Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][O:23][C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)=[O:25]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: COC(=O)c1ccc(CCl)cc1
Product: COC(=O)c1ccc(CN2C(=O)C(CCO)Oc3ccccc32)cc1
Yield: 65 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by methods F and G, alkylating with 4-(methoxycarbonyl)benzyl chloride, to afford the alcohol as a white solid in 65% yield, mp=94°-95° C.; 1H NMR (CDCl3) δ 8.00 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 6.95-7.04 (m, 2H), 6.89 (dt, J=2.1, 8.0 Hz, 1H), 6.77 (dd, J=7.8, 1.5 Hz, 1H), 5.20 (s, 2H), 4.86 (dd, J=5.4, 7.7 Hz, 1H), 3.82-3.96 (m, 5H with 3H singlet at δ 3.89), 2.16-2.37 (m, 3H, one of which is exchangeable). 13C NMR (CDCl3) δ 166.8, 166.5, 144.1, 141.1, 130.1 (CH), 129.4, 128.4, 126.3 (CH), 124.2 (CH), 122.8 (CH), 117.3 (CH), 115.2 (CH), 75.1 (CH), 58.7 (CH2), 52.0 (CH3), 45.1 (CH2), 33.1 (CH2). IR 3450-3500 (br), 1719, 1660 cm-1. MS 342 (MH+), 324 (M--OH)+, 310 (M--OMe)+. Anal. Calc'd. for C19H19NO5 : C, 66.85; H, 5.61; N, 4.10. Found: C, 66.48; H, 5.47; N, 3.97.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:15]([CH2:16][CH2:17][Cl:18])[CH:14]=[N:13][C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].C1COCC1.CO>C1(C)C=CC=CC=1>[NH2:12][C:9]1[C:8]2[N:13]=[CH:14][N:15]([CH2:16][CH2:17][Cl:18])[C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(N)c2ncn(CCCl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1ncc(C(=O)O)c2c1ncn2CCCl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.5 %

Procedure:
To a mixture of 50 mg (0.19 mmol) of 4-amino-1-[2-chloro-ethyl]-1H-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester (example 10 step B) and 1.1 ml of a 2M aqueous solution of NaOH were added 0.3 ml of THF and 0.8 ml of MeOH. The mixture was stirred for 2.5 hours at room temperature. MeOH and THF were evaporated under reduced pressure and the pH of the remaining mixture was adjusted to pH=2 with 2N aqueous HCl. The product precipitated and was isolated by filtration. Toluene was added to the product and the solvent was evaporated. This process was repeated three times. Finally 24 mg (53%) of the desired product were isolated as a light grey solid.
Reaction SMILES: [C:1]([C:4]([CH3:6])=[O:5])([CH3:3])=[O:2].[OH-].[Na+].[O:9]1CCO[CH2:11][CH2:10]1>>[O:2]1[CH2:11][CH2:10][O:9][CH2:3][CH:1]1[C:4](=[O:5])[CH3:6]
Reactant: C1COCCO1
Reactant: CC(=O)C(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C1COCCO1
Temperature: 0 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of benzoic peroxide (20 g, 141 mmol) in 200 mL 1,4-dioxane at room temperature under nitrogen atmosphere was added biacetyl (24.3 g, 282 mmol). After the addition, the mixture was heated to reflux and stirred for 24 hours. The reaction mixture was cooled to 0° C. The pH was adjusted to around 9 by progressively adding 2N sodium hydroxide below 0° C., extracted with 2-methoxy-2-methylpropane (10 mL×3), and concentrated to give 1-(1,4-dioxan-2-yl)ethanone (13 g, 36%) as a yellow oil which was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8](=O)[NH:7][C:6]=2[CH:13]=1.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:13]=1
Reactant: O=C1CCSc2ccc(F)cc2N1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)NCCCS2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
7-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (76 mg, 0.38 mmol) dissolved in toluene (1 mL) and cooled to 0° C. in an ice bath. Red-Al (275 mL, 0.91mmol) was added and then the reaction allowed to warm to room temperature. The reaction was heated at reflux for 1.5 hours. 1 N sodium hydoxide was added slowly until pH>10, this was stirred for 10 minutes, extracted with dichloromethane (3×25 mL), washed with water, and dried (sodium sulfate). The concentrated organics were purified by preparative thin layer chromatography on silica gel and eluted with 50% ethyl acetate in hexanes to give 7-fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepine (30.8 mg, 93%). 1H NMR (CDCl3, 300 MHz): δ 7.32 (t, 1H, J=7.5 Hz), 6.53-6.42 (m, 2H), 4.09 (s-broad, 1H), 3.31-3.27 (m, 2H), 2.83-2.79 (m, 2H), 2.11-2.04 (m, 2H) ppm.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.[CH:45]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([NH2:55])[CH:53]=2)[CH:48]=[CH:47][N:46]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CO>O1CCOCC1.[NH4+].[Cl-].C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]3[C:2]([NH:55][C:52]4[CH:53]=[C:54]5[C:49]([CH:48]=[CH:47][N:46]=[CH:45]5)=[CH:50][CH:51]=4)=[N:3][CH:4]=[C:5]([CH2:34][N:35]4[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]4)[CH:6]=3)[N:9]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: Nc1ccc2ccncc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4ccncc4c3)n2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 31.3 %

