Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH2:30])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:28])[CH3:29])[CH2:23]3)=[C:16]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 3 h
Yield: 23.3 %

Procedure:
A solution of acryloyl chloride (0.044 mL, 0.54 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 93, 258 mg, 0.54 mmol) and DIPEA (0.103 mL, 0.59 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was suspended in CH3OH and filtered to give some of the title compound (67 mg). The filtrate was then concentrated in vacuo and purified by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2. Appropriate fractions were combined and concentrated in vacuo to give a solid which was suspended in CH3OH and collected by filtration to give more of the title compound (64 mg). The two batches of product were combined to give the title compound (131 mg, 46%) as a yellow solid; 1H NMR: 1.68-1.83 (1H, m), 2.04-2.16 (1H, m), 2.18 (6H, s), 2.63-2.77 (1H, m), 3.15-3.29 (3H, m), 3.35-3.46 (1H, m), 3.78 (3H, s), 5.66 (1H, dd), 6.16 (1H, dd), 6.49 (1H, dd), 6.54 (1H, s), 7.04 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 7.53 (1H, s), 8.23-8.4 (3H, m), 8.48 (1H, d), 9.34 (1H, s), 11.84 (1H, s); m/z: ES+ MH+ 532.5.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH:15]=2)(=O)=O)=CC=1.[CH3:25][O:26][C:27]1[CH:36]=[C:35]2[C:30]([CH:31]=[CH:32][CH:33]=[C:34]2[N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:29][CH:28]=1>ClCCl>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]=[C:14]2[CH2:13][CH2:12][N:40]1[CH2:39][CH2:38][N:37]([C:34]2[C:35]3[C:30](=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:36]=3)[CH:31]=[CH:32][CH:33]=2)[CH2:42][CH2:41]1
Reactant: COc1ccc2c(c1)C(CCOS(=O)(=O)c1ccc(C)cc1)=CC2
Reactant: COc1ccc2cccc(N3CCNCC3)c2c1
Solvent: ClCCl
Product: COc1ccc2c(c1)C(CCN1CCN(c3cccc4ccc(OC)cc34)CC1)=CC2
Temperature: 130 °C
Yield: 164 %

Procedure:
2.07 g (0.006 mol) of 2-(5-methoxy-1H-inden-3-yl)ethyl 4-methylbenzenesulphonate and 2.90 g (0.012 mol) of 1-(7-methoxynaphth-1-yl)piperazine are mixed and the mixture is stirred, is placed under an argon atmosphere and is heated in an oil bath at 130° C. for 2 h. The mixture is taken up in dichloromethane, the solution is washed with water, with dilute sodium hydroxide and then again with water, is dried over magnesium sulphate and is filtered and the filtrate is evaporated under reduced pressure. 4.08 g of an oil are obtained, which oil is purified by chromatography on a column of silica gel, elution being carried out with a 92/8 dichloromethane/acetone mixture.
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+:14]=[N-:15]>>[ClH:1].[C:19]1([CH2:18][CH2:17][CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=NCCCc1ccccc1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(CCCc3ccccc3)nn2)c[nH]1
Yield: 34.1 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.050 g, 0.269 mmol) was reacted with (3-azido-propyl) benzene (0.044 g, 0.273 mmol) following the general procedure for click reactions outlined above to produce 4-{3-[1-(3-Phenyl-propyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imidazol-2-ylamine hydrochloride (0.0318 g, 34%) as a pale yellow solid. 1H NMR (300 MHz, DMSO) δ 7.91 (s, 1H), δ 7.29-7.17 (m, 5H), δ 6.62 (s, 2H), δ 6.57 (s, 1H), δ 4.29 (t, 2H), δ 2.59 (t, 2H), δ 2.53 (t, 2H), δ 2.43 (t, 2H) δ 2.09 (m, 2H), δ 1.83 (m, 2H) ppm; 13C NMR (75 MHz, DMSO) δ 163.6, 156.2, 155.1, 147.4, 146.9, 141.4, 129.1, 127.1, 126.7, 122.6, 109.4, 49.4, 32.6, 32.0, 28.1, 24.9, 24.2 ppm; HRMS (ESI) calcd for C17H22N6 (M+) 310.1978. found 310.1977.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:48]1N=N[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NC1C=CC=CC=1>CN(C=O)C>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:39]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccccc3)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and aniline (7.51 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14.1 mg, 42%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[OH:13])([O-])=O.Cl.[H][H]>>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[OH:13]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Product: Nc1ccc(O)c(N)c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 118.6 %

