Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([CH2:13][CH2:14]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][N:24]=[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:22]=2[CH:32]=1.Cl>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][CH:26]([C:23]4[C:22]5[CH:32]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=5[O:25][N:24]=4)[CH2:31][CH2:30]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Clc1ccc2onc(C3CCNCC3)c2c1
Reactant: CC(=O)N1CCc2cc(CCCl)sc2C1
Agent: Cl
Product: CC(=O)N1CCc2cc(CCN3CCC(c4noc5ccc(Cl)cc45)CC3)sc2C1
Yield: 43.1 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.9 g of 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 1.0 g of 4-(5-chloro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.7 g of 6-acetyl-2-(2-(4-(5-chloro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 122°-124° C. (decomposition) as a hydrochloride thereof.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-])(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].[K+].C(#N)C.S1(CCCC1)(=O)=O>O.CC(N(C)C)=O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:3])(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])ccc1Cl
Agent: [K+]
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 0 °C

Procedure:
1,250 ml of phosphorus oxychloride was added dropwise to a mixture of 1,280 g of potassium 4-chloro-3-nitrobenzenesulfonate, 1,150 ml of acetonitrile, 250 ml of sulfolane, and 30 ml of dimethylacetamide in such a manner that the internal temperature thereof was kept at 60° to 70° C. After being allowed to react at a temperature of 73° C. for 3 hours, the reaction mixture was cooled with water, and 400 ml of water was gradually added to the reaction mixture. The cooled reaction mixture was then added to 5 l of ice water. The resulting crystals were filtered off, washed with water, and then dried. (Yield: 1,060 g (84%); m.p.: 55°-56° C.)
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]1[CH2:9][CH:8]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2]([N:6]1[CH2:9][CH:8]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:22]3)(=[O:19])=[O:20])=[CH:14][CH:13]=2)[CH2:7]1)=[O:3]
Reactant: COC(=O)Cl
Reactant: O=C(NC1CNC1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC(NC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Add methyl chloroformate (60 μL, 73 mg, 0.78 mmol, 3.1 equiv) to a suspension of N-azetidin-3-yl-4-(3-phenyl-indole-1-sulfonyl)-benzamide (108 mg, 0.250 mmol, 1 equiv) and triethylamine (140 μL, 100 mg, 1.0 mmol, 4.0 equiv) in anhydr (CH2Cl2 (3 mL). Observe a vigorous gas evolution. After stirring 4 h, rotary evaporate the reaction solution. Transfer the resultant material to a column of silica gel (80 mm×20 mm dia.) and elute (20-60% EtOAc/hex) to yield 84 mg (69%) of 3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylic acid methyl ester as an off-white foam. MS (m/e): 489.96 (M+1); 488.09 (M−1).
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=1.[Br:52]N1C(=O)CCC1=O>CC#N>[CH3:49][Si:46]([CH3:48])([CH3:47])[CH2:45][CH2:44][O:43][CH2:42][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:50])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:9]=1[Br:52]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccccc4c3)c2n1)C1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1nc2c(-c3cnc4ccccc4c3)cnn2c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To crude tert-butyl (7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl(tetrahydro-2H-pyran-4-yl)carbamate (Int-8d, 44 mg) in CH3CN (8 mL) was added N-bromosuccinimide (22 mg, 0.12 mmol), followed by additional CH3CN (4 mL). The reaction was then stirred at room temperature for 30 minutes, at which time LC/MS analysis confirmed full conversion of the starting material to the product. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give Int-8e as a yellow solid (8.7 mg, 0.02 mmol, 7% over three steps). LCMS: 0.82 mins, m/z=812.10 and 813.20 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Si:30]([CH3:47])([CH3:46])[C:31]#[C:32][Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.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>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:32]#[C:31][Si:30]([CH3:47])([CH3:46])[CH3:29])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: FC(F)(F)c1cccc2c(-c3cccc(Br)c3)c(Cc3ccccc3)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Temperature: 120 °C

