Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[CH:14]1([CH2:17][NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:16]C1>CN(C=O)C>[CH:17]1([NH:18][C:19]([C:20]2[CH:21]=[C:22]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[N:9]=4)=[CH:4][CH:3]=3)[C:23]([CH3:26])=[CH:24][CH:25]=2)=[O:36])[CH2:14][CH2:16]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc(-c2ccc(I)cc2)n1
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)n1

Procedure:
Example 24 was prepared using 5-(4-iodophenyl)-3-methyl-[1,2,4]oxadiazole (Intermediate 12) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 17) using DMF as the solvent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CO.[C:13]([O:17][C:18](=[O:36])[N:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][N:21]=1)([CH3:16])([CH3:15])[CH3:14].[OH-].[K+]>O>[C:13]([O:17][C:18](=[O:36])[N:19]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:5]2[C:4]3[C:8](=[N:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][CH:6]=2)[OH:27])=[CH:22][N:21]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)cn1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C(O)c2c[nH]c3ncc(Br)cc23)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 5-bromo-7-azaindole (44, 198.0 mg, 1.01 mmol) in methanol (30.0 mL, 0.741 mol) were added (4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (43, 355.0 mg, 1.02 mmol) and potassium hydroxide (80.0 mg, 1.42 mmol). The reaction was stirred at room temperature 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 8% methanol in dichloromethane to give compound (45, 200.0 mg, 36.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH:11]([NH2:14])([CH3:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:14][CH:11]([CH3:13])[CH3:12])=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)c1cccc(Br)c1
Reaction time: 24 h

Procedure:
A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (40 mL) was chilled to zero degrees and treated with isopropylamine (0.96 mL, 11.32 mmol). Reaction was allowed to come to room temperature and stir for 24 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to white solids (0.6 g, 66%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)=[CH:16][CH:15]=3)[N:11]=2)=[CH:4][C:3]=1[CH3:28].C(O)(=O)C>[Zn].O>[N:23]1([CH2:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]3[N:11]=[C:7]([C:5]4[S:6][CH:2]=[C:3]([CH3:28])[CH:4]=4)[O:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Cc1cc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)sc1Br
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1csc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)c1
Yield: 81.1 %

Procedure:
A mixture of 2-(5-bromo-4-methyl-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (700 mg), zinc powder (200 mg), acetic acid (5 ml) and water (5 ml) was heated for 4 hours under reflux. The residue was filtered off, the filtrate was concentrated. To the residue was added ethyl acetate, washed with saturated aqueous sodium bicarbonate and water, dried (MgSO4), and concentrated under reduced pressure to give crystals of 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(4-methyl-2-thienyl)oxazole (470 mg, 81%). Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 077-178° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:17]=4[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:29]=1.CCO.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:28]([O:24][C:21]1[CH:22]=[CH:23][C:17]2[CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]4[CH2:7][C:2]([CH3:27])([CH3:1])[NH:3][C:4]([CH3:26])([CH3:25])[CH2:5]4)[N:14]=3)[S:19][C:18]=2[CH:20]=1)[CH3:29]
Reactant: CC1(C)CC(Nc2nccc(-c3cc4ccc(O)cc4s3)n2)CC(C)(C)N1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc2cc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)sc2c1
Temperature: 25 °C

Procedure:
Compound of Example 153 (76 mg, 0.2 mmol), triphenylphosphine (80 mg, 0.3 mmol) and EtOH (30 mg, 0.65 mmol) were suspended in 8 ml of THF, then diethylazodicarboxylate (52 mg, 0.3 mmol) dissolved in 4 ml THF was added dropwise. This mixture was stirred at room temperature over night and afterwards evaporated. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 33 mg (40%).
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:28][S:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1>C(Cl)Cl>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:10][C:33]2[CH:34]=[CH:35][C:30]([S:29][CH3:28])=[CH:31][CH:32]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: CSc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC(C(=O)Oc1ccc(SC)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a flask containing 2-phenylbutyric acid (4.93 g, 30 mmol) in 40 mL of CH2Cl2 at 0° C. was added dicyclohexylcarbodiimide (6.19 g, 30 mmol) in 30 mL of CH2Cl2. Solid 4-methylmercaptophenol (4.21 g, 30 mmol) was added and the suspension stirred at room temperature overnight. The precipitated urea was filtered, the filtrate evaporated and the residue chromatographed on silica gel (CH2Cl2)to give 4-(methylmercapto)phenyl 2-phenylbutyrate (6.23 g, 73%) as a light yellow oil which was crystallized from EtOH to give white crystals (mp 28.0°-28.5° C.). 1H NMR (CDCl3) δ0.98 (t, 3H, J=7.3 Hz), 1.89 (m, 1H), 2.22 (m, 1H), 3.68 (t, 1H, J=7.6 Hz), 6.92 (d, 2H, J=8.6 Hz), 7.22 (d, 2H, J= 8.6 Hz), 7.30-7.45 (m, 5H, ArH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Cl.[CH:29]([N:32]([CH:36](C)C)[CH2:33]CCl)(C)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:33][N:32]([CH3:36])[CH2:29][CH2:30][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[C:5]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12]
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2CCN(C)C
Temperature: 0 °C
Yield: 34.5 %

