Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[C:20]3[C:26]([O:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:39]([O:43][C:44]([NH:46][C@H:47]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=1)[C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][C@@H:47]([NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42])[C:48]([N:36]2[CH2:35][CH2:34][N:33]([C:19]3[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[C:26]([O:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31])[C:20]=34)[CH2:38][CH2:37]2)=[O:49])=[CH:53][CH:54]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: OC[C@H](O)COc1n[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(OC[C@@H](O)CO)c23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.055 mL, 0.32 mmol) was added to a solution of (S)-3-(5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.050 g, 0.079 mmol), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.024 g, 0.079 mmol) and TBTU (0.031 g, 0.095 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, and the residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2 M) was added. The reaction was then stirred for an additional 10 minutes. Ethyl acetate (20 mL) was added, and the organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (ethyl acetate:MeOH, 20:1) to give tert-butyl(R)-3-(4-chlorophenyl)-1-(4-(3-((S)-2,3-dihydroxypropoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2 N) was added. The resulting solid was collected by filtration to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-((S)-2,3-dihydroxypropoxy)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.018 g, 36%). MS APCI (+) m/z 551.2 detected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([O:16][CH2:17][CH2:18]OC)[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(OC([N:41]1CC(OCCOC)C[CH:42]1[C:51]1N(COCC[Si](C)(C)C)C=C(C2C=CC(Br)=CC=2)[N:55]=1)=O)(C)(C)C>>[CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([O:16][C:17]2[CH:18]=[N:55][CH:51]=[CH:42][N:41]=2)[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COCCOC1CC(c2ncc(-c3ccc(Br)cc3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Reactant: COCCOC1CC(c2nc(-c3ccc(Br)cc3)cn2COCC[Si](C)(C)C)N(C(=O)OC(C)(C)C)C1
Product: COC(=O)NC(C(=O)N1CC(Oc2cnccn2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare {1-[2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxy-ethoxy)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (Example 1), substituting 2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-4-(pyrazin-2-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (94 mg) for 2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-4-(2-methoxy-ethoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (88 mg, 99%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:30])[O:6][CH:7]1[CH:11]([OH:12])[CH:10]([CH2:13][OH:14])[O:9][CH:8]1[N:15]1[C:19]2[N:20]=[C:21]([N:24]=CN(C)C)[N:22]=[CH:23][C:18]=2[S:17][C:16]1=[O:29])([CH3:3])[CH3:2].CC(O)=O>CO>[CH:1]([O:4][C:5](=[O:30])[O:6][CH:7]1[CH:11]([OH:12])[CH:10]([CH2:13][OH:14])[O:9][CH:8]1[N:15]1[C:19]2[N:20]=[C:21]([NH2:24])[N:22]=[CH:23][C:18]=2[S:17][C:16]1=[O:29])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)OC1C(O)C(CO)OC1n1c(=O)sc2cnc(N=CN(C)C)nc21
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)OC(=O)OC1C(O)C(CO)OC1n1c(=O)sc2cnc(N)nc21
Temperature: 35 °C
Yield: 68.4 %

Procedure:
Carbonic acid 2-[5-(dimethylamino-methyleneamino)-2-oxo-thiazolo [4,5-d]pyrimidin-3-yl]-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-3-yl ester isopropyl ester (15) (460 mg, 1.04 mmol) was dissolved in MeOH (5.0 mL) and HOAc (1.0 mL) was added. The reaction was warmed to 35° C. for 48 h, concentrated to a solid residue in vacuo, then subjected to flash chromatography (40-100% EtOAc-hexanes). The solids were triturated with a minimum of Et2O to yield 275 mg (69%) of 16 as a white powder: 1H NMR (400 MHz, DMSO-d6) δ 8.38 (1H, s), 6.86 (2H, bs), 5.87 (1H, d, J=5.6 Hz), 5.68 (1H, dd, J1=4.5 Hz, J2=8.3 Hz), 5.46 (1H, d, J=7.0 Hz), 4.66 (1H, septet, J=6.2 Hz), 4.58 (1H, t, J=5.8 Hz), 4.33-4.37 (1H, m), 3.96-4.03 (1H, m), 3.62-3.72 (2H, m), 1.17 (3H, d, J=6.3 Hz), 1.12 (3H, d, J=6.2 Hz); [M]+ @ m/z 386.9.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH2:8][N:9]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH2:10][CH2:11][O:12][CH3:13])(C)(C)C.Cl>C(O)C>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:6](=[O:5])[CH2:7][CH2:8][N:9]([CH2:10][CH2:11][O:12][CH3:13])[C:14]=2[N:15]=1
Reactant: COCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: COCCN1CCC(=O)Nc2cnc(Cl)nc21
Yield: 35.6 %

Procedure:
