Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C@H:13]([NH:23][C:24](=[O:39])[CH2:25][N:26]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[C:28]([C:35]([F:38])([F:37])[F:36])=[N:27]2)[CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.[C:40]([C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:48]=1[F:49])(=[O:42])[NH2:41].[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC.CN(C=O)C.O>[F:22][C:17]1[CH:16]=[C:15]([CH2:14][C@H:13]([C:3]2[C:2]([C:45]3[CH:46]=[CH:47][C:48]([F:49])=[C:43]([CH:44]=3)[C:40]([NH2:41])=[O:42])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][O:11][CH3:12])[N:4]=2)[NH:23][C:24](=[O:39])[CH2:25][N:26]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[C:28]([C:35]([F:36])([F:38])[F:37])=[N:27]2)[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: COCCNc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: NC(=O)c1cc(B(O)O)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Temperature: 150 °C

Procedure:
In a microwave tube were charged with compound 11I (29 mg, 0.1 mmol), (3-carbamoyl-4-fluorophenyl)boronic acid (27 mg, 0.15 mmol), LiCl (13 mg, 0.3 mmol), Na2CO3 (17 mg, 0.2 mmol), Pd(PPh3)2Cl2 (3.5 mg, 0.005 mmol). To the mixture was added 2 mL of DME/DMF/H2O (4/1/1). The mixture was heated up to 150° C. for 30 min in a Microwave Synthesizer. After cooled down and filtered through a syringe filter, purified on reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title product. 1H NMR (400 MHz, CD3OD) δ 8.61 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.48 (dd, J=6.9, 2.3 Hz, 1H), 7.40-7.33 (m, 1H), 7.22 (dd, J=10.7, 8.5 Hz, 1H), 6.70 (t, J=9.2 Hz, 1H), 6.45 (d, J=6.2 Hz, 2H), 5.24 (q, J=7.5 Hz, 1H), 4.76 (s, 2H), 3.85-3.56 (m, 4H), 3.41 (s, 3H), 3.01 (ddd, J=29.2, 13.3, 7.4 Hz, 2H), 2.63-2.34 (m, 4H), 1.88-1.60 (m, 4H). MS (m/z) 676.46 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[N:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[CH:12]=[C:11]1[CH:20]=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.CCO>[CH2:3]([N:10]1[C:18]2[C:13](=[N:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[CH:12]=[C:11]1[CH2:20][OH:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cc2nc(Cl)ccc2n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1cc2nc(Cl)ccc2n1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
K2CO3 (0.39 g, 2.8 mmol) and benzyl bromide (0.12 mL, 1.0 mmol) were added to a solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde (0.17 g, 0.94 mmol, from Step 1) in DMF (3.6 mL). After 15 minutes, the reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with two portions of water, one portion of brine, then dried over sodium sulfate, filtered and concentrated to afford 0.26 g of crude 1-benzyl-5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde as a yellow solid. Sodium tetrahydroborate (53 mg, 1.4 mmol) was added to a solution of the crude aldehyde in THF (5.0 mL) and EtOH (5.0 mL). After 15 minutes, the reaction mixture was quenched with saturated NH4Cl, and was extracted with EtOAc. The extracts were washed with water followed by brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes afforded purified product as a white solid (0.21 g, 82%). 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J=8.6 Hz, 1H), 7.33-7.25 (m, 3H), 7.06 (d, J=8.6 Hz, 1H), 7.03-6.88 (m, 2H), 6.66 (s, 1H), 5.47 (s, 2H), 4.78 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][C:15]#[C:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][C:5]1([CH3:20])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:26]3[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=3)[CH:3]=2)[N:7]([CH2:14][C:15]#[C:16][CH2:17][CH3:18])[C:6]1=[O:19]
Reactant: CCC#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Reactant: C1CCOC1
Product: CCC#CCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21

