Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH:3]=[O:4].S(N)(=O)(=O)[OH:43].Cl([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:5][C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)=[CH:32][C:25]=3[S:24]4)=[CH:19][CH:20]=2)=[O:13])[CH:7]=1)([CH3:1])[C:3]([OH:43])=[O:4]
Reactant: CC(C)(C=O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C(=O)O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C

Procedure:
Alternatively final compound 2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propionic acid (I-5) is prepared by following a general procedure given in US 2005/0070549 A1. To a stirred solution of 1-[5-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-4a) (1 equivalent) in a mixture of acetic acid and water at rt is added a solution of amidosulfuric acid (1.5 equivalents) and sodium chlorite (1.5 equivalents) in water, and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is neutralized with 30% aq sodium hydroxide and partitioned between water and either dichloromethane or a mixture of isopropanol and dichloromethane. The separated aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane, and the combined organic layers are washed with water or brine dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propionic acid (I-5).
Reaction SMILES: [CH3:1][NH2:2].[N:3]([C:6]1[CH:7]=[C:8]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:9]=[CH:10][CH:11]=1)=[C:4]=[O:5]>O1CCCC1.C(OCC)(=O)C>[CH3:1][NH:2][C:4]([NH:3][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=1)=[O:5]
Reactant: CN
Reactant: CC1(C)OB(c2cccc(N=C=O)c2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 0.08 h

Procedure:
Methyl amine (2.0 M in THF) was added to a solution of 2-(3-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.49 g, 2.0 mmol) and in tetrahydrofuran (6.0 mL) at 0° C. The mixture was stirred at this temperature for 5 min, then at r.t. for 2 h. The mixture was diluted with ethyl acetate, washed with water, 1N HCl aq. and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the desired product which was directly used in next step without further purification. LCMS (M+H)+: m/z=277.1
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)#[N:2].C([SH:10])C.[ClH:11]>>[ClH:11].[ClH:11].[NH:6]1[CH:7]=[C:3]([C:1](=[NH:2])[SH:10])[N:4]=[CH:5]1
Reactant: CCS
Reactant: N#Cc1c[nH]cn1
Agent: Cl
Product: N=C(S)c1c[nH]cn1
Reaction time: 0.33 h

Procedure:
To 900 mg. of 4-cyanoimidazole in 30 ml. of ethyl mercaptan cooled to 0° C. in a glass pressure bottle is added over 15 min. sufficient hydrogen chloride gas to saturate the solution. The sealed bottle is allowed to remain at room temperature for 20 min., and its contents then treated with 100 ml. of diethyl ether and filtered to give 1.7 g. of the product, m.p. 155°-158° C., dec.
Reaction SMILES: [OH:1][C@H:2]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)[C@H:3]1[CH2:7][CH2:6][CH2:5][C:4]1=O.C([O-])(=O)C.[Na+].Cl.NO.C([O-])(=O)C.[NH4+].C([BH3-])#[N:38].[Na+].[OH-].[Na+]>[Cl-].[Ti+3].[Cl-].[Cl-].CO>[NH2:38][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[C@@H:2]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)[OH:1]
Reactant: O=C1CCC[C@@H]1[C@H](O)C1(c2ccc(OC(F)(F)F)cc2)CCC1
Reactant: [BH3-]C#N
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Product: N[C@H]1CCC[C@@H]1[C@H](O)C1(c2ccc(OC(F)(F)F)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
The mixture of Example 222A (285 mg, 0.868 mmol), methanol (5 mL), sodium acetate (85 mg, 1.042 mmol) and hydroxylamine hydrochloride (72.4 mg, 1.042 mmol) was heated in a 50° C. oil bath. After 15 minutes, the reaction mixture was cooled to room temperature and added ammonium acetate (736 mg, 9.55 mmol), sodium cyanoborohydride (164 mg, 2.60 mmol), and titanium(III)chloride (2.414 mL, 1.910 mmol) (dropwise to keep the internal temperature at about 35° C.). After 10 minutes, 2N NaOH was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. Purification of the residue using a Waters C8 OBD SunFire 30 mm×75 mm eluted with acetonitrile/0.1% TFA afforded Example 222B as a trifluoroacetate salt in 34% yield. MS (ESI+) M/Z 330 (M+H). 1H NMR (500 MHz, CD3OD) δ ppm 7.47-7.49 (m, 2H), 7.21-7.23 (m, 2H), 3.87 (d, J=9.5 Hz, 1H), 3.35 (q, J=8.4 Hz, 1H), 2.51-2.58 (m, 1H), 2.39-2.47 (m, 1H), 2.32-2.39 (m, 1H), 2.24-2.32 (m, 1H), 1.90-2.05 (m, 2H), 1.76-1.85 (m, 1H), 1.57-1.76 (m, 3H), 1.25-1.45 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH:16]=[CH:17]2)[C@H:13]2[C@H:4]1[C:5]1[CH:6]=[CH:7][C:8]([OH:21])=[CH:9][C:10]=1[CH2:11][CH2:12]2.N1C=CC=CC=1.[CH2:28]([Si:30]([CH2:34][CH3:35])([CH2:32][CH3:33])Br)[CH3:29].O>C(OC)(C)(C)C>[CH3:1][O:2][C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH:16]=[CH:17]2)[C@H:13]2[C@H:4]1[C:5]1[CH:6]=[CH:7][C:8]([O:21][Si:30]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:28][CH3:29])=[CH:9][C:10]=1[CH2:11][CH2:12]2
Reactant: CO[C@H]1C[C@]2(C)C=CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@H]21
Reactant: CC[Si](Br)(CC)CC
Solvent: COC(C)(C)C
Solvent: O
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](OC)C[C@]2(C)C=CC[C@@H]12
Reaction time: 1 h

