Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2[CH2:22][CH2:21][CH2:20]C[N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2].N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@@H]1N(C(C2C=CC=CC=2)C2C=CC=CC=2)C[C@H](O)C1)[OH:61].FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.[Li+].[OH-]>CCO.O>[C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:38]=[C:39]([F:44])[CH:40]=[C:41]([F:43])[CH:42]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:22][C@@H:21]([OH:61])[CH2:20][NH:18]2)=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2]
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](O)CN1C(c1ccccc1)c1ccccc1
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](O)CN2)C1=O
Temperature: 25 °C

Procedure:
Step 14 (A): (3R,5R)-5-((1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl)-1-benzhydrylpyrrolidin-3-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)oxazolidin-2-one (Preparation J, 129 mg, 0.278 mmol) in EtOH (10 mL) was added a solution of LiOH (133 mg, 5.56 mmol) in H2O (2.5 mL). This reaction mixture was stirred at reflux for 3.5 h. After cooling down to rt, the mixture was concentrated to remove EtOH and the mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-10% MeOH/chloroform) gave the title compound: 1H NMR (CDCl3, 500 MHz) δ 2.00-2.05 (1H, m), 2.13-2.21 (1H, m), 2.40-2.61 (2H, m), 2.79-2.91 (2H, m), 3.21 (2H, d, J=15 Hz), 3.51 (1H, d, J=15 Hz), 4.26 (1H, m), 4.79 (1H, s), 6.62-6.70 (3H, m), 7.14-7.26 (4H, m), 7.30-7.35 (3H, m), 7.37-7.43 (3H, m). HPLC retention time: 1.19 min (method A). MS (ESI) (M+H)+ 439.22.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([N+:15]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)C>[Pd].O1CCOCC1>[CH3:1][C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]([NH2:15])=[C:10]([NH2:12])[CH:11]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: COC(=O)c1cc(N)c(N)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A mixture of 5.3 g of methyl 2-methyl-4,5-dinitrobenzoate, 1.06 g of 10% palladium on carbon (50% water wet), 53 mL of ethanol, and 53 mL of 1,4-dioxane was vigorously stirred at room temperature overnight under a hydrogen atmosphere. The insoluble material was filtered and washed with methanol. The filtrate was concentrated, and then dried under reduced pressure to obtain 3.98 g of methyl 4,5-diamino-2-methyl benzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([NH:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Yield: 78.8 %

Procedure:
A mixture of 2-chloro-5-nitro-pyridine (3.4 g, 0.021 mol), (S)-(−)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (4 g, 0.021 mol), and potassium carbonate (14.5 g, 0.105 mol) in acetonitrile (50 mL) was heated at reflux for 24 h. The reaction was monitored by LCMS and additional (S)-(−)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester was added until the reaction was driven to completion. The reaction mixture was then filtered and concentrated to give (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.1 g, 78.6%) as a yellow solid. LCMS calcd for C14H20N4O4 (m/e) 308, obsd 307.1(M−H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C.CCOC(C)=O.[Pd]>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(OCc1ccccc1)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 7-2 (3.6 g, 16 mmol) in DMF (50 mL) was added Cs2CO3 (7.8 g, 238 mmol). After 15 min., tert-butyl bromoacetate (3.2 mL, 35 mmol) was added and the reaction mixture stirred for 20 hrs at ambient temperature. The reaction mixture was diluted with EtOAc and then washed with H2O, and brine, dried (MgSO4), and concentrated to give a yellow oil. The crude yellow oil (5.4 g, 15.8 mmol), 10% Pd/C (500 mg), and EtOAc (100 mL) was stirred under a hydrogen atmosphere (1 atm) for 20 hr. The reaction mixture was then filtered through a celite pad and the filtrate concentrated to give 7-3 as a white solid.
Reaction SMILES: Cl.[CH2:2]([NH:5][O:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH3:4].N1C=CC=CC=1.[Br:16][CH2:17][C:18](Br)=[O:19]>C(#N)C>[CH2:2]([N:5]([O:6][CH2:7][CH2:8][CH3:9])[C:18](=[O:19])[CH2:17][Br:16])[CH2:3][CH3:4]
Reactant: O=C(Br)CBr
Reactant: CCCNOCCC
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCON(CCC)C(=O)CBr
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 197.8 %

