Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]=O.[N:20]1([CH2:25][C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])[CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:18][NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[C:26]([CH2:25][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH:27]=1
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: O=Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cl
Product: O=c1c2sccc2nc(CNc2cccc(CN3CCCC3)c2)n1-c1ccccc1Cl
Reaction time: 24 h

Procedure:
To a mixture of 3-(2-chloro-phenyl)-4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidine-2-carbaldehyde (0.326 g, 1.13 mmol) and 3-(pyrrolidin-1-yl-methyl)-aniline (0.132 g, 0.75 mmol) in dichloroethane (10 mL) was added sodium triacetoxyborohydride (0.477 g, 2.25 mmol) portionwise. The reaction was stirred for 24 hours, and then carefully poured into saturated aqueous sodium bicarbonate and repeatedly extracted with chloroform. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (12 g, packed in chloroform). After eluting with chloroform (25 mL), elution was continued with 2-5% methanol/chloroform. Fractions containing the product [silica gel tic R,=0.20 (9:1 chloroform/methanol with 1% triethylamine)] were combined and concentrated to afford 0.166 9 (53%) of the free base of the title product as a viscous oil which had: 1H NMR δ 7.84 (d, J=5.5 Hz, 1H), 7.65 (m, 1H), 7.52 (sym m, 2H), 7.40 (d, J=5 Hz, 1H), 7.37 (m, 1H), 7.07 (t, J=8 Hz, 1H), 6.66 (d, J=7.5 Hz, 1H), 6.61 (s, 1H), 6.37 (dd, J=2, 8 Hz, 1H), 5.02 (br t, J=5 Hz, 1H), 3.94 (dd, J=5, 17 Hz, 1H), 3.84 (dd, J=5, 17 Hz, 1H), 3.51 (s, 2H), 2.48 (br s, 4H), 1.75 (br s, 4H). This oil was taken up in ether and treated with 1 N ethereal hydrochloric acid (0.75 mL, 0.75 mmol). The resulting slurry was concentrated and dried to afford 0.115 g (31%) of 3-(2-chloro-phenyl)-2-[(3-pyrrolidin-1-ylmethyl-phenylamino)-methyl]-3H-thieno[3,2-d]pyrimidin-4-one hydrochloride as a tan solid which had: mp 148-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC>C1(C)C=CC=CC=1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:29]=[CH2:30])[CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cn1c(=O)cc(-c2cccc(I)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: C=Cc1cccc(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.8 %

Procedure:
To a solution of 1,4-bis(diphenylphosphine)butane (120 mg, 0.28 mMol) in toluene (15 mL) was added dichlorobis(benzonitrile)palladium(II) (108 mg, 0.28 mMol) under an atmosphere of dry N2. The reaction mixture was stirred at ambient temperature for 45 minutes after which time the solution was diluted with toluene (85 mL). To this solution was added 6-(4-chloro-benzoyl)-4-(3-iodo-phenyl)-1-methyl-1H-quinolin-2-one (14.0 g, 28.0 mMol) and tributyl(vinyl)tin (9.1 mL, 32.9 mMol). The reaction was heated to reflux and stirred at this temperature for 1 hour. The reaction mixture was concentrated under vacuum and chromatographed on flash silica gel eluting DCM until the tin impurities had eluted. The product was eluted off with DCM/MeOH (99:1) to give 9.61 g of the titled compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[C:25]([CH3:28])[NH:26][CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11].Br[CH:30]([CH3:33])[C:31]#[N:32]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[C:25]([CH3:28])[N:26]([CH:30]([C:31]#[N:32])[CH3:33])[CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Reactant: CC(Br)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C(C)C#N
Temperature: 10 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
Sodium hydroxide, 5 M (1.085 mmol, 0.217 ml) and (S)—N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (0.542 mmol, 200 mg) were dissolved in DMF (2 ml). The mixture was cooled to ˜10° C. with an ice bath and 2-bromopropanenitrile (0.813 mmol, 109 mg) was slowly added. The mixture was allowed to warm to RT and it was stirred for 2 h. Solvent was evaporated, DCM was added and the mixture was washed twice with water. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and trituration from diethyl ether. 63 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.04-1.12 (m, 3H), 1.77 (d, 3H), 2.42 (s, 3H), 4.23-4.49 (m, 3H), 5.72 (q, 1H), 6.92-6.97 (m, 1H), 7.79-7.85 (m, 2H), 7.95-8.01 (m, 2H), 8.08-8.11 (m, 1H), 8.15 (d, 1H).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][CH:9](NC)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:15][N:16](CC)CC.[C:21]([O:25][C:26](=[O:49])[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][C:37]2[N:42]=[C:41](SC#N)[C:40]([N+:46]([O-:48])=[O:47])=[CH:39][N:38]=2)[CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>CCO>[C:21]([O:25][C:26](=[O:49])[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:36][C:37]2[N:42]=[C:41]([NH:16][CH2:15][CH:9]3[CH2:8][CH2:7][CH:6]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH2:11][CH2:10]3)[C:40]([N+:46]([O-:48])=[O:47])=[CH:39][N:38]=2)[CH:30]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: CNC1CCC(N2CCCC2)CC1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNc2ncc([N+](=O)[O-])c(SC#N)n2)c1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cccc(CNc2ncc([N+](=O)[O-])c(NCC3CCC(N4CCCC4)CC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.9 %

