Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@H:20]([C:24](O)=[O:25])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CN.C[CH2:35][N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@H:20]([C:24]([NH:36][CH3:35])=[O:25])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@H](C(=O)O)C3)n3nccc3n2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Yield: 63.1 %

Procedure:
A solution of (S)-1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-3-carboxylic acid (Compound 86, 100 mg, 0.236 mmol), methylamine (65 μL, 0.472 mmol), EDCI (90 mg, 0.472 mmol), and HOBT (16 mg, 0.118 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC (30-40% MeCN/H2O gradient+0.01% TFA) provided the titled compound as a white solid (65 mg, 63%). 1H NMR (DMSO-d6) δ: 10.92 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.8 Hz, 3H), 7.61 (d, J=8.6 Hz, 2H), 7.38 (s, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.37 (d, J=8.8 Hz, 1H), 4.30 (d, J=12.1 Hz, 1H), 3.27 (dd, J=12.4, 10.6 Hz, 1H), 3.05 (d, J=11.4 Hz, 1H), 2.54-2.63 (m, 4H), 1.65-1.99 (m, 4H), 1.46 (s, 6H). ESI-MS: m/z 437.0 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH2:3]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)[CH3:4]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:3][CH3:4])=[CH:7][C:8]=1[F:12]
Reactant: BrBr
Reactant: CCSc1cccc(F)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCSc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Bromine (0.3 ml) was added to a solution of 1-ethylsulfanyl-3-fluoro-benzene (1 g) in chloroform (20 ml) at 0° C. then warmed to RT. After 2 h the mixture was diluted with DCM, washed with aq. sodium thiosulphate solution, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% diethylether/iso-hexane. Yield 1.2 g
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:16]2[C:33]([NH2:35])=O)=[CH:11][CH:10]=1>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:16]2[C:33]#[N:35])=[CH:11][CH:10]=1
Reactant: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(N)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C#N)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
To ice-cold DMF (1 ml) under an argon atmosphere was added oxalyl chloride (68 ml, 0.78 mmol). After stirring for 5 min at 0° C., a solution of (1RS,2SR,3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxamide (150 mg, 0.39 mmol) in DMF (2 ml) was added, and stirring was continued for an additional 10 min at 0° C. The reaction mixture was partitioned between EtOAc and 3M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to afford the title compound as a white solid (135 mg, 94%) which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[F:18].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([N:1]2[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]2)=[C:11]([F:18])[CH:12]=1)#[N:15]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: O=C(O)c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-n2cnc(C(=O)O)c2)c(F)c1
Temperature: 120 °C

Procedure:
A mixture of 1H-imidazole-4-carboxylic acid (500 mg), 4-fluoro-3-fluorobenzonitrile (0.93 g), and N,N-diisopropyl-ethyl amine (3.6 mL) in N,N-dimethylformamide (6 mL) is heated to 120° C. overnight. The crude product is purified by HPLC. LC (method 20): tR=1.85 min; Mass spectrum (APCI): m/z=232 [M+H]+.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH:40]([OH:47])[C:41]([O:43][CH:44]([CH3:46])[CH3:45])=[O:42])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]([NH:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH:40]([OH:47])[C:41]([O:43][CH:44]([CH3:45])[CH3:46])=[O:42])=[O:37])[CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(O)C(=O)OC(C)C
Reactant: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC(C)C
Yield: 10.3 %

Procedure:
To a solution of 50 mg of 2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionic acid and 70 mg of isopropyl(2RS,3S)-3-(L-histidyl)amino-2-hydroxy-5-methylhexanoate dihydrochloride in 4 ml of N,N-dimethylformamide were added 0.036 ml of diphenylphosphoryl azide and 0.064 ml of triethylamine with stirring under ice-cooling, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol=5/1 by volume; Rf2 =0.36) to obtain 10 mg of isopropyl(2RS,3S)-3-{N-[2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:17](CC)([O-])=O.C([O-])(=O)C.[Na+].C(O)(=O)C>O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:17]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccsc2)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc(OCc2ccsc2)cc1O

