Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NC[CH2:22][CH2:23][N:24]([CH3:26])C.Cl.CN1CCOCC1.N1CCC1>C(Cl)Cl>[N:24]1([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH3:15])[CH2:23][CH2:22][CH2:26]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC1
Temperature: 0 °C
Yield: 59.8 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)pentanoic acid (17.0 g, 78.25 mmol), which is commercially available, and EDC hydrochloride (18.00 g, 93.90 mmol) was mixed in DCM (300 mL). To the mixture was NMM (20.65 mL, 187.79 mmol) added. The mixture was cooled to 0° C. and azetidine (6.33 mL, 93.90 mmol) was added. The resultant mixture was stirred at 0° C. for 30 min. and at rt over night. The reaction mixture was washed with NaHCO3 (saturated, 2×300 mL) and brine (300 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (gradient; DCM/iso-propanol, 99:1 to 90:10, KP-SIL 340 g column). The solvent was removed under reduced pressure to give the title compound (12.0 g, 60%). 1H NMR (400 MHz, CD3OD) δ 0.92, 1.20-1.76, 2.30, 3.89-4.26, 4.26-4.46, 5.16. LCMS (M+H)+: 257.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B([O-])=O.[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCOc1cc(C=O)ccc1OCc1ccccc1
Agent: O=B[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCCCOc1cc(CO)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 31 g of 4-benzyloxy-3-(3-methoxypropyloxy)-benzaldehyde in 530 ml of ethanol/water=8:2 is added dropwise to a suspension, stirred at 0° C., of 11.74 g of sodium boranate in 530 ml of a mixture of ethanol/water=8:2. The reaction mixture is stirred for one hour at 0° C. and is then concentrated by evaporation. The residue is partitioned between diethyl ether and water. The combined organic phases are dried over sodium sulfate and concentrated by evaporation, and the residue is purified by FC (100 g of silica gel, dichloromethane/diethyl ether=1:1), yielding the title compound: Rf (dichloromethane/diethyl ether=1:1)=0.43.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]4)[C:14]3=[NH:17])=[CH:10][CH:9]=2)[CH2:3]1.C(OC)(OC)OC.CC(O)C.O=[C:38]([CH3:42])[C:39](=[S:41])[NH2:40]>CO.CCCCCCC.CCOC(C)=O>[F:1][C:2]1([F:25])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([C:14]53[NH:40][C:39](=[S:41])[C:38]([CH3:42])=[N:17]5)[CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]4)=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CC(=O)C(N)=S
Reactant: COC1CCC2(CC1)Cc1ccc(OCC3CC(F)(F)C3)cc1C2=N
Solvent: CCCCCCC
Solvent: CC(C)O
Solvent: COC(OC)OC
Product: COC1CCC2(CC1)Cc1ccc(OCC3CC(F)(F)C3)cc1C21N=C(C)C(=S)N1
Temperature: 60 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
HCl (4 M in 1,4-dioxane, 4.13 mL, 16.5 mmol) was added to a solution of N-(5′-((3,3-difluorocyclobutyl)methoxy)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 18, 750 mg, 1.65 mmol) in anhydrous 1,4-dioxane (25 mL). A white precipitate formed immediately and the resulting cloudy mixture was stirred under a nitrogen atmosphere overnight. The mixture was diluted with NaHCO3 (aq.) and extracted with DCM. The organic phase was dried and concentrated, to yield 6′-((3,3-difluorocyclobutyl)methoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (672 mg, 1.92 mmol). The imine, trimethyl orthoformate (0.557 mL, 5.08 mmol) and 2-propanol (5 mL) was placed into a MW tube and the mixture was heated at 60° C. in an oil bath. 2-oxopropanethioamide (Intermediate 1, 397 mg, 3.85 mmol) in MeOH (15 mL) was added and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo. The product was isolated using column chromatography (0-50% EtOAc in heptane) to give 106 mg (12% yield) of the title compound. MS (ES+) m/z 435 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:17]4[CH2:23][N:22]([C:31](=[O:33])[CH3:32])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CNCC3)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-n4ccnc4C)cc3)nc(CC3CCOCC3)c2C1
Yield: 15.3 %

Procedure:
1-(2-(4-(2-Methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (27.0 mg, 15.3%) was synthesised from N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 61a) and acetic anhydride according to the general procedure for N-acetylation. MS (ES+) m/z 447.2 (M+H)+
Reaction SMILES: O.[C:2](OC(=O)C)(=[O:4])[CH3:3].[NH2:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:2]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:4])[CH3:3]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 71 %

