Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[CH3:2][C:3]1([CH3:19])[CH:5]([CH:6]=[C:7]([Cl:15])[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:4]1[C:16]([OH:18])=[O:17].[F:20][C:21]1[C:26]([CH2:27]Br)=[C:25]([F:29])[C:24]([F:30])=[C:23]([F:31])[C:22]=1[F:32]>CN(C)C=O>[CH3:2][C:3]1([CH3:19])[CH:5]([CH:6]=[C:7]([Cl:15])[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:4]1[C:16]([O:18][CH2:27][C:26]1[C:25]([F:29])=[C:24]([F:30])[C:23]([F:31])=[C:22]([F:32])[C:21]=1[F:20])=[O:17]
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: CC1(C)C(C=C(Cl)c2ccc(Cl)cc2)C1C(=O)O
Agent: [K]
Solvent: CN(C)C=O
Product: CC1(C)C(C=C(Cl)c2ccc(Cl)cc2)C1C(=O)OCc1c(F)c(F)c(F)c(F)c1F
Yield: 74.4 %

Procedure:
10.7 g (0.033 mol) of the potassium salt of 2,2-dimethyl-3-(2-chloro-2-p-chlorophenyl-vinyl)-cyclopropanecarboxylic acid were dissolved in 100 ml of dimethylformamide and the solution was heated to 120° C., together with 6.8 g (0.026 mol) of pentafluorobenzyl bromide, for 3 hours. After the reaction had ended, the dimethylformamide was distilled off in vacuo and the residue which remained was taken up in 200 ml of methylene chloride. The methylene chloride solution was then extracted by shaking twice with 100 ml of water each time, the organic phase was dried over sodium sulphate and the solvent was stripped off in vacuo. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 9.0 g (74.4% of theory) of pentafluoro-benzyl 2,2-dimethyl-3-(2-chloro-2-p-chloro-phenyl-vinyl)-cyclopropanecarboxylate were obtained as a yellow oil with the refractive index nD25 :1.5382.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][Sn:12](Cl)([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>CCCCCC.CCOCC>[CH3:11][Sn:12]([CH3:14])([CH3:13])[C:7]1[S:6][CH:10]=[CH:9][N:8]=1
Reactant: c1cscn1
Reactant: C[Sn](C)(C)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Sn](C)(C)c1nccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To 99.99 ml of n-butyl lithium in hexane, dissolved in 200 ml of ether is added dropwise with stirring over 1 hour, at -78° C., a solution of 16 g of thiazole in 100 ml of ether over 1 hour. A solution of 49.81 g of trimethyltin chloride in 100 ml of ether is added dropwise over 20 minutes followed by additional stirring for 1 hour. The reaction mixture is poured into saturated sodium bicarbonate and the organic layer separated, dried and evaporated to a residue. The residue is vacuum distilled to give 33.4 g of the desired product as a colorless liquid, B.P. 60°-65° C./0.7 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[CH3:31][C@H:32]1[NH:37][C@@H:36]([CH3:38])[CH2:35][N:34]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:33]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:37]3[C@H:36]([CH3:38])[CH2:35][N:34]([C:39]4[CH:48]=[CH:47][C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]=4)[CH2:33][C@@H:32]3[CH3:31])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1
Product: COc1ccc(CNC(=O)C2(CCCCN3[C@H](C)CN(c4ccc5ccccc5n4)C[C@@H]3C)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline
Reaction SMILES: C([O:8][NH:9][C:10](=[O:41])[CH2:11][CH:12]([C:17](=[O:40])[NH:18][C@H:19]1[CH2:37][C:36]2=[CH:38][N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=32)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:39])[CH2:13][CH:14]([CH3:16])[CH3:15])C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][NH:9][C:10](=[O:41])[CH2:11][CH:12]([C:17](=[O:40])[NH:18][C@H:19]1[CH2:37][C:36]2=[CH:38][N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=32)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:39])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: [H][H]
Reactant: CC(C)CC(CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)CC(CC(=O)NO)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reaction time: 3 h

Procedure:
To a solution of the more polar stereoisomer of (11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,9-diazatricyclo-[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide (90 mg) in ethanol/tetrahydrofuran (350 mL; 2:1) was added 10% palladium on charcoal (30 mg). The material was stirred with a constant stream of hydrogen gas bubbling through it. After 3 hours TLC (10% CH3OH/CH2Cl2) showed the reaction was complete. The material was filtered through a bed of celite (3X) and concentrated under reduced pressure to an almost dry residue. Methylene chloride (15 mL) was added and the material was again concentrated under reduced pressure until almost dried and then repeated. To the residue was added 3-4 drops of methanol followed by methylene chloride (15 mL). The material was stirred with cooling (ice bath) and ether (5 mL) and then hexane (2 mL) was added. A crystalline material slowly emerged and was collected by filtration to yield 50 mg of the more polar stereoisomer of (11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo-[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide, m.p. 197-201° C., [α]D23 =-85.1° (3.5 mg/1.0 mL DMSO).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:2]#[CH:3].[Cl:16]N1C(=O)CCC1=O>CC(C)=O.C([O-])(=O)C.[Ag+]>[Cl:16][C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:13])([F:14])[F:15]
Reactant: C#CCOc1ccccc1OC(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: FC(F)(F)Oc1ccccc1OCC#CCl
Temperature: 25 °C
Yield: 91.4 %

