Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:51][S:52]([C:55]1[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=1)(=[O:54])=[O:53])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:50])[C@H:31]([CH:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:32][C:33]([O:35][CH3:36])=[O:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:83](O)[CH2:84][CH:85]([CH3:87])[CH3:86].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:51]([CH2:83][CH2:84][CH:85]([CH3:87])[CH3:86])[S:52]([C:55]1[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=1)(=[O:53])=[O:54])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:50])[C@H:31]([CH:37]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[NH:32][C:33]([O:35][CH3:36])=[O:34])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A solution of N-{2-[(3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-{[(4-nitrophenyl)sulfonyl]amino}butyl]phenyl}-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (9, 160 mg, 0.181 mmol), Ph3P (149 mg, 0.568 mmol) and isoamyl alcohol (89 mg, 1.01 mmol) (or any other suitable alcohol) in THF (1.5 ml) stirred at external temperature of 0° C. under N2 atmosphere, was treated with neat DIAD (150 μL, 0.771 mmol) and the mixture stirred at the same temperature for 30 min and then at room temperature in the dark for 16 h, concentrated and purified in a cromatographic cartridge of silicagel (24 g) eluted with 10% to 40% EtOAc in hexane, to get 143 mg (83%) of the title compound as white foam MS: m/z=955.3 (MH+).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[Br:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:2][CH2:3][CH2:4][O:5][CH3:6])[CH:9]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: COCCCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COCCCOc1cc(Br)ccn1
Temperature: 45 °C

Procedure:
11 mmol of silver carbonate and 20 mmol of 1-iodo-3-methoxypropane [61542-10-7] are added under an argon atmosphere to a solution of 21 mmol of 4-bromo-1H-pyridin-2-one [36953-37-4] in 30 ml of benzene. The reaction mixture is heated to 45° C. with exclusion of light for 2 days. The mixture is cooled to room temperature and filtered through Hyflo. The filtercake is washed with benzene and with saturated aqueous sodium hydrogencarbonate solution. The phases of the filtrate are separated and the aqueous phase is extracted with dichloromethane (3×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value by means of flash chromatography (SiO2 60F).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([NH:25][C@@H:26]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27]2)=[O:24])=[CH:21][C:20]=1[O:34][CH2:35][CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH2:35]([O:34][C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][C:19]=1[NH:18][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1)[C:23]([NH:25][C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27]1)=[O:24])[CH3:36]
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: CCOc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Product: CCOc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Yield: 60.7 %

Procedure:
10-Chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 10; 100 mg, 0.39 mmol), 4-amino-3-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide (Intermediate 166; 104 mg, 0.39 mmol) and 4-toluenesulphonic acid monohydrate (187 mg, 0.98 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140° C. for 3 hours. The cooled reaction mixture was absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by base modified preparative reverse phase HPLC to yield the title compound as a white solid (114 mg, 61%).
Reaction SMILES: CO[C:3](=[O:11])[CH2:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH2:16].CO>C1(C)C=CC=CC=1>[CH3:9][C:6]([CH3:7])([CH3:8])[C:5](=[O:10])[CH2:4][C:3]([NH:16][C:15]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:14]=1[O:13][CH3:12])=[O:11]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: COC(=O)CC(=O)C(C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)CC(=O)C(C)(C)C
Reaction time: 4 h

Procedure:
Methyl-4,4-dimethyl-3-oxovalerate (15.8 g, 0.1 mol) and 2-methoxy-5-nitroaniline (16.8 g, 0.01 mol) were taken up in toluene (150 mL) in a round bottomed flask fitted with a Dean-Stark trap. The mixture was heated to a vigorous reflux while the MeOH side-product was distilled off and removed. After 4 hours, the mixture was cooled and the toluene removed in vacuo. The residue was recrystallized from acetonitrile to yield 27 g of the desired condensation product.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[O:12][N:11]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[F:22][C@@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24]O.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([C:5]1[S:9][C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:24][C@@H:23]([F:22])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:19][CH:20]=3)[O:12][N:11]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2cc(-c3ccc(O)cc3)on2)s1
Reactant: CCCCCCCC[C@H](F)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCC[C@H](F)COc1ccc(-c2cc(-c3ccc(CCCC)s3)no2)cc1

