Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([CH:22]=O)=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[NH3:30]>CCOCC>[C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([C:22]#[N:30])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: CCOCC
Solvent: c1ccccc1
Product: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 24 h

Procedure:
A solution of 4.8 g (0.015 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde [see Example 1 a)] in abs. benzene is saturated with ammonia. After cooling of the solution to 0°, an addition is made portionwise, with a light flow of ammonia gas and in the course of 45 minutes, of 14.0 g (0.030 mole) of lead tetraactetate. The reaction mixture is then stirred for a further 24 hours at 25°; it is subsequently diluted with ether and filtered through kieselguhr. The filtrate is washed with 1N hydrochloric acid, water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is chromatographed through silica gel with the use of ethyl acetate as eluant. The fractions containing the desired nitrile [Rf = 0.63 in the eluant system ethyl acetate/isopropanol (7:1)] are combined, and concentrated by evaporation. The residue is crystallised from ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carbonitrile, M.P. 191°-192°.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][CH:14]=[N:15]N(C)C)=[O:4].C(OC(=O)C)(=O)C.[O:28]=[C:29]1[CH:38]=[CH:37][C:36](=[O:39])[C:35]2[NH:34][C:33](=[O:40])[CH:32]=[CH:31][C:30]1=2>C(#N)C.[Pd]>[OH:40][C:33]1[CH:32]=[CH:31][C:30]2[C:29](=[O:28])[C:38]3[C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[NH:5][C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])=[CH:13][CH:14]=[N:15][C:37]=3[C:36](=[O:39])[C:35]=2[N:34]=1
Reactant: O=C1C=CC(=O)c2[nH]c(=O)ccc21
Reactant: CN(C)N=CC=Cc1ccccc1NC(=O)C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: O=C1c2nc(O)ccc2C(=O)c2c(-c3ccccc3NC(=O)C(F)(F)F)ccnc21
Yield: 16.4 %

Procedure:
1.9 g (6.5 mmol) of 4-(2-trifluoroacetamidophenyl)-1-dimethylamino-1-aza-1,3-butadiene, 2.2 mL of acetic anhydride and 1.6 g of Pd/C (10%) are successively added to a solution of 5,8-dioxocarbostyril (1.04 g, 5.9 mmol) in 500 mL of acetonitrile. The reaction medium is refluxed for 15 hours under nitrogen. After evaporating off the solvent on a rotary evaporator, the crude product obtained is purified by flash chromatography on silica (CH2Cl2 and then 95/5 CH2Cl2/MeOH) to give 400 mg of a yellow powder of compound CRL 8249 (or of its oxo tautomer in position 8).
Reaction SMILES: I[C:2]1[N:14]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[N:31]=[C:30]2[Sn](C)(C)C>CN(C=O)C.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>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[N:31]=[C:30]2[C:2]1[N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=2)(=[O:16])=[O:17])[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Reactant: COc1ccc2c(c1)c([Sn](C)(C)C)nn2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)nn2C
Temperature: 80 °C
Yield: 46.2 %

