Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])=[CH:29][C:28]=1[N+:41]([O-])=O>>[NH2:41][C:28]1[CH:29]=[C:30]([C:33]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)=[O:34])[CH:31]=[CH:32][C:27]=1[O:26][CH3:25]
Reactant: COc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1ccc(C(=O)N2CCOCC2)cc1N

Procedure:
(3-Amino-4-methoxy-phenyl)-morpholin-4-yl-methanone was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with (4-Methoxy-3-nitro-phenyl)-morpholin-4-yl-methanone. LC/MS (E/I+) 237.05 (M+H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:12]=1)=[O:7])(=O)[CH3:2].[NH4+].[OH-]>>[Br:19][C:15]1[CH:14]=[C:13]([N:11]2[CH:12]=[C:8]([C:6]3[O:7][C:1]([CH3:2])=[N:4][N:5]=3)[N:9]=[CH:10]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)NNC(=O)c1cn(-c2cccc(Br)c2)cn1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nnc(-c2cn(-c3cccc(Br)c3)cn2)o1
Temperature: 155 °C

Procedure:
A suspension of 6 (50 mg, 0.15 mmol) in PPA was heated to 155° C. for 1 h and then allowed to cool to room temperature. the reaction mixture was carefully diluted using 6% NH4OH aqueous solution to pH=8. The precipitate formed was isolated by filtration to afford 715 mg (33%) as a white solid. HRMS (ESI+): m/z=305.1341 [M+H]
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=O)[CH:8]=[CH:9][CH:10]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[N:30][OH:31])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(C(=O)CC(c2cccc(CCCO)c2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(CCCO)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-[3-(3-hydroxy-propyl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a colorless oil, MS (ESI+): m/z=389.2 ([M+H]+).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])=[O:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1.[F:34][C:35]1[CH:40]=[C:39]([O:41][CH2:42][C@@H:43]2[CH2:45][O:44]2)[CH:38]=[CH:37][C:36]=1[O:46][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[CH2:25][NH:24][C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][NH:4][CH2:45][C@H:43]([OH:44])[CH2:42][O:41][C:39]3[CH:38]=[CH:37][C:36]([OH:46])=[C:35]([F:34])[CH:40]=3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])=[CH:20][CH:19]=1)=[O:23]
Reactant: NCC1CCN(S(=O)(=O)c2ccc(NC(=O)NCc3cc(F)ccc3F)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1F)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(NCc1cc(F)ccc1F)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3ccc(O)c(F)c3)CC2)cc1
Yield: 16 %