Procedure:
N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to −20° C. Pyridine (0.2 mL) was added. Bromoacetyl bromide (0.15 g) was added dropwise over 5 min. The solution was stirred at −20° C. for 30 min. The bath was removed and the solution was stirred for 6 hours at room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc (50 mL) and washed with water (1×25 mL), 1N phosphoric acid (3×25 mL), and brine (1×25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.35 g). The product is a mixture of chloro- and bromoacetamides in a ratio of ˜3:1.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32]([OH:34])=O)[CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[NH:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[NH:24][C:25]([O:27][CH3:28])=[N:26][C:22]=4[CH:21]=3)[C:32]([N:39]3[CH2:44][CH2:43][CH:42]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:47][CH2:46]4)[CH2:41][CH2:40]3)=[O:34])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Reactant: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Product: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(OC)nc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 7i from 150 mg (0.27 mmol) (R)-1-carboxy-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 85 mg (0.33 mmol) ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][C:21]([F:22])=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2ccc(F)c(Br)c2)cc1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and 3-bromo-4-fluoro-benzaldehyde (2.03 g, 10 mmol) in ethanol (100 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-4-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (1.6 g, 46%) as a white solid: LC/MS m/e calcd for C16H13BrCFNO2 M+: 350.2, observed: 350.2, 352.2.
Reaction SMILES: O1CCCCC1O[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.C(Cl)Cl.CC1C=CC(S(O)(=O)=[O:37])=CC=1>CO>[OH:37][C:9]1[CH:8]=[CH:13][CH:12]=[C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: FC(F)(F)c1ccc(C#Cc2ccc(OC3CCCCO3)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: Oc1cccc(C#Cc2ccc(C(F)(F)F)cc2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 9057.1 %

Procedure:
Compound 4 (13.84 g, 40 mmol), CH2Cl2 (75 ml) and MeOH (125 ml) were placed in a 250 ml round-bottomed flask, then TsOH (0.4 g, 0.4 mmol) was added. The reaction mixture was stirred at 30° C. for 1 hour. When the reaction was finished (TLC showed no starting material remaining), the solvent was removed by rotary evaporation and the residue was dissolved in EtOAc and filtered through silica gel. The solvent was removed and the solid was recrystallized from solvents of ethyl acetate and hexane (1:5) to give a pale yellow crystal 9.5 g (90%), mp 131-132° C., δH (CDCl3, 300 MHz): 7.59 (s, 4H, Ar—H), 7.44 (d, J=8.7, 2H, Ar—H), 6.82 (d, J=8.7, 2H, Ar—H), 5.16 (s, 1H, OH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C=Cc2ccccc2)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 34.7 %

