Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][CH:14]=1.I[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][CH:14]=2)=[CH:24][CH:25]=1
Reactant: Brc1csc2ccccc12
Reactant: COc1ccc(I)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(-c2csc3ccccc23)cc1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
A solution of butyl lithium in hexane (15 ml, 1.6M; 24 mmole) was added to a stirred solution of 3-bromobenzothiophene (5 g, 23.5 mmole) in diethyl ether (70 ml) at -78° C. The mixture was stirred at -75° C. for 30 minutes and then a solution of anhydrous zinc chloride (3.2 g, 23.5 mmoles) in diethyl ether (70 ml) was added. The mixture was maintained at -70° C. for a further 30 minutes and 4-iodoanisole (5.2 g, 22.2 mmole) and tetrakis triphenylphosphine palladium (0) (1.4 g, 1.2 mmole) were then added. The reaction mixture was allowed to warm to room temperature and after one hour 2N hydrochloric acid (50 ml) was added. The organic phase was separated, washed with water (2×50 ml) and dried. The solvent was evaporated and the crude product chromatographed on silica to obtain the desired product (2.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].C(N(CCCC)CCCC)CCC.[C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:47])[CH:45]=[CH2:46].Cl>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(OCC)(=O)C>[C:49]([O:48][C:44](=[O:47])[CH:45]=[CH:46][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21](=[O:22])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:25][CH:26]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: COc1cc(CC(=O)Nc2ccc(I)cc2)ccc1NC(=O)Nc1ccccc1C
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Nc2ccc(C=CC(=O)OC(C)(C)C)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-iodobenzene [4.0 g, Reference Example 9(a)], palladium acetate (50 mg), tri-(o-tolyl)phosphine (125 mg) and tributylamine (1.85 g) in anhydrous dimethylformamide (10 ml) was treated with tert-butyl acrylate (1.0 g). The reaction mixture was stirred at 100° C. under an atmosphere of nitrogen for 4 hours then cooled to room temperature and then poured into a mixture of ethyl acetate (50 ml) and hydrochloric acid (50 ml, 1M). The resultant solid was filtered and washed sequentially with 50 ml portions of saturated aqueous sodium bicarbonate solution, water and diethyl ether. The residue was dried under vacuum to give the title compound (3.6 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:11][C:12]([NH:14][CH2:15][C:16]2[CH:32]=[CH:31][C:19]3[C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:21][O:22][C:18]=3[CH:17]=2)=[O:13])=[N+:5]([O-:10])[C:6](Cl)=[CH:7][CH:8]=1)#[N:2].[F:33][C:34]([F:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:35][NH2:36].C(Cl)Cl.O>CS(C)=O>[C:1]([C:3]1[C:4]([CH2:11][C:12]([NH:14][CH2:15][C:16]2[CH:32]=[CH:31][C:19]3[C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:21][O:22][C:18]=3[CH:17]=2)=[O:13])=[N+:5]([O-:10])[C:6]([NH:36][CH2:35][C:34]([F:43])([F:33])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Nc1noc2cc(CNC(=O)Cc3c(C#N)ccc(Cl)[n+]3[O-])ccc12
Reactant: NCC(F)(F)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1noc2cc(CNC(=O)Cc3c(C#N)ccc(NCC(F)(F)c4ccccn4)[n+]3[O-])ccc12

Procedure:
