Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.[C:12]([O:16][C:17](=[O:21])[C@H:18](O)[CH3:19])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:18]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:21])[CH3:19])[CH:5]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(O[C@@H](C)C(=O)OC(C)(C)C)c1
Yield: 83.4 %

Procedure:
Cool a solution of 3-hydroxy-benzoic acid methyl ester (0.50 g, 3.42 mmol) in tetrahydrofuran (8 mL) to 0° C., and add (R)-2-hydroxy-propionic acid tert-butyl ester (0.52 g, 3.42 mmol) and triphenyl phosphine (0.90 g, 3.42 mmol). Add diethylazodicarboxylate (0.70 mL, 4.4 mmol) to this mixture via a syringe pump over a 1 hour period. Concentrate the reaction mixture under reduced pressure and purify the residue by flash silica gel chromatography to provide 0.80 g of 3-((S)-1-tert-butoxycarbonyl-ethoxy)-benzoic acid methyl ester as an oil.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:4]([NH2:6])=[O:5])#[N:2].O.[NH2:21][NH2:22]>C(O)C>[NH2:2][C:1]1[NH:22][N:21]=[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(Nc1ccc([N+](=O)[O-])cc1)=C(C#N)C(N)=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Temperature: 75 °C

Procedure:
2-cyano-3-(methylthio)-3-((4-nitrophenyl)amino)acrylamide was then suspended in 100 mL of ethanol and hydrazine hydrate (5.153 mL, 2.00 eq.) was added drop wise to the reaction. The reaction was then heated at 75° C. until the starting material was no longer present as confirmed via HPLC. Once starting material was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide as an off white to yellow powder as product. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>ClC(Cl)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:25]3[CH2:26][CH2:27][N:22]([C:28]4[N:29]=[CH:30][CH:31]=[CH:32][N:33]=4)[CH2:23][CH2:24]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Solvent: CC(Cl)Cl
Product: O[C@@H](COc1cccc(-c2noc3cc(F)ccc23)c1)CN1CCN(c2ncccn2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane and and 2-piperazin-1-yl-pyrimidine, essentially as described above in Example 57. Purity by LC/MS=100%, [M+H]+=450.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]12[CH2:33][C:29]([CH2:34]O)([CH2:30][CH2:31][CH2:32]1)[CH2:28][CH2:27][CH2:26]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:25]12[CH2:33][C:29]([CH2:34][O:11][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:12])([CH2:30][CH2:31][CH2:32]1)[CH2:28][CH2:27][CH2:26]2
Reactant: OCC12CCCN(CCC1)C2
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(OCC12CCCN(CCC1)C2)c1c[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of indole-3-carboxylic acid (1.62 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.70 g, 10.5 mmol),stirred for one hour, and degassed with a stream of nitrogen for 10 minutes giving a suspension. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.3.1]nonane-5-methanol (1.71 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5 N n-butyllithium/hexane (10.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The 1,1'-carbonyldiimidazole adduct suspension was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated m vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little isopropanol and saturated sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 7% methanol/methylene chloride). The filtrated was concentrated in vacuo and the residue was triturated from cold ether and recrystallized from acetonitrile (2 crops) to afford 1.79 g (60% ) of colorless crystals; m.p. 207°-209° C.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:5]([O:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reaction time: 8 h

