Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C(Cl)(=O)C(Cl)=O.O[NH:23][C:24](=[NH:42])[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:23]=[C:24]([C:25]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:26]=3[CH2:27][CH2:28][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]4)[N:42]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=N)NO)C1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
To a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848, 737 mg, 3.59 mmol) and oxalyl chloride (360 μl) in DCM (20 mL) was added DMF (20 μl). The solution was stirred at room temperature for 90 min, then concentrated in vacuo, and redissolved in dry DMF (6 mL). Separately, 1,1-dimethylethyl 5-[(hydroxyamino)(imino)methyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 1, 1.05 g, 3.60 mmol), 4-dimethylaminopyridine (20 mg) and N,N-diisopropylethylamine (1.31 ml, 7.50 mmol) were dissolved in DMF (10 mL). 5 mL of the first DMF solution was added to the second solution, and the yellow solution stirred at room temperature for 1 h and then at 95° C. for 18 h. The reaction was concentrated in vacuo then partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (50 mL). The organics were washed with saturated aqueous NaHCO3 (50 mL), then the combined aqueous extracted with DCM (20 mL). The combined organics were concentrated in vacuo to give a crude brown oil. Flash chromatography (gradient [0.5-4%] MeOH in DCM) and concentration in vacuo gave the title compound as a pale yellow solid (512 mg). 1H NMR (400 MHz, CDCl3) δ 8.42 (1H, d), 8.34 (1H, dd), 7.96 (1H, d), 7.34 (1H, t), 7.29 (1H, d), 7.13 (1H, d), 4.80 (1H, sept), 4.67 (2H, s), 3.68 (2H, t), 3.24 (2H, t), 1.51 (9H, s), 1.48 (6H, d); m/z (ES) 361 [M+H-100]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]([C:18]3([C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:30]([CH3:33])([CH3:32])[CH3:31])=[N+]=[N-].CO.[CH3:36][C:37](O)=[O:38]>[Pd]>[C:37]([NH:1][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]([C:18]3([C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:38])[CH3:36]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCN=[N+]=[N-]
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21

Procedure:
A solution of N-(1-(2-azidoethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (13 mg, 0.029 mmol) in MeOH-AcOH (0.2 mL, 99:1) in the presence of Pd—C (2 mg) was stirred at room temperature under 1 atm of H2 for 2 h, filtered through Celite, and concentrated under reduced pressure. The crude product was treated with AcCl (0.05 mL) and Et3N (0.05 mL) in anhydrous THF (0.2 mL) at 0° C. for 30 min and then 1 h at room temperature. The mixture was purified by preparative HPLC providing N-(1-(2-acetamidoethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) (M+H+) 462.0.
Reaction SMILES: CC(C)(O)[C:3]#[N:4].[C-]#N.[K+].[CH3:10][C@:11]12[CH2:28][CH:27]=[C:26]3[C@@H:16]([CH2:17][CH2:18][C:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21](=[O:29])[CH:20]=4)[C@@H:15]1[CH2:14][CH2:13][C:12]2=[O:30].CO>O>[C:3]([C@@:12]1([OH:30])[CH2:13][CH2:14][C@H:15]2[C@H:16]3[C:26](=[CH:27][CH2:28][C@:11]12[CH3:10])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)#[N:4]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C#N
Reaction time: 3.5 h

Procedure:
Acetone cyanohydrin (5 ml) and sufficient potassium cyanide to adjust the pH to 9.9 is added to a slurry of androst-4,9(11)-dien-3,17-dione (0, 5 g), methanol (40 ml) and water (2.5 g) at 40°. The reaction becomes homogeneous followed by precipitation of the product. After 3.5 hours, water (7.5 ml) is added dropwise and the reaction is allowed slowly to stir at 20°-25° overnight. The slurry is cooled on in ice bath, filtered, the solids washed with methanol/water (1/1) and dried under reduced pressure to give the title compound (4.54 g); [α]D (c=1, CHCl3)=+118°; MS=311, 296 and 284 m/e; NMR (CDCl3)=0.97, 1.37, 2.9, 5.5 and 5.70 δ.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([Cl:44])([CH2:11][C:12]([F:43])([F:42])[CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([O:35]C4CCCCO4)[CH2:26][CH2:27]2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[C:6](OCC)=[O:7])C>CCOCC>[Cl:44][C:5]([CH2:11][C:12]([F:42])([F:43])[CH2:13][C@H:14]([C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:23]([CH2:24][C@@H:25]([OH:35])[CH2:26][CH2:27]2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCOC(=O)C(Cl)(CC(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C)C(=O)OCC
