Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.Cl[C:11]1[N:16]=[C:15]2[NH:17][N:18]=[CH:19][C:14]2=[CH:13][N:12]=1>>[NH:17]1[C:15]2=[N:16][C:11]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=3)=[N:12][CH:13]=[C:14]2[CH:19]=[N:18]1
Reactant: Clc1ncc2cn[nH]c2n1
Reactant: Nc1cnn(CCO)c1
Product: OCCn1cc(Nc2ncc3cn[nH]c3n2)cn1

Procedure:
The title compound was made following the procedure in Example 1 (Step ii) using 2-(4-amino-1H-pyrazol-1-yl)ethanol and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine to form 2-(4-((1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol. This was followed by the procedure in Example 1 (Step i) using 4-(3-(bromomethyl)-2,4-difluorophenyl)morpholine. 1H NMR (d6-DMSO) δ 9.86 (s, 1H), 8.88 (s, 1H), 8.17 (br s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.14-6.97 (m, 2H), 5.56 (s, 2H), 4.88 (t, 1H), 4.18-4.09 (m, 2H), 3.77-3.73 (m, 2H), 3.70 (t, 4H), 2.92 (t, 4H); LC-MS method B, (ES+) 457.2, RT=6.98 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10]3([C:14](=[O:15])[C:13]([CH2:17][CH3:18])([CH3:16])[O:12][C:11]3([CH2:20][CH3:21])[CH3:19])[O:9]2)=[C:4]([CH2:22][CH3:23])[CH:3]=1.S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:14](=[O:15])[C:13]([CH2:17][CH3:18])([CH3:16])[O:12][C:11]([CH2:20][CH3:21])([CH3:19])[C:10]2=[O:9])=[C:4]([CH2:22][CH3:23])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C1OC12C(=O)C(C)(CC)OC2(C)CC
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(CC)OC(C)(CC)C1=O
Temperature: 7.5 °C
Reaction time: 0.92 h
Yield: 13.2 %

Procedure:
To an ice cold solution of 2-(4-bromo-2-ethylphenyl)-4,6-diethyl-4,6-dimethyl-1,5-dioxaspiro[2.4]heptan-7-one (15 g, 0.0397 mol) in dichloromethane (7.5 ml) is added concentrated sulphuric acid (45 ml), dropwise over 50-60 minutes, maintaining the temperature of the reaction mixture at 5-10° C. The reaction mixture is maintained at 5-10° C. for 10-15 minutes, quenched into crushed ice (225 g) and extracted with dichloromethane (3×100 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,6-diethyl-2,6-dimethylpyran-3,5-dione (2 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:16][C@@H:17]([C:22](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].OO.[O-:42]S([O-])=O.[Na+].[Na+]>>[CH2:9]([O:8][N:7]([CH2:16][C@H:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:22]([OH:23])=[O:42])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:37])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C[C@@H](CN(OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Product: CC(C)C[C@@H](CN(OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)O

Procedure:
A solution of tert-butyl((2S)-2-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-4-methylpentyl)(benzyloxy)carbamate (1.66 g, 3.25 mmol), LiOH (156 mg, 6.5 mmol, 2 eq.) and an aqueous solution of H2O2 (30%, 1.33 mL, 4 eq.), was stirred overnight. A saturated solution of Na2SO3 was added at 0° C. The mixture was extracted with a saturated solution of NaHCO3, washed with DCM (3×). The aqueous layer was saturated with NaCl, acidified up to pH 2 with an aqueous solution of HCl (5 N), then extracted with DCM (2×), EtOAc (2×), Et2O (2×). The combined organic layers were dried over MgSO4, filtered and evaporated to give 300 mg of the title product as a colorless oil used as such in the next step. M−(LC-MS (ESI)): 350.3.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([C:19]1([OH:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)#[CH:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9][N:22]2[CH2:23][CH2:24][C:19]([C:17]#[CH:18])([OH:25])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CC1(O)CCNCC1
