Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH:16]=[C:15]([C:27]([O:29]C)=O)[C:11]=3[NH:12][C:13]=2[CH:14]=1.[NH3:31]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH:16]=[C:15]([C:27]([NH2:31])=[O:29])[C:11]=3[NH:12][C:13]=2[CH:14]=1
Reactant: N
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(=O)OC)cc(-c3ccc(OC)cc3)nc12
Solvent: CO
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(OC)cc3)nc12
Temperature: 60 °C

Procedure:
A suspension of methyl 7-(2-methoxyethoxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (28 mg, 0.069 mmol) in 7 N ammonia in MeOH (3mL) in a sealed microwave vial was heated at 60° C. for 22 hr. The solvent was removed and the residue was purified by radial chromatography (step gradient elution with DCM containing 2 to 4% MeOH) to give 7-(2-methoxyethoxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (20 mg). MS (ESI) m/z 392.1 (M+H). 1H NMR (MeOD) δ ppm 8.26 (1H, d, J=8.55 Hz), 8.07 (1H, s), 8.01-8.06 (2H, m), 7.16 (1H, d, J=2.14 Hz), 7.06-7.11 (2H, m), 6.94 (1H, d, J=8.55 Hz), 4.21-4.29(2H, m), 3.89(3H, s), 3.83 (2H, dd), 3.45-3.51 (3H, s).
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][N:3]=[CH:2]1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:14][C:4]1[N:3]=[CH:2][S:1][C:5]=1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1cncs1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1scnc1Br
Reaction time: 1 h

Procedure:
To a solution of tert-butyl thiazol-5-ylcarbamate (WO 2007/071955) (607 mg, 3.0 mmol) in chloroform (50 mL) was added N-bromosuccinimide (542 mg, 3.04 mmol) at 0° C. After 1 h, reaction was quenched by addition of saturated NaHCO3 solution (50 mL). The layers were separated, and the mixture extracted with CHCl3 (3×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. 1H NMR (CDCl3) δ8.37 (d, J=0.6 Hz, 1H), 7.05 (br s, 1H), 1.55 (s, 9H); MH+ 278.9.
Reaction SMILES: C([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([CH:30]=[O:31])CC(O)=O)=[O:23])[CH3:21])=[O:18])C1C=CC=CC=1.C=O.[C:34]([OH:37])(=[O:36])[CH3:35]>CO>[CH2:8]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[C:9]1[C:17]([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([CH:30]=[O:31])[CH2:35][C:34]([OH:37])=[O:36])=[O:23])[CH3:21])=[O:18])[C:16]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)O
Reactant: C[C@H](NC(=O)c1[nH]c2ccccc2c1Cc1ccccc1)C(=O)N[C@H](C=O)CC(=O)O
Agent: C=O
Solvent: CO
Product: C[C@H](NC(=O)c1cc2ccccc2n1Cc1ccccc1)C(=O)N[C@H](C=O)CC(=O)O
Yield: 72 %