Procedure:
A solution of Compound 107 (1 g., 2.64 mmol), 2-(diisopropylamino) ethyl chloride hydrochloride (2.64 g, 13.2 mmol), and potassium carbonate (3.64 g, 26.4 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0–10% methanol in ethylacetate gradient to yield 409 mg (30%) of pale yellow solids. M.P. 110–117° C. 1H NMR (DMSO-d6): δ 0.93 (s, 12H), 2.40 (s, 3H), 2.59 (m, 2H), 3.01 (m, 2H), 3.61 (m, 4H), 3.91 (m, 4H), 4.15 (m, 2H), 7.16 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 506 (M+1). Anal. (C28H35N5O2S) C, H, N.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[OH:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:24]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: O[C@@H]1CCNC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CC[C@@H](O)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-pyrrolidin-3-ol (1.2 equiv) to give 176 (16.8 mg, M+1 383.1)
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:28]/[O:29][CH2:30][CH:31]=[CH2:32])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C=C1C2[C@](C)(CCC(=[O:52])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[CH2:30]([O:29]/[N:28]=[C:16]1/[C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:22]([CH2:17]/1)[CH2:21][C:20](=[O:52])[CH2:19][CH2:18]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:2])[CH:31]=[CH2:32]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C=CCO/N=C1\CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Product: C=CCO/N=C1\CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Yield: 76 %

Procedure:
The title compound II-av was prepared in 76% yield from 3,3:17,17-bis(ethylendioxy)-7-(E)-allyloxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 8/2). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 5.98 (1H, m), 5.24 (1H, m), 5.14 (1H, m), 4.48 (2H, m), 2.40-1.10 (20H, m), 1.00 (3H, s), 0.81 (3H, s).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[N:9]([CH2:12][CH3:13])=[C:10]=[S:11].[H-].[Na+]>CN(C=O)C>[CH2:12]([NH:9][C:10]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[S:11])[CH3:13]
Reactant: CC(C)(C)OC(N)=O
Reactant: CCN=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=S)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A solution of tert-butyl carbamate (5.0 g, 42.7 mmol) and isothiocyanatoethane (3.7 mL, 42.7 mmol) in dry DMF (30 mL) was added slowly to a stirred solution of sodium hydride (60% suspension, 1.9 g, 47 mmol) in dry DMF (15 mL) under nitrogen, such that the internal temperature was maintained <5° C. After complete addition the reaction was stirred in an ice bath for 1 h. The cooling bath was removed and the reaction was stirred at RT overnight, and then poured on to ice (25 g) and diluted with water (150 mL). The aqueous mixture was extracted with Et2O (3×100 mL). The combined extracts were washed with brine (1×50 mL), dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 4% to 8% EtOAc in n-hexane) to give the title compound (6.0 g, colourless solid). 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.33 Hz, 3H) 1.50 (s, 9H) 3.54-3.78 (m, 2H) 7.82 (br. s., 1H) 9.63 (br. s., 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:70]([NH2:74])[CH:71]([CH3:73])[CH3:72]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:74][CH2:70][CH:71]([CH3:73])[CH3:72])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NCC(C)C)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and isobutylamine (10.0 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (12.6 mg, 44%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2=[C:11]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:12]=[C:13]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:14]=[C:9]2[C:8]([CH3:30])=[C:7]1[CH3:31].I[CH2:36][CH3:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2=[C:11]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:12]=[C:13]([C:15]3[N:19]([CH2:36][CH3:37])[N:18]=[N:17][N:16]=3)[CH:14]=[C:9]2[C:8]([CH3:30])=[C:7]1[CH3:31]
Reactant: Cc1c(C)n(Cc2cccc(Cl)c2)c2c(N3CCc4ccccc4C3)nc(-c3nnn[nH]3)cc12
Reactant: CCI
Product: CCn1nnnc1-c1cc2c(C)c(C)n(Cc3cccc(Cl)c3)c2c(N2CCc3ccccc3C2)n1
Yield: 34 %

