Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[S:20][C:15]3=[CH:16][N:17]=[CH:18][CH:19]=[C:14]3[C:13]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1>CO.Cl>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[S:20][C:15]2=[CH:16][N:17]=[CH:18][CH:19]=[C:14]2[C:13]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2sc3cnccc3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1sc2cnccc2c1Nc1ccc(I)cc1F
Reaction time: 2 h
Yield: 59.6 %

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-thieno[2,3-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (40 mg, 0.07 mmol) was dissolved in methanol (1 ml) and concentrated hydrochloric acid (1 drop) added. The mixture was allowed to stir for 2 hours then evaporated to dryness to give a residue. The residue was partitioned between aqueous saturated NaHCO3 solution (3 ml), water (20 ml) and DCM (20 ml). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to give a yellow solid. The solid was purified by flash chromatography (Si-SPE, DCM:MeOH, gradient 99:1 to 92:8) to afford the title compound as a yellow solid (21 mg, 57%). LCMS (method A): RT=7.12 min, M+H+=504. 1H NMR (d4-MeOH, 400 MHz) 9.15 (s, 1H), 8.38 (d, J=5.7 Hz, 1H), 7.52 (dd, J=10.6 Hz, 2.0 Hz, 1H), 7.44 (dd, J=5.7 Hz, 1.0 Hz, 1H), 7.32 (ddd, J=8.5 Hz, 2.0 Hz, 1.0 Hz, 1H), 6.56 (dd, J=8.5 Hz, 8.5 Hz, 1H), 4.00-4.13 (m, 1H), 3.85-3.95 (m, 2H), 3.54-3.65 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH2:22][CH2:23][CH2:24][CH3:25])(=[O:21])=[O:20])=[CH:14][CH:13]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:27]1([CH2:26][NH:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH2:22][CH2:23][CH2:24][CH3:25])(=[O:21])=[O:20])=[CH:14][CH:13]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CCCCS(=O)(=O)Nc1ccc(CCCOCCCCCCBr)cc1
Solvent: ClCCl
Product: CCCCS(=O)(=O)Nc1ccc(CCCOCCCCCCNCc2ccccc2)cc1
Reaction time: 2 h
Yield: 55.5 %

Procedure:
The product of stage (ii) (0.85 g) was added dropwise over 5 min to stirred benzylamine (1.17 g) at 120° under nitrogen. The solution was stirred at 120° under nitrogen for 2 h, cooled and diluted with dichloromethane (100 ml). The mixture was washed with 2N hydrochloric acid (40 ml), the aqueous phase was re-extracted with further dichloromethane (2×40 ml), and the combined organic extracts were washed with 8% sodium bicarbonate solution (80 ml), dried and evaporated in vacuo to give the title compound as a yellow oil (0.5 g). T.l.c. (System C 39:10:2) Rf 0.49.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-])=O.[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccccc2N)sc2ccccc12
Yield: 78.3 %

Procedure:
Ethyl 2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate (4.9 g) was dissolved in ethyl acetate (200 ml) and 10% palladium-carbon (0.5 g) was added. The mixture was stirred with hydrogen (60 kg/cm2) at 60° C. for 5 hr. The reaction mixture was cooled and the catalyst was filtered off. The filtrate was evaporated under reduced pressure to give ethyl 2-(2-aminoanilino)benzo[b]thiophene-3-carboxylate (3.5 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])=[C:15]([C:21]([OH:23])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:23])[CH2:29][CH2:27]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.8 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-isobutyl-1H-1,2,3-triazole-4-carboxylic acid (510 mg, 1.61 mmol) obtained in Example 93b), HOBt (110 mg, 0.806 mmol, 0.5 eq.) and cyclopropylamine (0.150 ml, 2.10 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 8.0 ml), WSC (378 mg, 1.93 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate-hexane (4:1, 50 ml) and washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate and diethyl ether were added to the residue. The precipitate was collected by filtration, washed with ethyl acetate-diethyl ether (1:3) and diethyl ether and dried to give the title compound as a white powder (559 mg, 1.57 mmol, 98.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH2:14][C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.O.NN.[OH-].[K+].C(O)COCCOCCO>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:24][CH:25]=1
Reactant: O=C(CCCN1CCCC1Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: OCCOCCOCCO
Product: Fc1ccc(CCCCN2CCCC2Cc2ccc(Cl)cc2)cc1

