Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[NH4+].[Ce].[C:26]([OH:29])(=[O:28])[CH3:27]>>[C:26]([O:29][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[OH:11])(=[O:28])[CH3:27]
Reactant: Clc1ccccc1[C@H]1O[C@@H]1COCc1ccccc1
Reactant: CC(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Product: CC(=O)O[C@H](COCc1ccccc1)[C@@H](O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a solution of (±)-2-(benzyloxymethyl)-3-(2-chlorophenyl)oxirane (Preparation example 373, 2.9 g, 10.55 mmole) in Acetic acid (55 mL) was added Cerium Ammonium Nitrate (1.15 g, 2.11 mmole) at room temperature. The mixture was stirred for 18 hr at room temperature. The TLC showed complete consumption of SM. The reaction mixture was quenched with sat'NaHCO3 to pH7 at 0° C. then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H2O, then dried over MgSO4 and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (1.2 g, 34%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[I:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=3)[N:3]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.4) (0.27 g, 1.0 mmol) and commercially available 4-iodo-imidazole (0.21 g, 1.1 mmol) according to the general procedure Ia. Obtained as a light brown solid (0.35 g, 81%). MS (ISP) 432.1 [(M+H)+]; mp 193.5° C.
Reaction SMILES: C1(Br)CCCCC1.Cl[C:9]1[C:14]2[S:15][CH:16]=[C:17]([CH3:18])[C:13]=2[CH:12]=[CH:11][CH:10]=1.[Mg].C1C[O:23]CC1>>[OH:23][C:9]1[C:14]2[S:15][CH:16]=[C:17]([CH3:18])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: Cc1csc2c(Cl)cccc12
Agent: [Mg]
Solvent: BrC1CCCCC1
Product: Cc1csc2c(O)cccc12
Reaction time: 2 h

Procedure:
Cyclohexyl bromide (32.6 g.) and 7-chloro-3-methylbenzo[b]thiophene (18.3 g.) in THF (400 ml) is added to a suspension of magnesium turnings (7.3 g.) in THF. The mixture is stirred for two hours and heated on a steam bath for two hours. The reaction is cooled and oxygen is bubbled in slowly for two hours. The mixture is stirred for 18 hours at room temperature and extracted with chloroform. The organic extract is extracted with 5% sodium hydroxide. The aqueous extract is acidified with concentrated hydrochloric acid and extracted with ethyl ether. The ether extract is dried (MgSO4) and concentrated to a solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:14][CH:13]2[O:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:16])=[CH:9][CH:8]=3)[CH2:5]1)[C:2]#[CH:3].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl>C(O)(C)C.C([O-])(O)=O.[Na+]>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[O:15][CH:13]3[CH2:14][N:4]([CH2:1][C:2]#[CH:3])[CH2:5]2)=[N:19][CH:20]=1
Reactant: C#CCN1CC2OC(C1)c1cc(N)ccc12
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: C#CCN1CC2OC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Temperature: 140 °C
Yield: 50.4 %

Procedure:
10-Prop-2-ynyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (71 mg, 0.33 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (99 mg, 0.33 mmol) were combined with 4 N HCl (0.083 mL, 0.33 mmol) in isopropanol (2 mL) and heated in a microwave at 140° C. for 10 min. The resulting mixture was diluted with saturated aqueous NaHCO3 (5 mL), extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered, and concentrated. The remaining residue was purified with silica gel chromatography (30-100% EtOAc in hexanes) to obtain 2-[5-Chloro-2-(10-prop-2-ynyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a light yellow solid (79 mg, 50%). 1HNMR (400 MHz, CDCl3) δ 11.0 (bs, 1H), 8.6 (d, 1H, J=8.7 Hz), 8.1 (s, 1H), 7.6 (s, 1H), 7.5 (d, 1H, J=7.8 Hz), 7.4 (appt t, 1H, J=8.7 Hz), 7.3 (d, 1H, J=7.8 Hz), 7.2 (d, 1H, J=7.8 Hz), 7.1 (appt t, 1H, J=7.6 Hz), 7.0 (bs, 1H), 6.2 (bs, 1H), 5.1 (s, 1H), 5.0 (s, 1H), 3.2 (d, 2H, J=2.4 Hz), 3.1-3.0 (m, 5H), 2.6 (t, 2H, J=9.5 Hz), 2.2 (t, 1H, J=2.4 Hz); MS (m/e) 475 (M+1); mp 117-121° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1)(=O)=O>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:42]4[C:43]5[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH2:39][CH2:40][CH:41]=4)=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12
Reactant: O=S(=O)(Oc1cccc2ccccc12)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)OC1(C)C
Product: O=C(c1ccc(C2=CCCc3ccccc32)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 96.3 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 10, Step B (0.300 g, 0.668 mmol) and naphthalen-1-yl trifluoromethanesulfonate (0.205 g, 0.735 mmol) were reacted by the procedure described in Example 1, Step F. The crude product was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate in hexane to afford a clear oil. The oil was recrystallized from diethyl ether/petroleum ether to afford white crystals (0.290 g), m.p. 174–176° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCO.C(OCC)(=O)C.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>[C:20]([C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1)#[N:21]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Reactant: N#Cc1cccc(B(O)O)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: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(C#N)c2)cc1)C(C)C
Yield: 97 %