Procedure:
(3S)-3-[( -Benzylindole-2-carbonyl)alaninyl] amino-4-oxobutanoic acid, semicarbazone (176 mg, 0.37 mmol) was dissolved in methanol (4.5 mL), formaldehyde (1.5 mL, 37% wt. aq) and acetic acid (1.5 mL) and the resulting mixture was stirred for 4 hours under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated in vacuo, diluted with water, and extracted twice with ethyl acetate. The ethyl acetate solution was washed with brine, dried over sodium sulfate, and concentrated to give a crude product which was triturated with ether to afford the title product as a light green powder (113 mg, 72%). TLC: (methylene chloride:methanol:acetic acid, 20:1:1, silica gel): Rf=0.38; MS for C23H23N3O5; M+H+=422; M−H+420. 1H-NMR (CD3OD): δ7.65 (d, J=8.0, 1H), 7.37 (dd, J=8.2, 0.8, 1H), 7.24-7.04 (m, 8H), 5.87-5.73 (m, 2H) 4.60-4.49 (m, 2H), 4.32-4.23 (m, 1H), 2.69-2.44 (m, 2H), 1.41 (d, J=7.1, 2 sets, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(Cl)c(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3c(Cl)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Br:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][C:20](=[O:21])[CH2:19][Cl:18])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(Br)c1C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CCl)Nc1cccc(Br)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a stirred solution of 2-amino-6-bromo-benzoic acid (6) (3.06 g, 14.2 mmol) in toluene (75 mL) cooled to 0° C. in an ice-bath was added pyridine (0.60 mL, 7.10 mmol) followed by a solution of chloroacetyl chloride (2.26 mL, 28.4 mmol) in toluene (75 mL) drop-wise over 1 hr. The reaction mixture was allowed to warm to RT, and was heated at 115° C. for 3 hr and then allowed to cool to RT. The solvent volume was reduced by half by evaporation in vacuo. Upon standing overnight, the product precipitated and was collected by filtration to afford 2-bromo-6-(2-chloroacetamido)benzoic acid (7a) (1.44 g) as a white solid: m/z 290/292 (M+H)+ (ES+). The filtrate was concentrated in vacuo and the residue triturated with ethanol/heptane to afford 2-bromo-6-(2-hydroxyacetamido)benzoic acid (7b) (1.02 g, combined yield, 59%): m/z 274/276 (M+H)+ (ES+). Both 7a and 7b can be used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH3:27])=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[NH3:28]>CC(O)C.C(Cl)Cl>[CH3:27][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:28])[C:3]2=[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18]3)=[CH:13][CH:12]=2)[N:9]=1
Reactant: N
Reactant: Cc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(N)nccn12
Temperature: 110 °C

Procedure:
7-(8-Chloro-3-methyl-imidazo[1,5-a]pyrazin-1-yl)-2-phenyl-quinoline was dissolved in 10.0 mL of 2.0M NH3 in IPA and 5.0 mL of CH2Cl2. The reaction was heated to 110° C. for 64 h. The salts were filtered off and washed with CH2Cl2. Purified with silica gel column chromatography [Jones Flashmaster, 10 g cartridge, eluting with 1% MeOH:EtOAc] to yield a dark yellow solid; 1H NMR (400 MHz, CDCl3) δ 2.71 (s, 3H), 5.61 (brs, 2H), 7.13 (d, 1H, J=5.1 Hz), 7.2 (d, 1H, J=5.1 Hz), 7.48-7.56 (m, 3H), 7.89-7.97 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, 1H, J=8.6 Hz), 8.39 (s, 1H); MS (ES+): 352.06 (M+1), 353.07 (M+2), 354.09 (M+3).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=3[CH:13]=2)[N:3]=1.C=O.[C:22](O)(=O)C.[BH3-]C#N.[Na+]>CO.ClC(Cl)C>[F:1][C:2]1[C:7]([NH:8][CH3:22])=[CH:6][CH:5]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=3[CH:13]=2)[N:3]=1
Reactant: CC(=O)O
Reactant: COc1ccc2oc(-c3ccc(N)c(F)n3)cc2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: CNc1ccc(-c2cc3cc(OC)ccc3o2)nc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To a stirred solution of 2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-ylamine (97 mg, 0.376 mmol) in a mixture of MeOH (2 mL) and dichloroethane (1 mL), formaldehyde (37% solution in water, 0.167 mL, 2.23 mmol) and acetic acid (50 μL, 0.87 mmol) were added. The reaction mixture was stirred for 2 hours at room temperature, then NaCNBH3 (94 mg, 1.50 mmol) was added in one portion and the stirring was continued for 45 minutes. The reaction was then quenched by addition of water (2 mL). The volatiles were removed under reduced pressure and the residue was extracted with dichloromethane (50 mL). The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The product was purified by flash column chromatography using 20% ethyl acetate in hexane to afford [2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-yl]-methyl-amine (35.7 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.64 (d, J=8.2 Hz, 1H), 7.38 (d, J=8.98 Hz, 1H), 7.09 (s, 1H), 7.03 (d, J=2.34 Hz, 1H), 6.99 (dd, J=10.15, 8.20 Hz, 1H), 6.87 (dd, J=8.78, 2.54 Hz, 1H), 4.21 (br. s, 1H), 3.85 (s, 3H), 2.94 (d, J=5.07 Hz, 3H)
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.C(O)C.Cl.Cl.[CH2:19]([NH:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([N:26]1[CH:10]=[C:5]([C:4]([O:3][CH3:2])=[O:12])[CH:6]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 36.4 %