Procedure:
In 15 ml of water 8.26 g (50 mmol) of phenylalanine were dissolved. While vigorously stirring this aqueous solution, 10.2 g (100 mmol) of acetic anhydride were added thereto. After the exothermic reaction had been completed, the reaction mixture was further stirred for about 30 minutes and allowed to stand in a refrigerator for about 24 hours. The precipitates thus formed were filtered, washed with water and dried to obtain 7.4 g (yield: 71 %) of N-acetyl-phenylalanine. Then, 1.18 g (5.7 mmol) of this N-acetylphenyl-alanine were dissolved in a solution of 580 mg (5.7 mmol) of triethylamine dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the resulting solution in an ice bath, 690 mg (5.7 mmol) of pivalyl chloride were added thereto and the mixture was stirred for about 2 hours. To the resulting mixture was added a solution of 820 mg (5.7 mmol) of 8-aminoquinoline dissolved in 10 ml of tetrahydrofuran and the mixture was stirred for about 24 hours. After being added with chloroform, the resulting mixture was washed with a saturated sodium bisulfate solution and then with water, and dried over anhydrous sodium sulfate, followed by distillation in vacuo for the removal of the solvent. The residue was then subjected to column chromatography to obtain 890 mg of a product with a yield of 47%. The NMR, IR and MS spectra reveal that this product is 8-(N-acetylphenylalanylamino)quinoline of the formula (I) in which R1 is metyl and R2 is benzyl. The mass analysis shows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:43][CH:44]([F:46])[F:45])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:38][CH2:39][O:40][CH3:41])[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([C:24](=[O:37])[N:25]([CH3:36])[N:26]4C(OC(C)(C)C)=O)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:42])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:43][CH:44]([F:46])[F:45])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:38][CH2:39][O:40][CH3:41])[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([C:24](=[O:37])[N:25]([CH3:36])[NH:26]4)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:42])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: COCCC(C(=O)Nc1ccc2c(=O)n(C)[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
132 mg (0.19 mmol) of tert-butyl 6-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoyl)amino]-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 48 mg (45% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[F:31][C:32]1[CH:37]=[C:36]([CH:38]=[O:39])[CH:35]=[CH:34][C:33]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:33]2[CH:34]=[CH:35][C:36]([CH:38]=[O:39])=[CH:37][C:32]=2[F:31])[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: O=Cc1ccc(B(O)O)c(F)c1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C=O)cc2F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 93.1 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (300 mg, 0.62 mmol) and (2-fluoro-4-formylphenyl)boronic acid (158 mg, 0.94 mmol) in dioxane (3 mL), aqueous 2M Na2CO3 solution (1.13 mL, 2.26 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (300 mg, 91%).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)=O)=[CH:30][C:25]=2[O:24][CH2:23]1.O>C1COCC1>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)=[CH:9][C:10]#[N:11])=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cccc(C(=O)c2ccc3c(c2)OCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=CC#N)c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (2.1 mL, 13.6 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 13.6 mL, 13.6 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of benzo[1,3]dioxol-5-yl-(3-methoxy-phenyl)-methanone (1.74 g crude, 6.8 mmol) in THF (15 mL) and refluxed for one hour. The reaction mixture was poured into water (50 mL), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-benzo[1,3]dioxol-5-yl-3-(3-methoxy-phenyl)-acrylonitrile as an oil (0.87 g, 46% yield): 1H NMR (DMSO-d6) δ 3.77 and 3.78 (2s, 3H, OCH3), 6.10 and 6.13 (2s, 2H, CH2), 6.23 and 6.27 (2s, 1H, CH), 6.69-7.46 (m, 7H, Ar); 13C NMR (DMSO-d6) δ 55.2, 55.2, 94.4, 95.6, 101.6, 101.8, 107.4, 108.2, 108.3, 109.3, 113.7, 114.6, 115.0, 118.2, 120.9, 121.2, 123.7, 123.8, 129.7, 129.8, 130.6, 131.6, 138.6, 139.6, 147.3, 147.9, 148.5, 149.4, 159.1, 159.2, 160.9, 161.1. LC/MS showed desired peak at 280 for (M+1)+1 positive ion mass.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(O)(=O)C>[C:31]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)(=[O:33])[CH3:32]
Reactant: NCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 31 from (Z)-3-{1-[4-(2-aminoethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone and acetic anhydride in glacial acetic acid.
Reaction SMILES: [ClH:1].C(OC(=O)[N:8]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][C:24]=2[CH:25]=[CH:26][CH:27]=1)(=[O:17])=[O:16])(C)(C)C>C(OCC)C.C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[Br:34][C:31]1[CH:30]=[CH:29][C:28]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(CCNCCNS(=O)(=O)c1cccc2cnccc12)c1ccc(Br)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(=O)(NCCNCCNc1ccc(Br)cc1)c1cccc2cnccc12
Reaction time: 4 h
Yield: 89 %