Procedure:
A glass microwave reaction vessel was charged with 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (400 mg, 0.643 mmol) and isoquinolin-7-amine (139 mg, 0.965 mmol) (Ark Pharm, Inc, Libertyville, Ill.) in dioxane (2 mL) and the reaction mixture was cooled at 0° C. To this solution, sodium bis(trimethylsilyl)amide (1.0N in THF, 2 mL, 2 mmol) was mixed. The red solution was stirred at 0° C. for 1 h and 25° C. for 16 h. The reaction mixture was diluted with saturated NH4Cl and extracted with EtOAc (3×). The organic extract was washed with saturated NaCl and dried over MgSO4. The solution was filtered and concentrated under a vacuum. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 5% 2M NH3.MeOH in DCM, to provide N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoquinolin-7-amine (150 mg, 31.3% yield) as a yellow solid. m/z (ESI, positive ion): 746 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.63 (s, 3H) 2.82 (s, 3H) 3.06-3.10 (m, 4H) 3.57 (s, 2H) 3.70 (s, 3H) 3.75 (s, 3H) 4.86 (s, 4H) 6.84-6.97 (m, 4H) 7.30 (t, J=6.85 Hz, 4H) 7.72 (d, J=5.48 Hz, 1H) 7.74-7.79 (m, 1H) 7.82-7.88 (m, 1H) 8.35 (d, J=5.67 Hz, 1H) 8.39 (d, J=2.35 Hz, 1H) 8.58 (d, J=1.76 Hz, 1H) 8.75 (d, J=2.35 Hz, 1H) 9.13 (s, 1H) 12.19 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)=[O:5])[CH3:2].[NH2:22][C@@H:23]([CH3:40])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:37]=[C:36]([F:38])[C:33]([C:34]#[N:35])=[C:32]([Cl:39])[CH:31]=2)=[N:26]1>>[Cl:39][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C@@H:23]([NH:22][C:11]([C:9]3[N:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=3)=[O:13])[CH3:40])[N:26]=2)[CH:37]=[C:36]([F:38])[C:33]=1[C:34]#[N:35]
Reactant: CCOC(=O)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (3.18 mmol, 1 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (3.18 mmol, 890 mg). The product was purified by flash-chromatography. Yield 1.6 g. 1H-NMR (400 MHz; DMSO-d6): δ −0.01 (s, 9H), 0.80 (t, 2H), 1.15 (d, 3H), 1.30 (t, 3H), 3.48 (t, 2H), 4.34-4.49 (m, 5H), 5.69 (s, 2H), 6.98 (d, 1H), 7.78-7.82 (m, 2H), 7.87 (s, 1H), 8.03 (s, 1H), 8.21 (d, 1H). LC-MS: [M+1]=575.11.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([O:13][CH:14]2[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:20][CH:19]=3)[CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]2[CH2:15][N:16]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:20][CH:19]=3)[CH2:17]2)=[CH:30][CH:31]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(OCc4ccccc4)cc3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(O)cc3)C2)cc1

Procedure:
1.3 g (3.12 mmol) (S)—N-(1-{4-[3-(4-Benzyloxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide (Ex. 8.5) and 130 mg Pd/C (10%) in 50 mL MeOH are hydrogenated at 3 bar and 50° C. for 12 h. The mixture is filtered and concentrated in vacuo. The residue is titurated with diisopropyl ether to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.[I:25]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([I:25])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: II
Reactant: Cc1ccc(C)n1-c1ccn(-c2ccc(F)cc2)n1
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(I)n(-c2ccc(F)cc2)n1
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Under argon atmosphere, a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-1H-pyrazole (599 mg) in tetrahydrofuran (4 ml) was cooled to −78° C., n-butyllithium (1.8 ml, 1.6M solution in n-hexane) was added dropwise thereto, and the mixture was stirred for 30 minutes. To this reaction solution was added dropwise a solution of iodine (715 mg) in tetrahydrofuran (2 ml), the mixture was stirred for additional 30 minutes. To this reaction mixture was added a saturated aqueous solution of sodium sulfite, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the resulting solid residue was added a mixed solvent of ethyl acetate/n-hexane (=1/5), and the mixture was stirred. A solid was collected from this suspension by filtration, dried under reduced pressure to give the titled compound (625 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)C(C)N
Reactant: N#Cc1ccc(F)cc1Cl
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)Nc1ccc(C#N)c(Cl)c1

Procedure:
Following General Procedure AP above and using 2-chloro-4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared. The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as the eluant.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:19]=[N:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[C:32]([O:34]C)[CH:31]=[CH:30][C:29]=5[Cl:36])[CH:25]=[C:24]([CH3:37])[C:22]=4[N:23]=3)=[CH:13][N:12]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.[ClH:42].C(OCC)C>C(Cl)Cl.CO>[ClH:36].[N:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:19]=[N:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:29]=5[Cl:36])[CH:25]=[C:24]([CH3:37])[C:22]=4[N:23]=3)=[CH:13][N:12]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1.[ClH:42]
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(C(=O)NCCN5CCCC5)nc4)nnc3c2)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3ccc(C(=O)NCCN4CCCC4)nc3)nc12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-pyridine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (0.085 g, 0.164 mmol, 1 equiv) was diluted with 20 mL DCM and chilled to 0° C. using an ice bath. A 1.0 M solution of BBr3 in DCM (1 mL, 0.984 mmol, 6.0 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 6 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonication for 5 minutes. The resulting solids were filtered off, dried, and dissolved in DCM (10 mL) and MeOH (20 mL) mixture and treated with 2.0 M solution of HCl in diethyl ether (0.16 mL, 0.317 mmol, 2 equiv). The solvents were evaporated leaving desired product as HCl salt in a form of a yellow solid (0.084 g, 95% yield). MS (ESI+): m/z=504.1, LC retention time: 2.23 min. 1H NMR (DMSO-d6): δ 1.86-1.88 (m, 2H), 1.99-2.02 (m, 2H), 2.70 (s, 3H), 3.01-3.05 (m, 2H), 3.33-3.37 (m, 2H), 6.90 (dd, J=8.7 Hz, J=2.9 Hz, 1H), 6.97 (d, J=2.9 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.92-7.93 (m, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.22 (d, J=1.5 Hz, 1H), 8.51 (dd, J=8.6 Hz, J=2.5 Hz, 1H), 9.06 (t, J=5.9 Hz, 1H), 9.43 (d, J=2.4 Hz, 1H), 10.17 (bs, 1H), 11.50 (s, 1H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[Br:13][C:14]1[CH:25]=[C:18]2[C:19]([O:21]C(=O)[NH:23][C:17]2=[CH:16][CH:15]=1)=O>C(O)C.O>[NH2:23][C:17]1[CH:16]=[CH:15][C:14]([Br:13])=[CH:25][C:18]=1[C:19]([N:3]([O:4][CH3:5])[CH3:2])=[O:21]
Reactant: CNOC
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CON(C)C(=O)c1cc(Br)ccc1N
Yield: 67.8 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (9.42 g, 96 mmol) and triethyl amine (13.5 mL, 96 mmol) in ethanol and water (100 mL/10 mL) was added a solution of 5-bromoisatoic anhydride (20 g, 74 mmol) in ethanol and water (100 mL/10 mL) at ambient temperature under nitrogen. The reaction mixture was heated at reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL), washed with 1N aqueous sodium hydroxide solution (2×20 mL), brine (30 mL), and dried with MgSO4. After removal of the solvent, the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/3:2) to give 2-amino-5-bromo-N-methoxy-N-methylbenzamide as an off-white solid (13 g, 68%): mp 80-81° C.; 1H-NMR (CDCl3) δ 7.49 (d, 1H, J=2.1 Hz), 7.26 (dd, 1H, J=8.3, 2.0 Hz), 6.59 (d, 1H, J=8.4 Hz), 4.69 (br, 2H), 3.58 (s, 3H), 3.34 (s, 3H); Anal. Calc. For C9H11BrN2O2: C, 41.72; H, 4.28; N, 10.81. Found: C, 41.99; H, 4.16; N, 10.82.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[CH3:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][NH2:13].[BH4-].[Na+]>CO>[CH3:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][NH:13][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1
Reactant: Cn1ccnc1C=O
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ccnc1CNCCC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 1-methyl-2-imidazolecarboxaldehyde (4 g, 0.036 mol) and 3,3-dimethylbutylamine (4.9 mL, 0.036 mol) in MeOH (100 mL) was stirred at room temperature for 1 hour before NaBH4 (2.0 g, 0.053 mol) was added in portions. The resulting solution was stirred at room temperature for another hour before quenching with water. MeOH was removed under vacuum from the resulting mixture, and the residue purified by column chromatography (0-15% MeOH/EtOAc) to yield a light yellow liquid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[CH:12][C:11]=1[F:28])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:28][C:11]1[CH:12]=[C:13]([O:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@@H]3CCC[C@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@@H]1CCC[C@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 90.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (150 mg, 0.26 mmol) prepared in Example 128b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (98.0 mg, 89%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[C:11](O)([C:13]([F:16])([F:15])[F:14])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CNc1cc(Br)ccc1N
