Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:41]=[CH:40][C:33]4[O:34][C:35]([CH3:39])(C)[O:36][CH2:37][C:32]=4[CH:31]=3)[OH:29])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=[O:44]>O>[C:35]([O:34][C:33]1[CH:40]=[CH:41][C:30]([C@@H:28]([OH:29])[CH2:27][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:7])=[O:8])[CH:10]=2)=[CH:31][C:32]=1[CH2:37][OH:44])(=[O:36])[CH3:39]
Reactant: CC(=O)O
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(=O)(=O)C4CCCC4)c3)ccc2O1
Solvent: O
Product: CC(=O)Oc1ccc([C@@H](O)CNCCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)cc1CO

Procedure:
A stirred solution of (1R)-2-[(6-{4-[3-(Cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (110 mg) in glacial AcOH (5 ml) and water (0.3 ml) was heated at 85° C. for 40 min. The solution was evaporated to dryness and the residue was purified by Biotage™ column chromatography on silica using DCM-EtOH-ammonia (50:8:1) as eluent. The residue was dissolved in MeOH, treated with glacial AcOH and the solvent was removed to give the title compound (76 mg). LCMS RT=2.6 min ES+ve 548
Reaction SMILES: [C:1](=[S:3])=[S:2].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([NH:22][NH2:23])=N>CO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[S:2][C:1](=[S:3])[NH:23][N:22]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=N)NN)c1Cl
Reactant: S=C=S
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2n[nH]c(=S)s2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
Carbon disulfide (100 μl, 1.58 mmol) is added dropwise to a room temperature solution of 2-[(2,6-dichloro-3-methylphenyl)amino]benzene carboximidic acid hydrazide (183.4 mg, 0.595 mmol) in 5 ml of methanol. The solution is stirred under a nitrogen atmosphere at room temperature for two hours and then concentrated. The residue is purified by chromatography eluting with ethyl acetate:hexane (1:4) to give 107.0 mg (49%) of a yellow solid, mp 250°-252° C. with decomposition.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[C:6]1[CH:45]=[CH:44][C:9]([CH2:10][N:11]([CH2:25][C:26]2[CH:43]=[CH:42][C:29]3[N:30]([CH2:40][CH3:41])[C:31](=[O:39])[C:32]([CH3:38])([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:28]=3[CH:27]=2)[CH2:12][CH2:13][N:14]2[CH:19]=[CH:18][C:17]3[O:20][C:21]([CH3:23])=[CH:22][C:16]=3[C:15]2=[O:24])=[CH:8][CH:7]=1)C.[OH-].[Na+]>C1COCC1>[CH2:40]([N:30]1[C:31](=[O:39])[C:32]([CH3:38])([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:28]2[CH:27]=[C:26]([CH2:25][N:11]([CH2:10][C:9]3[CH:44]=[CH:45][C:6]([CH:5]=[O:4])=[CH:7][CH:8]=3)[CH2:12][CH2:13][N:14]3[CH:19]=[CH:18][C:17]4[O:20][C:21]([CH3:23])=[CH:22][C:16]=4[C:15]3=[O:24])[CH:43]=[CH:42][C:29]1=2)[CH3:41]
Reactant: CCOC(OCC)c1ccc(CN(CCn2ccc3oc(C)cc3c2=O)Cc2ccc3c(c2)N(C)C(=O)C(C)(C)C(=O)N3CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccc(C=O)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A 2N-hydrochloric acid (5 ml) was added to an THF solution (5 ml) of 7-({N-(4-diethoxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.52 g), and the mixture was stirred at room temperature for 1 hour. 2N-Sodium hydroxide solution (5 ml) was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. The residue was recrystallized from ethyl acetate and ether, and dried to give the title compound (0.35 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15]C)=[O:14].C[O-].[Na+].CO.Cl>O>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[S:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1sc(-c2ccncc2)cc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc(-c2ccncc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of methyl 3-amino-5-(pyridin-4-yl)thiophene-2-carboxylate (2.34 g, 10 mmol), sodium methoxide (1.62 g, 30 mmol), methanol (40 mL) and water (10 mL) was refluxed for 4 h. The mixture was allowed to cool to room temperature and stirring was continued overnight. The mixture was cooled under ice-bath, then conc. HCl (2.48 mL, 30 mmol) was added (pH was approx. 4). The resultant yellow precipitate was collected by filtration and washed with water and methanol to afford the title compound (2.02 g, 92%) as a yellow solid:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[O:23][CH3:24].[CH2:25](N1CCCCC1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)[C:7]=2[O:23][CH3:24])[CH2:8][CH2:7]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CN2CCCCC2)cc1
Reactant: COc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Product: COc1c(SCCCN2CCC(Cc3ccccc3)CC2)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
According to the procedure indicated in Example 1), reaction of 2-{[[4-(3-chloropropylthio)-3-methoxy-2-pyridinyl]methyl]thio}-1H-benzimidazole with N-benzylpiperidine gives the title compound; beige powder; m.p. 73-75° C. (hydrated).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=C)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:14]=[O+][O-].CSC>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[O+][O-]
Reactant: C=Cc1cccc(Cl)c1C(=O)OC
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1c(Cl)cccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Into a solution of methyl 2-chloro-6-vinylbenzoate (6.7 g, 34 mmol) in dry DCM (100 mL) was bubbled O3 at −78° C. over a 30 minute period. Next, nitrogen gas was bubbled into the solution until the solution was colorless. Dimethylsulfane (4.3 g, 68 mmol) was added dropwise and the resulting mixture was warmed to RT and stirred for 2 hours. The reaction mixture was subsequently washed with water (30 mL) and extracted with DCM (3×100 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0-90%) and PE to give the title compound (3.8 g, 56%). 1H NMR (400 MHz, CDCl3) δ ppm 9.89 (s, 1H), 7.728 (d, J=7.2 Hz, 1H), 7.606 (d, J=8.0 Hz, 1H), 7.489 (t, J=8.0 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[NH:4][C:3]1=[O:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:1][N:2]2[C:6](=[O:7])[C:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[NH:4][C:3]2=[O:12])=[O:22])=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CCC1(CC)NC(=O)N(N)C1=O
Solvent: Cc1ccccc1
Product: CCC1(CC)NC(=O)N(NC(=O)Nc2ccc(Br)cc2)C1=O
Temperature: 100 °C