Procedure:
3-(5-Butylthiophen-2-yl)-5-{4-[(S)-2-fluorodecyloxy]-phenyl}-isoxazole is prepared similar to Example 6, but 3-(5-butylthiophen-2-yl)-5-(4-hydroxyphenyl)-isoxazole is etherified with (S)-2-fluoro-1-decanol by the method of Mitsunobu (diethyl azodicarboxylate/triphenylphosphine in tetrahydrofuran; Synthesis 1981, 1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].CO>CCO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:3]1[CH:2]=[CH:1][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Sc1ccc2ccccc2c1
Solvent: CO
Solvent: CCO
Product: c1ccc2cc(Sc3ccc4ccccc4c3)ccc2c1

Procedure:
Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-(tert-butyldimethylsilyl) glycidyl ether (5.64 g, 30.0 mmol), AcOH (32 mL, 0.6 mmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-(tert-butyldimethylsilyl) glycidyl ether 5c (2.72 g, 14.5 mmol, 48%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 Torr). The product was determined to be present in >99% ee by derivatization through ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C. and direct analysis of the 2-napthylsulfide thus obtained (Chiralcel OD, 99.25:0.75 hexanes:EtOH, 1 mL/min, 230 nm).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7](C(NCCBr)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][N:17]1[C:22]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][C:20](=[O:29])[N:19]([CH3:30])[C:18]1=[O:31].C(N(CC)CC)C>C(O)(C)C>[CH3:16][N:17]1[C:22]([N:23]2[CH2:28][CH2:27][N:26]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=3)[CH2:25][CH2:24]2)=[CH:21][C:20](=[O:29])[N:19]([CH3:30])[C:18]1=[O:31].[CH3:16][N:17]1[C:22]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][C:20](=[O:29])[N:19]([CH3:30])[C:18]1=[O:31]
Reactant: O=C(NCCBr)c1ccc([N+](=O)[O-])cc1
Agent: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1c(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O

Procedure:
A mixture of 1.3 g of the compound 46 obtained in the paragraph (1), 1.8 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)pyrimidinedione (compound 37), 1.3 ml of triethylamine and 10 ml of isopropanol was heated under reflux for 3 hours.
Reaction SMILES: O.[NH2:2]N.[Cl:4][C:5]1[CH:6]=[C:7]([C:12](=O)[CH:13]=[CH:14][N:15](C)C)[CH:8]=[C:9]([Cl:11])[CH:10]=1>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:13]=[CH:14][NH:15][N:2]=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CN(C)C=CC(=O)c1cc(Cl)cc(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Clc1cc(Cl)cc(-c2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
2.4 g (0.05 mol) of hydrazine hydrate are added slowly and at room temperature to a solution of 9 g (0.0369 mol) of 1-(3,5-dichlorophenyl)-3-dimethylamino-2-propen-1-one in 100 ml of ethanol. The reaction mixture is stirred for 2 hours at room temperature and then concentrated to dryness. The residue of triturated in heptane. 7.1 g (90% yield, melting point 156° C.) of 3-(3,5-dichlorophenyl)-1H-pyrazole are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[C:17](=[O:31])[CH:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.BrC1C=NC(N2CCC(OC3C=CN([C:52]4[CH:57]=[CH:56][C:55](S(C)(=O)=O)=[CH:54][CH:53]=4)C(=O)C=3)CC2)=NC=1.C1(B(O)O)CC1>C1COCC1>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)=[CH:7][N:6]=4)[CH2:9][CH2:10]3)=[CH:16][C:17]2=[O:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ncc(Br)cn4)CC3)cc2=O)cc1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ccc(Br)cn4)CC3)cc2=O)cc1
Agent: OB(O)C1CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ccc(-c5ccccc5)cn4)CC3)cc2=O)cc1
Temperature: 120 °C

