Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:22]3[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=3)[NH2:17])=[CH:7][N:6]=1)[CH2:10]2
Reactant: Brc1cnc(OC2CN3CCC2CC3)nc1
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2cnc(OC3CN4CCC3CC4)nc2)c1

Procedure:
The product of Example 18A (160 mg, 0.57 mmol) was coupled with 3-aminophenylboronic acid (Lancaster, 157 mg, 1.14 mmol) according to the procedure of Example 1B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3—H2O, 90:10:1, Rf. 0.1) as solid (144 mg, yield, 86%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.62 (m, 1H), 1.65-1.90 (m, 2H), 2.01-2.15 (m, 1H), 2.21-2.29 (m, 1H), 2.74-3.04 (m, 5H), 3.36-3.47 (m, 1H), 5.12-5.20 (m, 1H), 6.75 (ddd, J=8.2, 2.1, 1.0 Hz, 1H), 6.89 (ddd, J=7.4, 1.7, 1.0 Hz, 1H), 6.93 (t, J=1.8 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 8.74 (s, 2H) ppm. MS (DCl/NH3) m/z 297 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C@@H:7]([C@H:9]1[C:15](=[O:16])[N:14]2[C@@H:10]1[C@@H:11]([CH3:26])[C:12]([S:23]([CH3:25])=O)=[C:13]2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:32][C:33]([N:35]1[CH2:39][C@@H](S)[CH2:37][C@H:36]1[CH2:41][O:42][CH2:43][CH2:44][F:45])=[O:34])[CH:30]=[CH2:31].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)C>[CH2:29]([O:32][C:33]([N:35]1[CH2:39][C@@H:25]([S:23][C:12]2[C@H:11]([CH3:26])[C@H:10]3[N:14]([C:15](=[O:16])[C@@H:9]3[C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:28])[CH3:27])[CH3:8])[C:13]=2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:37][C@H:36]1[CH2:41][O:42][CH2:43][CH2:44][F:45])=[O:34])[CH:30]=[CH2:31]
Reactant: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1COCCF
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a mixture of allyl (4R,5S,6S)-6-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (33 mg) and (2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-mercaptopyrrolidine (21 mg) in N,N-dimethylformamide (1.0 ml) was added diisopropylethylamine (10 mg). After stirring for 2 hours at ambient temperature, the solution was diluted with diethyl ether (10 ml) and washed with water, 1N hydrochloric acid, aqueous sodium bicarbonate solution and brine, dried, and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography [ethyl acetate-n-hexane (1:1.5, V/V)] to give allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)pyrrolidin-4-ylthio]-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (21 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:5]2[N:6]=[C:7]([NH:16][NH2:17])[CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:4]2[N:3]=1.C(O)(=O)C.[CH:23]1[CH:28]=[C:27]2[C:29]([CH:32]=O)=[CH:30][NH:31][C:26]2=[CH:25][CH:24]=1>C(O)C>[NH:31]1[C:26]2[C:27](=[CH:28][CH:23]=[CH:24][CH:25]=2)[C:29]([CH:32]=[N:17][NH:16][C:7]2[CH:8]=[C:9]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:4]3[N:3]=[C:2]([CH3:1])[CH:18]=[C:5]3[N:6]=2)=[CH:30]1
Reactant: Cc1cc2nc(NN)cc(N3CCOCC3)n2n1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2nc(NN=Cc3c[nH]c4ccccc34)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
There was dissolved, in ethanol (2 mL), (2-methyl-7-morpholin-4-yl-pyrazolo-[1,5-a]pyrimidin-5-yl)-hydrazine (24.5 mg, 0.0988 mM) and then acetic acid (5.0 μL, 0.087 mM) and indole-3-carboxyaldehyde (15.8 mg, 0.109 mM) were added to the solution and the mixture was stirred at room temperature for 2 hours. This reaction liquid was filtered and then the resulting solid was washed with methanol to thus give the title compound (26.4 mg, yield: 71%).
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.CN(C)C=O.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br.Br[C:26]1[N:27]=[C:28]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:24][C:23]1[CH:22]=[CH:21][C:18]([CH2:19][C:26]2[N:27]=[C:28]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[S:29][C:30]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:17][C:16]=1[F:15]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Br
Reactant: Fc1cc(CBr)ccc1Cl
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(F)c1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
In a 50 ml flame-dried round bottom flask, a suspension of zinc (0.183 g, 0.00280 mol), chlorotrimethylsilane (8.9 uL, 0.000070 mol) and 1,2-dibromoethane (6.0 uL, 0.000070 mol) in N,N-dimethylformamide (2.4 mL, 0.031 mol) was stirred for 15 minutes. To this was added a solution of 3-fluoro-4-chlorobenzylbromide (0.626 g, 0.00280 mol) in N,N-dimethylformamide (4.8 mL, 0.062 mol), and the resulting suspension was stirred overnight at room temperature. To a flame-dried 50 ml round bottom flask containing ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (0.300 g, 0.000934 mol) and bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.000070 mol) was added the organozinc solution from above, and the reaction was heated with stirring at 60° C. for 60 min. Reaction was quenched with saturated ammonium chloride, and then transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM, adsorbed onto silica gel and purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes) to afford ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (245 mg, yield 68.2%).
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([CH2:14][F:15])[C@@H:11]([OH:16])[C@H:10]([O:17]CC2C=CC=CC=2)[CH2:9]1)C1C=CC=CC=1.[ClH:25]>CCO>[ClH:25].[F:15][CH2:14][C@@H:12]1[CH2:13][NH:8][CH2:9][C@@H:10]([OH:17])[C@@H:11]1[OH:16]
Reactant: O[C@@H]1[C@H](CF)CN(Cc2ccccc2)C[C@H]1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: O[C@@H]1[C@H](CF)CNC[C@H]1O
Reaction time: 8 h