Solvent: CCOCC
Product: C[C@H](CC(F)(F)CC(Cl)(CO)CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of the chlorodiester (10) (730 mg, 1.1 mmol) in ether (15 ml) lithium aluminium hydride (48 mg) was added and the mixture was stirred at 0° C. for 1 hr. and then stirred at room temperature for 2 hr. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (50 g). Elution with dichloromethane provided the chlorodiol (11) (250 mg, 39%) mp 152°-153° C. (n-hexane-ether). 1H-NMR δ(CDCl3 -acetone d6 -DMSO d6): 0.77 (3H, s, 18-H3), 1.00 (3H, s, 19-H3), 1.10 (3H, d, J=6 Hz, 21-H3), 3.50-4.50 (7H, m, 3-H, 26-H2, 27-H2, and THP), 4.77 (3H, m, 26-OH 27-OH and THP), 5.38 (1H, m, 6-H); δ(CDCl3 -acetone d6 -DMSOd6 -D2O): 3.60 (2H, m, THP), 3.77 (4H, s, 26-H2 and 27-H2), 4.77 (1H, m, THP). MS m/z: 434, 416, 404. Anal. Calcd for C32H51O4ClF2 : C, 67.05; H, 8.97; Cl, 6.19; F, 6.63. Found: C, 67.08; H, 8.89; Cl, 5.99; F, 6.53.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([CH2:41][CH2:42]O)=[N:9]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>C(Cl)(Cl)Cl>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:28][CH2:29]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:45][CH:44]=3)[N:9]=[C:10]([CH2:41][CH2:42][N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)[C:11]=12
Reactant: CN1CCNCC1
Reactant: COc1ccc(Cn2nc(CCO)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2nc(CCN3CCN(C)CC3)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg, 0.16 mmol; prepared as in Example 8, Step C), DIEA (0.057 mL, 0.33 mmol), and chloroform (5 mL), cooled in an ice bath under N2 was added methanesulfonyl chloride (0.0189 mL, 0.244 mmol). The reaction was allowed to warm to room temperature slowly as the ice melted. The solution was stirred for 30 minutes at room temperature. A portion of the reaction mixture (1.25 mL) was transferred to a second flask and concentrated in vacuo. To the residue was added 1-methylpiperazine (0.023 mL, 0.20 mmol). The neat reaction mixture was heated to 100° C. for 1 hour. The crude was partitioned between DCM (2 mL) and a 1:1 saturated aqueous NaHCO3/water mixture (2 mL). The phases were separated, and the organic phase was dried (Na2SO4) and loaded directly on to a preparative TLC plate, eluting with 10% MeOH (containing 7N NH3) in CHCl3. Yield: 4 mg, 12%. 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.36 (s, 1H), 8.28 (d, J=6 Hz, 1H), 7.76 (m, 1H), 7.47 (m, 2H), 7.30 (d, J=9 Hz, 2H), 7.26 (m, 1H, overlaps chloroform), 7.18 (t, J=9 Hz, 1H), 7.06 (t, J=9 Hz, 2H), 6.82 (d, J=9 Hz, 2H), 6.18 (d, J=6 Hz, 1H), 5.57 (s, 2H), 3.76 (s, 3H), 3.29 (m, 2H), 2.93 (m, 2H), 2.5-2.8 (m, 8H), 2.42 (s, 3H), 1.82 (m, 2H), 1.64 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:60][CH2:59][CH:58]([C:61](O)=[O:62])[C:57]2=[O:64])=[CH:52][CH:51]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:61]([CH:58]1[CH2:59][CH2:60][N:56]([C:53]2[CH:54]=[CH:55][C:50]([O:49][CH3:48])=[CH:51][CH:52]=2)[C:57]1=[O:64])=[O:62]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: COc1ccc(N2CCC(C(=O)O)C2=O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 42.