Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][C@@H:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([O:27]CC)=[O:26])[CH2:20]3)[CH2:14][O:15]2)=[CH:10][CH:9]=1.[OH-].[Na+].[ClH:44].Cl.O1CCOCC1>CCO.O1CCOCC1.C1COCC1>[ClH:44].[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][C@@H:34]([CH3:39])[C:35]([F:36])([F:37])[F:38])[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([OH:27])=[O:26])[CH2:20]3)[CH2:14][O:15]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CC2=Cc3ccc(OCc4ccc(O[C@@H](C)C(F)(F)F)c(C(F)(F)F)c4)cc3OC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(COc2ccc3c(c2)OCC(CN2CCC[C@@H](C(=O)O)C2)=C3)cc1C(F)(F)F)C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylate (271 mg) in EtOH (5.4 mL)-THF (2.7 mL) was added a 1 M aqueous NaOH solution (923 μL), followed by stirring at 50° C. for 2 hours. The reaction liquid was cooled to room temperature, then 1 M hydrochloric acid (923 μL) was added thereto, and the vehicle was evaporated. The residue was purified by reverse phase chromatography (H2O:MeCN=100:0 to 30:70) to obtain a yellow oily substance, which was dissolved in dioxane (3 mL), treated with 4 N HCl/dioxane (1 mL), and washed with IPE to obtain (3R)-1-[(7-{[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzyl]oxy}-2H-chromen-3-yl)methyl]piperidine-3-carboxylic acid hydrochloride (215 mg) as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:13][N:12]=[C:11]2[C:7]=1[CH2:8][CH:9]1[C:14]([CH3:16])([CH3:15])[CH:10]12)=[O:5])C.CO.[OH-].[Li+]>C1COCC1>[CH3:15][C:14]1([CH3:16])[CH:9]2[CH2:8][C:7]3[C:11]([CH:10]12)=[N:12][NH:13][C:6]=3[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]nc2c1CC1C2C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)C2Cc3c(n[nH]c3C(=O)O)C21

Procedure:
(±)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (0.0390 g, 0.177 mmol) was stirred for 18 hours at room temperature in a solution of 1:5:1 methanol:THF:1M aqueous lithium hydroxide (14 mL). Solvent was removed under reduced pressure, the residue was taken up in 1M aqueous hydrochloric acid (5 mL) and extracted into ethyl acetate (40 mL). Solvent was removed under reduced pressure and the residue purified by preparative HPLC to give a white solid. m/z (ES+): 215 [M+Na]+, 193 [M+H]+, 175 [M−OH]+; 1H NMR (CD3CN): δ 2.91 (dd, 1H, J1=17.4, J2=6.8), 2.66 (d, 1H, J=17.4), 2.11 (dd, 1H, J1=6.3, J2=1.2), 2.05–1.95 (m, 1H), 1.19 (s, 3H, exo-CH3), 0.77 (d, 3H, J=2.0, endo-CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:5]=1[C:6]#[N:7])([O-])=O.C(O)(=O)C.C>[Fe].CC(O)C>[NH2:1][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:5]=1[C:6]#[N:7]
Reactant: COc1ccc([N+](=O)[O-])c(C#N)c1OC
Agent: [Fe]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1ccc(N)c(C#N)c1OC
Yield: 88.3 %

Procedure:
Iron powder (8.70 g, 156 mmol) was added to a suspension of 2-nitro-5,6-dimethoxybenzonitrile (9.30 g, 44.5 mmol) in an acetic acid (30 ml) and 2-propanol (30 ml) mixture. The mildly exothermic reaction which resulted was allowed to reach 100° and a gentle reflux was maintained for 1 hour with application of heat. Charcoal (10 g) was added, the reaction mixture filtered, and the solid residue obtained was washed with hot 2-propanol (100 ml). The combined filtrates were evaporated to an oily residue which was redissolved in CHCl3 and washed with 5% aqueous NaHCO3 and saturated aqueous NaCl solution. The CHCl3 phase was dried with Na2SO4 and evaporated in vacuo to yield 7.0 g (88.4%) of the target compound as an oil.
