Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([N:14]1[CH2:42][CH2:41][CH2:40][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.CCOC(C)=O.CN1CCOCC1.[N:64]1([C:79]([O:81][CH2:82][C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[O:80])[CH2:78][CH2:77][CH2:76][C@H:65]1[C:66]([O:68]N1C(=O)CCC1=O)=O>CCOCC>[N:64]1([C:79]([O:81][CH2:82][C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)=[O:80])[CH2:78][CH2:77][CH2:76][C@H:65]1[C:66]([NH:1][C@H:2]([C:12]([N:14]1[CH2:42][CH2:41][CH2:40][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:68]
Reactant: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 4.0 g of Boc-Ser(Bzl)-Pro-Arg(NO2)-OBzl, 20 ml of 4 N HCl-AcOEt, 1 ml of NMM and 2.2 g of Z-Pro-OSu in the same manner as in Example 26-(4). The ether treatment was performed to obtain the desired compound as a crystalline product.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=O)C1C=CC=CC=1.[CH2:23]([S:25]([Cl:28])(=[O:27])=[O:26])[CH3:24].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:28].[NH:19]=[C:17]([NH:18][S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[NH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:20]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:22])[NH2:11]
Reactant: CCS(=O)(=O)Cl
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Product: CCS(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-arginine, ethanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: [C:1]([C:5]1[C:12]2[S:11][C:10]([NH2:13])=[N:9][C:8]=2[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([C:5]1[C:12]2[S:11][C:10]([NH:13][C:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)=[O:26])=[N:9][C:8]=2[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)c1n[nH]c2nc(N)sc12
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1n[nH]c2nc(NC(=O)c3ccco3)sc12
Temperature: 70 °C
Reaction time: 23 h
Yield: 81 %

Procedure:
To a stirring solution of 3-tert-Butyl-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.153 mmol) and pyridine (74 μL, 0.92 mmol), or alternatively PS-DMAP (Argonaut resin, 6 equiv.), in THF (0.75 mL) was added furan-2-carbonyl chloride (75 μL, 0.76 mmol). The reaction mixture was stirred at 70° C. for 23 h, then cooled to room temperature and treated with THF (1 mL) and PS-trisamine (Argonaut resin, 20 equiv.) for 2 h. The resin was filtered, washed with DMF and the solvent was evaporated. The residue was treated with MeOH (1 mL) and a 4N aqueous solution of NaOH (0.25 mL) and the solution was stirred at room temperature for 2 h. The reaction mixture was neutralized to pH 7 with a 1N aqueous solution of HCl and extracted with ethyl acetate (3×). Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 36 mg (82%) of furan-2-carboxylic acid (3-tert-butyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-amide as an off-white solid. 1H-NMR (d6-DMSO) δ: 12.8 (broad s, 1H, NH), 12.7 (broad s, 1H, NH), 8.03 (d, 1H), 7.69 (broad s, 1H), 6.74 (dd, 1H), 1.36 (s, 9H); HPLC/MS m/z: 291 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:4][CH:3]=1.[H-].[K+].I[CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH2:19]([N:9]([C:10]1[CH:15]=[N:14][CH:13]=[N:12][CH:11]=1)[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Clc1ccc(CNc2cncnc2)cc1
Reactant: CCCCI
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(Cl)cc1)c1cncnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.2 g of N-[(4-chlorophenyl)methyl]-(5-pyrimidyl)amine dissolved in 50 ml of tetrahydrofuran was added 2 g of a 24.6% suspension of potassium hydride in oil. The reaction was allowed to stir at room temperature for approximately 1 hour at which time 2 g of iodobutane was added to the reaction mixture. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in diethyl ether and the organic phase was washed with water, separated and dried over anhydrous magnesium sulfate. Following concentration of the solution under reduced pressure the residue was chromatographed over silica gel. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford N-butyl-N-[(4-chlorophenyl)methyl]-(5-pyrimidyl)amine as a solid. mp=67°-68° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:35][CH2:34][O:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([OH:37])=[O:25])[CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1cccs1
Reactant: COC(=O)c1ccccc1OCCCl
Product: COc1ccc2c(c1)c(C1CCN(CCOc3ccccc3C(=O)O)CC1)cn2Cc1cccs1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.4 g (7.4 mmol) of 5-methoxy-3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole and 1.8 g (8 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After standard work-up, 1.3 g (36% of yield) of the expected acid were obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[N:5][O:6][CH:7]=1.C(OCC)(=O)[CH2:21][C:22]([O:24]CC)=[O:23].[H-].[Na+].Cl>O1CCCC1>[C:14]1([C:11]2[CH:12]=[CH:13][C:8]([C:4]3[C:3]([CH2:2][CH2:21][C:22]([OH:24])=[O:23])=[CH:7][O:6][N:5]=3)=[CH:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1conc1-c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1conc1-c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 4-chloromethyl-3-(4-phenylphenyl)isoxazole (3.20 g) in tetrahydrofuran (100 ml) was added to a mixture of diethyl malonate (5.70 g), sodium hydride (60%, oil, 1.40 g) and tetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then at room temperature overnight. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give 3-[3-(4-phenylphenyl)-4-isoxazolyl]propionic acid (2.89 g, yield 83%). The crystals were recrystallized from acetone-hexane. melting point: 169–170° C.
