Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]C)=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)c(Cl)cc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a cooled (−78° C.) solution of 6-chloro-5-methoxy-1H-indole-2-carboxylic acid ethyl ester (930 mg, 1.0 eq.) in dichloromethane (20 mL), was slowly added a 1M solution of boron tribromide in dichloromethane (7.33 mL, 2.0 eq.). The mixture was stirred at room temperature for 1 h, partitioned between ethyl acetate and ice water. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with 10% sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, evaporated to dryness and purified on silica gel, eluting with a 4:1 to 3:1 gradient of cyclohexane/ethyl acetate, to yield 655 mg (74%) of the title compound as a light-brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH:9]([O:8][C:7]1[N:6]=[CH:5][C:4]([OH:12])=[CH:3][CH:2]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(O)cc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)Oc1ccc(O)cn1
Yield: 97.5 %

Procedure:
5-Chloro-6-isopropoxypyridin-3-ol (0.288 g, 1.54 mmol) was dissolved in absolute ethanol (5 mL) and heated to reflux. Then 10% palladium on Carbon (0.085 g, 0.799 mmol) and ammonium formate (1.35 g, 0.0214 mol) were added and the mixture was stirred at reflux under nitrogen for one hour. The reaction mixture was filtered on a pad of Arbocel® under a nitrogen stream and washed with MeOH (15 mL). The filtrate was concentrated in vacuo. The resulting crude was then diluted in EtOAc (20 mL) and washed with water (30 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give title compound as a white solid (0.23 g, 97%):
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[N:6]=1)C.[ClH:20]>O>[OH2:3].[ClH:20].[ClH:20].[CH3:10][N:9]1[C:5]([CH:4]=[O:3])=[N:6][C:7]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: CCOC(OCC)c1nc(-c2cnccn2)nn1C
Agent: Cl
Solvent: O
Product: Cn1nc(-c2cnccn2)nc1C=O
Temperature: 60 °C
Yield: 209.2 %

Procedure:
The acetal from step 2, 2-[5-(diethoxymethyl)-1-methyl-1H-1,2,4-triazol-3-yl]pyrazine (44.5 g, 0.17 mol) was dissolved in water (150 mL) and conc. HCl (30.0 mL of 12 M, 0.36 mol, ˜2 equiv). The solution was degassed with nitrogen for 2 min and heated in an oil bath at a bath temperature of 60° C. for 2 h, resulting in complete hydrolysis of the acetal group. The volatiles were removed in vacuo, affording a yellow solid (49.8 g). This was suspended in dichloromethane (1 L), refluxed under nitrogen for 1 h, then filtered while still hot. The filter cake was washed with dichloromethane and dried in vacuo at 50° C. for 4 h, affording the title product (41.0 g, 81%) as a hygroscopic yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 4.21 (s, 3H), 8.50 (br s, 4H), 8.75 (m, 2H), 9.27 (s, 1H), 10.01 (s, 1H). MS (APCI) calcd for C8H7N5O: 189.07, found (M+H+): 190.1, 208.1 (hydrate); Anal. Calcd. For C8H11Cl2N5O2: C, 34.30; H, 3.96; N, 25.00; O, 11.42; Cl, 25.31. Found: C, 33.43; H, 3.98; N, 24.70; O, 11.17; Cl, 25.44.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[Cl:27]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.CO.CC#N.O>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[C:17]=1[Cl:27])[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc2cccc(-c3[nH]c4c(c3Cl)C(=O)NCC4)c2nc1NC(C)(C)C
Yield: 15.8 %

Procedure:
A solution of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (68 mg, 0.19 mmol) and 1-chloropyrrolidine-2,5-dione (39 mg, 0.29 mmol) in CHCl3 (2 mL) was stirred at RT for 4 h. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give impure product. The impure product was dissolved in MeOH (˜20 mg/mL) and injected (2×1.0 mL) onto the Shimadzu preparatory LC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% MeCN/water with 0.1% TFA); the pure fractions were combined, basicified with NaHCO3 (saturated, aq.), extracted with DCM, separated, dried over Na2SO4, and concentrated via rotary evaporation to give 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-3-chloro-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (348) (12 mg, 0.03 mmol, 16% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.62 (s, 9H) 2.56 (s, 3H) 2.96 (t, J=6.85 Hz, 2H) 3.63 (td, J=6.85, 2.74 Hz, 2H) 4.87 (s, 1H) 5.66 (br. s., 1H) 7.44 (t, J=7.92 Hz, 1H) 7.72 (dd, J=8.02, 1.37 Hz, 1H) 8.68 (dd, J=7.73, 1.27 Hz, 1H) 12.63 (br. s., 1H). MS (ESI, pos. ion) m/z: 384.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[C:14](C(OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3]1
Reactant: CCOC(=O)C(C(=O)OCC)=C1CN(C)C(=O)c2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C=C1CN(C)C(=O)c2ccccc2N1

