Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-])=O)=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].CCOC(C)=O>CCO>[NH2:11][C:3]1[C:2]([OH:1])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:10])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1C#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)c(O)cc1C#N
Yield: 98.6 %

Procedure:
5-hydroxy-2-methyl-4-nitrobenzonitrile (D91, 185 mg, 1.04 mmol) was dissolved in EtOH:EtOAc (24 mL, 1:1) and was reduced using an H-Cube (full H2 mode, 25° C., 1 mL/min). The reaction was concentrated by rotary evaporation to give 4-amino-5-hydroxy-2-methylbenzonitrile (D92, 152 mg, 95%) as a pale yellow solid.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:48][O:49][C:50](=[O:54])[C@@H:51]([CH3:53])[NH2:52].CCN(CC)CC>CCOC(C)=O>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([NH:52][C@@H:51]([C:50]([O:49][CH3:48])=[O:54])[CH3:53])=[O:14])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of Boc-Ser(OBn) (4.12 g, 13.95 mmol) in EtOAc (100 mL) at 0° C. was added HOBT (2.35 g, 15.35 mmol) and DCC (3.17 g, 15.35 mmol). D-Alanine methyl ester hydrochloride (1.95 g, 13.95 mmol) was added followed by Et3N (2.14 mL, 15.35 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered, and the filtrate was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), and concentrated. Flash chromatography (40% EtOAc/hexane) gave 2.60 g of the title compound as a colorless oil; CI-MS 381 (m+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27].C(OC)(C)(C)C>C(#N)C>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27]
Reactant: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)CCO3
Solvent: COC(C)(C)C
Solvent: CC#N
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2[C@]12COc1cc3c(cc12)CCO3
Yield: 66 %

Procedure:
1′-[(2R)-Tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was resolved on chiral semi-prep HPLC IA column with 99% tert-butylmethyl ether and 1% acetonitrile to afford (3S)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (66%): 1H NMR (300 MHz, CDCl3) δ7.34-6.97 (m, 4H), 6.48 (s, 1H), 6.38 (s, 1H), 4.77 (ABq, 2H), 4.50 (t, J=8.6 Hz, 2H), 4.32-4.21 (m, 1H), 3.92-3.68 (m, 4H), 2.96 (t, J=8.4 Hz, 2H), 2.10-1.64 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.2, 161.7, 161.2, 142.8, 132.7, 128.6, 123.6, 123.2, 120.4, 119.8, 118.9, 109.5, 93.1, 80.7, 76.8, 72.3, 68.1, 57.6, 44.5, 29.0, 29.0, 25.6; MS (ES+) m/z 363.8 (M+1).
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#N.O1CCN(N=CC2C=CC(C([NH:26][C:27]3C=C4C(CCC(CC(OCCO)=O)C4)=CC=3)=O)=CC=2)CC1.O1CCN(N=CC2C=CC(C(NC3C=C4C(CCC(CC(OCCOC)=O)C4)=CC=3)=O)=CC=2)CC1.S(Cl)([Cl:83])=O.C(Cl)(=O)C(Cl)=O.P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:27]([C:5]1[CH:4]=[CH:3][CH:11]=[CH:10][C:6]=1[C:7]([Cl:83])=[O:9])#[N:26]
Reactant: O=S(Cl)Cl
Reactant: O=C(CC1CCc2ccc(NC(=O)c3ccc(C=NN4CCOCC4)cc3)cc2C1)OCCO
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: COCCOC(=O)CC1CCc2ccc(NC(=O)c3ccc(C=NN4CCOCC4)cc3)cc2C1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClP(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C(=O)Cl

