Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[N:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[N:7]=[N:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[N:4][CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Fc1cccc(F)c1-c1ncc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1cccc(F)c1-c1ncc(Oc2cccc(Cl)c2)nn1
Reaction time: 2 h

Procedure:
325 mg of 6-chloro-3-(2,6-difluorophenyl)-[1,2,4]triazine (see Example 1.7 b) are placed in 10 ml of acetonitrile; 230 mg of 3-chlorophenol and 190 mg of potassium carbonate are added and stirring is carried out at room temperature for 2 h. The reaction mixture is then poured into water and extracted with ethyl acetate; the ethyl acetate phase is concentrated and the crude product is purified by means of flash chromatography. In this way the title compound having a melting point of 132-137° C. is obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:17]=2)[NH:12][C:11]=1[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:21])[N:22]([CH3:24])[CH3:23])[CH:17]=2)[NH:12][C:11]=1[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCN)c1
Yield: 96.8 %

Procedure:
{2-[2-(3,5-dimethylphenyl)-5-(3,3-dimethylureido)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester (295 mg) was dissolved in a ternary solvent mixture comprising methylene chloride (6 mL), trifluoroacetic acid (2 mL) and anisole (2 mL) for 2.5 h. The volatile solvent components were removed on a rotary evaporator and the residues taken up in methanol and purified on four (20×20 cm 1000μ) preparative silica gel plates and eluted with a solvent system comprising methanol and methylene chloride in the ratio (1:9 v/v). The product (222 mg) was isolated as a foamy material.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:29]=1)[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[Si:30]([O:37][C@@H:38]1[CH2:42][CH2:41][N:40]([C:43]([C:45]2[CH:50]=[CH:49][C:48](C3OC(C)(C)C(C)(C)O3)=[CH:47][CH:46]=2)=[O:44])[CH2:39]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>>[Si:30]([O:37][C@@H:38]1[CH2:42][CH2:41][N:40]([C:43]([C:45]2[CH:50]=[CH:49][C:48]([C:2]3[CH:3]=[CH:4][C:5]4=[C:6]([CH:29]=3)[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:11]4)=[CH:47][CH:46]=2)=[O:44])[CH2:39]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CC1(C)OC(c2ccc(C(=O)N3CC[C@@H](O[Si](C)(C)C(C)(C)C)C3)cc2)OC1(C)C
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CC[C@@H](O[Si](C)(C)C(C)(C)C)C4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and (R)-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)methanone. MS APCI (+) m/z 689 (M+1) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][O:27][CH:28]1[CH2:31][N:30]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][NH:40][CH3:41])=[CH:35][CH:34]=2)[CH2:29]1.C[Al](C)C>ClCCCl>[CH3:26][O:27][CH:28]1[CH2:31][N:30]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:41])[C:21]([C:19]3[O:20][C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:25])(=[O:12])=[O:11])[CH3:14])=[N:17][N:18]=3)=[O:22])=[CH:35][CH:34]=2)[CH2:29]1
Reactant: CNCc1ccc(CN2CC(OC)C2)cc1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3ccc(CN4CC(OC)C4)cc3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), 1-{4-[(3-methoxyazetidin-1-yl)methyl]phenyl}-N-methylmethanamine (30 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). A portion of the crude product was purified using prep method D to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH2:9][CH:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CC=C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: COc1ccc2cccc(CCNC(C)=O)c2c1
Reaction time: 48 h
Yield: 48 %

Procedure:
To a solution of the compound obtained in Step E (100 mg, 0.41 mmol) in dichloromethane (4 mL) there is added, at ambient temperature, DDQ (111 mg, 0.49 mmol). The reaction mixture is stirred for 2 days and then washed with saturated NaHCO3 solution. The aqueous phase is extracted with ethyl acetate, and the organic phases are collected and then dried using brine and then over MgSO4. After filtration, the solvents are evaporated off under reduced pressure and the crude reaction mixture obtained is purified by chromatography on a silica column (eluant: ethyl acetate/petroleum ether 90/10, then ethyl acetate/methanol 90/10) to yield the title product in a yield of 48%.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:37][C:38]1[CH:39]=[N:40][C:41](I)=[N:42][CH:43]=1.C(#N)C.C1COCC1>O.CC(=O)OCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:37][C:38]1[CH:39]=[N:40][C:41]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:13]([NH:12][C:10]([C:8]3[S:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[O:11])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:27][CH:26]=2)=[N:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)c1ccc(C(C)(C)C)s1
Reactant: Brc1cnc(I)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)s1
Temperature: 120 °C
Yield: 63 %