Procedure:
284 mg (1 mmol) of 11β-methoxy-estra-1,3,5(10),16-tetraen-3-ol is reacted in 10 ml of tert-butylmethyl ether and 1 ml of pyridine with 0.6 ml of triethylbromosilane. After 1 hour, 30 ml of water is added to the reaction suspension. The organic phase is separated, washed, dried and concentrated by evaporation in a vacuum. The oily product that is thus obtained is used immediately in the next stage (hydroboration). Yield: 380 mg (95% of theory)
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.ClC1[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]2C=N[NH:35][C:36](=O)[C:31]=2C=1I.CC1(C)C(C)(C)OB(C2C=NN(COCC[Si](C)(C)C)C=2)O1.C1(B(O)O)C=CC=CC=1>>[CH3:25][Si:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][O:21][CH2:20][N:4]1[C:5]2[CH:6]=[N:7][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:9](=[O:11])[C:10]=2[C:2]([C:31]2[CH:36]=[N:35][N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=2)=[CH:3]1
Reactant: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(Br)cn2COCC[Si](C)(C)C)c1=O
Agent: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Agent: OB(O)c1ccccc1
Product: C[Si](C)(C)CCOCn1cc(-c2cn(COCC[Si](C)(C)C)c3cnn(COCC[Si](C)(C)C)c(=O)c23)cn1
Yield: 46 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 31 except for using 289 mg (0.61 mmol) of 3-bromo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 20-(a) in place of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one, and using 619 mg (1.91 mmol) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilylethoxymethyl)-1H-pyrazole obtained in Reference example 32-(a) in place of phenylboronic acid, respectively, whereby 166 mg of the title compound was obtained as a slightly yellowish oil. (Yield: 46%)
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[N:13]=[CH:12][NH:11][C:10]2=[O:18].[N+:19]([O-])([OH:21])=[O:20]>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[CH3:17])[N:13]=[CH:12][NH:11][C:10]2=[O:18]
Reactant: Cc1cc2nc[nH]c(=O)c2cc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc2c(=O)[nH]cnc2c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To H2SO4 (98%, 15 ml) was added 6-bromo-7-methylquinazolin-4(3H)-one (1.0 g, 4.2 mmol) and the mixture was stirred at rt until dissolution was complete. The mixture was cooled to 0° C. and then nitric acid (fuming) (0.26 g, 4.2 mmol) was added dropwise at 0° C. and stirred for 10 min, and then stirred at rt for 5 h. The mixture was poured onto ice (300 g) and extracted with EtOAc (3×80 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO4 and concentrated in vacuo. The product was recrystallized from MeOH (˜15 ml). MS (M+H)+ 284, 286.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[O:12][C:13]([CH3:16])=[CH:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1B(O)O)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[O:12][C:13]([CH3:16])=[CH:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cc1cnc(Nc2cc(Br)cn(C)c2=O)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ncc(C)o3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 33.9 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 262a (150 mg, 0.53 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (421 mg, 1.06 mmol), Pd(dppf)Cl2 (37 mg, 0.050 mmol), K3PO4 (225 mg, 1.06 mmol), sodium acetate (87 mg, 1.06 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 262b as yellow solid (100 mg, 34%). MS-ESI: [M+H]+ 556.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]([CH:27]2[CH2:39][C:30]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:29]=3[CH2:28]2)([F:26])[C:12]2[O:16][C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-].C[N:43]1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]([CH:27]2[CH2:39][C:30]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:29]=3[CH2:28]2)([F:26])[C:12]2[O:16][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:43])=[O:23])=[CH:24][CH:25]=3)=[N:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1ccc(-c2nnc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3cccc(Br)c3)o2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2nnc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3cccc(Br)c3)o2)cc1
Temperature: 0 °C

