Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:8]3[C:9]=2[C:4](=[CH:5][CH:6]=[CH:7]3)[C:3]1=[O:18].[Br:19]N1C(=O)CCC1=O>C(O)(=O)C>[Br:19][C:15]1[C:14]([O:16][CH3:17])=[CH:13][C:10]2[C:11](=[O:12])[N:2]([OH:1])[C:3](=[O:18])[C:4]3[C:9]=2[C:8]=1[CH:7]=[CH:6][CH:5]=3
Reactant: COc1cc2c3c(cccc3c1)C(=O)N(O)C2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: COc1cc2c3c(cccc3c1Br)C(=O)N(O)C2=O
Yield: 26.3 %

Procedure:
2-Hydroxy-5-methoxy-benzo[de]isoquinoline-1,3-dione (0.32 g, 1.3 mmol, from Example 13) and N-bromosuccinimide (0.33 g, 1.8 mmol) were reacted in acetic acid (10 mL) following the procedure of Example 31 to give 0.11 g of the title compound, mp 250-253° C.;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
A mixture of (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (500 mg, 1.88 mmol), DCC (467 mg, 2.26 mmol), and HOBT (346 mg, 2.26 mmol) in dry THF (15 ml) was stirred for 30 minutes at RT. Then (R)-quinuclidin-3-ol (288 mg, 2.26 mmol) was added portionwise and the reaction was stirred at RT for 16 hours. The solvent was evaporated, the residue was dissolved in EtOAc, and the insoluble was removed by filtration. The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to obtain (S)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-3-phenylpropanoate (600 mg, 85% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.II.C(N(CC)CC)C.[F:21]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:21][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: FF
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1nc2ccccc2cc1Br
Yield: 47.9 %

Procedure:
A solution containing 3-bromoquinoline (1.0 g, 4.8mmol), iodine (1.22g, 4.8mmol) and triethylamine (0.48 g, 4.8 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (5 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown oil (0.95 g). GC/MS analysis showed a 56% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2fluoro-3-bromoquinoline (0.52g, 85%); mp 75°-76° C. (vacuum sublimation oil bath temp. 50° C./<1 mmHg) as white needles; RF 0.69 (CH2Cl2); (Found: C, 47.5; H, 2.1; N, 6.2. C9H5NBrF requires: C, 47.8; H, 2.2; N, 6.2%); δH (400 MHz, CDCl3, Me4Si) 7.55 ppm (1H, d d, JH5,H6 =JH6,H7 8.0, H-6), 7.74 (1H, d d d, JH7,H8 8.4, JH6,H7 7.2, JH5,H7 1.2, H-7), 7.76 (1H,d, JH5,H6 8.0, H-5), 7.91 (1H, d d, JH7,H8 8.4, JH6,H8 0.8, H-8), 8.42 (1H, d, JH4,F 8.4, H-4); δC (100 MHz, CDCl3, Me4Si) 104.0 (d, 2J 43.2, C-3), 126.6 (s, C-6), 127.0 (d, 4J 2.7, C-8), 128.0 (d, 5J 1.9, C-5) 128.0 (d, 4J 2.2, C-4a), 130.9 (d, 5J 1.1, C-7), 143.5 (d, 3J, 3.7, C-4), 144.2 (d, 3J 15.1, C-8a), 157.3 (d, 1J 238.1, C-2); δF (235 MHz, CDCl3, CFCl3) -60.8ppm (s); m/z (E1+) 225 (M+, 100%), 227 (M+, 74), 146 (56), 126 (23), 101 (18), 75 (14).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.Cl.[N:40]1([CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:55][C:52]1[CH:53]=[CH:54][C:49]([O:48][CH2:47][CH2:46][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:50][CH:51]=1)=[N:6]2
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2)n2nc(Nc3ccc(OCCN4CCCCC4)cc3)ncc12
Yield: 8.2 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), (4-{[2-(1-piperidinyl)ethyl]oxy}phenyl)amine hydrochloride (45 mg, 0.17 mmol), triethylamine (0.024 mL, 0.17 mmol) and ethanol (2.5 mL) to afford 5-methyl-7-phenyl-N-(4-{[2-(1-piperidinyl)ethyl]oxy}phenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (6 mg) as a yellow solid. MS m/z 429 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[Br:22]N1C(=O)CCC1=O>O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[C:9]([Br:22])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1[nH]c(C)c(Br)c1C
Temperature: 4 °C
Yield: 75.9 %

