.3 mL) was added slowly with agitation. The reaction mixture was cooled to 20-25° C., and the suspension was stirred for at least 1 h at 20-25° C. and then stirred at least for 1 h at 0-5° C. The suspension was filtered and the cake was washed two times with 5:1 heptane/ethyl acetate (2× 12.8 mL). The cake was dried under nitrogen and/or vacuum to provide the title compound, (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide, (14, 12.54 g, >99% ee) as a white to off white solid.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8](=[O:28])[CH2:9][N:10]([S:18]([C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[C:29]([NH2:33])(=[O:32])[CH:30]=[CH2:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:6][O:7][C:8](=[O:28])[CH2:9][N:10]([S:18]([C:21]1[CH:26]=[CH:25][C:24](/[CH:31]=[CH:30]/[C:29]([NH2:33])=[O:32])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: COC(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(Br)cc1
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(/C=C/C(N)=O)cc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Sodium acetate was dissolved in water (0.5 mL). The carboxylic acid methyl ester builiding lock III, e.g. methyl{[(4-bromophenyl)sulfonyl]-4-methylanilino}acetate (398 mg, 1 mmol), in DMW (3.5 mL) was added, followed by acrylamide (78 mg, 1.11 mmol), triphenylphosphine (26.2 mg, 0.11 mmol, 10 mol %) and palladium diacetate (11.2 mg, 0.05 mmol, 5 mol %). The resulting mixture was degazed for 5 min with argon and was heated at 80° C. for 3 h. It was filtrated through celite. Water (5 mL) was added and the desired product was extracted with ethyl acetate (3×7 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent The desired product, e.g. methyl[({4-[(1E)-3-amino-3-oxo-1-propenyl]phenyl}sulfonyl)-4-methylanilino]acetate was obtained as a colorless oil, in 88% purity by HPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:16]([O:18]CC)=[O:17])=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O>CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:16]([OH:18])=[O:17])=[C:10]([C:12]([F:14])([F:13])[F:15])[N:11]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1sc(N2CCOCC2)nc1C(F)(F)F
Yield: 98.9 %

Procedure:
Add ethyl 2-morpholino-4-(trifluoromethyl)thiazole-5-carboxylate (4.58 g, 14.8 mmol) to a mixture of 1 N NaOH (20 mL) in MeOH (20 mL), and heat the reaction to 50° C. for 1 h. Concentrate the reaction under reduced pressure, and add H2O to the residue. Acidify the mixture to pH 4, and filter the solid. Wash the solid with H2O, and dry to obtain the title compound (4.13 g, 99%). ES/MS m/z 283.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].CI.[C:14](=O)([O-])O.[K+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Cc1cccc(Br)c1C(=O)O
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-6-methylbenzoic acid (5.02 g) and methyl iodide (2.9 mL) in N,N′-dimethylformamide (30 mL) was added powdered potassium hydrogen carbonate (4.67 g). The mixture was stirred at ambient temperature for 16 hours and concentrated. The concentrate was partitioned between ethyl acetate and water. The extract was washed with brine and concentrated, and the concentrate was purified by flash chromatography on silica gel with 60% ethyl acetate in hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[F-:13].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:13]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(F)c(Cl)c1
Reaction time: 15 h

Procedure:
A mixture of 3,4,5-trichloronitrobenzene (13.55 g, 59 mmol), potassium fluoride (4.65 g, 80 mmol) and dimethylformamide (DMF; 66 ml) is heated at 140° for 15 hours. An additional 2.5 g of potassium fluoride is added and the mixture is stirred an additional 15 hours at 140°. The reaction mixture is poured into water and extracted with ether. The combined organic layers are washed with water and with brine and filtered, and the solvent is removed to give a dark solid, which is purified by column chromatography to give 3,5-dichloro-4-fluoronitrobenzene, a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[I:10]I>C(O)C.C(Cl)Cl.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[CH:8]=[C:7]([I:10])[C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: II
Reactant: Nc1ccc(Cl)cc1F
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: Nc1c(F)cc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silver sulphate (1.7 g, 8.3 mmol), then followed by addition of I2 (2.1 g, 8.3 mmol) in portions. After the addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2 M sodium hydroxide (40 mL×2), saturated Na2S2O3 (40 mL×2) and water (40 mL×2). The resulting solution was dried over MgSO4 and then evaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98%).
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].C([Sn]([C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Temperature: -18 °C
Yield: 80.9 %

Procedure:
22.2 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 30.2 g of tributylstannyl-trimethylsilyl-acetylene and 3.48 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 3 hours in 300 ml of absolute toluene under a nitrogen atmosphere. After the reaction mixture has cooled to approx. -18° C., the solid is filtered off with suction, washed with toluene and dried. 18.8 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate (80% of theory) are obtained.