Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15]1)=[O:4].Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][N:35]2[CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:31]2[N:39]=[CH:38][N:37]=[C:36]3[C:32]=2[N:33]=[CH:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH3:29])=[C:7]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:15]2)[CH:8]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
A mixture of 2,2-dimethylpropionic acid 2-{(S)-3-[2-((S)-2-aminopropionylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester, (0.591 g, 1.45 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.346 g, 1.45 mmol), and DIPEA (0.74 mL, 4.32 mmol) in n-butanol (7 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 2-8% 2M NH3/MeOH in DCM) affording the title compound as a colourless gum (0.583 g, 66%). LCMS (Method J): RT 2.39 min [M+H]+ 611.
Reaction SMILES: Cl[C:2]1([S:20]([CH2:22][CH3:23])=[O:21])[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[CH:3]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].N12CCCCC1C=NCCC2>C(OC(=O)C)C>[CH2:22]([S:20]([C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])=[O:21])[CH3:23]
Reactant: CCS(=O)C1(Cl)CC2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOC(C)=O
Product: CCS(=O)C1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A suspension of benzyl 3-chloro-3-ethylsulphinyl-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (54) (0.020 g) in ethylacetate (2 ml) was stirred at room temperature under argon and treated with 1,5-diazabicyclo[5.4.0]undec-5-ene (0.009 g). After a period of 15 minutes the reaction mixture was washed with brine and dried over sodium sulphate. It was concentrated to give a single diastereoisomer of benzyl 3-ethylsulphinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (55) (0.017 g) as a gum; νmax (CHCl3) 2980, 1795 and 1730 cm-1 ; τ(d6 -acetone) 2.5-2.8 (5H, m, phenyl), 4.78 (2H, s, benzyl CH2), 5.71 (1H, tdd J9,5 and 3 Hz, C5-H), 6.49 (1H, dd J17 and 5 Hz, C6-H), 6.82 (2H, d J 9 Hz, C4-H2), 6.84 (1H, dd J17 and 3 Hz, C6-H), 7.13 and 7.15 (2H, 2q J71/2 Hz, SCH2) and 8.80 (3H, t J71/2 Hz, CH3).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[O:8])[N:6]=1.[Br:33]N1C(=O)CCC1=O>>[Br:33][C:18]1[O:17][C:16]([CH2:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:8])=[N:20][C:19]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3)co2)c(-c2ccccc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3)c(Br)o2)c(-c2ccccc2)s1
Yield: 69.1 %

Procedure:
The title compound (0.075 g) was prepared by treating the compound of example 168 (0.093 g) with N-bromosuccinimide (0.037 g) according to the method of example 164.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[C:3]=1[Cl:10].[Cl-:11].[Al+3].[Cl-:13].[Cl-:14].Cl[CH:16]([Si:19]([Cl:22])([Cl:21])[Cl:20])[CH2:17]Cl>>[Cl:1][C:2]1[C:3]([Cl:10])=[C:4]([Cl:9])[C:5]([Cl:8])=[CH:6][C:7]=1[CH:17]([C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([Cl:13])=[C:7]([Cl:14])[C:2]=1[Cl:1])[CH2:16][Si:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: ClCC(Cl)[Si](Cl)(Cl)Cl
Reactant: Clc1ccc(Cl)c(Cl)c1Cl
Reactant: [Cl-]
Agent: [Al+3]
Product: Clc1cc(C(C[Si](Cl)(Cl)Cl)c2cc(Cl)c(Cl)c(Cl)c2Cl)c(Cl)c(Cl)c1Cl
Reaction time: 0.5 h
Yield: 220.1 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1 above, 43.18 g (200 mmol) of 1,2,3,4-tetrachlorobenzene and 1.07 g (8.0 mmol) of aluminum chloride were alkylated with 9.30 g (40.0 mmol) of (1,2-dichloroethyl)trichlorosilane for 10 min at 130° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 30 min to complete the deactivation. Freshly distilled hexane(100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane was distilled, the reaction products were vacuum distilled to give 10.41 g of [2,2-bis(2,3,4,5-tetrachlorophenyl) ethyl]trichlorosilane (bp; 218-222° C./0.5 torr, yield; 44%).
Reaction SMILES: [H][H].[C:3](=[O:6])(O)[O-:4].[Na+].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16]CO.Cl>O.[Pt]=O>[C:3]([OH:4])(=[O:6])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: [H][H]
Reactant: O=C([O-])O
Reactant: COCCOCCOCCO
Agent: O=[Pt]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COCCOCCOCC(=O)O
Yield: 84.6 %