Procedure:
In another process, p-cyanobenzoic acid or the compounds of formula (4) or (5) is reacted with thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride in the presence of a catalytic amount of N,N-dimethylformamide to give o-cyanobenzoyl chloride or the compounds of formula (6) or (7). p-Cyanobenzoyl chloride or the compounds of formula (6) or (7) thus obtained can be reacted with the compounds of formula (2) or (3), or the compounds of formula (8) to give the desired compounds.
Reaction SMILES: [Cl:1]C1C=CC([C@H]2[C@H](O)[C@@H](O)[C@H](O)C(OC)O2)=CC=1CC1C=CC(OCC)=CC=1.C(Cl)(C)=O.C([Si](C)(C)[O:38][C@H:39]1[C@H:46]2[C@H:42]([O:43][C:44](C)(C)[O:45]2)[O:41][C@H:40]1[C@H:49]([C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH3:67])=[CH:61][CH:60]=2)[CH:52]=1)[OH:50])(C)(C)C>CO>[ClH:1].[Cl:57][C:54]1[CH:55]=[CH:56][C:51]([C@H:49]2[C@H:40]([OH:41])[C@@H:39]([OH:38])[C@H:46]([OH:45])[CH:42]([O:43][CH3:44])[O:50]2)=[CH:52][C:53]=1[CH2:58][C:59]1[CH:60]=[CH:61][C:62]([O:65][CH2:66][CH3:67])=[CH:63][CH:64]=1
Reactant: CCOc1ccc(Cc2cc([C@H](O)[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@@H]3O[Si](C)(C)C(C)(C)C)ccc2Cl)cc1
Agent: CCOc1ccc(Cc2cc([C@@H]3OC(OC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: CO
Solvent: CC(=O)Cl
Product: Cl
Temperature: 25 °C

Procedure:
Preparation of (2S,3R,4R,5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol. A solution of 0.35 M HCl in MeOH was prepared by adding AcCl (0.25 ml, 3.5 mmol) to MeOH (10 ml) and stirring for 15 minutes The alcohol from step D (0.84 g, 1.5 mmol) was treated with this solution for 16 hours at room temperature and 2 hours at 80° C. in a sealed vial. The reaction was cooled to room temperature, quenched with K2CO3 until basic, diluted with CH2Cl2, filtered, and concentrated under vacuum. The product was purified by flash chromatography (40 g SiO2, 0-10% MeOH: CH2Cl2, 60 minutes, 35 ml/min), suspended in H2O, and lyophilized to give (2S,3R,4R,5S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol (0.46 g, 1.1 mmol, 75%) as a white solid. NMR revealed a 1.2:1 ratio of α and β anomers.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]#[N:12])[CH:5]=1.[Li+].[OH-].CO>O1CCCC1>[C:11]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([I:10])[CH:7]=1)[C:3]([OH:13])=[O:2])#[N:12]
Reactant: COC(=O)c1cc(I)cc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(I)cc(C(=O)O)c1
Yield: 94 %

Procedure:
A solution of methyl-3-cyano-5-iodobenzoate (640 mg, 2.3 mmol) in tetrahydrofuran (8 mL) was treated with 0.5M LiOH (5.5 mL, 2.75 mmol) and methanol. The reaction mixture was heated at reflux for 1 hour. The solvent was concentrated in vacuo and the mixture treated with 1N HCl. The resulting white precipitate was filtered and the filtrate was extracted with dichloromethane. The residue and the extracted filtrate were combined and concentrated in vacuo to afford 590 mg (94%) of 3-cyano-5-iodobenzoic acid, as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=[O:22])[CH2:14][C@@H:15]1[CH3:21])[CH2:10][CH2:9]3.C1(C)C=CC(S(O)(=O)=[O:30])=CC=1.[CH:34]1[CH:39]=CC=CC=1>CCOCC>[CH2:34]1[CH2:39][O:30][C:13]2([CH2:14][C@H:15]([CH3:21])[C@@:16]3([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]4[C@@H:18]3[CH2:19][CH2:20][C@@:3]3([CH3:4])[C@H:5]4[CH2:6][CH2:7][C@@H:2]3[OH:1])[CH2:12]2)[O:22]1
Reactant: C[C@H]1CC(=O)C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccccc1
Solvent: CCOCC
Product: C[C@H]1CC2(C[C@@H]3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31C)OCCO2

Procedure:
50 g of 17β-hydroxy-1α-methyl-5α-androstan-3-one were heated at reflux in 1000 ml of absolute benzene, 125 ml of ethylenegycol and 1.25 g of p-toluenesulphonic acid for 7 hours while stirring under a water separator. The solution was then diluted with ether, washed with sodium hydrogen carbonate solution and water, dried and evaporated to dryness. 55 g of 3,3-ethylenedioxy-17β-hydroxy-1α-methyl-5α-androstane were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1ccc(CN2CCOCC2)cc1
Reaction time: 1 h

