Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CO[C:13]1[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.4 %

Procedure:
A mixture of 2-fluorobenzoyl chloride (15.86 g, 0.1 mole) and 1,4-dimethoxybenzene (13.82 g, 0.1 mole) in 1,2-dichloroethane (200 ml) was cooled in an ice bath and treated cautiously with AlCl3 (13.82 g, 0.103 mole) portionwise. The temperature of the reaction mixture was kept at 0-5° during the addition, and then warmed to room temperature over 4 hrs after completion of addition. The resulting deep red reaction mixture was further refluxed for 1.5 hrs, followed by stirring at room temperature overnight. The reaction was quenched by addition of ice and 6N HCl solution in an ice bath with continued stirring at 0° for an hour. The mixture was then extracted three times with CH2Cl2. The combined organic layers were washed with 50% NaCl solution, dried over anhydrous Na2SO4 and filtered through a silica gel plug, yielding the intermediate benzophenone (24.68 g, 100%) as an orange colored oil which was used for cyclization without further purification. IR (neat): 3070, 2998, 2936, 2736, 1605, 1477, 1445, 1328, 1265, 1226, 1212, 1135, 1038, 960, 870, 792, 758 and 646 cm-1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22]C=3)[N:14]=[N:13]2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].CC1N=C(N2C=C(CC(C3C=CC=CC=3)C)N=N2)SC=1C(OCC)=O>>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:14]=[N:13]2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-n2cc(CCCc3ccccc3)nn2)nc1C
Agent: CCOC(=O)c1sc(-n2cc(CC(C)c3ccccc3)nn2)nc1C
Product: Cc1nc(-n2cc(CCc3ccccc3)nn2)sc1C(=O)O
Yield: 70 %

Procedure:
Following the procedure as described in Example 13, making variations as necessary to replace ethyl 4-methyl-2-(4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(4-(2-phenylpropyl)-1H-1,2,3-triazol-1-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 70% yield: 1H NMR (300 MHz, CDCl3) δ 11.21 (s, 1H), 8.08 (s, 1H), 7.31-7.21 (m, 5H), 3.19-3.05 (m, 4H), 2.75 (s, 3H); MS (ES+) m/z 315.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:26].[Li]CCCC.[O:32]=[C:33]1[CH2:36][CH:35]([C:37]2[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:34]1.CC(=O)OCC>C1COCC1>[Cl:26][C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)[CH:24]=[CH:25][C:2]=1[C:33]1([OH:32])[CH2:34][CH:35]([C:37]2[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:36]1
Reactant: Clc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Reactant: COC(=O)c1cccc(C2CC(=O)C2)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C2CC(O)(c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3Cl)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a stirring solution of compound 1a (1.67 g, 3.5 mmol) in dry THF (30 mL) was added n-BuLi (2.5 M in hexane, 1.2 eq, 1.69 mL) dropwise over 10 min at −78° C. under a nitrogen atmosphere. This was stirred for 1 h at this temperature before adding a solution of compound 1c (0.72 g, 1 eq) in dry THF (10 mL) dropwise and stirred for 1 h at this temperature. The reaction mixture was allowed to warm to rt slowly and left stirring overnight. The reaction was quenched with a solution of saturated ammonium chloride solution (50 mL) and EA (250 mL). The organic layer was separated and the aq. layer was washed with EA (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the crude product as a brown oil. The product was isolated following CC with PE/EA (19:1 to 3:1). The reaction and purification was repeated twice on the same scale and the combined product (3.13 g) was repurified under the same conditions to afford the final product 1 (1.7 g, 19%). 1H NMR (CDCl3): 7.93 (m, 1H), 7.90-7.85 (m, 1H), 7.50-7.30 (m, 5H), 6.88 (s, 1H), 6.75-6.72 (m, 1H), 4.80 (s, 2H), 3.88 (s, 3H), 3.20-3.10 (m, 1H), 3.00-2.91 (m, 2H), 2.60-2.49 (m, 2H), 2.15-2.08 (m, 1H), 1.30-1.25 (m, 2H), 1.15-1.10 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[O:16]1[CH2:21][CH2:20][CH:19]([Mg]Cl)[CH2:18][CH2:17]1>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[O:16]1[CH2:21][CH2:20][CH:19]([C:2]2[C:3]([O:8][C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:18][CH2:17]1
Reactant: Cl[Mg]C1CCOCC1
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2nccnc2C2CCOCC2)cc1