Procedure:
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (204 g), 177 g of potassium carbonate and 1428 mL of acetonitrile were stirred and cooled to 4° C. in an ice bath. N-Bromosuccinimide (228 g) was added in portions with vigorous stirring keeping the temperature under 17° C. The mixture was warmed to 20° C. and 2856 mL of water was slowly added. The precipitate was collected by vacuum filtration and washed three times with 400 mL of ethanol:water 1:2 each time. The solids were dried under vacuum at 60° C. to give 228 g (76% yield) of 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as an off-white solid. 1H-NMR (dimethylsulfoxide-d6) δ 1.26 (t, 3H, CH3), 2.14, 2.17 (2×s, 2×3H, 2×CH3), 4.20 (d, 2H, CH2O), 11.75 (br s, 1H, NH). MS m/z 246, 248 [M+1].
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[N:6][CH2:5]1)[C:3]#[N:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si](C)(C)C)=[CH:13][C:12]=1[NH2:23]>>[NH2:23][C:12]1[CH:13]=[C:14]([C:17]#[C:18][C:8]2[CH:7]=[N:6][CH:5]=[C:2]([CH:9]=2)[C:3]#[N:4])[CH:15]=[CH:16][C:11]=1[F:10]
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(N)c1
Reactant: N#CC1(Br)C=CC=NC1
Product: N#Cc1cncc(C#Cc2ccc(F)c(N)c2)c1
Yield: 64.5 %

Procedure:
Prepare essentially as described in EXAMPLE 138 using 3-bromonicotinonitrile (3.4 g, 18.3 mmol) and 2-fluoro-5-trimethylsilanylethynyl-phenylamine, (prepared as described in PREPARATION 41), (3.8 g, 18.3 mmol) to give the title compound as a white solid (2.8 g, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.C([Li])CCC.[C:27](=[O:29])=[O:28]>C(OCC)C>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=[C:2]([C:27]([OH:29])=[O:28])[CH:7]=1
Reactant: O=C=O
Reactant: CN(C)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
2-bromo-4-dimethylamino-6-[3-(trifluoromethyl)phenoxy] pyridine (5.00 g, 0.0138 mol) was dissolved in about 200 ml of diethyl ether. While cooling in a dry ice-acetone bath in an argon atmosphere, the obtained solution was mixed with n-butyl lithium [9.2 ml (ca. 1.66 M in hexane solution), 0.0138×1.1 mol], and then stirred for about 10 minutes. After the interior of the reactor was replaced with a carbon dioxide gas, the solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 15 ml of a 4 N aqueous hydrochloric acid solution, distributed in ethyl acetate-water, and then washed with saturated brine. The organic phase separated from the solution was dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][N:2]1C(OC(C)(C)C)=O.[Cl:17][C:18]1[C:23](N2CCNCC2)=[CH:22][C:21]([C:30]#[N:31])=[CH:20][C:19]=1[NH:32][C:33]1[N:38]=[C:37]([N:39]([CH:49]2[CH2:51][CH2:50]2)CC2C=CC(OC)=CC=2)[C:36]2=[N:52][CH:53]=[C:54]([C:55]#[N:56])[N:35]2[N:34]=1>>[Cl:17][C:18]1[C:23]([N:7]2[CH2:6][CH2:5][C:4]3([CH2:1][NH:2][CH2:3]3)[CH2:9][CH2:8]2)=[CH:22][C:21]([C:30]#[N:31])=[CH:20][C:19]=1[NH:32][C:33]1[N:38]=[C:37]([NH:39][CH:49]2[CH2:51][CH2:50]2)[C:36]2=[N:52][CH:53]=[C:54]([C:55]#[N:56])[N:35]2[N:34]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCC3(CC2)CNC3)c1