Procedure:
(4-Formyl-benzyl)-carbamic acid tert-butyl ester Compound 15a (555 mg, 2.37 mmol, prepared as described in Far A R, Cho Y L, Rang A, Rudkewich D M, Rebek J, Tetrahedron, 2002, 58(4), 741-756) was added to a solution of morpholine (207 μL, 2.37 mmol) in MeOH (5 mL) and acetic acid (0.20 mL). The mixture was stirred for 1 hr and then 95% NaBH3CN (198 mg, 3.0 mmol) was added. The reaction was diluted after 2 hr with saturated NaHCO3 and extracted with EtOAc to provide (4-morpholin-4-ylmethyl-benzyl)-carbamic acid tert-butyl ester Compound 15b (230 mg), isolated by flash chromatography as a white solid. MS 307 (MH+). Compound 15b (230 mg, 0.752 mmol) was deprotected with 20% TFA in DCM (10 mL) to provide 4-morpholin-4-ylmethyl-benzylamine Compound 15c (63 mg) upon work-up. MS 207 (MH+).
Reaction SMILES: ClC1C=C(C=[CH:9][N:10]=1)C(O)=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=[O:21].C(=O)(O)[O-].[Na+]>CCOC(C)=O>[N:11]1([C:9]([NH2:10])=[O:21])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 315 mg of 2-chloroisonicotinic acid and 209 mg of morpholine in EtOAc (4.0 mL) was stirred as 1.27 g of a 50% solution of 1-propanephosphonic acid cyclic anhydride was added. This mixture was stirred at room temperature for six h. and another 1.27 g of the anhydride was added followed by stirring for another 18 h. The reaction was poured into saturated sodium bicarbonate solution and extracted with EtOAc (3×). The organic layers were dried over sodium sulfate, filtered, and concentrated to provide the morpholine amide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([CH3:20])([CH3:19])[CH:6]=[C:5]2[CH3:21].C([Li])(C)(C)C.[B:27](OC)([O:30]C)[O:28]C>C1COCC1>[C:15]([O:14][C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([B:27]([OH:30])[OH:28])=[CH:11][CH:10]=2)[C:5]([CH3:21])=[CH:6][C:7]1([CH3:20])[CH3:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(Br)cc21
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Yield: 43.8 %

Procedure:
A 25 mL r.b. flask, equipped with a magnetic stirring bar, was charged with Compound 8 (3.765 g, 10.67 mmol) under N2. The oil was dissolved in 11 mL THF (anhydrous) and cooled to -78° C. tert-Butyllithium (12.6 mL, 21.4 mmol, 1.70M) was added by syringe over a period of 10 min (maintaining temperature below -70° C.) turning the reaction mixture from pale yellow to bright yellow. The reaction was allowed to continue at -75° C. until all of the starting material had been consumed as judged by TLC (15% ethyl acetate/hexane). Trimethyl borate (1.22 g, 1.33 mL, 11.7 mmol, 1.1 equiv) was added by syringe over 5-10 minutes (temperature between -70° C. and -65° C.). The reaction was monitored by TLC. Upon completion, the product mixture was quenched with saturated NH4Cl (200 mL). Addition of ethyl acetate (200 mL) partitioned the mixture into 2 phases. The organic phase was washed with saturated NH4Cl (100 mL) and brine (100 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL). The organic layers were combined and dried (Na2SO4). The crude mixture was applied to a small column containing 200 mL silica and 15% ethyl acetate/hexane. The higher Rf impurities were eluted with 2 L of 10% ethyl acetate/hexane. The boronic acid, Compound 9, was eluted with 500 mL ethyl acetate followed by 750 mL ethanol to provide 1.483 g (44%) of Compound 9. Data for Compound 9: 1H NMR (400 MHz, acetone-d6) 7.73 (d, J=1.2, 1H), 7.66 (dd, J=8, 1.2, 1H), 7.13 (d, J=8, 1H), 5.49 (s, 1H), 2.01 (d, J=1.6, 3H), 1.50 (s, 9H), 1.46 (s, 6H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH2:11])=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH:22]1[CH:21]=[C:20]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH2:11])=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:24]=[N:23]1
Reactant: Nc1nc2ccc(Br)nc2s1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2ccc(-c3cn[nH]c3)nc2s1
Temperature: 150 °C

