Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([CH3:53])[N:44]2[C:43]1=[O:54]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([CH3:53])[N:44]2[C:43]1=[O:54])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,7R,10aS)-7-methyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (13 mg, 0.024 mmol) and Intermediate 72 (5.7 mg, 0.026 mmol) to give a white solid (14 mg, 77% yield). Anal. Calcd. for C43H54N4O5S m/z 738.7. found: 739.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.35-6.88 (m, 14H), 5.28 (d, J=4.5 Hz, 1H), 4.97-4.89 (m, 1H), 4.85-4.73 (m, 1H), 4.66-4.54 (m, 1H), 3.98 and 3.79 (s, 3H), 3.96-3.83 (m, 1H), 3.54-3.29 (m, 2H), 3.14-2.90 (m, 2H), 2.88-2.66 (m, 4H), 2.64-2.36 (m, 3H), 2.12-1.40 (m, 16H), 1.32 (d, J=6.9 Hz, 3H), 1.30-1.13 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]=3[CH2:27][CH2:28][CH3:29])=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C1COCC1.O>[C:30]1([N:25]2[C:26]([CH2:27][CH2:28][CH3:29])=[C:22]([C:20]([NH:19][CH2:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:11][CH:10]=4)=[CH:13][CH:14]=3)=[O:21])[CH:23]=[N:24]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCCc1c(C(=O)NCc2ccc(-c3ccc(OCC(=O)OC)cc3)cc2)cnn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(C(=O)NCc2ccc(-c3ccc(OCC(=O)O)cc3)cc2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A mixture of methyl({4′-[({[1-phenyl-5-propyl-1H-pyrazol-4-yl]carbonyl}amino)methyl][1,1′-biphenyl]-4-yl}oxy)acetate (250 mg, 0.517 mmol), prepared in the previous step, and 1 N NaOH (620 μL, 0.620 mmol) in 40 mL of THF and 20 mL of water was stirred at room temperature for 19 h (overnight). The reaction was acidified by the addition of 620 μL of 1 N HCl and then concentrated under reduced pressure to remove the THF. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (214 mg, 87%) as a white solid, mp 190-192° C. Elemental Analysis for C28H27N3O4+0.43 H2O. Calc'd: C, 70.46; H, 5.88; N, 8.80. Found: C, 70.37; H, 5.98; N, 8.44
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].[Li]CCCC.B(F)(F)F.[CH3:20][Si:21]([CH3:30])([CH3:29])[CH2:22]/[CH:23]=[CH:24]\[CH2:25][C@@H:26]1[CH2:28][O:27]1>C1COCC1>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH2:1][C:2]#[C:3][CH2:28][C@H:26]([OH:27])[CH2:25]/[CH:24]=[CH:23]\[CH2:22][Si:21]([CH3:30])([CH3:20])[CH3:29]
Reactant: C[Si](C)(C)C/C=C\C[C@@H]1CO1
Reactant: C#CCOC1CCCCO1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C/C=C\C[C@@H](O)CC#CCOC1CCCCO1
Reaction time: 0.83 h
Yield: 93.1 %

Procedure:
24.5 ml (174 mmol) of Tetrahydro-2-(2-propynyloxy)2H-pyran was dissolved in 285 ml of abs. THF and deprotonated at -13°--6° by adding slowly 112 ml of nBuLi (1.55 M, hexane). 20 Minutes later, the solution was cooled to -75° and 21.85 ml of BF3 oEtOEt was added. Afterwards, 10.51 g of (Z)-(R)-trimethyl-(4-oxiranyl-but-2-enyl)-silane, dissolved in 96 ml of abs. THF, was added within 75 minutes while maintaining the temperature below -70°. The reaction mixture was kept for another 50 minutes at this temperature and then poured onto crushed ice/NaHCO3, extracted with ether, washed with brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) produced 17.83 g of (Z)-(5R)-9-(tetrahydro-pyran-2-yloxy)-1-trimethylsilanyl-non-2-en-7-yn-5-ol as colorless oil (1:1 epimeric mixture).
Reaction SMILES: CO[CH:3]([Cl:12])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].O.[BH4-].[Na+].[O:16]1CCOC[CH2:17]1>>[Cl:12][CH2:3][CH:4]([OH:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[O:16][CH3:17]
Reactant: COC(Cl)C(=O)c1ccccc1
Reactant: C1COCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1C(O)CCl

