Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[CH2:10][C:11]#[N:12].Cl[C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]#[C:28][CH3:29])[N:22]=[CH:21][N:20]=1.[Cl-].[NH4+]>O1CCCC1>[C:11]([CH:10]([C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]#[C:28][CH3:29])[N:22]=[CH:21][N:20]=1)[C:9]1[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:8]=1[Cl:7])#[N:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: N#CCc1c(F)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(C(C#N)c2c(F)cccc2Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
In 5 ml of tetrahydrofuran was suspended 0.46 g of potassium t-butoxide, to which 0.56 g of 2-chloro-6-fluorobenzylcyanide of formula and 0.5 g of 4-chloro-6-(2-butynyloxy)pyrimidine were added, followed by stirring at room temperature 8 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.25 g of 4-(α-cyano-2-chloro-6-fluorobenzyl)-6-(2-butynyloxy)pyrimidine (the present compound (84)).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].C(N)C.[F:31]C1C=CC(N2C3C=CC=C(NCC4(C(F)(F)F)CO4)C=3C=N2)=CC=1>>[CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][C:25]([F:31])=[CH:24][CH:23]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: Fc1ccc(-n2ncc3c(NCC4(C(F)(F)F)CO4)cccc32)cc1
Agent: CCN
Product: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 15 from ethylamine (2M in tetrahydrofuran) and 1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-indazol-4-amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[C:9]2=[O:37])=[CH:4][CH:3]=1.[CH:38]([N-]C(C)C)(C)C.[Li+].CI.C(O)=O.N.O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[N:12]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)[C:9]2=[O:37])=[CH:4][CH:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1C(c2ccc(Br)cc2)N(CCN2CCOCC2)C(c2ccccc2)N1c1ccc(C(F)(F)F)cc1
Agent: N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(c2ccc(Br)cc2)C(=O)N(c2ccc(C(F)(F)F)cc2)C(c2ccccc2)N1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 5-(4-bromo-phenyl)-1-(2-morpholin-4-yl-ethyl)-2-phenyl-3-(4-trifluoromethyl-phenyl)-imidazolidin-4-one (2.30 g, 4.00 mmol) in anhydrous THF (40 mL) at −78 degrees Celcius was added lithium diisopropylamide (5.3 mL, 1.5M solution of LDA in cyclohexane) and this stirred for 1 h. Methyl iodide (1.13 g, 8.00 mmol) was then added at −78 degrees Celcius and the reaction allowed to warm to room temperature over 2 hours. The reaction was then quenched with 2 equivalents of formic acid followed by NH3.H2O to basify the solution, diluted with ethyl acetate, washed with water and brine, and then dried over Na2SO4. After filtering and concentrating in vacuo, the crude product was purified by flash column chromatography eluting with ethyl acetate:petroleum ether gradient (10%-50%) to afford the product as a pale yellow solid (1.0 g, 43%).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:39]([CH3:40])=[CH:38][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[N:33]([CH3:37])[N:32]=[CH:31]5)[CH:23]=3)[S:21][C:17]=2[C:16]=1Br)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC1(C)C(C)(C)OB([C:50]2[CH:59]=[CH:58][C:53]3[O:54][CH:55]([CH3:57])[O:56][C:52]=3[CH:51]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:39]([CH3:40])=[CH:38][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[N:33]([CH3:37])[N:32]=[CH:31]5)[CH:23]=3)[S:21][C:17]=2[C:16]=1[C:50]1[CH:59]=[CH:58][C:53]2[O:54][CH:55]([CH3:57])[O:56][C:52]=2[CH:51]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: CC1Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2O1
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: [K+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc3c(c2)OC(C)O3)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 110 °C

Procedure:
To a solution of (S)-2-(7-bromo-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (16 mg, 0.025 mmol) and 4,4,5,5-tetramethyl-2-(2-methylbenzo[d][1,3]dioxol-5-yl)-1,3,2-dioxaborolane (13 mg, 0.050 mmol) in 1,4-dioxane was added Pd(PPh3)4 (4 mg, 3.1×10−3 mmol) and 2M K2CO3 (66 μL, 0.133 mmol). The reaction was degassed for 5 minutes with N2 and then heated to 110° C. for 1 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C41H44N3O5S: 690.30; found: 690.4.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[F:40][C:41]([F:45])([F:44])[CH2:42][O-:43].[Na+]>>[Cl:36][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=1)[C@:17]1([C@H:16]([OH:37])[C@@H:15]([OH:38])[C@H:14]([OH:39])[C@@H:13]([CH2:12][O:43][CH2:42][C:41]([F:45])([F:44])[F:40])[O:18]1)[O:19][CH2:20]2
Reactant: [O-]CC(F)(F)F
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: [Na+]
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COCC(F)(F)F)[C@@H](O)[C@H](O)[C@H]2O)cc1

