Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[C:26]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)([CH3:32])[CH2:25][CH2:24]2.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([C:18]#[C:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)([OH:31])[C:26]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)([CH3:32])[CH2:25][CH2:24]2
Reactant: COc1ccc(C2(C)CCc3cc(OC)ccc3C2=O)cc1
Reactant: C#CCCCCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2(C)CCc3cc(OC)ccc3C2(O)C#CCCCCOC2CCCCO2)cc1
Reaction time: 0.5 h

Procedure:
n-Butyllithium (8.4 ml. of a 1.55 molar solution in hexane) was added to a solution of 6-tetrahydropyranyloxyhex-1-yne (2.25 g.) in tetrahydrofuran (25 ml.) at 10° C., the mixture was allowed to warm up to laboratory temperature and was stirred at that temperature for 30 minutes, and was then recooled to 10° C. A solution of 3,4-dihydro-6-methoxy-2-p-methoxyphenyl-2-methylnaphthalen-1(2H)-one (2.0 g.) in tetrahydrofuran (20 ml.) was added dropwise and the mixture was allowed to warm up to laboratory temperature and stirred at that temperature for 30 minutes. Saturated aqueous ammonium chloride solution (50 ml.) was added and the mixture was extracted with ethyl acetate. The extract was dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 3:1 v/v mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate as eluant. The product was crystallised from ethanol and there was thus obtained, as a mixture of isomers, 6-methoxy-2-p-methoxyphenyl-2-methyl-1-(6-tetrahydropyranyloxyhex-1-ynyl)-1,2,3,4-tetrahydronaphth-1-ol, m.p. 80°-82° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](O)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CN(C=O)C>CCOC(C)=O>[C:22]1([NH:21][C:18]([C:13]2[CH:14]=[C:15]3[C:16](=[CH:11][CH:12]=2)[CH2:17][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)Nc3ccccc3)ccc2C1
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (0.2 g, 0.721 mmol) and aniline (0.066 mL, 0.721 mmol) and TEA (0.251 mL, 1.803 mmol) in EtOAc (5 mL) was added a 50% solution of T3P in DMF (0.408 mL, 1.442 mmol). After 24 h, the reaction was partitioned with dilute HCl (10 mL) and EtOAc (20 mL). The organic layer was washed with brine (10 mL) and dried (MgSO4). Purification by silica gel chromatography afforded 0.238 g of Intermediate 19A. MS (ESI) m/z: 352.9 (M+H)+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:12]([CH2:33][CH3:34])[C:13]([N:15]1[CH:19]=[C:18]([CH2:20]O)[C:17]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[CH3:32])(=[O:24])=[O:23])=[N:16]1)=[O:14])[CH3:11].O>C(Cl)Cl>[CH2:10]([N:12]([CH2:33][CH3:34])[C:13]([N:15]1[CH:19]=[C:18]([CH2:20][F:7])[C:17]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[CH3:32])(=[O:24])=[O:23])=[N:16]1)=[O:14])[CH3:11]
Reactant: CCN(CC)C(=O)n1cc(CO)c(S(=O)(=O)c2cccc(Cl)c2C)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)n1cc(CF)c(S(=O)(=O)c2cccc(Cl)c2C)n1
Reaction time: 1 h
Yield: 95 %

Procedure:
20 μl of diethylaminosulfur trifluoride were added at 0° C. to a solution of 54 mg of 1-(diethylcarbamoyl)-3-(2-methyl-3-chlorophenylsulfonyl)-4-hydroxymethylpyrazole (prepared as described in Example 10) in 1.8 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, eluted with an 8:1 by volume mixture of hexane and ethyl acetate, to afford 51 mg (yield 95%) of the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].[OH-].[K+].[CH3:28][CH2:29][OH:30]>>[CH2:29]([O:30][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:2])=[O:25])=[O:7])[N:9]=1)[CH3:28]
Reactant: COC(=O)CNC(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOc1nc(C(=O)NCC(=O)O)c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of [(1-Chloro-4-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester (177 mg, 0.5 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at ambient temperature for 90 min before the solvent was evaporated in vacuo. The residue was dissolved in water (10 ml). The solution was acidified by addition of concentrated aqueous HCl and extracted with EtOAc (2×15 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a slightly yellowish solid (169 mg); MS-(+)-ion: M+1=351.0.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17]([OH:19])=O)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=O.C(N)C.O>O1CCCC1>[CH3:20][NH:22][C:17](=[O:19])[CH2:16][C:15]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Agent: CCN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccccc2)nn2cccnc12
Reaction time: 3 h
Yield: 85.5 %