Procedure:
A solution of 63 mg (0.1 mmol) of (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,3,4]oxadiazol-2-yl}-benzoic acid (example 113) in 0.5 mL of DMF was treated with 27 mg (0.511 mmol) of NH4Cl, 61 mg (0.6 mmol) of N-methylmorpholine, 3 mg (0.02 mmol) and of 1-hydroxybenzotriazole. The mixture was stirred for 15 at 0° C. and treated with 29 mg (0.15 mmol) of EDCI and stirred at RT for 10 hrs. A diluted aqueous solution of HCl was added and the mixture extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and the solvent evaporated to give 60 mg of (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,3,4]oxadiazol-2-yl}-benzamide as a brown solid, MS: 630 (MH+, 1Br).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[Li+].CC([N-]C(C)C)C.[C:22](=[O:24])=[O:23].[OH-].[Na+]>C1COCC1.CCOCC.O>[Br:1][C:2]1[CH:6]=[C:5]([C:22]([OH:24])=[O:23])[N:4]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1
Reactant: Clc1cccnc1-n1ccc(Br)n1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-(3-Bromo-pyrazol-1-yl)-3-chloro-pyridine (9.2 g) was dissolved in dry THF (80 mL) and cooled to −78° C. A solution of LDA (21.3 mL, 2.0 M) was added over a period of 10 min and stirred for further 15 min at −78° C. The solution was poured on crushed dry ice in THF (50 mL) and stirred for additional 1 h. Water and Et2O were added and 2N NaOH-solution was added to adjust the pH to 10-12. The layers were separated and the aqueous layer was washed 2× with Et2O and acidified with 2N HCl (pH ˜3). The resulting suspension was 3× extracted with MTB-ether, the combined org. layers were washed with brine, dried over MgSO4 and concentrated to afford 7.96 g of the title compound of the formula
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](C3N(C)C=CN=3)[S:17][C:10]=12.[CH2:39]([N:41]1[CH:45]=[C:44](C2SC3C(=NC=CC=3OC3C=CC(N)=CC=3F)C=2)[N:43]=[CH:42]1)[CH3:40]>>[CH2:39]([N:41]1[CH:45]=[C:44]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[O:28])=[CH:3][C:2]=3[F:1])[CH:15]=2)[N:43]=[CH:42]1)[CH3:40]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1
Yield: 69 %

Procedure:
Following the procedure described above for the compound 28a (example 8, step 2) but replacing amine 9 for amine 15, title compound 28b was obtained in 69% yield. 1H NMR (DMSO-d6) δ (ppm): 10.78 (s, 1H), 9.62 (s, 1H), 8.66 (d. 1H), 8.37 (broad, s, 1H), 8.33 (s, 1H), 8.05 (dd, 1H), 7.94 (s, 1H), 7.92 (dd, 1H), 7.55 (t, 1H), 7.47 (dd, 1H), 7.07 (m, 2H), 6.96 (d, 1H), 6.89 (m, 1H), 4.13 (q, 2H), 3.84 (s, 2H), 1.42 (t, 3H). MS (m/z): 546.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15].N12CCN(CC1)CC2>ClCCl>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc2ncccc2c1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc2ncccc2c1)c1ccccc1
Yield: 69.4 %