Procedure:
A 0.5 g quantity of platinum oxide is hydrogenated in 60 ml of water at 25° C. and atmospheric pressure until the uptake of hydrogen ceases. To the resultant mixture is added a mixture of 0.6 g (7.14 mmoles) of sodium bicarbonate and 1.0 g (6.1 mmoles) of triethylene glycol monomethyl ether dissolved in 20 mL of water. Air is bubbled through the above mixture for 4 hr following the consumption of staging material by TLC. The reaction is then filtered though Celite and the Celite washed with water. The combined washes are treated with 7.2 mL (7.2 mmoles) of 1N hydrochloric acid and the resultant solution freeze-dried. The residue is washed with acetone and filtered. The filtrate is evaporated to dryness under vacuum. The residual oil is chromatographed over 100 g of CC-4 silica gel eluted with (50-50)acetone-methylene chloride, collecting 20 mL fractions. Concentration of fractions 11-16 gives 0.92 g of the desired 3,6,9-trioxadecanoic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[CH3:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[CH2:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:3](=[O:4])[CH2:2][NH:1][C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=1)=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1Cc1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2Cc2ccccc2)c1
Yield: 60.1 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(2-benzylphenyl)acetamido]acetate (8.1 g) and 3-methylphenyl isocyanate (3 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-(2-benzylphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (6.6 g), m.p 183° C., is obtained
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH2:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:22]1=[O:37])[CH3:20].[H-].[Na+]>>[CH2:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30]2[CH:31]=[CH:32][C:33]([O:36][C:2]3[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]4[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=4[N:3]=3)=[CH:34][CH:35]=2)[C:22]1=[O:37])[CH3:20]
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 200 °C
Yield: 94.5 %

Procedure:
2-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (1.861 g) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.4 g) and sodium hydride (0.263 g) in DMF(dry) (10 mL) at room temperature. The mixture was heated at 200° C. for 1 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.60 g) as a colorless solid. A mixture of 1-ethyl-3-{4-[(1-{([2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (194 mg) and 2 M HCl in EtOH (6.0 mL) was stirred at 70° C. for 4 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was recrystallized from EtOH-ether to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride (154 mg).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[C:14]([O:19][C:20]3[CH:21]=[C:22]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[CH:27]=3)=[O:24])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=[N:9]1)C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[NH:8]1[CH:12]=[C:11]([C:13]2[C:14]([O:19][C:20]3[CH:21]=[C:22]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[CH:27]=3)=[O:24])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=[N:9]1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Oc1ncccc1-c1cnn(Cc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Oc1ncccc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(3-(1-benzyl-1H-pyrazol-4-yl)pyridin-2-yloxy)-N-(3-isopropylphenyl)-4-methylbenzamide (65 mg, 0.13 mmol) in EtOAc (4 mL) and MeOH (4 mL) was added Pd/C (10%, 300 mg). The reaction was purged with hydrogen gas and then stirred at rt under a balloon of hydrogen for 16 hours. The reaction was filtered through Celite with EtOAc, concentrated, and purified by Gilson reverse-phase HPLC (0.1% TFA in water/acetonitrile). After a basic workup involving CH2Cl2 and saturated sodium bicarbonate, 3-(3-(1H-pyrazol-4-yl)pyridin-2-yloxy)-N-(3-isopropylphenyl)-4-methylbenzamide was obtained as a white solid. MS m/z=413 [M+1]+. Calc'd for C25H24N4O2: 412.50.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.F[C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:41]2[CH2:44][CH2:43][CH2:42]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1.[H-].[Na+].O>CN1CCCC1=O>[N:41]1([S:38]([C:35]2[CH:36]=[CH:37][C:32]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[CH:33][CH:34]=2)(=[O:40])=[O:39])[CH2:44][CH2:43][CH2:42]1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCC3)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 57.5 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (60.0 mg, 0.139 mmol) synthesized in Example (38d) and 1-[(4-fluorophenyl)sulfonyl]azetidine (60.0 mg, 0.279 mmol) synthesized in Example (55a) were dissolved in N-methylpyrrolidone (5.0 mL), and sodium hydride (60%, 24 mg, 0.60 mmol) was added, followed by stirring at 100° C. for 6 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-35%) to afford the desired compound (42 mg, yield 57%) as a white solid.
Reaction SMILES: [I-].C(OC([NH:12][C:13]([CH3:19])([CH3:18])[CH2:14][S+:15]([CH3:17])[CH3:16])=O)C1C=CC=CC=1.CO.C(O)(=O)C.[ClH:26]>O.[Pd]>[ClH:26].[Cl-:26].[NH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][S+:15]([CH3:17])[CH3:16]
Reactant: C[S+](C)CC(C)(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: [I-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: C[S+](C)CC(C)(C)N
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
A solution of (2-(benzyloxycarbonylamino)-2-methylpropyl)dimethyl-sulfonium iodide (1.20 g, 3.03 mmol) in a mixture of water (25 mL), methanol (10 mL) and acetic acid (0.4 ml, 2 equiv, 6.06 mmol) was cooled in an ice bath for 5 min, then Ag2O (0.46 g, 0.65 equiv, 1.97 mmol) was added in one portion. The black suspension immediately changed to a cream color suspension and stirred for 30 min. This suspension was filtered through a pad of Celite® and the solid was washed with water (30 mL). The filtrate was acidified to ˜pH 2 with 6 N HCl and filtered through Celite® and the residue was washed with water (50 mL). The filtrate was concentrated on a rotovap to give a yellow oil. The crude hydrochloride salt was dissolved into water (20 mL) and 10% Pd/C (300 mg) was added to the reaction in one portion followed by 6 N HCl (1 mL, 2 equiv). The flask was sealed and degassed with vacuum and flushed with hydrogen from a balloon (3×). The reaction was stirred at room temperature for 20 h. The suspension was filtered through a pad of Celite® and the solid was washed with water (2×50 mL). The solution was concentrated in vacuo to a light yellow oil which upon repeated addition and evaporation of isopropyl alcohol (3×10 mL) provided the desired compound (0.62 g, quant). 1H NMR (D2O, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H). LRMS (ESI−) for C6H16NS+ (134.1); Found: 134 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][C:18]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([C:20]1[N:21]=[CH:22][O:23][CH:24]=1)[CH3:19]>N1C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:28]2[CH:27]=[CH:26][C:25]([C:18]([CH3:19])([C:20]3[N:21]=[CH:22][O:23][CH:24]=3)[CH3:17])=[CH:30][CH:29]=2)(=[O:32])=[O:33])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1cocn1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1)c1cocn1