Procedure:
A mixture of 2-hydroxy-4-(3-thienylmethoxy)benzaldehyde (7.7 g), nitroethane (4.74 mL), sodium acetate (5.4 g) and glacial acetic acid (6.6 mL) is heated at reflux for 14 hours. The mixture is then cooled, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts are washed with saturated aqueous sodium bicarbonate solution (3×50 mL), dried over magnesium sulphate, and concentrated in vacuo. The resulting residue is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (3:7 v/v), to give 2-hydroxy-4-(3-thienylmethoxy)benzonitrile (7.6 g), in the form of a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=O)=[CH:4][N:3]=1.O.[CH3:21][N:22](C=O)[CH3:23]>S(=O)(=O)(O)O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]2[N:8]=[C:6]([C:5]3[CH:18]=[CH:19][C:2]([N:22]([CH3:23])[CH3:21])=[N:3][CH:4]=3)[O:17][C:10]=2[CH:11]=1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(O)c1
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc2nc(-c3ccc(N(C)C)nc3)oc2c1
Reaction time: 0.33 h

Procedure:
6-Chloro-N-(2-hydroxy-4-methoxyphenyl)nicotinamide (40 mg, 0.14 mmol) was dissolved in DMF (1.5 mL) and one drop of sulfuric acid was added. The reaction was run at 230° C. for 20 minutes in a microwave reactor. The mixture was added to water, the solid was collected, rinsed with water and dried. The crude product was purified by flash column chromatography using 40% ethyl acetate in hexane, giving the title compound (14 mg) as an orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.96 (d, 1H) 8.19 (dd, 1 H) 7.57 (d, 1H) 7.10 (d, 1H) 6.92 (dd, 1H) 6.60 (d, 1H) 3.88 (s, 3H) 3.20 (s, 6H); MS m/z (M+H) 270.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.O.ClCCl>ClCCl>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)=[CH:24][N:25]=1
Reactant: COc1ccc(O)cn1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
10.1 g (119.9 mmol, 1.5 eq.) of 3,4-dihydro-2H-pyran and 1.4 g (8.0 mmol, 0.1 eq.) of 4-toluenesulphonic acid were added to a solution of 10.0 g (79.9 mmol) of 6-methoxypyridin-3-ol in 150 ml of dichloromethane, and the mixture was stirred at RT for 5 d. After addition of water/dichloromethane and phase separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 17.3 g (100% of theory)
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:3]([CH2:8][C:9]([OH:11])=[O:10])([CH2:4][C:5](O)=[O:6])[O:2]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:1]1[CH2:13][O:12][C:3]2([CH2:8][C:9](=[O:11])[O:10][C:5](=[O:6])[CH2:4]2)[O:2]1
Reactant: O=C(O)CC1(CC(=O)O)OCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C1CC2(CC(=O)O1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of 3,3-(ethylenedioxy)glutaric acid (12.26 g, 64.50 mmole) in 300 ml of tetrahydrofuran maintained at 0° C. under nitrogen was added dropwise a solution of dicyclohexylcarbodiimide (13.60 g, 65.91 mmole) in 100 ml of tetrahydrofuran. The resulting suspension was stirred at room temperature overnight under nitrogen and the solvent was evaporated under vacuum. The residue was suspended in benzene, shaken thoroughly and filtered through silica gel packed in a column (10 cm long, SiO2, 60-200 mesh, benzene). The filtrate was evaporated under vacuum to provide the anhydride (8.268 g, 75% yield) as a white crystalline solid melting at about 111° C. to about 112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12].O1CCCC1.Cl>CO.[Pd]>[ClH:1].[NH2:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:2]([Cl:1])[CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CN)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 167.6 %

Procedure:
A mixture of N-(2-chloro-4-cyanophenyl)methanesulfonamide (0.5 g, 2.2 mmol) and 10% Pd—C (100 mg) in methanol (7.5 ml)-tetrahydrofuran (7.5 ml)-12M aqueous solution of hydrogen chloride (3.0 ml) was stirred under H2 balloon pressure for 2 hours at ambient temperature. Then, filtration to remove 10% Pd—C, evaporation gave the crude residue, which was applied to recrystallization from methanol and diisopropylether to furnish 500 mg (85% yield) of title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH2:7][CH:6]2[CH:4]([CH2:5]2)[C:3]=1[CH:8]=O.[CH2:10]([O:12][C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14])[CH3:11]>>[Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:4]([CH2:5]2)[C:3]=1/[CH:8]=[CH:15]/[C:13]([O:12][CH2:10][CH3:11])=[O:14]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1=C(Cl)CC2CC12
Product: CCOC(=O)/C=C/C1=C(Cl)C[C@@H]2C[C@H]12