To a solution of 3.3 g (0.0092 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-methoxy-ethyl)-amino]-propanoic acid tert-butyl ester (IV-40) in 30 mL of ethanol was added 5.2 g (0.023 mole) of stannous chloride dihydrate and 1 mL of hydrochloric acid. The mixture was heated to 60 degrees for 2 hours and then concentrated under reduced pressure. The residue was taken up in 50 mL of water and extracted with three times with 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5) gave 0.84 g of 2-chloro-9-(2-methoxy-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-40) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.[NH2:33][NH2:34]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:33][NH:34]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Product: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Yield: 29.2 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-phenyl-3-piperidinecarboxamide (10 g, 23.2 mmol) in EtOH (400 mL) was added hydrazine (22.8 mL, 465 mmol). The resulting mixture was heated in seal tube at 100° C. overnight, cooled down, and concentrated in vacuo. The crude solution was purified by the silica gel chromatography (200 g column) eluting from 100% CHCl3 to CHCl3/CH3OH/NH4OH (9:1:0.1). The pure fractions that contained the desired product were combined and concentrated in vacuo to afford the title compound (3 g). LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.8 Hz, 3H), 1.75 (s, 2H), 1.83 (m, 1H), 1.92 (m, 1H), 5.37 (s, 2H), 6.10 (s, 2H), 6.64 (s, 1H), 7.03 (s, 1H), 7.32 (s, 2H), 7.29-7.34 (m, 2H), 7.64 (d, J=7.3 Hz, 4H), 7.96 (s, 1H), 8.32 (s, 1H), 10.06 (s, 1H), 11.49 (s, 1H). The rest of fractions that contained the desired product and a small amount of impurities were combined, concentrated in vacuo and crystallized from CH3OH (˜10 mL). The crystalline material was obtained (3.6 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.Br[CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](Cl)=[O:31].[Na+].[Cl-]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([N:15]2[CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]2=[O:31])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC(C)(CCBr)CC(=O)Cl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)CCN(C2c3cc4nonc4cc3OC(C)(C)C2O)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To 654 mg of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole dissolved in 10 mL of ethyl acetate were added 337 mg of triethylamine and dropwise added 696 mg of 5-bromo-3,3-dimethylvaleryl chloride at the room temperature over a 10-minute period, followed by stirring at the room temperature for one hour. The reaction mixture was added with 20 ml of saturated aqueous NaCl solution, and extracted twice with ethyl acetate (each 20 mL). After the extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 66 g of dimethylformamide and was dropwise added with 2.7 g of 20% tetraethylammonium hydroxide solution over 20 minutes under ice-cooling. Under ice-cooling, the mixture was reacted for 30 min. and then, the solvent was distilled off under reduced pressure and was added with 20 mL of saturated aqueous NaCl solution and extracted thrice with methylchloride (each 20 mL). After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure The residue was subjected to a silica gel column chromatography (ethyl acetate:n-hexane=1:1, Rf=0.5) to obtain 598 mg of the intended compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:30])([CH3:29])[CH2:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:11][CH:10]=2)[CH3:2].[H-].[Na+].[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39]([C:42]2[CH:53]=[CH:52][C:45]([CH2:46]OS(C)(=O)=O)=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:30])([CH3:29])[CH2:6][C:7]1[N:8]([CH2:46][C:45]2[CH:44]=[CH:43][C:42]([C:39]3[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)=[CH:53][CH:52]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:11][CH:10]=2)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1[nH]c2ccc(OCc3ccccn3)cc2c1SC(C)(C)C
Reactant: COc1ccc(-c2ccc(COS(C)(=O)=O)cc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
3-[3-tert-Butylsulfanyl-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester (A-4; 20.0 g, 45.4 mmol) was dissolved in DMF (150 mL) and cooled to −10° C. under N2. Sodium hydride (60% dispersion in mineral oil; 2.0 g, 50.0 mmol) was added portionwise, and the reaction was stirred at −10° C. for 45 minutes until the foam had disappeared. To this dark brown-reddish solution was added methanesulfonic acid 4-(6-methoxy-pyridin-3-yl)-benzyl ester (Int-72; 16.0 g, 54.5 mmol) in DMF dropwise. The reaction was then stirred at −10° C. for 1 hour and allowed to warm to room temperature slowly. After 16 hours, LCMS confirmed the formation of the product. The reaction was quenched with saturated NH4Cl and diluted with methyl tert-butyl ether (MTBE) and water. The aqueous phase was extracted twice with MTBE. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude product was purified by column chromatography to give the desired product (A-5).
