Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1NCCN(S(C2C=CC(C)=CC=2)(=O)=O)C(CC(N[C@H]2C3C(=CC(CN4CCCCC4)=CC=3)CCC2)=O)[CH2:3]1.[O:40]=[C:41]1[NH:47][CH2:46][CH2:45][N:44]([S:48]([C:51]2[CH:57]=[CH:56][C:54]([CH3:55])=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH:43]([CH2:58][C:59]([OH:61])=[O:60])[CH2:42]1.N1(CC2C=C3C(=CC=2)[C@H](N)CCC3)CCCCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[O:40]=[C:41]1[NH:47][CH2:46][CH2:45][N:44]([S:48]([C:51]2[CH:57]=[CH:56][C:54]([CH3:55])=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH:43]([CH2:58][C:59]([O:61][CH2:2][CH3:3])=[O:60])[CH2:42]1
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)CC2CC(=O)N[C@@H]2CCCc3cc(CN4CCCCC4)ccc32)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)CC2CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CC(=O)NCCN1S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
A solution of the product of step A (1.34 g, 5.44 mmol) was stirred in THF (30 ml) at 0*C. Bu3SnOTf (90%, 2.73 g, 5.60 mmol) in THF 8.0 ml was added dropwise over 6 min, and the mixture was heated to reflux for 22 h. The reaction was cooled to 0° C., and triethylamine (1.52 ml, 10.9 mmol) and dimethylaminopyridine (0.135 g, 1.11 mmol) were added followed by p-toluenesulfonyl chloride (2.09 g, 11.0 mmol) in THF 4.0 ml. The reaction was allowed to r.t. and after 4 h concentrated under reduced pressure. AcOEt (100 ml) was added to the residue and washed with 0.1 N HCl aq. (100 ml×2), sat'd NaHCO3 aq. (100 ml×2) and sat'd NaCl aq. (100 ml×2), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (AcOEt→AcOEt/-MeOH=80/1) to yield the title compound. MS:355.2 C. 2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (3) To a solution of the product of step B (0.416 g, 1.17 mmol) in 1,4-dioxane (24 ml) and MeOH (24 ml), 0.13 N LiOH (28 ml, 3.6 mmol) was added, and the mixture was heated to reflux for overnight. The reaction was cooled to r.t. and AcOEt (400 ml) was added and washed with sat'd NaCl (400 ml×5), dried over Na2SO4 and concentrated under reduced pressure to yield the title compound. MS: 327.1 D. (R)-2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide. To a mixture of 2-(7-oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (0.115 g, 0.352 mmol), (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (0.0945 g, 0.387 mmol) and HOBt (<5% H2O, ˜0.398 mmol) in DMF (3.0 ml) was added EDCI*HCl (0.0805 g, 0.420 mmol), and stirred overnight under N2. AcOEt (60 ml) was added and washed with sat'd NaHCO3 aq. (60 ml×3) and sat'd NaCl aq. (60 ml×3), dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica (CH2Cl2/MeOH with 2N NH3=10/1) to yield the title compound. MS: 553.1
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[Br:27][C:28]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][C:28]=4[Br:27])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)c1ccc([N+](=O)[O-])cc1Br)c1ccnc2cc3c(cc12)OCO3

Procedure:
To a solution of compound 7 (259 mg, 1.0 mmol) and triethylamine (0.5 mL) in dry CH2Cl2 (20 mL) was added a solution of 2-bromo-4-nitrobenzoic acid chloride in 20 mL of CH2Cl2 (which was prepared by refluxing of 295 mg, 1.2 mmol of 2-bromo-4-nitrobenzoic acid in 10 mL of thionyl chloride for 4 h). The reaction mixture was heated to reflux for 6 h. The reaction mixture was allowed to cool and was then washed with saturated NaHCO3 solution, water and brine and dried over anhydrous Na2SO4. The solvent was then removed in vacuo to give a yellow solid; yield 345 mg (70.8%); mp 111–112° C.; 1H NMR (CDCl3) δ (2.29, S, 6H), 2.60 (t, 2H, J=6.2), 3.62–3.72 (m, 1H), 4.49–4.62 (m, 1H), 6.19 (d, 2H, J=5.6), 7.12 (d, 1H, J=8.2), 7.37 (s, 3H), 7.75 (d, 1H, J=8) 8.26 (s, 1H), 8.5 (d, 1H, J=4.6); 13C NMR(CDCl3) δ 45.4, 46.6, 56.4, 97.8, 102.4, 106.7, 119.5, 120.6, 121.7, 122.7, 127.6, 128.1, 143.6, 144.4, 147.9, 148.2, 148.5, 149.5, 151.4, 166.8.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CC1C=CC(S(O[CH2:17][CH:18]2[CH2:22][S:21][C:20]3([CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]3)[O:19]2)(=O)=O)=CC=1>CC(C)=O>[C:1]([S:3][CH2:17][CH:18]1[CH2:22][S:21][C:20]2([CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)[O:19]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOC(=O)CC1CCC2(C1)OC(COS(=O)(=O)c1ccc(C)cc1)CS2
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC1CCC2(C1)OC(CSC(C)=O)CS2