Reaction SMILES: C([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]2[S:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:18][C:10]=2[CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].[Cl:30]C(OC(Cl)C)=O>C(Cl)Cl.CCO>[ClH:30].[CH3:14][C:12]1([CH3:15])[CH2:13][NH:8][CH2:9][C:10]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:16][C:11]1=2
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCOC(=O)c1cc2c(s1)C(C)(C)CN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc2c(s1)C(C)(C)CNC2
Product: Cl
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A solution of ethyl 5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (14.6 g, 0.044 mol) in anhydrous DCM was cooled to 0° C. whereupon K2CO3 (6.1 g, 0.044 mmol) and α-chloroethyl chloroformate (6.97 g, 0.049 mol) were added. Upon complete addition, the reaction was heated at reflux overnight. The reaction was cooled to room temperature and diluted with DCM, then washed with saturated aqueous NaHCO3 and brine respectively. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford an oily residue which was taken up in EtOH and refluxed for 2 hours. The solvent was evaporated to dryness and the residue was washed with ethyl acetate to afford the desired product (9.6 g, 79%). 1H NMR (400 MHz, DMSO) δ 9.82 (s, 2H), 7.64 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.15 (s, 2H), 3.26 (s, 2H), 1.42 (s, 6H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:31][C:28]3[CH:27]=[CH:26][C:25]([O:24][C:19]4[N:18]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:30][CH:29]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(Oc2ncccn2)cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was suspended in EtOH and 4-(2-pyrimidinyloxy)benzenecarbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain B64 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[O:11]([C@H:15]1[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]1)[N+:12]([O-:14])=[O:13].C(OCC)(=O)C>O>[CH:1]([NH:21][C@H:18]1[CH2:17][CH2:16][C@H:15]([O:11][N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=CN[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.8 ml (0.072 mol) acetic acid anhydride and 2.8 ml (0.072 mol) formic acid is heated for 2 h to 60° C. and thereafter mixed, with cooling at 5° C., with 1.9 g (0.012 mol) trans-4-nitroxycyclohexylamine. One leaves to stir overnight at room temperature, subsequently dilutes with 100 ml ethyl acetate and adds 100 ml of water thereto. After neutralisation with saturated sodium hydrogen carbonate solution, the organic phase is dried with sodium sulphate and distilled off in a vacuum. After trituration with ether, the crystals are filtered off with suction. One obtains 1.5 g of the title compound of the m p 148°-150° C., i.e. 66% of theory.
Reaction SMILES: [CH2:1]([Li])CCC.[Br-].[CH3:7][CH:8]([CH3:30])[CH2:9]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=O>O1CCCC1>[Br:31][CH:32]([CH3:1])[CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:7][CH:8]([CH3:30])[CH3:9]
Reactant: CC(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCCCCBr
Reactant: [Li]CCCC
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)CC=CCCCC(C)Br
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
n-Butyl lithium (1.5M solution in hexane, 6.8 ml) was added to a stirred suspension of (3-methylbutyl)-triphenylphosphonium bromide (4.1 g) in dry tetrahydrofuran (50 ml) at -60° C. under nitrogen. The dark mixture was stirred for 40 minutes at -70° C. then a solution of 6-bromohexanal (1.8 g) in dry tetrahydrofuran (6 ml) was added. The pale mixture was stirred for a further 1 hour at -70° C. then evaporated under vacuum. The residue was extracted with ether and the extract was evaporated to a pale oil which was chromatographed on silica gel, eluting with 1:1 ether:hexane, to give the title compound as a colourless oil. MS M+ 232/234.