Procedure:
To a round bottomed flask was added 4-(3-chloropyrazin-2-yloxy)aniline (1.2276 g, 5.54 mmol) dissolved in a mixture of THF (8.86 mL) and NMP (2.215 mL). Iron(iii) acetylacetonate (0.098 g, 0.277 mmol) was added and the temperature was brought to 0° C. (Tetrahydro-2H-pyran-4-yl)magnesium chloride (8.31 mL, 6.65 mmol) was added dropwise to the reaction mixture. Upon completion, the reaction was quenched with saturated ammonia chloride solution. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:39](=[O:38])[CH2:40][OH:41])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f26) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=2.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=2)[N:3]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]=1[CH3:1]
Reactant: Sc1ccccc1Cl
Reactant: CCOC(=O)Cn1c(C)cc2cc(NS(C)(=O)=O)ccc21
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Sc2ccccc2Cl)c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-acetic acid, ethyl ester (0.31 g) and 2-chlorobenzenethiol (0.27 g) were dissolved in dimethyl formamide (3 ml) followed by addition of iodine 0.30 g) for the whole to be stirred at room temperature overnight. The mixture was poured into aqueous sodium thiosulphate (50 ml) and the resultant white precipitate collected by filtration and rinsed with water, dried under vacuum to be recrystallised from ethanol. The crystals were harvested and rinsed with isohexane and dried under vacuum to give the sub-title compound (0.20 g)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:14])[CH:11]=1)[C:5]([O:7]C)=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:52].Cl.[NH2:54][C@@H:55]([CH2:69][C:70]1[CH:75]=[C:74]([F:76])[CH:73]=[C:72]([F:77])[CH:71]=1)[C@H:56]([OH:68])[CH2:57][NH:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([CH2:66][CH3:67])[CH:61]=1>O1CCCC1.CO.O.O.[OH-].[Li+].C(Cl)Cl>[ClH:52].[ClH:52].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:14])[CH:11]=1)[C:5]([NH:54][C@@H:55]([CH2:69][C:70]1[CH:71]=[C:72]([F:77])[CH:73]=[C:74]([F:76])[CH:75]=1)[C@H:56]([OH:68])[CH2:57][NH:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([CH2:66][CH3:67])[CH:61]=1)=[O:7]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCN(C)Cc1cc(Br)cc(C(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCCCN(C)Cc1cc(Br)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)c1
Reaction time: 16 h

Procedure:
Methyl 3-bromo-5-{[butyl(methyl)amino]methyl}benzoate prepared by the method in EXAMPLE SP-190, Step 1 (170 mg, 0.54) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (45 mg, 1.1 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (5 mL), and diisopropylethylamine (375 μL, 2.16 mmol), HATU (256 mg, 0.68 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method in EXAMPLE SP-272 (265 mg, 0.65 mmol) are added. The reaction stirred at room temperature 1 h. The reaction mixture is diluted with methylene chloride, washed with water, and saturated sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (1 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 616.2 [M+H]+.
Reaction SMILES: [N+:1]([CH2:4][C:5]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2)([O-])=O.[OH-].[Na+].N>C(O)C.[Ni].C1(C)C=CC=CC=1>[NH2:1][CH2:4][C:5]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2
Reactant: O=[N+]([O-])CC12CCCN1CCC2
Agent: [Ni]
Agent: N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: NCC12CCCN1CCC2
Temperature: 20 °C
Reaction time: 12 h
Yield: 86.8 %

Procedure:
To a homogenous solution of 7a-nitromethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine (1.00 g, 5.88 mmol) and NaOH (0.235 g (5.88 mmol) in 5 ml of ethanol, 0.40 g of Raney nickel were added to stir the mixture under hydrogen atmosphere at 20° C. for 12 hours. The catalyst was filtered off, and then the filtrate was poured into 33% HCl/ipropanol (5.0 ml) below 20° C. The reaction mixture was evaporated to dryness to give crude crystal. The crude crystal was suspended in toluene (5.0 ml) and to the suspension was introduced NH3 gas to stir at 20° C. for 12 hours. The precipitate was filtered off and the filtrate was evaporated to afford 716 mg of the desired compound (Yield: 86.9%).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[C:6]([CH:10]3[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14](O)([C:21]([F:24])([F:23])[F:22])[NH:13][C:12]([CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[C:11]3[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:7][CH:8]=[CH:9][C:2]=12.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>ClCCl>[N:1]1[O:5][N:4]=[C:3]2[C:6]([CH:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[NH:13][C:12]([CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[C:11]3[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(O)(C(F)(F)F)C(C(=O)OCC)C1c1cccc2nonc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)C1=C(C(OCC)OCC)NC(C(F)(F)F)=C(C(=O)OCC)C1c1cccc2nonc12