Procedure:
A suspension of methyl N-[(4-bromophenyl)sulfonyl]valinate obtained in Reference Example 92 (5.00 g, 14.3 mmol), (3-cyanophenyl)boronic acid (2.52 g, 17.1 mmol), tetrakis(triphenylphosphine)palladium (0.330 g, 0.286 mmol) and 2N aqueous sodium carbonate solution (8.57 mL, 17.1 mmol) in EtOH (15 mL)-toluene (50 mL) was heated under reflux for 8 hr under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from hexane-ethyl acetate to give the title compound as a yellow powder (5.18 g, 97%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH2:8]([O:15][C:16](ON1C(=O)CCC1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>O1CCCC1>[CH2:8]([O:15][C:16]([NH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(CN)CO
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-amino-2,2-dimethyl-1-propanol (2 g) in tetrahydrofuran (20 mL) was added N-(benzyloxycarbonyloxy)succinimide (7.25 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-1/1) to give 3-benzyloxycarbonylamino-2,2-dimethyl-1-propanol (4.6 g) To this material were added carbon tetrachloride (40 mL), acetonitrile (40 mL), water (48 mL), sodium periodate (11.6 g) and ruthenium trichloride (0.2 g) successively, and the mixture was stirred at room temperature overnight. To the reaction mixture were added sodium periodate (11.6 g) and ruthenium trichloride (0.2 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in a saturated aqueous potassium carbonate solution. The solution was washed with ethyl acetate, and the aqueous layer was acidified with 2 mol/L hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid (3.6 g). This material was dissolved in tetrahydrofuran (25 mL). To the solution was added 1,1′-carbonylbis-1H-imidazole (3.39 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (25 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethylacetate. The extract was washed with 1 mol/L hydrochloric acid, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-benzyloxycarbonylamino-2,2-di(methyl)propionamide (3.35 g). The obtained 3-benzyloxycarbonylamino-2,2-di(methyl)propionamide (0.13 g) was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (61 mg).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4]>C(OC(=O)CCC)(=O)CCC>[CH2:2]([C:1]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1)[CH2:8][CH3:7]
Reactant: Nc1ccccc1C(=O)O
Agent: CCCC(=O)OC(=O)CCC
Product: CCCc1nc2ccccc2c(=O)o1

Procedure:
A solution of anthranilic acid (3.40 g, 25.0 mmol) in butyric anhydride (10 mL) was heated at 150° C. for 1 hOUR. The bath temperature was lowered to 90° C. and the excess butyric anhydride was removed by distillation. The residue was distilled to provide 2-propyl-4H-3,1-benzoxazin-4-one (1—1) as a colorless liquid (bp 110–112° C./2 mm Hg), which solidified upon standing. 1H NMR (500 MHz, CDCl3) δ8.19 (d, 1H, J=8 Hz, 1H), 7.80 (t, J=7 Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.50 (t, J=7 Hz, 1H), 2.68 (t, J=7 HZ, 2H), 1.87 (m, 2H), 1.05 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:20])[CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH:21]1([C:24]2[CH:33]=[C:32]([C:34](Cl)=[O:35])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH2:23][CH2:22]1>>[CH:21]1([C:24]2[CH:33]=[C:32]([C:34]([NH:20][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=3)[CH2:14][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[O:35])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH2:23][CH2:22]1
Reactant: O=C(Cl)c1cc(C2CC2)nc2ccccc12
Reactant: CCCS(=O)(=O)c1ccc(C(N)CN2CCCC2)cc1
Product: CCCS(=O)(=O)c1ccc(C(CN2CCCC2)NC(=O)c2cc(C3CC3)nc3ccccc23)cc1

