Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]1([N:33]=[C:34]=[O:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:34]([NH:33][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:35])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1cccc2ccccc12
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc5ccccc45)cc3)c2cc1OC
Yield: 52 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, 1-naphthyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 20 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 41 mg of the title compound (yield: 52%).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.[N+:24]([C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30])([O-:26])=[O:25]>ClCCl>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[N+:24]([O-:26])=[O:25])[CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc21
Reaction time: 12 h
Yield: 107.9 %

Procedure:
To a stirring solution of 1-Boc-6-aminoindazole (1.5 g, 6.4 mmol) in dichloromethane (25 mL) was added pyridine (1.55 mL, 19.2 mmol) followed by 2-nitrobenzoyl chloride (1 mL, 7.1 mmol). After stirring for 12 h, the solvent was removed by rotary evaporation and the residue was partitioned between ethyl acetate (250 mL) and water (250 mL). The aqueous phase was separated and the organic phase was washed with 1 M citric acid, brine, satd aq NaHCO3, and brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo to give 2.64 g of off-white solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.I[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]3[N:7]([C:11]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=4)=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[N:13]=3)[CH:8]=[CH:9][N:10]=2)[CH2:2][CH2:3]1
Reactant: Fc1ccc(-c2cn3ccnc(CC4CC4)c3n2)cc1
Reactant: CSc1nccc(I)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(CC4CC4)nccn23)n1
Temperature: 100 °C
Yield: 60.5 %

Procedure:
Into a flask were added 8-cyclopropylmethyl-2-(4-fluorophenyl)imidazo[1,2-a]pyrazine (5.84 g, 21.8 mmol), 4-iodo-2-(methylthio)pyrimidine (Frontier, 8.27 g, 32.8 mmol), Cs2CO3 (10.7 g, 32.8 mmol), PPh3 (2.29 g, 8.73 mmol), and DMF (50 mL). The mixture was degassed by bubbling Ar through it for about 5 min, before being charged with Pd(OAc)2 (0.981 g, 4.37 mmol) and heated at about 100° C. for about 18 h. The reaction was cooled to ambient temperature, the solvent was removed in vacuo, and the residue taken up in DCM and water. After filtration through a pad of Celite®, the organic layer was separated and the aqueous layer extracted about five more times with DCM, filtering through Celite® in every extraction step to break emulsions. The combined organic phase was dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography with heptane/EtOAc (gradient 20-80% EtOAc). After concentration, the residue was twice re-dissolved in DCM and re-concentrated to give 5.16 g (60%) of the title compound as a greenish solid: LC/MS (Table 1, Method g) Rt=3.43 min; MS m/z: 392.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH:9]([NH2:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:18][CH:9]([C:8]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:29])=[O:28]
Reactant: CC1CCN(C(=O)C(N)CCc2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CCN(C(=O)C(CCc2ccccc2)NS(=O)(=O)c2ccccc2Cl)CC1
Reaction time: 16 h

Procedure:
A mixture of 29 mg (0.11 mmol) of 1-(4-methylpiperidin-1-yl)-1-oxo-4-phenylbutan-2-amine, 2-chlorobenzenesulfonyl chloride, and 0.19 mL (0.11 mmol) of iPr2NEt in 4 mL of CH2Cl2 is stirred for 16 h, concentrated, and purified by preparative HPLC to provide Example 1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)=O.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([N:26]2[C:13](=[O:15])[C:12]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[C:5]([C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Cl:1])[CH:3]=3)=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccnc1C(=O)c1cccc(Cl)c1
Reactant: NNc1ccccc1
Solvent: CCO
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)nn1-c1ccccc1
Yield: 71.5 %