Procedure:
A stirred slurry of potassium thioacetate (1.14 g, 10 mmol) in a solution of the tosylate of Example P (4.15 g, 10 mmol) in acetone (30 ml) is refluxed under nitrogen for 5 hrs. The reaction mixture is filtered and the filtrate is concentrated on a rotary evaporator. The residue is dissolved in ethyl acetate, washed with water and dried over sodium sulfate. The drying agent is filtered, the solvent is removed using the rotary evaporator and the residue is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]=2[CH:15]=1.Cl.Cl.[CH3:18][NH:19][CH2:20][C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:23]=2[N:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O.ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:19]([CH3:18])[CH2:20][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:23]=4[N:22]=3)=[O:14])[C:6]=2[CH:15]=1
Reactant: CNCc1nc2cc(C(F)(F)F)ccc2[nH]1
Reactant: O=C(O)Cn1c(=O)oc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(Cc1nc2cc(C(F)(F)F)ccc2[nH]1)C(=O)Cn1c(=O)oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a mixture of (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid (300 mg), N-methyl-1-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]methanamine dihydrochloride (420 mg), and dichloromethane (10 mL) were added TEA (552 μL), HOBt (214 mg), and WSC.HCl (303 mg), followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc. The organic layer was washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The resulting solid was collected by filtration and washed with EtOAc. To a mixture of the obtained solid (325 mg) and MeOH (5 mL) was added 4 M hydrogen chloride/EtOAc (330 μL), followed by stirring at room temperature for 1 hour. To the reaction mixture was added EtOAc. The resulting solid was collected by filtration and then washed with EtOAc to obtain 2-(5-chloro-2-oxo-1,3-benzoxazol-3 (2H)-yl)-N-methyl-N-{[5-(trifluoromethyl)-1H-benzimidazol-2-yl]methyl}acetamide hydrochloride (277 mg).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]2[N:19]=[CH:18][CH:17]=N2)[CH:11]=[CH:10][C:9]=1[OH:20].[CH3:21][O:22][C:23](=[O:28])[NH:24][CH2:25][CH2:26]Cl.[Cl-].[NH4+]>CN(C)C=O>[CH3:21][O:22][C:23](=[O:28])[NH:24][CH2:25][CH2:26][O:20][C:9]1[CH:10]=[CH:11][C:12]([CH2:14][N:15]2[CH:1]=[CH:17][CH:18]=[N:19]2)=[CH:13][C:8]=1[Cl:7]
Reactant: Oc1ccc(Cn2nccn2)cc1Cl
Reactant: O=C([O-])[O-]
Reactant: COC(=O)NCCCl
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)NCCOc1ccc(Cn2cccn2)cc1Cl
Temperature: 60 °C
Yield: 74.2 %

Procedure:
To a mixture of potassium carbonate (435 mg), 2-chloro-4-(2-2H-1,2,3-tri-azolyl)methylphenol (300 mg) and anhydrous N,N-dimethylformamide (30 ml) was added dropwise an anhydrous N,N-dimethylformamide solution (2 ml) of 2-chloroethylcarbamic acid methyl ester (216 mg) at room temperature under stirring. This mixture was then heated at 60° C. under stirring for 6 hours, and poured into ice-cooled saturated aqueous ammonium chloride solution, which was extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 329 mg of 2-[2-chloro-4-(1-pyrazolyl)methylphenoxy]ethylcarbamic acid methyl ester (compound 7). Yield, 74%.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]1([P:9](=[O:12])([OH:11])[OH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.O>[C:3]1([P:9](=[O:10])([O-:12])[O-:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Zn+2:2]
Reactant: O=P(O)(O)c1ccccc1
Agent: [O-2]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Product: O=P([O-])([O-])c1ccccc1