Procedure:
A mixture of 3.5 g (0.013 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.24 g (0.013 mole) of 1,1'-carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 3 hours under a nitrogen atmosphere. A solution of monoethylamine in tetrahydrofuran (16 ml; 0.041 mole; 2.59M) was added, and the mixture was stirred at room temperature for one hour. Water (50 ml) was added to dissolve a precipitate that had formed. The solvents were evaporated under reduced pressure, and the residue was triturated in isopropanol to give 2.96 g of solid, mp 211°-213° C. Recrystallization from a mixture of isopropanol and water provided 2.58 g (70%) of product, mp 212°-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH3:38][CH:39]([CH3:43])[C:40](Cl)=[O:41]>>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:40](=[O:41])[CH:39]([CH3:43])[CH3:38])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using 2-methylpropanoyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([NH2:9])=[C:7]([NH2:10])[NH:6][C:5](=[O:11])[N:4]=1.[CH3:12][C:13]([CH:15]=O)=O>O>[NH2:2][C:3]1[C:8]2[C:7](=[N:10][C:13]([CH3:15])=[CH:12][N:9]=2)[NH:6][C:5](=[O:11])[N:4]=1
Reactant: Nc1nc(=O)[nH]c(N)c1N
Reactant: CC(=O)C=O
Agent: Cl
Solvent: O
Product: Cc1cnc2c(N)nc(=O)[nH]c2n1

Procedure:
In 50 mL of H2O is dissolved 1.77 g (0.01 mole) of 4,5,6-triamino-pyrimidine-2-one hydrochloride (19). The pH of the solution is adjusted to 5 and then, 4 mL of 40% aqueous methylglyoxal (FLUKA AG, Switzerland) is added and the solution is heated under reflux for 30 minutes. The resulting precipitate is collected and purified by recrystallization from a large amount of H2O to give 20.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[CH3:31].[C:32](OCC)(=[O:37])[CH2:33][C:34]([CH3:36])=O.N>O>[CH3:36][C:34]1[NH:20][C:21]2[C:30]([C:32](=[O:37])[CH:33]=1)=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[CH3:31]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)c1ccc(N)c(C)c1
Agent: N
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: COC(=O)c1cc(C)c2[nH]c(C)cc(=O)c2c1
Temperature: 140 °C
Yield: 42.9 %

Procedure:
A mixture of phosphorus pentoxide (37 g) and phosphoric acid (46 g) was heated under stirring in an oil bath at 140° C., and methyl 4-amino-3-methylbenzoate (3.0 g) and ethyl acetoacetate (2.8 g) were added thereto, followed by heating under stirring for an additional 2 hours. The reaction mixture was cooled to 60° C., poured into water, and neutralized with a 29% aqueous ammonia solution, and the precipitate was collected by filtration to obtain methyl 2,8-dimethyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (1.8 g).
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:3](OC)=[O:4].[BH4-].[Na+]>CCO>[NH2:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][OH:4]
Reactant: COC(=O)C(C)(N)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(N)(CO)c1ccccc1