Procedure:
Into the reactor described in Example 6 there are placed 30 g of 2,4-dinitrophenol and 30 ml of a 37% aqueous solution of hydrochloric acid. The resulting suspension is thoroughly intermixed. The reactor is then hermetically closed with a cover, whereinto a thin-wall coiled tube is soldered. Hydrogen is continuously admitted into the tube under the pressure of 60 atm at the rate of 25 ml/min. The reactor is heated to the temperature of 150° C. and pressure therein over the suspension is increased to 60 atm. Under these conditions hydrogenation is carried out for 4 hours. After cooling and precipitation with a 37% hydrochloric acid the resulting product is filtered-off and washed with methanol to give 24 g of 2,4-diaminophenol which corresponds to 77% as calculated for the starting 2,4-dinitrophenol.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[SH:32]>>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[S:32][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: COC(=O)c1cccnc1S
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Product: COC(=O)c1cccnc1Sc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and 2-mercaptonicotinic acid methylester.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C@@:2]21[CH:14]1[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]1)[CH2:10]2.[N+:17]([O-])([OH:19])=[O:18].O.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[N+:17]([C:8]1[CH:9]=[C:4]2[CH2:3][C@:2]3([CH:14]4[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]4)[CH2:10]3)[O:1][C:5]2=[N:6][CH:7]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reaction time: 1 h
Yield: 98.6 %

Procedure:
(R)-(−)-Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (3.03 g, 14 mmol) was dissolved in concentrated sulfuric acid (7 ml) at 0–5° C., fuming nitric acid (3.3 ml, 70.2 mmol) was added over 10 minutes, the mixture was stirred for 1 hour, and heated at 65–70° C. for 24 hours, cooled, poured onto ice (200 g), added 300 ml of water, basified to pH 10 with solid potassium carbonate, stirred for 1 hour, filtered off and dried, provided the solid title compound (3.6 g, 13.8 mmol, 98%): electrospray MS 262 ([MH]+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][C:11]([NH2:13])=[O:12])#[CH:2].Cl[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1.F[B-](F)(F)F.CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:13][C:11](=[O:12])[CH2:10][C:4]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:19]1[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:15][N:16]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]3)=[CH:28][CH:27]=2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccc(F)cc1CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Temperature: 120 °C

Procedure:
A suspension of 2-(2-ethynyl-5-fluorophenyl)acetamide (A35) (0.114 g, 0.643 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.267 g, 0.585 mmol), PdCl2(PPh3)2 (0.021 g, 0.029 mmol), t-Bu3PH.BF4 (8 mg, 0.03 mmol) and CuI (6 mg, 0.03 mmol) in anhydrous DMF (4 mL) was degassed with nitrogen for 10 minutes. Et3N (1 mL) was added and the resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes. The volatiles were removed under reduced pressure, then the residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A36 as a yellow solid (0.198 g, 57%); 1H NMR (400 MHz, d6-DMSO) δ 10.41 (s, 1H), 8.81 (s, 1H), 7.69-7.62 (m, 3H), 7.47 (s, 1H), 7.31-7.19 (m, 4H), 7.07 (s, 1H), 4.05 (s, 2H), 3.72 (s, 2H), 2.80 (s, 2H), 2.69-2.59 (m, 1H), 1.74 (d, J=13.5 Hz, 2H), 1.55-1.44 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.554 min; m/z 596 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:13]=[CH:12][C:11]3[CH:10]=[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:8](=[O:20])[NH:7][C:6]=3[N:5]2[N:21]=1.[Li]C.[C:24](OCC)(=O)C>C1COCC1.O=[Mn]=O>[CH3:1][C:2]1[CH:3]=[C:4]2[N:13]=[C:12]([CH3:24])[C:11]3[C:6](=[N:7][C:8]([OH:20])=[C:9]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:10]=3)[N:5]2[N:21]=1
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Reactant: CCOC(C)=O
Agent: O=[Mn]=O
Agent: [Li]C
Solvent: C1CCOC1
Product: Cc1cc2nc(C)c3cc(-c4ccccc4)c(O)nc3n2n1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
In a 20 mL scintillation vial, Compound [IV] (0.15 g, 0.543 mmol, 1.0 eq.) was dissolved in THF (10 mL). The solution was cooled to −78° C. and MeLi (15 mL of 1.6 M THF solution, 24 mmol, 44.19 eq.) was added dropwise and the reaction mixture was stirred for 16 hours at 0-20° C. The reaction mixture was carefully and slowly poured into ethyl acetate 20 (mL) and stirred for 10 minutes. The quenched reaction mixture was concentrated. The residue was treated with 100 mL of THF and the THF solution was separated from the solid by filtration. The organic solution was stirred with MnO2 (0.47 g, 5.4 mmol, 10 eq.) for 4 hours at room temperature. The reaction was filtered and the solids washed with CHCl3/MeOH (10%) (50 mL). The combined organic solution was concentrated and the crude was purified by silica gel chromatography using CHCl3/MeOH (10%) as the eluant to give Compound [CIX]: LCMS m/e 291 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.51 (s, 3H) 2.77 (s, 3H) 6.40 (s, 1H) 7.36-7.51 (m, 3H) 7.71 (d, J=7.22 Hz, 2H) 7.97 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1>>[CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=2)=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CNCc1ccccc1)c1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Product: CC(CNCc1ccccc1)c1ccc(Oc2ccc(C(N)=O)cn2)cc1