Procedure:
N-(4-{[4-(aminomethyl)-1-piperidinyl]sulfonyl}phenyl)-N′-(2,5-difluoro-benzyl)urea formate (0.433 g, 1.00 mmol) was reacted with t-butyl(diphenyl)silyl 2-fluoro-4-[(2S)oxiranylmethoxy]phenyl ether (0.422 g, 1.00 mmol) according to example 37 to give the title compound (0.1 g, 0.16 mmol).
Reaction SMILES: [CH2:1]([P:3](=[S:5])=[S:4])[CH3:2].[CH3:6][C:7]([CH3:11])([SH:10])[CH2:8][CH3:9].C(N(CC)CC)C>O1CCCC1>[CH3:6][C:7]([S:10][P:3]([CH2:1][CH3:2])([SH:5])=[S:4])([CH3:11])[CH2:8][CH3:9]
Reactant: CCP(=S)=S
Reactant: CCC(C)(C)S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)SP(=S)(S)CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 16.5 grams (g) of ethylthionophosphine sulfide in tetrahydrofuran, under nitrogen at room temperature, was added 13.8 g (0.133 mole) 1,1-dimethyl-1-propanethiol (tertiary amyl mercaptan). To this mixture was added 18.5 milliliters (ml) (0.133) triethylamine, dropwise. The mixture was stirred one hour at room temperature, then refluxed for 1/2 hour and stripped of solvent. There was obtained 30.1 g (87% of theoretical yield) of the triethylamine salt of S-(1,1-dimethylpropyl)ethylphosphonotrithioic acid).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22][C:23]1([CH3:34])[O:27][C@@H:26]([CH2:28]OS(C)(=O)=O)[CH2:25][O:24]1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:28][C@H:26]2[CH2:25][O:24][C:23]([CH3:34])([CH3:22])[O:27]2)=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: CC1(C)OC[C@H](COS(C)(=O)=O)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
(R)-tert-Butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (200 mg, 0.75 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) followed by the addition of sodium hydride (60% dispersion in mineral oil) (63 mg, 1.57 mmol) at room temperature. The reaction was stirred for 30 minutes followed by the dropwise addition of methanesulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan4-ylmethyl ester (189 mg, 0.90 mmol) dissolved in N,N-dimethylformamide (2 mL) at room temperature. The mixture was heated to 100° C. overnight. The reaction was cooled to room temperature, acidified to pH=4 with 0.2 M aqueous hydrochloric acid, poured into ethyl acetate and diluted with water. The organic layer was washed with brine and dried over sodium sulfate. Removal of solvents gave (R)-tert-butoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolan4-ylmethoxy)-phenyl]-acetic acid as a foam (280 mg, 98%).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:47][C@@H:48]1[CH2:53][NH:52][CH2:51][CH2:50][N:49]1[S:54]([C:57]1[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=1)(=[O:56])=[O:55]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O.O>[CH3:47][C@H:48]1[N:49]([S:54]([C:57]2[CH:58]=[CH:59][C:60]([C:63]([F:66])([F:64])[F:65])=[CH:61][CH:62]=2)(=[O:56])=[O:55])[CH2:50][CH2:51][N:52]([C:10]([C:3]2[CH:2]=[N:1][N:5]3[CH:6]=[CH:7][CH:8]=[N:9][C:4]=23)=[O:12])[CH2:53]1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: C[C@@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)c2cnn3cccnc23)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 65.2 %

Procedure:
To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (56.8 mg, 0.348 mmol) in DCM (2.0 ml) was added HATU (132 mg, 0.348 mmol) and DIPEA (0.152 ml, 0.870 mmol) and the mixture stirred for 15 minutes before addition of (2R)-2-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine hydrochloride (may be prepared as described in Description 4) (100 mg, 0.290 mmol) in DMF (2 ml). The resultant mixture was stirred for 72 hours at rt. Water (20 ml) and EtOAc (20 ml) were added and the mixture was filtered through a sinter to remove precipitate. The collected filtrate was separated and the aqueous layer was then re-extracted with EtOAc (15 ml), the organic layers were combined and washed with saturated brine solution (20 ml). The organic layers were then separated, dried (MgSO4) and concentrated to dryness. The crude material was then dissolved in DMSO and purified by MDAP. The collected fractions were concentrated in vacuo to give the title compound (85.8 mg) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](OCC)=[O:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[CH2:12][OH:13])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(C(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(/C=C/CO)cc1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a suspension of ethyl (E)-3-(4-isopropylphenyl)-2-propenoate (20.0 g, 91.6 mmol) in tetrahydrofuran (200 ml) was added in four portions at −40° C. for 30 minutes lithium aluminum hydride (2.61 g, 68.7 mmol) and the resulting mixture was stirred at the same temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 8:1) to obtain 10.5 g (65% yield) of the oily title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:32])[C@@H:18]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:32])[C@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[NH:23][CH3:24])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl(S)-1-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate (60 mg, 0.135 mmol) from Example 222 was combined with 4 N hydrogen chloride in 1,4-dioxane (0.698 mL, 2.79 mmol). The reaction was stirred at room temperature for 16 hours and then concentrated. The material was purified using a 12 g silica gel cartridge with a gradient of 1-10% methanol (2 N ammonia)/dichloromethane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.16-8.19 (m, 1H), 7.44-7.46 (m, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.28 (t, J=7.3 Hz, 1H), 4.42-4.48 (m, 1H), 3.61 (d, J=13.1 Hz, 1H), 3.46 (d, J=13.1 Hz, 1H), 3.22 (dd, J=8.2, 5.8 Hz, 1H), 2.87 (d, J=10.3 Hz, 1H), 2.51-2.61 (m, 2H), 2.44 (dd, J=8.8, 7.1 Hz, 1H), 2.43 (s, 3H), 2.37 (dd, J=9.0, 2.0 Hz, 1H), 2.25-2.29 (m, 1H), 2.09-2.17 (m, 1H), 1.95-2.07 (m, 1H), 1.82-1.95 (m, 2H), 1.72 (ddd, J=13.5, 7.8, 5.8 Hz, 1H), 1.55-1.64 (m, 2H), 1.38-1.45 (m, 1H), 0.92 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H); MS (ESI+) m/z 344 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=4)[CH:18]=3)[C:13](O)=[O:14])=[CH:8][CH:7]=[N:6]2)[CH2:3][CH2:2]1.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][NH2:34])=[N:31][CH:32]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=4)[CH:18]=3)[C:13]([NH:34][CH2:33][C:30]3[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][N:31]=3)=[O:14])=[CH:8][CH:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccnn3CC3CC3)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(-c3ccnn3CC3CC3)c2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.7 %