Procedure:
A mixture of 3-amino-5,5-diethylimidazolidine-2,4-dione CAS 1007-61-0 (70 mg, 0.4 mmol), 4-bromophenylisocyanate CAS 2493-02-9 (80 mg, 0.4 mmol) in toluene (5 mL) was heated at 100° C. for 8 h. Upon cooling the reaction to ambient temperature, Compound 1 separated as a white solid, which was collected by filtration and dried under high vacuum.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Br:11][C:12]1[C:13]([NH2:21])=[C:14]([NH2:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18].C>[OH-].[Na+]>[Br:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]2[C:13]=1[NH:21][C:2](=[O:4])[C:1](=[O:8])[NH:20]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(F)c(F)c(Br)c1N
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2cc(F)c(F)c(Br)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.70 g, 18.5 mmol) and 3-bromo-4,5-difluoro-1,2-diaminobenzene (410 mg, 1.85 mmol) was heated to reflux under N2 for 15 h. The reaction was allowed to cool to room temperature and the dark-brown solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 215 mg (42%). A portion of this solid (150 mg) was taken and dissolved in 20 mL 1N NaOH with heating. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 1N HCl (pH=1). Pale yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 20 mL of H2O and dried under vacuum (0.1 torr, 78° C.) to yield 67.8 mg of powdery pale yellow crystals, mp 306°-310° C. (dec). 1H NMR (d6 -DMSO) δ 7.09 (dd, 1H, J=7.5, H-8), 11.3 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/z 278 (M+2, 75), 276 (M+, 77), 250 (56), 248 (57), 14 1 (bp). EIHRMS calc. for C8H4BrF2N2O2 275.9346, found 275.9331.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]([OH:7])=O.[CH3:29][NH:30][CH2:31][CH2:32][OH:33]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([N:30]([CH2:31][CH2:32][OH:33])[CH3:29])=[O:7]
Reactant: CNCCO
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: CN(CCO)C(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (98 mg, 0.251 mmol) and 2-(methylamino)ethanol (24 μl, 0.301 mmol). MS (ESI) m/z: Calculated: 447.1; Observed: 448.1 (M++1).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH3:7][C:8]([CH3:10])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCC)C>ClCCl>[CH3:7][C:8]1([CH3:10])[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1
Reactant: CC(O)CCS
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCNCC
Product: CC1CCSC(C)(C)O1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 3.2 grams (0.055 moles) of acetone is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with diethyl amine to a pH of about 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 7.2 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[OH-:24].[Na+].[Cl-].[NH4+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](=[O:24])[NH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Reactant: [OH-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1noc2c1-c1cc[nH]c(=O)c1C(c1ccc(Cl)cc1)=NC2
Temperature: 110 °C
Yield: 87.1 %