Procedure:
To a microwave vial, 5-bromothiazolo[5,4-b]pyridin-2-amine (1B, 100 mg, 1.0 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5A, 2.0 equivalent), Na2CO3 (4.0 equivalents), DMF (0.15 M) and H2O (0.73 M) were added. While mixture was under N2, Pd(PPh3)4 was added and the mixture was then heated in a microwave for 3 h at 150° C. The crude mixture was filtered, and purified by preparatory LCMS. Intermediate 5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine (5B) was obtained as a white solid. ESI-MS: m/z 218.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.C(N(CC)CC)C.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O>[CH:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:4]1)=[O:1]
Reactant: CC(C)(C)OC(=O)NC1CCCC(CO)C1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)cyclohexylcarbamate (1.4 g, 6.11 mmol) in dimethylsulfoxide (10 mL) was added triethylamine (1.853 g, 18.32 mmol) followed by the pyridine-sulfur trioxide (2.92 g, 18.32 mmol) in 5 mL of dimethylsulfoxide, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with ice water and extracted into ethyl acetate (30 mL×2). The organic layer was washed with water and brine solution (25 mL each), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C@@H:6]([NH:21][C:22]1[C:27]([Br:28])=[CH:26][N:25]=[C:24](Cl)[N:23]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2].[CH3:31][NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CC(O)C>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C@@H:6]([NH:21][C:22]1[C:27]([Br:28])=[CH:26][N:25]=[C:24]([N:32]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH3:31])[N:23]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CNC1CCCCC1
Reactant: CCOC(=O)C[C@@H](Nc1nc(Cl)ncc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Solvent: CC(C)O
Product: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (R)-3-(5-bromo-2-chloropyrimidin-4-ylamino)-3-(4-(tert-butyldimethylsiloxy)phenyl)propanoic acid ethyl ester (1.0 eq) and N-methylcyclohexylamine (10.0 eq) in iPrOH in a sealed tube was stirred at 130° C. for 5 h, and then the iPrOH was evaporated. The residue was partitioned between water and EtOAc, and then the EtOAc extracts were treated with MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel using 9:1 hexanes/EtOAc to give (R)-3-(5-bromo-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(tert-butyldimethylsiloxy)phenyl)propanoic acid ethyl ester.
Reaction SMILES: C(OC([NH:8][CH:9]([CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:25]=[C:24]3[C:19]([C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22][N:23]3[CH:26]3[CH2:28][CH2:27]3)=[CH:18][C:17]=2[F:33])[CH2:12]1)[CH3:10])=O)(C)(C)C.Cl>C(O)C>[NH2:8][CH:9]([CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:25]=[C:24]3[C:19]([C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22][N:23]3[CH:26]3[CH2:27][CH2:28]3)=[CH:18][C:17]=2[F:33])[CH2:12]1)[CH3:10]
Reactant: CC(NC(=O)OC(C)(C)C)C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Agent: Cl
Solvent: CCO
Product: CC(N)C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C

