Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br.Cl[C:10]1[C:11]([CH3:21])=[C:12]([CH3:20])[C:13]2[N:14]([C:16]([NH2:19])=[N:17][N:18]=2)[N:15]=1>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:10]2[C:11]([CH3:21])=[C:12]([CH3:20])[C:13]3[N:14]([C:16]([NH2:19])=[N:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Reactant: OCC1CC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OCC2CC2)nn2c(N)nnc2c1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (2.84 ml) was initially charged in DMF (20 ml), admixed under argon with sodium hydride (862 mg) and stirred at 50° C. for 1 h. Subsequently, 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.006, 2 g), dissolved in DMF (20 ml), and one equivalent of the alkoxide solution were added. After stirring at 50° C. for one hour, two further equivalents of alkoxide solution were added and the mixture was stirred further at 50° C. Then the reaction mixture was dried and purified using silica gel (40 g cartridge, dichloromethane/methanol gradient of 0-10% in 40 min). 625 mg of the title compound were obtained. LC-MS rt: 0.62 min [M+H]+: 234.1 (met. b)
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:6]2[N:11]=[C:10]3[N:12]([CH3:16])[C:13]([CH3:15])=[N:14][C:9]3=[CH:8][C:7]=2[CH2:17][N:18]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:19]#[N:20])[CH2:3][CH2:2]1.[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[F:35][C:32]([F:33])([F:34])[C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=1)[CH2:21][N:18]([CH2:17][C:7]1[CH:8]=[C:9]2[N:14]=[C:13]([CH3:15])[N:12]([CH3:16])[C:10]2=[N:11][C:6]=1[N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH2:36][CH:37]1[CH2:39][CH2:38]1)[C:19]1[N:40]=[N:41][NH:42][N:20]=1
Reactant: Cc1nc2cc(CN(C#N)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(N(CC3CC3)CC3CC3)nc2n1C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)nc2n1C
Temperature: 90 °C
Yield: 926.6 %

Procedure:
A mixture of [5-(bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-6-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide (0.220 g, 0.04 mmol), sodium azide (0.130 g, 2 mmol.) and ammonium chloride (0.106 g, 2 mmol) were taken in DMF (15 mL) and heated at 90° C. for 2 h. The reaction mixture was taken in ethyl acetate (250 mL) and washed with water (250 mL×4) and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.220 g of colorless gummy liquid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[N:26]2[CH2:27][CH2:28][N:29]([C:15](=[O:17])[CH2:14][N:3]3[CH2:4][CH2:5][CH2:6][CH:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:2]3=[O:1])[CH2:30][CH2:31]2)=[CH:37][CH:36]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.050 g, 0.214 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (0.068 g, 0.236 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.062 g, 0.322 mmol) in dichloromethane (0.5 mL) was allowed to stir at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 15 minutes, maintaining 100% ethyl acetate for an additional 10 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.16-7.38 (m, 9H), 6.93-7.04 (m, 4H), 4.42 (d, J=15.5 Hz, 1H), 4.23 (s, 1H), 4.00 (d, J=15.5 Hz, 1H), 3.70 (dd, J=5.8, 4.6 Hz, 1H), 3.59-3.66 (m, 2H), 3.52-3.60 (m, 1H), 3.44-3.50 (m, 2H), 3.37-3.46 (m, 1H), 2.33-2.41 (m, 4H), 2.15-2.27 (m, 1H), 1.92-2.05 (m, 2H), 1.78-1.91 (m, 1H); MS (ESI−) m/z 502 (M−H)−.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:10][OH:11]>CCO>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1](=[N:10][OH:11])[NH2:9]
Reactant: N#Cc1ccccc1N
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccccc1N
Yield: 90.3 %

Procedure:
Anthranilonitrile (1 g, 8,5 mmol) and hydroxylamine (50% in water, 0.57 cm3, 9.3 mmol, 1.1 eq) in EtOH (42.5 cm3) were stirred under reflux for 24 hours, after which the volatiles were removed under reduced pressure and residue was partitioned between water (5 cm3) and CH2Cl2 (100 cm3). The organic phase was evaporated to dryness in the rotary evaporator followed by high vacuum line to give the product 2-amino-N′-hydroxybenzimidamide (1.16 g, 90.3%) as a solid, mp 85-86° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)=[O:4].[H-].[Na+].CI.[C:27](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:22])[C:3]([N:5]([CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: Cc1nnc2ccc(-c3cccc(NC(=O)N(C)C)c3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nnc2ccc(-c3cccc(N(C)C(=O)N(C)C)c3)nn12
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g of N,N-dimethyl-N'-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]urea and 0.09 g of sodium hydride in 100 ml of dry dimethylformamide was stirred for 30 minutes, then 0.23 ml of methyl iodide was added. This solution was stirred overnight, then poured into saturated aqueous sodium bicarbonate and extracted with four 100 ml portions of dichloromethane. The extracts were combined and treated as described in Example 19, giving 0.8 g of the desired product as off-white crystals mp 159°-161° C.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][C:18](N)=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].[O:22]=[N+]=O>OS(O)(=O)=O>[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][C:18]([OH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Reactant: O=[N+]=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
NaNO2 (0.20 g, 2.76 mmol) was added in portions to concentrated H2SO4 (1.4 mL) at 0° C. The mixture was heated at 50° C. until all of the NaNO2 had dissolved and the mixture was again cooled to 0° C. A solution of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinamine (0.51 g, 2.05 mmol) in concentrated H2SO4 (4.2 mL) was added dropwise to the nitronium solution. The ice bath was removed, and the mixture was warmed to ambient temperature and stirred for 15 min, then heated to 45° C. for 30 min. The mixture was cooled to ambient temperature and poured into ice water. The pH was adjusted to about 4 with 4N NaOH and the solid was collected, washed with water, and air dried to give 0.415 g (81%) of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 12.77 (bs, 1H), 8.30-8.05 (m, 4H), 7.92 (d, 2H, J=8.6 Hz), 3.21 (s, 3H); LRMS (ESI), m/z 251 (M+H).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8](/[CH:11]=[N:12]/O)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.CO>CC(O)=O.[Zn]>[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[C:4]([CH3:15])([CH3:14])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(/C=N/O)ccc21
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)OB(O)c2cc(CN)ccc21
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of crude compound (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde oxime (47.4 mmol) in AcOH (60 mL) at rt was added zinc dust (12.3 g, 190 mmol). The reaction mixture was stirred at 40° C. for 4 h under argon atmosphere. Methanol was added and the mixture was filtered over Celite. The filtrate was concentrated and dissolved in ethyl acetate. The organic layer was washed with water. The water layer was lyophilized to give the crude compound 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol as a light yellow solid. It was used in next step without further purification. MS: m/z=192.0 (M+1, ESI+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=1[OH:19]>C(O)(=O)C>[OH:19][C:18]1[CH:17]=[C:16]([CH3:20])[CH:15]=[CH:14][C:13]=1[N:12]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc(N)c(O)c1
Solvent: CC(=O)O
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 0 °C
Yield: 95.2 %

Procedure:
A solution of phthalic anhydride (14.81 g, 0.10 mole) and 6-amino-m-cresol (12.32 g, 0.10 mole) in 200 mL of acetic acid was stirred at ambient temperature for 30 minutes and then refluxed for 6 hours. The solution was cooled and poured into 500 mL ice-water with rapid stirring and the resultant solid was collected by suction filtration, washed with ice-cold water several times and air dried overnight to afford 24.1 g (95% yield) of product 1 as a light brown solid, mp 251-254° C. TLC (silica ; EtOAc), Rf =0.68.