Procedure:
3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid (0.120 g, 0.36 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (0.044 g, 0.36 mmol), EDCI (0.103 g, 0.54 mmol), HOBt (0.073 g, 0.54 mmol), and NMM (0.183 g, 1.80 mmol) were added to 7 mL of dichloromethane. The reaction mixture was stirred for 48 hours at room temperature, then concentrated under reduced pressure. The residue was purified via flash chromatography (5:1 EtOAc/hexanes) to give 0.14 g of 3-(2-cyclopropylmethyl-2H-pyrazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=439.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([NH:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1)=[O:17]>C(O)C>[CH:16]([NH:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[S:28])=[CH:22][CH:21]=1)=[O:17]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=CNNc1ccc(N=C=S)cc1
Solvent: CCO
Product: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Dibenzylamine (0.20 g, 0.001 mole) and 4-(2-formylhydrazino)phenyl isothiocyanate (0.19 g, 0.001 mole) were mixed in ethanol (25 ml) and the resulting mixture was heated to reflux for 20 minutes. The reaction mixture was cooled to room temperature, then was chilled in ice. After scratching the flask walls, a white crystalline solid was separated out of solution. The solid was filtered off, washed thoroughly with ether, and allowed to dry. This gave 0.31 g (80 percent) of product as a white crystalline powder, m.p. 174°-176° C.
Reaction SMILES: C([NH:5][C:6]([C:8]1[S:9][C:10]([C:15]2[CH:20]=[C:19]([C:21](=[O:26])[NH:22][CH:23]3[CH2:25][CH2:24]3)[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:11][C:12]=1[CH:13]=O)=[O:7])(C)(C)C.C(O)(=O)C.[NH2:32]N>>[CH:23]1([NH:22][C:21](=[O:26])[C:19]2[CH:18]=[CH:17][C:16]([CH3:27])=[C:15]([C:10]3[S:9][C:8]4[C:6](=[O:7])[NH:5][N:32]=[CH:13][C:12]=4[CH:11]=3)[CH:20]=2)[CH2:25][CH2:24]1
Reactant: NN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc(C=O)c(C(=O)NC(C)(C)C)s1
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cn[nH]c(=O)c2s1
Temperature: 150 °C
Yield: 37.1 %

Procedure:
A 5 ml glass microwave reaction vessel was charged with N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-formylthiophene-2-carboxamide (0.350 g, 0.910 mmol), glacial acetic acid (2.63 ml, 45.5 mmol), hydrazine (0.0875 g, 2.73 mmol). The reaction mixture was heated in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 20 min. The crude was concentrated and azeotropically dried with toluene, the residue was partioned between water and DCM, and the aqueous layer was extracted with DCM (2×25 ml). Combined organic solution was washed with saturated solution of NaHCO3(aq), and dried over MgSO4. The organic solutions were evaporated under reduced pressure and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide N-Cyclopropyl-4-methyl-3-(7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)benzamide (0.110 g) MS (ES+): 328 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([I:15])=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[C:14]([I:15])=[CH:13][N:12]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(I)c(OCc2ccccc2)n1
Reactant: NC(=O)c1ccc(N)cc1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccc(Nc2ncc(I)c(OCc3ccccc3)n2)cc1
Temperature: 60 °C
Reaction time: 9 h
Yield: 117.3 %