Procedure:
A 1N HCl in diethyl ether solution (3 mL) is added to a stirred solution of (4-bromo-phenyl)-{2-[2-(isoquinoline-5-sulfonylamino)-ethylamino]-ethyl}-carbamic acid tert-butyl ester (138 mg, 0.251 mmol) in methylene chloride (3 mL). The mixture is allowed to stir for 4 hours to form a suspension. After concentration, methylene chloride (3 mL) is added to the solid. The suspension is sonicated and filtered to give 124 mg (89% yield) of the title compound as a solid. ESIMS: m/z 449 [(M+H)+, 79Br], 451 [(M+H)+, 81Br].
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[OH:5].[I-:13].[Na+]>>[Cl:12][C:8]1[CH:7]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][I:13])[CH:11]=[CH:10][CH:9]=1
Reactant: OC(CCCl)c1cccc(Cl)c1
Reactant: [I-]
Agent: [Na+]
Product: OC(CCI)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To 3-chloro-1-(3-chlorophenyl)propan-1-ol (2.85 g, 13.90 mmol) was added sodium iodide (2.66 M in dry acetone) (21 mL, 55.9 mmol) and the mixture was placed under nitrogen and brought to reflux for overnight. After overnight stirring, the solvent was removed under reduced pressure. The residue was taken up in Et2O and water and the phases separated. The organic layer was washed further with water and brine. The organic layer was then dried (Na2SO4), filtered and evaporated to give the desired product as colorless oil (3.9 g, 94%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:9]=2[N:10]=1.[H][H]>C(O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[NH:7][C:8]=2[CH:14]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccco3)[nH]c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2nc(-c3ccco3)[nH]c2c1

Procedure:
A solution of 2-(2-furyl)-5-nitrobenzimidazole (52 g, 0.2 mole) in 1 liter of absolute ethyl alcohol is reduced (Parr apparatus) using 5 percent palladium on carbon (50 percent wet) catalyst. An uptake of 44 lbs. (100 percent of theory) of hydrogen in one-half hr is noted. After the reduction is complete the catalyst is removed by filtration. The filtrate is used in part D.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Cl:9][C:10]1[N:11]=[C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[CH3:29])[C:13]2[CH2:18][S:17](=[O:20])(=[O:19])[C:16]([CH3:22])([CH3:21])[C:14]=2[N:15]=1.CI>C1COCC1>[Cl:9][C:10]1[N:11]=[C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[CH3:29])[C:13]2[CH:18]([CH3:2])[S:17](=[O:19])(=[O:20])[C:16]([CH3:21])([CH3:22])[C:14]=2[N:15]=1
Reactant: CC(C)[N-]C(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CS(=O)(=O)C2(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1c2c(N3CCOC[C@@H]3C)nc(Cl)nc2C(C)(C)S1(=O)=O
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
LDA (2.5 mL, 5 mmol) was added dropwise to a solution of (S)-2-chloro-7,7-dimethyl-4-(3-methylmorpholino)-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (Step vi, 1.5 g, 4.5 mmol) in THF (30 mL) at −78° C. The mixture was stirred at this temperature for 0.5 h, MeI (0.7 g, 5 mmol) in THF (5 mL) was added dropwise to the above mixture. The resulted mixture was stirred at room temperature for 2 h. Then the mixture was poured into sat.NH4Cl, extracted with EtOAc (3×30 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to give 2-chloro-5,7,7-trimethyl-4-((S)-3-methylmorpholino)-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (1.2 g, yield 77%) as a yellow solid. 1H NMR (400 MHz, CDCl3) 1.38-4.31 (m, 1H), 4.29-4.21 (m, 1H), 3.99-3.96 (m, 1H), 3.78-3.43 (m, 5H), 1.65-1.25 (m, 12H).
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)[CH3:9]
Reactant: CCN
Reactant: O=Cc1cncs1
Solvent: C1CCOC1
Product: CCNCc1cncs1