Procedure:
Prepared using General Procedure 10. Into a degassed solution of tert-butyl (S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate INT-16 (510 mg, 1.0 mmol) and 5-bromo-2-iodopyrimidine (570 mg, 2.0 mmol) in 2/2/1 ACN/THF/saturated aqueous NaHCO3 (10 mL) was added Pd(dppf)Cl2 (30 mg, 0.4 mmol). The reaction mixture was heated at 120° C. for 1 h in a microwave reactor. The reaction mixture was diluted with water (100 mL) and EA (50 mL) and filtered over Celite. The aqueous layer was extracted with EA (3×30 mL) and the combined organic layer was dried over MgSO4, concentrated, and purified by chromatography (EA/hexanes) to provide 342 mg (63%) of tert-butyl (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoate INT-17. LCMS-ESI (m/z) calculated for C26H30BrN3O3: 543.1. found: 488.0 [M−tBu+H]+, tR=10.95 min (Method 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14](CC(NC3C=C4C(=CC=3)C[C@@]3(C(=O)NC(=O)N3C)C4)=O)[C:13](=[O:35])[C:12]([CH3:37])([CH3:36])[S:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[NH:14][C:13](=[O:35])[C:12]([CH3:37])([CH3:36])[S:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN3C(=O)C(C)(C)SC[C@H]3c3cc(F)cc(F)c3)cc1C2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1(C)SC[C@@H](c2cc(F)cc(F)c2)NC1=O
Reaction time: 2 h

Procedure:
To a solution of 2-[(5R)-5-(3,5-difluorophenyl)-2,2-dimethyl-3-oxo-4-thiomorpholinyl]-N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]acetamide (Example 2) in 1.5 mL chloroform at 0° C., was added 3-chloroperoxybenzoic acid (21 mg with a purity of 77%, 0.121 mmol). An LCMS of the reaction mixture after two hours showed that all starting material was consumed. Calcium hydroxide (14 mg, 0.185 mmol) was added to the reaction and stirred for forty minutes. The mixture was then vacuum filtered through filter paper and the solid was washed with chloroform (3×10 mL). The filtrate was concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2—1:99 to 5:95, to give the title compound. MS: m/z=545 (M+H). HRMS: m/z=545.1653; calculated m/z=545.1665 for C26H26F2N4O5S.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH2:29]([NH2:31])[CH3:30]>>[CH2:29]([NH:31][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:20])[CH3:30]
Reactant: CCN
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: Cl
Product: CCNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (45 mg) was coupled to ethylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 10.6 mg of 170. MS (Q1) 409.2 (M)+.
Reaction SMILES: C[O:2][C:3](=[O:49])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([Br:20])=[CH:18][C:17]([C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:16][C:15]=2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)=[CH:6][C:5]=1[OH:48].[OH-].[Na+]>CCO>[Br:20][C:19]1[C:14]([O:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:49])=[O:2])=[C:5]([OH:48])[CH:6]=2)=[C:15]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[CH:16]=[C:17]([C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:18]=1
Reactant: COC(=O)c1ccc(OCCOc2c(Br)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCOc2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of 4-{2-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3′-trifluoromethyl-biphenyl-2-yloxy]-ethoxy}-2-hydroxy-benzoic acid methyl ester (1.16 mmol, 1 eq) in EtOH (20 mL) was added 1M NaOH (10 mL) and the reaction was heated at reflux 90 min. It was then cooled to rt, concentrated in vacuo, diluted with H2O, and acidified with 2M HCl to pH 1. It was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:Hexane +1% Formic acid) to afford the title compound (0.607 g, 79%) as a white foam. 1H NMR (DMSO-d6) δ 13.55 (bs, 1H); 11.49 (bs, 1H); 8.58 (t, 1H); 8.14 (d, 1H); 7.90-7.84 (m, 3H); 7.73-7.61 (m, 3H); 7.26-7.12 (m, 5H); 6.27-6.23 (m, 2H); 4.00 (m, 2H); 3.92 (m, 2H); 3.23 (dd, 2H); 2.52 (t, 2H); 1.52 (m, 4H); 1.28 (m, 8H); IR (KBr) 3400, 2950, 2850, 1660, 1620, 1550, 1450, 1420, 1330, 1220, 1160, 1120 cm−1; mass spectrum [(−)ESI], m/z 726/728 (M−H)−; Anal. Calcd. for C37H37F3NO6: C, 60.99; H, 5.12; N, 1.92, Found: C, 60.32; H, 5.17; N, 1.83.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[CH:45]1[CH2:50][CH2:49]C[CH2:47][CH2:46]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH:15]3[CH2:49][CH2:50][CH2:45][CH2:46][CH2:47]3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: BrCC1CCCCC1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC3CCCCC3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (bromomethyl)cyclohexane and isolated as white solid (6.1 mg, 39%). MS (m/e): 379.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C@H:9]2[C@@H:13]([CH2:14][OH:15])[O:12][C:11]([CH3:17])([CH3:16])[N:10]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:4][N:3]=1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1>>[Si:29]([O:15][CH2:14][C@H:13]1[O:12][C:11]([CH3:17])([CH3:16])[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:9]1[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C