Procedure:
A solution of 3-benzyl-4-(3-bromo-phenyl)-8-trifluoromethyl-quinoline (1.0 g, 23 mmol) and trimethyl-tributylstannanylethynyl-silane (1.3 g, 34 mmol) in toluene (25 mL) is treated with Pd(PPh3)4 (270 mg) and heated at 120° C. for 3 h. The reaction is then cooled and concentrated in vacuo. The residue is chromatographed with 10:90 ethyl acetate:hexane to afford 3-benzyl-8-trifluoromethyl-4-(3-trimethylsilanylethynylphenyl)-quinoline as an oil. MS (ESI) m/z 460.0.
Reaction SMILES: [N:1]1([C:10]([O:12]C2C=CC(Cl)=CC=2C(=O)NC2C=CC([N+]([O-])=O)=CC=2Cl)=O)[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])OC(Cl)(Cl)[Cl:36].Cl.N1CCC[C@H]1C(OC)=O.C(N(C(C)C)CC)(C)C.ClC1C=CC(O)=C(C=1)C(NC1C=CC([N+]([O-])=O)=CC=1Cl)=O>C(Cl)(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:36][C:10]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH3:9])=[O:7])=[O:12]
Reactant: O=C([O-])OC(Cl)(Cl)Cl
Reactant: COC(=O)C1CCCN1C(=O)Oc1ccc(Cl)cc1C(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Agent: CN(C)c1ccncc1
Agent: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1CCCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-(4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl 2-methyl pyrrolidine-1,2-dicarboxylate (Compound 25). (S)-Methyl 1-(chlorocarbonyl)pyrrolidine-2-carboxylate was prepared following the procedure disclosed in U.S. Pat. No. 4,866,087 to Greenlee et al with minor modification. A solution of 5.63 g (19.0 mmol) bis(trichloromethyl carbonate in chloroform (15 mL) was added dropwise to a solution of (S)-Methyl pyrrolidine-2-carboxylate hydrochloride (2.62 g., 15.82 mmol) and diisopropylethylamine (11.0 mL, 63.28 mmol) in chloroform (15 mL) at ice-bath temperature. After one hour, the solution was washed with 1N aqueous HCl and water, and dried over magnesium sulfate. The dried solution was concentrated and placed on a 85 mm i.d.×35 mm column of silica gel. The product was eluted in 20 percent ethyl acetate in hexanes and concentrated to a colorless oil. This was dissolved in chloroform (10 mL) and added to a suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (645 mg, 1.97 mmol) in pyridine (15 mL) containing 20 mg of 4-dimethylaminopyridine. After stirring for 120 hours at room temperature, the reaction solution was partitioned between 1N aqueous HCl and ethyl acetate. The ethyl acetate phase was washed with water, then brine, and dried over magnesium sulfate. Concentration afforded an off-white solid which was recrystallized from ethyl acetate/hexanes. The 1H NMR spectrum is complex and reveals the existence of rotational isomers due to restricted rotation about the pyrrolidine-1-carboxylate bond. 1HNMR (300 MHz, DMSO-d6): δ1.823-2.003 (m, 3H, pyrrolidine C4 methylene and pyrrolidine C3 syn-H), 2.213 (m, 1H, pyrrolidine C3 anti-H), 3.450 (m, 1H, pyrrolidine C5), 3.599 (m, 1H, pyrrolidine C5), 3.600 (s, 1.5H, methyl ester), 3.621 (s, 1.5H, methyl ester), 4.252 (m, 0.5H, pyrrolidine methine), 4.541 (m, 0.5H, pyrrolidine methine), 7.108 (d, J=8.5 Hz, 0.33H, H3), 7.216 (d, J=8.5 Hz, 0.33H, H3), 7.361 (d, J=9 Hz, 0.33H, H3), 7.545 (m, 0.33H, H4), 7.665 (m, 0.66H, H4), 7.763 (m, 0.66H, H6), 7.974 (m, 0.33H, H6), 8.133 (m, 0.66H, H6′), 8.287 (m, 1H, H5′), 8.302 (m, 0.33H, H3′), 8.539 (m, 0.33H, H3′), 8.446 (m, 0.33H, H3′), 8.822 (d, J=9.5 Hz, 0.33H, H6′), 10.313 (s, 0.33H, NH), 10.385 (s, 0.33H, NH), 11.367 (br s, 0.17H, NH), 12.519 (br s, 0.17H, NH).
Reaction SMILES: [BH4-].[Li+].[Si:3]([O:20][C@H:21]([CH3:39])[C@H:22]([NH:32][CH2:33][C:34](OCC)=[O:35])[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Si:3]([O:20][C@H:21]([CH3:39])[C@H:22]([NH:32][CH2:33][CH2:34][OH:35])[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=1)([C:16]([CH3:18])([CH3:19])[CH3:17])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NCCO)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
Lithium borohydride (20 mg) was added to a solution of ethyl [(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamino]acetate (158 mg) in THF (3 ml) in a nitrogen atmosphere, and the reaction solution was stirred at room temperature for one day. A saturated sodium sulfate solution was added to the reaction solution, and then the precipitated insoluble matter was removed by filtration through celite. Methanol was added to the filtrate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain 103 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:8][C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:4]=1
Reactant: Cc1[nH]nc(N)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1c(Cl)c(N)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.18–7.22 (d, 1H), 6.78–6.84 (d, 2H), 4.8 (s, 2H), 4.4 (s, 2H), 3.72–3.82 (m, 4H), 3.08–3.18 (m, 4H), 2.14 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl[CH:33]([CH3:41])[CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([S:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:41][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:26][CH:25]=2)=[O:22])(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: CC(Cl)CN1CCCCC1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc(OCCCN3CCCCC3)cc2)C(=O)O)cc1