Procedure:
A solution of tert-butylchlorodiphenylsilane (5.56 mL, 21.36 mmol) in DCM (20 mL) was added dropwise to a stirred solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (CAS no. 142253-56-3) (4.0 g, 21 mmol) and anhydrous N-ethyl-N-isopropylpropan-2-amine (9.1 mL, 53 mmol) in DCM (45 mL) cooled to 10° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 3 hours 4-dimethylaminopyridine (100 mg) was added and the reaction was left overnight. The reaction mixture was concentrated and diluted with EtOAc (75 mL), and washed sequentially with saturated NaHCO3 (25 mL), water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the crude product (9.87 g) which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][SH:9].[Br:13][C:14]1[C:15](F)=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH:17]=O.O>CC#N>[Br:13][C:14]1[C:15]2[S:9][C:8]([C:7]([O:11][CH3:12])=[O:10])=[CH:17][C:16]=2[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(Br)c1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc2cc(C(F)(F)F)cc(Br)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (1.44 g, 10.42 mmol) then methyl thioglycolate (0.487 g, 4.59 mmol) were added to a degassed solution of 3-bromo-2-fluoro-5-(trifluoromethyl)benzaldehyde (1.13 g, 4.17 mmol) in CH3CN (11 mL). The mixture was stirred at room temperature for 30 minutes then refluxed at 100° C. overnight. The mixture was allowed to cool to room temperature, then water (20 mL) was added. The resulting light yellow solid was collected by vacuum filtration, washed with water, then dried in vacuo. The resulting ester was used directly for the following step. 1H NMR (500 MHz, CDCl3) δ 8.24 (br s, 1H); 8.15 (br s, 1H); 7.86 (br s, 1H); 4.02 (br s, 3H). LC1: 4.00 min. Compound does not ionize.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:19]=1[CH2:20][C:21](O)=[O:22]>>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:2]([NH:1][C:21]([CH2:20][C:19]1[CH:24]=[CH:25][C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]=1)=[O:22])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(O)Cc1ccc2ccccc2n1
Reactant: Cc1ccccc1C(N)CCN1CCCCC1
Product: Cc1ccccc1C(CCN1CCCCC1)NC(=O)Cc1ccc2ccccc2n1
Yield: 91.6 %

Procedure:
The procedure of Example 4 was repeated using 465 mg (2.0 mmol.) of 1-[3-amino-3-(2-methylphenyl)propyl]piperidine and 347 mg (2.0 mmol.) of quinaldinic acid, to obtain 736 mg (yield: 95%) of the subject compound as a pale yellow oily product.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=CN=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:12][CH2:11]2)[N:6]=[CH:5]1.C([Sn](CCCC)(CCCC)C1[S:45]C=CC=1)CCC>>[ClH:1].[ClH:1].[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[S:45][CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:12][CH2:11]2)[N:6]=[CH:5]1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccn3)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3cccs3)cc2C1
Yield: 10 %

Procedure:
Example 39 was prepared as a green solid in 10% yield from Compound A of Example 37 and 2-(tributylstannyl)thiophene as described for Compound B of Example 37.
Reaction SMILES: [CH3:1]OCOC.[ClH:6].Cl.Cl.[CH3:9][O:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[NH:22])=[NH:19])=[CH:13][CH:12]=1>C(O)CCC>[ClH:6].[CH2:24]([NH:23][C:21]1[NH:20][C:18]([NH:17][CH2:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:35][CH:34]=2)=[N:19][CH2:1][N:22]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCCc1ccc(OC)cc1
Reactant: COCOC
Agent: Cl
Solvent: CCCCO
Product: CCCCCCCCCCNC1=NCN=C(NCCc2ccc(OC)cc2)N1

Procedure:
200 ml of n-butanol, 6 ml (67.8 mmol) of methylal and 0.7 ml of concentrated hydrochloric acid were added to 2.5 g (5.6 mmol) of N1-(4-methoxyphenethyl)-N5-decyl-biguanide dihydrochloride, and the mixture was refluxed for 68 hours. The solvent was distilled of f under reduced pressure, and dissolved in 80% aqueous acetonitrile. The solvent was distilled off under reduced pressure to give a residue, which was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.7:0.7)) to obtain 0.7 g of a colorless resinous solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Si:12]([O:19][C@@H:20]([C@H:22]1[C:30](=[O:31])[N:29]2[C@@H:23]1[CH2:24][C:25](=[O:45])[CH2:26][CH:27]=[C:28]2[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])[CH3:21])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>ClCCl>[C:8]([O:45][C:25]1[CH2:24][C@H:23]2[N:29]([C:30](=[O:31])[C@@H:22]2[C@H:20]([O:19][Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13])[CH3:21])[C:28]([C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])=[CH:27][CH:26]=1)(=[O:10])[CH3:9]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCC(=O)C[C@H]12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
Triethylamine (1.1 ml, 7.5 mmol) followed by acetyl chloride (0.295 ml, 4.1 mmol) were added to a solution of 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-5,9-dioxo-1-azabicyclo[5.2.0]non-2-ene-2-carboxylate (1.67 g, 3.4 mmol) in anhydrous dichloromethane (220 ml) cooled with an ice bath. After 5 minutes, the reaction mixture was washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue purified by flash chromatography, eluting with dichloromethane/ethyl acetate (95:5) to give 4-nitrobenzyl (7R,8S)-5-acetoxy-8-[(1R)-1-(tertbutyldimethyl-silyloxy)ethyl]-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate (1.4 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](S(C)(=O)=O)=[CH:20][CH:19]=3)[S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3C=CC=C([O:92][CH2:93][CH2:94][N:95]4[CH2:100][CH2:99][O:98][CH2:97][CH2:96]4)C=3)SC=12>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[S:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:92][CH2:93][CH2:94][N:95]4[CH2:100][CH2:99][O:98][CH2:97][CH2:96]4)[CH:19]=3)[S:17][C:10]=12
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Yield: 29 %