Reaction SMILES: C([O:3][C:4](C1NC2C(C=1)=CC=CC=2)=[O:5])C.[NH2:15][C:16]1[CH:37]=[CH:36][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22]2)=[CH:18][CH:17]=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:30]1([C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([NH:15][S:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)(=[O:46])=[O:45])=[CH:37][CH:36]=3)[C:22]=2[C:4]([OH:5])=[O:3])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Nc1ccc(Cn2cc(-c3ccccc3)c3ccccc32)cc1
Product: O=C(O)c1c(-c2ccccc2)c2ccccc2n1Cc1ccc(NS(=O)(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-(4-amino-benzyl)-3-phenyl-1H-indole indolecarboxylic acid ethyl ester and benzenesulfonyl chloride followed the procedure of Example 3 Step 2 as an off-white solid: 1H NMR (DMSO-d6) δ 5.72 (s, 2H), 6.95-7.00 (m, 4H), 7.09-7.13 (m, 1H), 7.27-7.31 (m, 1H), 7.33-7.37 (m, 1H), 7.42-7.45 (m, 5H), 7.49-7.55 (m, 3H), 7.57-7.61 (m, 1H), 7.72 (dd, J=7.1, 1.4 Hz, 2H), 10.26 (br s, 1H), 12.83 (br s, 1H); MS (ESI) m/z 481 ([M−H]−); HRMS calcd for C28H21N2O4S: 481.1224; found (ESI−): 481.1228.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([C:12]2[C:21]3[C:16](=[C:17]([CH3:25])[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[CH:14][C:13]=2[C:26]#[N:27])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:28]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.S(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:28][CH2:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[C:21]2[C:16]=1[N:15]=[CH:14][C:13]([C:26]#[N:27])=[C:12]2[N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(C)cc([N+](=O)[O-])cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(CBr)cc([N+](=O)[O-])cc12
Yield: 119 %

Procedure:
A stirred mixture of 4-[(3-bromophenyl)-N-acetylamino]-8-methyl-6-nitro-quinoline-3-carbonitrile (10.6 g, 25 mmol), N-bromosuccinimide (6.68 g, 37.5 mmol), 0.30 g of dibenzoyl peroxide, and 200 ml of carbon tetrachloride was refluxed for 2 h, treated with an additional 0.30 g of dibenzoyl peroxide, and refluxed an additional 2.5 h, cooled, diluted with methylene chloride, and stirred with aqueous sodium bisulfite. The organic layer was separated and washed successively with water, sodium bicarbonate solution, and water. The solution was dried and evaporated to give 15 g of a white foam, NMR (CDCl3) d 5.19 (dd, CH2Br).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:10][Mg]Cl>O1CCCC1>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([CH3:10])([OH:9])[CH2:5][CH2:4]1
Reactant: O=C1CCC(CO)CC1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)CCC(CO)CC1
Temperature: 25 °C

Procedure:
4-(Hydroxymethyl)cyclohexanone (800 mg) in tetrahydrofuran (15 mL) was treated with 3 M methylmagnesium chloride in tetrahydrofuran (6.24 mL) at 0° C. The reaction was warmed to room temperature over 2 hours and quenched with methanol and water. The resulting mixture was concentrated and the residue was suspended in ethyl acetate. The precipitates were filtered off and the filtrate was concentrated. The residue was purified by chromatography, eluting with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: CN[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1F)[C:21]#[N:22].C[CH2:28][N:29](C(C)C)C(C)C.O>CS(C)=O>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([N:5]2[CH2:6][CH2:7][CH:3]([C:25]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([NH:29][CH3:28])[C:18]=3[F:17])[CH2:4]2)=[N:13][CH:12]=1
Reactant: CN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1ccc(F)c(F)c1
Solvent: CS(C)=O
Solvent: O
Product: CNc1c(C#N)ccc(C2CCN(c3ncnc4[nH]ccc34)C2)c1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
