Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH2:13][NH:12][C:11](=[O:14])[N:10]2[C:15]3[N:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=[C:9]12>C(Cl)Cl>[OH:7][CH:8]1[CH2:13][NH:12][C:11](=[O:14])[N:10]2[C:15]3[N:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=[C:9]12
Reactant: O=C1NCC(OC2CCCCO2)c2cc3cccnc3n21
Solvent: ClCCl
Product: O=C1NCC(O)c2cc3cccnc3n21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 117.2 %

Procedure:
To a solution of 10a (6 g, 21 mmol) in CH2Cl2 (400 ml) 4N aq. HCl (400 ml) was added. After 45 min. stirring at room temperature the two layers were separated. The organic solution was extracted with 4N aq. HCl. The aqueous solution was filtered and evaporated to obtain 6,7,8,9-Tetrahydro-6-hydroxypyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidin-9one (5 g, 100%) as hydrochloride salt as a light orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH2:12][C:11]=2[CH:18]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+]>C(OC(=O)C)(=O)C>[C:22]([N:14]1[CH:15]=[CH:16][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]3[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=3)=[CH:18][C:11]=2[CH2:12][C:13]1=[O:17])(=[O:24])[CH3:23]
Reactant: O=C1Cc2cc(OCc3cccc(F)c3)ccc2C=CN1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C=Cc2ccc(OCc3cccc(F)c3)cc2CC1=O
Temperature: 140 °C
Yield: 77.7 %

Procedure:
In a dried flask under an inert atmosphere, 103 mg (0.36 mmol) of 8-(3-fluoro-benzyloxy)-1,3-dihydro-benzo[d]azepin-2-one and 72 mg (0.9 mmol) of sodium acetate were suspended in 0.3 ml of acetic acid anhydride. The solution was heated to 140° C. for 4 h. For the working-up, the reaction mixture was cooled, then evaporated under reduced pressure. The residue was treated with 1.5 ml of ice/water and 4 ml of ethyl acetate. The aqueous layer was separated and re-extracted with 4 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, thereafter the solvent evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a gradient of heptane to a 4:1-mixture of heptane and ethyl acetate as the eluent. There were obtained 91 mg (77% of theory) of 3-acetyl-8-(3-fluoro-benzyloxy)-1,3-dihydro-benzo[d]azepin-2-one as a light yellow solid; MS: m/e=325 (M)+.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[C:19]([CH2:23]O)[CH:20]=[N:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1>ClCCl>[Cl:3][CH2:23][C:19]1[CH:20]=[N:21][CH:22]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=2)[CH:18]=1
Reactant: OCc1cncc(-c2cccc(Cl)c2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cncc(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
271 mg (0.165 ml, 2.28 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 250 mg (1.14 mmol) [5-(3-Chloro-phenyl)-pyridin-3-yl]-methanol in 20 ml dichloromethane and stirred for 3 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase was extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (248 mg, 84%) used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.[OH-].[Na+].CO>C(O)CCC>[S:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCOC)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1nc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Product: COCCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2-(2-methoxyethyl)-4oxobutanoate (75 mg, 0.21 mmol) in butanol (4 mL), 2-chloro-benzothiazole (43 mg, 0.25 mmol) was added and the reaction mixture was heated at 90° C. overnight. The solvent was removed by rotary evaporation, the residue was redissolved in DMF (1 mL), a solution of 1 N aqueous NaOH (0.63 mL, 0.63 mmol) was added, and the mixture was stirred at rt overnight. A solution of 1 N aqueous HC1 (0.3 mL, 0.3 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2-(2-methoxyethyl)-4-oxobutanoic acid as a white solid (30 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 2H), 7.95 (d, 2H), 7.70 (m, 5H), 7.60 (d, 1H), 7.30 (t, 1H), 7.15 (t, 2H), 3.35 (m, 2H), 3.25 (s, 3H), 3.20 (m, 2H), 2.90 (m, 1H), 1.95-1.75 (m, 2H); LC-MS ret. time 3.29 min (method 2), m/z 461.15 (MH+).
Reaction SMILES: Br[C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:14]C(N)=O.Cl.[OH-].[Na+]>C(O)=O>[NH2:14][C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: NC(N)=O
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CC12CC3CC(C)(C1)CC(N)(C3)C2
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To 100 g of 1-bromo-3,5-dimethyl adamantane and 10 g of urea, adding 60 ml of anhydrous formic acid, heating to 150° C. and hold for 1 hour. Cooling to the room temperature and adding 95 ml of concentrated hydrochloric acid to hydrolyze at 100° C. for 1 hour. Adjusting with 30% sodium hydroxide solution until the solution becomes basic. Extracting with toluene twice, combining the organic layers and washing with water. Concentrating under reduced pressure to yield a limpid yellow solution as 1-amino-3,5-dimethyl adamantane crude. To the crude, adding 150 ml of ethanol and concentrated hydrochloric acid, heating to dissolve and crystallizing to yield white solid. Drying the solid and re-crystallizing with acetone to yield 61.7 g of pure Memantine Hydrochloride. The yield is 69.5% (GC 99.9%).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][CH2:32]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:30][O:31][CH3:32])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1
Reactant: CC(C)(C)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(C)(C)C)c1