Reaction SMILES: [CH3:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3].C1CCCCC1.[Cl:17][C:18]1[CH:19]=[C:20]([C:27]([CH3:36])([CH3:35])[CH2:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:21]2[O:25][CH2:24][CH2:23][C:22]=2[CH:26]=1.C1COCC1>>[Cl:17][C:18]1[CH:19]=[C:20]([C:27]([CH3:36])([CH3:35])[CH2:28][C@:29]([CH2:1][S@:2]([C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=2)=[O:3])([OH:34])[C:30]([F:31])([F:32])[F:33])[C:21]2[O:25][CH2:24][CH2:23][C:22]=2[CH:26]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:27]([CH3:36])([CH3:35])[CH2:28][C@@:29]([CH2:1][S@:2]([C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=2)=[O:3])([OH:34])[C:30]([F:31])([F:32])[F:33])[C:21]2[O:25][CH2:24][CH2:23][C:22]=2[CH:26]=1
Reactant: Cc1ccc([S@@](C)=O)cc1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc([S@](=O)C[C@@](O)(CC(C)(C)c2cc(Cl)cc3c2OCC3)C(F)(F)F)cc1
Product: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(Cl)cc3c2OCC3)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 25 %
Yield: 55 %

Procedure:
To a suspension of (R)-(+)-methyl p-tolylsulfoxide (1.00 g, 6.48 mmol) in 10 mL, of anhydrous THF at −78° C. was added LDA mono(tetrahydrofuran), 1.5 M solution in cyclohexane (4.32 mL, 6.48 mmol) over 5 minutes. The resulting clear yellow solution was stirred for an additional 15 minutes. 4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one (1.81 g, 5.90 mmol) was then added via cannula with the aid of 4 mL of THF over 5 minutes. After 1 hour at −78° C., the reaction mixture was quenched with 50 mL of water and extracted with three 50 mL portions of EtOAc. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 15%-25% EtOAc-hexanes) afforded sequentially (S)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (1.49 g, 55%) and (R)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (670 mg, 25%). The diastereomeric excess was determined to be >99% for both isomers (HPLC peak area).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20](S)[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23](C)[CH:22]=2)=[O:18].O[O:31][S:32]([O-:34])=O.[K+].[CH2:36](O)C(F)(F)F>>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([S:32]([CH3:36])(=[O:34])=[O:31])[CH:22]=2)=[O:18]
Reactant: O=S([O-])OO
Reactant: OCC(F)(F)F
Reactant: Cc1ccc2cc(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)n(S)c2c1
Agent: [K+]
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccc(S(C)(=O)=O)cc5[nH]4)c3N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(6-methyl-sulfanyl-1H-indol-2-yl)-methanone (23 mg, 0.057 mmol) was dissolved in trifluoroethanol (5 ml), and an aqueous solution (0.5 ml) of oxone (105 mg, 0.171 mmol) was added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 1.75 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by amino gel column chromatography (dichloromethane/methanol=99/1 to 92/8). Thus, [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(6-methanesulfonyl-1H-indol-2-yl)-methanone was obtained as a pale yellow solid (8 mg, 32%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][NH:7][CH:8]=1)[CH2:2][CH3:3].[Br:13]N1C(=O)CCC1=O>N1C=CC=CC=1>[Br:13][C:8]1[NH:7][CH:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1c[nH]cc1C(=O)OC
Solvent: c1ccncc1
Product: CCCc1c(C(=O)OC)c[nH]c1Br
Yield: 71.8 %

Procedure:
Using methyl 4-propyl-1H-pyrrole-3-carboxylate (2.8 g), N-bromosuccinimide (3.0 g) and pyridine (0.5 mL), a procedure as in Reference Example 40 was performed to give the title compound as colorless crystals (yield 2.96 g, 72%).