Procedure:
To a solution of 4-(benzyloxy)-2-chloro-5-iodopyrimidine (J1, 2.02 g) and 4-aminobenzamide (3.97 g) in N-methylpyrrolidone (20 mL), (1S)-(+)-10-camphorsulfonic acid (6.76 g) was added at room temperature, and the mixture was stirred at 60° C. for 9 hours. The reaction mixture was cooled on ice, and then poured into saturated aqueous sodium hydrogencarbonate. The solid matter was taken by filtration, washed with a mixed solvent of ethyl acetate and methanol, and then dried under reduced pressure to obtain 4-((4-(benzyloxy)-5-iodopyrimidin-2-yl)amino)benzamide (J10, 3.05 g) as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH:28]4[CH2:31]OC4)=[O:26])=[CH:20][CH:19]=3)=[N:6][C:5]=2[CH:4]=[N:3]1.Cl.[CH3:33][S:34](CCN)(=[O:36])=[O:35]>>[CH3:1][N:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:31][S:34]([CH3:33])(=[O:36])=[O:35])=[O:26])=[CH:20][CH:19]=3)=[N:6][C:5]=2[CH:4]=[N:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3COC3)cc2)nc2cnn(C)c12
Reactant: CS(=O)(=O)CCN
Agent: Cl
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCS(C)(=O)=O)cc2)nc2cnn(C)c12

Procedure:
This compound was prepared in an analogous fashion to (S)-1-(4-(1-methyl-7-(3-methylmorpholino)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-3-(oxetan-3-yl)urea, using 2-(methylsulfonyl)ethanamine hydrochloride as the starting material. 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.96 (s, 1H), 8.25 (d, J=8.8 Hz, 2H), 8.21 (s, 1H), 7.51 (d, J=8.8 Hz, 2H), 6.42 (t, J=5.9 Hz, 1H), 4.25 to 4.13 (m, 4H), 3.96 to 3.83 (m, 2H), 3.78 to 3.79 (m, 1H), 3.79 to 3.60 (m, 2H), 3.60 to 3.47 (m, 3H), 3.37 to 3.30 (m, 5H), 1.27 (d, J=6.5 Hz, 3H); LC-MS m/z (method C1)=474.2 [M+H]+, RT=3.13 min
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([O:29][CH3:30])=[CH:21][C:16]=2[C:17]([NH:19][CH3:20])=[O:18])=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.[Pd]>[C:25]([C:23]1[C:22]([O:29][CH3:30])=[CH:21][C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]([C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=2)[CH:24]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CNC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1ccc[nH]c1=O
Reaction time: 0.5 h

Procedure:
step 3—A mixture of 62 (95 mg) and 10% Pd/C (10 mg) in MeOH (5 mL) at RT was stirred under 1 atmosphere of H2 for 0.5 h. The catalyst was filtered off, and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 8% MeOH/DCM to afford 41 mg of I-9 as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[CH2:4][NH2:5].[C:13]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:20]=1)([O:15][CH3:16])=[O:14].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:13]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][NH:5][CH2:4][CH:3]([O:2][CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=2)=[CH:23][CH:24]=1)([O:15][CH3:16])=[O:14]
Reactant: COC(=O)COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COC(CN)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)COc1ccc(CCNCC(OC)c2cccc(Cl)c2)cc1
Temperature: 55 °C

