Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)=O.CC(O)=O.[CH:9]1[C:10]([NH:16]/[C:17](/[NH2:42])=[N:18]/[C:19](/[NH2:41])=[N:20]/[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[N:27]=[C:28](\[NH2:40])/[N:29]=[C:30](\[NH2:39])/[NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1.OCC(CO)O>C(O)C.O>[CH:11]1[C:10]([NH:16][C:17]([NH:18][C:19]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:29][C:30]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[NH:39])=[NH:40])=[NH:41])=[NH:42])=[CH:9][CH:14]=[C:13]([Cl:15])[CH:12]=1
Reactant: NC(=N\CCCCCC/N=C(N)/N=C(\N)Nc1ccc(Cl)cc1)/N=C(\N)Nc1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: N=C(NCCCCCCNC(=N)NC(=N)Nc1ccc(Cl)cc1)NC(=N)Nc1ccc(Cl)cc1

Procedure:
The formulation was prepared by dissolving 500 mg (0.68 mmol) of lecithin E-80, 125 mg (0.2 mmol) of chlorhexidine diacetate, 120 mg (0.4 mmol) of SLS and 120 mg of Tween-80 in a mixture of 2 ml absolute ethyl alcohol and 3 ml 2-propanediol (propylene glycol) to form a stock solution. The stock solution was diluted with 95 ml of distilled water and 2 g of glycerol was added to form a suspension. The suspension was treated with a high pressure homogenizer (EmulsiFlex® C-5, “Avestin”, Ottawa, Canada), 6 cycles at 12000-15000 psi. The final particle size was about 50 nm with 85% of the drug bound to particles.
Reaction SMILES: [CH2:1]([CH:8]1[C:31](=O)[N:30]([CH3:33])[CH:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[O:27][CH:26]([CH3:39])[CH2:25][N:24]([CH3:40])[CH:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:22](=[O:45])[O:21][CH:20]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:19](=O)[N:18]([CH3:54])[CH:17]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:16](=[O:59])[O:15][CH:14]([CH3:60])[CH2:13][N:12]([CH3:61])[CH:11]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:10](=[O:66])[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1CCCCC1.C(OCC)(=O)C>C1COCC1>[CH2:46]([CH:20]1[CH2:19][N:18]([CH3:54])[CH:17]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:16](=[O:59])[O:15][CH:14]([CH3:60])[CH2:13][N:12]([CH3:61])[CH:11]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:10](=[O:66])[O:9][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31][N:30]([CH3:33])[CH:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[O:27][CH:26]([CH3:39])[CH2:25][N:24]([CH3:40])[CH:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:22](=[O:45])[O:21]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)CC1C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN1C
Agent: B
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CC1C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)CN(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)CN1C

Procedure:
By the method of Example 1, 2.99 g (3.25 mmol) of 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone (1-b) (for example from Ex. 1) in 20 ml of THF were reacted with 9.75 ml (9.75 mmol) of a 1M solution of borane. Column chromatography (silica gel, Ø=4.5 cm, l=25 cm; cyclohexane:ethyl acetate 50:1 to 5:1) gave 0.72 g of tetrareduction product 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,12,18,24-tetraon (2) (cf. Ex. 2), 0.22 g of trireduction product (1-c) and 0.91 g of unreacted starting material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@@H:16]([C:19]([NH2:22])([CH3:21])[CH3:20])[CH2:15]1)=[N:9][C:8]([O:23][CH3:24])=[CH:7][CH:6]=2.CCO.[O:28]=[C:29]1[CH2:34][S:33][C:32]2[CH:35]=[CH:36][C:37]([CH:39]=O)=[N:38][C:31]=2[NH:30]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][C@@H:16]([C:19]([NH:22][CH2:39][C:37]3[CH:36]=[CH:35][C:32]4[S:33][CH2:34][C:29](=[O:28])[NH:30][C:31]=4[N:38]=3)([CH3:21])[CH3:20])[CH2:15]1)=[N:9][C:8]([O:23][CH3:24])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(CCN3CC[C@@H](C(C)(C)N)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3CC[C@@H](C(C)(C)NCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 12 h
Yield: 36.8 %