Procedure:
A solution of 6-hydroxyquinoline (1.00 g, 6.89 mmol), N-methyl-N-phenylcarbamoyl chloride (1.17 g, 6.89 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.77 g, 6.89 mmol) in dichloromethane (20 mL) was stirred at room temperature for 1.25 hours. More dichloromethane was added and the solution was extracted with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50). Evaporation of the solvent and recrystallised from ethylacetate/heptane yielded the title compound (1.33 g, 69% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>C(N(CC)CC)C>[CH2:20]([NH:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCCCN
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 mol.) are dissolved in about 500 ml. of methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. n-butylamine are added dropwise. After the addition is completed, the heating is continued for 10 minutes. The solvent is then removed in vacuo and 500 ml. of ethyl acetate are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting yellow oil, 4-butylamino-6-chloro -2methyl-5nitropyridine-3-carboxylic acid, ethyl ester is crystallized with 300 ml. of methanol, yield 110 g. (70%); m.p. 33°-35° (methanol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:35]Br.[Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(Cl)Cl.CO.O.C(=O)(O)[O-].[Na+]>[Br:35][C@H:10]1[C@H:11]2[C@H:12]([C:14](=[O:16])[O:15]2)[CH2:13][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N[C@H]1C=C[C@H](C(=O)O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2C(=O)O[C@H]2[C@@H]1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To (1R,4R)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylic acid (400.00 g, 1.7601 mol; prepared in a procedure analogous to that described in Examples 1 to 3 above) dissolved in methylene chloride (6 L) was added tetrabutylammonium hydroxide in methanol (1.0M, 1800 ml), and the mixture was stirred at ambient temperature for 60 minutes. The reaction mixture was then cooled to −25° C. under a blanket of Nitrogen. Bromine (181 ml, 3.52 mol) in methylene chloride (2 L) was then added slowly over 60 minutes, maintaining an internal temperature lower than −20° C. On completion of the bromine addition, the mixture was stirred at −25° C. for a further 30 minutes, and then warmed slowly to 0° C. over 30 minutes. The mixture was then allowed to stir at 0° C. for 1 hour. At 0° C., a mixture of L-ascorbic acid sodium salt (523.0 g, 2.640 mol) in water (3 L) and saturated sodium bicarbonate in water (3 L), was added slowly over 30 minutes maintaining an internal temperature lower than 10° C. The resulting bi-phasic mixture was stirred and allowed to warm to ambient temperature over 1 hr. The methylene chloride layer was separated and the aqueous layer was extracted with methylene chloride (2 L). The methylene chloride layers were combined and concentrated to a volume of about 4 L. Ethyl acetate (8 L) was added, and the mixture was concentrated to a volume of about 5 L. Ethyl acetate (5 L) was added, and the resulting mixture was washed 3 times with water (4 L). The organic layer was then washed with saturated sodium chloride in water (2 L) and concentrated to afford the title compound (460 g, 85%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 5.09 (d, 1H), 4.80 (m, 1H), 4.71 (m, 1H), 4.47 (m, 1H), 4.04 (m, 1H), 2.39 (m, 1H), 1.89 (m, 1H) and 1.46 (bs, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([CH:24]=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:28][OH:29].C(N(CC)CC)C.C([BH3-])#N.[Na+].Cl>C1COCC1.CO.O1CCOCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([CH2:24][NH:28][OH:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](CNO)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
To a solution of {(S)-2-[4-(4-chloro-phenoxy)-phenyl]-1-formyl-ethyl}-carbamic acid tert-butyl ester (68 mg, 0.18 mmol, 1 eq.) in THF (0.5 ml) and methanol (4 ml) was added hydroxylamine HCl salt (75 mg, 1 mmol, 5.6 eq.) followed by triethylamine (0.2 ml, 1.5 mmol, 8.3 eq.). The mixture was shaken in a shaker at room temperature overnight. Sodium cyanoborohydride (10 mg, 0.29 mmol, 1.6 eq.) was added in one portion. Then 4 N HCl in dioxane was added dropwise until the reaction mixture was acidic. The mixture was stirred at room temperature for 2 hr. Then the reaction mixture was concentrated to dryness. The residue was partitioned between water and ethyl acetate. NaOH aq. was added to bring pH of the mixture to 10. After excess NH4Cl aq. was added, the mixture was extracted with ethyl acetate. After dried over anhydrous MgSO4, the volatile material was removed under reduced pressure and the residue was purified by chromatography on silica gel using DCM/MeOH (100:1 to 25:1) as eluent to give the desired product (76 mg, 100% yield) as white solid, which was re-purified by chromatography on silica gel using EA/hexane (1:2 to 2:1) followed by EA as eluent to give the desired product (52 mg, 73% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH:12]([N: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)[CH3:13].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1.C1(C)C=CC=CC=1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:7]2\[O:8][C:4]3[C:3]([CH:12]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]4)[CH3:13])=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:28]1
Reactant: CC(c1c(O)ccc2c1OCC2=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(c1c(O)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperazine-1-carboxylate (0.11 g, 0.30 mmol) in methanol (5.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.040 g, 0.27 mmol). Then, the mixture was added with 7 drops of piperidine, and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was added with toluene, then the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (95:5)) to obtain tert-butyl (Z)-4-{1-[2-(1H-indazol-3-yl)methylene-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl]ethyl}piperazine-1-carboxylate (0.075 g, 51%).