Reaction SMILES: CN(C=O)C.CS([O:10][CH2:11][C:12]1[O:13][C:14]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:37])[C:23]([F:36])([F:35])[C:24]2([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)=[N:15][N:16]=1)(=O)=O.[C:38]1(O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>O>[F:35][C:23]([F:36])([C:24]1([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]1)[C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[O:13][C:12]([CH2:11][O:10][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:16][N:15]=1)=[O:37]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2nnc(COS(C)(=O)=O)o2)C1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2nnc(COc3ccccc3)o2)C1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 97.6 %

Procedure:
To a DMF (1.0 mL) solution of the compound (32.5 mg) obtained in Example 9-(6) and phenol (13 mg), K2CO3 (37 mg) was added and the mixture was stirred at 50° C. for 3.5 hours. The reaction mixture was added to water (20 mL) and the organic layer extracted with AcOEt (20 mL×2) was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (31.6 mg, colorless amorphous.)
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:34]([O:35][C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:33][C:32]([C:43]([OH:45])=O)=[N:31]1.[NH2:46][C@H:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH3:58])[CH2:48][C:49]([OH:51])=[O:50]>>[C:49]([CH2:48][C@H:47]([NH:46][C:43]([C:32]1[CH:33]=[C:34]([O:35][C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])[N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])[N:31]=1)=[O:45])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH3:58])([OH:51])=[O:50]
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Reactant: O=C(O)c1cc(OC(=O)N2CCCC2)n(-c2ccccc2F)n1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(OC(=O)N2CCCC2)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
0.675 mmol of TOTU and 1.35 mmol of EDIA were added to the filtrate containing 1-(2-fluoro-phenyl)-5-(pyrrolidine-1-carbonyloxy)-1H-pyrazole-3-carboxylic acid obtained in step 1. The mixture was stirred for 5 min at room temperature, and then 0.675 mmol of (S)-3-amino-3-(2-methyl-phenyl)-propionic acid were added and the mixture was stirred overnight at RT. Then the solvent was evaporated and the residue subjected to preparative HPLC to give the title compound in a yield of 67%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:9]([NH:11][C@@H:12]2[C@@H:19]3[C@@H:15]([CH2:16][NH:17][CH2:18]3)[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]([CH3:43])[C@@H:35]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([NH:11][C@@H:12]2[C@@H:19]3[C@@H:15]([CH2:16][N:17]([C:36](=[O:37])[C@@H:35]([N:34]([CH3:43])[C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:18]3)[CH2:14][CH2:13]2)=[O:10])=[CH:25][CH:24]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: O=C(N[C@H]1CC[C@@H]2CNC[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C(=O)N1C[C@H]2CC[C@H](NC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)[C@H]2C1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,2-Bis(4-fluorophenyl)-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (30 mg, 0.084 mmol) and (S)-2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoic acid (22.71 mg, 0.093 mmol) were dissolved in dichloromethane (0.5 mL) and then treated with 1-hydroxybenzotriazole hydrate (14.18 mg, 0.093 mmol). After 10 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.016 mL, 0.093 mmol) was added, and the reaction mixture was stirred at ambient temperature overnight followed by quenching with water. The material in the organic layer was purified with a 4 g silica gel cartridge eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give tert-butyl(S)-1-((3aR,4S,6aS)-4-(2,2-bis(4-fluorophenyl)acetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-yl(methyl)carbamate: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.25 (s, 1H), 7.46 (td, J=8.5, 5.5, 4H), 7.08-6.96 (m, 4H), 5.08 (s, 2H), 4.29-4.18 (m, 1H), 3.80 (s, 2H), 3.69 (s, 1H), 3.43 (dd, J=11.7, 3.5, 1H), 2.93 (s, 3H), 2.63 (s, 2H), 2.10 (td, J=12.9, 6.9, 1H), 1.91-1.69 (m, 3H), 1.63 (dt, J=13.2, 6.5, 2H), 1.51 (s, 9H), 1.40-1.26 (m, 1H), 0.97 (d, J=6.5, 3H), 0.92 (d, J=6.6, 3H); MS (ESI+) m/z 584 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:12]2=[O:30])[S:5]([CH3:8])(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>C(#N)C>[CH3:37][O:38][CH2:39][CH2:40][NH:41][CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:12]2=[O:30])[S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: CS(=O)(=O)N(CCBr)c1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCNCCN(c1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O)S(C)(=O)=O
Temperature: 130 °C
Yield: 52 %

Procedure:
To a solution of benzyl 2-(5-(N-(2-bromoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.300 g, 0.606 mmol) in acetonitrile (6 ml), K2CO3 (0.126 g, 0.908 mmol) and 2-methoxyethanamine (0.079 ml, 0.908 mmol) were added, and the resulting mixture was heated under MW irradiation for 1 hour at 130° C. The insoluble inorganic salts were filtered off and the filtrate was evaporated to dryness. The crude was purified by flash chromatography on silica gel column (DCM:MeOH=95:5) affording benzyl 2-(5-(N-(2-(2-methoxyethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.154 g, 0.315 mmol, 52.0% yield, MS/ESI+ 490.0 [MH]+).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[O:13])=[C:10]([CH3:23])[C:9]2[C:4](=[CH:5][C:6]([C:24]([F:27])([F:26])[F:25])=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH2:29]([NH2:31])[CH3:30].CCN(C(C)C)C(C)C.[OH-].[Na+]>CCOC(C)=O.CC#N>[CH2:29]([NH:31][C:2]1[C:11]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[O:13])=[C:10]([CH3:23])[C:9]2[C:4](=[CH:5][C:6]([C:24]([F:27])([F:26])[F:25])=[CH:7][CH:8]=2)[N:3]=1)[CH3:30]
Reactant: Cc1c(C(=O)NCc2cccc(F)c2)c(Cl)nc2cc(C(F)(F)F)ccc12
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1cccc(F)c1
Temperature: 180 °C
Yield: 83.3 %

Procedure:
A mixture of 238 mg (0.6 mmol) 2-chloro-N-(3-fluorobenzyl)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid amide, 146 mg (1.8 mmol) ethylamine hydrochloride, 469 μl (2.7 mmol) DIPEA and MeCN (1,6 ml) was heated in a sealed vessel with microwave radiation to 180° C. for 2 h. After cooling to RT, dilution was carried out with EtOAc (30 ml) and a 2M aq. NaOH sol. (5 ml). The organic phase was then separated, washed with water and brine, dried over MgSO4 and concentrated in a vacuum. After column chromatographic separation (silica gel, EtOAc/hexane 3:7) of the residue, 188 mg (0.5 mmol, 77%) 2-ethylamino-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (example 1) was obtained. MS: m/z 406.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:16]=[C:17]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1cc(C)c(Sc2cc(Br)cc(OCC(C)C)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1cc(C)c(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid ethyl ester (400 mg; 0.86 mmol) and 4-prop-2-ynyl-morpholine (321.3 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 350 mg; 80%. HPLC-MS: m/z: 512.2 (M+H)+; Rt: 2.09 min.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[OH-].[K+].CS([C:12]1[N:17]=[C:16]([CH3:18])[C:15]([C:19]([O:21]CC)=[O:20])=[CH:14][N:13]=1)(=O)=O>O>[CH2:1]([O:5][C:12]1[N:17]=[C:16]([CH3:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCOc1ncc(C(=O)O)c(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To 1.5 ml of butanol, 0.72 g (11 mmol) of 85.5% potassium hydroxide powder was suspended, followed by drop-wise adding, under ice-cooling, a 1.5 ml of butanol solution dissolving with 1.22 g (5.0 mmol) of ethyl 2-methansulfonyl-4-methylpyrimidine-5-carboxylate. After the end of the drop-wise addition, the solution was stirred at room temperature for 3 hours. To the reaction liquid, 50 ml of water was added, and the water layer was washed with diisopropyl ether, followed by adding 10% hydrochloric acid to make acidic, and extracting with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to obtain 0.87 g (yield: 83%) of 2-butoxy-4-methylpyrimidine-5-carboxylic acid.