Procedure:
To a solution of 7 (7.5 g, 22.8 mmol) in EtOH (150 mL) was added 5N HCl in 2-PrOH (7 mL). The solution was evaporated in vacuo, then co-evaporated 2× more with EtOH. The resulting material was dissolved in EtOH (100 mL) and the resulting solution was hydrogenated overnight with Pd(OH)2 at 50 psi. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with acetone and a pale yellow solid was collected. The resulting solid was recrystallized from EtOH to give the title compound as an off-white solid mp 200-202° C. 1H NMR DMSO d6 consistent with previous spectra.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:35]=[CH:34][C:17]([O:18][CH2:19][C:20]3[N:24]([CH2:25][CH2:26][OH:27])[C:23]4[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:22]=4[N:21]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:40](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:35]=[CH:34][C:17]([O:18][CH2:19][C:20]3[N:24]([CH2:25][CH2:26][O:27][CH3:40])[C:23]4[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:22]=4[N:21]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3nc4cc(C#N)ccc4n3CCO)cc2)C1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COCCn1c(COc2ccc(OC3CCN(C(=O)OC(C)(C)C)C3)cc2)nc2cc(C#N)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-[4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)-phenoxymethyl]-5-cyano-1-(2-hydroxyethyl)benzimidazole (270 mg) in tetrahydrofuran (5 ml) was added 60% sodium hydride (271 mg) at room temperature, and the mixture was stirred for 30 min. Thereto was added methyl iodide (0.105 ml), and the mixture was stirred for 24 hours. After completion of the reaction, 10% aqueous citric acid solution was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=4:1) and dried under reduced pressure to give the title compound (199 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>ClCCl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)=[O:22]
Reactant: Nc1cccc2cccnc12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2cccnc12)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution of 8-aminoquinoline (2.88 g, 20 mmol) in dichloromethane (100 mL) was treated sequentially with triethylamine (3.1 mL, 2.23 g, 22 mmol) and trichloroacetyl chloride (2.5 mL, 4.0 g, 22 mmol). The reaction mixture was allowed to stir at ambient temperature for 16 hours, and the solvent removed under reduced pressure. The residue was taken into ethyl acetate, washed sequentially with water and saturated aqueous ammonium chloride. The isolated organic layers were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give 5.79 g of the title compound (99% yield) which was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 11.18 (br s, 1H, NH), 9.00 (dd, 1H, J=4.4 and 1.7 Hz), 8.53 (m, 2H), 7.89 (d, 1H, 7.1 Hz), 7.73 (m, 2H). MS (ESI) m/e 289 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([N:20]([CH3:30])[C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH:18]3[CH2:17][CH:14]2[CH:15]([N:20]([CH3:30])[C:21]2[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=2)[CH2:16]3)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(c1ncnc2[nH]ccc12)C1CCCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Solvent: CO
Solvent: ClCCl
Product: CN(c1ncnc2[nH]ccc12)C1CC2CC1N(C(=O)CNc1cc(Cl)cc(Cl)c1)C2