Procedure:
Prepared from 480 mg (1.10 mmol) of N-(2-bromo-5-chloro-pyridin-3-yl)-3-tert-butyl-4-chloro-benzenesulfonamide, 400 mg of potassium carbonate and 170 μL (1.57 mmol) of methoxymethyl chloride in 2 mL THF using procedure x. Yield: 160 mg of a white solid. LC-MSD, m/z for C17H19BrCl2N2O3S [M+H]+=480.9, 482.9, 484.9
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.[H-].[Na+].Cl[CH2:26][O:27][CH3:28]>CN(C=O)C>[F:21][C:19]1[CH:18]=[C:15]([CH:14]=[C:13]([C:11]2[CH:10]=[CH:9][C:4]3[N:5]([CH2:26][O:27][CH3:28])[C:6](=[O:8])[O:7][C:2]([CH3:22])([CH3:1])[C:3]=3[CH:12]=2)[CH:20]=1)[C:16]#[N:17]
Reactant: COCCl
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)OC(C)(C)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile (0.150 g, 0.51 mmol) in DMF (5 mL) was treated at rt with sodium hydride (0.061 g, 1.53 mmol). The mixture was stirred for 30 minutes and treated with chloromethyl methylether (0.062 g, 7.7 mmol). Upon completion of the reaction, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3×30 mL), dried over MgSO4, and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 3-fluoro-5-(1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)benzonitrile as a white solid (0.11 g, 65%): mp 169-171° C; 1H-NMR (DMSO-d6) δ8.17 (bs, 1H), 8.03 (dt, 1H, J=10.4, 2.13 Hz), 7.85-7.77 (m, 3H), 7.31 (d, 1H, J=8.49 Hz), 5.33 (s, 2H), 3.35 (s, 3H), 1.7 (s, 6H); MS (APCI) m/z 341 ([M+H]+], 50%); Anal. Calc. For C19H17FN2O3: C, 65.32, H, 5.19, N, 8.02. Found: C, 64.92, H, 4.96, N, 7.73.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2([NH:14][CH:15]=[O:16])[CH2:10][CH:9]([C:11]([OH:13])=O)[CH2:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:29][O:30][NH:31][CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2([NH:14][CH:15]=[O:16])[CH2:8][CH:9]([C:11]([N:31]([O:30][CH3:29])[CH3:32])=[O:13])[CH2:10]2)=[CH:17][CH:18]=1
Reactant: CNOC
Reactant: O=CNC1(Cc2ccc(Cl)cc2)CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CC(Cc2ccc(Cl)cc2)(NC=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A solution of 3-(4-chlorobenzyl)-3-formamidocyclobutanecarboxylic acid (1.3 g, 4.87 mmol), DIPEA (2.17 mL, 12.6 mmol), O,N-dimethylhydroxylamine hydrochloride (617 mg, 6.33 mmol) in dichloromethane (20 mL) was treated with HATU (2.2 g, 5.84 mmol) and stirred at room temperature for 16 h. The solution was diluted with dichloromethane (20 mL), washed successively with 1 M HCl (2×), 5% aqueous NaHCO3 and saturated aqueous sodium chloride, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (gradient 0.5-1.0% methanol in dichloromethane) to give the subject compound (0.5 g, 33.3%). ESI MS found for C15H19ClN2O3 m/z [211.4 (M+1), 233.4 (M+Na+)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:32])[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH2:26][C:27]1[O:31][CH:30]=[CH:29][CH:28]=1)=[O:20]
Reactant: NCc1ccco1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CC#N
Product: O=C(NCc1ccco1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), furfurylamine (0.320 g, 3.29 mmol), and acetonitrile (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred for 2 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-furfuryl-3,4,5,6-tetrahydrophthalamide as light brown crystals (0.860 g, 68.0% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:22])[CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>C(NCC)C.C(Cl)Cl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:22])[CH:15]=[C:16]([C:28]#[C:27][CH2:26][OH:29])[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)cc(F)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)cc(F)c21

