Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)=O.CCO.[CH2:7]([N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:26])[CH2:24][CH3:25])=[CH:22][C:17]=2[O:16][C:15]1=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[CH:29]([CH2:34][CH2:35][CH3:36])[C:30]([O:32][CH3:33])=[O:31].Cl>C1COCC1>[CH2:7]([N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:26])[CH:24]([CH:29]([CH2:34][CH2:35][CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH3:25])=[CH:22][C:17]=2[O:16][C:15]1=[O:27])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCC(I)C(=O)OC
Reactant: CCC(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Agent: Cl
Agent: O=C=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)C(C)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Temperature: -2 °C
Reaction time: 0.5 h

Procedure:
200 mL (0.5 mol/l in toluene, 100 mmol) bis-(trimethylsilyl)-potassium amide in 1.50 L THF are placed under protective gas and cooled to −60° C. with dry ice/EtOH. 20 g (71 mmol) of 3-benzyl-6-propionyl-3H-benzoxazol-2-one dissolved in 500 mL THF are slowly added dropwise. The reaction mixture is stirred for 30 min at −2° C. and then cooled to −60° C. again. 20 g (83 mmol) methyl 2-iodo-pentanoate are added and the mixture is stirred for 45 min at −60° C. Then the reaction mixture is combined with 500 mL of 2M HCl and extracted at RT with diethyl ether. The organic phase is washed with saline solution, suction filtered through cellulose and the solv. is eliminated i.V. The residue is purified through silica gel (DCM/MeOH)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][O:21]C(C)(C)[O:19]3)=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[O:32][CH:33]=2)[N:3]=1.O>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:22][OH:21])=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[O:32][CH:33]=2)[N:3]=1
Reactant: CC1(C)OC[C@@H](COc2ccc(-c3c(C#N)c(N)nc(SCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cn2)O1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
95 mg (0.17 mmol) of the compound from example 32A are dissolved in 4 ml of acetic acid. 2 ml of water are then added. The reaction solution is stirred at RT for 12 h. The solvent is then removed on a rotary evaporator, and the residue is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). If required, the product may be purified further by HPLC chromatography on a chiral phase [column: Daicel Chiralpak AS 10 μm, 250 mm×20 mm; mobile phase: isohexane/ethanol 60:40 (v/v); flow rate: 15 ml/min; temperature: 40° C.; detection: 220 nm].
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][S:43]([CH:46]=[CH2:47])(=[O:45])=[O:44])[CH2:4][CH2:3]2.[OH-:48].[Na+]>O1CCOCC1>[OH:48][CH2:47][CH2:46][S:43]([CH2:42][CH2:41][NH:40][C@:5]12[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]1[C@@H:7]1[C@@:2]([CH3:1])([CH2:3][CH2:4]2)[C@@:19]2([CH3:20])[C@@H:10]([C@:11]3([CH3:33])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:45])=[O:44]
Reactant: C=CS(=O)(=O)CCN[C@]12CC[C@@H](C(=C)C)[C@@H]1[C@H]1CC[C@@H]3[C@@]4(C)CC=C(c5ccc(C(=O)OC)cc5)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCS(=O)(=O)CCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C
Yield: 55.3 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(vinylsulfonyl)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (25 mg, 0.038 mmol) and sodium hydroxide (0.189 mL, 0.189 mmol) in dioxane (1 mL) was heated at 78° C. for 3 h. The reaction mixture was filtered and the clear solution was purified by prep HPLC to provide the title compound as a white solid (14 mg, 53%). LCMS: m/e 666.39 (M+H)+, 2.48 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.27 Hz, 1H), 4.87 (s, 1H), 4.75 (s, 1H), 4.31-4.01 (m, 3H), 3.93-3.74 (m, 3H), 3.68-3.41 (m, 2H), 3.06-2.73 (m, 1H), 2.48-1.26 (m, 22H), 1.76 (s, 3H), 1.23 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13]CC2)CCCCC1.[CH2:16](O)C>>[CH3:16][N:7]([C:8]1[CH:13]=[CH:14][CH:15]=[CH:10][N:9]=1)[CH3:1]
Reactant: CCO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: CN(C)c1ccccn1

Procedure:
Alternatively, a compound of the formula XLII may be esterified by reaction with ethanol in the presence of dicyclohexylcarbodiimide and a catalyst such as dimethylaminopyridine to give a compound of the formula ##STR72##
Reaction SMILES: [CH3:1]/[C:2](/[C:5]([CH3:7])=[O:6])=[N:3]\[OH:4].[CH3:8][CH:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[CH3:10].Cl>C(O)(=O)C>[CH3:1][C:2]1[N+:3]([O-:4])=[C:15]([C:14]2[CH:17]=[CH:18][C:11]([CH:9]([CH3:10])[CH3:8])=[CH:12][CH:13]=2)[O:6][C:5]=1[CH3:7]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(C)C)cc2)[n+]([O-])c1C