Procedure:
To a solution of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine from Example 19 (0.244 g, 0.744 mmol) in 1,4-dioxane (5 mL) was added an aqueous solution of sodium hydroxide (1M) (5.00 mL, 5.00 mmol) at room temperature. The reaction was heated to 110° C. for 90 min, then cooled to room temperature before a saturated solution of ammonium chloride was added. The product was extracted with CH2Cl2 (repeated 4 times), and the organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The product was purified twice by flash chromatography (hexane/EtOAc 8:2 to 1:9) to give 6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one as a white solid (0.211 g). 1H NMR (400 MHz, DMSO-d6) δ 11.92 (br.s., 1H), 7.66 (d, J=6.64 Hz, 1H), 7.38 (d, J=8.00 Hz, 2H), 7.33 (d, J=8.47 Hz, 2H), 6.60 (d, J=6.87 Hz, 1H), 5.19 (d, J=13.05 Hz, 1H), 4.07 (d, J=13.05 Hz, 1H), 2.50 (s, 3H); LC/MS m/z 326 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17]>CN(C)C=O.O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:17]
Reactant: COc1ccccc1S
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CSc1ccccc1OC)OCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.6 %

Procedure:
To a suspension of 2-methoxybenzenethiol (10 g, 71.4 mmol) and potassium carbonate (20 g, 143 mmol) in dry N,N-dimethylformamide (100 mL) was added dropwise over 20 mins a solution of bromoacetaldehyde diethyl acetal (10.3 mL, 71.4 mmol) in dry N,N-dimethylformamide (50 mL). The resulting suspension was allowed to stir at room temperature for 45 mins before being diluted with water (500 mL) and extracted with hexane (200 mL). The organic phase was further extracted with brine (4×100 mL), with the resulting organic phase being dried (MgSO4) and the solvent removed in vacuo to give a pale yellow oil (18.6 g) which was ca 95% pure. This material was further purified by flash chromatography eluting silica gel with hexane:ether [10:1] to give a colourless oil (18 g, 98%). δH (300 MHz, CDCl3) 7.34 (1H, d, Ar), 7.2 (1H, m, Ar), 6.92–6.80 (2H, m, Ar), 4.62 (1H, t, J=7 Hz, CH(OEt)2), 3.85 (3H, s, OCH3), 3.70–3.42 (4H, m, OCH2CH3), 3.10 (2H, d, J=7 Hz, SCH2), 1.12 (6H, t, J=7 Hz, OCH2CH3).
Reaction SMILES: [OH:1][C@@:2]([CH2:57][CH2:58][CH3:59])([C@@H:10]([C:34](N1[C@@H](C(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)OC1=S)=[O:35])/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1([CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:23][CH2:22][CH2:21][O:20]1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:60][C@@H:61]([CH2:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][CH2:74][C:75]#[C:76][CH3:77])=[CH:69][CH:68]=1)[C:62]([O:64][CH3:65])=[O:63]>ClCCl>[CH2:74]([O:73][C:70]1[CH:69]=[CH:68][C:67]([CH2:66][C@H:61]([NH:60][C:34]([C@@H:10](/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2([CH2:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:20][CH2:21][CH2:22][O:23]2)[C@@:2]([OH:1])([CH2:57][CH2:58][CH3:59])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[O:35])[C:62]([O:64][CH3:65])=[O:63])=[CH:72][CH:71]=1)[C:75]#[C:76][CH3:77]
Reactant: CCC[C@@](O)(C(=O)OC(C)(C)C)[C@H](/C=C/CCCCCCC1(CCCCc2ccccc2)OCCO1)C(=O)N1C(=S)OC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCc3ccccc3)OCCO2)[C@@](O)(CCC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 61.9 %

Procedure:
tert-Butyl (E)-(2S,3S)-2-hydroxy-3-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidine-3-carbonyl)-11-[2-(4-phenyl-butyl)-[1,3]dioxolan-2-yl]-2-propyl-undec-4-enoate (124 mg, 0.150 mmol) and methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate (70.0 mg, 0.283 mmol) were dissolved in dichloromethane (3.0 mL). Dichloromethane was distilled off under reduced pressure. The residue was then stirred at an outer temperature of 50° C. for 24 hours. The reaction mixture was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 72.0 mg (0.0928 mmol, 62% yield, purity 78%) of tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-11-[2-(4-phenyl-butyl)-[1,3]dioxolan-2-yl]-2-propyl-undec-4-enoate (ESI (LC/MS positive mode) m/z 776 (M+H); Rt 2.47 min.).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:61])[NH2:60]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:60][N:59]([CH3:61])[CH3:58])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N,N-dimethyl-hydrazine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.43 (m, 2H) 1.53-1.92 (m, 8H) 2.92 (s, 6H) 3.32 (s, 3H) 3.96 (s, 3H) 4.14 (t, J=13.0 Hz, 2H) 4.42-4.52 (m, 1H) 7.44-7.52 (m, 2H) 8.20-8.27 (m, 2H) 8.49 (br. s., 1H). [M+H] calc'd for C24H31F2N7O3 504. found 504.
Reaction SMILES: [I-].C([N+:9]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:10]1)C1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])N.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[C:17]1([CH3:22])[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:11]1[C:12](=[O:15])[CH2:13][CH2:14][N:9]([C:28]2[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:26]([O:25][CH3:24])[CH:27]=2)[CH2:10]1
Reactant: Cc1ccccc1C1C[N+](C)(Cc2ccccc2)CCC1=O
Reactant: COc1cc(N)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CCC(=O)C(c3ccccc3C)C2)cc(OC)c1OC
Yield: 78.3 %