Procedure:
A similar procedure was used as describe for the synthesis of 2-(3,5-dichloro-phenylamino)-1-{3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-azepan-1-yl}-ethanone to afford a residue which was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (60 mg 45%) of the titled compound. 1H NMR (DMSO-d6, 400 MHz): 11.70 and 11.62 (2s, 1H), 8.20 and 8.12 (2s, 1H), 7.18-7.06 (m, 1H), 6.64 and 6.58 (2s, 2H), 6.62 and 6.54 (2s, 1H), 6.36-6.24 (m, 2H), 4.68 and 4.62 (2s, 1H), 3.96-3.72 (m, 1H), 3.60-3.52 (m, 2H), 3.18 and 3.16 (2s, 3H), 3.14-3.12 (m, 1H), 2.70-2.64 (m, 1H), 2.14-1.98 (m, 2H), 1.92-1.52 (m, 3H), LC-MS: m/z [M+1]=445.
Reaction SMILES: C(=O)([O:7][CH:8]1[C:12]2[CH:13]=[C:14]([CH:26]=[O:27])[C:15]([N:18]3[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]3)=[C:16]([F:17])[C:11]=2[O:10][NH:9]1)OC(C)(C)C.Cl>CO>[CH3:25][C@H:20]1[O:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:15]2[C:14]([CH:26]=[O:27])=[CH:13][C:12]3[C:8]([OH:7])=[N:9][O:10][C:11]=3[C:16]=2[F:17])[CH2:19]1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(c2F)ONC3OC(=O)OC(C)(C)C)C[C@H](C)O1
Agent: Cl
Solvent: CO
Product: C[C@@H]1CN(c2c(C=O)cc3c(O)noc3c2F)C[C@H](C)O1
Temperature: 75 °C

Procedure:
To a stirred solution of tert-butyl 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-5-formyl-2,3-dihydro-1,2-benzisoxazol-3-yl carbonate (Intermediate 533, 0.5 g, 1.2 mmol) in methanol (5 ml) was added 5 ml of 5% aqueous HCl before heating at 75° C. for 2 hours. The reaction mixture was quenched with 10% aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer were washed with water, dried (sodium sulfate), and concentrated. The residue purified over a silica gel flash column (elution with 50-70% EtOAc in hexanes) to give product.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C@@H:6]1[CH3:18])=[O:4].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:31])=[C:27]([Cl:30])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[Cl:31])[N:23]=[CH:22][N:21]=[C:20]2[NH:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C@@H:6]1[CH3:18])=[O:4]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)CCN1C(=O)CN
Reactant: Clc1cc2ncnc(Cl)c2cc1Cl
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)CCN1C(=O)CNc1ncnc2cc(Cl)c(Cl)cc12