Procedure:
To ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (14 mg, 0.024 mmol) was added 1 mL of freshly prepared sodium trifluoroethoxide solution (1.5 M). After refluxing for 5 h at temperature, the reaction was quenched with 2 mL of water. The organic solvent was distilled off and the water layer was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over Na2SO4. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 6 mg of title compound. 1H NMR (CD3OD, 300 MHz) δ 7.36 (s, 1H), 7.19 (s, 1H), 7.09 (s, 4H), 5.12 (d, J=13.2 Hz, 1H), 5.07 (d, J=13.2 Hz, 1H), 4.11 (d, J=15.5 Hz, 1H), 4.05 (d, J=15.5 Hz, 1H), 3.89-3.66 (m, 7H), 3.48 (t, J=9.2 Hz, 1H), 2.59 (q, J=7.8 Hz, 2H), 1.19 (t, J=7.8 Hz, 3H); MS ESI (m/z) 503 (M+1)+, calc. 502.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:10]([C:27]#[C:28][C:29]2[CH:30]=[C:31]([CH:44]=[CH:45][CH:46]=2)[O:32][CH2:33][CH2:34][CH2:35][NH:36]C(=O)OC(C)(C)C)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:13][N:14]=1>C(Cl)Cl>[NH2:36][CH2:35][CH2:34][CH2:33][O:32][C:31]1[CH:30]=[C:29]([C:28]#[C:27][C:10]2[C:9]([NH2:8])=[N:14][CH:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH:24]([CH3:25])[CH3:26])(=[O:23])=[O:22])=[CH:19][CH:20]=3)[N:11]=2)[CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(OCCCNC(=O)OC(C)(C)C)c3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(OCCCN)c3)n2)cc1
Reaction time: 6 h
Yield: 37 %

Procedure:
TFA (1 mL) was added to a stirred solution of tert-Butyl (3-(3-((3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)ethynyl)phenoxy)propyl)carbamate (crude residue used directly from Step 1) in DCM (5 mL) at ambient temperature. The reaction was allowed to stir at this temperature for 6 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The reaction mixture was passed through a 5 g SCX-2 cartridge and washed with MeOH. The product was eluted by washing the cartridge with 2M NH3 in MeOH. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the mono-TFA salt of the title compound as a yellow solid (24 mg, 37% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 2.00-2.06 (m, 2H), 2.97-3.02 (m, 2H), 3.46 (sept, 1H), 4.13 (t, 2H), 7.05-7.08 (m, 1H), 7.17 (s, 2H), 7.39-7.41 (m, 3H), 7.71 (s, 3H), 7.91 (d, 2H), 8.23 (d, 2H) and 8.77 (s, 1H) ppm; MS (ES+) 451.2.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]=[C:13]=S)=[CH:4][CH:3]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].N=C=N.O>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[NH:22][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]=2)=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Br)c2ccccc12
Reactant: Nc1ccccc1N
Agent: N=C=N
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc(Nc2nc3ccccc3[nH]2)c2ccccc12

Procedure:
A slurry of 1-bromo-4-isothiocyanatonaphthalene (1.0 g, 3.8 mmol), o-phenylene diamine (0.45 g, 4.2 mmol), and polymer-supported carbodiimide (9.0 g, 11 mmol, 1.27 mmol/g) in 72 mL THF was heated to 70° C. with a water-cooled reflux condenser for 3 h. The reaction was filtered, rinsing with dichloromethane. The solution was concentrated to a yellow solid, suspended in dichloromethane, and filtered, rinsing with a small quantity of diethyl ether to give N-(4-bromonaphthalen-1-yl)-1H-benzo[d]imidazol-2-amine as a white solid. MS m/z=338 [M+1]+. Calc'd for C17H12BrN3: 337
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH:18]=3)=[CH:9][N:8]=2)[CH2:4]1.Cl.O1CCOCC1>[C].[Pd].CCO>[CH3:1][O:2][CH:3]1[CH2:4][N:5]([C:7]2[N:8]=[CH:9][C:10]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[CH:11][N:12]=2)[CH2:6]1
Reactant: COC1CN(c2ncc(C3=CCN(C(=O)OC(C)(C)C)CC3)cn2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COC1CN(c2ncc(C3CCNCC3)cn2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.3 %