Procedure:
In accordance with the same procedures as in Example 853, except for using 2-[1-(3-chlorobenzyl)-2,3-dimethyl-5-(1H-tetrazol-5-yl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline prepared in Example 852 and iodoethane, the titled compound was obtained as a white solid. (Yield: 34%)
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.FC(F)(F)C([O-])=O.[Br-:19].[K+].BrBr>O>[Br:19][C:10]1[S:9][C:5]2[CH2:6][N:7]([CH3:8])[CH:2]([CH3:1])[CH2:3][C:4]=2[CH:11]=1
Reactant: CC1Cc2ccsc2CN1C
Reactant: [Br-]
Agent: BrBr
Agent: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: O
Product: CC1Cc2cc(Br)sc2CN1C
Temperature: 0 °C

Procedure:
1.0 g (3.6 mmol) 5,6-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (as the trifluoroacetate salt) are dissolved in 60 ml of water and at the temperature of an ice bath combined with a solution of 1.0 g (8.5 mmol) potassium bromide and 182 μl (3.6 mmol) bromine in 20 ml of water. The mixture is stirred for 2.5 hours in the ice bath and then extracted twice with 100 ml ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, then dried on sodium sulphate and evaporated down i. vac. The crude product thus obtained is purified by chromatography on silica gel (eluant DCM/methanol 50:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[N:6]1[C:13](Cl)=[N:12][C:10](Cl)=[N:9][C:7]=1Cl>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:7]1[N:9]=[CH:10][N:12]=[C:13]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:6]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCOc1ncnc(OCCOC)n1
Temperature: 110 °C
Yield: 1608.9 %

Procedure:
In 100 ml of dry toluene containing 10 g of anhydrous sodium carbonate was dissolved 20 g of monomethoxypolyethylene glycol having an average molecular, weight of 4000 (Nippon Oil and Fats) and the solution was heated at 110° C. for 30 minutes. Then, 500 mg of cyanuric chloride was added and the mixture was heated at 110° C. for 24 hours. The reaction residue was filtered off, followed by addition of 300 ml of petroleum ether to cause precipitation. The precipitate was washed with several portions of petroleum ether to recover 10 g of 2,4-bis(O-methoxypolyethylene glycol)-6-chloro-s-triazine (yield 50%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](C(Cl)(Cl)Cl)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH2:16]([O-:19])[CH2:17][CH3:18].[Na+].Cl>C(O)CC>[NH2:1][C:2]1[N:7]=[C:6]([O:19][CH2:16][CH2:17][CH3:18])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: Nc1nc(C(F)(F)F)nc(C(Cl)(Cl)Cl)n1
Reactant: CCC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCO
Product: CCCOc1nc(N)nc(C(F)(F)F)n1
Temperature: 75 °C

Procedure:
20.0 g (71 mmol) of 2-amino-4-trichloromethyl-6-trifluoromethyl-1,3,5-triazine were added at 22° C. to a solution of 0.58 g (7.1 mmol) of sodium propanolate in 40 ml of propanol. The resulting yellow mixture was then heated at 75° C. for 30 minutes, after which a further 0.58 g (7.1 mmol) of sodium propanolate in 10 ml of propanol was added and the mixture was heated at 75° C. for 10 minutes. The reaction mixture was cooled to 20° C. and then neutralized with 2 normal aqueous hydrochloric acid. After this, most of the solvent was removed under reduced pressure, and the residue was slowly diluted with 40 ml of water. The solid which formed was separated off, washed with 5 ml of water and dried at 40° C. under reduced pressure.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]2[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]2)=[N:18]1.O>CS(C)=O>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]2[CH2:31][CH2:30][N:29]([C:2]#[N:1])[CH2:28][CH2:27]2)=[N:18]1
Reactant: CN1CCC(c2nn(-c3ccccc3F)c3ccccc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCC(c2nn(-c3ccccc3F)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 31 %