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[Br:12]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:12][C:7]1[C:8]([CH3:9])=[C:3]([C:1]#[N:2])[C:4]([OH:11])=[N:5][C:6]=1[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c(C#N)c(O)n1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(O)c(C#N)c(C)c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.8 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 14.9 grams (0.10 mole) of 3-cyano-2-hydroxy-4,6-dimethylpyridine is cooled in an ice bath and a solution of 18.1 grams (0.10 mole) of N-bromosuccinimide in 50 mL of N,N-dimethylformamide is added dropwise during a 15 minute period. Upon completion of addition the reaction mixture is stirred at ambient temperature for about 72 hours. After this time, the reaction mixture is diluted to 1000 mL with water and filtered to collect a solid. The solid is dried under vacuum at about 60° C., yielding 22.2 grams of 5-bromo-3-cyano-2-hydroxy-4,6-dimethylpyridine, mp 254°-262° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([C:11]([O:13]C)=O)=[C:4]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].[NH2:22][CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:3](=[O:21])[C:4]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:5]2[C:11](=[O:13])[N:22]([CH2:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[C:8](=[O:10])[C:6]2=[CH:7]1
Reactant: NCCc1ccc2ccccc2n1
Reactant: COC(=O)c1c(C(=O)O)cn(C)c(=O)c1-c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc2c(c(-c3ccncc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 1-methyl-2-oxo-1,2-dihydro-3-(4-pyridyl)-4-methoxycarbonyl-pyridine-5-carboxylic acid (500 mg, 1.7 mmol, see Example b3)), 2-aminoethyl quinoline (358 mg, 2.0 mmol), PyBOP (1.2 g, 2.2 mmol) and DIPEA (671 mg, 5.2 mmol) in DCM (20 ml) was stirred at r.t. overnight. The solvent was removed, the residue was purified by column chromatography on silica gel (PE:EA=10:1) to give the title compound as a white solid (600 mg, 84%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O-:12])=O)[CH2:6][CH2:5]1.[Li+].[CH2:26]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:34]([N:33]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]([CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH2:5][CH2:6]1)=[O:12])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C([O-])C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 18 h

Procedure:
Lithium (R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate (32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. Dibenzylamine (41) (62 mg; 0.312 mmol), N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357 mmol) are added sequentially. The reaction is stirred for 18 hr. at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography with gradient elution (90% ethyl acetate in hexanes, then 50%→100% acetone in hexanes) affording the desired product (42) as a solid. CIMS (NH3Cl): 510 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of methyl 5-chloro-2-hydroxybenzoate (2.35 g, 12.6 mmol), 2-chloro-5-nitropyridine (2.00 g, 12.6 mmol), and potassium carbonate (5.23 g, 37.8 mmol) in N,N-dimethylformamide (50 mL) was stirred at 120° C. for 1 h. The reaction mixture was poured into water and the aqueous mixture was extracted with a mixture (3/1) of ethyl acetate and toluene. The organic extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to afford 3.79 g (97%) of the title compound: 1H-NMR (CDCl3) δ 8.94 (1H, d, J=2.8 Hz), 8.52 (1H, dd, J=9.0, 2.8 Hz), 8.05 (1H, d, J=2.8 Hz), 7.60 (1H, dd, J=8.6, 2.8 Hz), 7.18 (1H, d, J=8.6 Hz), 7.14 (1H, d, J=9.0 Hz), 3.73 (3H, s).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7].[CH2:17]([CH:19]1[O:21][CH2:20]1)[Br:18].[OH-].[K+]>ClCCl.O>[C:6]([CH:10]1[CH2:11][CH2:12][C:13]2([O:21][CH:19]([CH2:17][Br:18])[CH2:20][O:16]2)[CH2:14][CH2:15]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: BrCC1CO1