Procedure:
A solution of 2-(3-chlorobenzoyl)-3-methoxycarbonylpyridine (0.30 g, 1.09 mmoles), phenylhydrazine (0.27 ml, 2.72 mmoles) in ethanol (18 ml) was stirred at 100° C. for 72 hours. The solution was cooled and the solvent was removed. The residue was triturated with methanol to give a white solid, which was collected and air dried, yielding 0.26 g of 6-phenyl-8-(3-chlorophenyl)pyrido[2,3-d]pyridazin-5-one (71.5%), mp 144°-145° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:11][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1H-indole-3-carboxylic acid (5 g, 31 mmol) in DMF (70 mL) under nitrogen atmosphere at 0° C. was added cesium carbonate (11 g, 31 mmol) and benzyl bromide (4.05 mL, 34.1 mmol). The reaction mixture was stirred at RT for 48 h and poured into water. EtOAc was added and the layers were separated, the aqueous one being back extracted three times with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The residue was taken up in Et2O and the resulting precipitate was filtered-off to give the title compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.55; MS (LC-MS): 252.1 [M+H]+, 274.0 [M+Na]+, 525.1 [2M+Na]+, 250.1 [M−H]−; tR (HPLC conditions a) 3.77 min.
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].CCN(C(C)C)C(C)C.O=S(Cl)[Cl:45]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:33])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)[Cl:45])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(Oc2ccc(C(O)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Oc2ccc(C(Cl)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of alcohol (535 mg, 1.14 mmol) from step 2 and i-Pr2NEt (436 mL, 2.5 mmol) in 10 mL of anhydrous toluene, was slowly added SOCl2 (145 mnL, 2.0 mmol). The resulting yellow solution was stirred 30 minutes at 0° C., 10 minutes at room temperature, quenched with water and diluted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was used directly for the next step without any purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)[CH2:11][O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[N:16]=2)[CH2:11][O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C#Cc2cccc(C(F)(F)F)n2)COC1(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2cccc(C(F)(F)F)n2)COC1(C)C

Procedure:
To a solution of (S)-2,2-dimethyl-4-(6-trifluoromethyl-pyridin-2-ylethynyl)-oxazolidine-3-carboxylic acid tert-butyl ester (0.58 g, 1.56 mmol) in methanol (8 ml) were added ammonium formate (0.983 g, 15.6 mmol) and palladium on charcoal (10% Pd, 0.58 g). The mixture was refluxed for 1 hour. After cooling the solid was filtered off, the filtrate was evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=7:3 to yield a light colourless liquid, (0.538 g, 92%); MS (ISP): 375.5 ((M+H)+/).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH:22]=[CH:23][C:24](Cl)=[O:25]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:24](=[O:25])[CH:23]=[CH:22][C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)C=Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Product: CCOC(=O)c1cc(C(=O)C=Cc2ccc3ccccc3c2)c(C)[nH]1

