Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:21])[NH:15][C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14](=[O:21])[NH:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Fc1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)cn2)C1
Yield: 30.9 %

Procedure:
Prepare the title compound by essentially following the procedure as described for Preparation 49, using 5-bromo-2-fluoro-pyridine (6.26 g, 35.61 mmol), and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (6.632 g, 35.61 mmol) to give 3.77 g (30%) of the title compound. LC-MS/ES m/z (81Br) 344.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Nc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2ccncc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (150 mg, 0.29 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.10 mL, 0.57 mmol) and 4-aminopyridine (76 mg, 0.59 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (39 mg, 28% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[N:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:20]([CH2:30][CH2:31][CH3:32])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:33][CH2:34][C:35](Br)=[O:36]>ClCCl>[CH2:1]([O:8][C:9]([C:18]1[N:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:35](=[O:36])[CH2:34][Br:33])[CH2:26][CH2:25]2)=[C:20]([CH2:30][CH2:31][CH3:32])[CH:19]=1)([C:10]([F:11])([F:12])[F:13])[C:14]([F:16])([F:15])[F:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCNCC1
Solvent: ClCCl
Product: CCCc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ncc1N1CCN(C(=O)CBr)CC1
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
1-{6-[2-(Benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-4-propylpyridin-3-yl}piperazine (27 mg, 0.0563 mmol) was dissolved in dichloromethane (1.0 mL). Under ice-cold conditions, N,N′-dimethylaniline (15 μL, 0.118 mmol) and bromoacetylbromide (5.1 μL, 0.0591 mmol) were added, and the mixture was stirred under ice-cold conditions for 20 minutes. The reaction solution was concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone), and the title compound (25 mg (yield 78%)) was obtained as a yellow oil.
Reaction SMILES: [CH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.C([C:9]1[C:15](=O)[C:14](Cl)=[C:13](Cl)[C:11](=[O:12])[C:10]=1C#N)#N>>[C:1]1([CH:10]2[CH2:9][CH2:15][CH2:14][CH2:13][C:11]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=CCC=CC1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: O=C1CCCCC1c1ccccc1
Yield: 56 %

Procedure:
Rh2(S-DOSP)4-catalyzed decomposition of the cyclic vinyldiazoacetate 58 in the presence of 1,3-cyclohexadiene 40 resulted in the formation of the 1,4-cyclohexadiene 59 in 73% yield and 97% ee. The absolute configuration of compound 59 was determined by DDQ oxidation and ozonolysis to afford the 2-phenylcyclohexanone in a 56% yield. Found [α]26D=−17 (c=1.66, PhH) . Lit. value: [α]24D=−113.5 (c=0.60, PhH), S-isomer. (Berti et al., J. Chem. Soc., pp. 3371-3377 (1971), which is hereby incorporated by reference.) Similarly, decomposition of the dienyldiazoacetate 60 in the presence of 1,3-cyclohexadiene 40 resulted in the formation of 61 (60% yield and 99% ee), in which both diene components have moved out of conjugation.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:32])[NH:28][CH:29]3[CH2:31][CH2:30]3)=[CH:23][CH:22]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:33]1([NH2:40])[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1.C(O)(C(F)(F)F)=O>>[NH2:39][C@H:36]1[CH2:37][CH2:38][C@H:33]([NH:40][C:2]2[CH:3]=[C:4]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:32])[NH:28][CH:29]4[CH2:31][CH2:30]4)=[CH:23][CH:22]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:34][CH2:35]1
Reactant: O=C(NC1CC1)c1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4)cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccc(C(=O)NC4CC4)cc3)c3ncc(C(=O)Nc4ccncc4)n3n2)CC1
Temperature: 160 °C