Procedure:
Following the general procedure for synthesis of N-arylbenzenesulfonamides, 73 mg (0.32 mmol) of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 36 mg (0.13 mmol) of 4-(1-Methyl-1-oxazol-4-yl-ethyl)-benzenesulfonyl chloride were combined in 1 ml of anhydrous pyridine at 60° C. to give, after purification, the title product as a pale yellow solid: 1H NMR (CDCl3): δ (ppm): 1.61 (s, 6H), 7.26-7.66 (m, 12H), 8.90 (br, 1H), 10.13 (br, 1H) ppm; MS: (M+H)/z=482.0.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[CH2:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[C:13](=[S:15])=[S:14]>C(OCC)C>[S:1]1[CH2:5][CH2:4][N:3]([C:13]([S-:15])=[S:14])[CH2:2]1.[CH2:6]([NH+:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7]
Reactant: C1CSCN1
Reactant: CCN(CC)CC
Reactant: S=C=S
Solvent: CCOCC
Product: CC[NH+](CC)CC
Product: S=C([S-])N1CCSC1
Reaction time: 2.5 h

Procedure:
To a solution of 70g (0.79 mole) thiazolidine ** and 160g (1.58 moles) triethylamine in one liter ethyl ether was added 120g (1.58 moles) carbon disulfide at 21°-2° over a period of 30 minutes. After the mixture was stirred at ambient temperatures for an additional 2.5 hours, it was filtered to give a pale yellow solid which was then washed with 1.51. (5 × 300ml) ether to yield 201 g (96% conversion) of desired product, m.p. 101°-3° C. (gas evol.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.Cl[C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:19]=[C:18]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:31]=3[N:30]=[C:29]2[CH:39]([F:41])[F:40])[N:17]=1>C1COCC1.C(O)(=O)C.O>[F:41][CH:39]([F:40])[C:29]1[N:28]([C:18]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:21]=[C:16]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[O:8][CH3:9])[N:17]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:31]=2[N:30]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: COc1ccncc1N
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccncc1Nc1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3c(OC)cccc32)n1
Reaction time: 0.25 h
Yield: 41.9 %