Procedure:
prepared by reaction of the commercially available thiazole-5-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]5[N:29]=[C:28]([NH:30]C(=O)OC)[NH:27][C:26]=5[CH:35]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.[OH-].[K+].Cl.C(OCC)(=O)C>CO>[F:1][CH2:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]5[N:29]=[C:28]([NH2:30])[NH:27][C:26]=5[CH:35]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[O:10])[CH2:7][CH2:8]1
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCC(CF)CC3)CCO4)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCC(CF)CC3)CCO4)cc2[nH]1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of methyl [6-(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate (example 8) (181 mg, 0.38 mmol, in methanol (6 mL) was added a 2 M aqueous solution of potassium hydroxide (6 mL), and the resulting mixture was stirred at 65° C. overnight. The pH was adjusted to 9 with 1 N aqueous hydrochloric acid, ethyl acetate was added (50 mL), and the organic layer was washed with brine (2×25 mL), dried over sodium sulfate, filtered and concentrated. Purification by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided the title compound as the acetate salt (56 mg, 31% yield) as a colorless solid. 1H NMR (400 MHz, methanol-d4): 7.47 (m, 1H), 7.43 (m, 2H), 7.30 (m, 2H), 7.02 (d, 1H), 4.48 (s, 2H), 4.29 (dd, 2H), 4.19 (m, 2H), 3.71 (m, 4H), 2.85 (m, 2H), 1.95 (s, 3H), 1.87 (m, 1H), 1.72 (m, 2H), 1.36 (m, 2H); MS (EI) for C23H26FN5O2: 424 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]3[CH:13]=[C:12]([C:14](OCC)=[O:15])[N:11]=[C:9]3[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][C:2]1[C:7]2[N:8]3[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[C:9]3[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c(n1)sc1cccc(C)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cccc2sc3nc(CO)cn3c12
Yield: 68.7 %

Procedure:
5-methyl imidazo[2,1-b]-benzthiazole-2-methanol was prepared according to the procedure outlined in Example 1, (Step 2). Starting from ethyl 5-methylimidazo[2,1-b]-benzthiazole-2-carboxylate (5.2 g, 20 mmol) and LiAlH4 solution (22 ml, 0.5 M solution in THF), 3 g (69% yield) of the alcohol derivative was isolated as a brown solid. (M+H) 219.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[CH2:15][O:14]1>C(O)C.[Pt]=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[CH2:15][O:14]1
Reactant: CC1(C)CON(Cc2cc([N+](=O)[O-])c(F)cc2Cl)C1=O
Agent: O=[Pt]
Solvent: CCO
Product: CC1(C)CON(Cc2cc(N)c(F)cc2Cl)C1=O

Procedure:
By the method of Example 3, Step C, 16.0 g (0.052 mole) of 2-[(2-chloro-4-fluoro-5-nitrophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone was hydrogenated in the presence of 0.2 g of platinum oxide in 250 ml of ethanol, yielding 2-[(2-chloro-4-fluoro-5-aminophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH2:9]([OH:12])[CH:10]=[CH2:11].C([O-])(O)=O.[Na+].O>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:11]=[CH:10][CH:9]=[O:12]
Reactant: Clc1ccccc1I
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=CC=Cc1ccccc1Cl
Temperature: 30 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
A mixture of 2.2 mL (18 mmol) of 2-chloroiodobenzene, 1.8 mL (27 mmol) of allyl alcohol, 81 mg (0.36 mmol) of Pd(OAc)2, 5.3 g (18 mmol) of Bu4NCl, and 3.8 g (45 mmol) of NaHCO3 in 50 mL of DMF is stirred under Ar2 at 30° C. for 24 h. Water is added and the mixture is extracted with EtOAc. The extract is washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (0-50% EtOAc in hexanes) provides 2.2 g (74%) of 3-(2-chlorophenyl)propenal.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15](=[O:18])[CH2:16][CH3:17])[C:5](=[O:14])[O:6][C:7]=1[CH:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12].[Na].C([O-])(O)=O.[Na+]>ClCCl.N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([C:15](=[O:18])[CH2:16][CH3:17])[C:5](=[O:14])[O:6][C:7]=1[CH:8]([CH3:13])[CH2:9][CH2:10][CH:11]=[O:12]
Reactant: CCC(=O)c1cc(O)c(C(C)CCCO)oc1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)c1cc(O)c(C(C)CCC=O)oc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(5-Hydroxy-2-oxo-3-propionyl-2-H-pyran-6-yl)pentanol (V; 0.38 g; 1.5 mmol; Aldrich) was dissolved in 20 ml dichloromethane and 0.6 ml pyridine. Sodium periodinate (0.7 g; 1.65 mmol; Aldrich) was added and stirred for 2 h at 25° C., after which reaction mixture was neutralized with saturated NaHCO3 and extracted with 3×20 ml CH2Cl2. The pooled organic extracts were dried with anhydrous Na2SO4, evaporated, and purified via silica chromatography (20% EtOAc in hexanes).
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[OH-].[Na+]>[ClH:1].[C:23]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:11]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 88.1 %

Procedure:
A mixture of 3.22 g of ethyl 4-(diphenylmethoxy)-1-piperidinepropionate hydrochloride in 30 ml of methanol and 12.0 ml of 2N sodium hydroxide aqueous solution was refluxed for 1 hour and concentrated. Water was added to the residue and made acidic with hydrochloric acid. The precipitate was collected by filtration and recrystallized from water to give 2.64 g of colorless needles, mp 183°~185° C.