Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:23]2[NH:32][C:26]3=[N:27][CH:28]=[C:29]([F:31])[CH:30]=[C:25]3[CH:24]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.B(Br)(Br)Br>ClCCl>[F:31][C:29]1[CH:30]=[C:25]2[CH:24]=[C:23]([CH:15]([C:12]3[CH:13]=[CH:14][C:9]([S:6]([CH2:5][CH2:4][OH:3])(=[O:7])=[O:8])=[CH:10][CH:11]=3)[CH2:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[NH:32][C:26]2=[N:27][CH:28]=1
Reactant: CCOCCS(=O)(=O)c1ccc(C(CC2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(CCO)c1ccc(C(CC2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To a solution of 2-[1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-2-(tetrahydro-pyran-4-yl)-ethyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (95 mg, 0.2 mmol) in dichloromethane (10 mL) at 0° C. was added a solution of boron tribromide (0.1 ml, 1 mmol) in dichloromethane (10 ml). The mixture was stirred at 0° C. for 1 h. The reaction was quenched with a saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (2×50 mL), washed with a saturated aqueous sodium bicarbonate solution (3×20 mL) and brine (3×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded (2-{4-[1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethyl]-benzenesulfonyl}-ethanol (27 mg, 30%) as a white solid: LC/MS m/e calcd for C22H25FN2O4S [M+H]+ 433.52, observed 433.0; 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (t, J=2.1 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.58-7.66 (m, 3H), 6.41 (s, 1H), 4.43 (t, J=8.0 Hz, 1H), 3.81-3.91 (m, 4H), 3.38 (t, J=6.2 Hz, 2H), 3.24-3.29 (m, 2H), 2.18-2.26 (m, 1H), 2.01 (dt, J=14.0, 7.1 Hz, 1H), 1.70 (t, J=14.1 Hz, 2H), 1.28-1.51 (m, 3H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:18])[CH:6]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:7]C(=O)C>CCC(=O)CCCC>[NH2:7][C@H:6]([C:5]([OH:18])=[O:4])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC(=O)CC
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The aqueous layer obtained was adjusted to pH 8 by adding 1 N aqueous sodium hydroxide. To this aqueous layer was added a solution of 1 g of the N-acetyl-DL-phenylalanine methyl ester obtained in step (iv) of Example 3 in 5 ml of 3-heptanone. The resultant two-layer-system mixture was shaken in the same manner as above at a temperature of 37° C. for 12 hours (repeated reaction run No. 1). When the reaction was completed, the pH of the aqueous layer was 5.50. Upon cooling the reaction mixture composed of the aqueous layer and 3-heptanone layer to room temperature, a supersaturation portion (0.11 g) of L-phenylalanine precipitated out on the aqueous layer side. Crystals of L-phenylalanine were separated by filtration. Then the filtrate was allowed to separate into the aqueous layer and 3-heptanone layer and the organic layer was removed. The aqueous layer was subjected to pH adjustment (pH 8) and reaction with N-acetyl-DL-phenylalanine methyl ester in 3-heptanone solution with shaking in the same manner as mentioned above and the resultant crystalline L-phenylalalnine precipitate (0.15 g) was collected by filtration (repeated run No. 2). By using the aminoacylase-containing aqueous layer of the filtrate in the above manner, the overall procedure comprising pH adjustment, reaction and L-phenylalanine separation was further repeated. The yields of L-phenylalanine in repeated runs No. 3, No. 4 and No. 5 were 0.16 g, 0.13 g and 0.12 g, respectively. The L-phenylalanine crystals obtained in the above repeated runs Nos. 1-5 (0.67 g in total) were combined and washed with methanol. The optical purity of the L-phenylalanine after washing (0.65 g) was found to be 98.9 percent.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][OH:27])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CNCCO
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 2-(methylamino)ethanol were converted to yield 2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-methyl-amino]-ethanol, MS: 436 (MH+, 1Br).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:14])=[O:7])(C)(C)C.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](C(O)=O)=[CH:19]2.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O>CN(C)C=O.ClCCl>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:14])=[O:7])=[CH:19]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1N
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: N[C@@H]1CCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 23 h
Yield: 138.9 %

Procedure:
trans-N-tert-Butoxycarbonyl-1,2-cyclopentane-diamine (1.40 g) was dissolved in N,N-dimethylformamide (15 ml), and to the solution 5-chloroindole-2-carboxylic acid (1.64 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.68 g) and 1-hydroxybenzotriazole monohydrate (473 mg) were added. The mixture was stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, and dichloromethane and a saturated solution of sodium hydrogencarbonate were added to the residue to collect precipitates by filtration. The precipitates were washed with ethyl acetate, dichloromethane and methanol. On the other hand, the filtrate was separated to give an organic layer,which was taken out and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by medium-pressure flash column chromatography on silica gel (dichloromethane:methanol=19:1) to obtain a pale yellow solid. This pale yellow solid was combined with the precipitates obtained by the filtration and dissolved in dichloromethane (10 ml), and trifluoroacetic acid (10 ml) was added to stir the mixture at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and dichloromethane and a 1N aqueous solution of sodium hydroxide were added to the residue to collect precipitate by filtration. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate. The precipitates collected by the filtration were added to this solution, and a 4N dioxane solution (20 ml) of hydrochloric acid was further added. The solvent was distilled off under reduced pressure, and dichloromethane (10 ml) and a 4N dioxane solution (10 ml) of hydrochloric acid were added to the residue. The solvent was distilled off again under reduced pressure. Ethyl acetate was added to the residue to collect precipitates by filtration, thereby obtaining the title compound (1.83 g) as a gray solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]=[N:10][NH:9]1.[CH2:14]([N:17]([CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1)[C:18](Cl)=[O:19])[CH2:15][CH3:16]>CN(C)C1C=CN=CC=1>[CH2:14]([N:17]([CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1)[C:18]([N:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[N:10]1)=[O:19])[CH2:15][CH3:16]
Reactant: CCCN(C(=O)Cl)C1CCOC1
Reactant: O=c1nn[nH]n1-c1ccccc1F
Agent: CN(C)c1ccncc1
Product: CCCN(C(=O)n1nnn(-c2ccccc2F)c1=O)C1CCOC1

Procedure:
1.4 g (7.8 mmol) of 1,2-dihydro-1-(2-fluorophenyl)-5H-tetrazol-5-one, 1.5 g (7.8 mmol) of N-propyl-N-(tetrahydro-furan-3-yl)carbamoyl chloride and 1.29 g (10 mmol) of 4-dimethylaminopyridine were reacted by the method of the process described in Example 1. Yield 2.1 g.
Reaction SMILES: C(N(CC)CC)C.CN(C1C=CC=CN=1)C.C(O[C:21](=[O:23])[CH3:22])(=O)C.[NH2:24][C:25]1[CH:45]=[CH:44][C:28]([CH2:29][C:30]2[NH:31][C:32](=[O:43])[C:33]3[N:38]([CH3:39])[N:37]=[C:36]([CH2:40][CH2:41][CH3:42])[C:34]=3[N:35]=2)=[CH:27][CH:26]=1>ClCCl>[CH3:39][N:38]1[C:33]2[C:32](=[O:43])[NH:31][C:30]([CH2:29][C:28]3[CH:44]=[CH:45][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:26][CH:27]=3)=[N:35][C:34]=2[C:36]([CH2:40][CH2:41][CH3:42])=[N:37]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(C)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (160 μl, 0.0011 mol), dimethylaminopyridine (10 mg), and acetic anhydride (50 μl, 0.0005 mol) were added to a solution of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (110 mg, 0.00037 mol) in dichloromethane (9 ml). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was then partitioned between 2M aqueous hydrochloric acid solution (15 ml) and dichloromethane (15 ml) and the aqueous phase extracted with dichloromethane/methanol (30 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give, after crystallisation from ethyl acetate/methanol, the title compound as an off white solid (105 mg), m.p.272-275° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[CH3:14][O:15][C:16]([C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)=[O:17].CCOC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH3:14][O:15][C:16]([C:18]1[N:19]=[CH:20][N:21]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:22]=1)=[O:17]
Reactant: COC(=O)c1c[nH]cn1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cn(-c2ccc3ccccc3c2)cn1
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A suspension of 2-naphtylboronic acid (1.4 g, 8 mmol), 1H-imidazole-4-carboxylic acid methyl ester (1.0 g, 8 mmol) and cupric acetate (1.4 g, 8 mmol) in CH2Cl2 (20 ml) was stirred at 20° C. for 24 h AcOEt (100 ml) and saturated aqueous Seignette salt solution (50 ml) was added and the resulting mixture was stirred for another 2 h. After separation the organic phase was dried (Na2SO4), concentrated and chromatographed (silica, elution with CH2Cl2/MeOH=99:1) to yield the title compound (0.49 g, 24%) of the title compound as a white crystalline material. Mp. 143-144° C. (AcOEt), MS: m/e=252 (M+).