Procedure:
To a solution of 0.121 g (0.98 mmol) of 3-amino-4-methoxypyridine in THF (3 mL) was added 0.44 mL of butyllithium (2.5 M solution in hexanes), and the mixture stirred for 15 min. A solution of 0.128 g (0.32 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried, and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (8:2) and then with CH2Cl2/EtOAc (2:1) to CH2Cl2/EtOAc (1:1) gave a yellow powder. Recrystallization from ethanol/CH2Cl2 gave 0.065 g (42% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 239-241° C.; 1H NMR (CDCl3) δ9.43 (br s, 1H), 8.31 (d, J=5.6 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.54 (t, JHF=53.4 Hz, 1H), 7.39-7.35 (m, 2H), 6.89 (d, J=5.6 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.94 (s, 4H), 3.82-3.80 (m, 4H); Anal. Calcd. for C22H22F2N8O3: C, 54.5; H, 4.6; N, 23.1. Found: C, 54.4; H, 4.5; N, 22.9%.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH:30]([CH3:32])[CH3:31])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([CH3:32])[CH3:31]
Reactant: CC(C)N1CCC[C@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
To a suspension of NaH (60% in mineral oil, 142 mg, 3.56 mmol) in DMF (2.00 mL) was added (1R,4S)-4-amino-1,2,3,4-tetrahydro-naphthalen-1-ol Intermediate A (145 mg, 0.88 mmol) and the reaction stirred for 20 min. A solution of Intermediate 58b (220 mg, 0.88 mmol) in DMF (2.00 mL) was added and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 2-10% [2M NH3 in MeOH] in DCM, gave the title compound (145 mg, 44%). LCMS (Method 4): Rt 0.29 min, m/z 392.2 [MH+].
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:21])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:13]2)=[CH:8][CH:7]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:21])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:13]2[CH3:22])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1c[nH]c2cc(C3OCCO3)ccc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2cc(C3OCCO3)ccc2c1=O
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Compound 8 was dissolved in anhydrous DMF (Aldrich) in a 500 mL 1-neck round bottom flask. Anhydrous potassium carbonate (EM Science) was added and the mixture was stirred for 15 min. After addition of iodomethane (Aldrich), the mixture was stirred at room temperature overnight, after which it was concentrated and partitioned between CH2Cl2 and aq. sodium thiosulfate. The CH2Cl2 layer was rinsed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to 19.30 g crude 9 (brownish solid). 1H NMR spectrum was satisfactory; however, TLC (MeOH:DCM 1:9) shows small amounts of lower polarity impurities and some high polarity impurities (possibly largely inorganic). Attempts to purify via re-precipitation from THF/water or CH2Cl2/hexane were unsatisfactory. Chromatography on a silica gel plug (gradient 1-2-4-6-10% methanol in CH2Cl2) provided purified product (17.93 g, 95% yield).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16](Br)[C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15].[C:22]([O-])(=[S:24])[CH3:23].[K+]>CO>[C:22]([CH:16]([C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=1)[C:17]([O:19][CH3:20])=[O:18])(=[S:24])[CH3:23]
Reactant: CC([O-])=S
Reactant: COC(=O)C(Br)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(C(C)=S)c1ccc(Cl)c(Cl)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
A toluene (403 mL) solution of methyl 2-(3,4-dichlorophenyl)-2-bromoacetate (134 g, 0.451 mol) was dropwise added to a methanol (403 mL) solution of potassium thioacetate (67.7 g, 0.586 mol, 1.3 equivalent amounts based on the starting material) at 5° C. over a period of 15 minutes, followed by stirring at 5° C. for 1 hour. The formed solid was subjected to filtration, and the filtrate was mixed with toluene (403 mL), sequentially washed with water, a saturated sodium hydrogencarbonate aqueous solution, a saturated ammonium chloride aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a yellow oil (136 g, yield: 103%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[CH:11]([F:13])[F:12]>CC(O)C.[OH-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([F:13])[F:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: FC(F)Cl
Reactant: Oc1cc(F)cc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Fc1cc(Br)cc(OC(F)F)c1
Temperature: 82.5 °C
Yield: 81.6 %

Procedure:
A mixture of 3-bromo-5-fluorophenol (6.1 g, 31.0 mmol; see step (ii) above) and chlorodifluoromethane (13.0 g, 150.0 mmol) in i-PrOH (100 mL) and 30% KOH (80 mL) was heated in a sealed flask for 18 h at 80-85° C. The reaction mixture was cooled to room temperature and the layers were separated. The organic layer was concentrated in vacuo to afford a colourless oil. The aqueous layer was extracted with Et2O (3× 30 mL). The crude oil and the combined organic extracts were washed with 2N NaOH (3× 30 mL) and H2O (3× 30 mL). The organics were then dried (Na2SO4), filtered through a small silica gel plug, and concentrated in vacuo to afford the sub-title compound (6.1 g, 79%) as a colourless oil that was used without further purification.