Procedure:
To a solution of the hydrochloride salt of 2-((3R)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)-2-propanamine (100 mg, 0.25 mmol) in DCM:EtOH (6 mL, 1:1) were added NaHCO (210 mg, 2.5 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (47 mg, 0.25 mmol). After 12 h at 25° C., NaBH (10 mg, 0.28 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM and water. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO, concentrated and purified via column chromatography (silica, 0-1% MeOH in DCM (1% NH OH)) yielding the title compound (47 mg, 37%) as an off-white solid: LC/MS (ES) m/e 512 (M+H)+; H NMR (CDCl, 400 Hz) δ 8.59 (s, 1H), 8.17 (d, J=9.1 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.05 (d, J=9.0 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 4.07 (s, 3H), 3.76 (s, 2H), 3.39-3.43 (m, 4H), 2.76-2.96 (m, 4H), 2.55-2.64 (m, 2H), 2.39-2.44 (m, 1H), 1.85-1.88 (m, 1H), 1.72-1.78 (m, 1H), 1.09 (s, 3H), 1.08 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[C:24]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3cc(C(C)=O)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 1-[4-cyclopropylmethoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethanone (example A46) the title compound is obtained as colorless solid.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].C(OC([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:17](=C)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[C:3]([CH:2]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:17][CH2:16]1)([OH:5])=[O:4]
Reactant: C=C1CC(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (10 ml) was added to 4-tert-butoxycarbonyl-methylene-N-CBZ-piperidine (20 g, 60.3 mmol) in methylene chloride (30 ml) and the solution was stirred at room temperature for 1.5 hours. After evaporation of the solvent, the residue was triturated with diethyl ether to give 4-carboxymethylene-N-CBZ-piperidine as a crystalline white solid.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:30])([CH3:29])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]2([OH:28])[CH2:27][CH:26]=[CH:25][CH2:24]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.O=[Pt]=O>[C:1]([SiH2:5][O:6][C:7]([CH3:30])([CH3:29])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(F)c(-c2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc2C2(O)CC=CC2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc2C2(O)CCCC2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 20.3 (100 mg, 212 μmol) in 2 mL of EtOAc, was added 10% PtO2/C (50 mg). The resulting mixture was stirred under a hydrogen atmosphere for 0.5 hours and then filtered. The filtrate was concentrated to give an oil which was used in the next step.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2>CC(O)=O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]=[C:4]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:1][C:2]3=[O:3])=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C1=Nc1ccc2[nH]ncc2c1
Yield: 62.9 %

Procedure:
The title compound (165 mg, 63%) was synthesized as a yellow solid according to the method described for Example A74 using isatin (147 mg, 1 mmol), 5-aminoindazole (133 mg, 1 mmol) and 2 drops of HOAc. 1H NMR indicated a 5:1 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H, NH), 11.00 (s, 1H, NH), 8.07 (s, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.35 (s, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.07 (dd, J=9.2 Hz, 1.6 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.67 (t, J=8.0 Hz, 1H), 6.45 (d, J=7.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[C:13](#[N:15])C.[C-]#N.[K+].O>C(O)C>[C:13]([CH2:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])#[N:15]
Reactant: CC#N
Reactant: COc1ccc(C#N)c(CBr)c1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C#N)c(CC#N)c1
Reaction time: 4 h

Procedure:
2-(Bromomethyl)-4-methoxybenzonitrile (36 g, example 235, step 1) was suspended in 200 ml of ethanol, 200 ml of acetonitrile was added followed by KCN (8.3 g) and 150 ml of water. Mixture was stirred and the colorless solution turned to yellow. The reaction was complete after 4 hours of stirring. The volatiles were removed under vacuum, and the residual solid was redissolved in ethyl acetate (200 ml) and washed with water (100 ml) and brine (100 ml). The organics were then dried over sodium sulfate. Ethyl acetate was removed and the residue was recrystallized from ethyl acetate and dichloride methane to provide 17 g of 2-(cyanomethyl)-4-methoxybenzonitrile.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C.CN(C=O)C.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:9]1[C:8]2[C:2]3[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=3[O:4][CH2:5][CH2:6][C:7]=2[CH:11]=[CH:10]1
Reactant: Ic1ccccc1OCCc1ccsc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OCCc1ccsc1-2