Procedure:
1.7 g of 2-methoxy-α-chloroacetophenone are dissolved in 30 ml of dioxane, and 12 ml of water are added thereto. 600 mg of sodium borohydride are added gradually to the solution at 10° to 20° C. Then, the mixture is treated in the same manner as described in Example 2-(1). 1.4 g of α-chloromethyl-2-methoxybenzylalcohol are obtained as a crude oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[Cl:11]Cl>C(Cl)Cl>[Cl:11][C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]=1[CH3:9]
Reactant: ClCl
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: ClCCl
Product: CC1=C(Cl)C(=O)OC(C)(C)O1
Temperature: 20 °C
Yield: 100 %

Procedure:
A solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.2 mol, 28.4 g) in 100 ml of CH2Cl2 was cooled to -50° C. and liquid chlorine (0.25 mol) was added dropwise over five minutes. The solution was allowed to warm to 20° C. over 30 minutes, and the solvent was then removed in vacuo, leaving 35.8 g (100% yield, 92% assay) of a pale yellow oil. A portion of this mixture was purified by flash chromatography (10% Et2O/hexanes on silica) to provide the title compound as white crystals.
Reaction SMILES: C(O)(=O)CC.[Si:6]([O:13][C:14]1[C:22]([CH2:23][CH:24](O)[C:25]([CH3:27])=[CH2:26])=[C:21]([O:29][CH3:30])[C:20]([CH3:31])=[C:19]2[C:15]=1[C:16](=[O:32])[O:17][CH2:18]2)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:33][O:34][C:35](OC)([O:40]C)[CH2:36][CH2:37][CH2:38][Br:39]>>[Br:39][CH2:38][CH2:37][CH:36]([CH2:26][C:25]([CH3:27])=[CH:24][CH2:23][C:22]1[C:14]([O:13][Si:6]([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:7])[CH3:8])=[C:15]2[C:19](=[C:20]([CH3:31])[C:21]=1[O:29][CH3:30])[CH2:18][O:17][C:16]2=[O:32])[C:35]([O:34][CH3:33])=[O:40]
Reactant: C=C(C)C(O)Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reactant: COC(CCCBr)(OC)OC
Solvent: CCC(=O)O
Product: COC(=O)C(CCBr)CC(C)=CCc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2

Procedure:
A solution of trimethyl 4-bromoorthobutyrate (20 ml), propionic acid (0.22 ml) and 4-(4-tert -butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-hydroxy-2-methylbut-1-ene (3.18 g) was heated at 110° C. in a three-necked flash with a slow nitrogen stream passing over the reaction mixture. After 1 hr 40 min the excess orthoester was removed in vacuo at 55° C. Flash chromatography of the residue on silica gel eluting with 20-30% ethyl acetate/hexane gave methyl 2-(2-bromoethyl)-6-(4-t -butyldimethylsiloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl -hex-4-enoate (2.66 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClS([N:23]=[C:24]=[O:25])(=O)=O.O>C(OCC)(=O)C>[O:1]=[C:2]1[N:3]([NH:8][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:18])[CH2:4][CH2:5][CH2:6][N:7]1[C:24]([NH2:23])=[O:25]
Reactant: O=C(NN1CCCNC1=O)OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)N1CCCN(NC(=O)OCc2ccccc2)C1=O
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a suspension of (tetrahydro-2-oxo-1(2H)-pyrimidinyl)carbamic acid, phenylmethyl ester (35.5 g, 135.9 mmol) in 500 ml ethyl acetate, chlorosulfonyl isocyanate (24.0 g, 169.9 mmol) was added. The resulting solution was stirred for one hour and hydrolyzed by adding 175 ml water. The phases were separated, the organic phase washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent and trituration of the residue with ether yielded 38.0 g of the desired product, melting point 135.6° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1)([CH3:23])[CH3:24]
Reactant: CC(C)c1ccc(NCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 34.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-isopropylphenyl)[(4-trifluoromethylphenyl)methyl]amine (2.4 g) and 2,6-diisopropylphenyl isocyanate (2.1 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-[(4-trifluoromethylphenyl)methyl]urea (1.4 g) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:9])[CH3:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>C1COCC1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:9][CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH3:8])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(C)c2ccncc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 1-(pyridine-4-yl)ethanol (400 mg, 3.25 mmol) in THF (10 mL) was added sodium hydride (301 mg, 12.54 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. 4-methylbenzene-1-sulfonyl chloride (744 mg, 3.90 mmol) was added and the mixture was stirred at room temperature for 4 hr. Water (10 mL) was added and THF was removed under reduced pressure. The residue was extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=2/1) to give 1-(pyridine-4-yl)ethyl 4-methylbenzenesulfonate (0.56 g, 62.2%). LCMS 278 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:18][C@@H:19]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)[C@H:20]([OH:32])[CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[CH:25]=1>C(Cl)Cl.O1CCCC1>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:18][C@@H:19]([CH2:33][C:34]3[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=3)[C@H:20]([OH:32])[CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[CH:25]=3)=[O:16])[CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C)c2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCc1cn(C)c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 40 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a mixture of 3-Butyl-1-methyl-1H-indole-5-carboxylic acid (0.15 g) in methylene chloride (5 mL) and tetrahydrofuran (10 mL) was added 1,1-carbonyldiimidazole (0.105 g). The mixture was stirred at 40° C. at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.2 g) in methylene chloride (5 mL) was added. The mixture was stirred at 40° C. for 18 h then poured into methylene chloride (50 mL). The mixture was washed with water then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 85:10:5 (methylene chloride: hexanes: methanol) as eluent to give 0.102 g of the title compound: MS (ESI+) for C33H39F2N3O2 m/z 547.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.[OH-].[K+]>CS(C)=O.O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: N#Cc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1cccc(Oc2ccc(C#N)cc2)c1
Yield: 49.3 %