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].Cl.[CH3:18][NH2:19]>ClC(Cl)C>[C:11]([C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([NH:19][CH3:18])([CH3:16])[CH3:15])[O:10][N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CN
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)no1
Agent: Cl
Solvent: CC(Cl)Cl
Product: CNC(C)(C)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 85 °C
Yield: 58.5 %

Procedure:
To a solution of 2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide (prepared according to method B, step 1, 1.45 g, 1.5 mmol) in anhydrous dichloroethane (25 mL) are added methylamine hydrochloride (0.66 g, 10.0 mmol) and 1,8-diazabicyclo[5.40]undec-7-ene (3.81 g, 25.0 mmol). The reaction is heated to 85° C. for 16 h. After cooling the reaction mixture to ambient temperature it was washed with saturated NaHCO3 (25 mL). The water layer was extracted with dichloromethane (25 mL). The combined organic layers were dried over MgSO4, filtered and the filtrate is concentrated under reduced pressure. The crude product is purified by chromatography on silica eluting with 0% to 10% methanol/DCM to provide N-(3-tert-butyl-isoxazol-5-yl)-2-methylamino-2-methyl-propionamide (0.21 g, 17%). To a solution of N-(3-tert-butyl-isoxazol-5-yl)-2-methylamino-propionamide (36 mg, 0.15 mmol) in anhydrous dichloroethane (1 mL) are added N-methylmorpholine (82 μL, 0.75 mmol) and 4-chlorobenzenesulfonyl chloride (63 mg, 0.30 mmol). The reaction is concentrated under reduced pressure to give a yellow oil, which is purified by mass-triggered preparative HPLC to afford N-(5-tert-Butyl-isoxazol-3-yl)-2-[(4-chloro-benzenesulfonyl)-methyl-amino]-2-methyl-propionamide (32 mg, 52%). m/z 414 [M+H+]
Reaction SMILES: C(OC([N:6]=[S:7]([CH2:35][CH3:36])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:33][CH3:34])[CH:10]=1)=[O:8])=O)C.ClCCl.CO>CO>[CH2:35]([S:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:33][CH3:34])[CH:10]=1)(=[NH:6])=[O:8])[CH3:36]
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(Nc4nccs4)c3cc2OC)c1
Solvent: CO
Solvent: ClCCl
Product: CCS(=N)(=O)c1cccc(COc2cc3ncnc(Nc4nccs4)c3cc2OC)c1
Yield: 66 %

Procedure:
According to GWP 6, the conversion of (RS)-N-(ethoxycarbonyl)-S-ethyl-S-[3-({[6-methoxy-4-(thiazol-2-ylamino)quinazolin-7-yl]oxy}methyl)phenyl]-sulphoximide (40 mg, 0.076 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 66% yield (23 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:10][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(Br)ccc1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2.03 g (10.91 mmol) of 4-bromo-2-methylaniline in 40 ml of DMF was added 2.07 g (14.98 mmol) of K2CO3 and 0.63 ml (10.12 mmol) of iodomethane, and the mixture was stirred at room temperature for 14 hours. After this time, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 20:1) to give the title compound. 1H-NMR (CDCl3) δ 2.18 (s, 3H), 2.90 (s, 3H), 3.60 (brs, 1H), 6.49 (d, J=8.6 Hz, 1H), 7.19 (s, 1H), 7.29 (d, J=8.5 Hz, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([OH:9])=[O:8].Cl.O[C@H:12]1CCN[C@@H:13]1C(OCC)=O>>[CH3:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([O:9][CH2:12][CH3:13])=[O:8]
Reactant: C[C@H]1CCN[C@@H]1C(=O)O
Reactant: CCOC(=O)[C@H]1NCC[C@@H]1O
Agent: Cl
Product: CCOC(=O)[C@H]1NCC[C@@H]1C

Procedure:
The title compound was prepared from (3S)-3-methyl-L-proline, using the methods used to prepare ethyl(3S)-3-hydroxy-L-prolinate hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.8 Hz, 3H) 1.2 (t, J=6.8 Hz, 3H), 1.6 (m, 1H), 2.1 (m, 1H), 2.3 (m, 1H), 3.2 (m, 2H), 3.8 (m, 1H), 4.2 (m, 2H), 4.7 (m, 1H), 9.0(s, 1H), 10.4 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1([CH2:17][CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1)[CH2:17][C:14]1([C:13]([F:12])([F:31])[F:32])[CH2:16][CH2:15]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=486.1, tR (minutes, Method F)=2.77. [α]D20==+31.03 (c=5.80 mg/mL,CHCl3)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[CH2:17][CH:18]1[CH2:22][O:21][C:20](=[O:23])[CH2:19]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:17][CH:18]1[CH2:19][C:20](=[O:23])[O:21][CH2:22]1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CC(CO)CO1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C1CC(COS(=O)(=O)C(F)(F)F)CO1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of trifluoromethanesulfonic anhydride (15.0 g, 53.2 mmol) in DCM (25 mL) was added dropwise to a solution of 4-(hydroxymethyl)dihydrofuran-2(3H)-one (4.75 g, 41.0 mmol) and 2,6-lutidine (7.15 mL, 61.4 mmol) in DCM (111 mL) at 0° C. The mixture was stirred at 0° C. for 20 minutes. The product mixture was diluted with DCM (100 mL) and was washed with water (3×100 mL). The organic phase was dried over magnesium sulfate and evaporated under vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[Cl:16][C:3]1[C:2]([NH:1][S:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:24])=[O:23])=[C:10]2[C:6]([CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a mixture of ethyl 7-amino-6-chloro-1H-indole-2-carboxylate (1.59 g) and pyridine (10 mL) was added thiophene-2-sulfonyl chloride (1.46 g) and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (2.17 g, yield 85%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate. melting point 191-192° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:17][CH2:18][CH:19]=[C:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]=2[CH2:24][O:23][C:22]2[CH:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:34][C:21]1=2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:17][CH2:18][CH:19]=[C:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[N:30][C:25]=3[CH2:24][O:23][C:22]3[CH:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:34][C:21]2=3)[CH2:8][CH2:7]1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: Clc1ccccc1OC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(Oc3ccccc3Cl)CC1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
4-(2-Chloro-phenoxy)-piperidine hydrochloride (0.067 g, 0.268 mmol) was dissolved in a mixture of acetonitrile (1.32 mL) and water (0.17 mL). To this mixture was added 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.050 g, 0.134 mmol) and potassium carbonate (0.074 g, 0.536 mmol). The mixture was stirred at room temperature for 24 hrs and then concentrated in vacuo. The resulting white solid was suspended in ethyl acetate (5 mL) and an equal volume of water was added. The product was extracted into ethyl acetate (2×5 mL). The pooled organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford an oil. The residue was purified by silica gel chromatography (ethyl acetate to 87/10/3 ethyl acetate/methanol/triethylamine gradient) to afford the title compound (46 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:12])[CH:3]=1.Cl.[F:14][C:15]([F:20])([F:19])[C@@H:16]([NH2:18])[CH3:17].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:18][C@@H:16]([CH3:17])[C:15]([F:20])([F:19])[F:14])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1F
Reactant: C[C@H](N)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cc(F)c(Cl)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2,5-difluorobenzoyl chloride (29.6 mg, 0.140 mmol) (Oakwood, Cat. #: 001628) was added to a mixture of (2S)-1,1,1-trifluoropropan-2-amine hydrochloride (20.0 mg, 0.134 mmol) (SynQuest Lab, Cat. #: 3130-7-S1) and diisopropylethylamine (58 μL, 0.33 mmol) in dichloromethylene (4.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 30 min., worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=288.0/290.0.