Procedure:
N-(3,3-Dimethyl-6-nitro-2-oxo-1-pent-2-ynyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide is prepared as described in Example 25a starting from A7 (73 mg) using THF (3 ml) as solvent. The crude material (106 mg) is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[N:17][OH:18])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)C(C)(C)C(=NO)CC2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-napthalen-2-one (25.4 g, 98 mmol) in methanol (175 mL) was added a solution of hydroxylamine hydrochloride (20.5 g, 295 mmol) and sodium acetate (24.2 g, 295 mmol) in water (175 mL) and the reaction mixture was heated at 70° C. for 3 h, and cooled in ice over 30 min. The solid was collected on a Buchner funnel, stirred with methanol (125 mL) at 50° C. for 30 min, and then stirred at RT overnight. The reaction mixture was cooled to 0° C.; solid was collected on a Buchner funnel, rinsed with cold methanol (20 mL) and dried under vacuum to give the title compound (14.7 g).
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][C:6]([C:17]([F:20])([F:19])[F:18])=[CH:5][N:4]=1)#[N:2].[I-].[N:22]1([C:32](N2C=C[N+](C)=C2)=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1>ClCCl>[C:1]([C:3]1[C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:32]([N:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][CH2:23]3)=[O:33])=[CH:14][CH:15]=2)=[CH:7][C:6]([C:17]([F:20])([F:18])[F:19])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc(C(F)(F)F)cc1Oc1ccc(O)cc1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Solvent: ClCCl
Product: N#Cc1ncc(C(F)(F)F)cc1Oc1ccc(OC(=O)N2CCCc3ccccc32)cc1

Procedure:
The title compound was prepared from 4-(2-cyano-5-trifluoromethyl-pyridin-3-yloxy)-phenol and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (Quad flash 12, dichlormethane) (43%, oil).
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].O>Cl>[C:19]([O:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([OH:6])=[O:5])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCC(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCC(CC(=O)O)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Then 5.0 g of this β-hydroxynonanoic acid was mixed with 20 ml of anhydrous pyridine and 3.2 ml of acetic anhydride under ice cooling, and the mixture was stirred at room temperature overnight and cooled with ice. Then, 5 ml of distilled water was added to the mixture, the mixture was dissolved in 1N hydrochloric acid, and the solution was extracted with ether. The ether layer was washed with a saturated aqueous sodium chloride solution and dehydrated on magnesium sulfate. Then, the ether was evaporated and the residue was concentrated to obtain 5.4 g of β-acetoxynonanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[C:19]([CH3:31])([CH3:30])[CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.FC(F)(F)C(O)=O.Cl>ClCCl.CO.C(OCC)C>[CH3:30][C:19]1([CH3:31])[NH:20][CH2:21][CH2:22][C:17]([C:15]2[NH:14][C:10]3=[N:11][CH:12]=[CH:13][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:32][CH3:33])=[C:9]3[CH:16]=2)=[CH:18]1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC(C)(C)N(C(=O)OC(C)(C)C)CC3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC(C)(C)NCC3)cc12

Procedure:
A mixture of Example 271C (0.249 g, 0.551 mmol) and 2,2,2-trifluoroacetic acid (1 mL, 12.98 mmol) in dichloromethane (1 mL) was stirred for 24 hours at room temperature and concentrated. The hydrochloride salt was prepared by dissolving the resultant solid in methanol and adding 2M hydrogen chloride in diethyl ether. After concentrating under reduced pressure, the title compound was obtained. MS (ESI) m/e 352.1 (M+1)+.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:33])[C:11]([N:17]([C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:20])[CH3:18])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([C:19]([N:17]([CH3:18])[C:11]([CH3:16])([C:12]([NH:14][CH3:15])=[O:13])[C:10]([NH:9][OH:8])=[O:33])=[O:20])=[CH:26][CH:25]=1
Reactant: CNC(=O)C(C)(C(=O)NOCc1ccccc1)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)C(C)(C(=O)NO)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Yield: 47.6 %