Procedure:
A mixture of 33.2 g (0.1 mol) of diethyl (1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene)malonate, 8.0 g (0.2 mol) of sodium hydroxide and 400 ml of absolute ethanol is heated to reflux for 3 hours. The mixture is subsequently left to crystallise at 0° C. and the separated solid material is filtered off under suction and transferred to a separating funnel. 100 ml of chloroform and 25 ml of water are added thereto. Then, the aqueous phase is separated. The organic phase is washed with 25 ml of water, dried over sodium sulphate and evaporated. There is obtained crystalline ethyl (1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene)acetate of melting point 154°-155° C.
Reaction SMILES: B(O)O.[F:4][C:5]([F:26])([F:25])[CH2:6][N:7]1[C:12](=[O:13])[C:11](Cl)=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:9]=[N:8]1.[F-:27].[Cs+].N>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:4][C:5]([F:26])([F:25])[CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:17]2[CH:18]=[CH:19][C:20]([F:27])=[C:15]([CH3:10])[CH:16]=2)=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:9]=[N:8]1
Reactant: [F-]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cl)cc1
Agent: [Pd]
Agent: N
Agent: OBO
Solvent: COCCOC
Product: Cc1cc(-c2c(-c3ccc(S(C)(=O)=O)cc3)cnn(CC(F)(F)F)c2=O)ccc1F

Procedure:
The boronic acid (231 mg, 1.5 mmol), prepared in example 210A, 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (500 mg, 1.36 mmol), tetrakis-(triphenylphosphine)-palladium(0) (47 mg, 0.041 mmol), and CsF (413 mg, 2.72 mmol) were stirred at reflux in DME (20 mL) under N2 for 5 hours. TLC (1:1 hexanes/ethyl acetate) indicated that all the starting material was consumed. Volatiles were removed in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. An off white powder was obtained (yield: 275 mg, 46%). mp 88-91° C.; 1H NMR (300 MHz, CDCl3, a mixture of rotamers) δ 2.2, 2.25 (2d, J=1.5 Hz, 3H) 3.05, 3.09 (2 s, 3H) 4.78-4.92 (m, 2H) 6.61-6.8 (m, 1H) 6.82-6.98 (m, 1H) 7.35 (d, J=9 Hz, 1H) 7.78 (d, J=9 Hz, 1H) 7.86-8.09 (m, 4H). MS (DCI/NH3), m/z 441 (M+H)+. Anal. calc. for C20H16F4N2O3S.0.5H2O: C, 53.45; H, 3.81; N, 6.23. Found C, 53.17; H, 3.65; N, 5.88.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl.[OH-].[Na+]>O>[O:13]1[CH2:12][CH:11]1[CH2:9][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc(OCC2CO2)cc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To an ice-cooled solution of 55 g. (0.5 mole) of hydroquinone and 46 g. (0.5 mole) of epichlorohydrin in 900 ml. of water was added an ice-cooled solution of 20 g. (0.5 mole) of sodium hydroxide in 900 ml. of water. The mixture was allowed to stand at 0° C. for 3 days. After washing with ether, the solution was added to 72 g. of sodium hydroxide in 4 l. of water and stored at 10° C. for 3 hours. The solution was saturated with ammonium carbonate and extracted with chloroform. After drying (Na2SO4) and concentrating the chloroform, the residual oil was predominantly 4-(2,3-epoxy-1-propoxy)phenol (23%) which was used in later steps without further purification.
Reaction SMILES: CCCCCCCCCCCCCCCC(OCC(O)[C@H]1OC[C@H](O)[C@H]1O)=O.[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]CC(O)[C@H]1OC[C@H](O)[C@H]1O)=[O:47]>>[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O-:48])=[O:47].[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O-:48])=[O:47]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Agent: CCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
sorbitan monopalmitate, sorbitan monooleate,
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1
Reactant: N#Cc1cnc(Cl)nc1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloropyrimidine-5-carbonitrile. ESI-MS (m/z): 427 [M+1]+.
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([OH:24])=O)=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25][N:26]1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([NH:26][OH:25])=[O:24])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nc(C(=O)O)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1nc(C(=O)NO)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Yield: 66.1 %