Procedure:
A mixture of 2-methoxy-2-(3-chlorophenyl)ethanamine (1.81 g), 2-(4-carbomethoxymethoxyphenyl)-1-(p-toluenesulphonyloxy)ethane (4.0 g) and triethylamine (4 ml) in dimethyl sulphoxide (50 ml) was heated at 55° C. After 24 h the solution was poured into saturated sodium carbonate solution and the aqueous layer extracted with dichloromethane. The organic extract was separated, dried and evaporated. Chromatography over silica gel (eluting with 2% methanol-dichloromethane) gave N-[2-(4-carbomethoxymethoxyphenyl)ethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine which was converted into the title compound, mp 167°-169° C. (ethyl acetate-hexane) by an analogous procedure to that described in Example 4.
Reaction SMILES: [CH:1]1([CH2:11][CH2:12]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[N:14]1([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[C@@H:1]1([CH2:11][CH2:12][N:17]2[CH2:18][CH2:19][N:14]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:15][CH2:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: OCCC1OCCc2ccccc21
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: NS(=O)(=O)c1ccc(N2CCN(CC[C@H]3OCCc4ccccc43)CC2)cc1

Procedure:
Following the general procedure of EXAMPLE 49 and making non-critical variations 2-(isochroman-1-yl)ethanol (LXXIX, (+)-enantiomer, 0.6045 g) and 4-(piperazin-1-yl)benzenesulfonamide (IV, 0.9824 g) are combined to give the title compound, mp 189-190°; MS (m/z) 401; [α]D +48 (c 0.877, DMF); IR (mineral oil) 1662, 1594, 1150, 1101, 614 cm-1.
Reaction SMILES: [C:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:5][CH2:6][NH:7][CH3:8])#[N:2].[CH2:22]1[O:25][CH:23]1[CH3:24]>CO>[C:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:5][CH2:6][N:7]([CH2:22][CH:23]([CH3:24])[OH:25])[CH3:8])#[N:2]
Reactant: CNCCCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C
Reactant: CC1CO1
Solvent: CO
Product: COc1ccc(C(C#N)(CCCN(C)CC(C)O)C(C)C)cc1OC
Temperature: 20 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
A solution of 18.9 g of 4-cyano-4-(3,4-dimethoxyphenyl)-5,N-dimethyl-hexylamine and 4.5 g of propylene oxide in 40 ml of methanol was allowed to stand for 24 hours at 20° C. A further 0.75 g of propylene oxide was then added, and after 24 hours at 20° C. the solution was refluxed for 1 hour and then evaporated to dryness in vacuo. The oil thus obtained was purified by silica gel chromatography using chloroform containing increasing amounts of methanol as eluent. The unitary TLC fractions (chloroform:methanol:5N methanolic ammonia 95:5:0.5 by volume) were evaporated to dryness to give 18.78 g of the title compound as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COC(=O)Cc1cccc(-c2ccc(OC)c(OCc3ccccc3)c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(O)c2)c1
Yield: 95.6 %

Procedure:
1.35 g of Methyl (3′-benzyloxy-4′-methoxybiphenyl-3-yl)acetate was dissolved in a mixed solvent of 10 ml of ethyl acetate and 30 ml of ethanol, then 500 mg of 10% palladium-carbon was added thereto, and the mixture was stirred overnight in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 970 mg of the title compound in the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: CN(C)C=[O:4].[CH3:6][O:7][C:8]1[C:14]([O:15][CH3:16])=[C:13]([O:17]C)[CH:12]=[C:11]([CH3:19])[C:9]=1N>O=O.C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[CH3:16][O:15][C:14]1[C:13](=[O:17])[CH:12]=[C:11]([CH3:19])[C:9](=[O:4])[C:8]=1[O:7][CH3:6]
Reactant: CN(C)C=O
Reactant: COc1cc(C)c(N)c(OC)c1OC
Agent: [Co+2]
Agent: O=O
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Product: COC1=C(OC)C(=O)C(C)=CC1=O

Procedure:
To a dimethylformamide solution (35 ml) of 2,3,4-trimethoxy-6-methyl aniline (3.4 g) is added bis(salicylidene)ethylenediiminocobalt(II) (120 mg), followed by stirring in oxygen streams at atmospheric temperature and pressure for 72 hours. The reaction product is isolated in the same manner as Example 7 and recrystallized from hexane. The above procedure yields 2,3-dimethoxy-5-methyl-1,4-benzoquinone (2.9 g) as orange-yellow needles melting at 59° C.-60° C.