Reactant: BrCC=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC1(O)CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A solution of 16.5 g of 3,3-diphenyl-2-propenyl bromide in 70 ml of acetone is added dropwise to a mixture of 7.5 g of 4-ethynyl-4-hydroxypiperidine, 8.5 g of anhydrous potassium carbonate and 75 ml of anhydrous acetone at room temperature over 45 minutes, then the reaction mixture is stirred at room temperature for one hour. After filtering off the inorganic salts the solution is evaporated under reduced pressure. The residue is taken up in benzene, washed with water, dried over anhydrous sodium sulfate and the solution is evaporated under reduced pressure. After recrystallizing the residue from acetonitrile the title product is obtained in 68.4% yield, m.p.: 122°-123° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[C:24]([F:26])[CH:25]=1.O>CN(C=O)C>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([F:26])[CH:25]=1)[O:27][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Oc1cc(F)cc(F)c1
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Oc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
5-Fluoro-2-nitro-benzonitrile (5 g, 30.1 mmol) in dry DMF (60 mL) was treated first with cesium carbonate (11.7 g, 36.12 mmol) followed by 3,5-difluoro-phenol. The reaction was stirred at room temperature for 1 hour and then poured into iced water (600 mL). After stirring for 2 hours, a pale yellow solid was filtered with suction, washed with water furnishing, after drying at 50° C. under vacuum, 7.73 g of title compound in 93% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([OH:29])[CH2:15][C@H:16]([CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2C=CC([C@@H](O)C[C@H](CCCC3C=CC=CC=3)C(O)=O)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:29])[CH2:15][CH:16]([CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H](CCCc1ccccc1)C[C@@H](O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=C(O)[C@@H](CCCc1ccccc1)C[C@H](O)c1ccc(-c2ccc(Cl)cc2)cc1
Product: O=C(O)C(CCCc1ccccc1)CC(O)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
the more active of the compounds [2S, 4R]-4-[4-(4-chlorophenyl)phenyl]-4-hydroxy-2-(3-phenylpropyl)-butanoic acid and [2S, 4S]-4-[4-(4-chlorophenyl)phenyl]-4-hydroxy-2-(3-phenylpropyl)-butanoic acid;
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:14][CH2:15][CH2:16]Br.[OH-].[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:16][CH2:15][Br:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Oc1ccc(Cn2cccn2)cc1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccc(Cn2cccn2)cc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
To a mixture of 4-(1-pyrazolyl)methylphenol (15 g), 32.35 g of 1,2-dibromoethane and water (150 ml) was added dropwise an aqueous solution of sodium hydroxide (4.13 g) dissolved in water (30 ml) while stirring under heating at reflux over 30 minutes. The reaction mixture was then heated at reflux under stirring for further 1 hour, and then cooled to room temperature, which was extracted with diethyl ether (300 ml). The organic layer was washed with 5N aqueous sodium hydroxide solution and then water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 2-[4-(1-pyrazolyl)methylphenoxy]ethyl bromide (11.44 g) as white crystals. Yield, 47%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[C:9]2[CH:8]=[C:7]3[O:22][CH2:23][O:24][C:6]3=[CH:5][C:4]=2[N:3]=1>O1CCOCC1.[Pd]>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[C:9]2[CH:8]=[C:7]3[O:22][CH2:23][O:24][C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2)c2cc3c(cc2n1)OCO3
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccc(N)cc2)c2cc3c(cc2n1)OCO3
Reaction time: 7 h

Procedure:
A mixture of 6-methyl-8-(4-nitrophenoxy)[1,3]dioxolo[4,5-g]quinoline (2.0 g, 6.18 mmol) in dioxane (100 mL) and 10% Pd/C (500 mg) was hydrogenated for 7 h at 35 psi. The reaction mixture was filtered through a pad of Celite and the filter cake was washed with dioxan. The combined filtrate and washings was evaporated in vacuo to dryness. The solid residue recrystallized from CHCl3 to yield 4-[(6-methyl[1,3]dioxolo-[4,5-g]quinolin-8-yl)oxy]phenylamine, 1.680 g (92.43%); mp 251-253° C.; 1H NMR (DMSO-d6) δ 2.43 (3H, s, Me), 5.56 (2H, brs, exchangeable, NH2), 6.21 (2H, s, CH2), 6.32 (1H, s, ArH), 6.66 (2H, d, J=8.6 Hz, ArH), 6.90 (2H, d, J=8.6 Hz, ArH), 7.28 (1H, s, ArH), 7.49 (1H, s, ArH). Anal. Calcld. for (C17H14N2O3): C, 69.38; H, 4.79; N, 9.25. Found: C, 69.57; H, 4.88; N, 9.32.