Procedure:
To a flask was added 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.090 g, 0.20 mmol, Preparation #1), Pd(Ph3P)4 (0.018 g, 0.016 mmol) and 5-methoxy-1-methyl-3-(trimethylstannyl)-1H-indazole (0.071 g, 0.22 mmol) in DMF (3 mL) and the mixture was heated to about 80° C. for about 17 h. The mixture was cooled to rt and then loaded directly on 12 g silica column and eluted with 0 to 100% EtOAc/DCM to provide 7-(5-methoxy-1-methyl-1H-indazol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.045 g, 47%): LC/MS (Table 2, Method c) Rt=1.47 min; MS m/z 487 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([NH2:13])[CH:4]=1.C[N:15](C)C=O.Cl.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33](=N)OCC)[CH2:29][CH2:28]1)=[O:26].[H-].[Na+]>O>[CH3:12][O:11][C:10]1[CH:9]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:13]=[C:33]([N:30]1[CH2:31][CH2:32][N:27]([C:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)=[O:26])[CH2:28][CH2:29]1)[N:8]=[C:7]2[NH2:15]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CN(C)C=O
Reactant: CCOC(=N)N1CCN(C(=O)c2ccco2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.78 g. (0.01 mole) of 4,5-dimethoxy-2-aminobenzonitrile in 30 ml. of N,N-dimethylformamide is added 2.88 g. (0.01 mole) of ethyl 4-(2-furoyl)piperazin-1-ylformimidate hydrochloride, followed by 855 mg. (0.02 mole) of a 56.1% dispersion of sodium hydride in mineral oil. The reaction mixture is stirred at ambient temperature for 30 minutes, and then it is heated to ca. 100° C. and maintained at that temperature for 12 hours. The reaction mixture is cooled to ambient temperature, diluted with an excess of water, and then extracted with chloroform. The chloroform extract is washed several times with water, dried using anhydrous magnesium sulfate, and then evaporated to dryness in vacuo. This affords crude 6,7-dimethoxy-4-amino-2-[4-(2-furoyl)piperazin-1-yl]quinazoline, which is purified further by recrystallization from aqueous ethanol.
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH2:28][O:29][CH3:30])=[CH:22]2)=[O:18].[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH:34]=O.[OH-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH2:34][C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:20]=2)[NH:24][C:23]=1[CH2:28][O:29][CH3:30]
Reactant: COCc1cc2cc(C(=O)OC)ccc2[nH]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCc1[nH]c2ccc(C(=O)OC)cc2c1Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
Trifluoroacetic acid (1.14 g) and triethylsilane (2.33 g) are dissolved in dichloromethane (10 ml), and the resulting solution is cooled at 0° C., to which is dropwise added a solution of 5-methoxycarbonyl-2-(methoxymethyl)indole (1.10 g) and 2,4-dichlorobenzaldehyde (0.96 g) dissolved in dichloromethane (20 ml). The reaction mixture is stirred at 0° C. for 3 hours, and thereafter an aqueous solution of 10% sodium hydroxide (5 ml), chloroform (40 ml) and a saturated saline solution (40 ml) are added thereto in that order for liquid-liquid separation. The organic layer is dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified through silica gel column chromatography (ethyl acetate/hexane=3/7) to obtain 3-(2,4-dichlorobenzyl)-5-methoxycarbonyl-2-(methoxymethyl)indole (161) (0.61 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:21]2[CH2:25][C@H:24]([N:26]3[N:30]=[N:29][C:28]([CH2:31][CH3:32])=[N:27]3)[C@@H:23]([OH:33])[C@H:22]2[OH:34])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=[C:63]3C=2N=[CH:61][N:62]3[C@@H:76]2[CH2:80][C@H:79]([N:81]3[CH:85]=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.CN(C)[C@@H]1CCNC1>>[ClH:20].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([N:81]3[CH2:79][CH2:80][C@@H:76]([N:62]([CH3:61])[CH3:63])[CH2:85]3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:21]2[CH2:25][C@H:24]([N:26]3[N:30]=[N:29][C:28]([CH2:31][CH3:32])=[N:27]3)[C@@H:23]([OH:33])[C@H:22]2[OH:34])=[CH:4][CH:3]=1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Agent: CN(C)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1
Product: Cl

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-2-chloro-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (BF1) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) replacing 1-(2-amino-ethyl)piperidine with (3R)-(+)-3-(dimethylamino)pyrrolidine. MS (ES+) m/e 656 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][CH2:21][CH2:22][CH3:23])(=[O:19])=[O:18].[H-].[Na+].O>CS(C)=O>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([NH:20][CH2:21][CH2:22][CH3:23])(=[O:19])=[O:18])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCCNS(=O)(=O)c1ccccc1N
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (90 μL, 0.70 mmol) and 2-amino-N-propyl-benzenesulfonamide (100 mg, 0.47 mmol), sodium hydride (54.2 mg, 0.56 mmol) in DMSO (1.0 mL) is added and the resulting solution is stirred at 80° C. for 3.0 h. The mixture is poured into water and extracted with ethyl acetate three times. The organic layer is washed with water and then brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford the title compound as a slightly yellow solid.
Reaction SMILES: [P:1](Cl)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[P:1]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2]
Reactant: CCSP(=O)(Cl)OC
Reactant: O=Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCSP(=O)(OC)Oc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of O-methyl S-ethyl chlorothiophosphate (0.03 mole) in methylene chloride (50 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Triethylamine (0.03 mole) is added and the mixture is cooled to a temperature of about 0° C. A solution of 4-hydroxybenzaldehyde (0.03 mole) in methylene chloride (15 ml) is slowly added with stirring while maintaining the temperature of the reaction mixture at about 0° C. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is transferred to a separatory funnel and methylene chloride (100 ml) is added. The resulting solution is then washed with water, dilute aqueous sodium hydroxide and again with water. The washed solution is dried over anhydrous magnesium sulfate, is filtered and stripped of solvent under vacuum to yield the desired product O-methyl S-ethyl O-(4-formylphenyl) thiophosphate.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.C1([Li])C=CC=CC=1.[N+:18]([O-])([O:20]C)=[O:19]>CCOCC>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][N+:18]([O-:20])=[O:19])=[C:4]([CH3:10])[CH:3]=1
Reactant: CO[N+](=O)[O-]
Reactant: Cc1cc(Br)cc(C)c1N
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: Cc1cc(Br)cc(C)c1N[N+](=O)[O-]
Temperature: -10 °C
Yield: 27.6 %

