Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([NH2:23])=[CH:21][N:22]=3)[N:19]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.Cl.N1CC([OH:41])C1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([NH:23][C:29]([N:31]4[CH2:32][CH:33]([OH:41])[CH2:35]4)=[O:30])=[CH:21][N:22]=3)[N:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc2ccc(N3CCCCC3c3cccc(F)c3)nn12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OC1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc2ccc(N3CCCCC3c3cccc(F)c3)nn12)N1CC(O)C1
Reaction time: 5 h
Yield: 52.2 %

Procedure:
To a DCM (2 mL) solution of 6-(2-(3-fluorophenyl)piperidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (45 mg, 0.14 mmol) was added CDI (35 mg, 0.22 mmol) at ambient temperature in one portion. After stirring for five hours, azetidin-3-ol hydrochloride (54 mg, 0.33 mmol) was added in one portion, followed by DIEA (0.05 mL, 0.29 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was diluted with DCM, washed with water, dried over Na2SO4 and concentrated. The crude product was purified by reversed phase column, eluting with 0 to 55% CH3CN/water to obtain the desired product as a solid (30 mg, 51% yield). MS (apci) m/z=411.2 (M+H).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=NC=1[Cl:3].[CH3:10][N:11]([CH3:14])[CH:12]=O.[C:15](=O)=O>COC(C)(C)C>[Cl-:3].[CH3:10][N:11]([CH3:14])[CH:12]=[N:1][CH:8]=[N+:7]([CH3:15])[CH3:5]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C=O
Reactant: CN(C)C=O
Solvent: COC(C)(C)C
Product: CN(C)C=NC=[N+](C)C
Product: [Cl-]
Reaction time: 8 h

Procedure:
Cyanuric chloride (46.67 g, 0.252 mol) was heated with N,N-dimethylformamide (121.33 g, 1.66 mol) in 250 ml of tert-butyl methyl ether over the course of from 30 to 40 min. An exothermic reaction then took place, and CO2 gas was liberated over the course of from 1 to 2 hours. The reaction mixture was boiled overnight. After the reaction mixture had cooled, the title product was isolated by rapid filtration under a nitrogen atmosphere and washing with tert-butyl methyl ether. Drying in a desiccator gave the title product in a yield of from 112.15 g (90.7%) in the form of a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>C(Cl)Cl>[C:9]([OH:27])(=[O:8])[CH3:10].[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:1][S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O
Product: CCCS(=O)(=O)Nc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.0 g (0.00194 mole) of 3-amino-4-benzyloxybenzene were mixed with 150 ml of methylene chloride in a nitrogen atmosphere and 3.3 ml (0.0236 mole) of triethylamine and 2.74 ml (0.0236 mole) of 1-propanesulfonyl chloride were added. It was stirred overnight at ambient temperature. It was washed with water, the two phases were separated and the organic phase was dried over sodium sulfate; it was filtered and the solvent was evaporated off under reduced pressure. The residue was taken up in isopropyl ether and the precipitate was filtered. The compound of the heading was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:22])[C:20]=1I)[CH2:16][OH:17].ClC1C=C(C=C(Cl)C=1)CO>>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:16][OH:17])[CH:18]=[C:19]([Cl:22])[C:20]=1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: OCc1cc(Cl)c(I)c(Cl)c1
Agent: OCc1cc(Cl)cc(Cl)c1
Product: OCc1cc(Cl)c(-c2ccc(F)cc2F)c(Cl)c1
Yield: 72.5 %

Procedure:
Using essentially the same coupling procedure as for Example 8-1, Step 1, but heating 2,4-difluorophenylboronic acid (456 mg, 2.89 mmol) and 3,5-dichloro-4-iodobenzyl alcohol (350 mg, 1.155 mmol) in a microwave at 115° C. for 120 minutes, afforded the title intermediate (242 mg) without formation of any appreciable 3,5-dichlorobenzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:40]([NH2:42])[CH3:41]>O.C(Cl)Cl>[CH2:40]([NH:42][C:20]([C@@H:17]1[CH2:16][CH2:15][C@H:14]([N:13]2[C:12]3[CH:23]=[C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:25]=[CH:26][C:11]=3[NH:10]/[C:9]/2=[N:8]\[C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:35][CH:34]=2)[CH2:19][CH2:18]1)=[O:22])[CH3:41]
Reactant: CCN
Reactant: O=C(/N=c1\[nH]c2ccc(CN3CCCCC3)cc2n1[C@H]1CC[C@@H](C(=O)O)CC1)c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
cis-4-((E)-2-(4-Fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (0.025 g, 0.052 mmol) was cooled to 0° C. under nitrogen. To this mixture was added thionyl chloride (0.381 mL, 5.22 mmol), and the resulting reaction mixture was stirred for 10 minutes. The mixture was concentrated under reduced pressure and dried under high vacuum. The residue was suspended in THF (0.5 mL) and cooled to 0° C. under a nitrogen atmosphere. To this mixture was added ethanamine (2M in THF) (0.059 mL, 1.045 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with water (10 mL) and DCM (20 mL), and the layers were separated. The organic phase was dried over sodium sulfate, filtered, and solvent was concentrated under reduced pressure to afford (E)-N-(1-(cis-4-(ethylcarbamoyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide (0.025 g, 95% yield). MS m/z=506.2 [M+H]. Calc'd for C29H36FN5O2: 505.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.19 Hz, 3H) 1.42-1.50 (m, 2H) 1.50-1.63 (m, 4H) 1.63-1.89 (m, 4H) 2.14-2.28 (m, 2H) 2.32-2.47 (m, 4H) 2.57-2.66 (m, 1H) 2.67-2.89 (m, 2H) 3.21-3.32 (m, 2H) 3.56 (s, 2H) 4.77-5.03 (m, 1H) 7.17-7.23 (m, 1H) 7.25-7.35 (m, 2H) 7.53 (d, J=8.12 Hz, 1H) 7.63 (s, 1H) 7.83-7.94 (m, 1H) 8.29-8.43 (m, 2H) 12.79 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:27])[CH:17]=3)[CH2:13][CH:12]([C:28](OC)=[O:29])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:33]=[C:34]([NH2:38])[CH:35]([CH3:37])[CH3:36]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:11][CH:12]([C:28]3[O:29][N:38]=[C:34]([CH:35]([CH3:37])[CH3:36])[N:33]=3)[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[C:18]([CH3:27])[CH:17]=3)[CH2:15]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)C(N)=NO
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)c(C)c2)CN(C(=O)N2CCC(O)CC2)C1
Product: Cc1cc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F

Procedure:
500 mg (1.12 mmol) of the compound from Example 169A and 125 mg (1.23 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 1. Yield: 373 mg (67% of theory).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.S(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:28]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:28]=1
Reactant: CS(=O)(=O)OCCc1cccc(N2CCCC2)c1
Reactant: CNCCN1c2ccccc2COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(CCc1cccc(N2CCCC2)c1)CCN1c2ccccc2COc2ccccc21
Temperature: 90 °C

Procedure:
5,11-Dihydro-5-[2-(N-methylamino)ethyl]dibenzo[b,e][1,4]oxazepine (254 mg, 1.00 mmol, prepared by a method disclosed in International Patent No. 0040570A1), 3-pyrrolidinophenethyl mesylate (296 mg, 1.10 mmol), sodium carbonate (138 mg, 1.30 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to acetonitrile (20 ml), and they were heated at 90° C. under reflux for 6.5 hours. The solvent was evaporated under reduced pressure, and the residue was distributed into ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (10:1) and then with hexane and ethyl acetate (3:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain 5,11-dihydro-5-[2-[N-methyl-N-(3-pyrrolidinophenethyl)amino]-ethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (331 mg, 78%).
Reaction SMILES: [CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:15][O:14][C:12]([CH:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[N:6]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:13]
Reactant: COC(=O)C1CCCC1NC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C1CCCC1N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
To an ice cooled solution of 9.56 g (0.045 mole) of (rac)-2-cyclopentylamino-cyclopentanecarboxylic acid, methyl ester and 200 mL of ethyl acetate was added 9.5 g (0.0475 mole) of 2,4-dichloro-5-nitro-pyrimidine and 9.6 g (0.113 mole) of sodium bicarbonate. The mixture was heated overnight at 65 degrees, then cooled and washed with water, extracting the aqueous layer twice with ethyl acetate. The combined ethyl acetate layers were washed successively with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromography, eluting with hexanes-ethyl acetate (100:0-80:20), to give 11.4 g of (rac)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-cyclopentanecarboxylic acid methyl ester (IV-68).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].CN1CCOCC1.[Cl:40][CH2:41][C:42](Cl)=[O:43]>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([N:21]([CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)[C:42](=[O:43])[CH2:41][Cl:40])=[CH:20][C:13]=3[N:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(NCc3cccc4ccccc34)ccc21
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N(Cc3cccc4ccccc34)C(=O)CCl)ccc21
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4.0 g (9.6 mmol) of 2-[2-(4-cyanophenyl)-ethyl]-1-methyl-5-naphth-1-ylmethylamino-benzimidazole and 1.1 mL (10.0 mmol) of N-methylmorpholine in 80 ml of dichloromethane was cooled to 10° C. A solution of 0.8 mL (10.0 mmol) of chloroacetylchloride in 15 ml of dichloromethane was added dropwise to the solution within 15 min. The mixture was then stirred for 30 min at ambient temperature. It was washed with water and dilute potassium carbonate solution, dried and concentrated by evaporation. The product is chromatographed on silica gel.
Reaction SMILES: [ClH:1].Cl.Cl.[CH2:4]([N:6]([CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH2:28])=[NH:27])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)[CH3:5].Cl.[C:33](=[NH:38])(OCC)[CH3:34].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:33]([N:17]1[CH2:16][CH2:15][CH:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([N:6]([CH2:20]/[CH:21]=[CH:22]/[C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([NH2:28])=[NH:27])[CH2:4][CH3:5])=[CH:8][CH:9]=2)[CH2:19][CH2:18]1)(=[NH:38])[CH3:34]
Reactant: CCN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 189.1 %

Procedure:
To a solution of 3-[3-[N-ethyl-N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (420 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (319 mg) and triethylamine (0.72 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 20% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (287 mg, yield 63%) as a colorless amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([Cl:17])[CH:3]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)=[CH:11][N:12]=2)=[C:4]([Cl:17])[CH:3]=1
Reactant: Cc1cc(Br)cc(Cl)c1Oc1ccc(O)cn1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(Cl)c1Oc1ccc(OC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 95 h

Procedure:
To a solution of 6-(4-bromo-2-chloro-6-methylphenoxy)pyridin-3-ol (5.00 g) in CH2Cl2-THF (70 mL, 5:2) were added 3,4-dihydro-2H-pyran (4.35 mL) and PPTS (200 mg) at room temperature. After stirring at room temperature for 95 hours, the solvent was removed under reduced pressure. To the residue was added saturated aqueous NaHCO3, and extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=4/1 to 1/1) to give 2-(4-bromo-2-chloro-6-methyl-phenoxy)-5-(tetrahydro-2H-pyran-2-yloxy)pyridine as a yellow oil (6.30 g).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:19]12CC(C=C1)C=[CH:20]2>O1CCOCC1>[F:18][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:20]=[CH:19][N:3]=[N:2]3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[I:17]
Reactant: C1=CC2C=CC1C2
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Temperature: 100 °C

Procedure:
(5R)-5-(Azidomethyl)-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidin-2-one (Intermediate 5, 30.3 g, 72.9 mmol) was stirred in 1,4-dioxane. Bicyclo[2.2.1]hepta-2,5-diene (40.3 g, 437 mmol) was added and the reaction was heated at 100° C. overnight. The resulting brown mixture was filtered and the desired product was obtained as a light brown solid (14.8 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccnc(-c2ccccc2)c1
Yield: 84.4 %

Procedure:
A 1 L round bottom flask was charged with 2-chloro-4-methylpyridine (25 g, 196 mmol), phenylboronic acid (23.9 g, 196 mmol), potassium carbonate (81 g, 588 mmol), Pd(PPh3)4 (2.3 g, 1.9 mmol), dimethoxyethane (500 mL) and water (150 mL). The reaction mixture was degassed with nitrogen and heated to reflux for 22 h. After cooling, the aqueous layer was extracted with EtOAc; the organic portion was combined and subjected to column chromatography (SiO2, 5% EtOAc in hexane to 10% EtOAc in hexane) to give 28 g (78%) of 4-methyl-2-phenylpyridine. The product was confirmed by NMR and GC/MS.
Reaction SMILES: [C:1]([O:4]O)(=O)[CH3:2].C([O-])(=O)C.[Na+].[CH:11]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)CC=[CH:13][CH2:12]1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH2:16][CH:11]2[CH2:2][CH:1]3[CH:13]([O:4]3)[CH2:12]2)=[CH:22][CH:21]=1
Reactant: CC(=O)OO
Reactant: C1=CCC(Cc2ccc(-c3ccccc3)cc2)C1
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: c1ccc(-c2ccc(CC3CC4OC4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Peracetic acid in acetic acid (60 ml; 40%) was added over 5 min. to a cooled mixture of sodium acetate (8g) and 4-(3-cyclopenten-1-ylmethyl)-1,1'-biphenyl (20 g) in chloroform (150 ml). The mixture was stirred vigorously at room temperature for 4 h., then it was cooled and a solution of sodium metabisulphite was slowly added. The chloroform layer was washed with water, dilute sodium hydroxide solution, water and brine, dried and evaporated to give a 1:3 mixture (TLC) of two products (20 g). Crystallisation from methylene dichloride-ether gave two crops, rich in the slower running isomer (TLC). Recrystallisation from methylene dichloride/ether gave pure (±)-(1α,3α,5α)-3-([1,1'-biphenyl]-4-ylmethyl)-6-oxabicyclo[3.1.0]hexane (9.6 g), m.p. 130°-132° C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10](=[O:21])[C:9]([C:22]([OH:24])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:27])=O>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10](=[O:21])[C:9]([C:22]([Cl:27])=[O:24])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1nn(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1nn(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Yield: 81 %

Procedure:
Intermediate k (3.0 g, 0.01 mol) was added to thionyl chloride (10 V/W, 30 mL). The mixture was warmed up under stirring to react under reflux for 6 h. The solvent was evaporated off to produce a clear yellow crystal (2.8 g) in a yield of 81%.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])#N.[OH-:15].[Na+].Cl.[OH2:18]>>[C:1]([CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([OH:18])=[O:15]
Reactant: O
Reactant: [OH-]
Reactant: N#CCCNc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Product: O=C(O)CCNc1cccc(C(=O)O)c1

Procedure:
266.0 g of N-(2-cyanoethyl)-3-aminobenzoic acid together with 336.0 g of sodium hydroxide in 3 l of water were heated under ref lux for 5 hours. After cooling, the pH was adjusted to 3 with hydrochloric acid, the mixture was cooled and the precipitate was filtered off with suction.
Reaction SMILES: [OH:1][C@:2]12[CH2:19][CH:18]=[CH:17][CH2:16][C@:15]1([CH3:20])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C:9]([Br:21])=[CH:8][CH2:7]3)[CH2:4][C@H:3]2O.CS([Cl:27])(=O)=O>N1C=CC=CC=1>[OH:1][C@:2]12[CH2:19][CH:18]=[CH:17][CH2:16][C@:15]1([CH3:20])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C:9]([Br:21])=[CH:8][CH2:7]3)[CH2:4][C@H:3]2[Cl:27]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H](O)[C@@]4(O)CC=CC[C@]34C)[C@@H]1CC=C2Br
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H](Cl)[C@@]4(O)CC=CC[C@]34C)[C@@H]1CC=C2Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
95 g (0.258 mole) of 5α,6β-dihydroxy-17-bromo-androsta-2,16-diene are dissolved in 950 ml of anhydrous pyridine, and 21 ml (0.276 mole) of methanesulfonic acid chloride are added under stirring at room temperature to the solution. The reaction mixture is allowed to stand for 16 hours and then poured under vigorous stirring into 9 liters of ice water. The precipitating difficulty separable substance is extracted with 1600 ml of dichloro methane. The dichloro methane extract is washed with aqueous 10% hydrochloric acid solution to remove the pyridine and then with water until neutral, dried over sodium sulfate and evaporated to dryness. The evaporation residue, which is a mixture of 5α-hydroxy-6β-chloro-17-bromo-androsta-2,16-diene and 5α,6β-epoxy-17-bromo-androsta-2,16-diene, is dissolved in diethyl ether and etheral hydrochloric acid solution is added thereto until pH = 2 to 3. The so obtained 5α-hydroxy-6β-chloro-17-bromo-androsta-2,16-diene is separated and purified by mixing it with 10-fold amount of petroleum ether. 79.0 g of 5α-hydroxy-6β-chloro-17 -bromo-androsta-2,16-diene (79.0%) are obtained; m.p. 125°-126° C; [α]D25 = + 3.8° (c = 1 in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]=[CH:11][N:12]([CH3:14])C)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.NC1[N:19]=[CH:20][NH:21][C:22]=1[C:23]([NH2:25])=[O:24]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:19]3[CH:20]=[N:21][C:22]([C:23]([NH2:25])=[O:24])=[C:14]3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3ccc(Cl)c(Cl)c3)ccnc12
Reaction time: 16 h
Yield: 49.6 %

Procedure:
A stirred mixture of 12.0 g of 3',4'-dichloro-3dimethylaminoacrylophenone (prepared as described in Example 9) and 6.3 g of 4-amino-5-imidazolecarboxamide hydrochloride in 450 ml of glacial acetic acid was heated at reflux for 24 hours. The reaction mixture was allowed to stand at room temperature for 16 hours then the mixture was filtered and the crystals that were collected were washed with 300 ml of saturated sodium bicarbonate and then were washed with water. This material was dried, washed with hot methanol and filtered to give 5.9 g of the desired product as yellow crystals, mp 302°-304° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>>[C:14]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)(=[O:17])[CH:15]=[CH2:16]
Reactant: CC(C)Nc1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N(c1ccc([N+](=O)[O-])cc1)C(C)C

Procedure:
Prepared from 4-isopropylamino-nitrobenzene and acrylic acid chloride