Procedure:
Example 116 was prepared according to procedures described in Example 105 substituting 4-(1-(5-bromopyridin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one for 4-(1-(5-bromopyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one, substituting phenylboronic acid (Aldrich) for cyclopropylboronic acid and substituting DMF for THF. The reaction was heated under microwave conditions at 120° C. for 10 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (d, J=2.45 Hz, 1 H), 7.95 (d, J=8.31 Hz, 2 H), 7.77 (dd, J=9.05, 2.20 Hz, 1 H), 7.51-7.63 (m, 5 H), 7.34 (t, J=7.58 Hz, 2 H), 7.21 (t, J=7.82 Hz, 1 H), 6.90 (d, J=8.80 Hz, 1H), 5.98-6.04 (m, 2 H), 4.65-4.73 (m, 1 H), 3.92-4.00 (m, 2 H), 3.26-3.34 (m, 2 H), 3.20 (s, 3 H), 1.92-2.00 (m, 2 H), 1.51-1.61 (m, 2 H). MS (ESI) 502 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.B([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)(O)O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:20]([CH3:26])[CH:21]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Product: Cc1cc(C(=O)C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 74, step 6, from (R)-3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one (example 282, step 1) and 4-boronobenzoic acid was prepared the title compound a brown foam, MS (ESI+): m/z=470.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Product: CN1c2cc(OCc3ccc(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[C:11]([OH:12])=[C:10]([O:13][CH:14]2CCCC2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>CS(C)=O>[Br:3][C:4]1[C:11]([O:12][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(OC2CCCC2)c(O)c1Br
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a stirred suspension of potassium fluoride (125 mg, 2.104 mmol) in dry DMSO (2.5 ml) was added a solution of 2-bromo-4-cyclopentoxy-3-hydroxy-benzaldehyde (500 mg, 1.754 mmol) in DMSO (2.5 ml). A solution of 4-fluoronitrobenzene (500 mg, 2.631 mmol) in DMSO (2.5 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 6 h. The reaction mixture was cooled to room temperature and the contents were poured into water (100 ml) and extracted with ethyl acetate (50 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (25 ml×2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vacuo to give 2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde as a pale yellow solid (500 mg) mp: 115–117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][C:28](=[O:39])OC2C=CC([N+]([O-])=O)=CC=2)([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.ClCCCl.Br.[F:45][C:46]1([F:51])[CH2:50][CH2:49][NH:48][CH2:47]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][C:28]([N:48]2[CH2:49][CH2:50][C:46]([F:51])([F:45])[CH2:47]2)=[O:39])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: FC1(F)CCNC1
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: ClCCCl
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)N1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
To a crude solution of (S)-4-nitrophenyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylcarbamate in DCE (1 mL) (67 mg, 0.13 mmol) was added 3,3-difluoropyrrolidine hydrobromide (24 mg, 0. 12 mmol). The reaction mixture was stirred at room temperature for 2 h and the solution turned yellow. The solution was concentrated, dissolved in MeOH (1.5 mL), filtered and purified by reverse phase prep. HPLC YMC ODSA 30×100 mm, 20-100% MeOH/H2O (0.1% TFA) gradient over 10 mins at 20 mL/min flow rate. (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3,3-difluoropyrrolidine-1-carboxamide (0.011 g, 17% yield) eluted at a retention time of 11.2 mins and was isolated as colorless oil. LCMS: 2.15 min [M+1] 528.2 (2 min gradient, MeOH/H2O 0.1% TFA) 1H NMR (CDCl3, 400 MHz): 8.20 (d, J=2.0 Hz, 1H), 7.60 (dd, J=2 Hz, J=8 Hz, 1H), 7.46 (s, 1H), 7.30 (d, J=8 Hz, 1H), 7.15 (m, 2H), 7.05 (m, 1H), 7.03 (m, 3H), 6.44, (d, J=8 Hz, 1H), 4.37, (d, J=12 Hz, 1H), 3.74, (q, J=12 Hz, 1H), 3.54, (m, 1H), 3.44, (m, 2H), 3.32, (q, J=8 Hz, 1H), 2.32, (m, 2H).
Reaction SMILES: [Br-].[OH:2][C:3]1[N+:10]2[C:9]3[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=3[S:7][C:6]=2[S:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)Cl>O>[C:15]1([CH:4]2[S:5][CH:6]3[S:7][C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[N:10]3[C:3]2=[O:2])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1c(-c2ccccc2)sc2sc3c([n+]12)CCCC3
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: O=C1C(c2ccccc2)SC2SC3=C(CCCC3)N12
Yield: 63 %

