Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COc1c(N)ccc2c1CCCC(N1CCOCC1)C2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1c(Nc2ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n2)ccc2c1CCCC(N1CCOCC1)C2

Procedure:
The title compound was prepared from 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (149 mg, 0.54 mmol) and N-[(1R,2R)-2-(2,5-dichloropyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (204 mg, 0.60 mmol) in an analogous manner to Example 946 to afford a white foam (227 mg, 73%). Mp: 110-12° C. LCMS (m/e) 579 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.96 (m, 2H), 7.31 (d, J=9 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 5.47-5.27 (m, 2H), 3.91 (m, 1H), 3.73 (m, 7H), 3.26 (m, 2H), 2.88 (m, 2H), 2.81 (s, 3H), 2.70 (m, 2H), 2.60 (m, 2H), 2.39 (m, 2H), 2.23 (m, 2H), 2.15 (m, 2H), 1.85 (m, 3H), 1.63 (br s, 1H), 1.42 (m, 4H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32](=[O:38])[CH2:33][CH2:34][S:35]([O-:37])=[O:36].[Na+]>CS(C)=O.[Cu]I>[CH3:30][O:31][C:32](=[O:38])[CH2:33][CH2:34][S:35]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:6][N:7]=1)(=[O:37])=[O:36]
Reactant: COC(=O)CCS(=O)[O-]
Reactant: O=C(NC1(c2ccc(Br)nc2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCS(=O)(=O)c1ccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)cn1
Temperature: 110 °C

Procedure:
A solution of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-amide (0.250 g, 0.553 mmol), sodium 3-methoxy-3-oxopropane-1-sulfinate (289 mg, 1.66 mmol) and copper (I) iodide (316 mg, 1.66 mmol) in DMSO (2 mL) is placed in a microwave tube and evacuated and purged with argon three times. The reaction mixture is heated in a microwave at 110° C. for 2 hours, diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride (4×100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. The resulting residue is purified by silica gel chromatography eluting with a gradient of 50-100% ethyl acetate in heptane to afford the title compound as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[C:28]([F:31])([F:30])[F:29])[C:4]=1[C:32]([O:34]CC)=O.[CH3:37][NH:38][NH2:39]>O1CCOCC1>[CH3:37][N:38]1[CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[C:7](=[O:19])[NH:6][CH:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[C:28]([F:29])([F:31])[F:30])[C:4]=2[C:32](=[O:34])[NH:39]1
Reactant: CNN
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1C(F)(F)F
Solvent: C1COCCO1
Product: CN1CC2=C(C(=O)N1)C(c1ccc(C#N)cc1C(F)(F)F)NC(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, ethyl 6-(bromomethyl)-4-[4-cyano-2-(trifluoro-methyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (576 mg, 1 mmol; Example 21A) was initially charged in dioxane (20 ml). Methylhydrazine (128 mg, 3 mmol) was added dropwise to the reaction mixture, and the mixture was then stirred at boiling point for 8 h (bath temperature 120° C.). The reaction mixture was then concentrated, and the residue was purified by preparative HPLC (column: Gromsil C18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the target compound as a solid which was reprecipitated from acetonitrile/water (Yield: 205 mg, 41% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.Br[CH2:31][CH2:32][C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH2:31][CH2:32][C:33]([NH2:35])=[O:34])[CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(S(C)(=O)=O)cc1
Reactant: NC(=O)CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CCC(N)=O)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 161, step 1, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)pyridin-2(1H)-one (example 339, step 2) was reacted with 3-bromopropanamide in the presence of potassium carbonate and a catalytic amount of tetrabutylammonium iodide to give the title compound as a light yellow solid, MS (ESI−): m/z=499.1 [M−H]−.