Procedure:
The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with 1-(2-chloropropyl)piperidine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7 as a solid, mp=122-125° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:8][C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[C:10]([F:13])([F:12])[F:11])[CH:7]=1.ClC1C=C(O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)N=NC=1.[CH2:53]1[C:57]2([CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:56][CH:55]([C:63]([O:65][CH2:66][CH3:67])=[O:64])[N:54]1[C:68]([O:70][CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)=[O:69].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:9]([O:8][C:6]2[CH:7]=[C:2]([N:60]3[CH2:59][CH2:58][C:57]4([CH2:53][N:54]([C:68]([O:70][CH2:71][C:72]5[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=5)=[O:69])[C@H:55]([C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH2:56]4)[CH2:62][CH2:61]3)[N:3]=[N:4][CH:5]=2)[C:10]([F:12])([F:11])[F:13])=[C:15]([N:21]2[CH:25]=[CH:24][C:23]([CH3:26])=[N:22]2)[CH:16]=1
Reactant: CCOC(=O)C1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cnnc(Cl)c2)C(F)(F)F)n1
Agent: [Pd]
Agent: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(Cl)cnn2)C(F)(F)F)n1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)cnn3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of the (R)-3-chloro-5-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazine/(R)-5-chloro-3-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazine mixture from step 1 in 1,4-dioxane (19 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (980 mg, 2.83 mmol), Cs2CO3 (2.30 g, 7.07 mmol), Pd2(dba)3 (432 mg, 0.471 mmol), and rac-BINAP (587 mg, 0.940 mmol), and the reaction mixture was heated to 60° C. for 60 h. Then the reaction mixture was cooled to RT, filtered through celite, washed with EtOAc, and the filtrate concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:16])=[CH:6][C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)[CH3:2].[CH3:17]O.S(=O)(=O)(O)O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([OH:16])=[CH:6][C:7]2[S:11][C:10]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][C:8]=2[CH:15]=1)[CH3:2]
Reactant: CCOc1cc2cc(C(=O)O)sc2cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc2cc(C(=O)OC)sc2cc1O

Procedure:
A solution of 0.71 g. of 5 -ethoxy-6-hydroxybenzothiophene-2-carboxylic acid, 0.29 g. of methanol, and a catalytic amount of sulfuric acid in methylene chloride was heated to reflux for 48 hours. The solution was diluted with ethyl acetate and was washed first with a 10% aqueous sodium bicarbonate solution and then with water. The organic solution was dried over sodium sulfate and evaporated to dryness providing the desired ester intermediate which was used without further purification.
Reaction SMILES: [Mg].Cl[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([O:10][CH3:11])[CH2:8][CH3:9].Cl[CH:13]1[CH2:17][CH2:16][CH:15]=[CH:14]1.[Cl-].[NH4+]>O1CCCC1>[CH3:11][O:10][CH:7]([CH2:8][CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:17]1[CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: ClC1C=CCC1
Reactant: CCC(CCCCCl)OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CCCCC1C=CCC1)OC
Temperature: -25 °C