Procedure:
tert-Butyl (2S,3R)-1-(2-(6,7-dichloroquinazolin-4-ylamino)acetyl)-2-methylpyrrolidin-3-ylcarbamate was synthesized from tert-butyl (2S,3R)-1-(2-aminoacetyl)-2-methylpyrrolidin-3-ylcarbamate and 4,6,7-trichloroquinazoline using general procedure M. RP-HPLC (Table 1, Method d) Rt 5.67; m/z: (M+H)+ 454.
Reaction SMILES: [BH4-].[Li+].CO.[H][H].C([O:9][C:10](=O)[C:11]([CH3:30])([CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24])C.Cl.[Cl-].[NH4+]>ClCCl>[CH3:29][C:11]([CH3:30])([CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][OH:24])[CH2:10][OH:9]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCCC(C)(C)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCCCC(O)CCCCC(C)(C)CO
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
Under Ar atmosphere, to a stirred suspension of lithium borohydride (0.30 g, 95%, 13 mmol) in dichloromethane (80 mL) was added dropwise methanol (0.42 g, 13 mmol), keeping a gentle reflux while hydrogen gas was formed. The mixture was stirred for 10 min at 45° C. and a solution of 2,2,13,13-tetramethyl-7-oxo-tetradecanedioic acid 1-ethyl ester (1.57 g, 4.36 mol) in dichloromethane (10 mL) was added dropwise at such a rate as to maintain a gentle reflux. The reaction mixture was heated at reflux for 24 h, then cooled to room temperature and carefully hydrolyzed with 2 N hydrochloric acid (50 mL) and saturated ammonium chloride solution (120 mL). The aqueous layer was extracted with dichloromethane (4×50 mL). The combined organic layers were washed with water (100 mL) and dried over anhydrous magnesium sulfate. The reaction mixture was concentrated to yield the crude product as a yellow oil (1.28 g). Purification by column chromatography on silica gel eluting with hexanes/ethyl acetate (4:1, then 3:1) followed by recrystallization from dichloromethane gave pure 2,2,13,13-tetramethyltetradecane-1,7,14-triol (0.86 g, 65%) as white needles. M.p.: 79-80° C. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 3.57 (br. s, 1H), 3.29 (s, 4H), 2.17 (br. s, 3H), 1.46-1.40 (m, 4H), 1.33-1.24 (m, 12H), 0.85 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 71.8, 71.7, 71.5, 38.7, 37.5, 37.3, 35.1, 30.7, 26.6, 25.7, 24.2, 24.0, 23.9, 23.8. HRMS (LSIMS, gly): Calcd. for C18H39O3 (MH+): 303.2899, found: 303.2897. HPLC: 97% purity.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][NH:7][N:6]=1)=[O:4].N#N.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][NH:7][N:6]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: COC(=O)c1n[nH]cc1N
Temperature: 29 °C
Yield: 98.9 %

Procedure:
A 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10% wet paste, 0.170 Kg, 0.14 wt) under nitrogen. In a separate vessel a slurry of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.210 Kg, 7.07 mol, 1 wt) in ethanol (12.10 L, 10 vol) was warmed to 30 to 35° C. to effect dissolution and the solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 30° C. until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (d6-DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (0.987 Kg, 98.9%).
Reaction SMILES: [CH:1]([N:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH:1]([N:4]1[C:5](=[O:17])[CH:6]=[CH:7][C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:12][CH2:11]2)=[CH:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc(C2CCC(=O)CC2)ccc1=O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CC(C)n1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)ccc1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-isopropyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: C(N=C(NC)NCCSC[C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#N.[OH-].[Na+]>Cl>[NH:15]([C:13]1[S:12][N:11]=[CH:10][N:14]=1)[C:16]([NH2:18])=[NH:17]
Reactant: CNC(=NC#N)NCCSCc1nsc(NC(=N)N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)Nc1ncns1