Procedure:
A slurry in methanol-water of zinc oxide was prepared by charging a 300 mL reaction flask equipped with a stirrer with 10.0 g (123 mmol) of zinc oxide (JIS grade 2, available from HakusuiTech Ltd.) and 90.0 g of 50% by mass methanol-water. A solution of 1.9 g (12 mmol) of phenylphosphonic acid (Nissan Chemical Industries, Ltd.) dissolved in 11.0 g of 50% by mass methanol-water was gradually added dropwise at room temperature (about 25° C.) to this slurry with stirring, thereby effecting a reaction for one hour. The slurry was then filtered and the wet cake was thoroughly rinsed with methanol. The wet cake was subsequently dried at 120° C. for at least 12 hours, yielding a white powder of zinc phenylphosphonate-containing zinc oxide.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[O:35][CH2:36][CH2:37][NH:38][CH3:39])[N:28]=[CH:27][N:26]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[O:35][CH2:36][CH2:37][N:38]([CH3:39])[C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[CH2:2][OH:1])[N:28]=[CH:27][N:26]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(CO)C(=O)O
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)C(C)(C)CO
Yield: 25 %

Procedure:
The procedure described in Example 1 was repeated using 3-hydroxy-2,2-dimethylpropanoic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 25% yield; NMR spectrum (DMSO-d6) 1.07 (s, 6H), 3.15 (s, 3H), 3.35 (d, 2H), 3.91 (t, 2H), 4.41-4.48 (m, 3H), 5.30 (s, 2H), 7.18 (d, 1H), 7.24 (d, 1H), 7.34 (d, 1H), 7.35-7.39 (m, 1H), 7.56-7.61 (m, 2H), 7.71-7.76 (m, 1H), 7.86-7.91 (m, 1H), 7.98 (d, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.81 (s, 1H); Mass spectrum MH+ 536.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH:34]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:34][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1nccc2ccccc12
Reactant: Cc1cnc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2nccc3ccccc23)C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and 1-isoquinoline-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil. Deprotection with TFA using General Procedure F gave (3,5-Dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-piperidin-4-yl-amine as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([CH2:18][OH:19])[C@H:14]([CH2:16][CH3:17])[CH3:15].CCN(CC)CC>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C@H:13]([CH2:18][OH:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chlorobenzenesulfonyl chloride (1.93 g, 9.1 mmol) in CH3CN (25 mL) and (S)-isoleucinol (1.07 g, 9.1 mmol) was added Et3N (1.91 mL, 13.7 mmol). The reaction mixture was stirred at 25° C. for 30 minutes. The solvent was removed and the oil was dissolved in CH2Cl2 (20 mL). The solution was washed with water (2×20 mL) and dried over Na2SO4. The solvent was removed to give N-4-chloro benzenesulfonyl isoleucinol, which was carried on without further purification.
Reaction SMILES: CS([Cl:5])(=O)=O.[Cl:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:16](=[O:28])[C:17]3[S:24][C:23]([CH2:25]O)=[C:22]([CH3:27])[C:18]=3[N:19]([CH3:21])[CH:20]=2)=[O:14])=[CH:9][CH:8]=1.N1C(C)=CC(C)=CC=1C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:16](=[O:28])[C:17]3[S:24][C:23]([CH2:25][Cl:5])=[C:22]([CH3:27])[C:18]=3[N:19]([CH3:21])[CH:20]=2)=[O:14])=[CH:29][CH:30]=1
Reactant: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
Methanesulfonyl chloride (0.23 mL, 3.0 mmol) was added to a mixture of N-(4-chlorobenzyl)-2-(hydroxymethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (446 mg, 1.19 mmol), collidine (0.39 mL, 3.0 mmol) and DMAP (22 mg, 0.18 mmol) in DMF (21 mL). The reaction was stirred at room temperature for 1 hour 15 minutes, going to an orange/amber solution. The reaction was cooled in an ice bath before diluting with water to a total volume of 100 mL. The mixture was stirred vigorously for 5 minutes before the solid precipitate was collected by filtration, washed with water and dried in vacuo, leaving the title compound as a white solid (460 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28](I)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:50]5[CH:49]=[N:48][N:47]([CH2:46][C:45]6[CH:61]=[CH:62][CH:63]=[C:43]([F:42])[CH:44]=6)[CH:51]=5)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(I)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(Cc5cccc(F)c5)c3)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Yield: 18.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(methylsulfonamido)phenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 50) (150 mg, 0.215 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (78 mg, 0.258 mmol) using sodium carbonate (68 mg, 0.645 mmol) and Pd(PPh3)2Cl2 (8 mg, 0.0107 mmol) in toluene/ethanol/water (5/2.5/1 ml) to afford 30 mg (18.7% yield) of titled compound after purification by preparative TLC (Silicagel-1000 micron) using 1% methanol in DCM as eluent.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][CH2:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH3:14])=[CH:9][CH:8]=1.C([O-])([O-])=O.[Na+].[Na+].O(C(C)C)C(C)C>ClCCl.O>[CH3:5][O:4][C:2](=[O:3])[N:15]([C@H:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)[CH3:14])[CH2:16][CH2:17][C:18](=[O:19])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[C@H](NCCC(=O)c1ccccc1)c1ccc(Cl)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: O
Product: COC(=O)N(CCC(=O)c1ccccc1)[C@@H](C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (15.5 mL) dissolved in dichloromethane (100 mL) was added to a mixture of 3-[(S)-1-(4-chloro-phenyl)-ethylamino]-1-phenyl-propan-1-one (38.0 g) and Na2CO3 (23.5 g) in a mixture of dichloromethane (100 mL) and water (100 mL) at such a rate that the solution temperature maintains between 20 and 26° C. After complete addition, the solution was stirred at ambient temperature for an additional 30 min. Then, the organic phase was separated and the aqueous phase was extracted once with dichloromethane. The combined organic phases were washed with brine and dried (MgSO4). Then, silica gel (20 g) was added and the resulting mixture was stirred vigorously for 30 min. The silica gel was separated by filtration, washed with dichloromethane (200 mL), and the combined filtrate was concentrated under reduced pressure to give an oil. The oil was treated with iPr2O (150 mL) to precipitate the title compound that was separated by filtration, washed with petroleum ether (30 mL), and dried. The filtrate was concentrated and the residue was taken up in petroleum ether (60 mL). The precipitate formed after a while of stirring was separated by filtration, washed with petroleum ether (20 mL), dried, and combined with the precipitate obtained before.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]#N)=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.OS(O)(=O)=O.[C:30](=O)(O)[O-:31].[Na+].C(=O)(O)[O-:36].[Na+].ClCCl>ClCCl.CO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:31][CH3:30])=[O:36])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Temperature: 20 °C
Yield: 97.7 %