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([O:30][CH2:31][CH3:32])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:29].[Li+].[OH-]>>[CH2:31]([O:30][C@@H:4]([CH2:5][C:6]1[C:7]([CH3:29])=[CH:8][C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:10][C:11]=1[CH3:12])[C:3]([OH:33])=[O:2])[CH3:32]
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccc(F)c(C)c3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{4-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:17]([OH:22])[OH:18])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Under nitrogen stream, 1-(benzyloxy)-4-bromo-2-fluorobenzene (12.0 g, 43 mmol) was dissolved in tetrahydrofuran, followed by addition of triisopropyl borate (11.8 mL, 51 mmol), and then the mixture was cooled to −78° C. Butyl lithium (1.55M hexane solution) (30 mL, 47 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour at −78° C. A 1N aqueous hydrochloric acid solution (100 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off under reduced pressure. The aqueous phase was extracted with ethyl acetate, the extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was suspended in hexane, and was then collected by filtration to give the title compound (9.27 g, 88%).
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:35]([C@@:37]1([N:46]2[C:56]3[N:55]=[C:53]([NH2:54])[NH:52][C:50](=[O:51])[C:49]=3[N:48]=[CH:47]2)[O:45][C@H:42]([CH2:43][OH:44])[C@@H:40]([OH:41])[C@H:38]1[OH:39])=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(OCC1C=CC=CC=1)=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]>CN(C=O)C.[Pd]>[C:1]([NH:18][C@H:19]([C:35]([C@@:37]1([N:46]2[C:56]3[N:55]=[C:53]([NH2:54])[NH:52][C:50](=[O:51])[C:49]=3[N:48]=[CH:47]2)[O:45][C@H:42]([CH2:43][OH:44])[C@@H:40]([OH:41])[C@H:38]1[OH:39])=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2]
Reactant: Nc1nc2c(ncn2[C@]2(C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(=O)OCC3c4ccccc4-c4ccccc43)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Pd]
Solvent: CN(C)C=O
Product: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
A solution of 1.0 g of (Nα-FMOC-Nε-CBZ-lysyl)guanosine in 150 mL of DMF was hydrogenated for 3.5 hr at 48 psi in the presence of 0.7 g of 10% Pd/C. The mixture was filtered and the filtrate evaporated and then treated with 30 mL of EtOH followed by 20 mL of H2O. The resulting solid was recrystallized from MeOH-EtOAc.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[N:8]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:9]=[O:10]>ClCCl>[CH:11]([NH:8][C:9]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:10])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CNCCN1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C1CN(C(=O)NC(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of piperazin-2-one (100 mg, 1 mmol) was added (isocyanatomethylene)dibenzene (209 mg, 1 mmol) in dichloromethane (5 mL). The solution was stirred for 2 hours at room temperature and concentrated in vacuo. The residue was diluted with EtOAc and then washed consecutively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (2:98 MeOH/DCM) to give desired compound N-benzhydryl-3-oxopiperazine-1-carboxamide (Compound 1) (232 mg, 75%) as a white powder.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH2:16][OH:17])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)(O)[O-].[Na+]>C(#N)C>[OH:17][CH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@@H:10]1[N:9]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: C[C@H](N[C@H]1CCCC[C@@H]1CO)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1CO
Yield: 102.4 %

Procedure:
A solution of (1S,2S)-2-[(S)-1-phenylethylamino]cyclohexyl)methanol (11, 120.9 g, 0.524 mol, 1.0 equiv. based on HCl salt 10) dissolved in acetonitrile (610 mL) was charged to a 2 L reactor, which is equipped with mechanical stirrer and thermocouple under nitrogen atmosphere. To this solution, ethyl bromoacetate (12, 104.9 g, 0.628 mol, 1.2 equiv.) and anhydrous sodium bicarbonate (57.2 g, 0.681 mol, 1.3 equiv.) were added sequentially with agitation. The contents were heated to reflux temperature for NLT 18 h with vigorous agitation under nitrogen atmosphere. Acetonitrile was distilled out under vacuum to about 300 mL volume and the mixture was cooled to less than 30° C. temperature and diluted with 327 ml, of heptanes and 423 mL of water. The contents were mixed for NLT 15 min and allowed settle to form two layers. The bottom aqueous layer was separated and further extracted with 2×327 mL of heptanes. The two heptanes extracts were combined with the organic layer in the reactor and washed sequentially with 1×327 mL of water and 1×327 mL 3.5 M aqueous sodium chloride solution. The heptanes solution was dried using anhydrous magnesium sulfate (13.5 g), filtered and concentrated under vacuum at NMT 60° C. temperature. The crude product was further dried under vacuum to afford 171.4 g of ethyl 2-(((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino) acetate (13) as viscous oil, which was carried to the next step without further purification. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150×4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-7.8): Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm, Column oven temperature: 55° C., Rt: 23.62 min; LC-MS (m/z): 320.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:14])[C:9](=O)[CH2:10][C:11]#[N:12])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[NH2:22][OH:23]>C(O)C.N1C=CC=CC=1>[NH2:12][C:11]1[O:23][N:22]=[C:9]([CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]([F:1])[CH:7]=2)[CH3:14])[CH:10]=1
Reactant: CC(C(=O)CC#N)c1ccc(-c2ccccc2)c(F)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1cc(N)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To 4-(2-Fluoro-4-biphenylyl)-3oxo-pentanenitrile (2.75 g, 10.3 mmol) in ethanol (70 ml) was added hydroxylamine hydrochloride (1.1 g, 15.8 mmol) in pyridine (10 ml). After addition, the mixture was stirred at room temperature overnight, then evaporated under reduced pressure to a residue, which was chromatographed and then recrystalyzed to afford 5-amino-3-(1-(2-fluoro-4-biphenylyl)ethyl)isoxazole (2.20 g, 76% yield) as crystalline material: mp 122°-123° C.