A mixture of 3-cyano-6-chloro-2-[3-(tert-butoxycarbonyl)amino-benzo[d]isoxazol-6-ylmethyl]aminocarbonylmethyl-pyridine 1-oxide (29 mg) and 2,2-difluoro-2-pyridin-2-yl-ethylamine (20 mg) (Organic Process Research & Development 8:192-200, 2004), in DMSO (0.5 mL) was heated overnight at 80° C. LC/MS (ESI) indicated the mono-Boc product (M+H+ 580.1) as the major component. To the reaction vial was added DCM (10 mL) and water (3 mL). The mixture was vigorously stirred. After removing the aqueous layer, the organic layer was further washed with water (4×3 mL) to remove DMSO and water soluble components. Rotary evaporation of solvent afforded a syrupy residue that was used without purification. LCAMS (ESI) showed the mono-Boc product (M+H+ 580.1) as the major component and the di-Boc product (M+H+ 680.0) as a minor component.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][CH2:5][C@H:6]1[O:10][C:9](C)(C)[O:8][C:7]1=[O:13]>CO>[CH3:1][O:2][CH:3]1[O:10][C@@H:6]([C:7]([O:8][CH3:9])=[O:13])[CH2:5][CH2:4]1
Reactant: COC=CC[C@H]1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)[C@H]1CCC(OC)O1

Procedure:
Methyl (2R)-Tetrahydro-5-methoxy-2-furoate was prepared as for the S-isomer from (R)-5-(3-methoxyallyl)-2,2-dimethyl-1,3-dioxolane-4-one in similar yield: [α]D25 -28.33° (c=0.1, CH3OH); IR (neat, cm-1) 2956, 1754, 1209, 1105; 1H NMR (CDCl3) diastereomer A (66%) δ 5.21 (m, 1H), 4.64-4.52 (m, 1H), 3.77 (s, 3H), 3.38 (s, 3H), 2.42-1.84 (m, 4H) for diastereomer B (33%) 5.08 (m, 1H), 4.64-4.52 (m, 1H), 3.77 (s, 3H), 3.42 (s, 3H), 2.42-1.84 (m, 4H); HRMS calculated for C7H12O4 (M+) 160.0735, found 160.0750.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([S:11]([C:14]1[CH2:18][C:17]([CH3:20])([CH3:19])[O:16][N:15]=1)(=[O:13])=[O:12])=[CH2:10].[OH-].[Na+].[CH:23]([Cl:26])(Cl)[Cl:24]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:24][C:23]1([Cl:26])[CH2:10][C:9]1([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[S:11]([C:14]1[CH2:18][C:17]([CH3:20])([CH3:19])[O:16][N:15]=1)(=[O:13])=[O:12]
Reactant: ClC(Cl)Cl
Reactant: C=C(c1c(F)cccc1F)S(=O)(=O)C1=NOC(C)(C)C1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(S(=O)(=O)C2(c3c(F)cccc3F)CC2(Cl)Cl)=NO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
3-[1-(2,6-Difluoro-phenyl)-ethenesulfonyl]-5,5-dimethyl-4,5-dihydroisoxazole (prepared according to Example P12) (purity 80%) (0.2 g, 0.53 mmol) and a catalytic amount of triethylbenzylammonium chloride were dissolved in chloroform (1 ml). A solution of sodium hydroxide (0.64 g, 16 mmol) in water (1 ml) was added dropwise. After stirring for 1.5 hours at room temperature the mixture was diluted with water and extracted several times with chloroform. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 1.45 of Table 27) as a light brown gum that slowly solidified (74 mg, 36% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1cccc(OC(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 1-(3-Trifluoromethoxyphenyl)ethanone (1.00 g, 4.90 mmol) in THF (5 mL) at 0° C. was added 1M LiAlH4 in THF (5.9 mL, 5.9 mmol), and the solution was allowed to warm to rt. A few drops of water were added to quench. The mixture was concentrated in vacuo, transferred to a separatory funnel, and extracted using DCM and sat. aq. Rochelle salt. The organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: C(N1CCC(C(O)=O)CC1)(OC(C)(C)C)=O.[Cl-].[CH3:18][N:19]([CH3:33])[CH:20]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28](NC)=[CH:27][CH:26]=2)[CH2:21]1.CN(C)C1CCN(C2C=C[C:44]([NH:47][C:48]([CH:50]3[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]3)=[O:49])=CC=2)C1>ClCCl.CN(C1C=CN=CC=1)C.C(N(CC)CC)C.N1C=CC=CC=1>[CH3:33][N:19]([CH3:18])[CH:20]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]([CH2:44][NH:47][C:48]([CH:50]3[CH2:51][CH2:52][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:54][CH2:55]3)=[O:49])=[CH:29][CH:30]=2)[CH2:21]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(C(=O)OC(C)(C)C)CC3)cc2)C1
Reactant: CNc1ccc(N2CCC(N(C)C)C2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN(C)C1CCN(c2ccc(CNC(=O)C3CCN(C(=O)OC(C)(C)C)CC3)cc2)C1
Reaction time: 16 h