Procedure:
To a solution of the product of Example 66A (13.0 g, 56.1 mmol) in acetone (200 mL) was added N-chlorosuccinimide (8.99 g, 67.3 mmol) and silver acetate (0.936 g, 5.61 mmol). The reaction was heated at reflux for 16 hours, cooled to ambient temperature, and the solvent removed under reduced pressure. The residue was taken up in a mixture of diethyl ether and water, and filtered to remove the silver salts. The filtrate was extracted with diethyl ether (300 mL). The combined organic layers were washed with saturated sodium bicarbonate (75 mL) and concentrated to give the title compound (12.85 g) which was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ 7.30-7.24 (m, 2H), 7.15-7.09 (m, 1H), 7.01 (td, J=7.8, 1.4 Hz, 1H), 4.77 (s, 2H); MS (DCI) m/z 268 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:6]=1[C:7](OC)=[O:8].C[Al](C)C.C1(C)C=CC=CC=1.O>C(Cl)Cl>[F:15][C:12]1[CH:13]=[CH:14][C:5]2[O:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[NH:1][C:7](=[O:8])[C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc(F)ccc1Oc1ccccc1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C1Nc2ccccc2Oc2ccc(F)cc21
Temperature: 0 °C
Yield: 72.6 %

Procedure:
Title compound 19 (802 mg, 3.07 mmol) was dissolved in DCM (10 mL) and the mixture was cooled to 0° C. Trimethylaluminum 2M in toluene (1.8 mL, 3.69 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. The mixture was then heated to 45° C. for 45 h. The mixture was cooled to room temperature for the slow addition of water. The solution was extracted with ethyl acetate then washed twice with HCl (10%), water and saturated solution of bicarbonate. The organic layer was then dried over sodium sulfate and concentrated in vacuo until the product precipitated. The solid was filtered and dried to afford title compound 20 (511 mg, 73%) as a white solid. LRMS (ESI): (calc) 229.05. (found) 230.1 (MS)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[Cl:19])[C:4]1=[O:20].C(N(CC)CC)C.[S:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[C:29]1[S:37](Cl)(=[O:39])=[O:38]>CC#N>[Cl:19][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:37]([C:29]4[S:28][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[CH:30]=4)(=[O:38])=[O:39])[C:4]3=[O:20])[CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: N[C@H]1CCN(Cc2ccc3nccc(Cl)c3c2)C1=O
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccccc3s2)CCN1Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
3-(S)-Amino-1-(4-chloroquinolin-6-ylmethyl)-pyrrolidin-2-one hydrochloride (0.12 g, 0.38 mmol) is suspended in 15 mL CH3CN. To this solution is added triethylamine (110 mL, 0.79 mmol) followed by benzothiophene-2-sulfonyl chloride (0.094 g, 0.40 mmol). The mixture is stirred overnight at room temperature, subjected to aqueous work up then concentrated to dryness. The crude product is purified by column chromatography eluting with 2-10% MeOH/CH2Cl2 to give the title compound (0.11 g, 0.23 mmol) as an off-white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][NH:6][CH2:7][CH3:8])[CH3:2].[C:9]1([CH:15](Cl)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][CH2:7][CH3:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: CCNCCNCC
Product: CCNCCN(CC)C(c1ccccc1)c1ccccc1
Yield: 41.3 %