Procedure:
The product of Example 96G (0.58 g, 3.2 mmol) and sodium borohydride (0.12 g, 3.2 mmol) in 75% aqueous EtOH (7.6 mL) were refluxed for 1.5 hours. The reaction mixture was concentrated and the residue was diluted with water (15 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was washed with water (2×10 mL) and brine, dried over MgSO4, concentrated to give the title compound as colorless viscous oil, which later crystallized (0.27 g, 55%). 1H-NMR (300 MHz, CDCl3) δ ppm: 1.46 (s, 3H), 1.86 (br-s, 2H), 3.59 (d, J=10.7 Hz, 1H), 3.65 (d, J=10.7 Hz, 1H), 7.22-7.30 (m, 1H), 7.31-7.41 (m, 2H), 7.41-7.49 (m, 2H). MS ESI+ m/z: 152 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:16])[NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>CO>[CH2:1]([N:3]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][S:16]/[C:4]/1=[N:5]\[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCNC(=S)Nc1ccc(C(=O)OC)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CO
Product: CCn1c(-c2ccccc2)cs/c1=N\c1ccc(C(=O)OC)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-(3-ethylthioureido)benzoate (2-3) (50 mg, 0.19 mmol) and 2-bromoacetophenone (39.8 mg, 0.20 mmol) in MeOH (1 mL) is heated to 80° C. for 2 hours and then cooled to room temperature and concentrated to provide (Z)-methyl 4-(3-ethyl-4-phenylthiazol-2(3H)-ylideneamino)benzoate (2-4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30]([C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1)([O:32][CH3:33])[CH3:31].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:40][C:37]2[CH:36]=[N:35][C:34]([C:30]([O:32][CH3:33])([O:29][CH3:28])[CH3:31])=[CH:39][N:38]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: COC(C)(OC)c1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(C)(OC)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 1.59 g, 4.805 mmol) in methylene chloride (24 mL) and N,N-dimethylformamide (2 drops) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (855 μL, 9.609 mmol). The reaction mixture was stirred at 0° C. for 30 min and then warmed to 25° C. where it was stirred for 2 h. The solution was then concentrated in vacuo. The yellow slurry was dissolved in methylene chloride (24 mL) and then cooled to 0° C. To this solution was added a solution of 5-(1,1-dimethoxy-ethyl)-pyrazin-2-ylamine (880.4 mg, 4.805 mmol) and pyridine (466 μL, 5.766 mmol) in methylene chloride (24 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction was then quenched with a saturated aqueous sodium chloride solution (50 mL), and the layers were separated. The aqueous layer was back-extracted with methylene chloride (50 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (75 mL), an aqueous copper(II) sulfate solution (2×50 mL), and a saturated aqueous sodium chloride solution (75 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 3/7 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1,1-dimethoxy-ethyl)-pyrazin-2-yl]-propionamide (1.25 g, 52%) as a white foam: mp 85–88° C. (foam to gel); (ES)+-HRMS m/e calcd for C23H30ClN3O5S (M+Na)+ 518.1487, found 518.1488.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:24])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[N:12]=1.[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26].N1CCCCC1.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH3:24])=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[C:27]([C:25]#[N:26])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][CH:17]=2)[N:12]=1
Reactant: CCOC(=O)CC#N
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc(C=O)cc1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: CCOC(=O)C(C#N)=Cc1ccc(OCCc2nc(-c3ccccc3Cl)oc2C)cc1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy]benzaldehyde (2.0 g), ethyl cyanoacetate (0.795 g), piperidine (0.15 g) and pyridine (30 ml) was stirred for 2 hours at 100°-110° C. The reaction mixture was poured into water. Resulting crystalline precipitate was collected by filtration and recrystallized from dichloromethane-ethanol to give ethyl 4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl]ethoxy]-α-cyanocinnamate (2.45 g, 96%) as colorless needles, m.p.120°-121° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=[O:20].[OH-].[K+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]=[CH:21][C:19](=[O:20])[C:18]([OH:23])=[O:22])=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-c2ccc(C=O)cc2)c1
Reactant: CC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cccc(-c2ccc(C=CC(=O)C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 42 %

Procedure:
To a mixture of 3′-ethoxy-biphenyl-4-carbaldehyde (4.6 g, 20.1 mmol) prepared in Step 1 and pyruvic acid (1.7 mL, 24.1 mmol) in methanol (15.0 mL), was slowly added a solution of potassium hydroxide (2.0 g, 36.2 mmol) in methanol (15.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 7 hours and then filtered. The resulting solid was diluted with a 1N hydrochloric acid solution and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 2.5 g of the titled compound as a brown liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C@@H:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1)[OH:15].[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C(Cl)Cl>[F:32][C:30]1[CH:29]=[C:4]([CH:3]=[C:2]([F:1])[CH:31]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][C@@H:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[O:15][C:33]1=[O:34]
Reactant: COc1ccc2nccc([C@@H](O)CNCCCN(C)CCOc3cc(F)cc(F)c3)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccc2nccc([C@@H]3CN(CCCN(C)CCOc4cc(F)cc(F)c4)C(=O)O3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
A mixture of (R)-2-(3-{[2-(3,5-difluoro-phenoxy)-ethyl]-methyl-amino}-propylamino}-1-(6-methoxy-quinolin-4-yl)-ethanol (105 mg, 0.24 mmol), DMAP-(38 mg, 0.31 mmol), 1,1′-carbonyldiimidazole (51 mg, 0.31 mmol) and methylene chloride stabilised on amylene (4 ml) was stirred at room temperature for 16 hours. The solvent was concentrated and the residue was chromatographed on silicagel eluting with methylene chloride-methanol (94-6) to give (R)-3-(3-{[2-(3,5-difluoro-phenoxy)-ethyl]-methyl-amino)-propyl)-5-(6-methoxy-quinolin-4-yl)-oxazolidin-2-one (70 mg, 62%).
Reaction SMILES: [P:1]([CH:5]([S:14]([OH:17])(=[O:16])=[O:15])[CH2:6][NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([OH:4])([OH:3])=[O:2]>[Pd].O>[P:1]([CH:5]([S:14]([OH:17])(=[O:15])=[O:16])[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)([OH:4])([OH:3])=[O:2]
Reactant: O=P(O)(O)C(CNc1cccnc1)S(=O)(=O)O
Agent: [Pd]
Solvent: O
Product: O=P(O)(O)C(CNC1CCCNC1)S(=O)(=O)O
Reaction time: 48 h

