Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:45])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][O:37]C3CCCCO3)[CH:31]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][OH:37])[CH:31]=4)[CH:25]=3)[CH2:22][C:21](=[O:45])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(isopropyl-methyl-amino)-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M280) (0.35 g, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (162 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH3:15]I.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH3:15])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Cl)c(C=O)c2ccccc21
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
A solution of 2-chloro-1H-indole-3-carboxaldehyde (1.0 g, 5.5 mmol) in DMF (30 mL) is treated portionwise over 10 min with 60% sodium hydride (440 mg, 11 mmol). After stirring for 30 min, methyl iodide (685 μL, 11 mmol) is slowly added and the resulting mixture is stirred 3 hr at room temperature. Water (5 mL) is cautiously added and the solvents are removed. The residue is dissolved in ethyl acetate and washed with water, with brine, dried, filtered and concentrated to give 2-chloro-1-methyl-1H-indole-3-carboxaldehyde (1.16 g, 105%), mp 94.5-95.5° C., as a white solid. MS 194 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C@H:22]([OH:25])[CH2:23][OH:24])[CH:20]=3)[CH:15]=[N:14]2)=[CH:10][CH:9]=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:25][C@@H:22]([C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[N:14][N:13]2[CH2:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:27][CH:26]=2)=[CH:17][CH:18]=1)[CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: COc1ccc(Cn2ncc3ccc([C@H](O)CO)cc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2ncc3ccc([C@@H](COS(C)(=O)=O)OS(C)(=O)=O)cc32)cc1
Yield: 83.2 %

Procedure:
Methanesulfonyl chloride (0.88 mL, 11.3 mmol) was added dropwise to a solution of (S)-1-(1-(4-methoxybenzyl)-1H-indazol-6-yl)ethane-1,2-diol (1.68 g, 5.63 mmol), Et3N (2.0 mL, 14.1 mmol) and CH2Cl2 (30 mL) at 0° C. After 1 h diluted with CH2Cl2 (100 mL) and washed with 0.5 M HCl, saturated aqueous NaHCO3, brine, and then dried over MgSO4. After the solvent was removed, purification using Biotage Isolera (silica gel, 50-66% EtOAc in hexane) gave the title compound as a sticky white solid (2.13 g, 83%); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.18-7.12 (m, 3H), 6.82 (d, J=8.5 Hz, 2H), 5.90-5.87 (m, 1H), 5.59-5.50 (m, 2H), 4.55-4.50 (m, 1H), 4.42-4.38 (m, 1H), 3.76 (s, 3H), 3.04 (s, 3H), 2.77 (s, 3H); MS ESI 455.1 [M+H]+, calcd for [C19H22N2O7S2+H]+ 455.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][OH:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of N-tert-butoxycarbonyl-D-valinol (10 g, 49.3 mmol) and benzylbromide (5.86 mL, 49.3 mmol) in anhydrous dimethyl formamide (50 mL) is added at -5° C. and under nitrogen, potassium-tert-butoxide (11.06 g, 98.6 mmol) as a solid, portionwise, an in such a way that the internal temperature does not exceed +5° C. The reaction mixture is stirred for 2 hours at 0° C., diluted with ethyl acetate (2×300 mL), extracted with a 1N solution of potassium hydrogen sulfate (50 mL) and water (250 mL) and is washed twice with water (2×200 mL). After drying of the organic phase over anhydrous sodium sulfate, filtration and concentration under vacuum, the oil is purified by flash chromatography (silica gel, ethyl acetate/petroleum ether: 1/9, Rf: 0.42) to provide N-tert-butoxycarbonyl-O-benzyl-D-valinol as a colorless oil (9.95 g, 69% yield).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S([O-])(=O)=O.[Sn+2].FC(F)(F)S([O-])(=O)=O.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:31]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:33])[CH3:32]
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CCCC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of trans-racemic-2-phenylcyclohexanol (4.63 g, 26.3 mmol) and tin(II)trifluoromethanesulfonate (219 mg, 0.525 mmol) under nitrogen in anhydrous DCM (100 ml) at room temperature was added acetic anhydride (3.72 ml, 4.02 g, 39.4 mmol) in one portion. The mixture was stirred for 18 hours at room temperature. The mixture was poured into saturated aqueous sodium bicarbonate (200 ml). The mixture was extracted with DCM (2×200 ml). The combined organic layers were washed with brine (70 ml), dried over sodium sulfate, and concentrated under reduced pressure to provide the desired product as a light yellow oil. LC-MS: calculated for C14H18O2 218.29 observed m/e: 219.33 (M+H)+ (Rt 0.93/2 min)
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@@H:7]1[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][C@@H:7]1[NH:19][CH:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1N[C@H](C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1NC(C)c1ccccc1
Yield: 14.7 %