Procedure:
A mixture of N-(4-chlorobenzyl)-8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 14 (0.600 g), propargyl alcohol (0.11 mL, 1.90 mmol), CuI (0.048 g, 0.25 mmol), and PdCl2(PPh3)2 (0.178 g, 0.25 mmol) in diethylamine (42.5 mL) and CH2Cl2 (50 mL) are warmed to 65° C. overnight. The reaction mixture is then concentratred in vacuo. Column chromatography (elution with 5-10% MeOH/CH2Cl2) gave the title compound as a solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.C([Si](C)(C)[O:32][C@@H:33]1[CH2:38][CH2:37][C@H:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=2[CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH2:35][CH2:34]1)(C)(C)C>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:26])[C:10]3([CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[CH2:51][C:49](=[O:50])[NH:48][CH:47]3[C:41]3[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=3[O:39][C@H:36]3[CH2:35][CH2:34][C@@H:33]([OH:32])[CH2:38][CH2:37]3)[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(Cl)ccc1O[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2O[C@H]2CC[C@@H](O)CC2)N1

Procedure:
In a manner similar to the method described in example 1e, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 1b (1.52 g, 3.8 mmol) was reacted 1-[2-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (9.8 mmol) in toluene to give racemic(2′R, 3R, 4′S)-6-chloro-2′-[5-chloro-2-(cis-4-hydroxy-cyclohexyloxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.4 g, 18%)
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2]>CO.[Pd].[H][H]>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH2:20][OH:21])[CH:10]=2)[NH2:2]
Reactant: [H][H]
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Agent: [Pd]
Solvent: CO
Product: NC(=O)OCC1c2c(O)cc(CO)cc2N2CC3NC3C1(O)O2
Yield: 74.5 %

Procedure:
A solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (140 mg) in methanol (10 ml) was subjected to catalytic reduction for 120 minutes using 10% palladium on carbon in hydrogen gas under atmospheric pressure at room temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo to give 6,9-dihydroxy-4-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (105 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.CN(C)CCN(C)C.C([Li])CCC.[I:24]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCCCCC.O>[I:24][C:9]1[CH:8]=[N:7][CH:6]=[CH:5][C:4]=1[C:3]([NH:2][CH3:1])=[O:10]
Reactant: II
Reactant: CNC(=O)c1ccncc1
Agent: CN(C)CCN(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CNC(=O)c1ccncc1I
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 1.36 g (10 mmol) N-methyl-isonicotin-amide in 20 ml tetrahydrofuran and 4.5 ml (30 mmol) N,N,N′,N′-tetramethylethylenediamine at −70° C. were added 25 ml (40 mmol) 1.6 M n-butyl lithium solution in hexane. After stirring for 2 h at −10 to 0° C. a solution of 7.6 g iodine in 20 ml tetrahydrofuran was added dropwise at −70° C. Stirring was continued for 1 h at room temperature and 100 ml saturated sodium thiosulfate solution in water were added. The aqueous layer was separated and washed twice with ethyl acetate. The combined organic layers were washed with 1 N sodium hydroxide solution, brine, dried (magnesium sulfate) and evaporated. The residue was purified by chromatography to give 1.035 g (39%) of the title compound as white crystals. M.p. 132-133° C.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[NH:5][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:29](I)([CH3:31])[CH3:30]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH:29]([CH3:31])[CH3:30])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c2nc(Br)n(Cc3c(F)cccc3Cl)c2c1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)n(C)c(=O)c2c1nc(Br)n2Cc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
A solution of 8-bromo-7-(2-chloro-6-fluorobenzyl)-1-methyl-3,7-dihydro-1H-purine-2,6-dione (67 mg, 0.17 mmol) and K2CO3 (239 mg, 1.7 mmol) in 1.7 mL DMF was treated with isopropyl iodide (85 μL, 0.86 mmol). The reaction was stirred at room temperature for 15 hr. The reaction mixture was filtered through a silica plug and rinsed with EtOAc. The solvent was removed under reduced pressure and the crude product was purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with EtOAc:hexane (1:3) to give 46 mg (63% yield) of 8-bromo-7-(2-chloro-6-fluorobenzyl)-3-isopropyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione. A solution of this intermediate (45 mg, 0.11 mmol) in 110 μL aqueous sodium carbonate (2 M), 270 μL toluene, and 45 μL ethanol was treated with 3-chlorophenylboronic acid (18 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium(0) (3.6 mg, 0.0032 mmol), and lithium chloride (catalytic). The reaction mixture was heated to 100° C. in a sealed vial and stirred overnight. The reaction mixture was cooled, filtered through a silica plug, and rinsed with 50% EtOAc:hexanes. The solvent was removed under reduced pressure and the crude product was purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 h64) eluting with ether:hexane (1:1) to give 38 mg (77% yield) of the title compound as a white solid: 1H NMR (CDCl3, 400 MHz) 7.41-7.37 (m, 1H), 7.37-7.22 (m, 3H), 7.13-7.06 (m, 1H), 7.05-7.00 (m, 1H), 6.82-6.74 (m, 1H), 5.86 (s, 2H), 5.25-5.13 (m, 1H), 3.35 (s, 3H), 1.58 (d, 6H, J=7); MS (ESP+) m/e 461 (MH+); TLC (ether:hexanes/1:1) Rf=0.37.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH2:2][CH3:3].[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH2:1][CH2:2][CH3:3])=[O:5])=[N:7]1)=[O:16])[CH2:12][CH3:13]
Reactant: CCCS(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(=O)CCC)n1