Procedure:
18.68 g of methyl 2-(dimethoxymethyl)-3-hydroxyacrylate sodium salt was added to 80 ml of ethanol, and 18.39 g of benzylhydrazine dihydrochloride was added. The mixture was stirred at 70° C. for 7 hours and then cooled to room temperature. After 100 ml of water was added, the mixture was concentrated to 100 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.39 g of methyl 1-benzyl-1H-pyrazole-4-carboxylate.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[O:32]=[C:27]1[NH:28][C:29](=[O:31])[C:30](=[CH:24][C:21]2[CH:20]=[CH:19][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:9])[CH3:8])[CH:13]=3)=[CH:23][CH:22]=2)[S:26]1
Reactant: O=C1CSC(=O)N1
Reactant: CCN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)OC(C)(C)C
Product: CCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Yield: 91.2 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 1.35 g (4 mmol) of tert-butyl ethyl(4′-formylbiphenyl-3-ylmethyl)carbamate with 470 mg (4 mmol) of 2,4-thiazolidine dione, 1.6 g (92%) of the expected product are obtained.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: BrCCCc1ccccc1
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Product: CCCCN(CCCC)C(=O)c1cn(CCCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 76.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271F, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.4 mmol) and (3-bromopropyl)benzene (97 mg, 0.48 mmol) were converted the title compound (187 mg, 74%). 1H NMR (CDCl3) 8.65 (d, J=1.6 Hz, 1H), 8.20 (dd, J=8.0, 1.6 Hz, 1H), 7.53 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.33-7.30 (m, 4H), 7.24-7.14 (m, 4H), 6.94 (d, J=8.0 Hz, 2H), 5.13 (s, 2H), 4.00 (s, 3H), 3.99 (br s, 2H), 3.52 (t, J=7.6 Hz, 2H), 3.46 (br s, 2H), 2.39 (t, J=7.6 Hz, 2H), 1.82-1.78 (m, 2H), 1.55-1.50 (m, 4H), 1.26-1.22 (m, 4H), 0.96-0.83 (m, 6H); MS(ESI+) m/z 610.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:15]([C:32]3[O:33][C:34]([CH2:37]Cl)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[CH3:39][C@H:40]1[O:45][C@@H:44]([CH3:46])[CH2:43][NH:42][CH2:41]1>>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:42]4[CH2:41][C@H:40]([CH3:39])[O:45][C@H:44]([CH3:46])[CH2:43]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: C[C@@H]1CN(Cc2nnc(-c3cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc4[nH]ncc34)o2)C[C@H](C)O1
Temperature: 90 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
N-(2-Chloro-5-{4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (50 mg, 0.084 mmol) and (2R,6S)-2,6-dimethylmorpholine (0.5 ml, 0.084 mmol) were placed a vial and heated in a microwave at 90° C. for 15 mins. The reaction was heated in the microwave for a further 20 mins. The (2R,6S)-2,6-dimethylmorpholine was removed and the residue placed into isopropanol (3 ml) and 2M sodium hydroxide (1 ml) and the mixture stirred at room temperature for 3 h. The solvent was removed and the residue purified by Mass Directed Automated Preparative HPLC (Method B). The desired product was not collected so the waste was concentrated in vacuo and the residue purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound as white solid (12 mg).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.O[NH:28][C:29]([C:31]1[C:32]2[CH:33]=[CH:34][C:35]([NH:41][C@H:42]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44][CH2:43]3)=[N:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)=[NH:30]>C(#N)C>[C@H:42]1([NH:41][C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[CH:40][C:31]=3[C:29]3[N:28]=[C:1]([CH3:2])[O:4][N:30]=3)[N:36]=2)[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43]1
Reactant: N=C(NO)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: Cc1nc(-c2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
To a stirred solution of acetic acid (127 mg, 2.12 mmol) in acetonitrile (8.5 ml) was added at room temperature 1-hydroxy-benzotriazole (403 mg, 2.98 mmol) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride (465 mg, 2.43 mmol). The mixture was allowed to stir for 3 h at room temperature and N-hydroxy-2-((R)-indan-1-ylamino)-quinoline-5-carboxamidine (450 mg, 1.41 mmol) was added together with acetonitrile (7.5 ml). The mixture was allowed to stir for 2 h at room temperature, evaporated to dryness and diluted with acetic acid (14 ml). The reaction mixture was allowed to stir for 2 h at 100° C., evaporated, poured into saturated NaHCO3 solution (50 ml) and extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (2×50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (ethyl acetate/heptane) to yield the title compound as light yellow solid (130 mg, 18%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7](C(=O)C)[N:6]=[CH:5]2.Cl.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2
Reactant: CC(=O)n1ncc2cc(Br)c(F)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Fc1cc2[nH]ncc2cc1Br
Temperature: 90 °C