Procedure:
The title compound was prepared from tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate using a method to prepare Intermediate 11 and method analogous to that used to prepare Example 1.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]1=[O:16].[Br:17]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]1=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2cccnc2n(C)c1=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc2cccnc2n(CBr)c1=O
Reaction time: 4 h
Yield: 72.5 %

Procedure:
10.71 g (49.0 mmol) of methyl 1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in carbon tetrachloride (200 mL), and 8.64 g (49.0 mmol) of N-bromosuccinimide and 0.1 g of 1,2-azobis(2-methylpropionitrile) were added thereto. While the mixture was irradiated with light, the mixture was stirred for 4 hours. 3.0 g (17.0 mmol) of N-bromosuccinimide was further added to the mixture, and the resulting mixture was stirred for 3 hours while the mixture was irradiated with light. The reaction mixture was poured into water, and the mixture was extracted with chloroform. The organic phase was washed with water, dried, and concentrated. The residue was purified by column chromatography (ethyl acetate:chloroform=1:19), and thus 10.56 g (yield: 73%) of the title compound was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-])=O.[N:16]([O-])=O.[Na+]>C(O)(=O)C.O>[NH:13]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[CH:1]=[N:16]1
Reactant: CCOC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2cn[nH]c2c1
Yield: 102 %

Procedure:
Ethyl 4-methyl-3-nitrobenzoate (105 g) was dissolved in glacial acetic acid (4 1), followed by stirring. To the solution, a solution of sodium nitrite (32 g) in water (80 ml) was added at once at a temperature of 10° C. to 15° C., and the resultant mixture was stirred at room temperature for 3 days. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to remove acetic acid. Water was added to the residue, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and dried. The obtained crystals was further washed with methanol and diethyl ether, and dried to give ethyl indazol-6-yl carboxylate (90 g), m.p. 125°-126° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([C:22]([NH:35][CH:36]2[C:56](=[O:57])[N:38]3[CH:39]([C:44](=[N:46][CH2:47][C:48]4[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=4)[NH2:45])[C:40]([CH3:43])([CH3:42])[S:41][C@H:37]23)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:58](O)(=[O:63])[CH2:59][C:60](O)=[O:61]>CN(C)C=O.C(Cl)Cl>[C:29]1([C:22]([NH:35][CH:36]2[C:56](=[O:57])[N:38]3[CH:39]([C:44]4[N:46]([CH2:47][C:48]5[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=5)[C:58](=[O:63])[CH2:59][C:60](=[O:61])[N:45]=4)[C:40]([CH3:43])([CH3:42])[S:41][C@H:37]23)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(CN=C(N)C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC(=O)N=C2C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 21.44 g. (104 mmoles) of N,N'-dicyclohexylcarbodiimide in 122 ml. of methylene chloride and 15 ml. dimethylformamide at -5° C., a solution of 29.9 g. (52 mmoles) of 6-(triphenylmethylamino)-2,2-dimethyl-3-[N'-(4-methoxybenzyl)amidino]penam and 5.41 g. (52 mmoles) of malonic acid in 122 ml. methylene chloride and 15 ml. dimethylformamide is added dropwise over 2 hours. The mixture is then stirred for 24 hours at 25° C. The N,N'-dicyclohexylurea precipitate (18.6 g., 79.8% of theory) is filtered off, and the filtrate washed with six 150 ml. portions of water. It is dried over anhydrous sodium sulfate and then rotoevaporated to yield the title compound in crude form as an orange foam (32.6 g.). The crude product is divided into two equal portions for silica gel chromatography (ethyl acetate elution) affording a total of 10.61 g. (31.6%) of the purified title compound. 1H-NMR (CDCl3) ppm (δ) 1.01 (3H, s, 2-CH3); 1.44 (3H, s, 2CH3); 3.80 (3H, s, --OCH3); 4.31-4.73 (3H, m; 3-, 5- and 6H); 5.25 (2H, s, --CH2 --); 4H, AB, Ha within a 7.18-7.68 multiplet, Hb centered at 6.91, J = 8 Hz, CH3O--C6-4H--); 7.18-7.68 (15H, m, C6-5H--).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=O)[CH3:6].[C:9]([O-])(=O)[CH3:10].[C:13]([O-])(=O)C.[Pb+4].[CH:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>CO>[CH3:13][O:8][C:5]1[CH:6]=[C:23]([CH3:22])[CH:18]=[CH:19][C:20]=1[CH2:2][C:1]([O:4][CH2:9][CH3:10])=[O:3]
Reactant: c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CO
Product: CCOC(=O)Cc1ccc(C)cc1OC