Procedure:
To a 1 dram vial was added 6-chloro-8-(4-(cyclopropylcarbamoyl)phenylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (39 mg, 0.087 mmol) and (trans)-cyclohexane-1,4-diamine (99 mg, 0.871 mmol). The reaction solution was heated neat at 160° C. for 1 hour. The solution was cooled and purified by preparative HPLC to yield 6-((trans-4-aminocyclohexyl)amino)-8-((4-(cyclopropylcarbamoyl)phenyl)amino)-N-4-pyridinylimidazo[1,2-b]pyridazine-3-carboxamide (11.90 mg, 0.023 mmol, 26.0% yield) as a TFA salt. 1H NMR (500 MHz, CD3OD) δ ppm 8.73-8.76 (2H, m), 8.28-8.32 (2H, m), 8.19 (1H, s), 7.86-7.90 (2H, m), 7.41-7.45 (2H, m), 6.48-6.50 (1H, m), 3.78-3.85 (1H, m), 3.14-3.21 (1H, m), 2.83-2.88 (1H, m), 2.32-2.38 (2H, m), 2.12-2.18 (3H, m), 1.55-1.64 (3H, m), 1.42-1.51 (3H, m), 0.78-0.84 (2H, m), 0.62-0.69 (2H, m) LC/MS, m/z 526.17 (M+1). HPLC Rt, 2.21 min. Waters Sunfire C18 column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].B1C2CCCC1CCC2.[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)#[N:15].[OH-].[Na+]>O1CCCC1>[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]/[CH:3]=[CH:2]/[CH2:1][OH:4])=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C#CCO
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C/C=C/CO)cc1
Temperature: 25 °C

Procedure:
To a solution of propargyl alcohol (166, Aldrich, 1.46 mL, 25 mmol) in anhydrous tetrahydrofuran (10 mL), was added 0.5M 9-BBN in THF (Aldrich, 100 mL, 50 mmol) through an addition funnel at 0° C. under nitrogen over a period of 1 hour. After the addition was complete, the flask was stored in a 5° C. refrigerator under nitrogen for 18 hours. The reaction mixture was warmed to room temperature under nitrogen. To the reaction mixture was added 4-bromotolunitrile (compound 160, Aldrich, 5.88 g, 30 mmol), tetrakis(triphenyl-phosphine)palladium (0) (Aldrich, 1.00 g, 0.86 mmol), and 2M sodium hydroxide solution (25 mL, 50 mmol). The reaction mixture was degassed with nitrogen three times, and then refluxed at 65° C. for 2 hours. The reaction mixture was cooled to room temperature. 30% hydrogen peroxide in water (30 mL) and 2M sodium hydroxide solution (10 mL) was added slowly. Copius amounts of gas released during addition of hydrogen peroxide:. The resulting solution was stirred at room temperature for an additional hour. The reaction mixture was extracted with ethyl acetate. The combined extracts were washed with brine and then dried over Na2SO4. After filtration and evaporation, the crude product was purified on a silica gel column, eluting with hexane-ethyl acetate (4:1 and 3:1). The product 167 was obtained as colorless oil (1.05 g, 24% yield). TLC Rf 0.30 (Hexane: EtOAc 1:1); 1H-NMR (400 MHz, CDCl3): δ7.58 (d, 2H, J 8.1 Hz), 7.29 (d, 2H, J 8.1 Hz), 5.82 (dt, 1H, J 15.6 Hz, J 6.4 Hz), 5.71 (dt, 1H, J 15.6 Hz, J 5.4 Hz), 4.14 (d, 2H, J 5.4 Hz), 3.44 (d, 2H, J 6.4 Hz), 1.62 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:10]=2)=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cc2n[nH]c3ccccc23)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(Cc2ccc([N+](=O)[O-])cc2)c2ccccc21
Yield: 48.6 %

Procedure:
Into a dry reaction vessel, 2.15 g (8.49 mmol) 3-(4-nitrobenzyl)-1H-indazole, 10 mL DMF, 1.70 g (10.2 mmol) ethyl bromoacetate, 5.54 g (17.0 mmol) cesium carbonate were respectively added, and reacted at room temperature overnight. It was chromatographed on a column to obtain 1.4 g red solid, at a yield of 48.5%.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH2:30][C:31](=O)[CH3:32])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH2:30][CH:31]([N:5]2[CH2:6][CH2:7][N:2]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:13](=[CH:18][CH:19]=3)[C:14](=[O:17])[O:15][CH2:16]4)[CH2:3][CH2:4]2)[CH3:32])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: COc1cc(CC(C)=O)ccc1C#N
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: Cl
Product: COc1cc(CC(C)N2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1C#N

Procedure:
2-Methoxy-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]propyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxopropyl)benzonitrile. LC-MS (IE, m/z): 420.6 [M+1]+. (0.21 μM)
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:1][CH2:2][C:3]([C:9]1[CH:10]=[CH:11][C:6]([CH3:12])=[CH:7][CH:8]=1)=[O:4]
Reactant: Cc1ccccc1
Reactant: O=C(Cl)CCl
Product: Cc1ccc(C(=O)CCl)cc1