Procedure:
A slurry of 1-benzyl-1-methyl-4-oxo-3-o-tolyl-piperidinium iodide (1000 mg) in water (5 ml) was added in one portion to a refluxing solution of 3,4,5-trimethoxy aniline (395 mg) and anhydrous potassium carbonate (37 mg) in ethanol (10 ml). The reaction was heated to reflux over night. Water was added and the reaction was extracted four times with DCM. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to leave a red-brown oil, which was purified by flash chromatography (diethyl ether) to give the product as a yellow oil (600 mg). MS (ESI): 356.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]3[N:13]([CH2:19][CH2:20][N:21]=3)[C:14](=[O:18])[C:15]=2[N:16]=O)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:34](O)=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]3[N:13]([CH2:19][CH2:20][N:21]=3)[C:14](=[O:18])[C:15]=2[NH:16][CH:34]=[O:35])=[CH:4][CH:3]=1
Reactant: CC(C)CN1C2=NCCN2C(=O)C(N=O)=C1NCc1ccc(Cl)cc1
Reactant: O=CO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CC(C)CN1C2=NCCN2C(=O)C(NC=O)=C1NCc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of the nitroso compound of Procedure 87 (0.1 mol) in 200 ml. formic acid, sodium dithionite (0.25 mol) is added portionwise. After one hour, the reaction mixture is concentrated in vacuo, the residue dissolved in water and filtered. The filtrate is made basic with concentrated aqueous ammonia, and the product collected.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:25]1[C:26]2[S:43][C:42]([NH2:44])=[N:41][C:27]=2[N:28]=[C:29]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[F:40])[N:30]=1>CN1C(=O)CCC1>[NH2:44][C:42]1[S:43][C:26]2[C:25]([NH:1][C@H:2]3[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)=[N:30][C:29]([S:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=3[F:40])=[N:28][C:27]=2[N:41]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](Nc2nc(SCc3cccc(F)c3F)nc3nc(N)sc23)C1

Procedure:
(3R,4R)- 3-Amino-4-hydroxy-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (0.73 g), diisopropylethylamine (1.0 ml) and the product of example 4 step b), were stirred is in NMP (10 ml) at 100° C. for 28 hrs. The cooled mixture was poured onto water and the solid produced collected, washed with water and air dried. The crude material was purified (SiO2, ethyl acetate as eluant) to give the subtitle compound as a colourless solid (0.58 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=2[CH3:16])[N:17]=1
Reactant: NC(N)=S
Reactant: CC(=O)Nc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: CC(=O)Nc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 86.4 %

Procedure:
A mixture of N-(4-(2-bromoacetyl)-3,5-dimethylphenyl)acetamide (7.34 g, 25.9 g mmol) and thiourea (1.97 g, 25.9 mmol) in 95% EtOH (36.9 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (50 mL). The solids were filtered and dried under vacuum to give N-(4-(2-aminothiazol-4-yl)-3,5-dimethylphenyl)acetamide (5.83 g) as yellow solids in 86% yield: 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1 H), 7.26 (s, 2 H), 6.90 (s, 2 H), 6.30 (s, 1 H), 2.06 (s, 6 H), 2.02 (s, 3 H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].BrBr.[Br:23]C1C(=O)C(Br)=C(C)N(C)C=1C1C=CC=CC=1>CO>[Br:23][C:9]1[C:8](=[O:12])[C:4]([C:5]([OH:7])=[O:6])=[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:2]([CH3:1])[C:10]=1[CH3:11]
Reactant: Cc1c(Br)c(=O)c(Br)c(-c2ccccc2)n1C
Reactant: Cc1cc(=O)c(C(=O)O)c(-c2ccccc2)n1C
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Br)c(=O)c(C(=O)O)c(-c2ccccc2)n1C

Procedure:
6.0 g of 1,6-dimethyl-2-phenyl-4-oxonicotinic acid is suspended in 200 ml of methanol. 1.0 g of sodium hydroxide is added. As soon as the acid dissolves a solution of 5.52 g of Br2 in 50 ml of methanol is slowly added with stirring. The pH of the reaction mixture is maintained at 8-9 by the addition of extra sodium hydroxide as required. A precipitate of 3,5-dibromo-1,6-dimethyl-2-phenyl-pyrid-4-one forms. This material is collected by filtration and discarded. Acidification of the clear filtrate yields 3.4 g of 5-bromo-1,6-dimethyl-2-phenyl-4-oxonicotinic acid as a white solid. mp=252°-253° C. (acetonitrile).