Procedure:
To a suspension of lead tetraacetate (16.8 g) in benzene (80 ml) was added a solution of 2-methoxy-4-methylacetophenone (5.35 g) in methanol (8.25 ml), and then boron trifluoride/diethyl ether complex (16.5 ml) was added dropwise to the mixture with stirring under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with cold water, and extracted with benzene, and the organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, water, and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give ethyl 2-methoxy-4-methylphenylacetate (3.22 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([OH:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(CC)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(O)cc2c1-c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1-c1ccccc1

Procedure:
Twenty-six grams (92.4 m mole) of 5-hydroxy-3-phenyl-1H-2-indole carboxylic acid ethylester were refluxed for four days with 27.6 g of potassium carbonate and 11 ml (92.4 mole) of benzylbromide in 700 ml of methyl-ethylketone. After filtration and evaporation, the residue was chromatographed on silicagel (solvent: toluene).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:9]=2[O:10][C:11]=1[CH3:12])(=[O:5])[CH3:4].I[CH2:21][CH3:22].O>CN(C)C=O>[C:3]([N:6]([C:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:9]=2[O:10][C:11]=1[CH3:12])[CH2:21][CH3:22])(=[O:5])[CH3:4]
Reactant: CCI
Reactant: CC(=O)Nc1c(C)oc2c([N+](=O)[O-])cccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1c(C)oc2c([N+](=O)[O-])cccc12
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Sodium hydride (60%, 54 mg) was added to a solution of 3-acetylamino-2-methyl-7-nitrobenzo[b]furan (280 mg) in N,N-dimethylformamide (3 ml) at 4° C. The mixture was stirred for 30 minutes and to the mixture was added iodoethane (240 mg). The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into cold water and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 3-(N-acetyl-N-ethylamino)-2-methyl-7-nitrobenzo[b]furan as a crystalline solid (310 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:8][NH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[N:8][N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][C:21]([F:20])([F:32])[F:33])[CH:24]=2)[C:10]=1[CH:11]1[CH2:12][CH2:13]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C1CC1
Product: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Yield: 23 %