Procedure:
To a solution of (4-pyrrolidin-1-yl-cyclohexyl)-methylamine(32 mg, 0.18 mmol) and Et3N (26 μL, 0.18 mmol) in EtOH (2 mL) was added {3-[(5-nitro-4-thiocyanato-pyrimidin-2-ylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (74 mg, 0.18 mmol). The reaction mixture was stirred at room temperature overnight before concentrating in vacuo. The residue was purified by chromatography using an ISCO combi-flash cartridge (silica gel, 50:50 to 0:100 DCM/80:18:2 DCM/MeOH/NH4OH) to afford impure [3-({5-nitro-4-[(4-pyrrolidin-1-yl-cyclohexylmethyl)-amino]-pyrimidin-2-ylamino}-methyl)-benzyl]-carbamic acid tert-butyl ester (132 mg), m/z 540 (M+1)+
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:14]=[C:15]([CH2:18][C:19]#[N:20])[S:16][CH:17]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.C(Cl)Cl>[N:1]1([C:11]([C:13]2[CH:14]=[C:15]([C:18]3([C:19]#[N:20])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:16][CH:17]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#CCc1cc(C(=O)N2CCC[C@@H]3CCCC[C@@H]32)cs1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: N#CC1(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CCOCC1
Yield: 32.8 %

Procedure:
cis-[4-(Octahydro-quinoline-1-carbonyl)-thiophen-2-yl]-acetonitrile (0.049 g, 0.17 mmol) and 1-bromo-2-(2-bromo-ethoxy)-ethane (0.04 g, 0.17 mmol) and caesium carbonate (1.0 mmol) in DMSO (2 mL) was stirred for 12 hr at room temperature. The mixture was diluted with water (5 mL) and DCM (5 mL). The organic layer was filtered and then evaporated to give an oil which was purified by HPLC eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.02 g). LCMS m/z 359.24 [M+H]+ RT=10.70 min (Analytical Method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[CH2:37]([NH2:39])[CH3:38].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28]([NH:39][CH2:37][CH3:38])=[O:34]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (200 mg) was dissolved in chloroform (5 ml) and triethylamine (1 ml), and a solution of triphosgene (179 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, ethylamine hydrochloride (246 mg) was added to the reaction solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 159 mg (yield 65%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([NH:23][NH2:24])=[O:22])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:24]/[NH:23][C:21](=[O:22])[C:20]2[CH:25]=[CH:26][CH:27]=[C:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH:19]=2)/[CH3:9])[CH:7]=1
Reactant: NNC(=O)c1cccc(N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 68.6 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (40 mg, 0.234 mmol) and 3-morpholinobenzohydrazide (51.9 mg, 0.234 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (60 mg) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1H, J=2.4 Hz), 7.42-7.32 (m, 4H), 7.20 (m, 1H), 6.94 (d, 1H, J=8.8 Hz), 3.77 (m, 4H), 3.19 (m, 4H), 2.48 (s, 3H). ESI-MS: 374.1 [M+H]+.
Reaction SMILES: [Cl:1]CCC[N:5](C)C(=O)C(C1C=CC(Cl)=CC=1C(=O)C1C=CC=CC=1)=O.[I-].[Na+].N1CCOCC1.Cl.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][N:44]([CH3:64])[C:45](=[O:63])[C:46]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=2[C:55](=O)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=O)[CH2:37][CH2:36]1>CC(CC)=O>[ClH:1].[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][N:44]([CH3:64])[C:45]([C:46]2[NH:5][C:55]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[C:49]3[C:48]=2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50]3)=[O:63])[CH2:37][CH2:36]1
Reactant: CN(CCCN1CCOCC1)C(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CN(CCCCl)C(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCN1
Solvent: CCC(C)=O
Product: CN(CCCN1CCOCC1)C(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
A solution of 7.6 g. of o-benzoyl-p-chlorophenylglyoxylic acid (3-chloropropyl)methylamide in 40 ml. of ethyl methyl ketone is treated with 3.0 g. of sodium iodide and 3.5 g. of morpholine and the mixture is boiled at reflux for 30 hours. After concentration under reduced pressure, the residue is partitioned between water and methylene chloride, the organic phase washed with water, dried over sodium sulfate and concentrated to dryness. The residual oily base is purified on 500 g. of aluminum oxide using methylene chloride/ethyl acetate (4:1) for the elution, dissolved in diethyl ether and treated with excess ethereal hydrochloric acid. The hydrochloride which crystallizes out is recrystallized from isopropanol/diethyl ether, and there is obtained 4.9 g. of o-benzoyl-p-chlorophenylglyoxylic acid [3-(morpholino)propyl] methylamide hydrochloride in the form of light yellow crystals having a melting point of 169°-172° C. (decomposition).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[O:19]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[CH:29]=[N+:30]([CH3:32])[CH3:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:29]([N:30]([CH3:32])[CH3:31])[C:28]2[CH:33]=[CH:34][CH:35]=[C:26]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:27]=2)=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2cccc(Oc3ccccc3)c2)N(C)C)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [CH2:1](OS(C)(=O)=O)[C:2]#[CH:3].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:3]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:2]#[CH:1]
Reactant: C#CCOS(C)(=O)=O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 120.3 %

