Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:39]=2[N:40]=[CH:41][N:42]=1)[C@@H:15]1[O:38][C@H:28]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:17](OC(OC2C=CC=CC=2)=S)[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([O:45]C(=O)/C=C\[Sn](CCCC)(CCCC)CCCC)[CH3:44].C[Sn](C)C.C[Sn](C)C.N([C:78]([CH3:82])([CH3:81])C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:39]=2[N:40]=[CH:41][N:42]=1)[C@@H:15]1[O:38][C@H:28]([CH2:29][O:30][Si:31]([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:32])[CH3:33])[C@@H:17]([C:43](=[O:45])[CH:44]=[CH:82][CH2:78][CH3:81])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1OC(=S)Oc1ccccc1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CCCC[Sn](/C=C\C(=O)OCC)(CCCC)CCCC
Agent: C[Sn](C)C
Solvent: Cc1ccccc1
Product: CCC=CC(=O)[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 87 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
N6 -Benzoyl-5'-O-tert-butyldimethylsilyl-2,'3'-dideoxy-3'-ethylacrylyladenosine (Compound 10, Table III) was prepared by dissolving N6 -Benzoyl-5'-O-tert-butyldimethylsilyl-2'-deoxy-3'-O-phenoxythiocarbonyladenosine (50 mg, 0.08 mmole), cis-ethyl-3-tributylstannyl-2-propenoate (92 mg, 0.236 mmole) and hexamethylditin (13 mg, 0.04 mmole) in 2 ml toluene in a 40 ml Schlenk tube, and then adding 15 mg (0.11 mmole) azo-bis-isobutyronitrile to the mixture. The resulting mixture was freeze-pump-thaw degassed 3 times and then heated at 87° C. in an oil bath for 3 days. Approximately every 12 hours, fresh 15 mg azo-bisisobutyronitrile was added to the reaction. Following the 3-day incubation period, the reaction was cooled, the solvent evaporated, and the residue chromatographed with 1% ethanol in dichloromethane as eluent. A yield of 19 mg N6 -Benzoyl-5'-O-tert-butyldimethylsilyl-2',3'-dideoxy-3'-ethylacrylyladenosine was obtained as a white solid after evaporation of the appropriate fractions (42% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14]/[C:15](/[NH2:19])=[CH:16]\[C:17]#[N:18].[CH2:20]([CH:23]1[CH2:28][C:27](=[O:29])[CH2:26][C:25](=O)[CH2:24]1)[CH2:21][CH3:22]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:26]3[C:27](=[O:29])[CH2:28][CH:23]([CH2:20][CH2:21][CH3:22])[CH2:24][C:25]=3[NH:19][C:15]([CH3:14])=[C:16]2[C:17]#[N:18])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: C/C(N)=C\C#N
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 3-bromo-4-hydroxy-5-nitro-benzaldehyde (18.26 g), 3-aminocrotonitrile (6.09 g) and 5-propylcyclohexane-1,3-dione (11.45 g) in ethanol (250 ml) was stirred at 80° C. for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in dichloromethane as eluent.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].Cl.[NH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=O.[Na]>C(O)(=O)C.C1COCC1.CO>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][N:32]2[CH2:33][CH2:34][CH2:35][C:36]2=[O:38])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CCOC(=O)CCCN
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCCC2=O)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (84 mg, 0.189 mmol; Example 91, Step C), ethyl 4-aminobutyrate hydrochloride (127 mg, 0.756 mmol) and acetic acid (3 drops) in DCE/MeOH (3/1, 4.0 mL) was added sodium triacetoxyhydroborate (200 mg, 0.945 mmol) at 25° C. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 solution and was extracted with DCM. The combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under reduced pressure. The residue was purified by reverse phase preparatory HPLC (acetonitrile in water with 0.1% TFA, gradient elution) to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O.C(OCC)(=O)C>O.O1CCOCC1>[C:17]([O:16][C:14]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-aminobenzoic acid (5 g, 36.5 mmol) in water (40.0 ml) was added aq. solution of sodium hydroxide (2.187 g, 54.7 mmol) followed by (BOC)2O (10.16 ml, 43.8 mmol) in dioxane (20.0 ml) under ice cooling. The mixture was stirred under ice cooling for 30 min and further at room temperature for 12 hrs. To the reaction mixture ethyl acetate (50.0 ml) was added and the aq. layer was separated. The aq. layer was acidified up to pH 4 using 2N HCl and precipitated crystals were collected by filtration (7.2 gm).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)[CH2:2]2.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:10](=[O:19])[O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Reactant: OB(O)c1ccccc1
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CN2CCC1CC2
Yield: 86.8 %

