Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CS(O)(=O)=O.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:29]1([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH2:31][O:30]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(Cl)Cl>[NH3:3].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:11][CH2:12][N:13]([CH2:31][C:29]([C:23]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=2[Cl:21])([OH:30])[CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH2:14][CH2:15]1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: N
Product: OC(CN1CCN(c2nc3ccccc3s2)CC1)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
A mixture of benzothiazol-2-yl-piperazine (0.4 g, 1.55 mmole), 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane methanesulphonate (see EP-A-44605) (0.57 g, 1.55 mmole) and potassium carbonate (2 g, 14 mmole) in dioxan (20 ml) was heated at reflux for 3 days. After cooling, the mixture was diluted with methylene chloride, the insoluble inorganic material removed by filtration and the filtrate concentrated under reduced pressure. The resulting oil was purified by flash chromatography on silica gel eluting with ether (93): ethanol (7): 0.88 ammonia solution (1) to yield the desired product as a foam, m.p. 68°-85° (0.34 g, 44%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25].CCN(CC)CC>C(Cl)Cl>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCC4N)ccc21
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC1CCCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Yield: 125.2 %

Procedure:
A cooled (0° C.) brown solution of (rac)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (intermediate A-2) (61.5 mg, 200 μmol) in CH2Cl2 (3.0 ml) was treated with ethanesulfonyl chloride (65.6 mg, 48.3 μL, 500 μmol) and Et3N (40.5 mg, 55.8 μL, 400 μmol). After ½ h the mixture was concentrated in vacuo and purified by flash chromatography (20 g SiO2, Telos-cartridge, CH2Cl2/MeOH (1 to 5%)) to give 100 mg of the title compound together with Et3N×HCl as impurity. Extraction with H2O/EtOAc (3×), and precipitation CH2Cl2/n-pentane gave the pure title compound (46 mg, 58%) as a yellow powder. MS: 400.2 (M+H+).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([C:35]3[O:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccco4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 72.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.650 g, 2.22 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 2-furoyl chloride (0.290 g, 2.22 mmol) was added and the mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-furylcarboxamide (0.51 g, 73%) as a white solid: mp 121–123° C.; 1H NMR (DMSO-d6) δ d 11.13 (s, 1H), 9.01 (t, J=5.7 Hz, 1H), 7.88–7.68 (m, 4H), 7.18 (d, J=3.3 Hz, 1H), 6.66 (m, 1H), 5.20–5.13 (dd, J=5.4 and 12.5 Hz, 1H), 4.90 (d, J=5.6 Hz, 2H), 2.97–2.84 (m, 1H), 2.65–2.49 (m, 2H), 2.10–1.98 (m, 1H); 13C NMR (DMSO-d6) δ d 172.73, 169.80, 167.52, 166.94, 158.09, 147.49, 145.27, 139.06, 134.80, 132.98, 131.52, 127.09, 121.88, 113.86, 111.91, 48.86, 37.64, 30.92, 21.97; Anal. Calcd. For C19H15N3O6+0.18 H2O: C, 59.34; H, 4.03; N, 10.93. Found: C, 59.47; H, 4.16; N, 10.49.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.Cl.[F:46][C:47]1([F:51])[CH2:50][NH:49][CH2:48]1.CN1CCOCC1>CN(C=O)C>[F:46][C:47]1([F:51])[CH2:50][N:49]([C:13](=[O:15])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:18])[CH3:17])[CH2:48]1
Reactant: FC1(F)CNC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](C(=O)N1CC(F)(F)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). 3,3-Difluoroazetidine hydrochloride (10.0 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. Following reaction, the product was purified by preparative HPLC (10-60% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (10 mg, 53%). 1H NMR (500 MHz, DMSO-d6) δ 0.80 (d, J=6.0 Hz, 3H), 0.96 (d, J=6.0 Hz, 3H), 2.30-2.41 (m, 1H), 4.26-4.36 (m, 2H), 4.41-4.51 (m, 1H), 4.70-4.79 (m, 1H), 5.00 (AB q, J=104.5, 22.0 Hz, 2H), 5.07 (d, J=23.0 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 12.40 (s, 1H). [M+H] calc'd for C17H17F3N4O2, 367; found, 367.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1([NH:38][CH2:39][CH2:40]O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:40][CH2:39][NH:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:40][CH2:39][NH:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCNc1ccccc1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: c1ccc(NCCOB(c2ccccc2)C(OC(B(OCCNc2ccccc2)c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
The entitled compound (43 mg) was obtained by allowing 40.6 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 14 mg of phenylglycinol to act in 1 mL of ethanol.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]#[CH:10])SC)#[N:2].[CH3:11][N:12]([CH2:14][C:15]1[O:19][C:18]([CH2:20][S:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1)[CH3:13]>>[C:1]([NH:3][C:4]([NH:7][CH2:8][C:9]#[CH:10])=[N:24][CH2:23][CH2:22][S:21][CH2:20][C:18]1[O:19][C:15]([CH2:14][N:12]([CH3:13])[CH3:11])=[CH:16][CH:17]=1)#[N:2]
Reactant: C#CCN=C(NC#N)SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: C#CCNC(=NCCSCc1ccc(CN(C)C)o1)NC#N