Procedure:
To a solution of 260 mg (0.81 mmol) of 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid in 50 mL of anhydrous dimethylformamide 111 mg of N-hydroxybenzotriazole (0.81 mmol), 0.16 mL of N -methylmorpholine, 205 mg (1.07 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 585 mg (2.13 mmol) of triphenylmethylhydroxylanine were added consecutively. After 48 hours at room temperature the solvent was removed under reduced pressure and the residue taken up with dichoromethane and washed with water. The organic layer was then dried over sodium sulfate and evaporated. The crude was treated with 10 mL of a mixture dichloromethane-trifluoroacetic acid and after 4 hours the volatiles were removed in vacuo. The residue was redissolved with dichoromethane and washed with aqueous NaHCO3 and the product purified by chromatography on a silica gel column, eluted with CH2Cl2—CH3COCH3 4/1, to give 180 mg (66% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:19][O:18][N:17]([CH3:16])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1
Reactant: CNOC
Reactant: Cc1ccc(C(=O)O)cc1S(N)(=O)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.63 g of 4-methyl-3-sulfamoyl-benzoic acid, 1.92 g of N,O-dimethylhydroxylamine hydrochloride, and 5.02 mL of triethylamine in methylene chloride (120 mL) is treated with 8.32 g of benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate. The reaction mixture is stirred overnight at room temperature, washed sequentially with saturated aqueous sodium bicarbonate, water and a saturated sodium chloride solution, dried (magnesium sulfate) and concentrated in vacuo. The crude material is purified by silica gel chromatography (1:2 hexanes/ethyl acetate) to give N-methoxy-4,N-dimethyl-3-sulfamoyl-benzamide as a white powder. MS (m/z): 257 (M−1); Rf 0.25 (1:2 hexanes/ethyl acetate).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=C(N[C@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide (example A148) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH2:15])=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[NH:15][CH2:14][C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CN
Product: Cc1noc(-c2ccc(Br)cc2)c1CNC(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using C-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methylamine and benzyl chloroformate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[NH:5]COC([Si](C)(C)C)C.[C:25](OCC)(=[O:27])C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:24])[C:4]([CH2:25][OH:27])([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[NH2:5]
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)NCOC(C)[Si](C)(C)C
Reactant: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)(CO)Cc1c[nH]c2ccccc12

Procedure:
α-Trimethylsilylethoxymethyl-DL-tryptophan methyl ester (1.0 g, 2.8 mmol) was stirred for 48 hours at room temperature in trifluoroacetic acid (10 mL). After evaporation of the acid in vacuo, the oily residue was treated with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to give an oil. Trituration with ethyl acetate gave 0.45 g (655) of α-hydroxymethyl-DL-tryptophan methyl ester, mp 148°-149° C.
Reaction SMILES: [C:1]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15]OC(=O)C)[CH2:13][S:14][C@H:9]12)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(=O)([O-])O.[Na+].[CH3:30][C:31]1[O:35][C:34]([SH:36])=[N:33][N:32]=1.P([O-])([O-])([O-])=O.P(=O)(O)(O)O>O.C(OCC)(=O)C>[C:1]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][S:36][C:34]3[O:35][C:31]([CH3:30])=[N:32][N:33]=3)[CH2:13][S:14][C@H:9]12)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Reactant: Cc1nnc(S)o1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)o3)CS[C@H]12
Yield: 48 %

Procedure:
A mixture of 0.178 g. of 7-acetoacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid, 0.42 g. of sodium hydrogen carbonate, 0.64 g. of 5-methyl-1,3,4-oxadiazole-2-thiol and 10 ml. of a phosphate buffer of pH 6.4 is heated at 55°-60° C for 16 hours. After cooling, the reaction mixture is shaken with ethyl acetate and the water layer is taken, adjusted to pH 2 with 50 % phosphoric acid and extracted three times with ethyl acetate. The extracts are pooled, washed with water and dehydrated over sodium sulfate. Then, the solvent is distilled off and ether is added to the residue, whereupon 0.10 g. (48 %) of 7-acetoacetamido-3-(5-methyl-1,3,4-oxadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained as crystals melting at 80°-85° C(decomp.).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[C:26]5[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=5)[N:20]=[CH:19][CH:18]=4)=[CH:15][C:10]=3[O:9][C:8]=2[CH3:28])=[O:6])[CH2:3][CH2:2]1.[Br:29][CH2:30][CH2:31]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:29][CH2:30][CH2:31][O:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][C:14]3[CH:13]=[CH:12][C:11]4[C:7]([C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:6])=[C:8]([CH3:28])[O:9][C:10]=4[CH:15]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1
Reactant: BrCCBr
Reactant: Cc1oc2cc(Oc3ccnc4cc(O)ccc34)ccc2c1C(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc2cc(Oc3ccnc4cc(OCCBr)ccc34)ccc2c1C(=O)NC1CC1
Yield: 61.8 %