Procedure:
A mixture of methanesulfonic acid prop-2-ynyl ester (3.44 g, 25.7 mmoles), prepared as described in example 136, morpholine (5.4 g) and Na2CO3 (3.3 g, 30.84 mmoles) in ethanol was stirred at room temperature for 6 hours. The solid was filtered off and the solution was concentrated and poured into water. The mixture was acidified with HCl, extracted with ethyl ether, alkalinised with NaHCO3 and extracted with ethyl acetate. The organic phase was anhydrified over Na2SO4 and dried to give 3.87 g of the title compound which was used as such in the subsequent step.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@@H:5]([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([Cl:58])=[N:11][C:12]=3[NH:16][C@@H:17]2[CH2:21][CH2:20][N:19]([C:22]3[N:30]=[C:29]4[C:25]([N:26]=[CH:27][N:28]4[C@@H:31]4[CH2:35][C@H:34]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[C@@H:33]([OH:41])[C@H:32]4[OH:42])=[C:24]([NH:43][CH2:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:23]=3)[CH2:18]2)[C@H:4]([OH:59])[C@@H:3]1[OH:60].CO.[C:63](Cl)(=[O:66])[CH2:64][CH3:65]>C1COCC1>[Cl:58][C:10]1[N:9]=[C:8]2[C:13]([N:14]=[CH:15][N:7]2[C@@H:5]2[CH2:6][C@H:2]([NH:1][C:63](=[O:66])[CH2:64][CH3:65])[C@@H:3]([OH:60])[C@H:4]2[OH:59])=[C:12]([NH:16][C@@H:17]2[CH2:21][CH2:20][N:19]([C:22]3[N:30]=[C:29]4[C:25]([N:26]=[CH:27][N:28]4[C@@H:31]4[CH2:35][C@H:34]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[C@@H:33]([OH:41])[C@H:32]4[OH:42])=[C:24]([NH:43][CH2:44][CH:45]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:23]=3)[CH2:18]2)[N:11]=1
Reactant: CCC(=O)Cl
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](Nc5nc(Cl)nc6c5ncn6[C@@H]5C[C@H](N)[C@@H](O)[C@H]5O)C4)nc32)[C@H](O)[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](Nc5nc(Cl)nc6c5ncn6[C@@H]5C[C@H](NC(=O)CC)[C@@H](O)[C@H]5O)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{(1S,2R,3S,4R)-4-[2-{(R)-3-[9-((1R,2S,3R,4S)-4-Amino-2,3-dihydroxy-cyclopentyl)-2-chloro-9H-purin-6-ylamino]-pyrrolidin-1-yl}-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (32 mg, 0.038 mmol) and TEA (0.016 mL, 0.113 mmol) are suspended in THF (0.5 mL). MeOH (0.5 mL) is added to aid solubility. Propionic acid chloride (0.0035 mL, 0.040 mmol) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is reduced in vacuo and purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water-0.1% TFA) to yield the title compound (MH+ 894/895).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[O:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH2:1]([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH2:12][C@@H:11]1[CH:31]1[O:32][CH2:33][CH2:34][O:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCO1
Reactant: O=C1C=C[C@@H](COCc2ccccc2)O1
Agent: O=C(c1ccccc1)c1ccccc1
Product: O=C1C[C@H](C2OCCO2)[C@@H](COCc2ccccc2)O1
Temperature: 0 °C
Reaction time: 9 h
Yield: 330.3 %