Procedure:
9.7 g. (0.026 moles) of 3-hydroxy-2-phenyl-5,6,7,8-tetrahydrothiazolo[2,3-b]benzothiazolium bromide, prepared according to Example 10, is suspended in a mixture of 1000 ml. methylene chloride and 500 ml. water, and the mixture is stirred at room temperature for 5 hours. The layers are separated and the methylene chloride layer is dried over anhydrous magnesium sulfate. The drying agent is removed by filtration and the filtrate is reduced in volume. The residual solid is triturated with ether and the yellow solid is collected. The crude material is recrystallized from 1.5 l. of acetonitrile to yield a yellow solid weighing 4.7 g. (63% yield). The product melts at ca. 200° C.(dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][S-:10].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:10][CH3:9])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,6-dibromopyridine (200 mg, 0.844 mmol) in DMF (2 mL), was added sodium methanethiolate (65.1 mg, 0.929 mmol). The mixture was stirred at rt for 16 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 20% EtOAc/hexanes gradient) to afford Intermediate 165.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.Cl.[Cl:24][CH2:25][CH2:26][NH2:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:27][CH2:26][CH2:25][Cl:24])=[O:12])=[C:4]2[N:3]=1
Reactant: NCCCl
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCl)c1cnn2ccc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a suspension of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (284 mg, 1.31 mmol) in DCM (10 mL) was added DIEA (1.14 mL, 6.57 mmol). The solution was cooled to 0° C., then treated with 2-chloroethylamine hydrochloride (183 mg, 1.58 mmol) and stirred for 1 hour. The mixture was partitioned between water (30 mL) and DCM (30 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford 5-chloro-N-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (290 mg, 85% yield) as a beige solid. MS (apci) m/z=258.9 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][C:9]([SH:11])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:7]2[O:8][C:9]([S:11][CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Sc1nc2ccnc(Br)c2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2ccnc(Br)c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.21 g (5.24 mmol) 4-bromo-oxazolo[5,4-c]pyridine-2-thiol, 0.8 g (5.76 mmol) K2CO3, 0.9 g (6.28 mmol) MeI in 12 ml DMF is stirred at room temperature for 1 h. The reaction mixture is then poured on water and extracted 2× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound in quantitative yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[Cs+]>O1CCOCC1>[C:10]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 140 mg (0.15 mmol) of {[(t-Bu)2P(OH)]2PdCl}2 (from Experiment 7), 1.43 g (10.0 mmol) of 4-chloroanisole, 1.83 g (15.0 mmol) of PhB(OH)2 and 4.56 g (30.0 mmol) of CsF in 30.0 mL of 1,4-dioxane. The resulting mixture was refluxed for 8 h until the starting material was completely consumed as judged by GC. The reaction was cooled to room temperature, transferred to a separatory funnel, and diluted with 300 mL of diethyl ether and 100 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the ether and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using 2% EtOAc/hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 0.97 g (53% yield) of 4-phenylanisole.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7](O)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O>COCCOC>[C:10]([NH:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.02 h
Yield: 92.2 %

Procedure:
In 5 ml of 1,2-dimethoxyethane (DME), 1.201 g of Boc-Ile-OH.1/2H2O was dissolved and 550 μl of N-methylmorpholine and 650 μl of isobutyl chloroformate were successively added dropwise at −15° C. After stirring for 1 min, the formed N-methylmorpholine hydrochloride was filtered off and washed twice with 2.5 ml each of DME. The filtrate and washings were combined and 284 mg of sodium borohydride in 2.5 ml of water was added in one portion. After 30 sec, 125 ml of water was added and the mixture was extracted with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure to give 1.040 g of the title compound.
Reaction SMILES: S(=O)(=O)(O)N.[C:6]1([N:12]2[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl([O-])=[O:20].[Na+]>O.CC(C)=O>[C:6]1([N:12]2[CH:16]=[C:15]([C:17]([OH:20])=[O:18])[CH:14]=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cnn(-c2ccccc2)c1
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cnn(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
Sulphamic acid (253 mg, 2.6 mmol) in water (0.5 mL) was added at 0° C. to a mixture of phenyl-1H-pyrazole-4-carbaldehyde (0.5 g, 2.34 mmol) in acetone (3 mL). After 5 minutes sodium chlorite (315 mg, 3.5 mmol) was added and the resulting mixture was stirred at 0° C. for 30 minutes. Water was added and the solid obtained was isolated by filtration to afford 140 mg (85% yield) of 1-phenyl-1H-pyrazole-4-carboxylic acid.