Procedure:
A solution of ethyl 3-hydroxyphenylacetate (28 g, 0.15 mole) and 4-fluorobenzonitrile (25 g, 0.21 mole) in dimethylsulfoxide (150 ml) was stirred with 87% potassium hydroxide (10 g, 0.15 mole) at 75°-80° C. for 80 minutes under nitrogen. The resulting mixture was allowed to cool, diluted with water (1000 ml), and extracted with diethyl ether (2×50 ml). The organic solution was washed with water (100 ml), dried (MgSO4), concentrated in vacuo and the residue eluted on silica gel (500 g) with ethyl acetate: hexane (0 to 1:6). A solution of the product in diethyl ether (125 ml) was washed with 1N NaOH (15 ml) to remove some residual phenol, dried (K2CO3 and MgSO4), and concentrated in vacuo to give ethyl 3-(4-cyanophenyloxy)phenylacetate (20.8 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.18 (t, J=7 Hz, 3H, CH3), 3.71 (s, 2H, Ar CH2) 4.08 (q, J=7 Hz 2H, ester CH2) 7.02-7 13 (m, 4H, Ar) 7.18 (d, J=8 Hz, 1H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 7.85 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C17H15NO3 : C, 72.58; H, 5.37; N, 4.98. Found: C, 72.67; H, 5.43; N, 4.94.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[C:8]=1[Cl:17])[CH:5]=C.CSC>CO>[Cl:17][C:8]1[C:9]2[CH2:13][O:12][C:11](=[O:14])[C:10]=2[CH:15]=[CH:16][C:7]=1[CH2:4][CH:5]=[O:1]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(c1Cl)COC2=O
Solvent: CO
Solvent: CSC
Product: O=CCc1ccc2c(c1Cl)COC2=O
Temperature: 25 °C

Procedure:
Ozone was bubbled through a solution of 5-allyl-4-chloro-2-benzofuran-1(3H)-one (80 mg, 0.38 mmol) in MeOH at −78° C. until it turned light blue. After excess ozone was removed by bubbling nitrogen through the solution, dimethyl sulfide (0.57 mL, 7.7 mmol) was added into the reaction. The solution was allowed to warm to RT. The crude material was purified by MPLC to provide (4-chloro-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. LC-MS (IE, m/z): 211 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]([C:18]4[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=4)=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[Br:25]N1C(=O)CCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:16]([Br:25])[NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2c[nH]c3ncnc(Nc4cccc(Br)c4)c23)cc1
Reactant: O=C1CCC(=O)N1Br
Product: Brc1cccc(Nc2ncnc3[nH]c(Br)c(-c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
Utilizing an analogous procedure as described in Example 26, 4-chloro-(5-phenyl)-7H-pyrrolo[2,3-d] pyrimidine, the intermediate, was made in 74% yield from 7-benzenesulfonyl-4-chloro-5iodo-7H-pyrrolo[2,3-d]pyrimidine and 3-bromo benzene boronic acid: TS-MS: 230 (MH+) This second intermediate was coupled with 3-bromoaniline in methanol in a sealed tube to provide (3-bromo-phenyl)-[5-(4-chloro-phenyl)7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine in 75% yield: TSMS: 365 (MH+). (3-bromo-phenyl)-[5-(4-chloro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine was brominated with N-bromosuccinimide impregnated onto silica gel. The reaction was complete after stirring at room temperature under nitrogen for 1.5 hours. The reaction was filtered and concentrated in vacuo to provide the title compound as a gray solid in 28% yield (128 mg): MP.: dec 300° C.; TSMS: 445/447 (MH+/MH+2); anal. RP1 8-HPLC RT=7.223 minutes.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([Br:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][NH2:13]>>[Br:11][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=[C:2]([NH:13][CH3:12])[N:3]=1
Reactant: CN
Reactant: Brc1cn2ccnc2c(Br)n1
Product: CNc1cn2ccnc2c(Br)n1
Reaction time: 12 h
Yield: 96 %