Procedure:
{1-[4-(Propylsulphonyl)phenyl]-2-pyrrolidin-1-ylethyl}amine, the intermediate described in Example 47e, was reacted with 2-cyclopropylquinoline-4-carbonyl chloride (see above) under the conditions described in Example 47f. 1H NMR δ (400 MHz, CDCl3) δ 0.97 (3H, t, J=7.4 Hz), 1.07-1.11 (2H, m), 1.16-1.20 (2H, m), 1.66-1.77 (6H, m), 2.18-2.24 (1H, m), 2.48-2.50 (2H, m), 2.63-2.71 (3H, m), 2.91-3.02 (3H, m), 5.19-5.24 (1H, m), 7.29 (1H, s), 7.42-7.48 (2H, m), 7.56 (2H, d, J=8.3 Hz), 7.62-7.66 (1H, m), 7.82 (2H, d, J=8.3 Hz), 7.96 (1H, d, J=8.4 Hz), 8.13 (1H, d, J=8.3 Hz); m/z (ES+) 492 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C1COCC1>[Ti](Cl)(Cl)(Cl)Cl.O>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[C:9]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH2:7]1
Reactant: Sc1ccccc1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC=C(Sc2ccccc2)c2cc(Br)ccc21
Reaction time: 5 h

Procedure:
To a stirred solution of 4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G, 1.48 g, 5.9 mmol), titanium tetrachloride (1.09 g, 5.7 mmol) and TBF (10 mL) was added a minire of thiophenol (660 mg, 6 mmol), triethylamine (1.16 g, 11.5 mmol) and THF (20 mL) via an addition funnel at ambient temperature. The mixture was stirred for 5 h, and water (10 mL) was added, extracted with ether (3×50 mL). The combined organic layer was washed successively with water (10 mL), 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (MgSO4) and the solvent distilled off at reduced pressure. After silicagel chromatography the title compound was obtained as a colorless oil .
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([S:7][CH3:8])[O:5][CH:6]=1.C(=O)([O-])[O-:10].[Na+].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([S:7]([CH3:8])=[O:10])[O:5][CH:6]=1
Reactant: CSc1nc(C)co1
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1coc(S(C)=O)n1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
4-Methyl-2-methylthiooxazole (6.06 g, 0.047 m) in dry chloroform (50 ml) was cooled to 0° C. with vigorous stirring and anhydrous sodium carbonate (6.06 g, 0.057 m) added. 96% 3-Chloroperbenzoic acid (8.90 g, 0.0495 m) in dry chloroform (100 ml) was then added dropwise over 45 minutes and the mixture stirred for a further 45 minutes at 0° C. Solid sodium sulphite (2.0 g) was added and the mixture allowed to warm to room temperature. The mixture was then filtered, the filtrate evaporated and the resulting oil was distilled under vacuum to give the title compound as a colourless oil 6.48 g (95%), b.p. (airbath)76° C./0.1 mm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[I:14].[I:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH2:3][CH2:2][O:23][C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[I:15])=[C:7]([I:14])[CH:8]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: Cc1cc(Cl)cc(I)c1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Cl)cc(I)c1OCCCOc1ccc(Cl)cc1I
Yield: 87.8 %