Procedure:
In a dry flask (3R,4R)-3-[(R)-1-phenyl-ethylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (31.32 g, 83.0 mmol) was dissolved in ethanol (400 mL). Potassium carbonate (68.72 g) was added and the mixture was refluxed for 6 hours. The reaction mixture was cooled, filtered through a bed of celite, and concentrated in vacuo to give a crude oil. Purification by flash column chromatography (20-50% ethyl acetate/hexanes) provided a colorless oil (4.59 g, 15%). Unepimerized ester was also isolated (23.49 g, 75%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=[CH:31][C:30]=1[N:44]1[CH2:56][CH2:55][N:47]2[C:48]3[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=3[CH:54]=[C:46]2[C:45]1=[O:57])(=[O:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:56][CH2:55][N:47]3[C:48]4[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=4[CH:54]=[C:46]3[C:45]2=[O:57])=[CH:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 130c (250 mg, 0.663 mmol), 2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 114a (338 mg, 0.729 mmol), Pd(PPh3)4 (38.3 mg, 0.033 mmol), Na2CO3 aqueous solution (1.0 N, 2.19 mL, 2.19 mmol), DME (2 mL) were added. The mixture was reacted in microwave at 135° C. for 15 min. CH2Cl2 (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 130d.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(F)c(Cl)c2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2cccnc2)c2ccc(F)c(Cl)c2)C1
Temperature: 25 °C

Procedure:
To a 10 ml of toluene solution containing 1.0 g of 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (3.2 mmol) and 0.75 g of 3-bromopyridine (4.75 mmol) were added 50 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS, 0.09 mmol), 21.4 mg of palladium acetate (0.10 mmol) and 11.6 g of sodium tert-butoxide (120 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 9 hours. After cooling to room temperature, the reaction solution was filtered using Celite. Water was added to the filtrate, and extraction with ethyl acetate was conducted. After drying over sodium sulfate and concentration under reduced pressure, the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure to thereby obtain 1.14 g of oily light yellow 3(S)-[(3-chloro-4-fluorophenyl)pyridin-3-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:37]([NH:41][C:42]([C@@H:44]1[C:48]([CH3:50])([CH3:49])[S:47][CH2:46][N:45]1[C:51](=[O:69])[C@@H:52]([OH:68])[C@@H:53]([NH:61][C:62](=[O:67])[C@@H:63]([NH2:66])[CH2:64][CH3:65])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C.C(OCC)(=O)C>[C:37]([NH:41][C:42]([C@@H:44]1[C:48]([CH3:50])([CH3:49])[S:47][CH2:46][N:45]1[C:51](=[O:69])[C@@H:52]([OH:68])[C@@H:53]([NH:61][C:62](=[O:67])[C@@H:63]([NH:66][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([N:2]([CH3:1])[CH3:14])[CH:4]=1)[CH2:64][CH3:65])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:43])([CH3:38])([CH3:39])[CH3:40]
Reactant: CN(C)c1cccc(OCC(=O)O)c1
Reactant: CC[C@H](N)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)COc1cccc(N(C)C)c1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NC(C)(C)C
Reaction time: 8 h
Yield: 73 %

Procedure:
3-dimethylaminophenoxyacetic acid (51 mg), HOBt (35mg), and EDC.HCl (53 mg) were added to a solution of H-Abu-Apns-Dmt-NHtBu (120 mg) obtained in the step 1 in DMF and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography to obtain the title compound (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C(Cl)[Cl:31]>>[ClH:31].[ClH:31].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCl
Agent: COc1cccc(CCNCCc2c[nH]cn2)c1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cl
Temperature: 10 °C

Procedure:
A stirred mixture of 5 g of the product of Step A, 2.5 g of lithium aluminum hydride and 50 ml of tetrahydrofuran was refluxed for 90 minutes and was then cooled to 10° C. 100 ml of tetrahydrofuran containing 20% water and 100 ml of methylene chloride were added thereto and the mixture was filtered. The filtrate was evaported to dryness and the 4.7 g of yellow oil residue were dissolved in 30 ml of isopropanol. A solution of ethyl acetate saturated with hydrogen chloride was added thereto to adjust the pH to 1 and the mixture was vacuum filtered. The recovered product was washed with isopropanol to obtain 3 g of N-[2-(3-methoxyphenyl)-ethyl]-1H-imidazol-4-ethanamine dihydroch1oride in the form of brilliant colorless platelets melting at 195°-198° C.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([S:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][C:20](=[O:33])[C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=3)[C@@H:14]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:13]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.O.[ClH:40]>CO.[OH-].[Na+].C(OCC)C>[ClH:40].[ClH:40].[CH:3]1([S:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][CH:20]([OH:33])[C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=3)[C@@H:14]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:13]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C[C@H]1CN(CCSC2CCCCC2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C[C@H]1CN(CCSC2CCCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 10 °C
Reaction time: 1 h