Procedure:
18.4 g of diacetyl monoxime and 29.6 g of 4(2-propyl)-benzaldehyde are added to 50 ml of glacial acetic acid, and HCl gas is introduced with ice-cooling for 30 minutes. The product is precipitated as the hydrochloride by addition of methyl tert-butyl ether and filtered off with suction, and the precipitate is washed with methyl tert-butyl ether. The precipitate is suspended in a mixture of dichloromethane and water, and a basic pH is established using ammonia. The mixture is extracted three times with, in each case, 500 ml of dichloromethane and ethyl acetate, the combined organic phases are dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 38.2 g 4,5-dimethyl-2-(4-(2-propyl)-phenyl)-oxazole 3-oxide as a yellowish solid.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[N+]([O-])=O.[CH3:17][OH:18]>[Pd]>[CH3:12][C:6]1([CH3:13])[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:17](=[O:18])[NH:8][C:7]1=[O:11]
Reactant: CC1(C)C(=O)Nc2cc(N)c([N+](=O)[O-])cc21
Reactant: CO
Agent: [Pd]
Product: CC1(C)C(=O)NC(=O)c2ccccc21

Procedure:
A solution of 18.7 g. (0.085 mol) 6-amino-3,3-dimethyl-5-nitroindolin-2-one in 200 ml. methanol is hydrogenated at 40° C. in the presence of 1.9 g. of 10% Pd/C. The catalyst is filtered off with suction, the filtrate is evaporated and the residue is crystallised from ethanol. Yield: 15.6 g. (96% of theory); m.p. 245°-247° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(OC)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 4-methoxyphenylboronic acid. beige powder (61 mg).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([N:10]([CH3:34])[C:11]([C:13]1[N:17]2[CH2:18][CH2:19][C:20]3[C:25]([C:16]2=[C:15]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH:14]=1)=[CH:24][C:23]([NH2:26])=[C:22]([O:27][CH3:28])[CH:21]=3)=[O:12])([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>ClCCl>[C:6]([N:10]([CH3:34])[C:11]([C:13]1[N:17]2[CH2:18][CH2:19][CH:20]3[CH:25]([C:16]2=[C:15]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH:14]=1)[CH:24]=[C:23]([NH:26][C:3](=[O:4])[CH2:2][Br:1])[C:22]([O:27][CH3:28])=[CH:21]3)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=CC2CCn3c(C(=O)N(C)C(C)(C)C)cc(-c4cccs4)c3C2C=C1NC(=O)CBr

Procedure:
Bromoacetyl bromide (0.137 ml) was added to a stirred solution of the product of example 95 (500 mg) and DIPEA (0.425 ml) in dichloromethane (20 ml) over a period of 6 h. The reaction mixture was concentrated in vacuo.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[F:23])(C(OC)=O)C(OC)=O)#[N:2].[Cl-].[Na+].O>CS(C)=O>[F:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[CH2:5][CH2:4][CH2:3][C:1]#[N:2]
Reactant: COC(=O)C(CCC#N)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCc1ccc([N+](=O)[O-])cc1F
Temperature: 21 °C
Yield: 64.3 %

Procedure:
A solution of compound Dimethyl 2-(2-cyanoethyl)-2-(2-fluoro-4-nitrophenyl)malonate (73) (0.19 g, 0.59 mmol), sodium chloride (0.10 g, 1.76 mmol) and water (0.15 mL) in distilled dimethylsulfoxide (DMSO, 4 mL) was heated to 155° C. overnight. The reaction mixture was allowed to cool to 21° C. and then worked up by adding water and extracting with ethyl acetate (2×50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (hexane:ethyl acetate, 8:1) to give desired 4-(2-Fluoro-4-nitrophenyl)butanenitrile (72) (79 mg, 65%): 1H NMR δ 8.02 (dd, 1H, J=8.3, 2.2 Hz), 7.94 (dd, 1H, J=9.5, 2.2 Hz), 7.42 (dd, 1H, J=8.3, 7.4 Hz), 2.93 (t, 2H, J=7.7 Hz) 2.41 (t, 2H, J=7.0 Hz) 2.01-2.07 (m, 2H).
Reaction SMILES: O=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>CCOCC>[CH2:21]([O:28][N:29]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NOCc1ccccc1
Reactant: COC(=O)CCC1CCCCCCCCCCC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)CCC1CCCCCCCCCCC1=NOCc1ccccc1
Temperature: 140 °C
Yield: 92.4 %