Procedure:
A mixture of 100 mg (0.36 mmol) of 6.8-dibromoimidazo[1,2-a]pyrazine in 5 ml of a 25% aqueous methylamine solution was stirred for 12 h. After the removal of solvent, the residue was purified by chromatography (silica column eluted with ether) to provide 78 mg (yield: 96%) of 8-bromo-6-methylaminoimidazo[1,2-a]pyrazine. ESI-MS (M+H+): 227.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:5]([C:14]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:15])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2>C(O)C>[CH3:1][NH:2][C:4]1[C:5]([C:14]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:15])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=C(Nc1nnn[nH]1)c1nc2ccccc2nc1Cl
Reactant: CN
Solvent: CCO
Product: CNc1nc2ccccc2nc1C(=O)Nc1nnn[nH]1

Procedure:
Methylamine in ethanol (20 ml., 33%) and 3-chloro-N(1H-tetrazol-5-yl)-2-quinoxalinecarboxamide (Example 5) (2 g) were stirred together at room temperature for 8 hours. The yellow solid was collected and crystallised from ethanol and heated at 120° in a vacuum. It had m.p. 292° (d) (50%).
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])=[CH:12][CH:11]=1)=O)(C)(C)C>C(OCC)(=O)C.CO>[ClH:34].[NH2:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:22])=[O:23])[CH2:17][C:16]2=[O:35])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 196 %

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (10 ml) was added to a solution of 1-[4-(tert-butoxycarbonylamino)benzyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (530 mg) in methanol (2 ml), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the resulting crystals were filtered, washed with ethyl acetate-ether and dried to give the title compound (457 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[Cl:18][CH2:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:23]([NH:22][CH2:21][CH2:20][CH2:19][Cl:18])=[O:24])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: O=C=NCCCCl
Solvent: ClCCl
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)NCCCCl)C1O
Reaction time: 5 h
Yield: 41.4 %

Procedure:
400 mg (1.70 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole and 40 ml of dichloromethane were stirred at room temperature, and 192 μl (1.87 mmol) of 3-chloropropyl isocyanate were added thereto and stirred for 5 hours. The crystals precipitated were taken out by filtration to obtain 250 mg of the intended compound as pale yellow crystals. (yield: 41%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22]CC3C=CC([N+]([O-])=O)=CC=3)=[O:21])=[C:14]([N:17]=[N+:18]=[N-:19])[CH2:15][S:16][C@H:11]12)=[O:8].C1COCC1.Cl>[Zn].O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([OH:22])=[O:21])=[C:14]([N:17]=[N+:18]=[N-:19])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 5 °C

Procedure:
A solution of 0.625 g. of p-nitrobenzyl 7β-(2-thienylacetamido)-3-azido-3-cephem-4-carboxylate in 24 ml. of THF was diluted with 10 ml. of cold water and cooled in an ice-water bath. To the cold solution were added portionwise over about two hours 1.58 g. of zinc dust and sufficient 0.1N to 1N hydrochloric acid to maintain the pH of the mixture at about 4.3. Throughout the addition of zinc and acid the temperature of the reaction mixture was maintained at about 5° C. After the zinc dust addition was completed, the pH was adjusted to 2.7 with 1N hydrochloric acid and the mixture filtered. The filtrate was mixed with ethyl acetate and extracted twice with aqueous sodium bicarbonate. The aqueous layer was separated, layered with ethyl acetate, acidified with cold 1N hydrochloric acid, the organic layer separated, washed with brine, dried, and evaporated to yield 0.116 g. of the title acid as a pale yellow solid. The product was triturated with diethyl ether, filtered, and air dried to provide 80 mg. of the product acid as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[OH:15])[CH2:3][OH:4].[C:16](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:3][OH:4]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(SC[C@@H](C)CO)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(SC[C@@H](C)CO)c1OC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
0.43 g (0.0019 mol) of 2-(S)-methyl-3-(2-hydroxy-3-methoxyphenylthio)propan-1-ol (XXg), 10 ml of acetone and 0.26 g (0.0019 mol) of potassium carbonate are introduced into a round-bottomed flask kept under an inert atmosphere. After 15 minutes, 0.12 ml (0.0019 mol) of methyl iodide is introduced and the mixture is heated at 60° C. for 8 hours. The mixture is concentrated under reduced pressure. The residue is taken up in water and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. The residue obtained is used without additional purification in the following stage.