Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[NH:5].[OH:12][C@H:13]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@H:15]([CH2:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@:19]3([OH:34])[CH2:20][CH2:21][C@@H:22]2[CH:32]=O)[CH2:14]1>Cl.O1CCOCC1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][NH:6][C:4](=[NH:5])[NH:3]/[N:2]=[CH:32]/[C@H:22]1[CH2:21][CH2:20][C@:19]2([OH:34])[C@H:18]3[C@H:27]([CH2:26][CH2:25][C@:23]12[CH3:24])[C@:28]1([CH3:31])[C@@H:15]([CH2:14][C@@H:13]([OH:12])[CH2:30][CH2:29]1)[CH2:16][CH2:17]3
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Reactant: CN(C)CCNC(=N)NN
Agent: Cl
Agent: I
Solvent: C1COCCO1
Product: CN(C)CCNC(=N)N/N=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 3 h
Yield: 14.3 %

Procedure:
To a solution of 0.64 g of 1-amino-3-(2-dimethylaminoethyl)guanidine hydroiodide (prepared following the procedure described in Houben-Weil, Metoden der Organischen Chemie, Band VIII, page 183) in 20 ml of 10-4M hydrochloric acid a solution of 1.10 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 25 ml of dioxane was added dropwise at room temperature. After 3 hrs, the solution was evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 78/20/2 as eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with di-iso-propyl ether to give 0.15 g of the title compound (I-ag) as hydroiodide, white solid.
Reaction SMILES: [C:1]([N:11]([CH3:19])[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1.O>C1COCC1>[C:1]([N:11]([CH3:19])[C@H:12]([C:16]([N:20]([CH3:37])[C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:24]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of Z-N-Me-Val-OH (700 mg, 2.64 mmol), N-Me-Tyr(3-tBu)-NH2 (0.55 g, 2.20 mmol) and CMPI (674 mg 2.64 mmol) in THF (22 ml), under cooling with ice, TEA (0.61 ml) was added and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=3:2) to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.98 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[F:39]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[C:34]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2c(F)cccc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9) (4.59 g, 20.6 mmol) in THF (45 ml) was cooled to 5° C. under nitrogen. A solution of 1.0 M lithium bis(trimethylsilyl)amide in THF (20.6 ml, 20.6 mmol) was added dropwise maintaining the temperature below 10° C. After 10 minutes a solution of 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (5.29 g, 20.6 mmol, JRD fluorochemicals Ltd) in THF (9 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched using 1 M hydrochloric acid (50 ml). The reaction mixture was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried with magnesium sulphate, filtered and solvent removed in vacuo. The crude material was dissolved in DCM and applied to a 330 g silica cartridge. The cartridge was eluted with 0-100% ethyl acetate in cyclohexane over 45 min. The required fractions were combined and evaporated in vacuo, to give the title compound as a white solid (6.75 g). The white solid (6.75 g) was dissolved in ethyl acetate (70 ml) and heated to 50° C. Cyclohexane (280 ml) was then added dropwise over 20 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34](O)=[C:33]([CH3:38])[CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:33]([CH3:38])[CH:32]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 4-hydroxy-3-methyl-benzoic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. Colorless oil (60%). MS (Turbo Spray): m/z=539.2 [M+H].
Reaction SMILES: C1[O:9]C1C1C=CC=CC=1.C1(C(O)CO)C=CC=CC=1.C1C2=C3C4C(C=C2)=C2C=CC=CC2=CC=4C=CC3=CC=1.[CH:40]1[CH:45]=[C:44]2[CH:46]=[CH:47][C:48]3[C:53]4[CH:54]=[CH:55][CH:56]5[O:58][CH:57]5[C:52]=4[CH:51]=[C:50]4[CH:59]=[CH:60][C:42](=[C:43]2[C:49]=34)[CH:41]=1>>[CH:41]1[C:42]2=[C:43]3[C:49]4[C:50]([CH:59]=[CH:60]2)=[C:51]2[CH:52]=[CH:57][C:56]([OH:58])=[C:55]([OH:9])[C:54]2=[CH:53][C:48]=4[CH:47]=[CH:46][C:44]3=[CH:45][CH:40]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: C1=CC2OC2c2cc3ccc4cccc5ccc(c21)c3c45
Agent: OCC(O)c1ccccc1
Agent: c1ccc2c(c1)cc1ccc3cccc4ccc2c1c34
Product: Oc1ccc2c(cc3ccc4cccc5ccc2c3c45)c1O