Procedure:
10% Pd—C (36 mg) was added to a methanol (3.0 mL) solution of N-(benzyloxy)-2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N′,2-dimethylpropanediamide (0.10 g) as obtained in Example 12-(3), and the mixture was stirred in a hydrogen atmosphere for 4 hours at room temperature. The reaction mixture was filtered through Celite, and the solvent was distilled off. The residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=14/1) to obtain 2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N-hydroxy-N′,2-dimethylpropanediamide (Compound 324, yellow solid) (38 mg, 48%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[N:26][C:25]([Br:28])=[CH:24][N:23]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:21]([C:22]3[CH:27]=[N:26][C:25]([Br:28])=[CH:24][N:23]=3)[CH2:20][CH2:19]2)[CH2:7][CH2:8]1)=[O:13])([CH3:17])([CH3:16])[CH3:18]
Reactant: CCOC(=O)C1(CCNc2cnc(Br)cn2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1cnc(Br)cn1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of 4-[2-(5-bromo-pyrazin-2-ylamino)-ethyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.825 g, 1.81 mmols) in THF (10 mL) was added a 1 M solution of potassium t-butoxide in THF (2.0 mL), and allowed to stir at room temperature. After 1 hour LCMS was taken and reaction was not complete. After 5 hours, an additional 1 mL of potassium t-butoxide was added. The reaction mixture was allowed to stir for 16 hours. The three reaction mixtures were diluted with ethyl acetate (20 mL), quenched with water (5 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to afford crude product. Purification over silica gel eluting with methanol in dichloromethane (0-10%) afforded 0.186 g (25%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:31][CH:15]([CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]([OH:25])=[C:21]([C:26](OCC)=[O:27])[N:20]=[C:19]31)[O:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1.CCN(CC)CC>CCO>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH:40][C:26]([C:21]2[N:20]=[C:19]3[N:18]([C:23](=[O:24])[C:22]=2[OH:25])[CH2:17][CH2:16][CH:15]2[CH2:31][C:12]3([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][O:14]2)=[O:27])=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCC1CC2(NC(=O)OCc2ccccc2)CO1
Reactant: NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NC12COC(CCn3c1nc(C(=O)NCc1ccc(F)cc1)c(O)c3=O)C2)OCc1ccccc1
Yield: 49.1 %

Procedure:
A mixture of ethyl 11-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-7,8,10,11-tetrahydro-4 H,6H-8,11-methanopyrimido[2,1-d][1,5]oxazocine-2-carboxylate (0.070 g, 0.163 mmol), (4-fluorophenyl)methanamine (0.125 g, 1 mmol) and Et3N (0.418 mL, 3 mmol) in EtOH (5 mL) was heated at reflux for 7 h. The reaction was cooled, concentrated and the residue purified by preparative-HPLC to afford title compound (0.0405 g, 0.080 mmol, 49%) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 11.99 (0.6 H, brs), 11.92 (0.4 H, brs), 7.82 (0.4 H, t, J=5.8 Hz), 7.58 (0.6 H, t, J=5.8 Hz), 7.32-7.39 (3 H, m), 7.17-7.28 (2 H, m), 7.09 (1 H, dd, J=8.1, 5.6 Hz), 7.01-7.06 (1 H, m), 6.91-6.99 (2 H, m), 5.60 (0.6 H, s), 5.41-5.51 (1 H, m), 5.10 (0.4 H, s), 5.02 (0.6 H, d, J=12.5 Hz), 4.89 (1 H, d, JAB=12.4 Hz.), 4.79 (0.6 H, d, J=10.7 Hz), 4.69-4.75 (2 H, m), 4.60 (0.4 H, d, J=10.4 Hz), 4.37-4.49 (2.8 H, m), 4.12 (0.6 H, dd, J=18.8, 6.0 Hz), 3.70 (0.6 H, t, J=13.7 Hz), 3.63 (0.4 H, t, J=13.7 Hz), 2.47-2.60 (1 H, m), 2.13-2.21 (1 H, m.), 1.97-2.05 (1 H, m). LCMS (M+H) calcd for C26H26FN4O6: 509.18; found: 509.14.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Br:19])[C:17]=1[OH:18])[CH:13]=O>CO>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:13]1[C:12]1[CH:11]=[C:10]([Br:9])[C:17]([OH:18])=[C:16]([Br:19])[CH:15]=1
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: Nc1ccccc1S
Solvent: CO
Product: Oc1c(Br)cc(-c2nc3ccccc3s2)cc1Br
Temperature: 25 °C
Yield: 16 %