Procedure:
reacting toluene with chloroacetyl chloride in the presence of a Friedel-Crafts catalyst in a suitable solvent to produce 4-(2-chloroacetyl)toluene,
Reaction SMILES: [C:1]1(O)[N:6]=[N:5][CH:4]=[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]=12.P(Br)(Br)(Br)=O.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:1]1[N:6]=[N:5][CH:4]=[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nncc2cnccc12
Agent: O=P(Br)(Br)Br
Product: Clc1nncc2cnccc12

Procedure:
A flask was charged with pyrido[3,4-d]pyridazin-1-ol (0.080 g, 0.54 mmol) (see Brzezinski, J. Z.; Bzowski, H. B.; Epsztajin, J. Tetrahedron, 1996, 52, 3261-72) and phosphorus oxybromide (0.62 g, 2.2 mmol) and heated at 80 C 2:30pm. Solid still stuck to walls of flask so 3 mL POCl3 was added and refluxed 4 h and the mixture concentrated in-vacuo. The mixture was quenched with ice and sat NaHCO3 and the brown solid collected. The solid is a mixture of the title compound and 1-bromopyrido[3,4-d]pyridazine (22 mg). MS (ESI pos. ion) m/z: 166 (MH+). Calc'd exact mass for C7H4ClN3: 165.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Yield: 5.2 %