Procedure:
Following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but substituting amine 49 for the amine 162, title compound 163a was obtained in 29% yield. Characterization of 163a is provided in the table 15.[LRMS (M+1) 643.3 (100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH:3]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccnc2)cc1
Temperature: 135 °C
Yield: 32.3 %

Procedure:
3-hydroxypyridine (6.17 g, 64.87 mmol) was dissolved in 100 mL of anhydrous DMF under argon atmosphere. Solid K2CO3 (8.96 g, 64.87 mmol) was added, followed by neat methyl 4-fluorobenzoate (10.0 g, 64.87 mmol). The reaction mixture was heated at 135° C. for 10 hrs. The absence of the starting material was confirmed by LC/MS. The reaction mixture was cooled down to ambient temperature and poured into ca. 500 mL of H2O. The resulting solution was extracted 3 times with ca. 150 mL of EtOAc (during the extraction small volumes of MeOH, Et2O and brine were added to facilitate the separation). Combined EtOAc layers were washed twice with sat. NaHCO3, twice with brine and dried over anhydrous Na2SO4. Solvent was removed in vacuo to give dark-red oil, which was purified by silica gel chromatography using 1:1 mixture of EtOAc/Hexane as eluent to give the title product (4.8 g, 32.3% yield) as yellow solid.
Reaction SMILES: [S:1](F)(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[NH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16].C(N(CC)CC)C>C(O)CCC>[OH:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][NH:12][S:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)(=[O:10])=[O:2]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: CC(C)(CN)CO
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(CO)CNS(=O)(=O)c1ccc(N)cc1

Procedure:
A mixture of sulphanilyl fluoride (1 g, 5.7 mmol), 3-amino-2,2-dimethylpropan-1-ol (884 mg, 8.6 mmol) and triethylamine (0.876 ml, 6.3 mmol) in butan-1-ol (20 ml) was heated at reflux for 24 hours. The volatiles were removed by evaporation and residue was purified by chromatography on silica gel to give the title compound. NMR: 0.72 (s, 6H), 2.52 (d, 2H), 3.08 (d, 2H), 4.40 (t, 1H), 7.19 (t, 1H), 7.60 (s, 1H), 7.64 (d, 2H), 7.96 (d, 2H), 8.40 (s, 1H), m/z 259 (MN)+.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([OH:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)(Cl)(Cl)Cl>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:22][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCOP(=O)(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a moisture protected solution of 28.4 ml of phosphorous oxychloride in 200 ml of carbon tetrachloride is added dropwise with stirring a solution of 50 g of 1-hexadecanol in 125 ml of carbon tetrachloride. After stirring at ambient temperature for 18 hours, the solvent is removed and the residue evaporated with toluene several times to give 71 g of the desired product as a vacuum dried water white oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)([O-:20])=[O:19].N1C=CC=CC=1>O>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:2]3[CH:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:5]=[C:4]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[N:3]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(c3cc(N4CCCC4)nc(N4CCCC4)n3)CC2)cc1
Temperature: 100 °C
Yield: 49 %