Procedure:
A solution of diethyl 4-(4-benzofurazanyl)-2-diethoxymethyl-1,4,5,6-tetrahydro-6-hydroxy-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (9.0 g, 17 mmoles), trifluoroacetic anhydride (4.77 ml, 34 mmoles) and pyridine (4.05 ml, 51 mmoles) in dry dichloromethane (100 ml) was stirred at room temperature. After 3 hours the solution was washed with water, 10% aqueous hydrochloric acid solution, brine and dried (MgSO4). Evaporation of the solvent left crude sub-title compound as an oil (8.8 g). Nmr (CDCl3) δ 6.1 (s,H), 5.6(s,H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1)=[O:3].[Na].[OH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>O1CCCC1>[O:13]=[C:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH2:9][O:8][C:7]2[CH:18]=[CH:19][C:4]([C:2]([O:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:3])=[CH:5][C:6]1=2
Reactant: O=C(O)CCO
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(O)CCOC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1.0 gm of 2-chlorocarbonyl-6,11-dihydro-11-oxodibenz[b,e]oxepin in 20 cc of tetrahydrofuran and add 1.0 gm of the sodium salt of β-hydroxypropionic acid. Stir the mixture at room temperature for 18 hours. Filter and evaporate the filtrate to dryness. Recrystallize the solid residue from ethanol to obtain the title product.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[N:13]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]3)[C:12]3[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1.Cl[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1C(=O)CCC1>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([O:30][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:31][CH:32]=1
Reactant: Clc1ccccn1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccc(F)cc3)nc3ccc(O)cc32)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(Oc4ccccn4)cc32)CC1

Procedure:
A microwave vial was charged with 4-fluoro-N-(6-hydroxy-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)benzamide (56 mg, 0.128 mmol), 2-chloropyridine (0.036 mL, 0.383 mmol), cesium carbonate (166 mg, 0.511 mmol), and NMP (0.6 mL) then irradiated in the microwave at 160° C. for 6 hours. The mixture was diluted with EtOAc, washed with water, the water layer back extracted with EtOAc, and the combined organics were washed with brine. The organic layer was dried over Na2SO4 and filtered. The mixture was purified via flash chromatography using a linear gradient of 0% to 10% MeOH in DCM. The material was further purified by reverse-phase preparative HPLC using a 0.1% TFA in ACN/H2O, gradient 10% to 90%. The material was partitioned between saturated aqueous NaHCO3 and 5% IPA/DCM, the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was isolated as an off-white solid (32 mg, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J=8.00 Hz, 6H) 1.54-1.82 (m, 4H) 2.01-2.14 (m, 2H) 2.42-2.56 (m, 1H) 2.56-2.77 (m, 2H) 3.75-3.93 (m, 1H) 4.80-4.95 (m, 1H) 6.97 (dd, J=8.56, 2.10 Hz, 1H) 6.95-7.10 (m, 1H) 7.00-7.18 (m, 1H) 7.20-7.29 (m, 2H) 7.48 (d, J=2.05 Hz, 1H) 7.51-7.62 (m, 2H) 7.80-7.90 (m, 1H) 8.07-8.19 (m, 1H) 8.27-8.38 (m, 2H) 12.81 (s, 1H). M/Z calc'd for C29H30FN5O3: 515.58. found 516 [M+H].
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14](O)=[O:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14]([NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])=[O:15]
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1ccc(C(=O)O)cc1Cl
Product: COc1ccc(C(=O)N[C@H](C)c2ccccc2)cc1Cl

Procedure:
Prepare in a similar manner to example 4 using (R)-1-phenylethanamine and 3-chloro-4-methoxy benzoic acid. MS (M+H, 290.0).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[Cl:11])[CH2:4][CH:3]1[CH3:17].[Cl:18]Cl>Cl.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:17])[Cl:18]
Reactant: ClCl
Reactant: CC1Cc2cc(OCC(=O)O)cc(Cl)c2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC1(Cl)Cc2cc(OCC(=O)O)cc(Cl)c2C1=O