Procedure:
Using a method similar to example 1, 4-(2-benzylamino-1-methyl-ethyl)-phenol is reacted with 6-chloronicotinamide to afford the title compound. The crude product is purified by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform gives the title compound: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 4.52 minutes, Purity: 99.1%; mass spectrum (ion spray): m/z=362.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[S:6][CH:7]=1)#[N:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.CO>C(Cl)Cl>[C:1]([C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10]([O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:9]2)[S:6][CH:7]=1)#[N:2]
Reactant: N#Cc1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)OC1CN(c2nc(C#N)cs2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100.4 %

Procedure:
To a solution of 1-(4-cyano-1,3-thiazol-2-yl)-3-hydroxyazetidine (0.78 g, 4.3 mmol) (obtained as described in Reference Example 4(2)) in methylene chloride (40 ml) were added methanesulfonyl chloride (1.0 ml, 12.9 mmol) and triethylamine (1.8 ml, 12.9 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 40 minutes. After checking the completion of the reaction, methanol was added to the reaction mixture in an ice bath and then the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (1:1) as the eluant to afford 1-(4-cyano-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (1.12 g, yield 100%) as a white solid.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[OH:16][NH:17][C:18]([NH2:20])=[O:19].ClC(Cl)(Cl)C(O)=O>O>[OH:16][N:17]([CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[C:18]([NH2:20])=[O:19]
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: NC(=O)NO
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: O
Product: NC(=O)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 20 h