Procedure:
The title compound (2.2 mg, 5%) was prepared from [4-(trifluoromethyl)phenyl]boronic acid (19 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 444 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1.C=O.Cl.[CH3:27]NC.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=[O:23])[C:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=[CH2:27]
Reactant: CNC
Reactant: COc1ccc(C(=O)Cc2ccc(OC)c(OC)c2)c(OC)c1
Agent: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: C=C(C(=O)c1ccc(OC)cc1OC)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
A mixture of Compound V (10.0 g, 31.6 mmol), paraformaldehyde (6.4 g), dimethylamine hydrochloride (9.4 g, 115 mmol) and sodium carbonate (13.3 g, 125 mmol) was dissolved in tetrahydrofuran (150 mL) and heated under reflux for 16 h. The reaction was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to give a brown oil. Purification by column chromatography on silica gel 60, eluting with hexane/ethyl acetate (2:1 to 1:1) afforded Compound IV (5.3 g, 16 mmol, 51%) as a yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:8]([C:6]3[S:7][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[O:10])=[N:13]2)=[CH:18][CH:17]=1
Reactant: CSc1ccc(C(=O)O)s1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Product: CSc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)s1
Yield: 75.9 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5-methylthio-2-thiophenecarboxylic acid (5.6 g), N,N'-carbonyldiimidazole (5.2 g) and 2-amino-7-chloro-1,8-naphthyridine (4.3 g). The product obtained by precipitation in water is purified by recrystallization in a dimethylformamide/methanol (5:5 by volume) mixture (200 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-5-methylthio-2-thiophenecarboxamide (6.1 g), m.p. 235° C., is thereby obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[CH:18]=[C:17]([Cl:19])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:31][O:32][CH2:33]Cl.[I-].[Na+]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH2:31][O:32][CH3:33])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[CH:18]=[C:17]([Cl:19])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(CN(C)S(=O)(=O)c1csc(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-chlorothiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 83) (1.33 g) in dichloromethane (7 mL) was added dropwise diisopropylethylamine (1.2 mL) and 0.34 mL of chloromethyl methyl ether (0.34 mL) on an ice bath. Sodium iodide (25 mg) was added, and the solution was stirred at room temperature for 4 hours at room temperature. In addition, diisopropylethylamine (1.2 mL) and chloromethyl methyl ether (0.34 mL) were added to this solution, and the solution was further stirred for 17 hours. After the solution was diluted with ethyl acetate, and was washed with water and saturated sodium chloride water. After drying the organic layer with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (646 mg) was obtained as a colorless solid. Recovery of raw materials was 557 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][CH3:14])[N:5]=[C:4]([NH2:15])[N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27])#[N:17].O1CCOCC1.C([O-])(O)=O.[Na+]>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.CCOC(C)=O>[NH2:15][C:4]1[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[C:19]([F:27])[CH:20]=2)[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][CH3:14])[N:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC[C@@H]1CCCN1c1cc(Cl)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@@H]1CCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To 4-chloro-6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-pyrimidinamine (40 mg, 0.176 mmol) and (4-cyano-3-fluorophenyl)boronic acid (29.1 mg, 0.176 mmol) was added 1,4-dioxane (3 mL) followed by sat. aq. NaHCO3 (0.5 mL), and the mixture was purged with N2 for 10 minutes into a sealable tube. Pd(Ph3P)4 (20.4 mg, 0.018 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100° ACHCl3 to 95:5:0.5 CHCl3:CH3OH:NH4OH) afforded the title compound (52 mg) as a solid. LC-MS (ES) m/z=312 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)[CH2:2][CH:3]=[CH2:4].[CH2:13]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[CH2:13])[CH2:2][CH:3]=[CH2:4]
Reactant: C1CCOC1
Reactant: C=CCCOC1CCCCC1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=CCCOC1CCCCC1=C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of methyltriphenylphosphonium bromide (22.30 g, 62.4 mmol) in THF (125 mL) at rt was added sodium hexamethyldisilylazide (2M in THF, 31.2 mL, 62.4 mmol) dropwise. The mixture was heated to 60° C. for 1 hr. 2-(but-3-en-1-yloxy)cyclohexanone (7.0 g, 41.6 mmol.) was then added and the mixture was stirred at 60° C. for 3 hr. The reaction was cooled to rt, quenched with sat'd. aq.NH4Cl, and extracted with Et2O. The combined organics were dried filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 5.78-5.90 (m, 1H), 5.00-5.13 (m, 2H), 4.82 (s, 1H), 4.78 (s, 1H), 3.74 (dd, 1H, J=3.9 Hz, 6.3 Hz), 3.35-3.49 (m, 2H), 1.12-2.38 (m, 10H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH3:18])[CH:12]=2)=[CH:5][CH:4]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:19])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([CH3:18])[CH:12]=1)([CH3:21])[CH3:22]
Reactant: Cc1ccc(NCc2ccc(N(C)C)cc2)cc1C
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: Cc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1C
Yield: 30.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](3,4-dimethylphenyl)amine (1.4 g) and 2,6-diisopropylphenyl isocyanate (1.5 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(3,4-dimethylphenyl)urea (0.77 g) was obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].C(OC([N:37]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49](O)=O)=[CH:45][CH:44]=2)[CH2:39][CH2:38]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:49][C:46]1[CH:45]=[CH:44][C:43]([CH:40]2[CH2:41][CH2:42][NH:37][CH2:38][CH2:39]2)=[CH:48][CH:47]=1)[C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2]
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Product: CCN(Cc1ccc(C2CCNCC2)cc1)c1cc2c(cc1C1CCc3cc(O)ccc3C1)OCO2
Yield: 40.8 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (60 mg) according to an analogous synthetic method to Example 209, the title compound (20 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:14]1.[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:14]1[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CBr
Reactant: Cc1ccc([N+](=O)[O-])c(N=C2NC3(CCCC3)CS2)c1C
Product: Cc1ccc([N+](=O)[O-])c(N=C2SCC3(CCCC3)N2CC(C)C)c1C

Procedure:
2,3-Dimethylaniline was converted to 2,3-dimethyl-6-nitroaniline according to Method A4a. The aniline was converted to 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method A2d. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method C1e to give 2-(2,3-dimethyl-6-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to afford 2-(2,3-dimethyl-6-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [O:1]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:8].[NH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>C1COCC1>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([NH:9][C:2](=[O:8])[CH2:3][CH2:4][CH2:5][C:6]([OH:1])=[O:7])=[CH:11][CH:12]=1)#[N:15]
Reactant: O=C1CCCC(=O)O1
Reactant: N#Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)CCCC(=O)O)cc1
Yield: 79.7 %

Procedure:
A solution of dihydro-2H-pyran-2,6(3H)-dione (483 mg, 4.23 mmol) and 4-aminobenzonitrile (500 mg, 4.23 mmol) in THF (15 mL) was heated with reflux for 14 hr. The reaction solution was concentrated under reduced pressure, and the precipitate was washed with ethyl acetate to give 5-(4-cyanophenylamino)-5-oxopentanoic acid (782 mg, 3.37 mmol, 80%) as a pale-yellow powder.