Procedure:
The product of Step A is reacted with about an equimolar amount of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine in a non-reactive solvent to give, after workup and chromatography as in Example 3, the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][C@H:13]3[CH2:15][C@H:16]([NH2:18])[CH2:17][C@H:12]3[CH2:11][O:10]2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:18][C@H:16]2[CH2:15][C@@H:13]3[O:14][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[O:10][CH2:11][C@@H:12]3[CH2:17]2)[CH:25]=1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](N)C[C@@H]3O2)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(C2OC[C@@H]3C[C@@H](Nc4cc(Cl)ncn4)C[C@@H]3O2)cc1
Temperature: 110 °C

Procedure:
A sealed tube containing (4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-amine (120. mg, 0.481 mmol), 4,6-dichloropyrimidine (143 mg, 0.963 mmol), DIPEA (0.0920 mL, 0.528 mmol) and EtOH (30.0 mL) was heated to 110° C. for 20 h. The cooled mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 5% MeOH in DCM (120. mg, 69%). LC/MS: Rt=1.74 min, ES+ 362 (AA standard).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16]Cl>>[Br:8][C:6]1[CH:7]=[C:2]([N:9]2[CH2:14][CH2:13][N:12]([CH3:16])[CH2:11][CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: ClCCl
Reactant: C1CNCCN1
Product: CN1CCN(c2cncc(Br)c2)CC1
Temperature: 180 °C

Procedure:
1-(5-Bromo-pyridin-3-yl)-4-methyl-piperazine was prepared from 3,5-dibromo-pyridine (1.00 g, 4.22 mmol) and piperazine, 1-methyl-(0.936 mL, 8.44 mmol) which were combined and heated in a microwave vial to 180° C. for 2 hours. The reaction mixture was taken up in dichloromethane and purified by silica gel chromatography 0-10% methanol in dichloromethane to afford a clear oil (37%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.20 (s, 1H), 8.11 (s, 1H), 7.29 (m, 1H), 3.25 (bm, 4H), 2.58 (bm, 4H), 2.35 (s, 3H). 108b) [5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-[5-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and 1-(5-bromo-pyridin-3-yl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as an off-white lyophilate (4% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.5 (bs, 1H), 9.86 (bs, 1H), 9.22 (s, 1H), 8.49 (s, 1H), 8.40 (d, J=7.9 Hz, 2H), 8.35 (s, 1H), 8.19 (d, J=7.6 Hz, 2H), 8.05 (d, J=16.5 Hz, 2H), 3.84 (bm, 2H), 3.55 (bm, 2H), 3.38 (s, 3H), 3.20 (bm, 2H), 3.09 (bm, 2H), 2.88 (s, 3H). MS=465.1 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)=[CH:4][CH:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[C:34](=[O:35])[CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([OH:25])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: Fc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1
Product: O=C(CCc1ccc(O)cc1)N(CCc1cccc(OCc2ccccc2)c1)c1ccc(F)cc1
Yield: 88.9 %