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.098 g; 0.425 mmol), PyBOP (0.332 g; 0.638 mmol), N,N-diisoprpylethylamine (0.220 mL; 1.28 mmol) and 1-(4-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.425 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.074 g (42%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:17]=2)[CH2:13][CH2:12][N:11]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[NH:11][CH2:12][CH2:13][N:14]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:17]=2)[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)[C@@H](COCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CCN[C@@H](COCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of (R)-tert-butyl 2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate (760 mg, 1.72 mmol) in 15 mL CH2Cl2 was added 10 mL of TFA. The reaction was stirred for 1 hour. TFA was removed under vacuum and the reaction was neutralized using a 1 M NaOH solution. The aqueous layer was extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated to obtain 2-(4-((R)-3-((benzyloxy)methyl)piperazin-1-yl)-7-methylquinazolin-2-yl)phenol (570 mg, 92%). This material was used in the next step without further purification. LC/MS: m/z 441.5 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: NCCCN1CCOCC1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Product: O=C(NCCCN1CCOCC1)c1c(Cl)ncnc1Cl
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (600 mg, 2.84 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (10 ml) and TEA (395 μl, 2.83 mmol) was added. To this solution, 3-morpholinopropan-1-amine (410 mg, 2.84 mmol) was added dropwise and the mixture was stirred for 30 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude (1.13 g, 87% purity, 100% yield) was used in the next synthetic step without further purification.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[C:25](=[O:40])[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([O:34][CH2:35][CH2:36][CH2:37][CH2:38]O)[N:28]=2.[O-]S([O-])(=S)=O.[Na+].[Na+].C(C1C(NC(=O)C(C)(C)C)=NC(OCCCCOC2CCCCO2)=CC=1)=O.Cl.[Cl:76][C:77]1[C:82]([Cl:83])=[CH:81][CH:80]=[CH:79][C:78]=1[N:84]1[CH2:89][CH2:88][NH:87][CH2:86][CH2:85]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C1COCC1.CCOCC.ClCCCl.CS(C)=O>[Cl:76][C:77]1[C:82]([Cl:83])=[CH:81][CH:80]=[CH:79][C:78]=1[N:84]1[CH2:89][CH2:88][N:87]([CH2:38][CH2:37][CH2:36][CH2:35][O:34][C:29]2[N:28]=[C:27]3[C:32]([CH:33]=[C:24]([F:23])[C:25](=[O:40])[NH:26]3)=[CH:31][CH:30]=2)[CH2:86][CH2:85]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=c1[nH]c2nc(OCCCCO)ccc2cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)C(=O)Nc1nc(OCCCCOC2CCCCO2)ccc1C=O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc2cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
To a suspension of Dess-Martin periodinane (1.09 g, 2.56 mmol, 1.2 eq) in CH2Cl2 (30 mL) was added a solution of 3-fluoro-7-(4-hydroxy-butoxy)-1H-[1,8]naphthyridin-2-one (0.538 g, 2.13 mmol) in THF (10 mL)/DMSO (2 mL). The mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with Et2O (100 mL) and quenched with aqueous NaHCO3 (30 mL) containing Na2S2O3 (2.36 g, 14.91 mmol, 7 eq). After extraction with Et2O (3×50 mL), the combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated to give the crude aldehyde as a pale yellow solid. To a solution of the aldehyde in 1,2-dichloroethane (40 mL) was added 1-(2,3-dichlorophenyl)piperazine monohydrochloride (0.803 g, 3.0 mmol, 1.4 eq), Et3N (0.54 mL, 4.0 mmol, 1.9 eq), and NaBH(OAc)3 (0.631 g, 3.0 mmol, 1.4 eq). The mixture was stirred at room temperature for 1 h and then quenched with water and saturated NaHCO3. After extraction with CH2Cl2 (3×50 mL), the combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (3% MeOH/CH2Cl2) to give the title compound (900 mg, 91% in two steps). 1H NMR (400 MHz, δ ppm): 12.60 (brs, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.30 (m, 2H), 7.10 (m, 1H), 6.75 (d, J=8.5 Hz, 1H), 4.40 (t, J=7.0 Hz, 2H), 3.00 (brs, 4H), 2.50 (brs, 4H), 2.40 (t, J=6.5 Hz, 2H), 1.80 (m, 2H), 1.60 (m, 2H); 19F NMR: −140 ppm; MS: 465 (M+H)+ (Exact Mass: 464.12).