Procedure:
A solution of 90-G (1.4 g, 3.7 mmol), Br(CH2)2Br 90-H (2.1 g, 11.2 mmol) and K2CO3 (1.5 g, 11.2 mmol) in DMF (40 ml) was heated to 50° C. overnight. The reaction mixture was extracted with EtOAc. The concentrated residue was purified by silica gel column chromatography using 5% MeOH/CH2Cl2 to yield 6-{[7-(2-bromoethoxy)quinolin-4-yl]oxy}-N-cyclopropyl-2-methyl-1-benzofuran-3-carboxamide 90-1 (1.1 g, 61%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12](B(O)O)[CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=1
Reactant: OB(O)c1cccnc1
Reactant: CSc1nccc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: CSc1nccc(-c2cccnc2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-pyrimidine (1.00 g, 6.22 mmol), 3-pyridine-boronic acid (918 mg, 7.47 mmol), Na2CO3 (791 mg, 7.47 mmol), triphenylphosphine (162 mg, 0.62 mmol) in nPrOH (60 ml), Pd(OAc)2 (41 mg, 0.19 mmol) was added and the mixture was stirred at 100° C. for 1 hour. The solvent was evaporated under vacuum, and the crude was dissolved in DCM and washed with water. The organic phase was dried (Na2SO4) and evaporated; the crude was purified by flash chromatography with DCM-MeOH—NH4OH (25-0.1-0.1 to 20-0.2-0.2) to give the title compound (1.18 g, 93% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCBr
Reactant: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCN(c1c(C=O)cccc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of 1.0 g (2.865 mmol) of the product of Example 321 in 7.5 mL of DMF was added 0.143 g (3.582 mmol) of 60% sodium hydride followed by 0.74 mL (4.30 mmol) of n-octyl bromide. The reaction was stirred overnight at room temperature then diluted with ether, washed with water, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with EtOAc/hexanes (1:3) to provide 0.592 g (49%) of the product as a white solid. Electrospray Mass Spec: 462.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:25])[CH2:14][N:15]3[C:19]([CH3:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]3)[CH2:9][CH2:8]2)[S:5][CH:6]=1.C(N(C(C)C)CC)(C)C.[CH:35]1([C:45](Cl)=[O:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][CH2:36]1>ClCCl>[CH3:20][C:19]1[N:15]([CH2:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:4]3[S:5][CH:6]=[C:2]([NH:1][C:45]([CH:35]4[C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:38][CH2:37][CH2:36]4)=[O:46])[N:3]=3)[CH2:8][CH2:9]2)=[O:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: O=C(Cl)C1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(N)cs2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(NC(=O)C3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (120 mg, 0.32 mmol) and diisopropylethylamine (0.2 mL, 0.96 mmol) in dichloromethane (5 mL) is added dropwise a solution of 1,2,3,4-tetrahydro-naphthalene-1-carbonyl chloride (74 mg, 0.38 mmol) in dichloromethane (3 mL) at 0° C. After stirring overnight at RT, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (ethylacetate/cyclohexane 1:1) to give 1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)amide (Compound No. 1.g.011, 82 mg, 48%). M.p.=179.2-181.3° C. 1H-NMR (400 MHz, CDCl3): δ=1.60-1.75 (m, 3H), 1.81-1.89 (m, 2H), 2.05-2.15 (m, 2H), 2.31 (s, 3H), 2.32-2.40 (m, 1H), 2.77-2.94 (m, 3H), 3.05-3.18 (m, 1H), 3.19-3.29 (m, 1H), 3.87 (t, 1H), 3.95-4.04 (m, 1H), 4.50-4.59 (m, 1H), 4.90-5.06 (2d, 2H, diastereotopic protons), 6.32 (s, 1H), 7.25-7.30 (m, 4H), 7.49 (s, 1H), 7.79 (br, 1H). MS: m/z=532 (M+1).