Procedure:
3-Chlorobicyclo[3.1.0]hex-2-ene-2-carbaldehyde (142 mg, 0.67 mmol) was olefinated according to General Procedure 1.1.B with ethoxycarbonylmethylene triphenylphosphorane ((487 mg, 1.4 mmol). The material was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 10% EtOAc to afford the title compound. 142 mg. 1H NMR (CHLOROFORM-d) δ: 7.57 (d, J=15.8 Hz, 1H), 6.11 (d, J=15.7 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 3.01 (dd, J=19.1, 7.3 Hz, 1H), 2.65 (dd, J=19.1, 2.9 Hz, 1H), 1.93-2.03 (m, 1H), 1.61 (qd, J=7.3, 4.3 Hz, 1H), 1.33 (t, J=7.1 Hz, 3H), 1.00 (td, J=7.5, 4.7 Hz, 1H), 0.13-0.21 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH2:4][CH2:3]1.Br[C:13]1[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=1>>[CH3:11][O:10][C:8]([CH:6]1[CH:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7]1)=[O:9]
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: FC(F)(F)c1cccc(Br)c1
Product: COC(=O)C1CN(C)CCC1c1cccc(C(F)(F)F)c1

Procedure:
3-methoxycarbonyl-1-methyl-4-(3-trifluoromethylphenyl)piperidine was prepared as the cis/trans mixture from arecoline and 3-bromo-trifluoromethylbenzene as described (J.Org.Chem. 22 (1957) 261). The product was purified by vacuum distillation. B.p. 90°-110° C./0.7 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24]>C(O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[N:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC1(C)CC(=NO)c2cc(OCc3ccccc3)ccc2O1
Yield: 105.1 %

Procedure:
By heating 11.3 g (40 mmol) of 6-benzyloxy-2,2-dimethylchroman-4-one with 3.1 g (44 mmol) of hydroxylamine hydrochloride in 27 ml of ethanol and 27 ml of pyridine to 70° C. for 3 h, 12.5 g of product, m.p. 105-108° C., were obtained after distilling off the solvt in vac. and precipitating with water. The product was dissolved in EA, dried, concentrated and crystallized using petroleum ether; m.p. 118-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:11]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:11]([CH2:20][C:21]([OH:23])=[O:22])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(Br)cc2)n1-c1ccc(O)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccc(Br)cc2)n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(5-(4-bromophenyl)-1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)acetate (2.0 g, 5.013 mmol) in THF/H2O (v/v=1/1, 20 mL) was added LiOH H2O (632 mg, 15.038 mmol). The solution was stirred at room temperature for 3 h. THF was evaporated in vacuo and the resultant aqueous solution was acidified with 10% HCl to pH=3.0. The resultant precipitate was isolated by filtration, rinsed with water (50 mL) and dried in vacuo to afford 4C, R2=4-bromophenyl (1.380 g, yield 74%) as a brown powder.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:26])[NH:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])([CH3:16])([CH3:15])[CH3:14].O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.ClCCl>[C:13]([O:17][C:18](=[O:26])[NH:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:23][N:28]1[C:32](=[O:33])[C:31]2[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]1=[O:38])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CNC(=O)OC(C)(C)C)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
Diethylazodicarboxylate (8.26 mL, 52.4 mmol) was added to a solution of (3-hydroxy-2,2-dimethyl-propyl)-carbamic acid tert-butyl ester (10.2 g, 49.9 mmol), N-hydroxyphthalimide (8.15 g, 49.9 mmol) and triphenylphosphine (13.1 g, 49.9 mmol) in THF (200 mL). The solution was stirred at room temperature for 16 hours after which time it was diluted with dichloromethane and passed through a plug of silica gel, eluting with dichloromethane. The product containing fractions were concentrated to a yellow liquid, which was further purified by flash column chromatography (dichloromethane to 4:1 dichloromethane/ethyl acetate) to provide pure desired product (1.98 g, 11%) as a waxy white solid.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[C:3]#[N:4].[C:7]([N:11]=[C:12]=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:3]([C:2]([NH:6][C:12]([NH:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])([CH3:5])[CH3:1])#[N:4]
Reactant: CC(C)(N)C#N
Reactant: CC(C)(C)N=C=O
Product: CC(C)(C)NC(=O)NC(C)(C)C#N
Reaction time: 0.08 h