Procedure:
A mixture of 3-[-2-(2-cyano-3-methylguanidino)ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole (0.2 g.) and 1 N hydrochloric acid (50 ml.) was heated under reflux for 30 minutes, cooled, neutralised with 1 N sodium hydroxide and extracted with ethyl acetate (6×25 ml.). The combined extracts were dried (MgSO4) and evaporated in vacuo to a white solid which was dissolved in ethanol (3 ml.) and added to a solution of oxalic acid (0.071 g.) in ethanol (2 ml.). The precipitated solid was filtered off, washed with ethanol and dried at 50°/0.1 m.m. to give 3-8 2-(2-carbamoyl-3-methylguanidino)ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole. 1.75 oxalate. Found: C, 31.0; H, 4.3; N, 25.7; S, 13.5; C9H17N9OS2. 1.75C2H2O4 requires C, 30.7; H, 4.2; N, 25.8; S, 13.1%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.O.[OH-].[Na+]>CC(N(C)C)=O>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1ccnc2ccccc12
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: c1ccc2c(N3CCNCC3)ccnc2c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 30.7 %

Procedure:
4-Chloroquinoline (25 g, 0.153 mol) and anhydrous piperazine (59.2 g, 0.69 mol) were dissolved in dimethylacetamide (400 ml) and stirred at 130° C. for 4 hours. The mixture was allowed to reach room temperature, water (600 ml) and 2M NaOH (150 ml) were added and the mixture was extracted with dichloromethane (600 ml). The organic phase was dried over magnesium sulfate, the solvent was removed at reduced pressure and the residue crystallized with diisopropylether. The raw product was mixed with a mixture of dichloromethane, diisopropylether and ethyl acetate (1:1:1), and stirred overnight at room temperature. The mixture was filtered, the filtrate evaporated under reduced pressure and the residue crystallized with diisopropylether to yield 10.0 g of off-white crystals (0.047 mol, 31%). NMR (1H, CDCl3, 300 MHz): 8.74 (s, 1H), 8.04 (m, 2H), 7.65 (m, 1H), 7.48 (m, 1H), 6.85 (d, 1H), 3.19 (m, 8H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=1)=[O:7].Cl>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[N:18]=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Reaction time: 15 h
Yield: 61 %

Procedure:
0.5 g (11.92 mmol) of lithium hydroxide monohydrate and 15 cm3 of water are added to a solution at a temperature in the region of 22° C. of 1.1 g (3.64 mmol) of 3-methoxycarbonyl-1-(isoquinol-3-yl)-1H-indole in 15 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), the residue is triturated in water and the resulting suspension is filtered. The solid obtained is suspended in 20 cm3 of water adjusted to pH 7 with N hydrochloric acid. After stirring at a temperature in the region of 22° C. for 1 hour, the solid is filtered off and dried under reduced pressure (2.7 kPa) to give 0.64 g of 3-carboxy-1-(isoquinol-3-yl)-1H-indole in the form of a white solid. IR spectrum (KBr): 1661, 1629, 1593, 1540, 1464, 1217 and 748 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:28])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:10][CH2:9]2)[CH:7]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:28])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(Cl)cc1N1CCN(CCCN)CC1
Temperature: 25 °C

Procedure:
A solution of 2-(3-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)propyl)isoindoline-1,3-dione (397 mg, 1.0 mmol) and hydrazine monohydrate (52 mg, 1.04 mmol) in ethanol (5 mL) was heated at 70° C. for 12 h. After the reaction cooled to room temperature, the solid was filtered off, and filtrate is evaporated to give the title compound, used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45]O>>[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(O)cc21
Reactant: CN(C)CCO
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CN(C)CCOc1ccc2c(c1)C(=O)C(c1cccnc1)=C2c1ccccc1
Yield: 45 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 6-hydroxy-3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 55 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(dimethylamino)ethanol instead of 4-(2-hydroxyethyl)morpholine, and being recrystallized with EtOAc to obtain the title compound (45%).