Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][NH2:10]>N1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:9][NH2:10])[CH:7]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1cc(Br)ccn1
Temperature: 75 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of 2-fluoro-4-bromopyridine (3.0 g, 17.15 mmol) in pyridine (30 mL) was added anhydrous hydrazine (11 mL, 0.17 mol). The resulting mixture was stirred at 75° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. To the residue was added water (60 mL), the resulting suspension was stirred at room temperature for 1 h, and then filtered. The collected solid was rinsed with water (2×), then dried in vacuum oven at 50° C. overnight to yield 2.912 g (91%) of the title compound as a light brown solid. The HPLC/MS (method B): retention time=0.60 min, [M+H]+=187.9, 189.9.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][CH2:13][OH:14])[N:9]=[C:10](I)[C:3]=12.[CH3:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([N:25]2[C:33]3[C:28](=[CH:29][C:30](B4OC(C)(C)C(C)(C)O4)=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[CH:19]=[CH:20][CH:21]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][CH2:13][OH:14])[N:9]=[C:10]([C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[N:25]([C:23](=[O:24])[CH2:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[CH:17]=3)[CH2:26][CH2:27]4)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2CCO
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4nn(CCO)c5ncnc(N)c45)ccc32)c1
Temperature: 120 °C

Procedure:
To a 25 mL pressure tube was charged 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol (63.8 mg, 0.209 mmol), 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (79 mg, 0.209 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8.54 mg, 0.011 mmol), and sodium bicarbonate (35.1 mg, 0.418 mmol) followed by dioxane (8 mL), and water (2 mL). The reaction was heated at 120° C. for 40 min in microwave. The reaction was cooled to room temperature, the mixture was transferred into a 100 mL flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube (total 100 mL of EtOAc was added to the mixture). The EtOAc solution was concentrated to dryness, and re-dissolved with CH2Cl2/MeOH (8 mL/2 mL). It was purified by flash column 25-100% EtOAc/hexane, then 0-10% MeOH/EtOAc, Si SF15-24g, to afford a brown solid. The brown solid was further purified by recrystallization in CH3CN to give a brown solid as the title compound. LC/MS (ES) m/z=429.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H), 3.24 (s, 2H), 3.80-3.88 (m, 4H), 4.19-4.27 (m, 2H), 4.37 (t, J=5.81 Hz, 2H), 4.89 (t, J=5.68 Hz, 1H), 7.07-7.14 (m, 3H), 7.20-7.28 (m, 1H), 7.45 (d, J=8.08 Hz, 1H), 7.51 (s, 1H), 8.21 (d, J=8.34 Hz, 1H), 8.23 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34]([CH3:36])=[N:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][C:34]1[NH:33][C:32]2[C:37]([CH3:39])=[CH:38][C:29]([NH:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:30][C:31]=2[N:35]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5[nH]c(C)nc5c4)ncn3)CC1)C(=O)N2

Procedure:
265 mg (0.962 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 250 mg (0.913 mmol) (6-chloro-pyrimidin-4-yl)-(2,7-dimethyl-1H-benzimidazol-5-yl)-amine and 1.00 mL (5.81 mmol) DIPEA were refluxed in 1.5 mL DMF. After the reaction had ended the reaction mixture was diluted with some DMF and microfiltered. The filtrate was purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[C:4]([CH3:3])[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]=1[NH2:8]
Reactant: BrBr
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: Cc1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of bromine (23.24 mL, 453.5 mmol) in glacial acetic acid (50 mL) was added dropwise over 2 h to a mechanically-stirred suspension of 4-methyl-2-nitroaniline (60.00 g, 394.3 mmol) in glacial acetic acid (200 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature 1 h, and then most of the acetic acid was removed under reduced pressure. The resultant orange solid was dissolved in a mixture of saturated aqueous sodium bicarbonate (1500 mL) and ethyl acetate (500 mL). The layers were separated and the aqueous solution was again extracted with ethyl acetate. The combined organic layers were washed once with water, dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step A as an orange solid melting at 64°-65.5° C. (89.694 g, 98%). 1H NMR (CDCl3): δ2.28 (s,3H), 6.45 (br s,2H), 7.55 (s, 1H), 7.94 (s, 1H).
Reaction SMILES: C(OCCNC(C(N)=S)=S)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].OCC[NH:26][C:27]([C:29]([NH2:31])=[S:30])=[S:28].C(Cl)(=O)CCCCCCCCCCC.C(OCCNC(C(N)=S)=S)(=O)CCCCCCCCC.C(Cl)(=O)CCCCCCCCC>>[C:3]1([CH2:2][NH:26][C:27]([C:29]([NH2:31])=[S:30])=[S:28])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCCCCCCCC(=O)OCCNC(=S)C(N)=S
Reactant: NC(=S)C(=S)NCCO
Agent: CCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCC(=O)OCCNC(=S)C(N)=S
Agent: CCCCCCCCCCCC(=O)Cl
Product: NC(=S)C(=S)NCc1cccc2ccccc12

Procedure:
Using the general procedure outlined in Experiment 2, N-(2-dodecanoyloxyethyl)dithiooxamide was synthesized from N-(2-hydroxyethyl)dithiooxamide and dodecanoyl chloride, and N-(2-decanoyloxyethyl)dithiooxamide was synthesized from N-(2-hydroxyethyl)dithiooxamide and decanoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=2)[N:3]=1.[CH3:39][C:40]1[C:48]2[C:43](=[CH:44][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:46][CH:47]=2)[NH:42][N:41]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:45]3[CH:44]=[C:43]4[C:48]([C:40]([CH3:39])=[N:41][NH:42]4)=[CH:47][CH:46]=3)=[CH:34][CH:33]=2)[N:3]=1
Reactant: Cc1n[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(COc4ccc(Br)cc4)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(COc4ccc(-c5ccc6c(C)n[nH]c6c5)cc4)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (350 mg, 0.56 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (285 mg, 1.1 mmol) and Pd(dppf)Cl2 (62 mg, 0.09 mmol) in dioxane (5 mL)/aq. Na2CO3 solution (2.0 M, 5 mL) was heated to 90° C. for 4 h. The reaction was cooled to RT, the solids filtered away, and the solution concentrated in vacuo. Purification on normal phase silica gel (CH2Cl2/MeOH) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH:20]=[CH:21][C:22]#[N:23])[CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][CH2:21][C:22]#[N:23])[CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: N#CC=CC1CCCC(Nc2c([N+](=O)[O-])cnc3ccsc23)C1
Agent: [Pd]
Solvent: CO
Product: N#CCCC1CCCC(Nc2c(N)cnc3ccsc23)C1

Procedure:
A mixture of 3-{3-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acrylonitrile (0.13 g, 0.40 mmol) and 10% Pd/C (0.05 g) in methanol (10 mL) was hydrogenated under balloon pressure of H2 at room temperature over weekend. The mixture was filtered, concentrated and purified on silica gel column (eluting with 0-10% MeOH in methylene chloride) to give the desired product. LCMS calculated for C16H21N4S (M+H)+: m/z=301.1. Found: 301.0.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([F:24])[CH:13]=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].CC(C)([O-])C.[Li+].ClC[C@@H](O)[CH2:34][N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>C(OCC)(=O)C.C(Cl)Cl>[CH2:43]([N:35]([CH2:34][C@@H:4]1[O:3][C:1](=[O:2])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:14]([F:24])[CH:13]=2)[CH2:5]1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
N-carbobenzoxy-3-fluoro-4-morpholinyl aniline (0.33 g, 1 mmol) and lithium tert-butoxide (0.19 g, 2.4 mmol) were added under nitrogen atmosphere to 10 mL of methylene dichloride and the mixture was stirred at room temperature for 0.5 hours. (S)-1-chloro-3-(dibenzylamino) propan-2-ol (0.32 g, 1.1 mmol) was added and the reaction mixture was heated to reflux and stirred for 5 hours. Saturated ammonium chloride solution, and ethyl acetate were added to separate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to provide 0.33 g of off-white solid in 69% yield.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(O)(C)C>[CH2:23]([N:15]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:12]1[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:21])([F:22])[F:1])=[CH:14][CH:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Reactant: BrCc1ccccc1
Solvent: CC(C)(C)O
Product: OC(c1ccc(N(Cc2ccccc2)CC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 100 °C
Reaction time: 10 h
Yield: 8 %

Procedure:
A solution of 100 mg (0.29 mmol) of 1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol in 0.5 mL tBuOH was treated with 0.1 mL (0.84 mmol) of benzylbromide and stirred at 100° C. for 10 hours in a sealed tube. Evaporation of the solvent and column chromatography on silicagel with n-heptane/EtOAc 8:1 yielded 10 mg (8%) of 2-{4-[benzyl-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, blue oil, MS: 432 (MH+).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].[N:13]([CH2:16][Si:17]([O:21][CH3:22])([O:19][CH3:20])[CH3:18])=[C:14]=[O:15]>>[CH3:20][O:19][Si:17]([CH2:16][NH:13][C:14]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:15])([O:21][CH3:22])[CH3:18]
Reactant: COC(=O)CC(=O)OC
Reactant: CO[Si](C)(CN=C=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C(C(=O)NC[Si](C)(OC)OC)C(=O)OC
Reaction time: 1.5 h
Yield: 56 %

Procedure:
A stirred mixture conditioned at a temperature of 30° C. of 6.74 g of dimethyl malonate and 90.0 mg of sodium methoxide (30% strength solution in methanol) was admixed dropwise with 8.06 g of (isocyanatomethyl)-dimethoxy(methyl)silane and the clear solution was stirred for 90 min. This gave dimethyl 2-{[dimethoxy(methyl)silyl]methylcarbamoyl}malonate after recrystallization from isohexane in 56% yield with a purity of >95% (analysis by 1H NMR).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:28]([OH:30])=[O:29])=[C:16]([C:17](=O)[NH:18][C:19]([C:24](=[O:26])[NH2:25])([CH3:23])[CH:20]([CH3:22])[CH3:21])[C:11]=2[N:10]=[C:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:28]([OH:30])=[O:29])=[C:16]([C:17]3[NH:25][C:24](=[O:26])[C:19]([CH:20]([CH3:22])[CH3:21])([CH3:23])[N:18]=3)[C:11]=2[N:10]=[C:9]1[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(C(=O)NC(C)(C(N)=O)C(C)C)c(C(=O)O)ccc2n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc2n1Cc1ccccc1
Reaction time: 4 h
Yield: 30.9 %

Procedure:
A mixture of 1-benzyl-4-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-2-methyl 5-benzimidazolecarboxylic acid (3.58 g, 8.47 mmol), 10N sodium hydroxide (5.08 mL, 50.8 mmol) and water is stirred for 4 hours at reflux temperature, cooled, acidified to pH 4 with hydrochloric acid and filtered. The filter cake is recrystallized from acetonitrile to give the title product as an off-white powder (1.06 g, 31.0%), mp 198°-208° C. (dec).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1.[C-:13]#[N:14].[Na+]>>[O:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:4]([CH:3]([CH3:2])[C:13]#[N:14])=[CH:5]1
Reactant: [C-]#N
Reactant: BrCCc1coc2ccccc12
Agent: [Na+]
Product: CC(C#N)c1coc2ccccc12

Procedure:
This compound was prepared by the same method as for intermediate 27, using 1.98 g (8.8 mmol) of 3-(2-bromoethyl)benzofuran and 0.86 g (17.6 mmol) of NaCN, to afford 1.5 g (quant.) of the title compound: MS (ESI) m/z 171 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[Br:24]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([Br:24])[CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a solution of 1.00 g (2.985 mmol) of the product of Example 3 in 100 mL of CHCl3 was added 0.531 g (2.985 mmol) of N-bromosuccinimide and 0.025 g of AIBN. The resulting mixture was heated to reflux for 18 h and then an additional 0.411 g of NBS and 0.013 g of AIBN were added to the reaction. After refluxing the reaction for another 5 h the reaction mixture was cooled to room temperature, washed with sodium sulfite solution and water, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether-hexanes to provide 0.62 g (50%) of the desired product as a white solid. EI Mass Spec 413 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:18])[CH:15]=[O:16])[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)CO)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(C)(C)C=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-amide (as prepared in the previous step, 1.00 g, 2.55 mmol) and NaHCO3 (1.07 g, 12.8 mmol) in 40 mL of DCM at 0° C. was added Dess-Martin periodinane (Adv. Syn. Chem., 2004, 346, 111-124, 2.16 g, 5.10 mmol). After stirring at 0° C. for 0.5 h, the reaction was warmed to RT and continued to stir for 2 h. The mixture was treated with 100 mL of EtOAc and washed with 10% aqueous Na2S2O3 (2×20 mL), aqueous saturated NaHCO3 (20 mL), H2O (20 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-3% MeOH/DCM) to afford the title compound (876 mg, 88%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C23H26N4O2, 391.2 (M+H). found 391.1.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:8][O:7][C:1](=[O:6])[C:2](=[CH:11][N:12]([CH3:14])[CH3:13])[C:3](=[O:4])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CC(C)=O
Product: COC(=O)C(=CN(C)C)C(C)=O
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of methyl acetoacetate (5.0 mL, 46.33 mmol) and N,N-dimethylformamide dimethylacetal (6.8 mL, 47.95 mmol) was heated to 80° C. for 2.3 h. At this time, the reaction was cooled to 25° C. and was then concentrated in vacuo to afford 2-dimethylaminomethylene-3-oxo-butyric acid methyl ester (7.43 g, 94%) as a red/black solid. This material was used without further purification.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)NC(=O)c3cccnc3)cc1)n2C)c1ccccn1
Yield: 56 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and nicotinic acid chloride. Yield: 56% of theory, C34H33N7O4 (603.7) Rf value: 0.52 (silica gel; dichloromethane/methanol=9:1) ##EQU97##
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)=O>C(#N)C>[C:23]1([CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:21][CH2:20][N:5]2[CH2:6][CH2:7][C:3]([CH3:2])([OH:8])[CH2:4]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: CC1(O)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(O)CCN(CCC(c2ccccc2)c2ccccc2)C1
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a 10 L reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (616 g, 4.48 mol), anhydrous potassium carbonate (1186 g, 8.6 mol) and acetonitrile (5 L). To the resulting mixture was slowly added a solution of 3,3-diphenylpropyl methanesulfonate (1000 g, 3.45 mol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the reaction solution was evaporated under reduced pressure to remove acetonitrile. A mixed solution of dichloromethane and water was added for extraction. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce a crude product, which was purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate=50:1 (volumetric ratio)) to produce 1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-ol (580 g) in a yield of 57%.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:8][C:7]1=[CH:6][C:5](=[O:15])[CH2:4][CH2:3]2.S(=O)(=O)(O)[OH:17].C([O-])([O-])=O.[K+].[K+]>C(O)=O>[CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]([OH:17])([CH3:14])[CH3:13])[CH2:8][C:7]1=[CH:6][C:5](=[O:15])[CH2:4][CH2:3]2
Reactant: O=S(=O)(O)O
Reactant: C=C(C)[C@@H]1CCC2(C)CCC(=O)C=C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: CC12CCC(=O)C=C1C[C@H](C(C)(C)O)CC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 39 %

Procedure:
1.2 g (5.87 mmol) of (6R/S,9R)6-Methyl-9-(1-methylvinyl)-bicyclo[4.4.0]dec-1-ene-3-one from step C of preparation A was dissolved in 20 mL of formic acid and added to 4 mL of 5% sulfuric acid solution. The reaction mixture was stirred at room temperature for 2 days, in refrigerator for 3 days, then neutralized with K2CO3 with cooling, and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried, and evaporated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 5/1) to give 500 mg of product as oil and 620 mg of recovered starting material, yield 39%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].C(N(CC)CC)C.[OH:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O>ClCCl.O>[Br:21][C:20]([Br:24])=[CH:35][C:34]1[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=1[OH:32]
Reactant: O=Cc1ccccc1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Oc1ccccc1C=C(Br)Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of triphenylphosphine (10.5 g, 40 mmol), carbon tetrabromide (6.6 g, 20 mmol) and triethylamine (3.0 g, 30 mmol) in dichloromethane (10 mL) was added 2-hydroxy-benzaldehyde (1.62 g, 13 mmol), and the mixture temperature was maintained at around 0° C. during the addition. After the addition was completed, the reaction mixture was stirred at room temperature for 1 hour. After the reaction, the mixture was poured into water (200 mL). And then the mixture was extracted with ethyl acetate (200 mL), washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:5) to give the pure product 2-(2,2-dibromovinyl)phenol as a pink solid (2.8 g, 76%). LRMS (M−H)−: calcd 275.9. found 275.