Procedure:
7-[3-(1-[N-tert-butoxycarbonylamino]ethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4 -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid isomer B (0.74 g, 0.0016 mole) in ethanol (35 mL)/1N HCl (14 mL) was heated at 90° for two hours. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was treated with isopropyl alcohol twice and the solvent was removed under reduced pressure. The solid was dried in an oven under vacuum at 70° for 60 hours. The solid was then stirred up in water, filtered, and the filtrate was placed on a freeze drying apparatus for 16 hours. 7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid isomer B was obtained (0.63 g, 80%) as a pale yellow solid, mp 281°-284° (dec).
Reaction SMILES: F[C:2](F)(F)C(O)=O.NN=CNC1C=C(C(NCC([NH:24][CH:25]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:26][C:27]([OH:29])=[O:28])=O)=O)C=CC=1.[ClH:40].O1CCOCC1>CO>[ClH:40].[NH2:24][CH:25]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH2:26][C:27]([O:29][CH3:2])=[O:28]
Reactant: O=C(O)C(F)(F)F
Reactant: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccc3ccccc3c2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CC(N)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
A suspension of the product of Step A (2.5 g) in methanol (100 ml) was treated with 4N HCl/dioxane (10 ml). The resulting solution was stirred overnight. The excess solvent was removed under reduced pressure and the semi solid was purified by HPLC (RP--CH3CN/H2O). The solid was dissolved in CH3CN/H2O, treated with 20% aqueous HCl (5 ml) and lyophilized to give methyl β-aminonaphthalene-2-propanoate hydrochloride (1.1 g). MS and 1H-NMR were consistent with the structure.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.P(Br)(Br)[Br:11].Br.S(=O)(=O)(O)O>C(OCC)C>[Br:11][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: BrP(Br)Br
Reactant: OCCC1CCCCC1
Agent: Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: BrCCC1CCCCC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 115.6 %

Procedure:
To a solution of 10 g of (2-hydroxyethyl)cyclohexane in 50 ml of dry diethyl ether was added dropwise a solution of 9.85 g of phosphorous tribromide in 20 ml of dry diethyl ether at -40° C., and the mixture was stirred at -40° to -10° C. for 30 minutes and at 2° to 4° C. for 2.5 hours. The reaction mixture was then poured into ice-water and extracted with diethyl ether. The extract was washed with water, an aqueous solution of sodium bicarbonate and water, dried over magnesium sulphate and concentrated under reduced pressure. To the residue thus obtained were added 50 ml of 47% w/v hydrobromic acid at -30° C. 20 ml of sulphuric acid were then added dropwise at the same temperature. The reaction mixture was refluxed at 100° to 110° C. for 3 hours and extracted with diethyl ether. The extract was washed with water, an aqueous solution of sodium bicarbonate and water, dried over magnesium sulphate and concentrated under reduced prssure. The residue was purified by distillation under reduced pressure to give 8.04 g of the title compound having the following physical characteristics:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH2:34][OH:35])(=[O:32])=[O:31])[CH:4]=1)#[N:2].C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:37])=[O:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH2:34][OH:35])(=[O:31])=[O:32])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)CCO)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(N)=O)C(c2ccc(C#N)cc2S(=O)(=O)CCO)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
The reaction was carried out under argon. (rac)-4-[4-Cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (910 mg, 1.79 mmol) and HATU (5 eq., 3396 mg, 8.9 mmol) were initially charged in dry DMF (20 ml) at 0° C., and ammonium chloride (5 eq., 478 mg, 8.9 mmol) and DIEA (10 eq., 2309 mg, 17.9 mmol) were added after brief stirring (20 min). The mixture was stirred at RT for 16 h (HPLC control) and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). The title compound was obtained as a solid (740 mg, 81% of theory).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:18]=[C:17]([OH:19])[N:16]([CH3:20])[N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)[Br:22].C(O)C>C(Cl)Cl>[BrH:22].[OH:19][C:17]1[N:16]([CH3:20])[N:15]=[C:14]([C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[CH:18]=1
Reactant: COc1cc(-c2cc(O)n(C)n2)cc([N+](=O)[O-])c1OC
Reactant: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: Br
Product: Cn1nc(-c2cc(O)c(O)c([N+](=O)[O-])c2)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g of 3-(3,4-dimethoxy-5-nitrophenyl)-1-methylpyrazol-5-ol are suspended in 100 ml of methylene chloride. After cooling to -40° a solution of 4.9 ml of boron tribromide in 60 ml of methylene chloride is added dropwise thereto within 1 hour. The mixture is subsequently stirred at room temperature for 16 hours, cooled to -20° and treated within 30 minutes with 100 ml of ethanol. After stirring at room temperature for 1 hour, the solvent is removed by distillation in a water-jet vacuum at 40°. The residue is treated three times with a mixture of 100 ml of ethanol/toluene each time, with the solvent being distilled each time. The residue is recrystallized from ethanol. There is obtained 5-(5-hydroxy-1-methylpyrazol-3-yl)-3-nitropyrocatechol hydrobromide in the form of yellow crystals of m.p.>250°.