Procedure:
In a methanol solvent, a solution including 2-aminothiophenol (1.0 eq.) and 3,5-dibromo-4-hydroxybenzaldehyde (1.0 eq.) was stirred at room temperature. The produced precipitate was filtered and the filtered product was washed with cold methanol to obtain Compound 27.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:17][C:18]([C@@:20]1([NH:33]C(OC(C)(C)C)=O)[CH2:22][C@@:21]1([CH2:29][N:30]=[N+:31]=[N-:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(OC([C@@]1(NC(OC(C)(C)C)=O)C[C@]1(CO)C1C=CC=CC=1)=O)(C)(C)C.O>C(#N)C>[C:13]([O:17][C:18]([C@@:20]1([NH2:33])[CH2:22][C@@:21]1([CH2:29][N:30]=[N+:31]=[N-:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)C[C@@]1(CN=[N+]=[N-])c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)C[C@]1(CO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@@]1(N)C[C@@]1(CN=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
p-Toluenesulfonic acid monohydrate (5.2 g, 27 mmol) was added to a solution of the crude product (5.0 g) of (1R*,2S*)-2-azidomethyl-1-t-butoxycarbonylamino-2-phenyl-cyclopropanecarboxylic acid t-butyl ester, which was made from (1R*,2S*)-1-t-butoxycarbonylamino-2-hydroxymethyl-2-phenyl-cyclopropanecarboxylic acid t-butyl ester obtained in Preparation Example 2-6 by general method step 5-3, in acetonitrile (40 mL). The mixture was stirred at room temperature for 14 hours. After water (16 mL) was added, the mixture was further stirred for 7 hours and separated into layers by adding ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), water (30 mL) and saturated aqueous sodium chloride solution (50 mL), and dried over sodium sulfate. The residue was filtrated and the solvent was evaporated to give a crude product of the title compound (2.8 g). The obtained product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1([N:19]2[C:28]3[C:23](=[CH:24][C:25]([F:31])=[C:26](F)[C:27]=3[F:29])[C:22](=[O:32])[C:21]([C:33]([OH:35])=[O:34])=[CH:20]2)[CH2:18][CH2:17]1>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:26]1[C:27]([F:29])=[C:28]3[C:23]([C:22](=[O:32])[C:21]([C:33]([OH:35])=[O:34])=[CH:20][N:19]3[CH:16]3[CH2:18][CH2:17]3)=[CH:24][C:25]=1[F:31])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC12CCC1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC12CCC1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 71 %