A mixture of (R)—N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.50 g, 2.3 mmol), 3,4-difluorobenzonitrile (0.48 g, 3.45 mmol) and DIPEA (0.59 g, 4.6 mmol) in DMSO (10 mL) was stirred at 90° C. for overnight. The mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts was washed with brine (2×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound (0.404 g, 52% yield). MS (m/z): 337 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5]CN.C1COCC1.[CH2:16]([N:18](CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][N:18]([CH3:16])[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCc1cccc(Br)c1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cccc(Br)c1)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
9 g (45 mmol) of (3-bromo benzyl)methylamine, 90 ml of THF and 6.9 ml (50 mmol) of triethylamine are introduced into a round-bottomed flask under a stream of nitrogen. 5.7 ml (50 mmol) of benzoyl chloride are added dropwise and the mixture is stirred for one hour. The reaction medium is poured into water and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluded with a mixture of ethyl acetate and heptane (15/85). After evaporation of the solvents, 13.7 g (64%) of the expected product are collected.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[OH:20].C(O)(=O)CCCCCC=C.N1CCC[C@H]1C(O)=O.C(C1N=C(C2C=C(O[CH:60]3[CH2:78][CH:77]4[N:62]([C:63](=[O:83])[CH2:64][CH2:65][CH2:66][CH2:67]C[CH2:69][CH:70]=[CH:71][CH:72]5[C:74]([C:80]([OH:82])=[O:81])([NH:75][C:76]4=[O:79])[CH2:73]5)[CH2:61]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:18])[CH3:19])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:60]1[CH2:78][CH:77]2[N:62]([C:63](=[O:83])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:69][CH:70]=[CH:71][CH:72]3[C:74]([C:80]([OH:82])=[O:81])([NH:75][C:76]2=[O:79])[CH2:73]3)[CH2:61]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Agent: C=CCCCCCC(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title compound was prepared from 8-chloro-4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxyquinoline (46), oct-7-enoic acid and intermediate 5 following the procedure (Step D-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=653 (M+H)+.
Reaction SMILES: ClC1C=CC(C(O[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O)=CC=1.[Cl:19][C:20]1[C:21]([F:34])=[C:22]([CH:32]=[CH2:33])[C:23]([O:29][CH2:30][CH3:31])=[C:24]([C:26](=[O:28])[CH3:27])[CH:25]=1.C(=O)([O-:37])N>O.C(#N)C.[Os](=O)(=O)(=O)=O>[C:26]([C:24]1[C:23]([O:29][CH2:30][CH3:31])=[C:22]([CH:32]([OH:37])[CH2:33][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:21]([F:34])=[C:20]([Cl:19])[CH:25]=1)(=[O:28])[CH3:27]
Reactant: NC(=O)[O-]
Reactant: CC(C)(C)OC(=O)NOC(=O)c1ccc(Cl)cc1
Reactant: C=Cc1c(F)c(Cl)cc(C(C)=O)c1OCC
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC#N
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.2 M Osmium tetraoxide in water (10 mL) was added to a solution of tert-butyl [(4-chlorobenzoyl)oxy]carbamate (Lawrence Harris, J. Org. Chem., 2011, 76, 358-372). (19 g, 70 mmol) in acetonitrile (210 mL) and stirred for 10 minutes. 1-(5-chloro-2-ethoxy-4-fluoro-3-vinylphenyl)ethanone (11.2 g, 46 mmol) (from Example 353, Step 1) as a solution in acetonitrile (210 mL) was added to the carbamate solution followed by the addition of water (50 mL) and the reaction was stirred for 3 hours at room temperature. The reaction was quenched with saturated 10 M dipotassium disulfite in water (240 mL) and stirred for 5 minutes. Water was added and the reaction mixture was extracted with ethyl acetate. The extracts were washed with saturated sodium bicarbonate solution, brine and dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes (0-100%) gave the desired compound as a racemic mixture, 16.6 g, 95%. LCMS calculated for C17H23ClFNO5Na (M+Na)+: m/z=398.1; found: 398.0.