Procedure:
The assay of styrene oxide hydrolase activity in the strains PES1-5 and PES1-53 demonstrates the formation from styrene oxide of approximately 1 to 2 nmol of 2-phenyl-2-hydroxyethanol per min and per mg of microsomal proteins. This activity is undetectable in the other strains of the PES1 series. The reductase activity of the strain PES1-53 is comparable to that of the strain PES1-34. The strain PES1-53 transformed with an expression plasmid which codes for cytochrome P450 1A1 is capable, on incubation with benzo(a)pyrene, of hydrolysing the benzo(a)pyrene 7,8-oxide formed in situ to benzo(a)pyrene-7,8-diol. These activities are demonstrated in FIG. 13, which shows an HPLC separation of the metabolites of benzo(a)pyrene formed on incubation of this pollutant with strains PES1-2, PES1-3 and PES1-53 transformed to express murine cytochrome P450 1A1. Clearly, only the strain PES1-53 permits the formation of benzo(a)pyrene-7,8-diol in large amounts. This molecule is an important intermediate in the degradation of the carcinogenic industrial pollutant, benzo(a)pyrene.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[C:16]3[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:14]=[CH:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=1)[CH3:2].C1C2C=CC3C(=CC([CH:40]=[O:41])=C4C=3C=CC=C4)C=2C=CC=1>C1COCC1>[CH2:1]([O:3][C:4]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH:40]=[O:41])[CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:5]=1)[CH3:2]
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CCOc1cc2c3ccccc3ccc2c2ccccc12
Solvent: C1CCOC1
Product: CCOc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Yield: 64 %

Procedure:
6-Ethoxychrysene (Cambridge Chemical, Inc., 48 g, 0.176 mol) was formylated according to the procedure outlined in 1A, except that CH2Cl2 (1L) was used as the reaction solvent. After isolation, the crude material was chromatographed on a plug of SiO2 (500 g) using CH2Cl2 as the eluting solvent to give (after removal of solvent and drying) 33.7 g (64%) of 12-ethoxychrysene-6-carbaldehyde mp 173.5°-176°, (C,H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][C:17]([NH2:19])=[O:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:5]2.C[O:21][C:22](=O)[C:23]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=O.CC([O-])(C)C.[K+].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]([C:16]2[C:17](=[O:18])[NH:19][C:22](=[O:21])[C:23]=2[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][N:13]([CH3:14])[CH3:15])=[CH:5]2
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CN(C)Cc1cnc2ccc(Cl)c(CC(N)=O)c2c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)Cc1cnc2ccc(Cl)c(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
To a solution of 2-(6-chloro-3-dimethylaminomethyl-quinolin-5-yl)-acetamide (100 mg, 0.36 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (110 mg, 0.54 mmol) in anhydrous THF was added dropwise a 1 M solution of t-BuOK in THF (1.8 mL) under an argon atmosphere at 0° C. The resulting deep red reaction mixture was stirred for 30 min. at 0° C., poured into a saturated aqueous NH4Cl solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford an orange solid. Purification by size exclusion chromatography (Sephadex LH-20, MeOH afforded the title compound as an orange solid (88.3 mg, 0.205 mmol, 57%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=11.88 (bs, 1H), 11.25 (bs, 1H), 8.69 (d, J=1.9 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 8.02 (s, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.85 (bs, 1H), 7.26 (d, J=8.1 Hz, 1H), 6.88 (t, J=7.4 Hz, 1H), 6.44 (t, J=7.4 Hz, 1H), 6.12 (d, J=8.1 Hz, 1H), 3.36 (AB-system: δA=3.48 (d, JAB=−13.2 Hz, 1H), δB=3.25 (d, JAB=−13.2 Hz, 1H)), 1.78 (s, 6H). MS (ES+): 431 (M(C24H1935ClN4O2)+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)=[C:9]([CH:20]([CH3:22])[CH3:21])[C:8](=[O:23])[NH:7][C:6]1=[O:24])[C:2]#[C:3][CH3:4].N1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1>CO.[Pd]>[CH2:1]([N:5]1[C:10]([O:11][C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:9]([CH:20]([CH3:21])[CH3:22])[C:8](=[O:23])[NH:7][C:6]1=[O:24])/[CH:2]=[CH:3]\[CH3:4]
Reactant: CC#CCn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: C/C=C\Cn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 33 mg (0.1 mmol) of the compound obtained from Example 11 in 1 ml of methanol were added 3 ml of pyridine, a drop of quinoline, and 4 mg of palladium on barium sulfate. The reaction mixture was then stirred for about 2 hours at room temperature under an atmosphere of hydrogen, filtered through Cellite pad, and evaporated under reduced pressure to give a light brown oil, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (1:3) as an eluent to afford 25 mg (yield 76%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:24]([NH2:31])[C@@H:23]1[OH:32]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:31][C@@H:24]4[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:22][CH:23]4[OH:32])=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: OC(CN[C@@H]1c2ccccc2CC1O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and (1S, 2R)-(−)-cis-1-amino-2-indanol in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=435.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:42]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:25]=[CH:24][C:23]([N:26]6[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]6)=[CH:22][CH:21]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=5[F:19])[N:11]=4)=[CH:34][CH:35]=3)=[CH:40][CH:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (prepared according to general procedures A, B and C subsequently) (56 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.NC[C:36](N)=[O:37]>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C@H:16]([OH:17])[CH2:36][OH:37])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)NC[C@H](O)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (S)-(−)-3-amino-1,2-propanediol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.81 (m, 1H), 3.55 (m, 3H), 3.39 (m, 1H), 2.20 (s, 3H). ESHRMS m/z 480.1131 (M+H calculated for C22H21ClF2N3O5 requires 480.1132).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]=[O:16])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH:17]1([CH:15]([C:11]2[C:12]([CH3:14])=[CH:13][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:10]=2)[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1cccc(-n2cc(C)c(C=O)n2)c1
Solvent: C1CCOC1
Product: COc1cccc(-n2cc(C)c(C(O)C3CCCCC3)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a solution (10 mL) of 1-(3-methoxyphenyl)-4-methyl-1H-pyrazole-3-carbaldehyde (0.84 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (7.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.62 g, 52%) as a pale-yellow oil.
Reaction SMILES: C1(C)C=CC(S(N[N:11]2[CH2:18][C:17](=[CH2:19])[CH2:16][CH:15](NS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13](=[CH2:31])N2)(=O)=O)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:15][C:17]1([CH:16]2[CH2:15][CH2:14][CH2:13][CH2:31][CH2:14][CH2:13][CH2:31]2)[CH2:18][NH:11][CH2:19][CH:17]([CH3:16])[CH2:18][NH:11][CH2:19]1
Reactant: C=C1CC(NS(=O)(=O)c2ccc(C)cc2)CC(=C)NN(NS(=O)(=O)c2ccc(C)cc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CNCC(C)(C2CCCCCCC2)CNC1
Reaction time: 42 h
Yield: 91.3 %

Procedure:
A suspension of 1,5-di(4-toluenesulfonamido)-3,7-bismethylenediazacyclooctane 1a (2.22 g, 4.98 mmol) in tetrahydrofuran (75 mL) containing lithium aluminum hydride (1.90 g, 50 mmol) was stirred under a nitrogen atmosphere for 42 h. The reaction mixture was quenched by the dropwise addition of 20% sodium hydroxide solution (4.5 mL) with external cooling. Stirring was continued at room temperature for 3 h and the white granular precipitate that formed was removed by filtration and washed with anhydrous ether (3×50 mL). The combined organic extracts were concentrated on a rotary evaporator to give 0.574 g (82%) of 5 as a colorless solid, mp XX° C. 1H NMR (CDCl3) δ0.99 (s, 6H), δ2.71 (d, J=11.2 Hz, 4H), δ2.92 (d, J=11.2 Hz, 4H), δ2.61 (s, 2H. br); 13C NMR (CDCl3) δ20.4, δ51.7, δ62.6. LRMS (EI) calc. for C8H16N2 140.1; found m/z, 140. Treatment of an ethanolic solution of 5 with picric acid afforded the picrate as a yellow solid, mp 258° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncn1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.23 (s, 9H), 7.40 (d, 2H, J=8.4 Hz), 7.51 (dd, 1H, J=8.8 Hz, 2 Hz), 7.71-7.80 (m, 6H), 9.03 (d, 1H, J=4.8 Hz), 9.33 (d, 1.2 Hz), 10.91 (b, 1H). MS: m/z 434.0 (M++1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([S:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[NH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([S:31]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[O:9])[NH:22][C:23]=2[C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(-c2nc(Sc3cccs3)[nH]c2-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Product: O=S(c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.90 g of 4,5-bis(4-chlorophenyl)-2-(2-thienylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, yielding 3.83 g of 4,5-bis(4-chlorophenyl)-2-(2-thienylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(N(CC)CC)C.[Cl:35][CH2:36][CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:39]([CH2:38][CH2:37][CH2:36][Cl:35])(=[O:41])=[O:40])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Reactant: O=S(=O)(Cl)CCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCCl)CC2)nc1N
Reaction time: 0.17 h

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (565 mg, 1.5 mmol, Example 120) and triethylamine (167 mg, 0.25 mL, 1.69 mmol) in tetrahydrofuran (20 mL) at 0° C., 3-chloropropane sulfonyl chloride (0.20 mL, 1.65 mmol, Aldrich) was added. The mixture was stirred for 10 minutes and the reaction was quenched with water. The mixture was extracted with ethyl acetate and the extracts were combined and dried with sodium sulfate. The solvent was removed and the residue was chromatographed (4% methanol/dichloromethane) to give 600 mg of yellow solid. Yield, 77%. MS (ES) MH+=518.
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].[Na+].[I-]>CN(C=O)C>[N:26]([CH2:12][C@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CN=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
(S)-tert-butyl 2-((tosyloxy)methyl)morpholine-4-carboxylate (63.7 g, 171.52 mmol) was dissolved in DMF (550 ml), and then NaN3 (44.59 g, 686.08 mmol) and NaI (2.5 g, 17.15 mmol) were added, followed by stirring at 70° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O and EA, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:5), to give (S)-tert-butyl 2-(azidomethyl)morpholine-4-carboxylate as a white solid (31.1 g, 75%).