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C1CCC2(CC1)OCC(CBr)O2
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
30.15 g (120 mmol) of tin(IV) chloride were added dropwise to 115.5 g (750 mmol) of 4-tert-butylcyclohexanone in 700 ml of absolute dichloromethane at 5° C., followed by the dropwise addition of 205.5 g (1.5 mol) of epibromohydrin ##STR9## in 370 ml of absolute dichloromethane in the course of 5 hours. The mixture was stirred overnight at room temperature (20° C.), hydrolyzed with a solution of 42 g of KOH in 180 ml of water while cooling, and worked up in a conventional manner. Distillation of the crude product (279 g) under reduced pressure gave 169 g (77.5%) of 8-tert-butyl-2-bromomethyl-1,4-dioxaspiro[4,5]decane of boiling point 110° C./0.2 mbar.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([N:21]2[CH2:42][CH2:41][C:24]3([NH:28]/[C:27](=[N:29]/[C:30]([C:32]4[C:37]([NH2:38])=[N:36][C:35]([NH2:39])=[C:34]([Cl:40])[N:33]=4)=[O:31])/[NH:26][CH2:25]3)[CH2:23][CH2:22]2)=[O:20])[CH:14]=1)(=[O:12])=[O:11])(C)(C)C.CCCC(C)C>Cl.O1CCOCC1>[NH2:38][C:37]1[C:32]([C:30](/[N:29]=[C:27]2/[NH:28][C:24]3([CH2:41][CH2:42][N:21]([C:19]([C:15]4[CH:14]=[C:13]([S:10]([NH:9][CH2:8][CH2:7][C:6]([OH:43])=[O:5])(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=4)=[O:20])[CH2:22][CH2:23]3)[CH2:25][NH:26]/2)=[O:31])=[N:33][C:34]([Cl:40])=[C:35]([NH2:39])[N:36]=1
Reactant: CC(C)(C)OC(=O)CCNS(=O)(=O)c1cccc(C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCC(C)C
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(S(=O)(=O)NCCC(=O)O)c4)CC3)N2)nc1Cl

Procedure:
A solution of 3-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid tert-butyl ester (step 1) (900 mg, 1.415 mmol) in 4N HCl in dioxane (10 ml) was stirred for 16 h at RT. Iso-hexane (10 ml) was added to the reaction mixture and resulting suspension was sonicated for 1 hour at RT. The solvent was decanted off and the solids washed with iso-hexane (10×25 ml). The resulting pale yellow crystals were dried under vacuum @ 45° C. for 36 h to afford the title compound; LC-MS Rt 0.80 mins; 580.0 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [CH2:1](C1(CC)C2C=C(C=O)C=CC=2C2C1=CC(Br)=CC=2)C.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].CS(C)=O>O>[S:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[CH:1]1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: Nc1ccccc1S
Solvent: O
Solvent: CS(C)=O
Product: c1ccc2scnc2c1
Temperature: 195 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
A mixture of 9,9-diethyl-7-bromo-fluorene-2-carboxaldehyde (49.35 g., 0.15 mol.), 2-aminothiophenol (20 ml. 0.187 mol., 1,25 eq.), and DMSO (110 ml) was heated in an oil bath to a bath temperature of 195° C., held there for 45 minutes, and then poured into water. The separated solids were collected, reslurried in 1:4 acetic acid-water (1000 ml.) filtered, and washed with water and dilute sodium bicarbonate solution. These solids, 80.05 g., were then reslurried in hot ethanol, (600 ml), cooled and filtered to get the product benzothiazole, 45.69 g., m.p. 133.6-135° C. An additional 6.6 g., m.p. 134.6-135.5° C., was obtained by chromatography of the ethanol filtrate. Total recovery was 52.29 g. (80.3% yield). Mass Spec: m/z 433, 435, (M+). Anal. Calculated for C24H20BrNS: C, 66.37; H, 4.64; Br, 18.40; N, 3.23; S, 7.37%. Found: C, 66.46; H, 4.52; Br, 18.54; N, 3.14; S, 7.19%.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)[CH:34]=[C:35]([F:38])[C:36]=1[F:37].O>C1COCC1>[F:30][C:31]1[CH:32]=[C:33]([CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][C:44](=[CH:2][O:3][CH3:4])[CH2:43][CH2:42]2)[CH:34]=[C:35]([F:38])[C:36]=1[F:37]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(CCc2cc(F)c(F)c(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC=C1CCC(CCc2cc(F)c(F)c(F)c2)CC1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