Procedure:
To a cooled (-60° C.) solution of 4-bromo-2,6-di-methylaniline (0.037 mole, 7.4 g) dissolved in anhydrous ether (100 ml) under nitrogen with stirring is added dropwise, phenyl lithium (21.5 ml, 0.040 mole). The solution is stirred for 1.5 hours at -60° C. The solution is allowed to warm to -10° C., then it is cooled to -60° C. The nitrogen flow is stopped while methyl nitrate (0.044 mole, 3.5 g) in anhydrous ether (25 ml) is added dropwise. The solution is stirred for 0.5 hour at -60° C., then it is allowed to warm to room temperature. The solution is stirred for 1.6 hours; the ether layer is evaporated. The solid is dissolved in water (250 ml), then is extracted with ether (2×100 ml). The cold water layer is acidified with 5% HCl. The precipitated product is filtered, washed with water, and dried in vacuo. Recrystallization from hot hexane yields 2.5 g of the desired product melting at 129°-131° C.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[C:20]([C:21]2[N:33]([CH3:34])[C:24]3=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:23]3[N:22]=2)=[CH:19][CH:18]=[C:17]([C:35]([F:38])([F:37])[F:36])[N:16]=1)C.[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:39]([C:15]1[C:20]([C:21]2[N:33]([CH3:34])[C:24]3=[N:25][CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:23]3[N:22]=2)=[CH:19][CH:18]=[C:17]([C:35]([F:37])([F:38])[F:36])[N:16]=1)(=[O:43])=[O:41])[CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1nc(C(F)(F)F)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1nc(C(F)(F)F)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
542 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 416 mg of 2-(2-ethylsulfanyl-6-trifluoromethylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 5 ml of chloroform, and the mixture was stirred at room temperature for 1 hour, then allowed to stand at room temperature overnight. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain 452 mg of 2-(2-ethylsulfonyl-6-trifluoromethylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 5).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1.[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>>[ClH:1].[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26]([C:2]2[N:11]=[C:10]([NH:13][CH:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:25]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(NC3Cc4ccccc4C3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, 2-aminoindan and 3,5-dimethylpyrazole. Mp. 212-215° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:14](O)(=[O:16])[CH3:15].C(OC(=O)C)(=O)C>O>[C:10]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:14](=[O:16])[CH3:15])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])(=[O:12])[CH3:11]
Reactant: CC(=O)O
Reactant: COc1ccc(N)c(O)c1C(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(NC(C)=O)c(O)c1C(C)=O
Temperature: 60 °C