Procedure:
Nitrile 6 (101 g) and methanol (1.01 L, 10 vol.) were charged to a 3-L flask equipped with stir bar and thermocouple. Concentrated H2SO4 (175 mL, 10.0 equiv.) was added drop wise to the solution over 15 minutes while maintaining a temperature below 60° C. Followed by 30% fuming sulfuric acid (124 mL) was added drop wise to the solution while maintaining a temperature below 60° C. The solution was then heated to reflux with a heating mantle and stirred overnight. When the reaction was deemed complete, it was cooled to 20° C. In a second flask (22 L), saturated sodium bicarbonate (10.7 L) and dichloromethane (1.1 L) were charged and cooled to 15° C. While maintaining a temperature below 20° C., the reaction mixture was added to the sodium bicarbonate/dichloromethane mixture. The quench was stirred for 15 minutes and the phases were separated. The aqueous phase was extracted with dichloromethane (1×550 mL, 1×300 mL). The combined organics were dried with magnesium sulfate and concentrated to dryness to give 105 g of an orange solid (94% crude yield, 97.7% AUC by HPLC).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].C([Mg]Cl)(C)C.[CH:13]1([C:16]2[CH:20]=[C:19]([NH:21][C:22]3[C:23]4[CH2:39][CH2:38][CH2:37][C:24]=4[N:25]=[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH:29]4[C:33](OC)=[O:34])[N:27]=3)[NH:18][N:17]=2)[CH2:15][CH2:14]1>C1COCC1>[CH:13]1([C:16]2[CH:20]=[C:19]([NH:21][C:22]3[C:23]4[CH2:39][CH2:38][CH2:37][C:24]=4[N:25]=[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH:29]4[C:33]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:34])[N:27]=3)[NH:18][N:17]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Reactant: Nc1cnccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Nc1cnccn1)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.3 %

Procedure:
To a solution of pyrazin-2-amine (284 mg, 2.99 mmol) in dry THF (12 mL) was added 2M solution of isopropylmagnesium chloride (1.5 mL, 2.99 mmol) in THF dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of methyl 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (200 mg, 0.746 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 1.5 h. The reaction was quenched with saturated ammonium chloride solution (20 mL). The product was extracted with EtOAc (2×40 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded an oily residue that was purified by reverse phase HPLC to afford 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide (120 mg). 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.57-0.67 (m, 2H), 0.78-0.95 (m, 2H), 1.70-1.81 (m, 1H), 2.02-2.18 (m, 4H), 2.25-2.39 (m, 2H), 2.63-2.78 (m, 2H), 2.79-2.85 (m, 2H), 3.60-3.77 (m, 1H), 3.78-3.94 (m, 1H), 4.73-4.81 (m, 1H), 6.25 (s, 1H), 8.26 (d, 1H), 8.30 (s, 1H), 9.31 (s, 1H). Separation by chiral HPLC provided enantiomers 6a and 6b.