Procedure:
A solution of 1-(5-bromo-6-fluoro-1H-indazol-1-yl)ethanone (29C, 5.0 g, 19.5 mmol) was treated with aq HCl (3M soln., 100 mL) and methanol (20 mL) and heated at 90° C. for 3 h, when the reaction turns homogenous. The reaction mixture was cooled to room temperature and basified with aq. NaOH. A colorless solid precipitated out which was filtered and dried to yield 5-bromo-6-fluoro-1H-indazole (29D)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[CH3:12][Li].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]([OH:5])[CH3:12]
Reactant: COc1cccc(F)c1C=O
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(F)c1C(C)O
Reaction time: 1 h

Procedure:
To a solution of 2-fluoro-6-methoxybenzaldehyde (0.5 g) in tetrahydrofuran (10 mL) was added methyllithium (1.15 mol/L diethyl ether solution, 3.4 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hour. Then the mixture was stirred at room temperature for 30minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.45 g).
Reaction SMILES: [CH2:1]([O:3]C(C1C=CC=CC=1)C=O)C.[CH2:13]([O:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:18]=[O:19])[CH2:14][CH3:15]>>[CH2:13]([O:16][C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:1][OH:3])[CH2:18][OH:19])[CH2:14][CH3:15]
Reactant: CCCOC(C=O)c1ccccc1
Reactant: CCOC(C=O)c1ccccc1
Product: CCCOC(CO)(CO)c1ccccc1

Procedure:
The procedure in Example 6 was repeated except that 2-ethoxy-2-phenylethanal was replaced with 2-propoxy-2-phenylethanal, to obtain 2-propoxy-2-phenyl-1,3-propanediol.
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[F:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24][NH2:25])=[O:23])=[CH:20][CH:19]=1>C(O)C.O.Cl>[F:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:24]/[N:25]=[C:14](/[C:11]2[NH:12][CH:13]=[C:9]([C@@H:2]([OH:1])[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6])[N:10]=2)\[CH3:15])=[O:23])=[CH:20][CH:19]=1
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: NNC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C/C(=N\NC(=O)c1ccc(F)cc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (172 mg, 0.74 mmol) was suspended in ethanol (4 ml) and water (1 ml). 4-fluorobenzoic acid hydrazide (131 mg, 0.85 mmol, 1.1 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 55° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with ethanol to yield the product, as one apparent isomer, as a white solid: 97 mg (35%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:13][C:14]1[N:15]2[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:16]2[S:17][CH:18]=1>CCOCC>[CH3:13][C:14]1[N:15]2[C:21]([CH:22]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[OH:23])=[CH:20][N:19]=[C:16]2[S:17][CH:18]=1
Reactant: Cc1csc2ncc(C=O)n12
Reactant: BrCCCCc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: Cc1csc2ncc(C(O)CCCCc3ccccc3)n12