Procedure:
A mixture of 1 g of 1-phosphono-2-(3-pyridinylamino)ethanesulfonic acid and 0.5 g of palladium on charcoal catalyst in 50 ml of distilled water is hydrogenated on a Parr apparatus at 40 PSI for about 2 days. The catalyst is removed by filtration, and the filtrate is concentrated to a few mls. Ethanol is added slowly to precipitate a solid, which is recrystallized from water/ethanol to afford 1-phosphono-2-(3-piperidinylamino)ethanesulfonic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CCO.[Cl-].[NH4+]>[Zn].O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([NH2:5])[C:3]=1[NH2:9]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1cccc(Cl)c1N
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-chloro-2-nitroaniline (684 mg) and EtOH (5 mL) were added ammonium chloride (353 mg) and water (1.5 mL), followed by adding zinc powder (1.38 g) at 80° C., and heating and stirring at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, filtered over Celite, and washed with EtOAc. This filtrate was washed with a saturated aqueous NaHCO3 solution and brine in this order, dried over MgSO4, and then concentrated under reduced pressure to obtain 3-chlorobenzene-1,2-diamine.
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH2:17][C@@H:16]([N:18]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:19]3[N:24]=[CH:23][C:22]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)=[CH:21][N:20]=3)[CH2:15][C@H:14]2[CH2:46][CH3:47])=O)=CC=1)([O-])=O.Cl.COC([C@H]1CC[C@H](CN)CC1)=O.[CH2:61]([N:63](CC)[CH2:64]C)C.[Cl-].[NH4+]>CN(C=O)C>[CH3:61][N:63]([CH3:64])[C:11]([N:13]1[CH2:17][C@@H:16]([N:18]([CH2:31][C:32]2[CH:33]=[C:34]([C:42]([F:43])([F:45])[F:44])[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=2)[C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)=[CH:21][N:20]=2)[CH2:15][C@H:14]1[CH2:46][CH3:47])=[O:10]
Reactant: CCN(CC)CC
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: COC(=O)[C@H]1CC[C@H](CN)CC1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)N(C)C
Temperature: 150 °C
Yield: 72 %

Procedure:
To a solution of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 4-nitro-phenyl ester (0.03 mmol, 20 mg) in 1 mL of DMF are added trans-4-(aminomethyl)cyclohexanecarboxylic acid methyl ester hydrochloride (0.04 mmol, 8 mg) and triethylamine (0.07 mmol, 0.01 mL). The mixture is stirred under microwave irradiation (150° C., 5 bar), then cooled to room temperature. The mixture is poured into a saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic phases is washed by water and brine, dried over anhydrous Na2SO4 and evaporated. The obtained residue is purified by column chromatography on silica gel (eluent: n-hexane-ethyl acetate) to obtain 12.3 mg (59%) of (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid dimethylamide as colorless oil. ESI-MS m/z: 570 [M+1]+, Retention time 4.05 min (condition B).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]Cl.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: COc1cc(CCl)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(CN2CCNCC2)cc(OC)c1OC

Procedure:
Synthesized according to General Procedure A: 3,4,5-trimethoxybenzyl chloride (4{16}, 5 g, 23.1 mmol, 1 equiv.), piperazine (11.9 g, 138.5 mmol, 6 equiv.), THF (50.5 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{16} (5.59 g, 91%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 6.46 (s, 2H), 3.75 (s, 6H), 3.72 (s, 3H), 3.30 (s, 2H), 2.78 (t, 4H, J=5.0 Hz), 2.29 (br s, 4H), 1.55 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 152.7, 136.4, 133.7, 105.4, 63.6, 60.5, 55.7, 54.2, 45.8.
Reaction SMILES: [CH3:1][C:2](=[O:10])[CH2:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]C.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:12]1([CH:3]([C:4](=[O:9])[CH2:5][CH2:6][CH3:7])[C:2](=[O:10])[CH3:1])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCC(=O)CC(C)=O
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCC(=O)C(C(C)=O)c1ccccc1
Temperature: 120 °C
Yield: 48.7 %

Procedure:
To a stirred mixture of 2,4-octanedione (568 mg, 4.0 mmol) and iodobenzene (408 mg, 2.0 mmol) in dimethylsulfoxide (10 mL) were added copper(I) iodide (380 mg, 2.0 mg) and potassium carbonate (1.10 g, 8.0 mmol). The mixture was heated at 120° C. for 4 h. The mixture was filtered through a pad of Celite and the filtrate was partitioned between ether and water. Organic layer was dried (Na2SO4) and the solvent was removed. The crude product was purified by TLC with hexane/ethyl acetate (4:1) to afford 199 mg (46%) of the title compound as colorless oil: 1H-NMR (CDCl3) δ 7.42-7.33 (3H, m), 7.18-7.15 (2H, m), 2.11 (2H, t, J=8.3 Hz), 1.87 (3H, s), 1.58-1.44 (3H, m), 1.25-1.16 (2H, m), 0.79 (3H, t, J=7.2 Hz).