Procedure:
A solution of N-Boc-piperidine-4-carboxylic acid (550 mg) and pyridine (0.47 ml) in dichloromethane (15 ml) was mixed with thinoyl chloride (0.21 ml) and, after 30 minutes, a solution of dimethyl[1-(4-methylaminophenyl)pyrrolidin-3-yl]amine (0.5 g), triethylamine (1.17 ml), DMAP (0.44 g) and dichloromethane (10 ml) was added dropwise. After 16 hours, the mixture was diluted with dichloromethane, washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 430.60 (C24H38N4O3); MS (ESI): 431 (M+H+). tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]carbamoyl}piperidin-1-carboxylate can be prepared analogously.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:30]#[N:31])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][N:19]4C(=O)C5C(=CC=CC=5)C4=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.NN>C(O)C>[NH2:19][CH2:18][C:16]1[CH:17]=[C:12]([C:7]2[N:8]([CH3:11])[C:9]3[C:5]([C:6]=2[C:30]#[N:31])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH:13]=[N:14][CH:15]=1
Reactant: Cn1c(-c2cncc(CN3C(=O)c4ccccc4C3=O)c2)c(C#N)c2ccc(Cl)cc21
Agent: NN
Solvent: CCO
Product: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-2-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile (8.96 g, 18.89 mmol) in ethanol (200 mL) is added hydrazine (12.10 mL, 378 mmol) and the reaction mixture is stirred overnight. The mixture is then filtered and the solids are washed with ethyl acetate. The filtrate is partially concentrated to remove ethyl acetate. 1M aqueous HCl is added, and the aqueous mixture is washed with EtOAc. The aqueous layer is then basified with 4M aqueous NaOH and extracted with dichloromethane thrice. The dichloromethane extracts are dried over Na2SO4 and concentrated in vacuo to afford 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile as a solid. MS (ESI) m/z 297.0 (M+H)+
Reaction SMILES: C(N(CC)CCCN1C2C(=C(Cl)C=CC=2)C(N)=N1)C.Br.Br[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[NH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)[NH:34][N:33]=1.Br.BrCCCN(CC)CC.NC1C2C(=CC=CC=2Cl)NN=1>>[N:25]1([CH2:24][CH2:23][CH2:22][N:34]2[C:35]3[C:40](=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[C:32]([NH2:31])=[N:33]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nc1n[nH]c2ccc(Cl)cc12
Reactant: BrCCCN1CCCCC1
Agent: Br
Agent: CCN(CC)CCCBr
Agent: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Product: Nc1nn(CCCN2CCCCC2)c2ccc(Cl)cc12

Procedure:
The same procedures for preparing 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole as described in Example 89 were repeated except that 3-bromopropylpiperidine hydrobromide and 3-amino-5-chloroindazole were employed instead of the 3-bromopropyldiethylamine hydrobromide and the 3-amino-4-chloroindazole, respectively. As a result, 1-(3-piperidinopropyl)-3-amino-5-chloroindazole was obtained.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][CH:48]([CH3:52])[C:49](Cl)=[O:50].O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:49](=[O:50])[CH:48]([CH3:52])[CH3:47])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 4.4 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.190 g, 0.33 mmol) in pyridine (2 mL) was added 2-methylpropanoyl chloride (0.042 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.005 g, 5% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 10.02 (s, 1H), 8.65 (s, 1H), 8.21 (s, 1H), 8.10 (br s, 1H), 7.78 (d, 1H), 7.65 (m, 2H), 7.45 (t, 1H), 2.63 (m, 1H), 1.19 (d, 6H); ES-MS (m/z) 347 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:41][C:5]([O:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:11][CH:12]=1)[C:4]([OH:42])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2ccc3ccccc3c2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Yield: 73.9 %

