Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C(=O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1.O[CH2:38][CH2:39][N:40]([CH:73]([CH3:75])[CH3:74])[C:41]([C:43]1[C:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[C:47]([OH:57])[N:46]=[C:45]([CH2:58][C:59]2([N:64]3[C:68]4=[N:69][CH:70]=[CH:71][CH:72]=[C:67]4[CH:66]=[CH:65]3)[CH2:63][CH2:62][CH2:61][CH2:60]2)[N:44]=1)=[O:42]>>[CH2:50]([O:49][C:48]1[C:47](=[O:57])[N:46]=[C:45]([CH2:58][C:59]2([N:64]3[C:68]4=[N:69][CH:70]=[CH:71][CH:72]=[C:67]4[CH:66]=[CH:65]3)[CH2:63][CH2:62][CH2:61][CH2:60]2)[N:44]2[CH2:38][CH2:39][N:40]([CH:73]([CH3:74])[CH3:75])[C:41](=[O:42])[C:43]=12)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O

Procedure:
9-Benzyloxy-2-isopropyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (411) was prepared following the same method as described for 9-benzyloxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (407) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (410) (110 mg, 0.21 mmol) and was obtained as an off-white solid (40 mg, 38%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5](C)=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].[Cl-].[NH4+].[CH3:28]O>C(OCC)(=O)C>[CH3:28][C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3
Reactant: NCCCN1CCCC1=O
Reactant: CO
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: Cc1nnc(NCCCN2CCCC2=O)c2c1cc1ccccn12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine, five equivalents of 1-(3-aminopropyl)pyrrolidinone, and one quivalent of ammonium chloride at reflux under nitrogen for 3 hours gave the title compound as the free base after flash column chromatography (silica gel, methanol:ethyl acetate). This was converted to the hydrochloride salt, mp 257°-258° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][OH:7])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]1([CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][C:41]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:35][CH2:34][CH2:33][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:3]
Reactant: CN(C)CCCO
Reactant: Oc1ccccc1CCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCCOc1ccccc1CCCc1ccccc1
Yield: 35.7 %

Procedure:
134 mg of 3-(N,N-dimethylamino)propanol and 342 mg of triphenyl phosphine were added to a solution of 230 mg of 2-(3-phenylpropyl)phenol (prepared as described in Preparation 29) in 10 ml of methylene chloride, and the mixture was cooled with ice and stirred. 227 mg of diethyl azodicarboxylate were then added dropwise to the solution, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and ethyl acetate and water were added to the residue and shaken. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 115 mg (yield 36%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=3)[S:13][C:6]=12.[BH4-].[Na+]>CO.C1COCC1.Cl[Ni]Cl>[F:1][C:2]1[CH:25]=[C:24]([CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=3)[S:13][C:6]=12)[NH2:26]
Reactant: CC(C)n1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reaction time: 1 h
Yield: 244.1 %

Procedure:
To a solution of the nitro compound 124 (1.47 g, 3.68 mmol) in MeOH/THF (50 ml/50 mL) was added NiCl2×6H2O (1.75 g, 7.37 mmol) and NaBH4 (550 mg, 14.75 mmol). The reaction mixture was allowed to stir for 1 hr then concentrated to dryness and the resultant solid was dissolved in 2 M HCl. The acidic solution was then made basic with aqueous ammonium hydroxide solution and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5, 9:1) to afford title compound 125 (3.31 g, 88% yield) as a pink solid. MS (m/z): 368.1 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:14][C@@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][C@H:15]([OH:16])[CH3:17]
Reactant: C[C@@H]1CO1
Reactant: Fc1ccc2[nH]ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ccc2c(Cl)c(F)ccc21
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A suspension of 0.11 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 4-chloro-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.4 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 30 g of silica gel with toluene-ethyl acetate (33:1). There was obtained 0.5 g (74.5%) of (R)-1-(4-chloro-5-fluoro-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:25])=O)=[N:21][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50].Cl>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:22][N:21]=2)=[O:25])[CH2:52][CH2:53]1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(Nc2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1ccc(Nc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
DIPEA (90 mg, 0.12 mL, 0.7 mmol) was added drop wise to 5-(phenyl-amino)-pyridine-2-carboxylic acid (50 mg, 0.23 mmol) in DMF (5 mL). EDCI (111 mg, 0.58 mmol) and HOBT (37 mg, 0.28 mmol) were added consecutively and, after 10 minutes, 2-amino-1-[4-(2-trifluoromethyl-5-fluoro-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (125 mg, 0.28 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 55 mg (44% yield) of 5-phenylamino-pyridine-2-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 99.28%. 1H-NMR (DMSO-d6): δ 8.9 (s, 1H), 8.5 (t, 1H), 7.9 (m, 2H), 7.6 (d, 3H), 7.4 (t, 2H), 7.2 (d, 2H), 7.0 (t, 1H), 4.2 (d, 2H), 3.6 (m, 5H), 3.2 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[C:25]1([N:31]=[C:32]=[S:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH:31]([C:32]([N:21]1[CH2:20][CH2:19][N:18]([C@H:16]([CH3:17])[C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:23][CH2:22]1)=[S:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: S=C=Nc1ccccc1
Product: C[C@@H](N1CCN(C(=S)Nc2ccccc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 80 %