Procedure:
Using general procedure E, quinuclidin-3-yl2-bromophenylcarbamate (130 mg, 0.400 mmol), phenylboronic acid (96 mg, 0.8 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (112 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 8.07 (br s, 1H), 7.55-7.33 (m, 6H), 7.25-7.21 (dd, J=7.6 & 1.6 Hz, 1H), 7.43 (td, J=8.0, 1.2 Hz, 1H), 6.65 (br s, 1H), 4.78 (m, 1H), 3.24 (m, 1H), 2.90-2.68 (m, 5H), 2.04 (m, 1H), 1.80-1.62 (m, 2H), 1.61-1.50 (m, 1H), 1.41-1.30 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 151.2, 135.9, 132.5, 129.5, 128.0, 127.0, 126.9, 126.2, 125.7, 121.4, 117.9, 69.9, 53.1, 45.1, 44.3, 23.1, 22.3, 17.2 ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.47 min; (M+1) 323.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:19]1[CH2:29][CH2:28][CH2:27][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]1>CC#N>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:19]2[CH2:29][CH2:28][CH2:27][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
4-Chlorobenzyl chloride (6.42 g, 39.9 mmol) and iPr2NEt (7.74 g, 40.0 mmol) were added to a solution of ethyl nipecotate (6.29 g, 40.0 mmol) in CH3CN (15 mL). The reaction mixture was stirred at 70° C. for 1.5 h. The solvent was removed under reduced pressure. Saturated aqueous NaHCO3 (50 mL) was added to the residue and the mixture was extracted with EtOAc (100 mL). The organic phase was washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to afford ethyl 1-(4-chlorobenzyl)nipecotate as a red yellow oil (11.025 g, 97.8%) used without further purification. The purity was determined by RPLC/MS (97%); ESI/MS m/e 382.2 (M++H, C15H21ClNO2).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[NH2:35])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[CH2:32][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[O:22])=[CH:19][CH:20]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: CN1CCN(Cc2ccccc2N)CC1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cc1

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 2-(4-methylpiperazin-1-ylmethyl)aniline (32.0 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum N-(6-methyl-4′-{[2-(4-methylpiperazin-1-ylmethyl)anilino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide (63 mg, 79%). NMR; δH [2H6]-DMSO includes 11.56,(1H, s), 9.94,(1H, s), 8.36-8.34,(2H, m), 8.02,(2H, d), 7-78,(1H, t), 7.68,(1H, dd), 7.64,(1H, d), 7.54,(2H, d), 7.35-7.25,(3H, m), 7.06,(1H, m), 6.98,(1H, m), 3.73,(2H, s), 2.22,(3H, s), 2.11, (3H, s). LCMS: retention time 2.60 min, MH+509.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:23][C:24](=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CCO>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:16]4[CH:23]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:21]=[C:17]4[CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)n1
Solvent: CCO
Product: CCOC(=O)c1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Temperature: 25 °C

Procedure:
A mixture of N-(1-adamantylmethyl)-6-aminopyridine-2-carboxamide (19.17 g, 65.2 mmol) and ethyl bromopyruvate (9.1 mL, 65.2 mmol) in EtOH (160 mL) is heated under reflux for 20 h. After cooling to RT, the solvent is removed in vacuo. The residue is partitioned between EtOAc and saturated aqueous sodium carbonate. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The brown residue is purified by re-crystallization from EtOAc and hexanes to give the title compound. 1H-NMR (δ, ppm, CDCl3 as internal standard): 9.03 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.26 (dd, J=6.9 and 9.0 Hz, 1H), 7.17 (d, J=6.9 Hz, 1H), 6.26 (m, 1H), 4.45 (q, J=6.9 Hz, 2H), 3.22 (d, J=6.6 Hz, 2H), 2.04 (m, 3H), 1.78-1.58 (m, 12H), 1.43 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH-].[K+].O.[CH3:4][C@:5]12[CH2:22][CH2:21][C@H:20]3[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH2:17][CH2:16][C:15](=[O:23])[CH:14]=4)[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[C:24]([O:26]C)=[O:25]>CO>[CH3:4][C@:5]12[CH2:22][CH2:21][C@H:20]3[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH2:17][CH2:16][C:15](=[O:23])[CH:14]=4)[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[C:24]([OH:26])=[O:25]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O