Procedure:
16 g (58 mmol) of 4-hydroxycyclophosphamide and 5.2 g (68 mmol) of hydroxyurea were dissolved in 160 ml of water, acidified with trichloracetic acid (pH 3-4) and left to stand for 20 hours at 0° C. in a refrigerator. The crystal sludge was then drawn off by suction, washed with water, dried over P2O5 under high vacuum and recrystallized from methanol/chloroform.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([CH3:14])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)CCCC(C)Br
Product: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
By utilizing the procedure of Example 19, by reacting p-hydroxybenzoic acid methyl ester with 2-bromo-6-methyl heptane, there is obtained p-[(1,5,-dimethylhexyl)oxy]benzoic acid methyl ester; B.P. 132°-134° C/.1 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)=[O:4].[ClH:14]>CN(C)C=O.O1CCOCC1>[Cl-:14].[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: Cl
Agent: COC(=O)c1ccc(C=NO)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-methoxycarbonylbenzaldehyde oxime (896 mg) in N,N-dimethylformamide (10 ml) was added 4N-hydrochloride acid in 1,4-dioxane (1.38 ml) and oxoneR (1.69 g). The suspension was stirred at ambient temperature for 16 hours and poured into ice-water. The object compound was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate. The solvents were removed under reduced pressure to give 4-Methoxycarbonylbenzaldehyde oxime chloride (1.05 g).
Reaction SMILES: [N:1]([CH:4]1[CH:10](O)[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5]1)=[N+:2]=[N-:3].COCCN(S(F)(F)[F:32])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[N:1]([CH:4]1[CH:10]([F:32])[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCN(C(=O)OCc2ccccc2)CCC1O
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1CCN(C(=O)OCc2ccccc2)CCC1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzyl 4-azido-5-hydroxyazepane-1-carboxylate (1.0 g, 3.45 mmol) in dry DCM (10 ml) was added deoxo-Fluor® (1.6 mL, 8.62 mmol, 50% in THF) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous NaHCO3 solution was added (20 mL) and the mixture was extracted with DCM (100 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (20 mL), separated, dried over MgSO4 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (20% EtOAc/isohexane) to give benzyl 4-azido-5-fluoroazepane-1-carboxylate as a mixture of syn and anti isomers as a pale yellow oil (0.76 g).
Reaction SMILES: [F:1][CH:2]([F:32])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[C:17]([CH2:19][NH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH:16]=[CH:15][C:14]=2[Cl:27])=[CH:7][C:6]=1[C:29]([OH:31])=O.[F:33][C:34]([F:43])([F:42])[C@H:35]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[F:32][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[C:17]([CH2:19][NH:20][C:21]([C:23]([CH3:25])([CH3:24])[CH3:26])=[O:22])[CH:16]=[CH:15][C:14]=2[Cl:27])=[CH:7][C:6]=1[C:29]([NH:41][C@H:38]1[CH2:39][CH2:40][C@H:35]([C:34]([F:33])([F:42])[F:43])[CH2:36][CH2:37]1)=[O:31]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(OCC(F)F)c(C(=O)O)c2)c1
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(OCC(F)F)c(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c2)c1

Procedure:
Prepared analogously to Example 4c from N-[4-(2,2-difluoroethyl)oxy-3-hydroxycarbonyl-phenyl]-2-chloro-5-(tert-butylcarbonylamino)methyl-benzamide and trans-4-trifluoromethyl-cyclohexylamine with TBTU and TEA in THF.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[CH3:11][C:12]([CH2:14][CH2:15]O)=[CH2:13]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH2:13][C:4]2([CH2:5][CH:6]([CH3:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3]2)[O:9][CH2:15][CH:14]=1
Reactant: C=C(C)CCO
Reactant: CC1CC(=O)CC(C)(C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=CCOC2(C1)CC(C)CC(C)(C)C2
Temperature: 115 °C
Yield: 69.6 %

Procedure:
A mixture of p-TSA (20 g, 0.105 mol) and toluene (2 L) was heated to 115° C. To this mixture were added 3,3,5-trimethyl cyclohexanone (1.4 kg, 10 mols) and isoprenol (946 g, 11 mols) and heated further for 3-6 h. Water was removed from the reaction azeotropically. The reaction mixture was then cooled to room temperature. The organic phase was washed with a 5% Na2CO3 solution, washed with water dried and concentrated and distilled further to provide to 4,8,8,10-tetramethyl-1-oxaspiro [5.5] undec-3-ene (1.45 kg) having a purity of 94% (sum of the isomers) for a total yield of 55%.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:27])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])(=[O:19])=[O:18])[O:13][CH:14]=1)C1C=CC=CC=1.OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1>>[OH:8][C:9]1[C:10](=[O:27])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])(=[O:19])=[O:18])[O:13][CH:14]=1
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)co1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1O
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(O)co1
Yield: 83 %

Procedure:
N-(5-Hydroxy-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (8-02) (14.0 g, crude) was synthesized as a light brown solid from N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (7-02) (22.0 g, 57.14 mmol) following the procedure described for N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-01).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(C)=O.Cl>O>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Clc1cnc(N2CCNCC2)cn1
Yield: 36.7 %

Procedure:
A mixture of 2,5-dichloropyrazine (14.9 g, 0.1 mol), piperazine (50.5 g, 0.59 mol), acetone (22.5 ml), water (20 ml) and concentrated aqueous HCl (1.8 ml) was heated at reflux for 3 hr. The reaction mixture was cooled, diluted with water, filtered and the acetone was removed by distillation. The aqueous solution was then extracted thrice with chloroform. The combined extracts were washed twice with water, dried (Na2SO4) and evaporated to dryness to afford 7.3 g of solid, m.p. 98°-102°. J. K. Boissier et al., J. Med. Chem., 6, 541 (1963) report a m.p. of 101° C.