Procedure:
The title compound was prepared similarly to example 8 starting from same piperazine derivative 2 and phenylisothiocyanate. The product was obtained as a colorless solid in 80% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[N:7]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH:6]=[CH:5]2
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc2c(=O)[nH]ccc2cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 9.17 g (51.8 mmol) of 6-fluoro-7-methyl-2H-isoquinolin-1-one in 80 ml DMF were added 20.2 g (62.1 mmol) caesium carbonate and then 8.92 g (56.9 mmol) 4-methoxybenzylchloride. After stirring at room temperature for 90 minutes the reaction mixture was poured into 600 ml water, stirred for 1 h, and then the precipitated product was filtrated by suction. From the mother liquor additional producted was isolated by chromatography with heptane/ethyl acetate (80:20). The combined products were recrystallized from ethyl acetate and 8.39 g 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one were received.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](Cl)(=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCCc2cccs2)cc1
Yield: 95.2 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with p-anisoyl chloride(74 μL, 0.57 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave 4-methoxy-N-(2-thiophen-2-yl-ethyl)-benzamid (105 mg,0.40 mmol, 95% yield) as a white powder after purification by chromatography on silica gel (eluent: EtOAc/hexane 5/95 to 20/80).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH:27](=O)[CH2:28][CH3:29].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][N:22]([CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:25][CH:26]=1
Reactant: O=C(Nc1ccc2cccc(N3CCNCC3)c2c1)c1ccc(Cl)cc1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1CCN(c2cccc3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1