Procedure:
A mixture of 4-bromo-2-nitrotoluene (0.432 g, 2.0 mmol), styrene (0.250 g, 2.40 mmol, 1.2 eq), palladium(II) acetate (4.5 mg, 0.020 mmol, 0.01 eq), tri-o-tolylphosphine (12.2 mg, 0.04 mmol, 0.02 eq), and triethylamine (0.405 g, 4.0 mmol, 2.0 eq) in dimethylformamide (2 mL) was heated in a 120° C. oil bath for 4 hours. The mixture was then cooled to room temperature and the solvent evaporated under a stream of nitrogen gas. The residue was partitioned between ethyl acetate and water and the aqueous layer further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a hexane/ethyl acetate gradient to provide the title compound as a yellow solid (166 mg, 35% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.CON(C)[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13]>C1COCC1>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:7][N:6]=1
Reactant: Cc1ccc(Br)cn1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 5-bromo-2-methylpyridine (1.25 g, 7.2 mmol) in anhydrous THF (15 mL) at −40° C. under an argon atmosphere, lithium dibutyl(isopropyl)magnesate (5.2 mL, 0.7 M, 3.6 mmol) was added. The stirring was continued at the same temperature for 1 h. The resulting mixture was cannulated into a solution of 8 (1.5 g, 5.5 mmol) in THF (20 mL) at −78° C. The solution was maintained at −78° C. for 1 h, and then quenched with sat. aqueous NH4Cl and allowed to warm to room temperature. The organic layer was separated and then the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with water, dried over Na2SO4, filtered, and evaporated under reduced pressure to give the crude product. The crude compound was purified by chromatography on silica gel to obtain the desired compound 9a (0.7 g, 42%). 1H NMR (CDCl3): δ 1.49 (s, 9H), 1.68-1.87 (m, 4H), 2.63 (s, 3H), 3.35 (m, 1H), 4.18 (br, 2H), 7.28 (d, J=8.4 Hz, 1H), 8.11 (dd, J=8.4, 2.1 Hz, 1H), 9.04 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:32])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:32])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[N:17]=2)[CH:14]=1
Reactant: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Yield: 99.9 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Example-113; 0.100 g, 0.207 mmol), KOH (0.034 g, 0.622 mol), water (5 mL) and THF (5.0 mL) to afford 0.080 g of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[F:26][CH:27]([F:37])[CH2:28][N:29]([CH3:36])[C@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[F:37][CH:27]([F:26])[CH2:28][N:29]([CH3:36])[C@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:31]1
Reactant: CN(CC(F)F)[C@H]1CCCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@H](N(C)CC(F)F)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N-(2,2-difluoroethyl)-N-methylpiperidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.93 (m, 3H) 1.98-2.06 (m, 1H) 2.33 (d, J=2.27 Hz, 3H) 2.52-3.90 (m, 9H) 4.26-4.73 (m, 1H) 5.99-6.62 (m, 1H) 7.63 (d, J=7.33 Hz, 1H) 7.74 (t, J=7.58 Hz, 1H) 8.08 (d, J=8.34 Hz, 1H) 8.13-8.51 (m, 2H) 8.54 (d, J=1.77 Hz, 1H). ESI-MS m/z [M+H]+ 499.3.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[C@@H:26]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[N:38][N:39]2[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:35][CH:34]=1)[CH2:27]OS(C)(=O)=O)(=O)=O>C1COCC1>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[C@:12]2([CH2:27][C@H:26]2[C:33]2[CH:41]=[C:40]3[C:36]([CH:37]=[N:38][N:39]3[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:35][CH:34]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)c1ccc2cnn(Cc3ccccc3)c2c1
Reactant: Cc1ccc2c(c1)CC(=O)N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cnn(Cc4ccccc4)c3c1)C(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 32.7 %

Procedure:
To a 250 mL round bottom flask charged with 60% NaH (1.20 g, 30 mmol) was added anhydr. THF (20 mL) and the resulting mixture was cooled to 0° C. A solution of 1-benzyl-5-methylindolin-2-one (2.37 g, 10 mmol) in dry THF (25 mL) was added over 2 min, followed by rinsing with THF (5 mL). After stirring for 20 min at 0° C., a solution of (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (4.24 g, 10 mmol) in dry THF (45 mL) was added dropwise through dropping funnel over 40 min, followed by rinsing with THF (5 mL). After addition, the resulting mixture was stirred for 30 min at 0° C. (TLC showed completion) then left O/N at rt. After cooling to 0° C., the reaction mixture was poured into an Erlenmeyer flask containing ice (100 mL) and sat. NH4Cl (30 mL) and extracted with EtOAc (150 mL×2), dried (Na2SO4). After removal of solvents, the residue was transferred to a 100 mL RBF using 30 mL of EtOAc and crystals formed. Suction filtration gave the title compound as a beige solid (1.537 g). The filtrate was concentrated and purified by Biotage Isolera (20-30% EtOAc in hexane) and triturated with EtOAc/hexane to give 2nd crop as off white solid (1.560 g). The filtrate was purified using the above procedure to give 3rd crop as a beige solid (115 mg). Total 3.212 g (68%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.36-7.20 (m, 9H), 7.14 (d, J=6.0 Hz, 2H), 6.94 (d, J=8.4 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.64 (d, J=7.2 Hz, 1H), 5.62 (d, J=16.8 Hz, 1H, partially overlapping with s at 5.59), 5.59 (s, 1H, partially overlapping with d at 5.62), 5.55 (d, J=16.8 Hz, 1H), 5.08 (d, J=16.0 Hz, 1H), 4.97 (d, J=15.6 Hz, 1H), 3.48 (t, J=8.4 Hz, 1H), 2.30-2.25 (m, 1H), 2.02-1.96 (m, 1H), 1.85 (s, 3H); MS ESI 470.3 [M+H]+, calcd for [C32H27N3O+H]+ 470.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:29][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCCN1CCOCC1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NCCN4CCOCC4)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.3 mmol) was reacted with 2-morpholinoethanamine (CAS 2038-03-1) (78 mg, 0.6 mmol), HATU (129 mg, 0.33 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-morpholinoethyl)benzamide 21. LC/MS (ESI+): m/z 379 (M+H). 1H NMR (400 MHz, DMSO) δ 8.73 (s, 1H), 8.60 (d, J=7.5 Hz, 2H), 8.50 (d, J=8.9 Hz, 1H), 8.43 (d, J=4.9 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.06 (d, J=13.7 Hz, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 3.67-3.53 (m, 4H), 3.47 (dd, J=13.2, 6.6 Hz, 2H), 2.53 (d, J=7.1 Hz, 2H), 2.48-2.40 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:8].[Li][CH2:10]CCC.CI>C1COCC1>[CH3:10][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:1][C:2]1=[O:8]
Reactant: [Li]CCCC
Reactant: O=C1CCCCCN1
Solvent: C1CCOC1
Solvent: CI
Product: CC1CCCCNC1=O
Reaction time: 2 h