Procedure:
To a stirred solution of 2-iodophenol (6.7 g, 30.6 mmol), 2-(3-thienyl)ethanol (3.57 g, 27.8 mol) and triphenylphosphene (8.00 g, 30.6 mmol) in THF, was slowly added a solution of DEAD (4.8 ml, 30.6 mmol). Reaction mixture was stirred at room temperature for 3 hours. Purification on silica gave 3-[2-(2-iodo-phenoxy)-ethyl]-thiophene. A mixture of 3-[2-(2-iodo-phenoxy)-ethyl]-thiophene (1.55 g, 4.69 mmol), palladium(II) acetate (105 mg, 0.47 mmol), potassium carbonate (3.2 g, 23.45 mmol), triphenylphosphene (246 mg, 0.94 mmol) and tetraethylammonium chloride (1.3 g, 4.69 mmol) in DMF was microwaved at 100° C. for 1 hour. The reaction was diluted with dichloromethane and filtered through celite. The filtrate was washed with water, dried (MgSO4), and concentrated in-vacuo. Purification on silica gave 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][CH2:20][CH:21]=O)[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:23]([S:27]([NH2:29])=[O:28])([CH3:26])([CH3:25])[CH3:24].CCOC(C)=O.[BH4-].[Na+]>C1COCC1.CCO.[Cl-].[Na+].O.CCCCCC>[C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:8]([CH2:19][CH2:20][CH2:21][NH:29][S:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:28])([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[O:9][CH2:10]2)#[N:18]
Reactant: CC(C)(C)S(N)=O
Reactant: N#Cc1ccc2c(c1)COC2(CCC=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)S(=O)NCCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
1-(4-fluorophenyl)-1-(3-oxopropyl)-1,3-dihydro-isobenzofuran-5-carbonitrile (3.0 g) was dissolved in THF (20 mL), followed by addition of (−)-tert-butylsulfinamide (1.5 g), and Ti (OEt)4 (20 mL, Aldrich) in EtOH. The reaction mixture was stirred at room temperature for 10 min, and 55° C. for 1 h. The reaction mixture was cooled to 5-10° C., was added brine (50 mL), and EtOAc (150 mL). The reaction mixture was stirred at room temperature for 10 min and filtered. The EtOAc layer in the filtrate was separated and washed with brine and concentrated to give a crude oil. It was dissolved in THF (20 ml), cooled to 5-10° C. and added NaBH4 (1.6 g) Methanol (10 mL). The reaction mixture was stirred for 14 h, quenched with water at 5-10° C., extracted with EtOAc (100 mL). The extract was washed with brine and concentrated to give the crude product (3.5 g). It was passed through a silica gel column using EtOAc and hexane (8:2) to give the pure product (2.5 g) as a mixture of possible diastereomers. 1H NMR (CDCl3, δ): 1.19 (s, 9H), 1.40-1.60 (m, 2H), 2.10-2.30 (m, 2H), 3.05-3.30 (m, 3H), 5.17 (m, 2H). 7.00 (m, 2H), 7.40-7.60 (m, 5H). 13C NMR(CDCl3, δ): 22.4, 25.6, 38.1, 45.4, 55.4, 71.1, 90.7, 111.6, 115.1, 115.4, 118.4, 122.6, 125.1, 126.5, 126.6, 131.8, 139.1, 140.1, 149.0, 160.2, 163.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[C:19](=[O:24])[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:25]C(C)([O-])C.[K+].CI.C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[C:19](=[O:24])[N:20]([CH3:25])[CH:21]=[CH:22][N:23]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: O=C(Cc1ccccc1F)C1CCN(Cc2ncc[nH]c2=O)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1ccnc(CN2CCC(C(=O)Cc3ccccc3F)CC2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
After dissolving 300 mg of 3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one in 5 ml of N,N-dimethylformamide, 113 mg of potassium tert-butoxide was added, the mixture was stirred for 30 minutes while cooling on ice, 0.063 ml of methyl iodide was added and the stirring was continued for 1 hour. Ice water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate/methanol). Diisopropyl ether was added and the mixture was filtered to obtain the title compound (61 mg, 20% yield).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:8]=1[C:9]([O:35][CH:36]([F:38])[F:37])=[C:10]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:33])[NH:28][CH:29]3[CH2:32][CH2:31][CH2:30]3)=[CH:23][C:22]=1[Cl:34])[C:11]([CH2:18][CH3:19])=[N:12]2)[CH3:5].[OH-].[Li+]>O1CCCC1>[Cl:34][C:22]1[CH:23]=[C:24]([C:27](=[O:33])[NH:28][CH:29]2[CH2:30][CH2:31][CH2:32]2)[CH:25]=[CH:26][C:21]=1[CH2:20][C:10]1[C:11]([CH2:18][CH3:19])=[N:12][C:13]2[C:8]([C:9]=1[O:35][CH:36]([F:38])[F:37])=[C:7]([O:6][C@@H:4]([CH3:5])[C:3]([OH:39])=[O:2])[CH:16]=[CH:15][C:14]=2[F:17]
Reactant: CCc1nc2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)NC2CCC2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(O[C@@H](C)C(=O)O)c2c(OC(F)F)c1Cc1ccc(C(=O)NC2CCC2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (S)-2-[3-(2-chloro-4-cyclobutylcarbamoylbenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]propionic acid methyl ester (0.18 g), tetrahydrofuran (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (1.0 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, acidified by the addition of sodium dihydrogenphosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on C-18 column, eluting with a mixture of water and methanol (9:1 to 0:1 by volume) gave title compound as a pale yellow solid, 0.13 g.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:24])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][OH:22])=[C:13]([CH3:23])[CH:12]=2)=[C:5]2[CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28][C:4]=12)[CH3:2].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C1COCC1.C(OCC)C>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:24])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][O:22][S:41]([CH3:40])(=[O:43])=[O:42])=[C:13]([CH3:23])[CH:12]=2)=[C:5]2[CH2:25][CH2:26][C:27]([CH3:29])([CH3:30])[CH2:28][C:4]=12)[CH3:2]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(OCCCO)c(C)c2)c2c1CC(C)(C)CC2
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1sc(C(=O)CCc2cc(C)c(OCCCOS(C)(=O)=O)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-propan-1-one (246 mg, 0.575 mmol) in THF (10 mL) and DIPEA (0.26 mL, 1.5 mmol) is added methane sulfonylchloride (0.08 mL, 1.00 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with diethyl ether, washed with sat. aq. NaHCO3 solution followed by 10% aq. citric acid solution, dried over Na2SO4 and evaporated to give methanesulfonic acid 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenoxy}-propyl ester (290 mg) as a brown resin; LC-MS: tR=1.20 min, [M+1]+=507.39.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([OH:19])[N:9]=1.Br[CH2:21][CH:22]([F:24])[F:23]>O>[Cl:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([O:19][CH2:21][CH:22]([F:24])[F:23])[N:9]=1
Reactant: Oc1cc2c(Cl)cccc2c(Cl)n1
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: FC(F)COc1cc2c(Cl)cccc2c(Cl)n1
Temperature: 50 °C
Yield: 90.8 %