Procedure:
1.9 g of 1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]heptane and 0.83 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were added to 15 ml of pyridine, followed by heating under reflux for 4 hours. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (using a 100:1 mixture of chloroform and methanol as the eluent) and recrystallization (from ethyl acetate-diisopropyl ether) to obtain 0.99 g of 7-[1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]hept-3-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (m.p. 211-215° C.).
Reaction SMILES: [CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C(C)(C)C)C)[CH2:6][CH2:5]1)[CH:2]=C.[O:24]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:4]2([CH2:1][CH2:2][OH:24])[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)=[CH:18][CH:19]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NCCC(CCO)(c2ccc(F)cc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of (R)-6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one [Isomer 1] (450 mg, 1.41 mmol) in dry CH2Cl2 (10 mL) was treated with O3 at −78° C. till the mixture turned blue. NaBH4 (157 mg, 4.23 mmol) was added, and the mixture was stirred at rt overnight. The solution was concentrated, and the residue was purified by preparative TLC followed by preparative HPLC to give (S)-3-(S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one [Isomer 1] (265 mg, 58%). LC-MS Method 2 tR=3.83, min, m/z=669.03; 1H NMR (CDCl3): 0.71 (s, 9H), 1.06-1.11 (d, 3H), 2.07-2.19 (m, 2H), 2.31-2.28 (m, 1H), 2.67-2.76 (m, 1H), 3.12-3.18 (m, 1H), 3.47-3.58 (m, 1H), 3.69-3.78 (m, 1H), 4.38-4.47 (m, 1H), 7.03-7.09 (m, 2H), 7.26-7.33 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C@@:6]1([CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)=O)[CH2:7]1)=O)C.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[O:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15][C@@H:14]1[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@:6]([CH2:4][OH:3])([CH3:24])[CH2:7]1
Reactant: CCOC(=O)[C@@]1(C)CCCN(C(=O)[C@H]2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]1(CO)CCCN(C[C@H]2COc3ccccc3O2)C1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of (S)-1-((R)-2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methylpiperidine-3-carboxylic acid ethyl ester (27.7 g, 83.1 mmol) and THF (150 ml) was added to a cooled (0° C.) mixture of dry THF (150 ml) and LiAlH4 (10 g, 264 mmol). The reaction mixture was refluxed for 2 h, after which it was cooled to RT and water was added. The mixture was extracted twice with EtOAc and dried with Na2SO4. Solvent was evaporated to give 21.93 g of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([S:10]([NH2:13])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=1)[NH2:18].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:18][C:17]1[CH:19]=[C:20]([C:2]2[S:6][C:5]([C:7]([S:10]([NH2:13])(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=2)[CH:21]=[C:15]([CH3:14])[CH:16]=1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(c1ncc(Br)s1)S(N)(=O)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(N)cc(-c2cnc(C(C)(C)S(N)(=O)=O)s2)c1
Temperature: 100 °C
Yield: 22.6 %

Procedure:
2-(5-Bromo-1,3-thiazol-2-yl)propane-2-sulfonamide (1.223 g, 4.29 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.00 g, 4.29 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.196 g, 0.214 mmol), X-phos (0.204 g, 0.429 mmol), and cesium carbonate (4.19 g, 12.87 mmol) were combined in a flask, sealed and purged with N2 (3×). Degassed dioxane (15 mL) and water (1.5 mL) were added and the reaction mixture was heated at 100° C. for 16 hrs. The reaction was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. Flash chromatography (SiO2, dry load, gradient elution 0 to 75% EtOAc in CH2Cl2) afforded 2-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]propane-2-sulfonamide (0.302 g, 0.97 mmol, 22.6% yield) as a tan foam. MS ESI: [M+H]+ m/z 312.1. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.99 (m, 2H), 6.59 (m, 2H), 6.34 (s, 1H), 5.18 (br s, 2H), 2.15 (s, 3H), 1.75 (s, 6H).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[O:3].[CH:11](OCC)(OCC)[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]([C:4]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[CH:11][O:12][CH2:13][CH3:14])=[O:3]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)Cc1ccncc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(C)=O)c1ccncc1

Procedure:
The process according to claim 2 where 4-pyridinylmethyl methyl ketone is first reacted with triethyl orthoformate, acetic anhydride and acetic acid to produce 2-ethoxy-1-(4-pyridinyl)ethenyl methyl ketone, said latter ketone is reacted with cyanoacetamide in the presence of at least a molar equivalent quantity of sodium hydroxide per mole of cyanoacetamide in methanol and the reaction mixture is neutralized to produce 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:26])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:26])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1ccc(-c2ccnc(Nc3cccc(Cl)c3)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1

Procedure:
10.0 g (32 mmol) of N-(3-chloro-phenyl)-4-(N-oxido-4-pyridyl)-2-pyrimidineamine are stirred for 24 h in 100 ml of phosphorus oxychloride at 110°. The reaction mixture is stirred at 50° into 2N sodium hydroxide solution and extracted with tetrahydrofuran. Concentration and crystallisation (tetrahydrofuran/ethanol) of the residue give N-(3-chloro-phenyl)-4-(2-chloro4-pyridyl)-2-pyrimidineamine; m.p. 196°-198°, Rf =0.7 (methylene chloride:methanol=95:5).