Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28](O)=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([NH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (150 mg), ethyl glycinate (73 mg) and HATU (402 mg) in DCM (20 mL) was added DIPEA (0.2 mL). The reaction was stirred at 40° C. for 3 h. The reaction mixture was cooled to room temperature and partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with water, dried over sodium sulphate and evaporated in vacuo to afford the crude product ethyl N-{3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoyl}glycinate as an off-white solid (D125) (100 mg), which was used directly in the next step. MS (ES): C26H27ClN4O5 requires 510; found 511.2 (M+H+).
Reaction SMILES: [OH-].[K+].[C:3](I)([C:6]([C:9]([C:12]([C:15]([C:18]([F:21])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(C)C>[CH:3]([C:6]([C:9]([C:12]([C:15]([C:18]([F:19])([F:20])[F:21])([F:16])[F:17])([F:13])[F:14])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Into a 1 l four-necked flask equipped with a stirrer, a distillation apparatus-equipped reflux condenser, a dropping funnel and a thermometer, 200 cc of isopropyl alcohol, 87.5 g (0.75 mol) of 48% potassium hydroxide and 1 g of tetrabutyl ammonium bromide were charged. The reactor was heated to bring the internal temperature to 60° C. Then, 223 g (0.5 mol) of C6F13I was dropwise added thereto over a period of one hour. After completion of dropwise addition, heating and refluxing were continued for 3 hours. The conversion at that time was 99.9%. A fraction with a boiling point of up to 75° C. was recovered by distillation from the reactor. This recovered liquid was washed five times with 200 g of water, and acetone and isopropyl alcohol were removed. Thus, 146 g of C6F13H having a purity of 99.9%, was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:29])[CH2:16][N:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=2[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:5])C.O1CCCC1.[OH-].[Na+].[ClH:45]>CO>[ClH:45].[CH2:31]([O:30][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:29])[CH2:16][N:17]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:13]2[C:8]=1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)N(CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(C(=O)O)cc12)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolecarboxylic acid ethyl ester is combined with 300 ml of tetrahydrofuran, 300 ml of methanol, and 100 ml of 2N sodium hydroxide solution and stirred for 4 hours at room temperature. Then 120 ml of 2N hydrochloric acid is added and the mixture concentrated until the onset of crystallization. The crystallized product is vacuum-filtered and the mother liquor once more concentrated. The resultant secondary crystallization product is combined with the first-obtained crystallized product, dried, and recrystallized from methanol/ethyl acetate, thus obtaining 8.8 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)indole-2-carboxylic acid hydrochloride, decomposition point 158° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[C:29](=[O:30])[CH:28]=[CH:27][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25]1=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[C:29](=[O:30])[CH:28]=[CH:27][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:25]3=[O:39])[CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH:3]=1
Reactant: Fc1ccc(N2CCNCC2)c(OCC(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc(=O)n(CCCCl)c1=O
Product: C[Si](C)(C)CCOCn1ccc(=O)n(CCCN2CCN(c3ccc(F)cc3OCC(F)(F)F)CC2)c1=O