Product: Cn1c(C(F)(F)F)nc2ccc(Br)cc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The mixture of 5-bromo-N1-methylbenzene-1,2-diamine (300 mg) and TFA (10 ml) was stirred at 90° C. overnight. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4, passed through NH silica gel pad and concentrated in vacuo. The precipitate was collected by filtration, washed with IPE/hexane and dried in vacuo to give the title compound (265 mg) as a purple solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH2:15][O:16][C:17]2[CH:25]=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C=O)C>[Br:1][C:25]1[C:17]([O:16][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: c1ccc(COc2ccc3c(c2)OCO3)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2c(cc1OCc1ccccc1)OCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-bromosuccinimide (10.7 g, 0.06 mol) in dry DMF (70 ml) was added dropwise and with stirring a solution of 5-phenylmethoxy-1,3-benzodioxole (13.68, 0.06 mol) in dry DMF (80 ml). The resulting solution was stirred for 24 h at room temperature, poured into 300 ml of H2O and extracted with chloroform (3×70 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from absolute EtOH affording 17.4 g (94.5%) of 6-bromo-5-phenylmethoxy)-1,3-benzodioxole as white crystals mp 61.5°-62° C.; NMR (CDCl3, 90 MHz) δ 5.04 (S, 2H, CH2Ph), 5.91 (S, 2H, OCH2O), 6.56 (S, 1H, ArH), 6.99 (S, 1H, ArH), 7.14-7.63 (m, 5H, CH2Ph). Anal. calcd. for C14H11BrO3 : C, 54.75; H, 3.61; Br, 26.01. Found: C, 54.81; H, 3.64; Br, 25.68.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]([F:21])([F:20])[CH2:18][CH3:19])[CH:15]=2)[C:10]([CH3:23])([CH3:22])[CH2:9]1)=O)(C)(C)C.CO>Cl>[F:20][C:17]([C:14]1[CH:15]=[C:16]2[NH:8][CH2:9][C:10]([CH3:22])([CH3:23])[C:11]2=[N:12][CH:13]=1)([F:21])[CH2:18][CH3:19]
Reactant: CCC(F)(F)c1cnc2c(c1)N(C(=O)OC(C)(C)C)CC2(C)C
Agent: Cl
Solvent: CO
Product: CCC(F)(F)c1cnc2c(c1)NCC2(C)C
Yield: 104.9 %

Procedure:
6-(1,1-Difluoro-propyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (0.245 g, 0.75 mmol) was dissolved in 5M aqueous HCl and MeOH (1:1, 10 mL) and the reaction was stirred at room temperature for 18 h. The solvent was removed in vacuo, to give the title compound (0.178 g) MS: [M+H]+=227.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].Cl[CH2:8][C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=2[Cl:22])[N:12]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:10]=1>C(OCC)(=O)C>[C:23]([C:11]1[N:10]=[C:9]([CH2:8][O:4][CH2:1][CH:2]=[CH2:3])[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=2[Cl:22])[N:12]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(CCl)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=CCOCc1nc(C(C)(C)C)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To 20 ml of allyl alcohol, 0.4 g (0.008 mol) of 50% sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. Then, 2.8 g (0.008 mol) of 5-chloromethyl-3-(tert-butyl)-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole was gradually added thereto under stirring at room temperature. After completion of the dropwise addition, the solution was heated and stirred under reflux for 2 hours. Then, 50 ml of ethyl acetate was added thereto, and the mixture was washed with water. The organic layer was dried, and the solvent was distilled off. The oily substance thereby obtained was purified by silica gel column chromatography to obtain 1.8 g (yield: 60.0%) of the desired compound as pale yellow prismatic crystals. Melting point: 34°-37° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[N:4]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[C:3](=[O:15])[N:4]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccn(C2CCC(=O)CC2)c1=O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1cccn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 3-methyl-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:2][C:3]([CH3:4])=[O:5])=[CH:10][CH:9]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCC(C)=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A solution of chloroacetone (3.7 g) and potassium iodide (65 mg) in acetone (7 mL) was stirred at approximately 25° C. overnight. In a second reactor, 6-methoxypyridin-3-ol (4.0 g, mmol) and potassium carbonate (1.3 g, 10 mmol) in acetone (5 mL) was refluxed for 15 min., then ¼ of chloroacetone/KI solution was added followed by additional potassium carbonate (1.3 g). This was repeated three times more, then the reaction stirred at approximately 25° C. overnight. The mixture was concentrated in vacuo. The residue was dissolved in Et2O and washed with H2O, brine and dried with Na2SO4. The solution was filtered and concentrated in vacuo yielding 3.5 g of clear oil that was used without further purification. This material darkened on standing over time.