Reaction SMILES: ICI.[CH2:4]([Zn]CC)C.[C:9]([O:12][CH2:13][C@@H:14]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:16]([C:44]2[CH:49]=[C:48]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[CH:53][CH:52]=3)[C:47]([Cl:60])=[CH:46][C:45]=2[O:61][CH2:62]/[CH:63]=[CH:64]\[CH2:65][OH:66])[O:15]1)(=[O:11])[CH3:10]>ClCCl>[C:9]([O:12][CH2:13][C@@H:14]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:17]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:16]([C:44]2[CH:49]=[C:48]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[CH:53][CH:52]=3)[C:47]([Cl:60])=[CH:46][C:45]=2[O:61][CH2:62][CH:63]2[CH2:4][CH:64]2[CH2:65][OH:66])[O:15]1)(=[O:11])[CH3:10]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OC/C=C\CO)cc2Cl)cc1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCC3CC3CO)cc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of diiodomethane (0.66 mL, 8.09 mmol) in dichloromethane (10 mL) was added diethyl zinc (1.1M solution in toluene, 3.7 mL, 4.05 mmol) at 0° C. and stirred for 15 min. The reaction mixture was cooled to −78° C. and ((2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-5-(4-ethoxybenzyl)-2-((Z)-4-hydroxybut-2-enyloxy)phenyl)tetrahydro-2H-pyran-2-yl)methyl acetate (46, 0.82 mg, 1.01 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture, slowly warmed up to −20° C. for 3 h. The reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, and dried over magnesium sulfate. The organic layer was filtered and evaporated in vacuo and the residue was purified on a Biotage® apparatus (silica gel, 5 to 40% ethyl tetrahydrofuran in hexanes gradient) to give the title compound (47, 835 mg, 1.01 mmol, 100%, diastereomer in about 1:2 ratio) as colorless oil.
Reaction SMILES: C([O-])(O)=[O:2].[Na+].[OH:6][CH2:7][C@@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1.[Na+].[Br-].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC(C)=O.CC1(C)N([O])C(C)(C)CCC1.CC(O)C>[C:17]([O:16][C:14]([N:10]1[CH2:11][CH2:12][O:13][C@@H:8]([C:7]([OH:2])=[O:6])[CH2:9]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [Br-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Temperature: 0 °C
Yield: 92 %

Procedure:
Satd aq NaHCO3 (15 mL) was added to a solution of (R)-tert-butyl 2-(hydroxymethyl)-morpholine-4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL), stirred and maintained at 0° C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added slowly within 20 min at 0° C. After addition, the mixture was warmed to rt and stirred overnight. 2-Propanol (3 mL) was added, and the resulting solution was stirred at rt for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with satd aq Na2CO3 (15 mL). The aqueous solution was washed with EtOAc (5 mL), acidified with 6 N HCl, and extracted with EtOAc (5×10 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed to give (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92%) as a white solid. 1H NMR (400 MHz, CDCl3): 4.20 (br, 1 H), 4.12 (d, 1 H), 4.02 (d, 1 H), 3.84 (m, 1 H), 3.62 (m, 1 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 232 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:22][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:14]=2
Reactant: COCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
2-{[2-(Methoxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.61 g) was dissolved in chloroform (20 mL) and cooled to 0° C. To this solution was then added N-bromosuccinimide (1.02 g) gradually, keeping the temperature at ˜2° C. The reaction was stirred at 2° C. for around 15 minutes before being allowed to warm to room temperature. The reaction mixture was then stirred under nitrogen for 5 hours. The reaction mixture was quenched with water (100 mL) and stirred rapidly before the organic layer was separated using a hydrophobic frit. The organic was evaporated under reduced pressure to give a dark brown gum. This material was purified by silica chromatography (ISCO) eluting initially with 0-70% ethyl acetate: cyclohexane holding isocratic at 70% ethyl acetate; cyclohexane until a minor impurity was eluted. The gradient was then resumed from 70%-95% ethyl acetate: cyclohexane. This gave the title compound as a white solid (1.4489 g)