Procedure:
A heavy walled reaction tube was charged with 3-(2-oxocyclododecyl)-propionic acid, methyl ester (6.0 g, 22.3 mmol), benzyloxyamine hydrochloride (3.99 g, 25 mmol), and pyridine (30 mL). The tube was sealed and heated in an oil bath at 140° C. for 2 hours. Upon cooling, the reaction mixture was diluted with ether (1L) and extracted with 2NN HCl until the aqueous layer was acidic, followed by extraction with water (2×50 mL). The organic phase was dried over magnesium sulfate, filtered through a silica gel plug, and the solvent removed in vacuo to afford 8.1 g (97%) of a crude oil. Purification by flash column chromatography on silica gel (100:1 ratio) and by elution with hexane/ethyl acetate (95/5) afforded 7.7 g (92% yield) of the title compound as a colorless oil with a 4:1 (E/Z) isomer ratio. 1H NMR (CDCl3, 400 Mhz) δ: 7.23-7.36 (m, 5H), 5.03 (s, 2H, (E) major isomer), 5.02 (s, 2H, (Z) minor isomer), 3.63 (s, 2.4H, (E) major isomer), 3.61 (s, 0.6H, (Z) minor isomer), 2.63 (ddd, J=13.3, 9.8, 4.8 hz, 1H), 2.36 (m, 1H), 2.24 (m, 2H), 2.05 (m, 1H), 1.75 -1.84 (m, 2H), 1.69 (m, 2H), 1.52-1.62 (m, 1H), 1.40-1.51 (m, 1H), 1.26 (m, 14H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Cl[CH2:23][C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH3:25]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]([CH3:26])([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:25])[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: CC(C)(CCl)c1ccccc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(CC(C)(C)c3ccccc3)n2)sc1C(=O)NCc1cccnc1
Yield: 20 %

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and (2-chloro-1,1-dimethyl-ethyl)benzene as described in Example 49 and isolated as a white solid, (0.025 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 8.65 (bs, 1H), 8.57 (d, J=4 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.23-7.49 (m, 6H) 6.69 (d, J=2 Hz, 1H), 6.63 (d, J=2 Hz, 1H), 6.12-6.18 (bm, 1H), 4.64 (d, J=4 Hz, 2H), 4.28 (s, 2H), 2.75 (s; 3H), 1.40 (s, 6H); MS (M+H)+=432.2; Rt=1.39 min; HRMS (M+H)+=432.19.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:23]1[S:24][C:25]([CH:29]=[O:30])=[C:26]([Cl:28])[N:27]=1>O1CCCC1>[Cl:28][C:26]1[N:27]=[C:23]([NH:10][CH2:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:11])([F:1])[F:12])=[CH:4][CH:5]=2)[S:24][C:25]=1[CH:29]=[O:30]
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: O=Cc1sc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1sc(NCc2ccc(C(F)(F)F)nc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (74, 1.0 g, 5.7 mmol) and N,N-diisopropylethylamine (2.0 mL, 11 mmol) in 100 mL of tetrahydrofuran, 2,4-dichloro-thiazole-5-carbaldehyde (73, 1.1 g, 6.2 mmol) in 10 mL of tetrahydrofuran was added dropwise at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (75, 1.2 g, 66%). MS (ESI)=[M+H+]+=322.11
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:17]([OH:19])=O)[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2].O=S(Cl)[Cl:22]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:17]([Cl:22])=[O:19])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CC(=O)Oc1ccc(-c2ccccc2)c(C(=O)Cl)c1
Yield: 114.3 %

Procedure:
5.7 g (2.23×10-2 mol) of p-acetyloxybiphenylcarboxylic acid was added to 20 g (1.68×10-1 mol) of SOCl2 and the mixture was heated at reflux for 3.5 hours. After cooling, the solvent was evaporated to give 7.0 g of p-acetyloxybiphenylcarboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=[CH:32][N:31](COCC[Si](C)(C)C)[N:30]=4)=[C:25]([F:42])[CH:24]=3)=[C:16]2[N:15]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=[CH:32][NH:31][N:30]=4)=[C:25]([F:42])[CH:24]=3)=[C:16]2[N:15]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccccc5Cl)nc34)cc2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC[C@H](c2ccccc2Cl)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.3 %