Procedure:
In a nitrogen atmosphere, 24.8 g. (0.3 mole) 2-methyl-2-aminopropionitrile and 30.7 g. (0.3 mole) t-butyl isocyanate, 97%, are combined and stirred for 5 minutes. At the end of this period, the mixture is filtered and 1 ml. of pyridine is added to the filtrate. This mixture is heated in an oil bath for one and one-half hours, keeping the temperature of the bath below 70°. The solid is recrystallized from methanol:water, 60:40, to give N-(1-cyano-1-methylethyl)-N'-(1,1-dimethylethyl)urea, m.p. 204°-5°; Anal. Calcd. for C9H17N3O; C: 58.99, H: 9.35, N: 22.93; Found: C: 59.21, H: 9.26, N: 22.59.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[N:4][N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cnn(-c2ccccn2)c1
Reactant: COc1cccc(B(O)O)c1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cnn(-c3ccccn3)c2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(4bromo-1H-pyrazol-1-yl)pyridine (0.669 g, 3.0 mmol), 3-methoxyphenylboronic acid (0.453 g, 3.0 mmol) and potassium carbonate (0.828 g, 6.0 mmol) in a mixture of ethyleneglycol dimethyl ether (20 mL) and H2O (4 mL) were degassed by argon bubbling for 15 min., then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) was added and degassing continued a further 15 min. The resulting solution was stirred at 70° C. for 14 h, whereupon H2O (30 mL) was added, then extracted with EtOAc (3×30 mL) and the combined extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo, and the crude residue was chromatographed on silica gel eluting with EtOAc:hexane (1:4) afford a white solid which was recrystallized from EtOAc/Hexane to give 2-[4(3-methoxyphenyl)-1H-pyrazol-1-yl]pyridine. MP=89-90° C. 1H NMR (CD3Cl, 300 MHz) δ 8.84 (s, 1H), 8.45 (dd, 1H), 8.03 (s, 1H), 8.02 (d, 1H), 7.84 (dd, 1H), 7.34 (t, 1H), 7.23˜7.15 (m, 3H), 6.84 (dd, 1H) 3.87 (s, 3H). MS (ESI) 252.1 (M++H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:12][O:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]1[CH:18]=[C:19]([OH:34])[CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][O:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:34][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reactant: CNC(=O)c1ccc(F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](C)O4)[nH]3)c2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
5-Fluoro-N-methylpyridine-2-carboxamide (122 mg, 0.79 mmol) synthesized in Example (123a) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (275 mg, 0.83 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (219 mg, 1.58 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (283 mg, yield 77%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19](Br)[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1>C(Cl)(Cl)(Cl)Cl>[CH3:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:9]([CH3:8])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCC(Br)c1cccc(OCc2c(C)cccc2C)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC=Cc1cccc(OCc2c(C)cccc2C)c1
Reaction time: 4 h

Procedure:
Add Triethylamine to a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-bromo-butyrate (Step E) in carbon tetrachloride. After stirring approximately for 4 hours, the mixture can be filtered through a pad of silica gel few times, and concentrate to give the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1([CH:10](O)[CH:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[N:8]N=C1.[N:27]1C=CC=C[CH:28]=1>ClCCl>[N:5]1([CH:10]=[C:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:12]([CH3:13])([CH3:14])[CH3:15])[CH:9]=[N:8][CH:28]=[N:27]1
Reactant: CC(C)(C)C(COc1ccc(Cl)cc1Cl)C(O)n1cnnc1
Reactant: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)C(=Cn1cncn1)COc1ccc(Cl)cc1Cl
Yield: 75 %

Procedure:
With stirring, 100 ml of dichloromethane and 10 ml of thionyl chloride are cooled to -30° C. and then 17.5 g (0.05 mole) of 1-(1H-1,3,4-triazolyl)-2-(2,4-dichlorophenoxymethyl)-3,3-dimethylbutanol are added in portions. The reaction mixture is stirred for 2 hours and then a solution of 15 ml of pyridine in 30 ml of dichloromethane is added dropwise and the mixture is stirred for about 12 hours at room temperature. The clear solution is concentrated in vacuo and, after addition of ice, the residue is made alkaline with sodium carbonate and extracted with diethyl ether. The combined extracts are dried over sodium sulfate, filtered and concentrated. The yellowish oily residue is purified by column chromatography over silica gel with ethyl acetate as eluant. Yield: 75% of theory.