Procedure:
1-(3-Amino-2-hydroxy-6-methoxy-phenyl)ethanone (12.9 g) was added to a mixture of acetic acid (3 mls) and water (20 mls) and heated to 60° C. Acetic anhydride (9.5 mls) was then added and the whole heated on a steam bath for thirty minutes. The reaction mixture was poured into water and extracted into ether, which was dried using magnesium sulphate, and after filtration the volatiles were removed in vacuo, affording a golden brown solid which was triturated with chloroform and dried under reduced pressure, yielding 3.7 g of the sub title compound, mp 160°-162° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6]=[C:7]([CH2:11]Br)[CH2:8][CH2:9][F:10])[CH3:2].[P:17]([O:26]C(C)C)([O:22][CH:23]([CH3:25])[CH3:24])[O:18][CH:19]([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6]=[C:7]([CH2:11][P:17]([O:22][CH:23]([CH3:25])[CH3:24])([O:18][CH:19]([CH3:21])[CH3:20])=[O:26])[CH2:8][CH2:9][F:10])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)CCF)NC=O
Product: CCOC(=O)C(C=C(CCF)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
1.43 g (4.82 mmol) of 4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester and 5.3 ml (19 mmol) of triisopropyl phosphite (96% ) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate. 4-diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@@H:6]([NH2:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Br:14])[CH3:2].[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@H:6]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Br:14])[NH:15][C:20](=[O:21])[CH2:19][C:18](=[O:22])[CH3:17])[CH3:2]
Reactant: C=C1CC(=O)O1
Reactant: CCOC(=O)C[C@@H](N)c1ccc(F)cc1Br
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](NC(=O)CC(C)=O)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A 500 mL round-bottom flask charged with 31D (13.3 g, 41 mmol) in 200 mL of DCM and TEA (22.8 mL, 3 equiv.) was added diketene (31E, 8.81 mL, 50% in DCM). The reaction was stirred at ambient temperature until completion (2 h, determined by LCMS). The reaction mixture was washed with 1 N NaHSO4, brine, dried over Na2SO4 and concentrated in vacuo to afford Compound 31F as a yellow solid (15.3 g, 99%). ESI-MS: m/z 374.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C1C(=O)N([Br:23])C(=O)C1.O>CC#N>[Br:23][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:13])([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.0 g, 9.791 mmol) was dissolved in CH3CN (40 mL), added with NBS (1.92 g, 1.1 eq.), and the mixture was stirred at room temperature for 2.5 hr. The reaction solution was added to water (40 mL), and the precipitated solid was filtered to obtain the title compound (white powder, 2.55 g, 92%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[C:11]1=[O:20].C(OC)(OC)OC.O.[C:29]1(C)[CH:34]=CC(S(O)(=O)=O)=C[CH:30]=1>CC(C)=O>[OH:9][CH2:8][C@@H:5]1[C@H:6]2[O:7][C:29]([CH3:34])([CH3:30])[O:1][C@H:2]2[C@H:3]([N:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[C:11]2=[O:20])[O:4]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1nccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O
Solvent: O
Solvent: CC(C)=O
Solvent: COC(OC)OC
Product: COC(=O)c1nccn([C@@H]2O[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1=O
Yield: 865.6 %

Procedure:
In 5 mL of acetone was suspended 0.50 g of methyl 4-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. Then, 1 ml of trimethyl orthoformate and 33 mg of p-toluenesulfonic acid monohydrate were successively added, the mixture thus obtained was heated under reflux for one hour, and the solvent was removed under reduced pressure. By purifying the residue by column chromatography [eluent: ethyl acetate], 0.49 g of methyl 4-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate was obtained as a white-colored solid product.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:9](/[CH:12]=[C:13](\CC2C=CC=CC=2)/[CH2:14][OH:15])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:32][C:33]([O:35]C)=[O:34]>C(COC)OC>[CH2:3]([C:7]1[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:9]([CH2:12]/[CH:13]=[CH:14]/[O:15][CH:32]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:33]([OH:35])=[O:34])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1ncc(/C=C(/CO)Cc2ccccc2)n1Cc1ccccc1Cl
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCc1ncc(C/C=C/OC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (2.3 mml)in 5 mL of glyme is added portionwise (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2-propenol prepared by the method of Example 18(i) from the methyl ester of the compound of Example 2. After stirring for 30 minutes, methyl bromoacetate (2.2 mmol) is added dropwise The reaction is stirred overnight at room temperature and then the mixture is poured into ice/water. The product is extracted into ethyl acetate (3×). The combined organic extracts are washed with water and brine and dried with anhydrous magnesium sulfate. The solvent is removed in vacuo. The residue is chromatographed on silica gel to give the esters of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](B(O)O)[CH:19]=1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=1>>[F:13][C:14]1[CH:19]=[C:18]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=3)=[N:3][CH:4]=2)[CH:17]=[N:16][CH:15]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1nccc(N)n1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Product: Cc1nccc(Nc2ncc(-c3cncc(F)c3)c3sc(C)nc23)n1

Procedure:
The title compound, MS: m/e=353.2 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 3-fluoro-5-pyridineboronic acid and 4-amino-2-methylpyrimidine.