Procedure:
To a stirred solution of 10.123 g. of potassium hydroxide in a mixture of 11.3 ml. of water and 180 ml. of methanol, is added 15 g. of the methyl carboxylate ester product of Step C. above, which is rinsed in with 22.5 ml. of additional methanol. The reaction mixture is placed in an oil bath and heated to reflux, where it is maintained overnight under a nitrogen atmosphere. The reaction mixture is then removed from the heat, concentrated briefly under the nitrogen stream, and then poured into a mixture of 750 ml. of ethyl acetate and 750 ml. of ice water containing 75 ml. of 2.5 N hydrochloric acid. The reaction mixture is shaken well and the resulting layers are separated. The aqueous layer is extracted again with 750 ml. of ethyl acetate and the combined ethyl acetate extracts are washed with 400 ml. of a saturated sodium chloride solution. The combined extracts are dried, filtered, and concentrated. The product is recrystallized from ethyl acetate to yield 11.78 g., m.p. 255° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I.O>CN(C)C=O.C(OCC)(=O)C>[CH3:15][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Reaction time: 0.17 h

Procedure:
4 g of 6-nitro-1H-indole are added batchwise at 0° C. to 800 mg sodium hydride (60% in mineral oil) in 20 mg dimethylformamide. The mixture is stirred for 10 minutes, then 1.86 ml methyl iodide are added dropwise and the mixture is left overnight to come up to ambient temperature. Then it is divided between water and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14](Cl)[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.CCOC(C)=O>[CH2:16]([O:15][CH2:14][N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(COCn2ccnc2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
To 2-phenylimidazole (500 mg, 3.47 mmol) in 10 mL THF at 0° C., was added 60% NaH (146 mg, 3.64 mmol). The mixture was stirred at 0° C. for 15 min, then BOM-Cl (80%, 656 μL, 3.82 mmol) was added. The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 630 mg of Intermediate 15.1 as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.[C:11](=[S:13])=[O:12].[CH3:14][CH:15]([O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25]Br)=[CH:21][CH:20]=1)[CH2:16][CH3:17]>C(O)(C)(C)C>[CH3:1][N:2]([CH3:3])[C:11](=[O:12])[S:13][CH2:25][CH2:24][O:23][C:22]1[CH:27]=[CH:28][C:19]([O:18][CH:15]([CH3:14])[CH2:16][CH3:17])=[CH:20][CH:21]=1
Reactant: CCC(C)Oc1ccc(OCCBr)cc1
Reactant: CNC
Reactant: O=C=S
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CCC(C)Oc1ccc(OCCSC(=O)N(C)C)cc1

Procedure:
Following procedure C in H. Tilles, JACS 81:714 (1959) a solution of dimethylamine (0.58 ml, 8.79 mmol) and triethylamine (1.22 ml, 8.79 mmol) in 3 ml of t-butyl alcohol is cooled to 15°, after which carbonylsulfide (0.71 g, 11.87 mmol) is passed in with vigorous stirring. The solution is then warmed to 30°, with stirring, and 2-[4-(1-methylpropoxy)phenoxy]ethyl bromide (2.40 g, 8.79 mmol) is added rapidly. The reaction mixture is heated slowly to 50° and maintained at 50° for 3 hours. The solvent is then distilled off and the product is worked up to give S-2-[4-(1-methylpropoxy)phenoxy]ethyl N,N-dimethylthiocarbamate (compound 36, Table B).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5](I)[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.[CH:33]([Sn](CCCC)(CCCC)CCCC)=[CH2:34]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH:33]=[CH2:34])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: Nc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=Cc1nc2c(N)ncnc2n1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
In 2 mL of dimethylformamide, 158 mg (0.28 mmol) of 1-[4-(6-amino-8-iodopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea was dissolved, and 262 mg (0.82 mmol) of vinyltributyltin and 20 mg (0.01 mmol) of tetrakistriphenylphosphine palladium was added thereto and the mixture solution was stirred at 95° C. for three hours. The reaction solution was concentrated and purified by a silica gel column (dichloromethane:methanol=9:1) to obtain 122 mg (93%) of a target product as a white solid.
Reaction SMILES: [NH:1]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:2]([C:11]([NH:13][C@H:14]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:31](OC)=[O:32])[CH2:29][OH:30])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:15][OH:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1.[NH2:45][NH2:46].[OH2:47]>CO>[NH:1]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[C@H:2]([C:11]([NH:13][C@H:14]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:29]([NH:45][NH2:46])=[O:30])[CH2:31][OH:32])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:15][OH:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:47])=[CH:6][CH:5]=1
Reactant: O
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(=O)NN
Reaction time: 18 h