Procedure:
A mixture of 4.8 g. 3-propylsulphinyl-1,2,4-triazole, 6.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give an oily residue which crystallized on trituration with petroleum ether (b.p. 60° - 80°C.). The resulting solid product was recrystallized from petroleum ether (b.p. 60° - 80°C.) to give 1-dipropylcarbamoyl-3-propylsulphinyl-1,2,4-triazole, m.p. 50° - 52°C. Elemental analysis satisfactory.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[N:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C@@H:25]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:26].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:26][C@@H:25]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:24])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1
Reactant: C[C@@H](CBr)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1)NC(=O)OCc1ccccc1

Procedure:
6-(4-Benzyloxyphenoxy)pyridin-3-ol (250 mg, 0.85 mmol) and benzyl ((S)-2-bromo-1-methylethyl)carbamate (232 mg, 0.85 mmol) were reacted with sodium hydride in DMF in analogy to example 1a. Yield: 118 mg (29%), M+H+: 485.11.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36](O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C.C(OCC)(=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([O:19][C:18]2[C:13]3[C:12]4[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]=4[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:8])=[O:9])[C:14]=3[CH:15]=[N:16][C:17]=2[C:20]#[N:21])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (200 mg, 0.46 mmol), 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (670 mg, 3.56 mmol) and triphenylphosphine (724 mg, 2.76 mmol) in anhydrous DMF (2 mL) was treated dropwise with diethyl azodicarboxylate (0.53 mL, 3.40 mmol) and the mixture stirred at ambient temperature for 3 h then left to stand overnight. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (3×15 mL), dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 20 g column, Si-SPE, 0-20% methanol in DCM). Collecting appropriate fractions afforded the title compound (160 mg, 57%). 1H NMR (CDCl3, 400 MHz): 9.57 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.46 (d, J=2.3 Hz, 1H), 8.24-8.23 (m, 1H), 8.23-8.21 (m, 1H), 7.71-7.61 (m, 1H), 7.58-7.45 (m, 2H), 5.88-5.83 (m, 1H), 4.36-4.11 (m, 1H), 3.87-3.36 (m, 2H), 2.48-2.26 (m, 2H), 2.13-2.05 (m, 1H), 1.46 (s, 9H). LCMS (Method B): RT=4.51 min, M+H+=598/600.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([NH:16][C:17]([CH2:18][OH:19])([CH3:21])[CH3:20])=[O:5]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C

Procedure:
In a methylene chloride solution containing 0.30 g of Boc-Thz-OH, 0.12 ml of 2-amino-2-methyl-1-propanol and 0.29 g of EDC hydrochloride were added and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 33 (Process 3) to give 190 mg of the title compound.