Procedure:
A solution of furanone (13) (1.2 g, 5.88 mmols) and benzophenone (108 mg, 0.588 mmols) in [1,3]-dioxolane (108 mg) was degassed for 40 min in a stream of argon. The mixture then was irradiated using one 450 watt ACE glass medium pressure mercury lamp, from a distance of 15 cm, for 9 hours. Progress of this reaction was observed via 1H-NMR. As the reaction mixture was degassed, and throughout all of the irradiation time, the reaction flask was held in a water cooled cooling mantel. The temperature of the cooling water was constantly maintained near 0° C. Upon completion of the reaction, solvent was removed under reduced pressure, followed by column chromatography on silica gel (35% EtOAc in hexanes as the eluent), yielding the title compound (1.34 g, 82%) as a clear oil, Rf=0.14 (30% EtOAc in hexanes), [α]25D 16.5° (c 1.2, CHCl3); 1H-NMR (500 MHz, CDCl3) δ: 2.50 (dd, 1H, J=3.9, 12.9 Hz), 2.70-2.79 (m, 2H), 3.58 (dd, 1H, J=3.5, 7.2 Hz), 3.75 (dd, 1H, J=2.8, 7.9 Hz), 3.87-3.92 (m, 2H), 3.97-4.00 (m, 2H), 4.51 (d, 1H, J=11.9 Hz), 4.57-4.61 (m, 2H), 4.88 (d, 1H, J=3.6 Hz), 7.26-7.36 (m, 5H); 13C-NMR (125.8 MHz, CDCl3) δ: 30.39, 40.53, 65.77, 71.74, 73.99, 79.52, 104.14, 128.00, 128.89, 138.07, 176.79.
Reaction SMILES: CC(C)(C)C(O[N:6]1[CH2:11][CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH2:8][CH2:7]1)=O.[C:23]([O-:26])([O-])=[O:24].[K+].[K+].Br[C:30]1[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:33]=[CH:34][C:35]=1[CH3:36]>CN(C=O)C>[C:38]([NH:37][C:32]1[CH:31]=[CH:30][C:35]([CH3:36])=[C:34]([C:9]2[CH2:8][CH2:7][N:6]([C:23]([O:26][C:35]([CH3:36])([CH3:34])[CH3:30])=[O:24])[CH2:11][CH:10]=2)[CH:33]=1)(=[O:42])[CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)(C)C(=O)ON1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 124 %

Procedure:
To a 50-mL RB flask containing 1-[(2,2-dimethylpropanoyl)oxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (500 mg, 1.62 mmol), K2CO3 (670 mg, 4.86 mmol) and PdCl2dppf (155 mg) was added a solution of N-(3-bromo-4-methylphenyl)-2-methylpropanamide (415 mg, 1.62 mmol) in DMF (10.0 mL) at room temperature under argon. The mixture was heated to 80° C. under argon overnight. After cooled to room temperature, the mixture was filtered through celite and the celite was washed with EtOAc (3×20 mL). The filtrates were washed with H2O (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified flash chromatography (20% EtOAc/hexane) to give tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (360 mg, 62.0%)
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CNC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)CNC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51.6 %

Procedure:
tert-Butyl ({3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}amino)acetate (0.27 g, 0.63 mmol) was dissolved in trifluoroacetic acid (1.5 ml), and the mixture was stirred at room temperature for 2.5 hrs. Isopropyl ether was added to the reaction mixture to precipitate crystals, which were collected by filtration and recrystallized from tetrahydrofuran-ethanol to give the titled compound (0.12 g, 49%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[N:3]=1)(=[O:30])=[O:29]
Reactant: Nc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
The compound 21-4 (200 mg) prepared in Step 4 was dissolved in dichloromethane (10 ml) and to the solution were added triethylamine (130 μl) and methanesulfonyl chloride (67 g), followed by stirring at room temperature for 24 hours. The resulting mixture was extracted with water and dichloromethane, dried, concentrated under reduced pressure, and then crystallized (dichloromethane/petroleum ether) to yield the compound 21-5 (260 mg, 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][NH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([OH:6])=O.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:37][CH2:38][CH:39]([F:41])[F:40])=[C:25]([CH:36]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[F:41][CH:39]([F:40])[CH2:38][O:37][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:4](=[O:6])[C:3]2[C:7]([F:19])=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[C:2]=2[Cl:1])=[CH:36][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27]
Reactant: Nc1ccc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)c1
Reactant: CC(C)(C)C(=O)NCc1ccc(F)c(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(F)c(C(=O)Nc2ccc(OCC(F)F)c(C(=O)Nc3ccc(Br)cc3)c2)c1Cl

Procedure:
Prepared analogously to 43b from 2-chloro-3-(tert-butylcarbonylamino-methyl)-6-fluoro-benzoic acid and 5-amino-N-(4-bromo-phenyl)-2-(2,2-difluoro-ethoxy)-benzamide with HATU and TEA in THF.