Procedure:
Heat 0.8 g of 2-(4-chlorobenzyl)-1-[3-(4-fluorobenzoyl)propyl]pyrrolidine to 170° for 2 hours with 1 ml of hydrazine hydrate, 0.5 g of potassium hydroxide and 5 ml of triglycol. After cooling the obtained reaction mixture to ambient temperature, add water and diethyl ether thereto. Dry the ethereal phase over sodium sulfate and distil off the solvent to obtain the title compound as brownish viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: Oc1ccncc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 10.1 g Pyridin-4-ol and 10 g 1-Fluoro-4-nitro-benzene and 46.1 g Cs2CO3 in 30 mL DMF was stirred at RT for 2 h. This solution was poured on to 300 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried under reduced pressure. Yield: 11.2 g.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([C:31]([OH:33])=[O:32])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:34][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:34][O:32][C:31]([CH:20]1[CH2:19][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[CH2:23][CH2:22][N:21]1[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperazine-1,2,4-tricarboxylic acid 1-tert-butyl ester 4-(9H-fluoren-9-ylmethyl) ester (2.21 mmol) in toluene:methanol (9:1) was added equimolar trimethylsilyldiazomethane (2.0 M in hexanes) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (30%). ESI-MS m/z: 467 (M+1), UV retention time: 3.04 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](Br)[CH:15]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][N:20]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:20]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]3=[N:18][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Reactant: Nc1cc(Cl)ccn1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3cc(Cl)ccn23)CC1
Yield: 62.5 %

Procedure:
The title compound was prepared from 350 mg of 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)-piperidine (from Example 292, Step C) and 162 mg of 2-amino-4-chloropyridine (prepared using procedures analogous to those described by R. J. Sundberg et al, Org. Preparations & Procedures Int. 1997, 29, (1), 117-122) in 10 mL ethanol using a procedure analogous to that described in Example 235, Step A to provide 240 mg of the title compound as a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]([NH2:15])=[NH:14])[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].C([O:21][C:22]([C:24]1[CH:29]=[CH:28][N:27]=[N:26][C:25]=1Cl)=O)C.C([O-])([O-])=O.[K+].[K+].Cl>CO.CN(C=O)C.O>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]2[NH:15][C:22](=[O:21])[C:24]3[CH:29]=[CH:28][N:27]=[N:26][C:25]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N=C(N)COCCc1cccc(Cl)c1
Reactant: CCOC(=O)c1ccnnc1Cl
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1[nH]c(COCCc2cccc(Cl)c2)nc2nnccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3.6 %

Procedure:
2-[2-(3-Chloro-phenyl)-ethoxy]-acetamidine hydrochloride (240 mg, 0.964 mmol; described in example 6.2) was dissolved in MeOH (2 ml) and NaOMe (30% solution in MeOH, 179 μl, 0.964 mmol) was added dropwise at 0° C. The suspension was stirred at ambient temperature for 15 min and then evaporated. To the remaining residue were added a solution of crude 3-chloro-pyridazine-4-carboxylic acid ethyl ester (180 mg) in DMF (3 ml) and subsequently K2CO3 (267 mg, 1.929 mmol) and the mixture was heated to 100° C. for 18 h. Then water was added, the pH was adjusted to 3 by addition of 0.1 N HCl and the mixture was extracted three times with CH2Cl2 and one time with ethyl acetate. The combined organic extracts were washed three times with diluted HCl (pH 3), dried (Na2SO4) and evaporated. The remaining residue was triturated with Et2O and the brown solid was filtered off and further purified by column chromatography (silica gel, CH2Cl2/MeOH 95:5) to give the title compound (11 mg, 0.035 mmol; 3.6%) as brown solid. MS: m/e=317.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[Cl:28]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[C:27]([Cl:28])[CH:26]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(Cl)c(Cl)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3,4-dichloro-phenylboronic acid (61 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][O:16][CH2:17][CH2:18][NH2:19]>O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:19][CH2:18][CH2:17][O:16][CH3:15])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: COCCN
Solvent: O
Product: COCCNc1cc(Cl)nc(-c2ccccc2)n1

Procedure:
Seven grams of 4,6-dichloro-2-phenylpyrimidine is added in small portions to 30 ml. of β-methoxyethylamine with slight warming and stirring. The resulting mixture is heated on a steam bath for several minutes and then poured into 500 ml. of water. The product thus obtained (5.1 g.) is recrystallized from n-heptane to afford 4-chloro-6-(2-methoxyethylamino)-2-phenylpyrimidine, 48.5°-50°C.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[O:9])[CH:5]([C:10]([O:12]CC)=[O:11])[CH2:4]1)[CH3:2].[Li+].[OH-].C(Cl)Cl>C1COCC1.O>[CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[O:9])[CH:5]([C:10]([OH:12])=[O:11])[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C1CN(CC)C(=O)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCN1CC(C(=O)O)C(=O)C1=O
Yield: 71.5 %