Procedure:
0.42 g of sodium borohydride was added portionwise for approximately 1 hour with stirring and under an inert atmosphere, to a solution cooled to a temperature in the region of 15° C., of 3.5 g of methyl (3R,4R)-1-[2-(cyclohexylthio)ethyl]-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate in 50 cm3 of methanol to which had been added 1 drop of 5N sodium hydroxide solution. The mixture was stirred for 2 hours at this temperature and then cooled to approximately 10° C. 10 cm3 of water were then added dropwise. The mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 45° C. After adding 100 cm3 of water to the residue obtained, the mixture was extracted with 2 times 100 cm3 of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and concentrated as above. An oil was obtained, which product was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3 cm; height 35 cm), elution was carried out with ethyl acetate, and 30-cm3 fractions were collected. Fractions 19 to 42 were combined and concentrated as under the above conditions 2.44 g of a product were obtained, the hydrochloride of which was prepared in the following way: 0.5 g of product was dissolved in 10 cm3 of diethyl ether and then the solution was poured into 5 cm3 of a 1 N solution of hydrochloric acid in ether. 10 cm3 of ether were added and then the mixture was left to act for 1 hour at a temperature in the region of 20° C. The mixture was filtered and the cake was washed with 2 times 10 cm3 of diethyl ether and dried under reduced pressure (5 kPa) at a temperature in the region of 20° C. and then in an oven under reduced pressure (10 Pa) at a temperature in the region of 60° C. 0.46 g of methyl (3R,4R)-1-[2-(cyclohexylthio)ethyl]-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate dihydrochloride was obtained in the form of a solid with a pale pink color melting at 80° C. while softening.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[N:34]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[C:38]([F:44])[CH:37]=4)[CH:33]=[N:32][CH:31]=3)[CH2:25][C:24]2=[O:45])[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[H][H]>CO.CCOC(C)=O.[Pd]>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[OH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[N:34]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[C:38]([F:44])[CH:37]=4)[CH:33]=[N:32][CH:31]=3)[CH2:25][C:24]2=[O:45])[CH:13]=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(Cn2cncc2CN2CCN(c3cc(Cl)ccc3-c3cccc(OCc4ccccc4)c3)C(=O)C2)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cn2cncc2CN2CCN(c3cc(Cl)ccc3-c3cccc(O)c3)C(=O)C2)cc1F
Reaction time: 4 h

Procedure:
To a solution of the crude product from Step F (ca 1.68 mmol) in 25 mL of 1:1 MeOH/EtOAc was added trifluoroacetic acid (0.10 mL) and 10% palladium on carbon (800 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 4 hours, the solution was filtered through celite, the filter pad was rinsed with 1:1 MeOH/THF, and the filtrate was concentrated in vacuo. The crude material containing the titled product was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:57])[C@@H:22]([NH2:56])[CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C=CC=CC=1.[C:64](Cl)(=[O:80])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]>C(Cl)Cl>[C:43]([O:42][C@H:26]([CH2:27][O:28][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:25][S:24][CH2:23][C@H:22]([NH:56][C:64](=[O:80])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[C:21](=[O:57])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (14R,18R)-14-amino-18-(dodecanoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontylphosphonic acid diethyl ester (1 eq, from example 18, step 6) in DCM (0.1 M) was cooled in an ice bath. Pyridine (1.2 eq) was added followed by palmitoyl chloride (1.1 eq). The reaction mixture was stirred for 10 minutes then warmed up to room temperature, and stirred for 2 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous NH4Cl. The aqueous phase was back extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the title product as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[C:8]1[CH:13]=CC=[CH:10][CH:9]=1.[C:15]1([CH3:43])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[C:23]1[C:24]([CH3:42])=[N:25][N:26]2[C:31](=O)[C:30]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]([CH3:41])[NH:28][C:27]=12.C(=O)([O-])[O-].[K+].[K+].C(N)CCC>C(#N)C.O>[CH2:13]([C:31]1[N:26]2[N:25]=[C:24]([CH3:42])[C:23]([C:16]3[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=3[CH3:43])=[C:27]2[N:28]=[C:29]([CH3:41])[C:30]=1[CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)CCCc1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Reactant: CN(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCCCN
Product: CCCCc1c(CCCC(=O)OCC)c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn12
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (11.3 g) and N,N-dimethylaniline (3 droplets) were added to ethyl 4-(3-mesityl-2,5-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)butanoate (700 mg, 1.77 mmol), followed by heating under reflux for 1.5 hours. After the reaction, it was treated with ice-water, neutralized with potassium carbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The resulting reaction residue was dissolved in acetonitrile (5 ml) and n-butylamine (2 mL) was added, followed by heating under reflux for six hours. After the reaction, it was treated with water, and then neutralized with potassium carbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10-25% ethyl acetate/hexane), to give the title compound (2.5 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:17]([CH3:28])[CH2:16]1)(=[O:14])=[O:13].[C:29](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C@H:17]1[CH2:16][N:15]([S:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[CH3:29])(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: C[C@H]1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 100 °C

Procedure:
1,1-dimethylethyl(2S)-4-{[2-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-1-piperazinecarboxylate (may be prepared as described in Description 19) (2.5 g, 5.13 mmol), potassium carbonate (1.134 g, 8.21 mmol) in 1,4-dioxane (80 ml) were stirred for 5 min then trimethylboroxin (1.142 ml, 8.21 mmol) and Pd(PPh3)4 (0.593 g, 0.513 mmol) were added and the reaction mixture heated at 100° C. for 1.5 h. Further trimethylboroxin (0.5 mL) was added and the reaction heated for 30 min before it was allowed to cool overnight.