Procedure:
The title compound was synthesized in a manner analogous to Example 407, step 1 via (4S,5S)-tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate in the presence of TBSCl and imidazole and was used without further purification.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5](Cl)[N:4]=1.Cl.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[C:5]([O:17][CH:14]([CH3:16])[CH3:15])[N:4]=1
Reactant: CC(C)O
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: Cl
Agent: [Na]
Product: CC(C)Oc1nc(N)nc2[nH]cnc12
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Sodium (Aldrich, lot #9621CL, 4.1 g, 176.9 mmol) was reacted with 150 mL of isopropanol, 2-Amino-6-chloropurine (Sigma, lot #69F4064, 6.0 g, 35.4 mmol) was added and the reaction stirred at 50° C. for 24 hours. The solution was cooled and brought to pH 7 with 1N HCl. The solvents were evaporated to one-half volume. The precipitate was filtered, washed with water and dried to give 5.9 g (30.5 mmol, 87%); mp=204°-206° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][C:10]1[N:14]=[CH:13][NH:12][N:11]=1.[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](Cl)=[O:19])[CH3:16]>N1C=CC=CC=1>[CH2:15]([N:17]([CH2:21][CH3:22])[C:18]([N:12]1[CH:13]=[N:14][C:10]([S:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[N:11]1)=[O:19])[CH3:16]
Reactant: CCN(CC)C(=O)Cl
Reactant: Cc1cccc(C)c1Sc1nc[nH]n1
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(Sc2c(C)cccc2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(2,6-Dimethylphenylthio)-1,2,4-triazole (2 g) is dissolved in pyridine (50 ml) and diethyl carbamoyl chloride (1.4 g) is added dropwise to the solution. The mixture is stirred first at room temperature for 1 h, then at 70° C. for 2 h. Thereafter, pyridine is distilled off. The residue is extracted with chloroform and dried with magnesium sulfate to obtain the crude product of 1-(diethylcarbamoyl)-3-(2,6-dimethylphenylthio)-1,2,4-triazole. After cooling to 0° C., m-chloroperbenzoic acid (4 g) is added and the mixture is stirred at room temperature for 4 h. The resulting product is washed with a 10% aqueous solution of potassium carbonate and dried with magnesium sulfate. After distilling off the solvent, the residue is recrystallized with n-hexane/ethyl acetate; m.p. 111°-112° C.; yield, 2.4 g (72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16]C)[CH:11]=[O:12])=[CH:4][C:3]=1[S:18]([CH3:21])(=[O:20])=[O:19].B(Br)(Br)Br.CO>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[OH:16])[CH:11]=[O:12])=[CH:4][C:3]=1[S:18]([CH3:21])(=[O:19])=[O:20]
Reactant: COc1ccc(C=O)cc1-c1ccc(F)c(S(C)(=O)=O)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(-c2cc(C=O)ccc2O)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a cooled solution (0° C.) of 3-(4-fluoro-3-(methylsulfonyl)phenyl)-4-methoxybenzaldehyde (27) (400 mg, 1.3 mmol, 1 eq.) in DCM (20 mL) was added BBr3 (0.4 mL). The reaction mixture was stirred room temperature for 3 h. After cooling to 0° C., methanol was added and the mixture was concentrated under vacuum. The residue was diluted with DCM and washed with water. The DCM was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (eluent: PE:EA=1:1) to give 340 mg (89%) of 3-(4-fluoro-3-(methylsulfonyl)phenyl)-4-hydroxybenzaldehyde (28).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH3:14]>>[CH3:14][C:10]1[N:9]([CH2:8][CH2:7][CH2:6][NH:1][C:2]([NH2:4])=[O:3])[CH2:13][CH2:12][N:11]=1
Reactant: NC(N)=O
Reactant: Cc1nccn1CCCN
Product: CC1=NCCN1CCCNC(N)=O
Yield: 95.7 %