Procedure:
A solution of ethyl 1-ethyl-4,5-dioxopyrrolidine-3-carboxylate (150 mg, 0.753 mmol) and LiOH (43.3 mg, 1.81 mmol) in THF (0.5 mL) and H2O (0.5 mL) was heated at 80° C. for 1 h using microwave irradiation. The reaction solution was concentrated under reduced pressure and acidified with 1 N aqueous HCl, whereupon a precipitate formed. CH2Cl2 was added to the suspension and the precipitate was collected by filtration and dried in vacuo to provide Intermediate 8 (92.1 mg, 71.4% yield). HPLC/MS (Method D) RT=0.48 min, [M+H]+ 172.1; 1H NMR (400 MHz, Solvent) (δ ppm): 1.11-1.24 (m, 3H), 3.53 (q, J=7.28 Hz, 2H), 3.84 (s, 0.47; H), 4.04 (s, 1.53; H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1>>[CH3:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][N:23]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccnc(C)c3)ccn2c1=O

Procedure:
Methyl 8-(2-methylpyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (2-methylpyridin-4-yl)boronic acid (56.3 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8])=O.[CH3:9][NH:10][CH2:11][CH2:12][NH:13][CH3:14]>C1(C)C=CC=CC=1>[CH3:9][N:10]1[CH2:11][CH2:12][N:13]([CH3:14])[CH:1]1[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CNCCNC
Reactant: Cc1ccsc1C=O
Solvent: Cc1ccccc1
Product: Cc1ccsc1C1N(C)CCN1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
2-Formyl-3-methylthiophene (3.0 g, 23.8 mmol) and N,N′-dimethylethylenediamine (2.3 g, 26.2 mmol) were dissolved in toluene (80 mL), and the mixture was stirred at 120° C. overnight. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (3.1 g, 15.8 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)[C:9]=2[F:34])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:24][NH:25][CH3:26])[C:9]=2[F:34])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(OC)c2)c(-c2cccnc2Cl)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.4 %

Procedure:
To a solution of tert-butyl ({5-(2-chloropyridin-3-yl)-4-fluoro-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (501 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 321 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8]CC)=[O:7].Cl>C(O)(=O)C>[Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C)Oc1ccc(Cl)c(C)c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(Cl)ccc(OC(C)C(=O)O)c1Cl
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 86.7 %

Procedure:
In 100 ml of ethanol was dissolved 10.0 g. (0.05 mole) of sodium 2,4-dichloro-3-methylphenolate. With stirring at room temperature, 9.1 g (0.05 mole) of ethyl 2-bromopropionate was added. The mixture was heated under relfux for 4 hours. The ethanol was distilled off under reduced pressure, and the residue was extracted with 50 ml of diethyl ether. The ethereal layer was washed with 25 ml of a 5% aqueous solution of sodium hydroxide and 25 ml of water, and dried over anyhdrous magnesium sulfate. The dessicant was removed by filtration, and the diethyl ether was distilled off to give 11.8 g of crude ethyl 2-(2,4-dichloro-3-methylphenoxy)propionate. The crude ester (11.8 g) was dissolved in 100 ml of glacial acetic acid. Concentrated hydrochloric acid (25 ml) was added, and the mixture was stirred at 100° C. for 40 minutes. The reaction mixture was cooled, and poured onto 300 ml of ice water. The precipitated crystals were filtered, washed with water, and dried to give 9.2 g of 2-(2,4-dichloro-3-methylphenoxy)-propionic acid. The yield was 73.9% based on the sodium 2,4-dichloro-3-methylphenolate, and the final product had a melting point of 149.5 to 150.5° C.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([F:14])=[N:9][CH:10]=[C:11]([F:13])[CH:12]=2)[CH2:3][CH2:2]1>CO.[Pd]>[F:14][C:8]1[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:12][C:11]([F:13])=[CH:10][N:9]=1
Reactant: Fc1cnc(F)c(C2=CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: Fc1cnc(F)c(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a solution of 3-(3,6-dihydro-2H-pyran-4-yl)-2,5-difluoro-pyridine (3.7 g, 18.8 mmol) in MeOH (40 mL) was added Pd/C (1.0 g). The reaction solution was stirred at RT overnight under H2 atmosphere until LCMS showed that the starting material was consumed completely. The mixture was filtered and the filtrate was concentrated to give the product (2.9 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:39])[NH:32][C:33]2([C:36]([OH:38])=O)[CH2:35][CH2:34]2)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.C1(C2C=CC=CC=2)C=CC=CC=1.[C:52]1([P:58](=[CH:60][C:61]#[N:62])=[O:59])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]1([C:15]2[CH:16]=[CH:17][CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:61]([C:60](=[P:58]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:59])[C:36]([C:33]1([NH:32][C:31]([NH:30][C@@:15]([C:4]2[CH:5]=[C:6]([O:8][C:9]([F:13])([F:14])[CH:10]([F:11])[F:12])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:39])[CH2:34][CH2:35]1)=[O:38])#[N:62]
Reactant: N#CC=[P+]([O-])c1ccccc1
Reactant: O=C(NC1(C(=O)O)CC1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Product: N#CC(C(=O)C1(NC(=O)N[C@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)CC1)=[P+]([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 81.3 %