Procedure:
To a stirred mixture of cyanogen bromide (15.5 g, 0.146 moles) and potassium carbonate (23.7 g, 0.167 moles) in dimethylsulfoxide (DMSO) [300 ml] was added dropwise a solution of 1-(2-fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole, the free base of example 36, (42.0 g, 0.137 moles) in dimethylsulfoxide (40 ml). The reaction temperature rose to 36° C. and the mixture was stirred at ambient temperature for 2.5 days. The reaction mixture was then poured into H2O and the product extracted with ether. The ether was dried (MgSO4) and concentrated which left 40 g of a solid. The product was recrystallized 5 times from isopropyl alcohol which yielded 13.6 g (31%) of 4-[1-(2-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile, m.p. 119°-121° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([N:10]2[CH2:11][CH2:12][S:13][CH2:14][CH2:15]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCSCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCSCC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a stirred solution of 4-(4-nitrobenzoyl)thiomorpholine (1.26 g, 5 mmol) in ethanol (80 mL) and water (20 mL) was added NH4Cl (2.65 g) and heated to 80° C. To this heterogeneous reaction mixture at 80° C. was added iron powder (2.75 g) portion wise manner under a vigorous stirring in nitrogen atmosphere and the stirring was continued for 2 h. The reaction mixture was filtered through a Celite pad when hot and washed the pad with methanol. The filtrate was concentrated, diluted with water, extracted with CH2Cl2 (3×75 mL), dried (Na2SO4), filtered and concentrated. Finally dried under high vacuum to afford 1.11 g (100%) of the 4-(4-aminobenzoyl)thiomorpholine. 1H NMR (CDCl3, 300 MHz): δ 7.21 (d, 2H, J=8.4 Hz), 6.64 (d, 2H, J=8.1 Hz), 3.86 (br s, 6H), 2.64 (t, 4H, J=4.5 Hz); LCMS (m/z): 223 (MH+).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[CH:25][C:26]=1[CH2:27]Cl>O>[CH3:32][O:31][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[O:29][CH3:30])[CH2:27][N:16]([S:13]([C:10]1[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=1)(=[O:15])=[O:14])[CH2:20]2
Reactant: COc1cc(CCl)c(CCl)cc1OC
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
100 ml of an N,N-dimethylformamide solution containing 34.2 g (0.20 mol) of p-toluenesulfonamide, was dropwise added over a period of 60 minutes under cooling with ice to a suspension comprising 19.7 g (0.41 mol) of 50% oily sodium hydride and 60 ml of N,N-dimethylformamide. The reaction solution was stirred at room temperature for 30 minutes at 60° C., and then 300 ml of an N,N-dimethylformamide solution containing 47 g (0.20 mol) of 4,5-bischloromethyl veratrol was dropwise added over a period of 90 minutes at 60° C. The reaction solution was stirred at room temperature for 3 hours, and then poured into 2000 ml of water. The precipitated crystals were collected and washed with water to obtain 60 g (yield: 90.0%) of the above identified compound.
Reaction SMILES: [C:1]([C:9]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]2[CH2:13][CH:14]3[C:19](=[O:20])[N:18]([CH:21]([CH3:23])[CH3:22])[C:17](=[O:24])[N:15]3[CH2:16][C:11]=2[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:33].[Na+].Cl>CO>[C:1]([C:9]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]2[CH2:13][CH:14]([C:19]([OH:20])=[O:33])[N:15]([C:17]([NH:18][CH:21]([CH3:22])[CH3:23])=[O:24])[CH2:16][C:11]=2[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1C(=O)C2Cc3c(nc(C(=O)c4ccccc4)n3Cc3ccccc3)CN2C1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)NC(=O)N1Cc2nc(C(=O)c3ccccc3)n(Cc3ccccc3)c2CC1C(=O)O

Procedure:
A suspension of 0.5 g of the product from Example 269, methanol (50 mL) and 1N sodium hydroxide (10 mL) is heated on a steam bath for 15 min. The resulting solution is cooled in an ice bath and treated with 1N hydrochloric acid (10 mL) to precipitate the product. Filtration and trituration of the damp cake with methanol (2 mL) gives pure product; mp 192°-194° C. (dec).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:6][C:7]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:14]([N:16]3[CH2:19][CH:18]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[CH2:17]3)=[O:15])=[C:8]([CH3:10])[N:9]=2)[CH2:2]1.C=O.[BH3-][C:35]#N.[Na+]>O1CCCC1>[CH3:31][C:30]1[CH:29]=[CH:28][C:13]([C:14]([N:16]2[CH2:17][CH:18]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[CH2:19]2)=[O:15])=[CH:12][C:11]=1[C:7]1[NH:6][C:5]([CH:3]2[CH2:4][N:1]([CH3:35])[CH2:2]2)=[N:9][C:8]=1[CH3:10]
Reactant: [BH3-]C#N
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CNC2)nc1C
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CN(C)C2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(1-(3-(2-(azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 189.2, 50 mg, 0.12 mmol) in tetrahydrofuran (1 mL). Formaldehyde (65 μL, 37% wt, 0.57 mmol) and NaBH3CN (30 mg, 0.48 mmol) were added to the reaction. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was extracted with 3×3 mL of ethyl acetate and the combined organic extracts were washed with 3×1 mL of brine and concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, XBridge Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.03% NH3H2O and MeCN (26.0% MeCN up to 40.0% in 7 min, up to 100.0% in 2 min, down to 26.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 1.8 mg (3%) of the title compound as a white solid. m/z (ES+) 426 (M+H)+.