Procedure:
A three-neck, round-bottomed flask containing magnesium metal turnings (7.2 g, 0.299 moles), is equipped with a Friedrich condenser and kept under a nitrogen atmosphere. Tetrahydrofuran (300 ml) is added and the contents are allowed to stir. A solution of 1-chloro-5-methoxyheptane (48.1 g, 0.292 moles) is added in small portions and refluxed. The mixture is allowed to stir for 3 hours. The resultant dark yellow solution is cooled to -25° C., and the condenser is removed and replaced with a dry ice addition funnel. A solution of 3-chlorocyclopentene (29.9 g, 0.292 moles) is added over a period of one hour. The viscous solution is poured into two liters of saturated ammonium chloride, extracted with ether, and dried over anhydrous sodium sulfate. Distillation yields 3-(5-methoxyhept-1-yl)cyclopentene {3-(5-methoxyheptyl)cyclopentene} (51.5 g, 0.262 moles) as clear, colorless oil boiling at about 90° C. at 0.3 mm and 54° C. at 0.1 mm.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:16])=[N+:2]=[N-:3].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CN(C=O)C.O.CCOC(C)=O>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:5]1=[O:16])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCc2c(F)cccc2NC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=NC1CCc2c(F)cccc2N(CC(F)(F)F)C1=O
Yield: 82 %

Procedure:
3-Azido-6-fluoro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.25 g, 10.22 mmol), cesium carbonate (4.65 g, 14.30 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.67 mL, 18.39 mmol) in DMF (34.1 mL) heated to 40° C. for 1 hour. The reaction mixture was diluted with water before EtOAc was added to extract the product. The organic phase was separated and washed with water (2×) and brine (1×) before being dried with Na2SO4 and evaporated to yield the crude product. This material was chromatographed on silica gel (0-80% EtOAc in hexanes) to yield 2.534 g of 3-azido-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one as an orange/brown solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[CH:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:5][CH:4]=1)[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]2[CH2:14][CH2:15][N:11]([CH:10]=[N:9][C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:23][N:22]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCc1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1ccc(N=CN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A mixture of 4.00 g of 1-(4-ethylphenyliminomethyl)-2-nitroiminoimidazolidine, 3.00 g of 2-chloro-5-chloromethylpyridine, 4.20 g of potassium carbonate, and 10 ml of DMSO was agitated at 60° C. for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and evaporated to give an oily residue, followed by purification with column chromatography [silica gel, eluent: hexane-ethyl acetate (1:2)] to obtain 2.70 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(4-ethylphenyliminomethyl)imidazolidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COc1ccc(Br)cc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2C(F)(F)F)cc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
To title compound of Step D (0.106 g, 0.296 mmol), 2-trifluoromethylphenylboronic acid (0.084 g, 0.444 mmol), K3PO4 (0.189 g, 0.888 mmol), Pd(dba)2 (0.007 g, 0.012 mmol) and QPhos (0.004 g, 0.006 mmol) was added PhCH3 (3 mL) and the reaction was heated to 80° C. for 18 h. The reaction was cooled to rt, diluted with EtOAc, filtered through a small silica plug and concentrated. Silica gel chromatography (0-30% EtOAc in hexanes) gave 0.062 g (49%) of the title compound. MS (ESI): mass calcd. for C22H24F3NO4, 423.17. m/z found, 368.1 [M-56]+, 446.2 [M+Na]+. 1H NMR (CDCl3): 7.73 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.3 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.93 (s, 2H), 6.56 (s, 1H), 4.92-4.83 (m, 1H), 4.26 (dd, J=10.5, 6.5 Hz, 2H), 4.10 (dd, J=10.5, 4.3 Hz, 2H), 3.93 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].I[CH2:12][CH2:13][CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:12][CH2:13][CH3:14])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: CCCI
Product: CCCOc1ccc(C=O)cc1F

Procedure:
3-Fluoro-4-propoxybenzaldehyde was synthesized starting from 3-fluoro-4-hydroxybenzaldehyde (0.83 g, 5.95 mmol) and 1-iodopropane (1.16 ml, 11.9 mmol) according to reaction conditions described by Liou et al., J. Med. Chem. 2004, 47 (11), 2903.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:17].O>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14]([CH:15]=[O:17])=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[Se]=O
Reactant: Cc1nccnc1OCc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1nccnc1OCc1ccccc1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
2-Benzyloxy-3-methylpyrazine (600 mg) was dissolved in 1,4-dioxane (12 mL), selenium dioxide (1 g) and water added (one drop) and the mixture heated at reflux for seventeen hours. The reaction mixture was allowed to cool to ambient temperature, filtered and the solvents removed. The residue was dissolved in water (30 mL), neutralised with aqueous sodium hydrogen carbonate solution (10%) and extracted with dichloromethane (3×40 mL), the organic phase was dried (MgSO4). After removal of the solvents the oil was purified by MPLC (15%ethyl acetate, hexane, silica) to give 2-benzyloxypyrazine-3-aldehyde (460 mg, mp 69.4° C.).