Procedure:
To (S)-4-(2-chlorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (20 mg, 0.033 mmol) in DCM (5 mL) was added TFA (1 mL) and the reaction was stirred at ambient temperature for 6 hours. The reaction was concentrated to dryness and the residue dissolved in MeOH/ammonia (7N). After stirring at ambient temperature for 30 minutes, the reaction was concentrated then purified by reverse phase chromatography (SP4, 12M, water/CH3CN 100:0 to 0:100, 20 column volumes) to yield (S)-4-(2-chlorophenyl)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (9 mg, 57% yield) as a pale yellow solid. LCMS (APCI+) m/z 476.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24]([OH:26])=O)[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:31][O:32][C:33]1[CH:44]=[C:43]2[C:36]([NH:37][CH:38]=[C:39]2[CH2:40][CH2:41][NH2:42])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@@H:7]([C:24]([NH:42][CH2:41][CH2:40][C:39]1[C:43]2[C:36](=[CH:35][CH:34]=[C:33]([O:32][CH3:31])[CH:44]=2)[NH:37][CH:38]=1)=[O:26])[NH:8][C:9](=[O:23])[CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1ccc2[nH]cc(CCNC(=O)[C@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c3ccccc3)c3ccccc3)c2c1
Yield: 36 %

Procedure:
Prepared analogously to Example 5d) from (R)-N5 -[amino (nitroimino) methyl]-N2 -(diphenylacetyl)-ornithine, 5-methoxytryptamine and TBTU in a yield of 36% of theory.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([NH:12]C(=O)OCC)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH3:18][O-:19].[Na+].CO>O>[CH3:18][O:19][C:2]1[C:3]2[N:11]=[C:10]([NH2:12])[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: CCOC(=O)Nc1nc2c(Cl)nc(C)nc2s1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(C)nc2sc(N)nc12
Temperature: 25 °C
Yield: 55.6 %

Procedure:
Ethyl 7-chloro-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbamate (300 mg, 1.100 mmol) was suspended in a 25% w/w solution of sodium methoxide in methanol (5 mL, 23.14 mmol) and the mixture was refluxed overnight. The mixture was cooled to ambient temperature, diluted with water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-amine (120 mg, 0.612 mmol, 55.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (s, 2 H) 3.98 (s, 3 H) 2.52 (s, 3 H).
Reaction SMILES: CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:28]([O:32][C:33]([NH:35][CH:36]([CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C:37]([OH:39])=O)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C.Cl.[CH3:59][NH:60][O:61][CH3:62]>C1COCC1>[C:28]([O:32][C:33](=[O:34])[NH:35][CH:36]([C:37](=[O:39])[N:60]([O:61][CH3:62])[CH3:59])[CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])([CH3:29])([CH3:30])[CH3:31]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
N,N-Dimethylaminopyridine (2.60 g, 21.3 mmol) and BOP reagent (18.15 g, 41.0 mmol) are added to a solution of 2-tert-butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propionic acid (12.37 g, 38.7 mmol), diisopropylethylamine (8.1 mL, 46.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.53 g, 46.4 mmol) in THF (260 mL) at RT. The resulting suspension is stirred at RT overnight then concentrated to dryness. The residue is diluted with EtOAc and washed with saturated NH4Cl, saturated NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the crude product which is purified by flash chromatography eluting with 10-30% EtOAc/Hexanes to yield the title compound (11.86 g, 30.37 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ5.35 (bd, 1H), 4.71 (bs, 1H), 3.78-3.85 (m, 2H), 3.72 (s, 3H), 3.20 (s, 3H), 1.42 (s, 9H), 0.90 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([OH:10])[C:8]#[CH:9]>C(#N)C.[Cu]I>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:9]#[C:8][CH2:7][OH:10]
Reactant: C#CCO
Reactant: Brc1nccs1
Agent: [Cu]I
Solvent: CC#N
Product: OCC#Cc1nccs1
Reaction time: 80 h
Yield: 16.3 %

Procedure:
Copper (I) iodide (28.5 mg) was added to a stirred solution of 2-bromothiazole (5 g), propargyl alcohol (1.68 g), BTPC (210 mg) and DEA (2.41 g) in acetonitrile (88 ml). The mixture was stirred under nitrogen for 80 h, concentrated and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried and concentrated to yield the crude product which was purified by FCC eluting with toluene/ethyl acetate (5:2) to give the title product as a brown oil (0.68 g), t.l.c. (toluene/ethyl acetate 2:1) Rf 0.27.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>CN(C)C=O.C(OCC)(=O)C.[Ag]=O>[CH3:24][N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23]
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: CI
Agent: O=[Ag]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Yield: 84.3 %

Procedure:
9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 200 ml of dimethylformamide, and 14.0 g of silver oxide are added thereto. 42.6 g of methyl iodide are added to the mixture at room temperature under stirring, and the mixture is further stirred for 2 days in the dark. The reaction mixture is filtered to remove insoluble materials, and the filtrate is condensed under reduced pressure. The residue obtained is dissolved in ethyl acetate. Then, the ethyl acetate solution is washed with water, dried and condensed under reduced pressure. The residue thus obtained is washed with n-hexane. 8.45 g of tert.-butyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are thereby obtained as colorless crystals. Yield: 84.3% M.p. 102°-103° C.