Procedure:
A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.20 g, 0.547 mmol, the product of Example 12), propionaldehyde (0.041 mL, 0.563 mmol) and sodium cyanoborohydride (0.103 g, 1.64 mmol)in methanol (12 mL) and acetic acid (1.2 mL) was stirred at ambient temperature for 20 hours. The solvent was removed at reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. Phases were separated and the organic layer was washed with brine, dried, concentrated onto silica gel and flash chromatographed (1×3 inches). Elution proceeded as follows: ethyl acetate (50 mL) unweighed forrun; ethyl acetate (250 mL) 0.164 g of yellow foam. The foam was triturated with pentane and 0.079 g (28%) of the title compound was collected as a white solid. mp 130°-132° C. Analysis calculated for C24H26ClN3O: C, 70.66; H, 6.42; N, 10.30. Found: C, 70.91; H, 6.66; N, 10.50.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[CH2:11][O:10][C@H:9]([CH2:12][O:13]C(=O)C)[CH2:8][O:7]1)(=O)C.O1CCOCC1.Cl>CO>[OH:4][CH2:5][C@H:6]1[CH2:11][O:10][C@H:9]([CH2:12][OH:13])[CH2:8][O:7]1
Reactant: CC(=O)OC[C@@H]1CO[C@@H](COC(C)=O)CO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: OC[C@@H]1CO[C@@H](CO)CO1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a stirred suspension of trans-2,5-bis-(acetoxymethyl)-1,4-dioxane (14.5 g, 220 mmol, Preparation #11: Step a) in MeOH (40 mL) was added 4N.dioxane.HCl (20 mL, 220 mmol) and heated to reflux for 1 h. Then reaction mixture was cooled to RT and the solvents were evaporated under reduced pressure. The resulting oily residue was triturated with 10% EtOAc in hexane (3×50 mL) to afford trans-2,5-bis-(hydroxymethyl)-1,4-dioxane 9.0 g (97%) as brown solid; 1H NMR (400 MHz, CDCl3): δ 3.85-3.82 (m, 2H), 3.67-3.52 (m, 10H), 2.05 (bs, 1H); MS: m/z 149.1 (m+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][N:32]3[CH2:33][CH2:34][CH:29]([C:25]4[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=4)[CH2:30][CH2:31]3)=[CH:12][CH:11]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2ccc(C=O)cc2)n1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4nc(C(C)(C)C)cs4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-tert-butyl-1,3-thiazol-2-yl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:52][OH:53])=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[N:37]=[CH:36][C:35]([N:38]5[CH2:51][C:40]6([CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]6)[CH2:39]5)=[CH:34][CH:33]=4)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([N:38]5[CH2:51][C:40]6([CH2:43][NH:42][CH2:41]6)[CH2:39]5)=[CH:36][N:37]=4)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=3)[C:18]=1[CH2:52][OH:53])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC4(CN(C(=O)OC(C)(C)C)C4)C3)cn2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC4(CNC4)C3)cn2)c1=O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 6-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (169 mg, 234 μmol) was combined with DCM (10 ml) and TFA (2 ml) to give a yellow solution. The reaction mixture was stirred at 25° C. for 21 h. conc. in vacuo to afford the title compound as a yellow solid in quantitative yield. (M+H)+=623 m/e.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>ClCCl>[CH2:16]([O:15][C:13](=[O:14])[NH:6][N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH3:17]
Reactant: Nn1cccc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 15 g of sodium bicarbonate and 9.2 g of (N-amino)pyrrole in 50 ml of dichloromethane was treated over a period of fifteen minutes with 11.4 ml of ethyl chloroformate. The reaction mixture was then stirred at ambient temperature for four hours and filtered. The filtrate was washed with water followed by a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Concentration afforded 17 g of N-(1H-pyrrol-1-yl)carbamic acid ethyl ester, m.p. 60°-61° C.; MS(EI)M+ @154(100%); IR(CHCl3)--NH @ 3430 cm1, C=O @ 1755 cm-1.
Reaction SMILES: [ClH:1].Cl.[O:3]=[C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][C@H:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:29]C)[CH:25]=4)[C@H:20]3[CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:17])[CH2:11][CH2:10]2)[C:7]2[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=2[NH:5]1.B(Br)(Br)Br.CO>ClCCl>[ClH:1].[ClH:1].[O:3]=[C:4]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:18][C@H:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([OH:29])[CH:25]=4)[C@H:20]3[CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:17])[CH2:13][CH2:14]2)[C:7]2[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=2[NH:5]1
Reactant: COc1ccc2c(c1)CC[C@H](NC(=O)CN1CCC(n3c(=O)[nH]c4ccccc43)CC1)[C@@H]2Cc1cccnc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)N[C@H]1CCc2cc(O)ccc2[C@H]1Cc1cccnc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of 4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-methoxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide 19 (0.28 g, 0.37 mmol) in dichloromethane (2 mL) was added dropwise to a solution of boron tribromide (1.8 mmol) in dichloromethane (22 mL) at 0° C. After stirring the resultant solution at 0° C. for 1.5 h, methanol (˜2 mL) was added and stirring was continued at 0° C. for an additional 0.5 h. The solvent was evaporated in vacuo, and the residue was purified by reverse phase C18 HPLC using a water/acetonitrile/TFA gradient, 90/10/0.1 to 10/90/0.1, as the eluant. The product was dissolved in methanol and treated with ethanolic hydrochloric acid. The solvent was evaporated and the process repeated twice to give 4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-[cis-1,2,3,4-tetrahydro-6-hydroxy-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide bis-hydrochloride salt 23 (0.148, 68%) as a colorless solid: 1H NMR(DMSO-d6) δ 1.73-2.03 (m, 4 H), 2.70-2.94 (m, 4 H), 3.05-3.20 (br s, 2 H), 3.27-3.47 (m, 3 H), 3.55-3.76 (m, 2 H), 3.92-4.15 (m, 3 H), 4.54-4.67 (m, 1H), 6.46 (d, 1H), 6.58 (s, 2 H), 7.05 (m, s, 3 H), 7.60 (br s, 1 H), 7.94 (t, 1 H), 8.30 (d, 1 H), 8.72-8.83 (m, 2 H), 8.96 (d, 1 H), 9.30 (br s, 1 H), 10.64 (br s, 1 H), and 11.05 (s, 1 H); MS m/e 512 (MH+) (Scheme 36).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-methyl benzenesulfonyl chloride (251 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12e as a solid (275 mg, 82%). HPLC: 99.62% (Rt=9.22 min).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.CC1C2C=C3[C:33]4([C:41]5[C:36](=[CH:37]C=C[CH:40]=5)N[C:34]4=[O:42])COC3=CC=2ON=1.BrCC1CCOCC1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:40][CH:41]4[CH2:36][CH2:37][O:42][CH2:34][CH2:33]4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: Cc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCOCC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)N(CC2CCOCC2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 4-bromomethyltetrahydropyrane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (55%) as a colorless solid: mp 199-201° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 1H), 7.14-7.12 (m, 1H), 7.05-7.00 (m, 2H), 6.91-6.89 (m, 1H), 6.75 (s, 1H), 6.41 (s, 1H), 4.71 (ABq, 2H), 4.12-3.95 (m, 2H), 3.75-3.54 (m, 2H), 3.39-3.28 (m, 2H), 2.19-2.02 (m, 7H), 1.62-1.28 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.9, 159.1, 142.8, 138.5, 132.6, 129.4, 128.7, 125.8, 124.0, 123.7, 123.2, 111.4, 108.5, 79.9, 67.4, 58.0, 46.0, 33.9, 30.8, 20.3, 19.3; MS (ES+) m/z 364.3 (M+1).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:18]([OH:22])[CH:19]([OH:21])[CH3:20].[CH3:23][O:24][CH2:25][CH:26]=O.C1CCCCC1>O>[CH3:23][O:24][CH2:25][CH:26]1[O:21][CH:19]([CH3:20])[CH2:18][O:22]1
Reactant: CC(O)CO
Reactant: COCC=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCCCC1
Solvent: O
Product: COCC1OCC(C)O1
Yield: 93 %