Procedure:
To a solution of azepan-2-one (0.5 g, 4.42 mmol, 1 equiv) in anhydrous THF (20 mL) under nitrogen, was added n-BuLi (4.4 mL, 2.5 M in n-hexane, 11.06 mmol) dropwise at 0° C. The reaction mixture was kept at 0° C. for 2 h, then MeI (0.3 mL, 4.86 mmol) was added. After stirring for 1 h, the mixture was quenched with water and extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration and concentration, the crude product was directly used for the next step without further purification. MS (ESI): 128 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](O)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.CC(C1C(C2C=CC([Cl:39])=CC=2)=NC=CN=1)(C(OCC)=O)C(OCC)=O.CC(C1C(C2C=CC(Cl)=CC=2)=NC=CN=1)C(OCC)=O.CC(C1C(C2C=CC(Cl)=CC=2)=NC=CN=1)C(O)=O.CC(C1C(C2C=CC(Cl)=CC=2)=NC=CN=1)C(N)=O>>[Cl:39][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: Oc1nccnc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1nccnc1-c1ccc(Cl)cc1
Agent: CC(C(=O)O)c1nccnc1-c1ccc(Cl)cc1
Agent: CC(C(N)=O)c1nccnc1-c1ccc(Cl)cc1
Agent: CCOC(=O)C(C)c1nccnc1-c1ccc(Cl)cc1
Product: Clc1ccc(-c2nccnc2Cl)cc1

Procedure:
2-Chloro-3-(p-chlorophenyl)pyrazine is prepared by the method of Karmas and Spoerri. (loc. cit.), using 3-(p-chlorophenyl)pyrazinol as the starting material. Starting with this material and using the procedures of Examples V, VI, IX, and XI, the products obtained are diethyl α-methyl-3-(p-chlorophenyl)pyrazinylmalonate, ethyl α-methyl-3-(p-chlorophenyl)pyrazineacetate, α-methyl-3-(p-chlorophenyl)pyrazineacetic acid, and α-methyl-3-(p-chlorophenyl)pyrazineacetamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:14])(=[O:13])[NH:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1ccc(S(=O)(=O)NCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (4-chlorosulfonyl-2-nitro-phenyl)-carbamic acid ethyl ester (2 g, Reference Example 63) in dichloromethane (50 ml) at 0° C., under a nitrogen atmosphere, was added diisopropylethylamine (2.71 ml) and benzylamine (0.850 ml). The reaction was warmed to ambient temperature and stirred for 12 hours. The reaction mixture was then washed with water (2×20 ml) and brine (2×20 ml), dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the title compound (2.29 g) as a brown solid. LC-MS (METHOD J): RT=3.83 minutes, 380.12 (M+H)+.