Procedure:
By following substantially the procedure described in Example 12, Step B, using as the reactants (1-oxo-2-methyl-7-chloro-5-indanyloxy)acetic acid (2.55 g., 0.01 mole), chlorine (710 mg., 0.01 mole), glacial acetic acid (50 ml.) and concentrated hydrochloric acid (1 drop) there is obtained (1-oxo-2-methyl-2,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1.[CH2:28]([O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:2]2[N:6]3[N:7]=[CH:8][CH:9]=[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[C:5]3=[N:4][C:3]=2[CH:17]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)=[CH:35][CH:34]=1)=[O:32])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3c(N4CCOCC4)ccnn3c2Br)C1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2c(C3CN(C(=O)OC(C)(C)C)C3)nc3c(N4CCOCC4)ccnn23)cc1

Procedure:
Compound 19d was coupled with (4-(ethoxycarbonyl)phenyl)boronic acid under Suzuki reaction conditions as described in Example 1, Step E, to obtain compound 19e. Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H34N4O5: 507.2 (M+H). found: 507.3.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:28][CH2:27]1)=O)(C)(C)C.[ClH:38]>>[ClH:38].[CH3:18][O:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:35]3[CH2:34][CH2:33][N:32]([CH:29]4[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]4)[CH2:37][CH2:36]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CCN(C4CCNCC4)CC3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 4-piperazin-1-yl-piperidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)[CH2:9][CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][C:6]3([CH2:4][OH:3])[CH2:9][CH2:8][CH2:7]3)=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: CCOC(=O)C1(Nc2ccc3[nH]ncc3c2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(Nc2ccc3[nH]ncc3c2)CCC1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
To a stirred solution of 1-(1H-indazol-5-ylamino)-cyclobutanecarboxylic acid ethyl ester (1.68 g, 6.49 mmol) in THF (37 mL) at 0° C. and under nitrogen was added LiAlH4 (13.0 mL of a 1.0 M solution in THF, 13.0 mmol) dropwise over 2 minutes then the reaction mixture was warmed to ambient temperature. After 2 hours the reaction mixture was quenched by the addition of sodium sulfate decahydrate (2 g). The reaction mixture was filtered and the filter cake washed with EtOAc. The combined filtrates were concentrated in vacuo to a yellow solid. Purification by chromatography (silica, 4 to 20% of a 9:1 MeOH:NH4OH solution in DCM) gave [1-(1H-indazol-5-ylamino)-cyclobutyl]-methanol (0.827 g, 3.81 mmol, 59%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:23][N:22](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:21]3)=[N:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(S)CCCCCC>C1COCC1.C1CCN2C(=NCCC2)CC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:15]2[O:16][C:17]([CH:20]3[CH2:21][NH:22][CH2:23]3)=[N:18][N:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)o2)CC1
Agent: CCCCCCCS
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CNC3)o2)CC1
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-(N-(9-fluorenylmethoxycarbonyl)azetidin-3-yl)-1,3,4-oxadiazol-2-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester(0.161 g, 0.260 mmol) and heptanethiol (0.398 mL, 2.60 mmol) in THF (2.6 mL) at rt was added DBU (2 drops). The mixture was allowed to stir for 18 h and then the solvent was removed in vacuo. The residue was dissolved in MeOH and purified by preparative HPLC (NH4OAc) to afford the title compound (0.077 g, 74%) as a colorless solid:
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17](=[N:20][C:21]#[N:22])SC)=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].[CH2:23]([CH2:25][NH2:26])[OH:24]>CN(C)C=O>[C:21]([N:20]=[C:17]([NH:26][CH2:25][CH2:23][OH:24])[NH:16][CH2:15][C:12]1[O:11][C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)=[CH:14][CH:13]=1)#[N:22]
Reactant: NCCO
Reactant: CSC(=NC#N)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Solvent: CN(C)C=O
Product: N#CN=C(NCCO)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[5-(3-cyano-2-methyl-1-isothioureido)methylfuran-2-yl]thiazole (1.10 g) and monoethanolamine (1 ml) in N,N-dimethylformamide (10 ml) was stirred at 70° C. for 7 hours. The solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of dioxane, methanol and diisopropyl ether to afford 4-[5-{2-cyano-3-(2-hydroxyethyl)guanidino}methylfuran-2-yl]-2-(diaminomethyleneamino)thiazole (0.80 g).