Procedure:
A solution of 2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (0.161 g, 0.284 mmol) in ethanol (8 mL) is treated with aqueous 5 N NaOH (0.75 mL) and heated to reflux 1 h. The reaction mixture is cooled, the solvent removed in vacuo. The resultant residue is acidified with aqueous 1 N HCl (10 mL) and extracted with CH2Cl2. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to afford 0.113 g (74%) 2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid. 1H NMR. HRMS (ES+) m/z exact mass calc'd for C33H35N2O5 (M+1) 539.2546. Found m/z 539.2548.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.CN(C)C=O.[Br:14][C:15]1[CH:16]=[CH:17][C:18](O)=[N:19][CH:20]=1>O>[Br:14][C:15]1[CH:16]=[CH:17][C:1](=[O:4])[N:19]([CH3:18])[CH:20]=1
Reactant: Oc1ccc(Br)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1cc(Br)ccc1=O
Reaction time: 16 h
Yield: 214.5 %

Procedure:
With cooling with ice, potassium carbonate (5.96 g, 43.1 mmol) and methyl iodide (1.29 mL, 20.7 mmol) were added to a dimethylformamide (50 mL) solution of 5-bromo-2-hydroxypyridine (3.0 g, 7.24 mmol), and stirred at that temperature for 16 hours. Water was added to the reaction mixture, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, ethyl acetate/hexane=1/1) to obtain the entitled compound (2.92 g, 90%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:13])=[O:12])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[S:4][CH:3]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:34](ON1C(=O)CCC1=O)=[O:35]>CN(C)C=O>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([CH:3]2[CH:2]([NH:1][C:34]([C:26]3[NH:25][C:33]4[C:28]([CH:27]=3)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:35])[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:13])=[O:12])[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[S:4]2)=[CH:23][CH:22]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2[nH]1
Reactant: NC(=O)CN1C(=O)C(N)C(c2ccc(Cl)cc2)Sc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)C(c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 65 °C
Reaction time: 13 h
Yield: 63.7 %

Procedure:
In 30 ml of dimethylformamide are dissolved 0.9 g of 3-amino-2-(p-chlorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine- 5-acetamide and 1.2 g of succinimido 2-indolecarboxylate, and the solution is stirred at 65° C. for 13 hours. The reaction mixture is concentrated under reduced pressure and a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate are added to the residue. The mixture is stirred for a while. The resulting crystals are collected by filtration, and the crystals are recrystallized from a mixed solvent of chloroform and methanol to give 0.8 g of 2-(p-chlorophenyl)-3-(2-indolecarboxamido)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, m.p. 275°-290° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:35]3[C:30]([CH3:29])=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: Cc1ncccc1B(O)O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cccnc2C)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and (2-methyl-3-pyridinyl)boronic acid (46 mg, 0.337 mmol). The product was collected as a white solid (68 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (br. s., 1H) 8.57 (br. s., 1H) 8.50 (dd, J=4.93, 1.64 Hz, 1H) 8.43 (s, 1H) 7.90 (s, 1H) 7.73 (dd, J=7.71, 1.64 Hz, 1H) 7.59 (d, J=1.26 Hz, 1H) 7.34 (dd, J=7.33, 4.80 Hz, 1H) 5.90 (s, 1H) 5.10 (quin, J=6.57 Hz, 1H) 4.40 (s, 1H) 4.38 (s, 1H) 2.46 (s, 3H) 2.12 (s, 3H) 1.50-1.58 (m, 2H) 1.50 (s, 3H) 1.48 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=458.3 [M+H]+