Reaction SMILES: [H-].[Na+].CCCCCC.C(OP([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH2:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[CH:22]=1)(OCC)=O)C.[CH2:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[C:32]=1[NH:39][C:40](=[O:56])[CH2:41][CH:42]1[C:55]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:49][C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:30]>CN(C)C=O>[CH2:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[CH:27][C:26](=[O:28])[CH2:25][CH2:24][CH2:23][C:21]2[CH:22]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:32]=1[NH:39][C:40](=[O:56])[CH2:41][CH:42]1[C:55]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:49][C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:30]
Reactant: CCc1cccc(C=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: CCOP(=O)(OCC)c1cccc(CCCC(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCc1cccc(C=CC(=O)CCCc2ccccc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
49 mg (1.13 mmol) of sodium hydride (as a 55% w/w suspension in mineral oil) were washed twice, each time with hexane, and were suspended in 6 ml of dimethylformamide. 2 ml of a dimethylformamide solution containing 289 mg (0.97 mmol) of 5-diethoxyphosphoryl-1-(4-oxopentyl)benzene were added to the suspension, whilst ice-cooling. The reaction mixture was then immediately allowed to return to room temperature, after which it was stirred for 30 minutes. 300 mg (0.808 mmol) of N-(2-ethyl-6-formylphenyl)-2-(9H-xanthen-9-yl)acetamide were then added to the reaction mixture, once again whilst ice-cooling. The mixture was then stirred for 1 hour at the ice-cooling temperature and then for 3 hours at room temperature. At the end of this time, the reaction solution was poured into ice-water and extracted with diethyl ether. The organic extract was washed with water. The solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of methylene chloride and diethyl ether, to give 220 mg (yield 53%) of the title compound as crystals, melting at 168°-170° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[N:48]1[CH:53]=[CH:52][N:51]=[CH:50][C:49]=1[C:54](Cl)=[O:55]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][N:48]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1cnccn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2cnccn2)CC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 36 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and pyrazine-2-carbonyl chloride as starting materials in 36% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.35 (s, 1H), 9.30 (s, 1H), 8.80 (s, 1H), 8.72 (s, 1H), 8.68 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 4.49 (m, 2H), 3.65 (m, 1H), 3.12 (m, 1H), 2.81 (m, 4H), 2.31 (m, 2H), 2.10 (m, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.22 (m, 2H). LCMS for C30H30ClN8O2 (M+H)+: m/z=569.2.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]>CO>[C:1]([NH:4][C@H:5]([CH3:9])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C=C(NC(C)=O)C(=O)O
Solvent: CO
Product: CC(=O)N[C@H](C)C(=O)O
Reaction time: 1 h

Procedure:
A solution of [Rh(COD)(R-1a)]BF4 (27 μl, 1.8×10-4 mmol) (prepared in example 4) and 2-acetamidoacrylic acid (580 mg, 4.5 mmol) in 15 ml methanol was charged into a 50 ml autoclave under a nitrogen atmosphere. The autoclave was pressurized with 1350 KPa H2 and the hydrogenation was carried out at room temperature for 1 hour. A portion of the reacting mixture was analyzed by gas chromatography to determine product composition. 100% conversion and 94.0% e.e. for the (R)-2-acetamido-propanoic acid product was obtained. The methanol was evaporated, ethylacetate (10 ml) and activated carbon (2 mg) were added and the mixture was refluxed for 10 min. After filtration, the hot ethyl acetate solution was allowed to cool to 0° C. White crystals were collected and washed with 5 ml of cold ethyl acetate to yield (R)-2-acetamidopropanoic acid (0.513 g) with 99.0% e.e. (87% isolated yield). mp 125° C., [α]D =65.4 (c=1, H2O), 1 H-NMR (400MHz, D2O) δ: 1.16 (d, 3H, J=7.2Hz), 1.77 (s, 3H), 4.07 (q, 1H, J=7.2Hz).