Procedure:
To a solution of (R)-1-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)-cyclopropanecarboxylic acid (84 mg, 0.153 mmol), prepared by the method described in Procedure 30, in DCM (0.5 mL) was added 2-(phenylphosphinylidene)acetonitrile compound with biphenyl (1:1) (51 mg, 0.168 mmol), EDCI (32 mg, 0.168 mmol) and DMAP (3 mg, 0.024 mmol). The reaction mixture was stirred at room temperature for 4.5 h, concentrated under reduced pressure and purified by ISCO chromatography (12 g column, eluting with 0-100% hexane/EtOAc) to yield (R)-1-(1-(2-cyano-2-(phenylphosphinylidene)acetyl)cyclopropyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea compound with biphenyl (1:1) as a white solid (53 mg, 42% yield). LCMS: RT=3.49 min [M+H] 836.4 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 50-100% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) ppm 0.78-1.00 (m, 2H), 1.34-1.49 (m, 2H), 3.79-3.95 (m, 2H), 5.62-5.98 (m, 3H), 6.67-6.94 (m, 7H), 6.98-7.20 (m, 5H), 7.37-7.66 (m, 15H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10](C3C=CC(OC)=CC=3)[C:11](=[S:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][OH:26].C(Cl)Cl>[OH-].[Na+]>[OH:26][CH2:25][CH2:24][S:14][C:11]1[S:12][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1
Reactant: OCCBr
Reactant: COc1ccc(-c2csc(=S)n2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(-c2nc(SCCO)sc2-c2ccc(OC)cc2)cc1

Procedure:
100 g of 4,3-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 320 ml of 2 N sodium hydroxide solution while stirring. 45 ml of 2-bromoethanol are then added, the mixture is stirred at room temperature for 15 minutes, 500 ml of methylene chloride are added, the mixture is filtered through diatomaceous earth, the organic layer is removed and extracted by washing with 200 ml of 2 N sodium hydroxide solution. The combined aqueous phases are subsequently extracted twice with methylene chloride. The organic phases are combined, dried over magnesium sulphate and concentrated by evaporation under reduced pressure. The remaining oil is dissolved in 700 ml of hot diethyl ether, stirred for 1 hour and caused to crystallise at 10°. The crystals are filtered with suction, then washed twice with 150 ml of ice-cold diethyl ether each time and dried under reduced pressure. 2-(2-Hydroxyethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 82°-83° is obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][C:15]([CH3:24])([CH3:23])[C:16]([OH:22])([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])=[CH:12][C:11]=1[CH3:27]>C(Cl)(Cl)Cl>[Br:1][CH2:20][CH:19]1[CH2:18][CH2:17][C:16]([C:15]([O:14][C:13]2[CH:25]=[CH:26][C:10]([Cl:9])=[C:11]([CH3:27])[CH:12]=2)([CH3:23])[CH3:24])([CH3:21])[O:22]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCCC(C)(O)C(C)(C)Oc1ccc(Cl)c(C)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(OC(C)(C)C2(C)CCC(CBr)O2)ccc1Cl
Yield: 86.6 %

Procedure:
60 g (0.37 mol) of N-bromosuccinimide are added in portions to 88.8 g (0.3 mol) of 6-(4-chloro-3-methylphenoxy)-5-hydroxy-5,6,6-trimethyl-1-hexene in 600 ml of absolute chloroform, while stirring and cooling, so that the reaction temperature does not exceed 40° C. When the addition has ended, the mixture is stirred at room temperature for a further 14 hours and then washed twice with water and dried over sodium sulphate and the solvent is removed in vacuo. 94 g (82% of theory) of 2-bromomethyl-5-[2-(4-chloro-3-methylphenoxy)-prop-2-yl]-5-methyl-tetrahydrofuran are obtained and are further reacted without purification.