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])(=[O:5])=[O:4].C(N=[C:23]=[O:24])CCC.C(Cl)(Cl)=O>C1N2CCN(CC2)C1>[CH3:1][N:2]([CH3:17])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:23]=[O:24])(=[O:15])=[O:14])(=[O:5])=[O:4]
Reactant: CCCCN=C=O
Reactant: CN(C)S(=O)(=O)Cc1ccccc1S(N)(=O)=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: CN(C)S(=O)(=O)Cc1ccccc1S(=O)(=O)N=C=O
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
A solution of 14.0 g of the product of Example 4, 5.0 g of n-butyl isocyanate and 0.1 g of DABCO in 90 ml of mixed xylenes was heated to 136°. To this solution was added 3.6 ml of liquid phosgene over a 2 hour period to maintain the temperature between 125° and 136°. The temperature was kept at 130° for 1/2 hour after the addition. The solution was cooled, and filtered under a nitrogen atmosphere and concentrated at 60°-70° in vacuo to give 16.0 g of crude 2-[(dimethylamino)sulfonylmethyl]benzenesulfonyl isocyanate as a moisture sensitive oil. An infrared peak at 2200 cm-1 confirmed the presence of the --SO2NCO group.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(CNCC2CCNCC2)cc1
Solvent: C1CCOC1
Product: c1ccc(CNCC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
Under ice-cooling, to 200 ml of a tetrahydrofuran (THF) solution containing 5.0 g of N-(4-piperidylmethyl)-N-benzylamine was added dropwise 50 ml of a THF solution containing 2.9 ml of benzyl bromide. After stirring the mixture at the same temperature for one hour, THF was removed from the reaction mixture under reduced pressure and a saturated sodium hydrogen carbonate aqueous solution was added to the residue. The mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. Precipitated crystals were recrystallized from an ethanol solution to give 3.6 g of N-(1-benzylpiperidin-4-ylmethyl)-N-benzylamine (yield: 50%, melting point: 240° C. or higher).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8][CH2:7][C:6]2=1.Cl.Cl[CH2:22][C:23]1[CH:38]=[CH:37][C:26]([O:27][CH2:28][CH2:29][NH:30][CH:31]2C[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:37][CH:38]=1)[C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8][CH2:7][C:6]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)COc1ccccc1-3
Reactant: ClCc1ccc(OCCNC2CCCCC2)cc1
Agent: Cl
Product: COc1ccc2c(c1)c1c(n2Cc2ccc(OCCN3CCCCC3)cc2)-c2ccccc2OC1

Procedure:
Following the procedure described in Example 102, using 8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (150 mg, 0.562 mmol) and [2-(4-chloromethyl-phenoxy)-ethyl]-cyclohexanyl-amine hydrochloride salt as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: O[CH:2]([C:7]1[C:15]2[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19]OC3CCCCO3)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=2[S:9][C:8]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].C([SiH](CC)CC)C.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl.O>[F:50][C:49]([F:52])([F:51])[C:47]([O:53][CH2:19][CH2:18][CH2:17][N:13]1[C:14](=[O:16])[C:15]2[C:7]([CH2:2][CH2:3][CH:4]([CH3:5])[CH3:6])=[C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:38])([F:39])[F:37])[CH:30]=3)[S:9][C:10]=2[N:11]([CH3:28])[C:12]1=[O:27])=[O:48]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CC(O)c1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)CCc1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)n2C
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
To a solution of 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 22, Step 3, 40 mg, 0.070 mmol) in TFA (2 mL) was added triethylsilane (1 mL). The reaction was stirred at RT for 48 h then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-isopentyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-3 (4H)-yl)propyl 2,2,2-trifluoroacetate (35 mg, 88.1% yield) as an oil. LCMS: MH+ 567 and TR=2.383 min.