Procedure:
substituting 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione;
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCNC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCN(C(=O)c1ccccc1)C1CCCCC1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of N-(6-((tert-butyldimethylsilyl)oxy)hexyl)cyclohexanamine (208 mg, 0.66 mmol) and triethyl amine (0.19 mL, 1.32 mmol) in methylene chloride (5 mL) at 0° C. was added benzoyl chloride (0.092 mL, 0.80 mmol). The mixture was stirred for 2 hours before it was diluted with ethyl acetate and washed with saturated bicarbonate solution nd brine. The organic phase was separated and concentrated. Purification on silica gel with ethyl acetate: hexanes from 0:1 to 2:8 provided desired product as a clear oil (242.2 mg, 88%). 1H NMR (300 MHz, CDCl3): δ 7.40-7.20 (m, 5H), 3.64-2.95 (m, 5H), 1.95-0.88 (m, 18H), 0.83 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[I:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([I:32])=[CH:34][CH:35]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(I)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-iodo-benzenesulfonyl chloride. Purity (ELSD, based on MW=687.5)=100%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:37]([NH:39][NH2:40])=O>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][N:31]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Reactant: NNC(=O)c1cnccn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Cl)c1Cl)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[(2,3-dichloro-4-fluorophenyl)carbonyl]-2-piperazinone (I34) (0.210 g, 0.721 mmol) was dissolved in Dichloromethane (DCM) (3 mL), and to this was added triethyloxonium tetrafluoroborate (0.144 g, 0.757 mmol), the solution was stirred for 20 minutes before 2-pyrazinecarbohydrazide (commercially available from e.g. TimTec, J&W PharmLab or AKos Consulting, 0.120 g, 0.866 mmol) was added. The solution was then allowed to stir for an additional 30 minutes before the solvent was concentrated and n-butanol (3 mL) was added. The solution was then stirred, under argon and reflux, for 3 hours before being allowed to cool to room temperature. The solvent was then removed in vacuo and the remaining residue was purified by flash chromatography (Biotage SP4, 25M cartridge) with a gradient of 0-10% 2M NH3/MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo. The remaining residue was then further purified by mass-directed automated HPLC, and the solvent evaporated in vacuo. The remaining residue was then triturated with ether and dried in a vacuum oven to yield the product in 0.112 g.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:58]=CC(N)=[CH:54][CH:53]=2)[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:58][C:52]([N:49]5[CH2:48][CH2:47][N:46]([CH3:45])[CH2:51][CH2:50]5)=[CH:53][CH:54]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:35][CH2:36][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:38][CH2:39]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5ccc(N6CCN(C)CC6)cc5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(4-methylpiperazino)aniline as the aniline component. (7%, MS=681.4 (M+H))
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]([CH3:41])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:26]([O:25][CH3:24])=[N:27][CH:28]=[C:29]([CH3:41])[CH:30]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Reactant: COc1ncc(C)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)ccc1C
Temperature: 80 °C
Yield: 76.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (0.1 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (98 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol) and the reaction mixture was heated to 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The aqueous layer was back extracted with ethyl acetate (5 mL). The organics were dried over sodium sulfate and evaporated. The resulting crude material was purified by silica gel chromatography (eluting with 0-30% ethyl acetate in hexanes) to yield the product (95 mg, 76%). ESI-MS m/z calc. 415.48. found 416.1 (M+1)+. Retention time 1.92 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[C:42](Cl)(=[O:45])[CH2:43][CH3:44].[Na]>O1CCCC1>[F:30][C:29]([F:31])([F:32])[C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]([NH:19][C:15]2[CH:14]=[C:13]([C:9]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:42](=[O:45])[CH2:43][CH3:44])[CH:7]=4)=[CH:12][NH:11][N:10]=3)[CH:18]=[CH:17][CH:16]=2)=[O:21])=[CH:24][CH:25]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
35 mg (0.08 mmol) of 1-{3-[4-(2-aminopyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)-phenyl]urea were dissolved in 2 ml of dry tetrahydrofuran and 27 μl (0.16 mmol) of N,N-diisopropylethylamine and 14 μl of propionyl chloride (0.16 mmol) were added consecutively. The mixture was stirred overnight at room temperature, then poured into aqueous sodium hydrogenocarbonate, extracted with dichloromethane, dried over sodium sulphate ed evaporated. Without any further purification the crude was redissolved with 10 mL of methanol and 5 mL of triethylamine were added. After 7 hours at room temperature the solvent was removed in vacuo, the residue partitioned between dichloromethane and water, dried over sodium sulphate and evaporated. After trituration with diethylether, 30 mg (77%) of the title compound were collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:18](=[O:20])[CH3:19])[CH2:11][C:4]=2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)CNc1ccccc1CO2
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N1Cc2cc(Cl)ccc2OCc2ccccc21
Temperature: 80 °C
Yield: 55 %