Procedure:
The title compound was prepared as described in Example 44.D using (4-fluorophenyl){2-[3-(phenyl methoxy)phenyl]ethyl}amine (1.4 g, 4.36 mmol) and 3-(4-hydroxyphenyl)propanoic acid (1.01 g, 6.11 mmol) to provide the title compound (1.82 g, 89% yield): ES-MS (m/z) 470 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[CH2:9]([N+](C)(C)C)[C:10]1[CH:15]=CC=[CH:12][CH:11]=1.CC(Cl)(C)C#C.[OH-].[Na+]>CO.C(Cl)Cl.O>[CH3:9][C:10]1([CH3:15])[O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:12]=[CH:11]1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: Oc1ccncc1
Agent: C#CC(C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC1(C)C=Cc2cnccc2O1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
p-Hydroxypyridine (32.0 g), 40% benzyltrimethylammonium hydroxide in MeOH (50.7 g) and 3-methyl-3-chlorobut-1-yne (37.4 g) were dissolved in CH2Cl2 (150 mL). To this stirred solution was added NaOH pellets (14.5 g) dissolved in H2O (150 mL) and the resulting mixture stirred vigorously at room temperature for 3.75 days. The layers were separated and the aqueous layer further extracted with CHCl3. The combined organic layers were evaporated and the resulting brown oil was taken up in Et2O and washed with 10% NaOH solution, H20 and brine before drying over anh. MgSO4. Filtration and evaporation yielded an orange oil (21.0 g) which was boiled in o-dichlorobenzene under N2 for 1 h. Evaporation of the solvent and distillation gave the title pyranopyridine (9.2 g): bp 110° C. /0.18 mmHg; NMR (CDCl3) δ 1.47 (s, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].C[C:12]1(C)[CH2:14][CH:13]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1(P([Pd-4](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)C=CC=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:12]2[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5]
Reactant: CC1(C)CC1B(O)O
Reactant: N#Cc1c(N)cccc1Br
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(N)cccc1C1CC1
Temperature: 25 °C
Yield: 40578.6 %

Procedure:
To a degazed solution of 2-amino-6-bromobenzonitrile (851 mmol, 168 mg), 2,2-dimethylcyclopropylboronic acid (1.106 μmol, 126 mg) (Example 270b), and Cs2CO3 (2.979 mmol, 970 mg) in DME (3.4 mL) and water (850 μL) was added tetrakis(triphenylphosphino)palladium(0) (43 μmol, 50 mg) under nitrogen and the reaction mixture microwaved for 2 hours at 160° C. The reaction mixture was cooled to room temperature and extracted with EtOAc (3×5 mL). The combined organic layers was washed once with brine (5 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified on silica gel (EtOAc/hexanes 10%-40%) to give the desired product (71 mg, 45%) as a waxy, yellow solid. 1H NMR (400 MHz, CDCl3) δ 0.82 (m, 1H), 0.82 (s, 3H), 0.85 (m, 1H), 1.33 (s, 3H), 1.92 (m, 1H), 4.36 (br. s, 2H), 6.47 (d, J=8 Hz, 1H), 6.56 (d, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:17])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[O:17]=[C:13]1[N:12]([C:6]2[CH:11]=[CH:10][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:8][CH:7]=2)[CH2:16][CH2:15][O:14]1
Reactant: O=C1OCCN1c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OCCN1c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under N2, chlorosulfonic acid (1.5 g, 12.87 mmol) was diluted in CCl4 (2 mL) and cooled to 0° C. Then 3-phenyl-1,3-oxazolidin-2-one (280 mg, 1.72 mmol) was diluted in CCl4 (2 mL) and added slowly to the reaction mixture. The reaction mixture was stirred for two hours at 0° C. The reaction was then slowly quenched with ice water (4 mL) and extracted with CCl4 (3×4 mL). The organic extracts were dried over sodium sulfate and concentrated to give 4-(2-oxo-1,3-oxazolidin-3-yl)-benzenesulfonyl chloride which was used without purification.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([SnH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.Cl[C:33]([O:35][CH3:36])=[O:34]>O1CCCC1>[C:33](=[O:34])([O:35][CH3:36])[O:29][CH:28]([C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[Sn:13]([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C(OC(=O)OC)c1ccc(OC)cc1
Reaction time: 0.08 h
Yield: 38 %

Procedure:
To dry tetrahydrofuran (80 mL) cooled to −78° C. was added a solution of lithium diisopropylamide (2.0 M in heptane/tetrahydrofuran/ethylbenzene, 18.36 mL, 37.5 mmol) followed by tri-n-butyltin hydride (9.81 mL, 37.5 mmol) dropwise. After 5 minutes, the mixture was placed in an ice water bath for 0.5 hours, then recooled to −78° C. 4-Methoxybenzaldehyde (4.45 mL, 37.5 mmol) was added dropwise, and the reaction mixture was stirred at this temperature for 1.5 hours. Afterwards, methyl chloroformate (3.41 mL, 44.1 mmol) was added dropwise, the cooling bath was removed, and the mixture was allowed to stir overnight at room temperature. Then a solution of saturated aqueous ammonium chloride (100 mL) was added followed by extraction with ethyl acetate. The organic extract was dried, filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate in hexanes) which afforded 6.7 g, (38%) of the title compound.
Reaction SMILES: O[C:2]1([C:10]([O:12][CH3:13])=[O:11])[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.S(Cl)([Cl:16])=O>>[ClH:16].[CH3:13][O:12][C:10]([C:2]1[CH:7]2[CH2:6][CH2:5][N:4]([CH2:9][CH2:8]2)[CH:3]=1)=[O:11]
Reactant: COC(=O)C1(O)CN2CCC1CC2
Reactant: O=S(Cl)Cl
Product: COC(=O)C1=CN2CCC1CC2
Product: Cl

Procedure:
Powdered 3-hydroxy-3-methoxycarbonyl-1-azabicyclo[2.2.2]octane (16.0 g, 0.086 mol) was added protionwise to thionyl chloride (100 ml) at 0°. Following the addition, the reaction mixture was stirred and heated under reflux for 48 h. The thionyl chloride was then removed under reduced pressure to afford a solid, which was recrystallised from acetone, giving 3-methoxycarbonyl-1-azabicyclo[2.2.2]oct-2-ene hydrochloride, m.p. 178°-179°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH2:21][CH2:20]2>>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][CH2:21][CH2:20]3)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: Clc1nc(Cl)nc(Nc2ccccc2)n1
Product: Clc1nc(Nc2ccccc2)nc(Nc2ccc3c(c2)CCC3)n1
Yield: 37 %

Procedure:
The reaction of 4,6-dichloro-N-phenyl-[1,3,5]triazine-2-amine with 5-aminoindan using the method described for the synthesis of CT-32028 provided CT-32099 (36 mg, 37% yield). 1H NMR (d6-DMSO) δ 10.15–10.28 (m, 2H), 7.56–7.72 (m, 3H), 7.05–7.39 (m, 5H), 2.75–90 (m, 4H), 1.94–2.09 (m, 2H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[N+:9]([O-:10])=[C:8]2[CH2:11][O:12][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]2=[CH:6][CH:5]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>CO>[OH:1][CH:2]([C:4]1[N+:9]([O-:10])=[C:8]2[CH2:11][O:12][CH:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:14][C:7]2=[CH:6][CH:5]=1)[CH2:3][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: [O-][n+]1c(C2CO2)ccc2c1COC(c1ccccc1)O2
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc2c([n+]1[O-])COC(c1ccccc1)O2

Procedure:
To 15.0 g. (0.055 mole) of 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide in 200 ml. of methanol was added 30 ml. tert-butylamine and the resulting reaction mixture was heated to the reflux temperature for 3 hours. Solvent and excess tertbutylamine were removed in vacuo to give 13.4 g. (73.6%) of 6-(1-hydroxy-2-tert-butylaminoethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide after recrystallization from ethyl acetate: m.p. 165°-168° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:29])[CH:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=2)[CH:19]=1)[CH3:17].C(N(CC)CC)C>CC(C)=O>[CH3:13][O:14][C:15](=[O:29])[CH:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)[CH:19]=1)[CH3:17]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)C(C)c1ccc2cc(OC(=O)COCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
Benzyloxy acetyl chloride (24 gm, 86.95 mmol) was added drop-wise to a mixture of 2-(6-Hydroxynaphthalen-2-yl)propionic acid methyl ester 6 (20 g, 86.95 mmol) and triethylamine (22.5 g, 222.35 mmol) in acetone (300 ml) and stirred for 2 hrs at room temp. Solids were filtered off, acetone distilled off, and water (100 ml) added. Crude 99 was extracted into chloroform, washed with 5% sodium bicarbonate (2×50 ml), water (2×50 ml), dried over sodium sulphate and distilled. Crude 99 was purified by recrystallising in chloroform:hexane (1:6) to get pure 99 (21 g, 63.9%) as a white powder. M.p: 58-60° C.
Reaction SMILES: [H-].[Na+].S(O[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+].O.O>[O:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:16][CH2:15][CH2:14][CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccccc2O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)CCCCO2
Reaction time: 8 h

Procedure:
To a mixture of 18.22 g of sodium hydride (60% dispersed in mineral oil) and 200 ml THF is added dropwise at 0° C. a solution of 146 g of o-tosyloxyphenol in 100 ml of THF. The reaction mixture is allowed to come to room temperature overnight. The reaction mixture is then chilled and 20 ml of H2O is added slowly. The mixture is then diluted with ethyl acetate and with brine and water. The organic layer is dried (MgSO4), filtered, and concentrated purification by flash column chromatography affords 2,3,4,5-tetrahydro-1-benzoxepin.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].CCCCCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([O:14][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Yield: 100.5 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl-4-piperidone (14.9 g, 74.8 mmol) in DMF (35 mL) was added TMSCl (11.4 mL, 89.7 mmol) and then Et3 N (25.0 mL, 179 mmol) dropwise at room temperature, and the reaction mixture was heated at 80° C. for 18 hr. Hexane was added to the reaction mixture, and the resulting mixture was washed with sat. NaHCO3 and brine, dried over Na2SO4, and concentrated to dryness. Chromatography of the residue with hexane-EtOAc (5:1, v/v) as eluent gave 1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine (20.4 g, 99%) as a yellow oil. 1H-NMR (CDCl3) δ 0.19 (s, 9H), 1.46 (s, 9H), 2.05–2.15 (m, 2H), 3.48–3.56 (m, 2H), 3.83–3.91 (m, 2H), 4.79 (broad s, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)#[CH:15].ClC1N=CC(C2N=NN(C3C=C(C=CC=3C)C(O)=O)C=2)=CC=1>>[CH3:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:1]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=[N:2]1
Reactant: C#Cc1ccccn1
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Agent: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Product: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccccn2)nn1

Procedure:
4-Methyl-3-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-benzoic acid was prepared from 3-azido-4-methyl benzoic acid and 2-ethynyl pyridine (Aldrich) in the same manner as 3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (Example 1).