Procedure:
tert-Butyl 4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate (483 mg) was mixed with EtOH (5 ml), and 10% palladium carbon (100 mg) was added thereto, followed by stirring at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (5 ml), and 4M hydrogen chloride/dioxane (3.5 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then mixed with EtOH (5 ml), and potassium carbonate (2.0 g) was added thereto, followed by stirring at 80° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 2-(3-methoxyazetidin-1-yl)-5-(piperidin-4-yl)pyrimidine (143 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:13]#[N:14])[CH2:11][C:10](=[O:12])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:13]#[N:14])[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2cccc(Br)c2)CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#CC1(c2cccc(Br)c2)CC(O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
1-(3-Bromophenyl)-3-oxocyclobutanecarbonitrile (2.00 g, 8.00 mmol) was dissolved in DCM (15 mL) and MeOH (15.00 mL), and the mixture was cooled to 0° C. Sodium borohydride (0.333 g, 8.80 mmol) was added to the reaction mixture, and stirring was continued at 0° C. for 1.5 hours. The reaction mixture was quenched with water at 0° C. then warmed to RT. DCM was added, and the mixture was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum to afford 2.02 g of 1-(3-bromophenyl)-3-hydroxycyclobutanecarbonitrile (2.02 g, 8.01 mmol, 100% yield) as a pale yellow oil. Mass cal'd: 250.99; MS (ESI pos. ion) m/z: 252.0 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12]3[C:14]([OH:21])=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:11]=3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].O=S(Cl)Cl.[CH3:26]O>>[CH3:26][O:19][C:18]([C:17]1[C:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[NH:13][C:12]=2[C:14]([OH:21])=[CH:15][CH:16]=1)=[O:20]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)c(Cl)c3)nc12
Temperature: 25 °C
Yield: 81 %

Procedure:
2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (800 mg, 2.64 mmol) obtained in step 3 was dissolved in methanol, SOCl2 (1.93 ml, 26.41 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (690 mg, 2.15 mmol) in a yield of 81%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([CH2:22][C:23]3[CH:24]=[N:25][C:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:28]=3)([C:18]([O:20][CH3:21])=[O:19])[C:14]([O:16][CH3:17])=[O:15])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C(#N)C.CN(C)C1C=CN=CC=1>[C:33]([O:32][C:30]([NH:29][C:26]1[N:25]=[CH:24][C:23]([CH2:22][C:13]([C:11]2[N:10]=[CH:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:44]([NH:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:45])=[CH:7][CH:6]=3)[CH:12]=2)([C:14]([O:16][CH3:17])=[O:15])[C:18]([O:20][CH3:21])=[O:19])=[CH:28][CH:27]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(-c2ccc(N)cc2)cn1
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1cn(-c2ccc(NC(=O)Nc3ccccc3)cc2)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
50 mg (0.10 mmol) of the compound from example 12f were dissolved in 10 ml of acetonitrile. The resulting solution was cooled to 0° C., and 14 mg (0.12 mmol, 13.2 μl) of phenyl isocyanate and 20 mg (0.20 mmol, 28 μl) of triethylamine were added. The mixture was warmed to RT, and a spatula tip of 4-dimethylaminopyridine was added. The reaction mixture was left to stand overnight and then evaporated, and the residue was chromatographed on silica gel. 47 mg of the title compound were obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([Cl:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:2][C:3]2[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=2)[CH2:6][NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:26]([Cl:30])=[CH:25][N:24]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(Nc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of N-(3-aminobenzyl)-3-nitrobenzamide hydrochloride (0.70 g, 2.3 mmol) and 2,4,5-trichloropyrimidine (0.237 mL, 2.07 mmol) in DMF (5.5 mL) was added potassium carbonate (1.0 g, 7.2 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give 1.25 grams of crude material, which was triturated with MeOH/EtOAc to give the desired product as an off-white powder (665 mg, 77%). LCMS for C18H13Cl2N5O3 (M+H)+: m/z=418.0, 420.0, 422.0. 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 9.49 (t, J=2.0 Hz, 1H), 8.74 (t, J=2.0 Hz, 1H), 8.36 (m, 3H), 7.78 (t, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.15 (d, J=8.0, 1H), 4.52 (d, J=6.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH2:26])[CH:20]=[CH:19]2.[S:27]1[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:32]([C:29]1[CH:30]=[CH:31][S:27][CH:28]=1)=[O:33])[CH:20]=[CH:19]2
Reactant: O=C(O)c1ccsc1
Reactant: COc1cc2nccc(Cc3ccc4cc(N)ccc4c3)c2cc1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Cc3ccc4cc(NC(=O)c5ccsc5)ccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(6,7-dimethoxy-quinolin-4-ylmethyl)-naphthalen-2-ylamine (Step g, 36 mg, 0.10 mmol) and 3-thiophenecarboxylic acid (15 mg, 0.115 mmol) in CH2Cl2 (1 mL), was added PyBop (163 mg, 0.314 mmol) and Et3N (44 μL, 0.314 mmol). The mixture was stirred at RT overnight. The solvent was evaporated and the crude material was purified by Prep-TLC with EtOAc/CH2Cl2 (3:2) to give the desired product. MS (ESI, pos. ion) m/z: 455.1 (M+1). Calc'd for C27H22N2O3S: 454.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH:14]=O)[C:7]=2[N:16]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:17]3[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]3)[C:7]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
[6-(Methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]acetaldehyde (0.250 g, 1.14 mmol) was combined with 1,1-dimethylethyl 4-piperidinylcarbamate (0.229 g, 1.14 mmol) in a 1:1 MeOH/DCM solution. Excess Na2SO4 was added as a drying agent and the solution was stirred at ambient temperature overnight. NaBH(OAc)3 (0.724 g, 3.42 mmol) was added and the reaction was stirred an additional 2 h. The solution was concentrated onto silica gel under vacuum and the crude residue purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired compound (0.271 g, 59%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12](OC3N(C)N=C(C(F)(F)F)C=3)[CH:13]=2)=[CH:5][C:4]([C:25]([F:28])([F:27])[F:26])=[N:3]1.[CH3:29][NH2:30]>O1CCCC1>[CH3:29][NH:30][C:12]1[CH:13]=[C:8]([O:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:25]([F:26])([F:27])[F:28])[CH:5]=2)[N:9]=[N:10][CH:11]=1
Reactant: CN
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Solvent: C1CCOC1
Product: CNc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 55 %