Reaction SMILES: [CH3:1]COCC.[Li]C.[Br:8][C:9]1[CH:20]=[CH:19][C:12]([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1>C1COCC1.[Cu]I>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([CH3:1])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1
Reactant: CCOCC
Reactant: COC(=O)C=Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: [Li]C
Solvent: C1CCOC1
Product: COC(=O)CC(C)c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
A flask under nitrogen atmosphere was charged with CuI (2.77 g, 14.54 mmol) and ether (50 mL). The slurry was cooled to 0 C in an ice-water bath before a solution of MeLi in THF (1.6M, 18.2 mL, 29.1 mmol) was added dropwise over 20 minutes. A clear solution formed. A solution of methyl 4-bromocinnamate (3.19 g, 13.2 mmol) in THF (30 mL) was added dropwise via syringe over 30 minutes, and the resulting reaction mixture was stirred at 0 C for 2 hours. Then the reaction was quenched with ammonium chloride and worked up. The resulting crude product was purified by MPLC (0 to 15% ethyl acetate in hexanes) to afford methyl 3-(4-bromophenyl)butanoate.
Reaction SMILES: [CH3:1][C:2]([NH:45]C(=O)OC(C)(C)C)([CH2:36][O:37][Si](C)(C)C(C)(C)C)[C:3](=[O:35])[NH:4][C@@H:5]([C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C:19]2([C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH:20]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18]1)=[O:16])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC.O>C(Cl)Cl.Cl>[NH2:45][C@@:2]([CH3:1])([CH2:36][OH:37])[C:3]([NH:4][C@H:5]([CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C:19]2([C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH:20]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18]1)=[O:16])=[O:35]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)C2)C1=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)[C@@](C)(N)CO)C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising tert-butyl (4R)-7,10,10,11,11-pentamethyl-4-(2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decane-7-carbonyl)-6-oxo-1-phenyl-2,9-dioxa-5-aza-10-siladodecan-7-ylcarbamate (150 mg, 0.204 mmol) in DCM (5 mL) and 2M HCl in Et2O (3.05 ml, 6.11 mmol) was treated with water (0.3 mL) dropwise at room temperature. The resulting colourless solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The resulting crude was dried in the vacuum oven at RT for 3 days to afford the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:15])[CH2:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9].[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][CH:7]([C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH3:17]
Reactant: O=C(CC(=O)c1cccs1)c1cccs1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C(=O)c1cccs1)C(=O)c1cccs1

Procedure:
Following a procedure analogous to that described in Example (2b), 1,3-di-(2-thienyl)-1,3-propanedione was alkylated by reaction with bromoacetic acid ethyl ester to form 3,3-di-(2-thienoyl)-propionic acid ethyl ester, which was reacted with phenylhydrazine in accordance with a procedure analogous to that set out in Example (2c) to form 1-phenyl-3,5-di-(2-thienyl)-pyrazol-4-acetic acid ethyl ester. This substance was saponified by a procedure analogous to that described in Example (1b). 1-Phenyl-3,5-di-(2-thienyl)-pyrazol-4-acetic acid, melting at 216°-218° C., was obtained in a yield of 56% based on the propanedione starting material.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:16])[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]([CH3:15])=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:16])=[O:5])[CH:21]=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1[nH]c2ccccc2c1C
Reactant: OB(O)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 12.5 %

Procedure:
Activated molecular sieves (18 g) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with N-methoxy-N,3-dimethyl-1H-indole-2-carboxamide (1.5 g, 6.9 mmol), (3-fluorophenyl)boronic acid (2.9 g, 21 mmol), cupric acetate (1.9 g, 10 mmol), methylene chloride (130 mL) and pyridine (2.2 mL, 27 mmol). The reaction mixture was stirred at room temperature for 2 days. The mixture was filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-30% EtOAc/hexane) to give the desired product (0.27 g, 12%). LCMS calculated for C18H18FN2O2(M+H)+: m/z=313.1. Found: 313.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35].O.CCOCC>CN1CCCC1=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NC(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (800 mg, 1.8 mmol) in 1-methyl-2-pyrrolidinone (8 mL) was added serinol (819 mg, 9 mmol, 5 eq) and the reaction mixture was heated to 50°. After 1 h, H2O (20 mL) was added, followed by Et2O (20 mL) and EtOAc (20 mL). The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and the solvent was evaporated. The yellow residue was then purified by Flash chromatography to afford 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (750 mg, 92% yield). 1H-NMR (CDCl3) δ 2.30 (s, 3H), 3.67 (m, 1H), 3.88 (m, 4H), 6.30 (br s, 1H), 6.41 (d, 1H, J=9.6 Hz), 7.08 (m, 4H), 7.24 (m, 1H), 7.31 (d, 1H, J=9.6 Hz), 7.49 (m, 1H). LC MS (m/e)=457 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]CC)=O)=[N:6][N:5]=[CH:4][NH:3]1.[NH3:13]>C(O)C>[O:1]=[C:2]1[C:7]([C:8]([NH2:13])=[O:10])=[N:6][N:5]=[CH:4][NH:3]1
Reactant: CCOC(=O)c1nnc[nH]c1=O
Reactant: N
Solvent: CCO
Product: NC(=O)c1nnc[nH]c1=O
Reaction time: 0.33 h

Procedure:
In 5 mL of ethanol is dissolved 0.06 g of ethyl 5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylate. At 10° C., the solution is saturated with ammonia by introducing gaseous ammonia thereinto for 20 minutes. The solution is allowed to stand at ambient temperature for 15 hours, and the resulting crystals are collected by filtration. The crystals thus obtained are washed successively with two 2 mL portions of ethanol and then two 1 mL portion of methanol to obtain 0.03 g of 5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N+:6]([O-:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH2:10][C:11]2[C:12]([Cl:18])=[CH:13][CH:14]=[CH:15][C:16]=2[Cl:17])=[O:27])=[N+:6]([O-:8])[CH:7]=1
Reactant: [O-][n+]1cc(Cl)ccc1SCc1c(Cl)cccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(Cc1c(Cl)cccc1Cl)c1ccc(Cl)c[n+]1[O-]
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
3.2 g of 5-chloro-2-(2,6-dichlorobenzylthio)pyridine-N-oxide was dissolved in 50 ml of chloroform, and a solution of 2.5 g of metachloroperbenzoic acid (content: 70%) dissolved in 30 ml of chloroform was added dropwise thereto at 5° to 10° C. over 10 minutes. The mixture was stirred at 5° to 10° C. for an additional 2 hours. The resulting mixture was washed twice with potassium carbonate solution and dried over magnesium sulfate. The chloroform was evaporated and the residue was recyrstallized from 1:1 benzene-hexane to obtain 3.2 g of 5-chloro-2-(2,6-dichlorobenzylsulfinyl)pyridine-N-oxide (Compound (1)). Yield, 95%. M.P., 176.5°-177.5° C.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([N:27]=[N+:28]=[N-:29])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O.[CH:32]1[C:44]2[CH:43]([CH2:45][O:46][C:47]([NH:49][C@@H:50]([CH2:58][SH:59])[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[N:27]([C@H:8]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][S:59][CH2:58][C@@H:50]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:49][C:47](=[O:48])[O:46][CH2:45][CH:43]1[C:44]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N+:28]=[N-:29]
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCCCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)N=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-azido-3-(hexadecyloxy)propyl trifluoromethanesulfonate (1 eq), (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-mercaptopropanoate (8, 2 eq) and K2CO3 (1 eq) in EtOH (0.1 M) was stirred for 30 min at 60° C. The reaction mixture was filtered and washed with DCM. The filtrate was concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% EtOAc/Hex to give (5R,9R)-tert-butyl 9-azido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(Cl)Cl.CO.[OH2:36].[OH2:37].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>[O-]S([O-])(=S)=O.[Na+].[Na+].O>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:25][CH2:26][S:27](=[O:37])(=[O:36])[CH2:28][CH2:29]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCSCC3)s2)c1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=S([O-])([O-])=S