Reaction SMILES: C(OC([NH:8][C:9](=[NH:37])[C:10]1[S:11][C:12]([S:35][CH3:36])=[C:13]([C:15]2[N:16]=[C:17]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH:30]([CH3:34])[CH2:29]4)[CH:22]=3)[S:18][CH:19]=2)[CH:14]=1)=O)(C)(C)C.[ClH:38].C(OCC)(=O)C>>[ClH:38].[CH3:34][CH:30]1[CH2:31][CH2:32][CH2:33][N:28]([CH2:27][C:23]2[CH:22]=[C:21]([NH:20][C:17]3[S:18][CH:19]=[C:15]([C:13]4[CH:14]=[C:10]([C:9]([NH2:37])=[NH:8])[S:11][C:12]=4[S:35][CH3:36])[N:16]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:29]1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1-c1csc(Nc2cccc(CN3CCCC(C)C3)c2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CSc1sc(C(=N)N)cc1-c1csc(Nc2cccc(CN3CCCC(C)C3)c2)n1
Yield: 100 %

Procedure:
4-[2-({3-[(3-Methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)]-5-methlylthiothiophene-2-carboxamidine hydrochloride: (tert-Butoxy)-N-(imino{4-[2-({3-[(3-methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)]-5-methylthio(2-thienyl)}methyl)carboxamide (8.2 mg, 0.014 mmol) was stirred 2 mL of a 10% 3N HCl-ethyl acetate solution at 0° C. for 30 min., at which time the solvent was removed in vacuo to give 8 mg (100% yield) of the 4-[2-({3-[(3-methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine hydrochloride. 1H NMR (DMSO-d6, 300 MHz) δ 0.83 (d, 3H, J=5.6 Hz), 1.54-2.48 (m, 5H), 2.52-2.63 (m, 4H), 2.66 (s, 3H), 4.23 (d, 2H, J=4.8 Hz), 7.15-7.23 (m, 2H), 7.41 (t, 1H, J=7.8 Hz), 7.86-7.92 (m, 2H), 8.63 (s, 1H), 9.01 (bs, 2H), 9.42 (bs, 2H), 10.63 (s, 1H); (Mass Spectrum (ESI) m/z calcd. for C22H27N5S3, 457.7 (M+H), found 458.2.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:30]=[N:29][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22]([C:25]([NH:27][NH2:28])=[O:26])=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]OC(OC)OC.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(O)(=O)C>[O:26]1[CH:31]=[N:28][N:27]=[C:25]1[C:22]1[N:23]=[CH:24][C:19]2[NH:18][C:17]3[N:29]=[CH:30][C:14]([C:11]4[CH:12]=[CH:13][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:9][CH:10]=4)=[CH:15][C:16]=3[C:20]=2[CH:21]=1
Reactant: COC(OC)OC
Reactant: NNC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: c1nnc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)o1
Yield: 10.9 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbhydrazide (53.8 mg, 0.134 mmol) and trimethoxymethane (1.21 mL, 11.0 mmol) in DMF (0.81 mL) was heated at 120° C. for 24 h. The mixture was cooled, treated with trimethoxymethane (1.0 mL) and a few drops of acetic acid and heated under reflux for 48 h. The mixture was allowed to cool, treated with saturated aqueous sodium bicarbonate solution, and the resultant white precipitate collected by filtration and washed with water. The filtrate was extracted with DCM, 20% methanol in DCM, and the combined organic phases dried over sodium sulfate, combined with the isolated solid and concentrated in vacuo. The resultant residue was purified by preparative HPLC [2-60% MeCN/water modified with 0.1% ammonium hydroxide] to afford a light-yellow flaky solid (6.0 mg, 27%). 1H NMR (DMSO-D6, 400 MHz): 12.77-12.69 (s, 1H), 9.41 (s, 1H), 9.26 (d, J=2.2 Hz, 1H), 9.18 (s, 1H), 9.08 (s, 1H), 9.00 (d, J=2.2 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (m, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=7.69 min, M+H+=411.
Reaction SMILES: [NH:1]([C:25]([O:27]C(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH3:7])=[O:4].Cl.O1CCOCC1.[NH:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40]C(O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[NH:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C:25]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:9])[CH3:7])=[O:4])=[O:27]
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 85.9 %

Procedure:
Compound II (65.03 g, 0.15 mole) was deblocked with HCl/dioxane and coupled to Boc-Gly-OH (26.3 g, 0.15 mole) using EDCI with HOBt in the same manner as that described for II to give 63.2 g (yield 85.9%) of III Rf1, 0.3; Rf2, 0.46.