Procedure:
1.00 Gram of Z-Tyr-Ser-Leu-Ser-OCH3 was dissolved in methanol, then under ice-cooled condition, 0.82 ml of 100%-NH2NH2.H2O was added thereto and the mixture was allowed to stand at a room temperature for 18 hours. Methanol was removed by distillation under a reduced pressure, the residue was solidified by adding ethyl ether, then washed with water to remove an excess of NH2NH2.H2O, reprecipitated from methanol-ether, washed with a hot methanol to obtain 0.81 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15]O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:38][CH2:15][CH2:14][CH2:13][C:5]1[CH:4]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: OCCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1cc(CCCBr)cc(C(F)(F)F)c1
Yield: 76.3 %

Procedure:
Compound 50-2 (3.48 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.73 g) and N-bromosuccinimide (2.5 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.27 g) as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][CH3:28])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[C@H:20]2[O:24][C:23](=[O:25])[NH:22][C@H:21]2[CH3:26])[CH:9]=1)([CH3:3])[CH3:2].[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34]Br>>[F:29][C:30]([F:43])([F:44])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=1)[CH2:34][N:22]1[C@@H:21]([CH3:26])[C@@H:20]([C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:27][CH3:28])[O:24][C:23]1=[O:25]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N[C@H]1C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1C

Procedure:
Following the procedure described in EXAMPLE 93, 40 mg of cis-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]4-methyl-1,3-oxazolidin-2-one and 42 mg of 3,5-bis(trifluoromethyl)benzyl bromide gave the title compound. Mass spectrum (ESI) 620.2 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.82-7.94 (m, 2H), 7.62-7.74 (m, 3H), 7.39, 7.37 (d, J˜8 Hz, 1H), 7.25, 7.17 (br d, J=8.5 Hz, 1H), 7.00, 6.78 (s, 1H), 6.87, 6.84 (d, J=8.5 Hz, 1H), 5.59, 5.56 (d, J=4.5 Hz, 1H), 4.96 (d, J=16 Hz, 1H), 4.22, 4.11 (d, J=16 Hz, 1H), 3.76 (s, 2H), 3.58 (s, 1H), 3.40 (m, 0.4H), 2.85-3.00 (m, 1H), 2.78 (m, 0.5H), 1.23 (d, J=7 Hz, 3H), 1.06 (m, 3H), 0.88, 0.69 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28]O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.[ClH:30]>>[Cl:30][CH2:28][CH2:27][NH:26][C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5](=[O:8])[NH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:25]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCO)c2n1
Reactant: Cl
Product: O=C(NCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 85 °C

Procedure:
To (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (77 mg, 0.192 mmol) in a pressure reaction tube was charged hydrogen chloride (4 N dioxane, 4.8 mL, 19.2 mmol) and the resulting white suspension was heated at 85° C. overnight. After cooling to ambient temperature, the reaction mixture was decanted to yield the crude product as brownish oily residue, which was dried in vacuo and directly used in the next step without further purification. MS (apci) m/z=405.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[NH:25][N:24]=NN=2)[CH:3]=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[C:4]([C:21]2[O:29][C:28]([CH2:27][Cl:26])=[N:24][N:25]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(Br)cc32)cc1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(Br)cc32)cc1
Temperature: 130 °C
Yield: 68.1 %

Procedure:
A stirred mixture of 6-bromo-1-[(4-methylphenyl)sulfonyl]-4-(1H-tetrazol-5-yl)-1H-indazole (0.237 g, 0.565 mmol) and chloroacetyl chloride (0.136 ml, 1.696 mmol) in toluene (3 ml) was heated at 130° C. in the microwave (biotage initiator) for 20 mins. The solvent was removed in vacuo and triturated with ether (10 ml) to give the title compound as a colourless solid (0.18 g).