Procedure:
2.52 g (10 mmol) of 4-chloro-2,6-di-pyrrolidin-1-yl-pyrimidine (J. Med. Chem. (1990) 33 (4), 1145-1151) and 2.07 g (10 mmol) of 4-nitrophenylpiperazine are dissolved in a 250 ml flask containing 20 ml of anhydrous pyridine, under an argon atmosphere. The reaction mixture is heated at 100° C. for 48 hours. After cooling down, the contents of the flask are poured into 250 ml of water and the product is extracted using twice 50 ml of CH2Cl2. The organic phase is then washed with 50 ml of brine, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is purified on a silica column (eluent: Heptane/AcOEt: 2/1). An orange solid is obtained with a yield of 49%. Melting point: 200-201° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[C@@H:19]1(O)[CH2:23][CH2:22][CH2:21][C@H:20]1[OH:24].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([C@@H:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[OH:24])[CH:7]=1
Reactant: O[C@@H]1CCC[C@H]1O
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@@H]1CCC[C@H]1c1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii), 2.3 g) and (trans)-cyclopentane-1,2-diol (1 g) in THF (50 ml) was added NaH (0.30 g) slowly and the reaction was then allowed to stir for 18 h at RT. The reaction mixture was then partitioned between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting clear oil was purified by column chromatography on silica gel EtOAc/iso-Hexane (2:8) to give the subtitle compound as a clear colourless oil. Yield 0.94 g
Reaction SMILES: C(OP([O:9][CH2:10][CH3:11])(OCC)=O)C.[CH:12]1[CH2:19][CH2:18]C=[CH:16][CH2:15][CH2:14][CH:13]=1>CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Co+2].C1C=CC=CC=1>[OH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:19][CH2:18]1
Reactant: CCOP(=O)(OCC)OCC
Reactant: C1=CCCC=CCC1
Agent: [Co+2]
Agent: CCCCC(CC)C(=O)[O-]
Solvent: c1ccccc1
Product: OCC1CCCCCCC1
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 8 millimols of cobalt 2-ethylhexoate and 20 millimols of triethylphosphate in 200 ml. of benzene was treated in an autoclave with 1:1 H2 :CO mixture for one hour at 170° C. and 3,700-114 3,750 psig. The autoclave was cooled and vented, and 250 g. of 1,5-cyclooctadiene was added. This mixture was treated with 1:1 H2 :CO at 145°-185° C. and 1,800-3,000 psig. for 3 hours. Distillation of the reactor effluent gave 203 g. of hydroformylation products boiling at 36°-75° C. at 5 mm. Hg pressure and 79 g. of residue. Reduction of a portion of the distilled oxygenated products over a nickel-based catalyst with hydrogen at elevated temperatures and pressures gave a 90% yield of hydroxymethylcyclooctane.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[F:11][C:12]1([F:16])[CH2:15][NH:14][CH2:13]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[C:21]#[N:22]>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:19]([CH2:18][N:14]2[CH2:15][C:12]([F:16])([F:11])[CH2:13]2)=[C:20]([CH:23]=1)[C:21]#[N:22]
Reactant: FC1(F)CNC1
Reactant: N#Cc1cc(Cl)ccc1CBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc(Cl)ccc1CN1CC(F)(F)C1
Yield: 55.9 %

Procedure:
DIEA (0.196 mL, 1.12 mmol) was added to a stirred mixture of 3,3-difluoroazetidine hydrochloride (64.8 mg, 0.50 mmol) and 2-bromomethyl-5-chlorobenzonitrile (121.0 mg, 0.52 mmol) in CH2Cl2 (7 mL). After 16 h the reaction was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was partitioned between 1N HCl and ether. The aqueous layer was made neutral with NaHCO3 and was extracted with CH2Cl2. The organic layer was dried with Na2SO4 and then evaporated to give 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzonitrile (67.8 mg) as a glass: 1H NMR (CDCl3, 400 MHz) δ 3.68 (t, J=11.9 Hz. 4H), 3.93 (s, 2H), 7.54 (m, 2H), 7.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])(=[N:14][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)Nc1ccc(Br)cc1
Reactant: CCN
Product: CCN=S(C)(=O)Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and ethylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.91 min; Mass spectrum (ESI+): m/z=277, 279 [M+H]+.