Reaction SMILES: C([NH:4][CH:5]1[C:19]2[C:9]([CH:10]=[C:11]3[NH:16][C:15](=[O:17])[C:14](=[O:18])[NH:13][C:12]3=2)=[C:8]([Cl:20])[CH:7]=[CH:6]1)(=O)C>Cl>[ClH:20].[NH2:4][CH:5]1[C:19]2[C:9]([CH:10]=[C:11]3[NH:16][C:15](=[O:17])[C:14](=[O:18])[NH:13][C:12]3=2)=[C:8]([Cl:20])[CH:7]=[CH:6]1
Reactant: CC(=O)NC1C=CC(Cl)=C2C=c3[nH]c(=O)c(=O)[nH]c3=C21
Agent: Cl
Product: NC1C=CC(Cl)=C2C=c3[nH]c(=O)c(=O)[nH]c3=C21
Temperature: 20 °C
Yield: 52.3 %

Procedure:
0.39 g of 5-acetamido-8-chloro-1,4-dihydro-5H-indeno[1,2-b]pyrazine-2,3-dione suspended in 5 ml of 6N hydrochloric acid is brought to reflux for 5 hours. After cooling to a temperature in the region of 20° C., the insoluble matter is filtered off, washed with water and then with methanol and taken up in 10 ml of a mixture of hot water and methanol (50:50 by volume). After a few minutes of stirring, the insoluble matter is filtered off and dried under a partial vacuum (1 mm Hg; 0.13 kPa) to yield 0.1 g of 5-amino-8-chloro-1,4-dihydro-5H-indeno [1,2-b]pyrazine-2,3-dione hydrochloride in the form of a grey solid, the melting point of which is above 260° C. (1H NMR spectrum [250 MHz, (CD3)2SO-d6, δ in ppm): 5.15 (s, 1H: CH 9); 7.39 (dd, J=8 and 2 Hz, 1H: H 7); 7.71 (d, J=2 Hz, 1H: H 5); 7.75 (d, J=8 Hz), 1H: H 8); from 8.70 to 9.20 (spread unres. comp., 3H: NH3+Cl-); from 12.00 to 12.70 (spread unres. comp., 2H: NHCOCONH).
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[CH3:37][N:38]([CH3:46])[C:39]1[CH:44]=[C:43]([NH2:45])[CH:42]=[CH:41][N:40]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:45][C:43]1[CH:42]=[CH:41][N:40]=[C:39]([N:38]([CH3:46])[CH3:37])[CH:44]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CN(C)c1cc(N)ccn1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)ccn1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (37.3 mg, 0.135 mmol) in dry dichloromethane (2.5 mL) was added triethylamine (0.047 mL, 0.338 mmol), 2-chloro-1-methylpyridinium iodide (38.3 mg, 0.15 mmol), and 2-dimethylamino-4-aminopyridine (21.7 mg, 0.158 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1.5 hours. LC/MS showed reaction complete. The reaction mixture was concentrated and purified by HPLC on a 30×100 mm Waters Sunfire column to afford the title compound as an off-white solid after lyophilization.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([NH:48][CH:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[CH:44][CH:43]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[CH:44][C:45]([NH:48][CH:49]5[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]5)=[CH:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(NC5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 63.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (150 mg, 0.280 mmol) was coupled with tert-butyl 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)piperidine-1-carboxylate (Intermediate 68)(137 mg, 0.34 mmol) using sodium carbonate (79 mg, 0.75 mmol) and Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) in DME/water (20/2 mL). This afforded 130 mg (63.4% yield) after purification by column (Silica gel 6/120) using 50% EtOAc/DCM as eluent. MS: m/z=720.8 (M+1).