Procedure:
Potassium carbonate (646 mg, 4.67 mmol) was added to a solution of 1,5-dichloroisoquinolin-3-ol (500 mg, 2.336 mmol) and 2-bromo-1,1-difluoroethane (677 mg, 4.67 mmol) and heated to 50° C. for 18 hrs. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with water (2×) followed by brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude product 1,5-dichloro-3-(2,2-difluoroethoxy)isoquinoline (590 mg, 90% yield) which was used as is in the next step. MS: MS m/z 278.1(M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[C:15]([N:17]([CH:25]2[CH2:27][CH2:26]2)C(=O)OC(C)(C)C)[N:14]2[N:28]=[CH:29][C:30]([CH:31]=[O:32])=[C:13]2[N:12]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[C:15]([NH:17][CH:25]2[CH2:26][CH2:27]2)[N:14]2[N:28]=[CH:29][C:30]([CH:31]=[O:32])=[C:13]2[N:12]=1)[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)N(c1cc(Nc2ccc(C#N)cc2Br)nc2c(C=O)cnn12)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)c(Br)c1
Reaction time: 1 h
Yield: 67 %

Procedure:
Tert-butyl 5-(2-bromo-4-cyanophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (105 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. After 1 h, the reaction was concentrated to dryness and the residue was triturated with Et2O. The yellow solid was collected and dried to give 3-bromo-4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile 2,2,2-trifluoroacetate (72 mg, 67%).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([C@@H:6]2[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[C:3]1=[O:24].C([O-])(O)=O.[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:4]1[C:3](=[O:24])[C@@H:2]([NH:1][C:31](=[O:32])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:5]1[C@@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(CN2C(=O)[C@@H](N)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To the crude organic solution from step 3 (EtOAc, 4 L) cooled to 0° C. was added saturated NaHCO3 (aq, 2.05 L) followed by benzyl chloroformate (205 mL, 1.43 mol), drop-wise over 1 h. After stirring at rt for 2 h the layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was treated with MeOH (2 L), filtered and washed with MeOH (2×200 mL) to afford pure title compound (155 g) as a white solid. The mother liquor was cooled to −20° C. for 12 h and the resulting precipitate was collected by filtration, affording additional title compound (90 g) for a combined 45% yield over 4 steps. LCMS: m/z=471.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[N:31]O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH2:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=NO
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.9 %

Procedure:
1-Hydroxyimino-3-phenyl-6-(3-phenylpropoxy)-1H-indene-2-carboxylic acid ethyl ester (0.5 g, 1.17 mmol) obtained in Step 1 was dissolved in methanol (30 mL) and 10%-palladium (400 mg) was added thereto. The mixture was stirred for 15 hrs at RT while providing H2 gas thereto using a balloon, filtered through celite, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 377 mg of the titled compound (yield: 78%).