Reaction SMILES: [CH3:1][C:2]([O-:4])=[O:3].[CH:5]1[N:9]([CH2:10][O:11][CH:12]([CH2:15]O)[CH2:13][OH:14])[C:8]2[N:17]=[C:18]([NH2:22])[N:19]=[C:20]([OH:21])[C:7]=2[N:6]=1.[CH3:23][CH:24]([C@H:26]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:27]([OH:29])=[O:28])[CH3:25]>C(OC(C)C)(=O)C.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:25][CH:24]([C@H:26]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C:27]([OH:29])=[O:28])[CH3:23].[CH3:1][C:2]([O:4][CH2:15][CH:12]([O:11][CH2:10][N:9]1[C:8]2[NH:17][C:18]([NH2:22])=[N:19][C:20](=[O:21])[C:7]=2[N:6]=[CH:5]1)[CH2:13][OH:14])=[O:3]
Reactant: Nc1nc(O)c2ncn(COC(CO)CO)c2n1
Reactant: CC(=O)[O-]
Agent: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CC(=O)OCC(CO)OCn1cnc2c(=O)nc(N)[nH]c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.0 g of the monoacetate of ganciclovir in 5 ml of isopropyl acetate and 5 ml of dimethylformamide was added 4.1 g of Z-valine-NCA and 0.08 g of 4-dimethylaminopyridine (DMAP). The solution was stirred for 3 hours at room temperature. An additional 0.8 g of Z-valine-NCA was added and stirring was continued for 1 hour. The solution was drowned with 75 ml of isopropyl acetate and stirred for 3 hours. The reaction mixture was then filtered and washed twice with 10 ml each of isopropyl acetate. The product was dried in a vacuum oven at ca. 500 mm of Hg (torr), (nitrogen sweep, 60°) overnight to give 5.6 g of Z-valine-ganciclovir monoacetate.
Reaction SMILES: [I:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18](O)=[O:19].[N:21]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH2:22]1>>[OH:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([CH:28]2[CH2:33][CH2:32][N:31]([C:18]([C:3]3[N:4]([CH3:17])[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:6][C:2]=3[I:1])=[O:19])[CH2:30][CH2:29]2)[CH2:22]1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)O
Reactant: OC1CCCN(C2CCNCC2)C1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC(O)C2)CC1

Procedure:
In analogy to the procedure described for example 2, 5-iodo-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazole-4-carboxylic acid (example 36) was coupled with (rac)-[1,4′]bipiperidinyl-3-ol to give the title compound as off-white solid. MS: 563.2 (MH+).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]3[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=3)[N:26]=2)=[CH:21][C:20]1=[O:38])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C>C(OCC)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=4)[N:26]=3)=[CH:21][C:20]2=[O:38])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: Cn1nccc1Nc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Solvent: CCOC(C)=O
Product: Cn1nccc1Nc1nccc(-c2ccn([C@H](CO)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
Crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (48 mg) was dissolved in ethyl acetate (4 mL) and treated dropwise slowly (over 2 minutes) with an ethyl acetate solution (1.0 mL, which had been saturated with HCl gas). The reaction stirred at room temperature for 15 minutes, after which time LCMS indicated complete consumption of the starting material. The reaction mixture was concentrated to an oily residue and purified by prep RP HPLC to yield (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (20.8 mg, 54.6% yield) as a lyophilized powder. 1H NMR (400 MHz, (CD3)2SO) δ 9.58 (s, 1H), 8.60 (d, J=5.1 Hz, 1H), 7.91 (t, J=9.0 Hz, 1H), 7.58 (t, J=8.1 Hz, 1H), 7.52-7.41 (m, 2H), 7.37 (d, J=1.8 Hz, 1H), 7.14 (dd, J=10.7, 5.1 Hz 2H), 6.86 (dd, J=7.3, 1.8 Hz, 1H), 6.27 (d, J=1.7 Hz, 1H), 5.97 (dd, J=7.7, 5.7 Hz, 1H), 5.31 (t, J=5.2 Hz, 1H), 4.15 (m, 1H), 4.10-3.95 (m, 1H), 3.69 (s, 3H); LCMS m/z 441 (M+H)+.