Procedure:
Magnesium (0.15 g) in ether (15 mL) was treated with 1-bromo-4-phenylbutane (prepared by the procedure described in Kamijo et al., Chem. Phar. Bull., 1983, 31, 4189) (1.50 g) at 0° and the mixture was reacted at 25° for 2.5 hours. The suspension was cooled to 0°, solid 3-Methylimidazo[2,1-b]thiazole-5-carboxaldehyde (FIG. C-6) (0.332 g) was added and the mixture was reacted at 25° for 3 hours. The solution was decanted into 5% NH4Cl solution and extracted with ethyl acetate. The extract was dried, evaporated and the residue (0.55 g) was crystallized from acetonitrile solution to yield pure 3-Methyl-α-(4-phenylbutyl)imidazo-[2,1-b]thiazole-5-methanol (FIG. C-7) (0.39 g), m.p. 120-121°.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].C(N(CC)CC)C.[C:24]12([C:34](Cl)=[O:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>O1CCCC1>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:34]([C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:35])[CH3:3]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
2.93 g (0.010 mol) of L-alanyl-L-proline ethylamide hydrobromide were dissolved in 50 ml of tetrahydrofuran and the mixture was cooled to 0° C. There were then added 2.8 ml (0.020 mol) of triethylamine followed by 2.15 g (0.010 mol) of 1-adamantoyl chloride. The mixture was stirred at 0° C. for 0.5 hour and at room temperature for 2 hours and then evaporated to dryness. The oily residue was dissolved in ethyl acetate and the solution washed successively with 0.5-N hydrochloric acid, water, 5% sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The resulting oil was crystallised from ethyl acetate/petroleum ether to yield 2.2 g (59%) of N-(1-adamantylcarbonyl)-L-alanyl-L-proline ethylamide of melting point 116°-118° C; [α]D20 =-88.1° (c=0.99% in methanol).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]1([S:15]([C:18](=[CH:23]OCC)[C:19](OC)=[O:20])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C2C=CC=CC=2)C=CC=CC=1.CCOCC>[OH:20][C:19]1[C:5]2[C:3](=[C:2]([F:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=[CH:23][C:18]=1[S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: Nc1ccccc1F
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1ccccc1
Solvent: CCOCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=S(=O)(c1ccccc1)c1cnc2c(F)cccc2c1O
Temperature: 260 °C
Reaction time: 6 h
Yield: 3.3 %

Procedure:
2-Fluoroaniline 7(1) (3.82 g, 0.0344 mol) and methyl 2-phenylsulfonyl-3-ethoxy-acrylate 7(2) (9.59 g, 0.0355 mol) were mixed together in biphenyl ether (21.5 ml). The mixture was stirred in an opened flask for 6 h at 250-270° C. Ethanol was distilled during the first 30 min. After the reaction was completed (LCMS control) the mixture was cooled, the formed solid was filtered off, dissolved in ethanol and solution was boiled with charcoal. After filtration from charcoal ethanol was evaporated, the residue was subjected to chromatography on silica, eluent—gradient of solvent system CHCl3:ethyl acetate=from 10:1 to 5:1. The residue after evaporation of fractions, comprising the final product was washed with ether, it gave 345 mg (3.3%) of 4-hydroxy-3-phenylsulfonyl-8-fluoroquinoline 7(3).