Procedure:
Reaction and treatment were carried out using 21 g of N,N'-diethylethylenediamine and 7.3 g of diphenylmethyl chloride in accordance with the same procedure as in Example 3-(a), in order to obtain 4.2 g of N-diphenylmethyl-N,N'-diethylethylenediamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[Cl:43][C:44]1[CH:53]=[C:52]2[C:47]([CH2:48][CH2:49][NH:50][CH2:51]2)=[CH:46][CH:45]=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[Cl:43][C:44]1[CH:53]=[C:52]2[C:47]([CH2:48][CH2:49][N:50]([C:14](=[O:16])[CH2:13][N:10]3[CH2:11][CH2:12][CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9]3=[O:17])[CH2:51]2)=[CH:46][CH:45]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Reactant: Clc1ccc2c(c1)CNCC2
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1CCc2ccc(Cl)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 216A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 7-chloro-1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.37-7.20 (m, 2H), 7.21-6.93 (m, 5H), 4.65 (d, J=26.2, 2H), 4.33 (d, J=15.9, 1H), 4.24-4.00 (m, 1H), 3.82 (t, 1H), 3.76-3.48 (m, 4H), 2.86 (dt, J=5.9, 11.4, 2H), 2.57 (d, J=3.8, 1H), 2.16 (dd, J=6.2, 14.6, 1H); MS (DCI) m/z 387.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]([F:38])([F:37])[F:36])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]([F:38])([F:36])[F:37])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
124 mg (0.22 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate (racemate) (Example 18.1E) were hydrolysed with TFA according to General Method 2. Yield: 85 mg (79% of theory)
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][C:12]2[CH:18]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:15][C:13]=2[NH2:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=2)[CH:27]=[CH:26]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[C:20]([NH:19][C:17]1[CH:18]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:23]=[CH:24][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[C:13]([NH:14][C:34]([C:31]2[CH:32]=[C:33]3[C:28]([CH:27]=[CH:26][NH:25]3)=[CH:29][CH:30]=2)=[O:35])=[CH:15][CH:16]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CC(=O)Nc1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(NC(=O)c2ccc3cc[nH]c3c2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Reaction time: 72 h
Yield: 71.1 %

Procedure:
To a stirring solution of 2-(4-t-butylbenzoyl)amino-4-(acetylamino)aniline (40 mg, 0.12 mmol), 6-indolecarboxylic acid (40 mg, 0.24 mmol) and bromotris(pyrrolidino)phosphonium hexafluorophosphate (112 mg, 0.12 mmol) in dichloromethane (10 mL) and DMF (1 mL) was added N,N-diisopropylethylamine (42 mg, 0.36 mmol). After 3 days, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed once with 1 N HCl, once with satd aq sodium bicarbonate, dried with MgSO4, filtered and concentrated in vacuo. The residue was then chromatographed over silica gel, eluting with 10% methanol/dichloromethane and the product containing fractions were combined and concentrated to give 40 mg (71%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([C:15](OCC2C=CC=CC=2)=[O:16])[N:12]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:10])[C:2]1C=CC=CC=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([CH:11]1[CH2:14][CH:13]([CH2:15][OH:16])[N:12]1[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:10])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CC(CO)N1Cc1ccccc1

Procedure:
This compound is obtained, as the result of a concomitant transesterification, when NaBH4 reduction is applied directly to cis-N-benzylazetidine-2,4-dicarboxylic acid dibenzyl ester. To 104 mg (0.25 mmol) of cis-N-benzylazetidine-2,4-dicarboxylic acid dibenzyl ester in 2.5 ml of absolute ethanol is added, at r.t. in small portions over a period of 1 h, 45 mg (1.25 mmol) of NaBH4. Quenching with 50 μl of acetic acid is followed by filtration through a medium porosity sintered glass funnel, repeated washing of the solids with methylene chloride, and evaporation. The residue is chromatographed on SiO2 ; EtOAc/hexanes (1:3) elutes benzyl alcohol, EtOAc/hexanes (1:1) the product. The product is a colorless oil obtained in 39.8 mg (64%) yield. 1H NMR (CDCl3): δ7.35-7.25 (m, 5H), 4.09 (q, 2H, J=7), 3.84, 3.67 (AB system, 2H, J=12.5), 3.66 (t, 1H, J=8.5), 3.38 (tt, 1H, J=8, 2.5), 3.25-3.15 (m, 2H), 2.81 (br., 1H), 2.37-2.21 (m, 2H), 1.20 (t, 3H, J=7). IR (neat): 3432, 3063, 2928, 2870, 1736, 1495, 1455, 1194, 1096, 1034, 961, 739, 704 cm-1.
Reaction SMILES: C1(C)C=CC(S([O:10][C@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)(=O)=O)=CC=1.[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:10]([C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccccc2)C1

Procedure:
Analogously to Method G, 1.01 g of tert-butyl (S)-3-(toluene-4-sulphonyloxy)pyrrolidine-1-carboxylate and 0.418 g of phenol are reacted. The title compound is obtained as a colourless oil. Rf=0.47 (2:1 EtOAc-heptane); Rt=4.88.
Reaction SMILES: C([O:8][C:9](=[O:22])[C@H:10]([CH3:21])[NH:11][C:12](=[O:20])[CH:13]([CH3:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:18][O:17][C:15]([CH2:14][CH:13]([CH3:19])[C:12]([NH:11][C@H:10]([C:9]([OH:22])=[O:8])[CH3:21])=[O:20])=[O:16]
Reactant: COC(=O)CC(C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC(C)C(=O)N[C@@H](C)C(=O)O
Reaction time: 16 h