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCS(=O)(=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]tetrahydro-2H-thiopyran-4-ol (Step 1, Example 132, 300 mg, 0.663 mmol) was taken up in a 2:1 v/v CH2Cl2/MeOH mixture (6 mL) and magnesium monoperoxyphthalate hexahydrate (615 mg, 0.994 mmol) was added. The reaction was stirred at room temperature for 2 h, diluted with aqueous 10% Na2S2O3 and water and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Column chromatography on silica (gradient elution, 0 to 75% EtOAc in hexanes) afforded 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]tetrahydro-2H-thiopyran-4-ol 1,1-dioxide (0.216 g, 0.446 mmol, 67% yield) as a yellow solid. MS ESI: [M+H]+ m/z 485.0.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:19][NH2:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:19][NH:20][CH2:15][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNCC1(c2ccc(C(F)(F)F)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
General Procedure H2 - Reductive Amination: A mixture of 1-(4-(trifluoromethyl)phenyl)cyclohexanecarbaldehyde (256 mg, 1.0 mmol) and methylamine (2.0 M in THF, 3 ml, 6.0 mmol) in 1,2-dichloroethane was stirred at room temperature for 30 min and was then treated with sodium triacetoxyborohydride (297 mg, 1.4 mmol). The reaction mixture was stirred at room temperature overnight and was then quenched with aqueous saturated NaHCO3 solution (10 ml). The product was extracted with EtOAc (3 ×10 ml). The combined organic layers were dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel column chromatography (MeOH/CH2Cl2, MeOH from 0% to 20%) to give N-methyl-1-(1-(4-(trifluoromethyl)phenyl)cyclohexyl)methanamine (178 mg, 66%). 1H NMR (CDCl3): δ 1.26-1.52 (m 4H), 1.54-1.61 (m, 2H), 1.66-1.73 (m, 2H), 2.13-2.18 (m, 2H), 2.28 (s, 3H), 2.63 (s, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H). 13C NMR (CDCl3) δ 22.3, 26.7, 34.7, 37.5, 42.9, 64.5, 125.4, 125.9, 127.6, 128.3, 150.2.ESI MS m/z 271.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:33]([CH2:34][CH3:35])[CH2:31][CH3:32])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)Cc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
100 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 54 μl of diethylamine and 15 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 170 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[O:27]CCBr)[C:17]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([CH2:17][CH2:16][O:23][C:24]3[CH:33]=[CH:32][CH:31]=[C:26]([OH:27])[CH:25]=3)[CH2:12][CH2:13]2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: BrCCOc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1cccc(OCCN2CCC(Cc3ccc(F)cc3)CC2)c1

Procedure:
The title compound was prepared from 4-(4-fluorobenzyl)piperidine hydrochloride (298 mg, 1.30 mmol), 2-(3-benzyloxyphenoxy)ethyl bromide (399 mg, 1.3 mmol) and potassium carbonate (449 mg, 3.2 mmol) in two steps as white-off solid (250 mg): mp 145-147° C. 1H NMR (CD3OD) 1.529 (m, 2 H), 1.821 (d, J=12.9 Hz, 2 H), 2.551 (d, J=6.3 Hz, 2 H), 3.003 (m, 2 H), 3.468 (m, 2 H), 3.541 (m, 2 H), 4.243 (t, J=5.4 Hz, 2 H), 6.369-6.422 (m, 3 H), 6.924-7.034 (m, 3 H), 7.120-7.167 (m, 2 H).
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12]([C:14]([C:16]3[C:17]([NH2:23])=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=3)=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:24][C:25]([F:31])([F:30])[CH2:26][C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.N=C=N>ClCCl>[NH2:23][C:17]1[N:18]=[CH:19][C:20]([Br:22])=[CH:21][C:16]=1[C:14]([C:12]1[N:13]=[C:8]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([C:27](=[O:28])[CH2:26][C:25]([F:31])([F:30])[F:24])[CH2:3][CH2:2]2)[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: O=C(O)CC(F)(F)F
Reactant: Nc1ncc(Br)cc1C(=O)c1cccc(N2CCCNCC2)n1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ncc(Br)cc1C(=O)c1cccc(N2CCCN(C(=O)CC(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
(6-(1,4-diazepan-1-yl)pyridin-2-yl)(2-amino-5-bromopyridin-3-yl)methanone (650 mg, 1.36 mmol) was added to a stirred suspension of 3,3,3-trifluoropropionic acid (0.13 ml, 1.50 mmol), 1-hydroxybenzotriazole (184 mg, 1.36 mmol), triethylamine (1.33 ml, 9.52 mmol) and PS-carbodiimide (2.08 g, 2.72 mmol) in dichloromethane (20 ml). The resulting mixture was stirred at room temperature for 18 hours. The crude mixture was filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion|, 40 g column, 0-50% EtOAc/Petroleum ether) to afford the title compound as an orange solid (355 mg, 54% yield).