Procedure:
5-Methyl-4-(3-naphthalen-2-yl-acryloyl)-1H-pyrrole-2-carboxylic acid ethyl ester (132) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and 3-naphthalen-2-yl-acryloyl chloride following the procedure described in Example 32. Reaction conditions: 1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS: 40%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH2:4][C@H:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].O1CCCC1.O.[Li+].[OH-].Cl>CCOCC>[NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH2:4][C@H:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: CCOC(=O)C1CCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N[C@@H]1CC(CN2CCC(C(=O)O)CC2)=CC[C@H]1c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of Example 11C (36 mg, 0.088 mmol) in mixture of tetrahydrofuran/H2O (0.3 mL/0.15 mL), LiOH (23 mg, 0.53 mmol) was added at room temperature. The reaction mixture was stirred overnight. It was acidified with 2N HCl in ether until pH=3 and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (25 mg, 75%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.90-8.07 (m, 3H), 7.67 (s, 1H), 7.47-7.58 (m, 2H), 6.01-6.14 (m, 1H), 3.66-3.96 (m, 2H), 2.57-3.04 (m, 4H), 1.65-2.46 (m, 9H). MS (ESI) m/z 383 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]=[O:27])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCSc1ccc(C=O)cc1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a solution of 3.15 g (10.0 mmol) of 1-bromo-4-(nonylthio)benzene in 50 mL anhydrous THF was slowly added 9.4 mL of n-BuLi (1.6 M in hexanes, 15 mmol) at −50° C. The mixture was aged at the same temperature for 1 h before the addition of 2.3 mL of anhydrous DMF. The reaction mixture was allowed to warm to 0° C. and was quenched with 2 N HCl to pH=1. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layer and extractions were washed with water and concentrated to oil. Flash chromatography on a Biotage 40M cartridge using 5% ethyl acetate/hexanes afforded 2.35 g (89%) of the title compound as light yellow oil: 1H NMR (500 MHz) δ 0.91 (t, J=7.0, 3H), 1.30-1.76 (m, 14H), 3.03 (t, J=7.4, 2H), 7.37 (d, J=8.5, 2H), 7.78 (d, J=8.5, 2H), 9.95 (s, 1H); LC-1: 4.8 min; ESI-MS 265 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[C:33](Cl)=[C:32](OC)[CH:31]=[C:30](OC)[C:29]=4Cl)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[S:62]1C=C(C2C3N=CC=NC=3C(C(O)=O)=CC=2)[C:64]2C=CC=C[C:63]1=2.S1C2C=CC=CC=2C(B(O)O)=C1>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:64][C:63]=5[S:62][CH:33]=4)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(-c2csc3ccccc23)c2nccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: OB(O)c1csc2ccccc12
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4csc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture at rt overnight and using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid. The carboxylic acid was synthesized as described in Steps 1.2-1.7 but using benzothiophene-3-boronic acid in Step 1.4. Title compound: ESI-MS: 494.9 [M+H]+; tR=3.77 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.[I:18]C1C=CC=CC=1.II.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([I:18])[CH:3]=1
Reactant: Ic1ccccc1
Reactant: COc1ccc(Br)cc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Bromo-anisole (4.417 g, 23.6 mmol) was dissolved in acetonitrile (200 mL) and placed under an argon atmosphere in the absence of light. Iodobenzene diacetate (9.18 g, 28.5 mmol) was added followed by iodine (3.6 g, 14.2 mmol). The mixture was stirred for 16 hours at ambient temperature. The mixture was then poured into 1M Na2S2O3 (200 mL) and stirred until the solution was colourless. The solution was then extracted with diethyl ether (3×100 mL). The combined organic extracts were then washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The crude product was filtered through a silica gel plug eluting with heptane/ethyl acetate (3:1) (200 mL). The filtrate was concentrated and the residue was distilled using a Kugelrohr apparatus collecting the compound at 75° C., 0.01 mbar.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:50][C:51]([F:64])([F:63])[C:52]1[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=1)[O:55][CH:56]1[CH2:59][NH:58][CH2:57]1>CN(C=O)C.O>[O:27]=[C:25]([N:58]1[CH2:59][CH:56]([O:55][C:54]2[CH:60]=[CH:61][CH:62]=[C:52]([C:51]([F:50])([F:64])[F:63])[CH:53]=2)[CH2:57]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 51.8 %