Procedure:
N-(3-methoxycarbonyl-2-methylpropanoyl)-L-alanine benzyl ester (50 g.) is dissolved in 95% ethanol, 10% palladium on charcoal (5 g.) is added and the mixture is hydrogenated at normal pressure for 16 hours. The catalyst is filtered off and the filtrate is concentrated to dryness in vacuo to yield N-(3-methoxycarbonyl-2-methylpropanoyl)-L-alanine.
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NCC4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH2:100][CH2:101][CH2:102][C:103]1[CH:111]=[CH:110][C:106]([C:107]([OH:109])=[O:108])=[CH:105][CH:104]=1>>[ClH:45].[C:94]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](=[O:71])[NH:100][CH2:101][CH2:102][C:103]4[CH:111]=[CH:110][C:106]([C:107]([OH:109])=[O:108])=[CH:105][CH:104]=4)[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: NCCc1ccc(C(=O)O)cc1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCCc6ccc(C(=O)O)cc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 4-(2-amino-ethyl)-benzoic acid. MS (ES+) m/e 787.51 (MH+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[CH:19]=2)=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: Cc1cccc(B(O)O)c1
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: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2cccc(C)c2)cc1
Temperature: 100 °C
Yield: 87.3 %

Procedure:
A mixture of 4-bromo benzoic acid ethyl ester (2.7 mL, 16.5 mmol), 3-methyl phenylboronic acid (2.2 g, 16.2 mmol) and sodium carbonate (7.5 g, 70.8 mmol) in toluene:ethanol:water (75 mL:37 mL:37 mL), was flushed with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine)palladium(0) catalyst (0.94 g, 0.81 mmol), the reaction was heated at 100° C. overnight. After cooling, the mixture was filtered through Celite which was then washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification of the residue by flash chromatography with a solvent gradient from 25% to 50% of dichloromethane in hexane provided the title compound (3.4 g, 87.3%) as a colorless oil.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:29])[CH2:12][CH2:11]1)(=[O:8])[C:2]1C=CC=CC=1.[K+].[Br-]>CO>[C:1]([NH:9][C@@H:10]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22]([OH:24])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:29])[CH2:12][CH2:11]1)(=[O:8])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)c3ccccc3)C(=O)N12
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O

Procedure:
was prepared from 211e the same method as compound 212e as a white glassy solid (595 mg, 77%): mp >250° C.; [α]D24 -153 (c 0.10, MeOH); IR (KBr) 3280, 2942, 1742, 1697, 1675, 1650, 1616, 1548, 1470, 1443, 1281, 1249, 1202, 1187, 1171; 1H NMR (CD3OD) δ 5.35-5.31 (1H, m), 4.81-4.71 (1H, m), 4.61-4.46 (1H, m), 3.59-3.44 (2H, m), 3.11-2.94 (1H, m), 2.58-2.39 (1H, m), 2.36-2.19 (2H, m), 2.11-1.83 (3H, m), 1.99 (3H, s), 1.78-1.56 (2H, m); Anal. Calcd for C12H17N3O5 : C, 50.88; H, 6.05; N, 14.83. Found: C, 50.82; H, 6.02; N, 14.58; MS (ES-) 282 (M-1, 100%): Accurate Mass calculated for C12H18N3O5 (MH+): 284.1246. Found: 284.1258.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16](Cl)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: CCCc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-chlorophenyl)-5-propyl-pyrazole-4-carbonyl chloride (commercially available, 302 mg, 1.07 mmol) in DCM (5 ml) was added 1 drop of DMF followed by cyclohexylamine (306 μL, 2.68 mmol). The reaction mixture was stirred at room temperature for two hours then stopped.
Reaction SMILES: [C:1]([N:9]1[CH2:13][C@@H:12]([O:14][CH2:15][CH2:16][OH:17])[C@H:11]([Br:18])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:1]([N:9]1[CH2:13][C@@H:12]([O:14][CH2:15][CH2:16][O:17][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C@H:11]([Br:18])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1C[C@@H](Br)[C@H](OCCO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CN(C(=O)c3ccccc3)C[C@H]2Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
92 g (0.239 mol) of trans-1-benzoyl-3-bromo-4-(2-hydroxyethoxy)-pyrrolidine, 32 g (0.316 mol) of triethylamine and 1 g of 4-dimethylaminopyridine are dissolved in 750 ml of toluene, and 60 g (0.31 mol) of tosyl chloride in 450 ml of toluene are added dropwise. The mixture is stirred for two days at room temperature, water is added, and the aqueous phase is separated off and extracted with toluene. The toluene solutions are washed with 10% hydrochloric acid, dried over magnesium sulphate, concentrated, dissolved in ethyl acetate and filtered through silica gel. The filtrate is concentrated.