Procedure:
In analogy to the procedure described in Example 160C], 5-cyclopropyl-3-pyridin-4-yl-1H-pyrazole-4-carboxylic acid ethyl ester and 3-(trifluoromethoxy)benzeneboronic acid gave the title compound as a colorless oil (23%). MS: 418.3 (MH+).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[C:15]([N+:24]([O-:26])=[O:25])=[C:16]([CH2:20][C:21]([OH:23])=O)[CH:17]=[CH:18][CH:19]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][CH2:29]1>C1COCC1.CCOC(C)=O>[CH2:34]([N:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:21](=[O:23])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=2[N+:24]([O-:26])=[O:25])[CH2:29][CH2:30]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)Cc1cccc(F)c1[N+](=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1cccc(F)c1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
17.0 g (102 mmol) CDI were added at RT to 18.3 g (91.9 mmol) (3-fluoro-2-nitro-phenyl)-acetic acid in 500 mL THF and stirred for 30 min. Then 20.0 mL (95.8 mmol) 4-amino-1-benzylpiperidine were added and the mixture was stirred for a further 2 h. The reaction mixture was diluted with EtOAc and the organic phase was washed with water and saturated sodium chloride solution. The organic phase was dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE and suction filtered.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].[CH3:14][CH:15]([C:21]([CH3:23])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([NH2:1])[C:3]=1[C:4]#[N:5])([CH3:14])[C:21](=[O:22])[CH3:23])[CH3:20]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(C)=O)c1ccc([N+](=O)[O-])c(N)c1C#N
Reaction time: 24 h
Yield: 45.5 %

Procedure:
To a solution of 2-amino-6-chloro-3-nitrobenzonitrile (1.97 g, 10 mmol) and ethyl 2-methylacetoacetate (3.6 g, 25 mmol) in DMF (10 mL) was added finely powdered K2CO3, and the mixture stirred vigorously for 24 h. The deep red mixture was diluted with EtOAc and washed in turn with 2 M HCl, water and brine. The residue after evaporation was purified by flash chromatography in hexane/EtOAc 3:1 to yield 2-(3-amino-2-cyano-4-nitrophenyl)-2-methyl-3-oxobutyric acid ethyl ester as an oil (1.39 g, 46%), MS (NH3 CI) 323 (M+NH4+), 293 (M+NH4−NO+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[NH:13][C:12](=[O:24])[C@H:11]1[CH2:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:12](=[O:24])[C@H:11]1[CH2:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)NC(=O)[C@H]1CC1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)[C@@H](CC2CCCCCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere 59 mg (1.4 mmol) sodium hydride were added at 0° C. to 0.50 g (1.2 mmol) (2R)-tert-butyl-2-(cycloheptylmethyl)-5-(3,5-difluorophenyl)-3-oxopiperazine-1-carboxylate (isomer 4.1) in 20 ml DMF. After 20 min at 0° C. 0.13 ml (1.4 mmol) methyl bromoacetate were added and the mixture was stirred for 30 min at 0° C. Then the reaction mixture was stirred for 5 h at RT. The reaction mixture was mixed with water and extracted twice with ethyl acetate. The combined organic phases were dried and evaporated down.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.C([O-])(O)=O.[Na+].[NH2:36][C:37]1[C:38]2[N:39]([N:44]=[N:45][N:46]=2)[N:40]=[C:41]([SH:43])[CH:42]=1.Cl>O>[NH2:36][C:37]1[C:38]2[N:39]([N:44]=[N:45][N:46]=2)[N:40]=[C:41]([S:43][CH2:5][C:6]2[CH2:7][S:8][C@@H:9]3[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]4[N:24]=[C:25]([NH2:28])[S:26][CH:27]=4)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]3[C:11]=2[C:12]([OH:14])=[O:13])[CH:42]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: Nc1cc(S)nn2nnnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cc(N)c4nnnn4n3)CS[C@H]12)c1csc(N)n1
Temperature: 50 °C

Procedure:
To a stirred solution of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer), (0.456 g, 0.001 mole) and NaHCO3 (0.143 g, 0.0017 mole) in water (10 ml), 8-amino-6-mercapto-tetrazolo[1,5-b]pyridazine (0.118 g, 0.0007 mole) was added. A slow stream of nitrogen was passed through the solution, and the mixture was heated at 50° C. for 12 hours, while keeping the pH at 6.8. After cooling, the solution was acidified with 10% HCl, the precipitate collected by filtration, washed with water and then with ethanol. There was thus obtained 0.215 g of compound (2) which was shown by NMR, TLC and IR, to be identical to the product described in Example 1, apart a minor contaminant of the anti-isomer. By using the same method, the following compounds were prepared: