Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24].[C:25]([O-:28])(=[S:27])[CH3:26].[K+]>>[C:25]([S:27][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:28])[CH3:26].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]
Reactant: BrCCCCCCCCCCCC[c-]1cccc1
Reactant: CC([O-])=S
Agent: [Fe+2]
Agent: [K+]
Agent: c1cc[cH-]c1
Product: CC(=O)SCCCCCCCCCCCC[c-]1cccc1
Yield: 91.3 %

Procedure:
12-Ferrocenyldodecyl bromide 25 (2.0 g, 4.6 mmol) was treated with potassium thioacetate (0.70 g, 6.0 mmol) for 20 h as described for 27 to form yellow crystals (1.8 g, 93%): mp 45-47° C.; 1H NMR δ 1.27 (s, 18H), 1.55 (m, 2H), 2.32 (m, 2H), 2.33 (s, 3H), 2.87 (m, 2H), 4.05 (s, 2H), 4.07 (s, 2H), 4.11 (s, 5H); 13C NMR δ 29.5, 29.8, 30.2, 30.3, 30.3, 31.3, 31.8, 67.7, 68.8, 69.2, 90.4, 196.8; FAB-MS obsd 428.1851, calcd exact mass 428.1836; Anal. Calcd for C24H36FeOS: C, 67.28; H, 8.47. Found: C, 67.25; H, 8.51.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:32][CH2:33][CH3:34])[C:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:9]2[O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:35][CH3:36].[OH-].[Na+]>C1COCC1.CCO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:32][CH2:33][CH3:34])[C:8]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:9]2[O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:35][CH3:36]
Reactant: CCCc1cc2cc(OC)c(F)cc2c(Oc2ccc(/C=C/C(=O)OCC)cc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1cc2cc(OC)c(F)cc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 79.4 %

Procedure:
Ethyl ester (139) (0.44 g, 0.91 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.33 g (80%) of the title compound (140) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.80 (t, J=7.3 Hz, 3H), 1.40-1.55 (m, 2H), 2.52 (t, J=7.8 Hz, 2H), 4.01 (s, 3H), 6.23 (d, J=15.9 Hz, 1H), 6.55 (d, J=8.8 Hz, 2H), 7.06-7.12 (m, 2H), 7.20-7.30 (m, 6H), 7.41 (d, J=12.1 Hz, 1H), 7.56 (s, 1H), 7.62 (d, J=15.9 Hz, 1H). LCMS (APCI): m/z 457 (M+H)+, m/z 455 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:3]([O:5]CC)=[O:4].[ClH:16]>O>[ClH:16].[CH3:1][CH:2]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)CCN1CCOCC1
Agent: Cl
Solvent: O
Product: CC(CCN1CCOCC1)C(=O)O
Reaction time: 20 h

Procedure:
32.0 g. (0.15 mole) of ethyl 2-methyl-4-morpholinobutyrate was combined with 200 ml. of concentrated hydrochloric acid and 200 ml. of water and refluxed with stirring for 20 hours. The solution was concentrated on a rotary evaporator to give a viscous, colorless residue. This material was triturated with acetone, filtered and dried to give 30.6 g. (92%) of colorless crystals, m.p. 155°-157°C.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:22]2[N:21]([CH3:20])[CH:25]=[CH:24][N:23]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1nccn1C
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: Cn1ccnc1C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Yield: 16 %

Procedure:
Similar to as described in General Procedure G 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1-methyl-1H-imidazol-2-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (22 mg, 16%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:15][CH:14]([CH2:16]OS(C)(=O)=O)[CH2:13][C:8]21[O:12][CH2:11][CH2:10][O:9]2)(=O)=O.[NH3:22]>>[CH2:11]1[O:12][C:8]2([CH2:13][CH:14]3[CH2:15][CH:7]2[CH2:6][NH:22][CH2:16]3)[O:9][CH2:10]1
Reactant: CS(=O)(=O)OCC1CC(COS(C)(=O)=O)C2(C1)OCCO2
Reactant: N
Product: C1COC2(CC3CNCC2C3)O1
Temperature: 60 °C
Yield: 100 %

Procedure:
6,8-Bis(methanesulfonyloxymethyl)-1,4-dioxaspiro[4.4]nonane (14.90 g, 43.3 mmol) was suspended in aqueous ammonia (35%, 150 ml) and heated for 18 h at 60° C. The reaction was cooled to ambient temperature and concentrated by rotary evaporation. The residue was treated with saturated sodium chloride solution (50 ml) and extracted with chloroform (3×50 ml). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated to yield a brown oil (7.69 g, 100%).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5](=O)[C:6]([CH3:32])([CH3:31])[CH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:11][N:12]=1)=[O:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:30][C:15]1[CH:16]=[C:17]([NH:19][C:20]2[N:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][N:21]=2)[CH:18]=[C:13]([C:10]2[S:9][C:8]([CH2:7][C:6]([CH3:31])([C:5]3[O:2][CH:1]=[N:3][N:4]=3)[CH3:32])=[N:12][CH:11]=2)[CH:14]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CC(C)(C)C(=O)NNC=O)s2)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CC(C)(C)c3nnco3)s2)c1
Temperature: 100 °C
Yield: 47.6 %

Procedure:
The product from Step 1 (70 mg, 0.146 mmol) was taken up in THF (2.0 mL) in a microwave vial, and Burgess reagent (70 mg, 0.293 mmol) was added. The reaction was heated in the microwave at 100° C. for 30 min. The orange reaction mixture was concentrated to dryness, and the resulting residue was purified by flash chromatography (10-100% ethyl acetate in hexanes) to provide N-(3-methyl-5-{2-[2-methyl-2-(1,3,4-oxadiazol-2-yl)propyl]-1,3-thiazol-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (32 mg, 48%) as a colorless foam. MS ESI: [M+H]+ m/z 461.0. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.16 (s, 1H), 8.80 (d, J=4.9, 1H), 7.94-7.83 (m, 2H), 7.42 (s, 1H), 7.25 (d, J=4.9, 1H), 7.08 (s, 1H), 3.39 (s, 2H), 2.27 (s, 3H), 1.43 (s, 6H). rhSYK activity=+++
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:24][OH:25])[CH:5]=[CH:4][N:3]=1.O=C1[NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=2[O:28]1>>[OH:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH:31][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:24][OH:25])[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(Br)c3)c2cc1OC
Reactant: O=c1[nH]c2ccccc2o1
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(Nc4ccccc4O)c3)c2cc1OC

Procedure:
1-(2-Bromo-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene and 2-oxobenzoxazolidine are treated in the same manner as Example 6-(2) to give 1-[2-(2-hydroxyphenyl)amino-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene which is a hydrolysis product of 1-[2-(2-oxobenzoxazolidin-3-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene and listed in Table 6.
Reaction SMILES: C(N1CCNC1=NC#N)C1C=CC=CC=1.[CH2:16]([N:23]1[CH2:27][CH2:26][NH:25][S:24]1(=[O:29])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[C:31]1[S:32][C:33]([C:37]([NH:39][CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:38])=[C:34]([CH3:36])[N:35]=1>>[CH2:16]([N:23]1[S:24](=[O:29])(=[O:28])[N:25]([C:31]2[S:32][C:33]([C:37]([NH:39][CH2:40][C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:38])=[C:34]([CH3:36])[N:35]=2)[CH2:26][CH2:27]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S1(=O)NCCN1Cc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Agent: N#CN=C1NCCN1Cc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)S2(=O)=O)sc1C(=O)NCc1cccnc1
Yield: 79 %

Procedure:
Following the procedure as described in Example 27, making variations as required to replace N-(1-benzylimidazolidin-2-ylidene)cyanamide with 2-benzyl-1,2,5-thiadiazolidine 1,1-dioxide to react with 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 79% yield: mp 140-142° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J=5.8 Hz, 1H), 8.49-8.43 (m, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.39-7.28 (m, 6H), 4.37 (d, J=5.8 Hz, 2H), 4.26 (s, 2H), 3.46 (t, J=6.6 Hz, 2H), 3.99 (t, J=6.6 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.3, 157.2, 152.9, 149.3, 148.5, 135.6, 135.2, 129.6, 129.0, 128.8, 128.5, 124.0, 119.6, 51.3, 46.0, 44.7, 40.9, 17.5; MS (ES+) m/z 444.3 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].C(N(C(C)C)CC)(C)C.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:47]([CH:44]3[CH2:46][CH2:45]3)=[O:48])[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (1S,2R,3S,5R)-3-Amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (200 mg, 0.4 mmol) in dry THF (2.5 ml) is treated with diisopropylethylamine (0.35 ml, 2 mmol) and cyclopropanecarboxylic acid chloride (0.036 ml, 0.4 mmol) and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure and the residue is purified by reverse-phase chromatography eluting with a gradient system of acetonitrile (0.1% TFA):water (0.1% TFA) (0:100 by volume) gradually changing to acetonitrile (0.1% TFA):water (0.1% TFA) (100:0 by volume) to afford the title compound. LCMS (electrospray): m/z [MH+] 533.25 1H nmr (MeOD, 400 MHz); 8.00(s, 1H), 7.40-7.25(m, 8H), 7.25-7.20(m, 2H), 4.75(m, 1H), 4.60(m, 1H), 4.50(m, 1H), 4.20(m, 2H), 4.00(m, 1H), 2.85(m, 1H), 2.10(m, 1H), 1.85(m, 1H), 0.95-0.80(m, 4H)
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:20]=[N:21][CH:22]=[CH:23][N:24]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[N:21]1[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:16]2[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:27]4[CH2:39][CH2:38][N:30]5[C:31]6[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=6[CH:37]=[C:29]5[C:28]4=[O:40])[C:6]=3[CH2:5][OH:4])[CH:17]=2)[N:20]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3nccnn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2nccnn2)c1=O
Temperature: 36 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
A mixture of 172b (350 mg, 0.65 mmol) and lithium hydroxide (273 mg, 6.5 mmol) in i-propanol/THF (1:1, 5 mL) and water (0.5 mL) was stirred at 36° C. for 0.5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed by reverse-phase prep-HPLC to afford 172 (90 mg, 28%). MS-ESI: [M+H]+ 499.2. 1H NMR (500 MHz, CDCl3) δ 8.77 (d, J=2.5 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.67 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.35 (d, J=5.0 Hz, 1H), 6.89 (s, 1H), 5.10 (t, J=6.5 Hz, 1H), 4.65-4.51 (m, 2H), 4.31-4.27 (m, 1H), 4.16-4.08 (m, 2H), 3.90-3.87 (m, 1H), 3.75 (s, 3H), 2.62-2.56 (m, 4H), 1.92-1.87 (m, 2H), 1.79-1.78 (m, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH:8]=[C:7]1[C:16]#[N:17].[N-:18]=[N+:19]=[N-:20].[Na+].Cl>O1CCCC1>[NH:18]1[C:16]([C:7]2[C:6](=[O:5])[C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][CH:8]=2)=[N:17][N:20]=[N:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1coc2ccccc2c1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=c1c(-c2nnn[nH]2)coc2ccccc12
Reaction time: 23 h

Procedure:
To 100 volume parts of dry tetrahydrofuran are added 4.28 parts of comminuted anhydrous aluminum chloride, 2.50 parts of 4-oxo-4H-1-benzopyran-3-carbonitrile and 4.18 parts of sodium azide in this order and, the whole mixture is refluxed under stirring for 23 hours. Then, to the resulting mixture 35 volume parts of 15 weight% hydrochloric acid are added, followed by distilling off tetrahydrofuran under reduced pressure. The resulting solid residue is recovered by filtration and recrystallized from dimethylformamide. This procedure yields 3-(1H-tetrazol-5-yl) chromone as colorless hairy needles. Melting point: 284°-285° C.(decomp. with foaming).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[CH:23]=[CH2:24].C(Cl)CCl.C(OCC)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:24]([O:20][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:23]=[CH2:22]
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: C=CCO
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCOC(=O)[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-(t-Butoxycarbonyl)-O-benzyl-D-serine (600 mg; 2.03 mmol) was dissolved in dry methylene chloride (5 ml), allyl alcohol (152 μl; 2.23 mmol) and DMAP (25 mg; 0.20 mmol) added and finally EDC (428.5 mg; 2.24 mmol) added to the acid. The reaction mixture was stirred at room temperature for 2.5 h and the resulting homogeneous solution quenched with water and extracted with methylene chloride. The methylene chloride layer was washed with 5% aqueous citric acid then 10% aqueous sodium carbonate solution. The methylene chloride layer was dried over anhydrous magnesium sulfate powder, filtered and evaporated under reduced pressure to give an oil. Chromatography of the oil using ethyl acetate and hexanes 1:2 v/v afforded the product (408 mg; 60%) as a pale yellow gum. FAB-MS:- Calculated for C36H33N5 335.1; found 336.1 (M+1).
Reaction SMILES: C1(OC([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:12][CH2:11]2)=O)C=CC=CC=1.C(O)C.[OH-].[K+].[ClH:30]>CCOCC.O>[ClH:30].[NH:10]1[CH2:11][CH2:12][CH:13]([C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:14][CH2:15]1
Reactant: O=C(Oc1ccccc1)N1CCC(c2noc3ccccc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: c1ccc2c(C3CCNCC3)noc2c1
Reaction time: 16 h
Yield: 57 %

Procedure:
A mixture of 5.0 g of 4-(1,2-benzisoxazole-3-yl)-1-piperidine carboxylic acid phenyl ester, 100 ml of ethanol, 50 g of (85%) potassium hydroxide and 50 ml of water was heated under reflux, with stirring, under nitrogen for 16 hrs. Most of the ethanol was removed in vacuo and the resultant aqueous suspension was extracted with ether (3×50 ml). The ether extracts were combined, washed with water, dried over anhydrous magnesium sulfate and the ether removed under reduced pressure to give an oil. The oil was dissolved in anhydrous ether and hydrogen chloride was introduced to precipitate a 3.0 g of a hydrochloride salt. Recrystallization from methanol-ether gave 2.0 g (57%) of product as the hydrochloride, mp, 313°-315° (dec.).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH:7]([CH2:9]O)[C:6]([NH:17][C:18]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[S:19])([C:11]2[S:12][C:13]([F:16])=[CH:14][CH:15]=2)[CH2:5]1)[CH:2]=[CH2:3].ClC(N(C)C)=C(C)C>ClCCl>[CH2:1]([N:4]1[CH2:8][CH:7]2[C:6]([C:11]3[S:12][C:13]([F:16])=[CH:14][CH:15]=3)([N:17]=[C:18]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:19][CH2:9]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2ccc(F)s2)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: C=CCN1CC2CSC(NC(=O)c3ccccc3)=NC2(c2ccc(F)s2)C1
Temperature: 10 °C
Yield: 60.7 %

Procedure:
To a stirred solution of racemic N-[[1-allyl-3-(5-fluoro-2-thienyl)-4-(hydroxymethyl)pyrrolidin-3-yl]carbamothioyl]benzamide (320 mg, 0.763 mmol) in dichloromethane (7.6 mL) at 0° C. under nitrogen is added 1-chloro-N,N,2-trimethylpropenylamine (0.2 mL, 1.53 mmol). The solution is stirred while slowly warming to 10° C. over 2 hours. The ice bath is removed and the reaction is warmed to room temperature over another 2 hours. The solution is diluted with dichloromethane (approximately 40 mL) and washed with dilute sodium bicarbonate (40 mL prepared from water (20 mL) and saturated sodium bicarbonate (20 mL)). The aqueous phase is re-extracted with dichloromethane (40 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated. The residue is purified by silica gel chromatography eluting with hexanes/ethyl acetate, two-step gradient from 60:40 to 50:50, to give the title compound (186 mg, 61%). ES/MS (m/e): 402 (M+H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:42]=1[F:56].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:43][C:42]=1[F:56]
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(C)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 82.8 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 128, 1.28 g, 2.4 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.01 mg, 2.4 mmol) and dichlorobis(triphenylphosphine)palladium (II) (170 mg, 0.24 mmol) in dioxane (10 mL) was added an aqueous sodium carbonate solution (2 M, 3.6 mL, 7.2 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (1.03 g, 83%) as a light yellow solid: LC/MS m/e calcd for C29H27FN2O4S [M+H]+ 519.61, observed 518.8.
Reaction SMILES: CC(P(C(C)(C)C)[C:6]1[C:11]([C:12]2C=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.[C:22]1([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(C1C=CC=CC=1)CCC#C>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:35]1)[CH3:33]
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Agent: [Au]
Agent: C#CCCCc1ccccc1
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccccc2)C=C(CCCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
Method 2—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, pent-4-ynylbenzene (86.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-phenyl-6-3-phenylpropyl-1,2-oxaphosphorin 2-oxide (72.3 mg, 68%) which is a title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH:27](OCC)OCC)[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9](=[CH:27][N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Br)ccc2N1
Reactant: CCOC(OCC)N1CCOCC1
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1=CN1CCOCC1
Temperature: 140 °C

Procedure:
A mixture consisting of 5 gm of 7-bromo-5-(2'-chloro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 17 ml of morpholino-diethoxy-methane was heated for 90 minutes at 140°C, while stirring, and the reaction mixture was then allowed to cool. The cool product was admixed with 150 ml of petroleum ether (b.p. 60°-80°C), the mixture was briefly brought to the boiling point, allowed to cool, and the crystalline substance which had separated out was collected by vacuum filtration and recrystallized from isopropanol, yielding the compound named in the heading, which decomposed slowly between 156° and 185°C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccccc1Cl
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccccc4Cl)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-chlorobenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-chlorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.