Procedure:
To a stirred solution of 2-Chloro-11,12-dihydro-6H-5-oxa-11-aza-dibenzo[a,e]cyclooctene Example 348C (43 mg, 0.18 mmol) and DMAP (4.27 mg, 34.9 μmol) in toluene (1.25 mL) was added acetic anhydride (36.0 μL, 0.39 mmol) and pyridine (13.9 mg, 0.18 mmol). This reaction mixture was heated at 80° C. for 50 min, cooled to room temperature and concentrated in vacuo. This was purified by a Shimadzu auto prep HPLC, employing 20% to 100% 10 min gradient elution with 0.1% TFA in MeOH-water solvent system, 220 nM detection, 20 mL/min elution with a YMC ODS S5 20×100 mm column to give 27.7 mg of desired 1-(2-Chloro-6H,12H-5-oxa-11-aza-dibenzo[a,e]cycloocten-11-yl)-ethanone Example 348D in 55% yield. HPLC Rt=3.09 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=288
Reaction SMILES: C([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([O:15][C:13]([C:12]([CH3:21])([O:11][C:10]1[CH:9]=[C:8]([CH2:7][C:5]([OH:6])=[O:4])[CH:24]=[CH:23][CH:22]=1)[CH3:20])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: C=CCOC(=O)Cc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 2-[3-(allyloxycarbonylmethyl)phenoxy]-2-methylpropionate (1.63 g, 4.42 mmol) was dissolved in tetrahydrofuran (40 mL). Subsequently, tetrakis(triphenylphosphine)palladium (508 mg, 0.44 mmol), triphenylphosphine (346 mg, 1.32 mmol), and piperidine (8.74 mL, 88.4 mmol) were added thereto, and the mixture was stirred for two hours at room temperature. The resultant mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (chloroform/methanol/acetic acid=50/1/0.2), whereby the target compound was obtained (1.45 g, 4.42 mmol, q).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([O-:30])(=[O:29])=[O:28])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[O:31]=[C:20]1[N:19]2[CH2:25][C@@H:22]([CH2:23][CH2:24][C@H:18]2[C:16]([NH:15][O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:17])[N:21]1[O:26][S:27]([OH:30])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOC1CCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium({[(2S,5R)-2-({[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 30 (0.64 g, 0.89 mmol) in DCM (36 mL) was added trifluoroacetic acid (1.78 mL, 23.1 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)-7-oxo-N-(piperidin-4-yloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 6 (Table 1) (0.08 g, 25%) as a white solid.
Reaction SMILES: [CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24](=[NH:41])[NH2:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)C1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)C1CCCC1
Yield: 60 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 60% of theory, C27H34N6O3 (490.6) EKA mass spectrum: (M+H)+ =491
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:4]=[N:3]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:33])=[CH:10][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cc1ccc(-n2cnn(C)c2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1ncn(-c2ccc(CBr)cc2)c1=O
Yield: 74.6 %

Procedure:
To a stirred solution of 2.6 grams (0.013 mole) of 4,5-dihydro-1-methyl-5-oxo-4-(4-methylphenyl)-1H-1,2,4-triazole in 150 mL of carbon tetrachloride were added 0.3 gram (catalyst) of benzoyl peroxide and 2.5 grams (0.014 mole) of N-bromosuccinimide. The reaction mixture was heated at reflux for three hours, after which it was cooled and concentrated under reduced pressure, yielding 2.6 grams of 4,5-dihydro-1-methyl-5-oxo-4-(4-bromomethylphenyl)-1H-1,2,4-triazole, which was used in the next reaction without further characterization.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19](CC)CC)[CH3:18].C(Cl)(=O)OCC.C(N)C>O.O1CCCC1>[CH2:17]([NH:19][C:14](=[O:16])[CH2:13][CH2:12][C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18]
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)CCc1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (1.00 g), triethylamine (1.0 ml) and tetrahydrofuran (50 ml) was added ethyl chlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ethylamine solution (10 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give N-ethyl-3-(5-phenyl-4-isoxazolyl)propionamide (0.93 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 75–76° C.
Reaction SMILES: [CH2:1]([O:5][P:6](Cl)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4].[O-:14][C:15]#[N:16].[Na+]>C(#N)C>[CH2:1]([O:5][P:6]([N:16]=[C:15]=[O:14])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[O-]
Reactant: CCCCOP(=O)(Cl)OCCCC
Agent: [Na+]
Solvent: CC#N
Product: CCCCOP(=O)(N=C=O)OCCCC

Procedure:
Analogously to Example 1, 200 g of dibutoxyphosphinic acid chloride were reacted with 58 g of sodium cyanate in 350 ml of absolute acetonitrile. 142 g of a faintly yellowish liquid (69% of theory) having a boiling point of 80°-83° C./0.67 Pa were isolated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][CH:7]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:11]([CH3:12])=[N:10][CH2:9][CH2:8]2
Reactant: CC(=O)NCCc1cccc(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2cccc(F)c21

Procedure:
In close analogy to the procedure described above, N-[2-(3-fluoro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.