Reaction SMILES: [C:1]([N:6]([C:10]1[CH:11]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])[S:12][CH2:13][C:14]=1[NH:15][C:16]([O:18][CH3:19])=[O:17])C(=O)C)([O:3][CH2:4][CH3:5])=[O:2].[OH-].[Na+]>O1CCCC1>[C:1]([NH:6][C:10]1[CH:11]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:25])[S:12][CH2:13][C:14]=1[NH:15][C:16]([O:18][CH3:19])=[O:17])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N(C(C)=O)C1=C(NC(=O)OC)CSC1CCCCC(=O)N1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)NC1=C(NC(=O)OC)CSC1CCCCC(=O)N1CCCCC1
Reaction time: 2 h
Yield: 89.5 %

Procedure:
0.1 g (.000219 moles) of 3-(N-carbethoxyacetamido)-4-carbomethoxyamino-2,5-dihydro-2-thiophenevaleric acid piperidide was dissolved in 10 ml of tetrahydrofuran, and to this solution, 2 ml of 1 N sodium hydroxide was added. The heterogeneous solution was stirred for 2 hrs. and was then worked up immediately. Tetrahydrofuran was removed under vacuum, and the aqueous basic residue was partitioned between 30 ml of water and 20 ml of dichloromethane. The aqueous phase was extracted three times with 20 ml portions of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated, giving 0.08 g (0.000196 moles, 90%) of 3-carbethoxyamino-4-carbomethoxyamino-2,5-dihydro-2-thiophenevaleric acid piperidide. Upon trituration with pet. ether, the product was obtained as a solid which could be recrystallized from ethyl acetate to give white crystals; m.p. 120°-122°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=3[CH:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.Cl(O)(=O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OC(C)(C)C)(=O)C>[C:5]([O:23][CH:18]([C:12]1[C:13]([CH3:17])=[N:14][N:15]([CH3:16])[C:11]=1[C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][CH2:4][C:5]=2[CH:10]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:10])([CH3:6])[CH3:4]
Reactant: COC(=O)C(O)c1c(C)nn(C)c1-c1ccc2c(c1)CCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C)nn(C)c1-c1ccc2c(c1)CCCO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 120.7 %

Procedure:
To a solution of methyl 2-[5-(3,4-dihydro-2H-1-benzopyran-6-yl)-1,3-dimethyl-1H-pyrazol-4-yl]-2-hydroxyacetate (27c) (72 mg, 0.227 mmol) in tert-butyl acetate (6 mL) at 0° C. was added perchloric acid (0.75 mL). The mixture was stirred at 0° C. for 3 hours at room temperature before being poured into a saturated aqueous solution of sodium carbonate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 50/50) to provide the desired product (27d) (51 mg, 0.137 mmol, 60%) as a colorless oil.