A suspension of methoxymethyltriphenylphosphonium chloride (112.3 g) in THF (300 ml) was stirred in a nitrogen gas stream, followed by adding potassium-t-butoxide (45.4 g) little by little while cooling at 0° C., stirring the reaction solution at room temperature for one hour, dropwise adding 4-(2'-(3",4",5"-trifluorophenyl)ethyl)cyclohexanone (70 g)in THF (200 ml), raising the temperature of the reaction mixture up to room temperature, further stirring for 2 hours, adding to water (500 ml) after completion of the reaction, extracting with ethyl acetate (500 ml), drying the organic layer over anhydrous MgSO4, concentrating under reduced pressure, and carrying out chromatography treatment on silica gel with ethyl acetate/heptane (1:5), to obtain 4-(2'-(3",4",5"-trifluorophenyl)ethyl)methoxymethylenecyclohexane (53.7 g).
Reaction SMILES: OC(C)(C)[C:3]#[C:4][C:5]1[C:26]([O:27][CH3:28])=[CH:25][C:8]2[C:9]([CH3:24])([CH3:23])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[C:19](=[O:20])[C:7]=2[CH:6]=1)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=4.[H-].[Na+].O>C1COCC1>[C:4]([C:5]1[C:26]([O:27][CH3:28])=[CH:25][C:8]2[C:9]([CH3:24])([CH3:23])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[C:19](=[O:20])[C:7]=2[CH:6]=1)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=4)#[CH:3]
Reactant: COc1cc2c(cc1C#CC(C)(C)O)C(=O)c1c([nH]c3cc(C#N)ccc13)C2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc2c(cc1OC)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-2-1, 21.3 mg, 0.05 mmol) and sodium hydride (3.2 mg, 1.5 eq.) were dissolved in THF, and the mixture was stirred overnight at 50° C. Water was added to the reaction solution and the residues obtained after concentration under reduced pressure were purified by HPLC to obtain the title compound (brown solid, 9.6 mg, 31%).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2].[I-].[Na+].[C-:30]#[N:31].[K+].O>CS(C)=O>[C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([C:30]#[N:31])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOCn1c(C#N)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 25 °C
Reaction time: 58 h
Yield: 60.3 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (1.83 g, 4.11 mmol) and sodium iodide (123 mg, 0.82 mmol) in anhydrous dimethylsulfoxide (40 ml) was added potassium cyanide (294 mg, 4.52 mmol). After stirring at room temperature for 58 hours, the mixture was treated with water (200 ml) and extracted with ethyl acetate (4×25 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (25 ml) and then dried over magnesium sulfate. After the solvent was evaporated under reduced pressure, the product was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide (R)-1-(5-Acetoxyhexyl)-8-cyano-7-ethoxymethyl-3-methylxanthine (970 mg, 60% yield) as a pale yellow oil.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][N:6]([CH3:8])[C@H:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH3:12]O>>[ClH:1].[OH:2][C@H:3]1[CH2:7][N:6]([CH3:8])[C@H:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1
Reactant: CN1C[C@H](O)C[C@H]1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C
Yield: 100 %

Procedure:
Concentrated hydrochloric acid (3 mL) was added to a suspension of (2S,4R)-4-hydroxy-1-methyl-2-pyrrolidinecarboxylic acid (3 g) in methanol (15 mL), and the mixture was refluxed for 4 hours. The solvent of the reaction mixture was removed by distillation under reduced pressure to give the title compound (4.0 g, yield 100%).