Procedure:
1 g of pyridinium p-toluenesulfonate was added to a mixture consisting of 152 g (2 moles) of 1,2-propanediol, 148 g (2 moles) of 85% strength methoxyacetaldehyde and 400 ml of cyclohexane, and the resulting mixture was refluxed under a water separator until water no longer separated off. The solution obtained was washed with water, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 245 g (93% yield) of 2-methoxymethyl-4-methyl-1,3-dioxolane of boiling point 79°-82° C./70 mbar were obtained.
Reaction SMILES: [OH:1][C@@H:2]([CH2:24][OH:25])[CH2:3][C:4]1[CH:5]=[C:6]([F:23])[C:7]([C:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]=2)=[N:8][CH:9]=1.Cl.C(OCC)C>ClCCl.O1CCOCC1>[F:23][C:6]1[C:7]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)=[N:8][CH:9]=[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:24][OH:25])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncc(C[C@@H](O)CO)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: OC[C@H](O)Cc1cnc(C2=CCNCC2)c(F)c1
Yield: 118.4 %

Procedure:
A solution of 4 (2.30 g, 6.53 mmol) in dichloromethane (10 mL) was stirred with 4 mol/L HCl in dioxane (25 mL) in a closed vessel at room temperature overnight. The resulting suspension was stirred for 1 h with ethyl ether. The solid precipitated was collected by filtration and washed several times with ethyl ether to afford 1.95 g (92%) of 5 as a pale yellow solid (HCl salt). The identity of compound 5 was confirmed by LC/MS and 5 was used directly for the next step.