Procedure:
60.0 g of urea was added to 139.2 g of 1-(3′-aminopropyl)-2-methylimidazole and reacted at 160° C. for 10 hours, and after the reaction, a volatile component was removed to obtain 176.1 g of a 1-{3′-(2″-methylimidazolinyl)propyl)urea composition. 117.4 g of dipropylene glycol was added thereto to prepare a solution containing 60% of a 1-(3′-(2″-methylimidazolinyl)propyl}urea composition (IZUM), which was subjected to the following foaming test. The composition of the solution is shown in Table 17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]12[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=1)[NH:22]C(=O)O[C:18]2=[O:19].C1(C)C=CC=CC=1>CCOCC>[C:18]([O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:12]1)(=[O:19])[C:17]1[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=1)[NH2:22]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: OCCN1CCN(c2cccc(Cl)c2)CC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Nc1ccccc1C(=O)OCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 70 %

Procedure:
7.2 G. (0.03 mol) of 2-(4-m-chlorophenyl-piperazino)-ethanol and 6.55 g. (0.04 mol) of isatoic anhydride in 125 ml. of toluene are refluxed for 3 hours. The hot toluene solution is filtered and the toluene is evaporated from the filtrate to give a residue which is taken up in ether in order to remove a small amount of unreacted isatoic anhydride, the solution is filtered and the ether is driven off. The remaining product is triturated in petroleum ether, filtered off and recrystallised twice from isopropyl alcohol to give 7.6 g. (yield = 70%) of 2-(4-m-chlorophenylpiperazino)-ethyl anthranilate, which melts at 76°C.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:12]=[C:13]1[NH:21][CH:20]=[N:19][C:18]2[N:17]([CH2:22][CH2:23][C:24](OCC)=[O:25])[CH:16]=[N:15][C:14]1=2>C(#N)C>[O:12]=[C:13]1[NH:21][CH:20]=[N:19][C:18]2[N:17]([CH2:22][CH2:23][C:24]([NH:11][CH2:10][CH2:9][CH2:8][N:7]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]3[CH3:1])=[O:25])[CH:16]=[N:15][C:14]1=2
Reactant: CC1CCCCN1CCCN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: CC1CCCCN1CCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
0.565 g (3.62 mmol) of 1-(3-aminopropyl)-2-pipecoline was placed into a 10 ml round bottom flask with a magnetic stirring bar. The flask was heated to 120° C. and 250 mg (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added. The mixture was heated for two hours at 120° C. and was allowed to cool. The resultant light orange viscous oil was treated with 8 ml acetonitrile and was stirred for about 25 min. The solution was filtered and the solid was washed with acetonitrile and then with ether. This yielded 254 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[3-(2-methylpipiridin-1-yl)propyl]propanamide (AIT-0044) as an off-white solid.
Reaction SMILES: [OH:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>C1COCC1.O>[N:29]1([C:27](=[O:28])[CH2:26][O:1][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@@H:5]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[CH2:4][CH2:3]2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](O)c2ccccc21
Reactant: O=C(CCl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CO[C@@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)c2ccccc21)N1CCOCC1
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
A solution of Intermediate 32a (115 mg, 0.39 mmol) in dry THF (4 mL) was added NaH (60% in mineral oil, 23 mg, 0.59 mmol) at RT and stirred for 15 min. 4-(Chloroacetyl)morpholine (56 μL, 0.43 mmol) was then added and the mixture heated at reflux for 3.5 h. After cooling, the dark brown mixture was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% MeOH in DCM, to give the title compound as light brown foam (103 mg, 62%). LCMS (Method 3): Rt 3.44 min, m/z 443 [MNa+].
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>[OH-].[Na+].C(O)C.C1C=CC=CC=1>[C:17]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)c1cc(OC(=O)C=Cc2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
3,5-di tert. butyl-4-hydroxyphenyl cinnamate was prepared by dissolving 22.2 grams of 2,6-di tert.butyl hydroquinone in a solution of 4 grams of sodium hydroxide in 100 milliliters of ethanol and adding drop wise to this solution a solution of 18.2 grams of cinnamoyl chloride in 50 milliliters of benzene. The addition was completed in 30 minutes and the reaction mixture was stirred for an additional 45 minutes. The reaction mixture was then poured into 150 milliliters of water and the layers were separated. The organic layer was washed three times with 10 per cent sodium hydroxide solution, once with water, dried over sodium sulfate, and then evaporated to dryness. The residue, after washing with cold hexane, yielded 10 grams of product which after recrystallization from hexane melted at 123.5° C. to 125.5° C.