Procedure:
DIPEA (158.2 mg, 1.22 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (75 mg, 0.30 mmol) in DMF (2 mL) followed by HOBt (43.4 mg, 0.32 mmol) and EDCI (61.6 mg, 0.32 mmol). After 2 minutes of stirring, 3-(3-trifluoromethyl-phenoxy)-azetidine hydrochloride (77.5 mg, 0.3 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added followed by extraction with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (using silica gel 60- and 100% ethyl acetate as eluent) to afford 69 mg (51.1% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[3-(3-trifluoromethyl-phenoxy)-azetidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 445.14, 90.72%. 1H NMR (300 MHz, DMSO-d6): δ 14.8 (s, 1H), 8.2 (t, 1H), 7.78 (t, 2H), 7.5 (t, 1H), 7.3 (m, 5H), 7.16 (d, 2H), 7.1 (d, 1H), 5.18 (m, 1H), 4.64 (q, 1H), 4.36 (m, 1H), 4.18 (m, 1H), 3.84 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:31][C:32]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH3:43])[CH:35]=2)=[O:33])=[CH:4][C:5]([F:30])=[C:6]([CH2:8][C:9]([N:11]2[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]2[CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH:23]([C:26]([O:28]C)=[O:27])[CH2:22][CH2:21]2)=[O:10])[CH:7]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([NH:31][C:32]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH3:43])[CH:35]=2)=[O:33])=[CH:4][C:5]([F:30])=[C:6]([CH2:8][C:9]([N:11]2[CH2:15][C:14]([F:16])([F:17])[CH2:13][C@H:12]2[CH2:18][O:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([C:26]([OH:28])=[O:27])[CH2:22][CH2:21]2)=[O:10])[CH:7]=1
Reactant: COC(=O)C1CCC(OC[C@@H]2CC(F)(F)CN2C(=O)Cc2cc(Cl)c(NC(=O)c3cn(C)c4ccccc34)cc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2cc(F)c(CC(=O)N3CC(F)(F)C[C@H]3CO[C@H]3CC[C@H](C(=O)O)CC3)cc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To methyl 4-(1-(5-chloro-2-fluoro-4-(1-methyl-3-indolylcarbonylamino)phenylacetyl)-4,4-difluoro-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylate (620 mg, 0.53 mmol) were added THF (4.5 ml) and 0.25N NaOH (4.5 ml). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl, followed by extraction with chloroform-methanol (5:1, v/v). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. By chromatography using a silica gel thin-layer plate (Whatman TLC), two diastereomers were separated from the residue, whereby from chloroform-methanol (40:1, v/v×3) eluate fractions, trans-4-(1-(5-chloro-2-fluoro-4-(1-methyl-3-indolylcarbonylamino)phenylacetyl)-4,4-difluoro-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylic acid (53 mg, 16%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:38])[C:22]([N:24]([CH:35]([CH3:37])[CH3:36])[CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:23])[C:17]1=[O:39])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:27][CH2:26][CH2:25][N:24]([CH:35]([CH3:37])[CH3:36])[C:22](=[O:23])[C@@H:21]([N:18]1[CH2:19][CH2:20][C@H:16]([NH:15][S:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH:8]=2)(=[O:13])=[O:14])[C:17]1=[O:39])[CH3:38]
Reactant: CC(C)N(CCNC(=O)OC(C)(C)C)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCN)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
tert-Butyl 2-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]ethylcarbamate (0.21 g) was dissolved in DCM (4 ml), and trifluoroacetic acid (4 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate solution and DCM, and the organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with DCM, diethyl ether, ethyl acetate, methanol and methanol:10% aqueous ammonia) to give the title compound (0.124 g) as a white solid.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19](C(Cl)(Cl)Cl)[N:18]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)[C:17]=2[CH:32]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19]([O:5][CH:3]3[CH2:4][O:1][CH2:2]3)[N:18]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)[C:17]=2[CH:32]=1
Reactant: OC1COC1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(OC3COC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of oxetan-3-ol (0.04 ml, 0.61 mmol) in DMF (5 ml) at 0° C. was added cesium carbonate (499.75 mg, 1.53 mmol) followed by 4-[6-bromo-2-(trichloromethyl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine (250 mg, 0.61 mmol). The reaction was stirred at RT overnight, then re-charged with oxetan-3-ol (3 eq) and stirred for a total of 5 days at RT. Water was added (15 ml) to the combined reaction mixtures and the product extracted into DCM (2×30 ml). The combined organic extracts were washed with water and brine (10 ml each), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound; 1H NMR (500 MHz, DMSO) delta 4.83-4.70 (2H, m), 5.03-4.89 (2H, m), 5.85-5.75 (1H, m), 7.19-7.05 (3H, m), 7.51-7.34 (2H, m), 8.40 (1H, d, J=5.5 Hz), 8.45 (1H, d, J=1.7 Hz); LC-MS: m/z=+362/364 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14](=[O:17])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.CO[C:20](OC)([CH3:22])[CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C:14](=[O:17])[CH2:15][O:16][C:20]3([CH3:22])[CH3:21])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: O=C(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OCC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 90 °C
Yield: 53.1 %

Procedure:
N-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-2-hydroxyacetamide (0.35 g, 1.12 mmol), prepared in the previous step, was suspended in 10 mL of toluene, dimethoxypropane (2.0 mL, 16.7 mmol) was added, which was followed by a catalytic amount of p-toluenesulfonic acid monohydrate (20 mg). The mixture was heated to 90° C. for 16 h, then cooled and concentrated under reduced pressure. Flash chromatography (5% acetone/hexane) provided the title compound (210 mg, 53%) as a white solid. HRMS: calcd for C14H13BrN2O2S+H+, 352.99538; found (ESI, [M+H]+), 352.9957. Analytical HPLC: retention time 11.1 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.