Procedure:
3,5-Bis[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (Compound No. 11, 1.50 g, 0.004 moles) and methylamine (3.1 mL of a 40% aqueous solution, 0.04 mole) were refluxed under N2 in tetrahydrofuran (100 mL) for 24 h. The mixture was then partitioned between ethyl acetate and water. The organic layer was dried (MgSO4), filtered and evaporated to give a crude solid which was purified by silica gel chromatography. N-Methyl-6-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]-4-pyridazinamine (0.6 g, 55% yield) was obtained as a light brown solid which was recrystallized from ethyl acetate/cyclohexane.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[N:9]1([S:14]([N:17]2[CH:21]=[CH:20][NH+:19](C)[CH2:18]2)(=[O:16])=[O:15])[CH:13]=[CH:12]N=[CH:10]1.N1CC[O:26][CH2:25]C1>C(#N)C>[N:17]1([S:14]([N:9]2[CH2:13][CH2:12][O:26][CH2:25][CH2:10]2)(=[O:16])=[O:15])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: C1COCCN1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: O=S(=O)(N1CCOCC1)n1ccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
3-(1H-Imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate (1.5 g, 3.0 mmol) was dissolved in acetonitrile (15 mL) and treated with morpholine (0.30 mL, 4.0 mmol) and stirred for 16 h at ambient temperature. The solvent was removed and the residue subjected to column chromatography (silica gel, heptane, ethyl acetate 1:1, 0:1) to yield 4-(imidazole-1-sulfonyl)-morpholine (0.62 g, 83%) as a white solid; MS: m/e=218.5 (M+H+).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[C:13]([NH:23][C@H:24]2[CH2:26][C@@H:25]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:14][CH:15]=[C:16]([CH:22]=1)[C:17](OCC)=[O:18].CO.C([O-])(=O)C(C(C([O-])=O)O)O.[K+].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:11][C:12]1[CH:22]=[C:16]([CH2:17][OH:18])[CH:15]=[N:14][C:13]=1[NH:23][C@H:24]1[CH2:26][C@@H:25]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1cnc(N[C@H]2C[C@@H]2c2ccccc2)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: OCc1cnc(N[C@H]2C[C@@H]2c2ccccc2)c(Cl)c1
Temperature: 0 °C
Yield: 94 %

Procedure:
A diisobutylaluminium hydride in toluene solution (4.6 mL) was dropwise added to a solution of ethyl 5-chloro-6-{[(1S,2R)-2-phenylcyclopropyl]amino}nicotinate (488 mg) in tetrahydrofuran (15 mL) with stirring at 0° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 0° C. for 1 hour. A methanol (1 mL) was added to a reaction mixture at 0° C. and allowed to warm to room temperature. Tetrahydrofuran (20 mL) and saturated sodium potassium tartarate aqueous solution (5 mL) was added and the resultant mixture was stirred at ambient temperature for 1 hour. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2:1 v/v) to give (5-chloro-6-{[(1S,2R)-2-phenylcyclopropyl]amino}-3-pyridinyl)methanol (398 mg).