Reaction SMILES: [C:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:13])=[CH:14][CH:15]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottom flask was charged with 4-pivaloylbenzoic acid (7.67 g, 37.2 mmol), ethyl 3-aminopropanoate hydrochloride (6.86 g, 44.6 mmol), HOAT (5.57 g, 40.9 mmol), DCM (93 mL) and TEA (7.80 mL, 55.8 mmol). EDC hydrochloride (7.92 g, 40.9 mmol) was then added in one portion and the reaction allowed to stir at room temperature for 2 hours. DCM added to the reaction mixture and organics washed with an ammonium chloride solution (sat.aq.; 1×), water (2×), brine (1×), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude material. Purification by silica gel flash chromatography (ethyl acetate/heptane) provide ethyl 3-(4-pivaloylbenzamido)propanoate as a yellow oil (4.25 g, 37.4%; over 3 steps). 1H NMR (400 MHz, CDCl3) δ 1.26 (m, J=7.02, 7.02 Hz, 3H) 1.32 (s, 9H) 2.63 (t, J=5.95 Hz, 2H) 3.72 (m, J=6.05, 6.05, 6.05 Hz, 2H) 4.16 (m, J=7.22, 7.22, 7.22 Hz, 2H) 6.92 (br. s., 1H) 7.64-7.68 (m, 2H) 7.75-7.79 (m, 2H); MS (M+1): 306.3.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH2:11]1[CH2:18][C:16](=O)[C:14](=O)[CH2:13][CH2:12]1>C(O)C.C(O)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:13]3[C:12](=[CH:11][CH:18]=[C:16]4[C:14]=3[NH:9][C:6]3[C:5]4=[CH:4][C:3]([Br:2])=[CH:8][CH:7]=3)[C:5]=2[CH:4]=1
Reactant: O=C1CCCCC1=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1ccc2[nH]c3c(ccc4c5cc(Br)ccc5[nH]c43)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
4-Bromophenylhydrazine hydrochloride (99%; 10.44 g, 1 eq) is introduced into a solution of 1,2-cyclohexadione (98%; 5.4 g, 1 eq) in absolute ethanol (50 ml). After adding 20 drops of glacial acetic acid, the mixture is stirred at room temperature for 1 h and then at 80° C. for 4 h. Then a further 5.3 g of 99% 4-bromophenylhydrazine hydrochloride are added to the reaction and, after a further 6 h at 80° C., another 5.3 g of 99% 4-bromophenylhydrazine hydrochloride are added. The reaction is stirred overnight. After 22 h, the mixture becomes viscous, so 150 ml of absolute ethanol and a further 3 g of 99% 4-bromophenylhydrazine hydrochloride are added. After a further 2 h at 80° C., the mixture is worked up. For this purpose, the solvent is distilled off. The residue is introduced gradually into polyphosphoric acid (50 g), heated to 120° C. and stirred for 1 h. The reaction output is added cautiously to ice-water and neutralized with 2M NaOH. The precipitate is filtered off and washed with distilled water. The residue is dried under reduced pressure. After recrystallization in glacial acetic acid, 5.8 g are obtained. Yield: 29.7%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:26])[CH:3]=1.[CH3:27][CH:28]([CH3:34])[CH2:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl>[CH2:18]([NH:17][C:15]([CH:14]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][CH:28]([CH3:34])[CH3:27])=[CH:3][C:4]=2[F:26])[CH2:9][CH2:10]1)=[O:16])[CH3:19]
Reactant: CC(C)CCC(=O)Cl
Reactant: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Solvent: ClCCl
Product: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)CCC(C)C)cc2F)CC1
Reaction time: 16 h
Yield: 97.2 %

Procedure:
A solution of 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N-ethyl-2-phenyl-acetamide (44 mg, 0.12 mmol) in DCM (2 mL) was treated with 4-methylvaleroyl chloride (20 mg, 0.15 mmol) followed by TEA (21 μL, 0.15 mmol). After 16 h, the mixture was purified directly by PTLC to give a beige solid (53 mg, 94%). MS (ESI): mass calcd. for C26H35FN4O2, 454.59; m/z found, 455.5 [M+H]+. 1H NMR (CDCl3): 7.38-7.28 (m, 5H), 7.10-7.04 (m, 2H), δ 7.00 (br s, 1H), 6.86 (t, J=9.0, 1H), 3.88 (s, 1H), 3.40-3.31 (m, 3H), 3.07-3.06 (m, 4H), 2.61-2.57 (m, 4H), 2.34-2.31 (m, 3H), 1.62-1.59 (m, 2H), 1.16 (t, J=7.2, 3H), 0.93 (d, J=6.1, 6H).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]2[CH:12]3[CH2:13][CH2:14][CH:9]2[C:10](=O)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]2[CH:12]3[CH2:13][CH2:14][CH:9]2[C:10](=[N:23][OH:24])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CC2CCC1C2=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: ON=C1CC2CCC1C2=C(c1ccccc1)c1ccccc1
Yield: 84.9 %

Procedure:
33.7 g (129 mmol) of 7-diphenylmethylenebicyclo[2.2.1]-heptane-2-one were stirred with 9.9 g (142 mmol) of hydroxylamine hydrochloride and 17.8 g (129 mmol) of potassium carbonate in 50 ml of ethanol at room temperature for four hours. Then 200 ml of water were added, and the mixture was extracted three times wit 100 ml of methylene chloride. The combined methylene chloride phases were washed three times with 300 ml of water, dried over sodium sulfate and concentrated in vacuo. 31.7 g of 7-diphenylmethylenebicyclo[2.2.1]heptane-2-one oxime were obtained as an amorphous solid. ##STR17##