Procedure:
In 70 mL of acetone combine 4.08 g (10.48 mmol) of 2-(3-bromopropoxy)-5-chloro-1-iodo-3-methylbenzene, 2.67 g (10.49 mmol) of 2-iodo-4-chlorophenol (Prepared in a manner similar to Preparation 7) and 3.06 g (22.14 mmol) of potassium carbonate. Reflux overnight, filter, cool and concentrate to give an off white solid, which is crystallized using acetonitrile to yield 5.18 g (88%) of 5-chloro-2-(3-(4-chloro-2-iodophenoxy)propoxy)-1-iodo-3-methylbenzene as a white powder. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=2.5 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.31-7.23 (m, 1H), 7.16-7.10 (m, 1H), 6.76 (d, J=8.8 Hz, 1H), 4.28 (t, J=5.8 Hz, 2H), 4.09 (t, J=6.0 Hz, 2H), 2.36 (p, J=5.9 Hz, 2H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.17, 155.57, 138.56, 136.17, 133.37, 131.34, 129.89, 129.24, 126.36, 112.21, 92.21, 86.64, 68.85, 65.57, 29.85, 17.02. GCMS (m/e): 562 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:11]([C:23]([O-:25])=[O:24])[N:10]([CH3:26])[N:9]=2)=[CH:4][CH:3]=1.B1([C:36]2[CH:41]=[CH:40][C:39]([C:42]([NH:44][CH3:45])=[O:43])=[N:38][CH:37]=2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].O.[OH-].[Li+]>C(O)C.[Pd].O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:36]4[CH:37]=[N:38][C:39]([C:42](=[O:43])[NH:44][CH3:45])=[CH:40][CH:41]=4)=[CH:3][CH:4]=3)=[N:9][N:10]([CH3:26])[C:11]=2[C:23]([OH:25])=[O:24])=[CH:16][CH:17]=1
Reactant: COc1ccc(COc2c(-c3ccc(Br)cc3)nn(C)c2C(=O)[O-])cc1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: *CC*
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CNC(=O)c1ccc(-c2ccc(-c3nn(C)c(C(=O)O)c3OCc3ccc(OC)cc3)cc2)cn1
Temperature: 115 °C

Procedure:
To a solution of 3-(4-bromophenyl)-4-(4-methoxybenzyloxy)-1-methyl-1H-pyrazole-5-carboxylate T-12 (400 mg, 0.96 mmol) in ethanol (10 mL) and water (1 mL) were added 2-(N-methylamidocarboxy)-5-pyridineboronic acid pinacol ester (254 mg, 0.97 mmol), potassium carbonate (138 mg, 1.0 mmol) and polyethylene supported palladium catalyst (FibreCat FC 1007, 3% Pd, 300 mg). The reaction mixture was heated in a microwave reactor at 115° C. for 15 minutes. To the reaction mixture was added lithium hydroxide monohydrate (127 mg, 3.0 mmol). The reaction mixture was heated in a microwave reactor at 115° C. for 20 minutes. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired 4-(4-methoxybenzyloxy)-1-methyl-3-(4-(6-(methylcarbamoyl)pyridin-3-yl)phenyl)-1H-pyrazole-5-carboxylic acid T-13 (304 mg, 0.64 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=O)[CH:7]=1.O.[NH2:23][NH2:24]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:21])[NH:24][N:23]=[C:8]2[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: NN
Reactant: O=C(c1ccc2ccccc2c1)c1cc(Br)c(F)cc1F
Solvent: O
Product: Fc1cc2[nH]nc(-c3ccc4ccccc4c3)c2cc1Br

Procedure:
A total of 7.0 g of (5-bromo-2,4-difluorophenyl)naphthalene-2-yl-methanone obtained in Production Example II-17-a was allowed to react with hydrazine monohydrate by the procedure of Production Example II-10-c and thereby yielded 1.5 g of the title compound as a colorless powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1.N1C=CC=CC=1.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN(C)C=O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([O:21][C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:18]3)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCOCCc1ccc2sccc2c1)N1CC(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
In 6.8 mL of toluene was dissolved 0.85 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-1-azetidinyl)-1-propanone, and to the solution were added 0.34 mL of pyridine, 0.02 g of 4-(dimethylamino)-pyridine and 0.93 g of trityl chloride, after which the resulting mixture was stirred at 50° C. for 3 hours. To the mixture was added 0.85 mL of N,N-dimethylformamide, followed by stirring at 50° C. for another 24 hours. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene ethyl acetate=5:1 to 3:1) to obtain 1.15 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-[3-(trityloxy)-1-azetidinyl]-1-propanone as an oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][N:31]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH:25][C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][NH:31]3)[CH3:24])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 90 °C

Procedure:
A mixture of (S)-1-[1-(trans-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (210 mg, 0.62 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (148 mg, 0.62 mmol) and DIPEA (0.55 mL, 3.09 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded onto an Isolute® SCX-2 cartridge which was washed with DCM, MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford the title compound as a colourless glassy solid (120 mg, 43%). LCMS (Method J): RT 2.72 min [M+H]+ 458