Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]2[NH:7][C:8]([C:14]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:15]=3[N:16]=[C:17]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:18]([CH3:24])=[N:19]4)=[CH:9][C:10]=2[C:11]([OH:13])=O)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[C:26]([NH:25][C:17]1[C:18]([CH3:24])=[N:19][C:20]2[C:15]([N:16]=1)=[C:14]([C:8]1[NH:7][C:6]3[C:3]4([CH2:4][CH2:5]4)[NH:2][C:11](=[O:13])[C:10]=3[CH:9]=1)[CH:23]=[CH:22][CH:21]=2)([CH3:27])([CH3:28])[CH3:29]
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC(C)(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)C3(CC3)NC4=O)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (324b) (1.1 g, 2.16 mmol) in 8 mL of dioxane and 8 mL of water was added LiOH monohydrate (0.45 g, 10.83 mmol) and heated in an oil bath at 110° C. for 18 h. It was concentrated under reduced pressure to half of its volume. The remaining mixture was lyophilized for 24 h to give a yellow solid. m/z (ESI, +ve) 480.2 (M+H)+. To the yellow solid suspended in 5 mL of dioxane at 0° C. was treated with 10 mL of 4 N HCl in dioxane. The resulting orange mixture was stirred at RT for 3 h. The mixture was concentrated to half of its volume. The insoluble solid was filtered, rinsed with 2×5 mL of ether. The filtrate was discarded. The orange solid was dried in a vacuum oven at 40° C. for 1 h to give 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (324c), which was used as crude material and based on theoretical yield. m/z (ESI, +ve) 380.2 (M+H)+. A suspension of the above obtained 2-(1-aminocyclopropyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (324c) in 12 mL of DMF and 12 mL of DCM was treated with DIEA (2.25 mL, 12.93 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.40 g, 2.70 mmol). The resulting homogeneous solution was stirred at RT for 2 h. It was diluted with 200 mL of DCM, washed sequentially with 25 mL of water, 25 mL of 1 N NaOH and 25 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (50% EtOAc in hexanes followed by 1-3% MeOH in EtOAc) to give 2′-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (324) (540 mg, 1.494 mmol, 69% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (1H, br.), 7.78 (1H, d, J=6.5 Hz), 7.67 (1H, s), 7.60 (1H, m), 7.35 (1H, t, J=7.8 Hz), 6.90 (1H, m), 6.00 (1H, s), 2.56 (3H, s), 1.52 (9H, s), 1.42 (2H, m), 1.33 (2H, m). m/z (ESI, +ve) 362.1 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].Cl[C:17](=[N+:19]([CH3:21])[CH3:20])Cl.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([S:7]([CH2:10][C:11]2[O:12][C:17]([N:19]([CH3:21])[CH3:20])=[N:14][N:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)CS(=O)(=O)c1ccccc1
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)c1nnc(CS(=O)(=O)c2ccccc2)o1

Procedure:
To 3.0 g (14.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 100 mL of CHCl3, 3.41 g (21.0 mmol, 1.5 eq) of dichloromethylene-dimethyl-ammonium chloride and 3.90 mL (28.0 mmol, 2 eq) of triethyl-amine were added. The solution was stirred at reflux for 1 hour, partitioned between aqueous NaOH 0.5M and EtOAc. The combined organic phases were dried over Na2SO4, filtered, evaporated, and column chromatography on silica gel with CH2Cl2/MeOH 100:1 afforded 0.59 g /15%) of (5-benzenesulfonylmethyl-[1,3,4]oxadiazol-2-yl)-dimethyl-amine as a white solid, MS: 268 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]([NH:28][C:29]3[N:33]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:32]=[C:31]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:30]=3)=[O:27])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:41]([C:31]1[CH:30]=[C:29]([NH:28][C:26](=[O:27])[NH:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:13]=3)=[CH:16][CH:17]=2)[N:33]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:32]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(N)c3)c3ccccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
Methoxyacetyl chloride (64.2 μl, 0.703 mmol) was added slowly to a mixture of 1-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (8) (89 mg, 0.176 mmol) and DIPEA (153 μl, 0.878 mmol) in THF (5 mL). The reaction mixture was stirred at 0° C. for a further 20 min and then warmed to RT. After 2.5 hr, the reaction was quenched by the addition of a solution of 1% NH3 in MeOH (3 mL), and the resulting mixture stirred for a further 45 min. The volatiles were removed in vacuo and the residue was dissolved in a mixture of MeOH (5 mL) and AcOH (2 mL) and subjected to SCX capture and release eluting with 1% NH3 in MeOH solution. The crude material was purified by flash column chromatography (SiO2; 12 g) eluting with 0 to 60% [5% MeOH in EtOAc] in iso-hexane to give N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (1) (62 mg, 61%) as a white solid: m/z 579 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.40 (3H, s), 3.31 (3H, s), 3.99 (2H, s), 6.41 (1H, s), 6.70 (1H, dd), 7.32-7.40 (3H, m), 7.44-7.48 (2H, m), 7.55-7.61 (1H, m), 7.63-7.67 (2H, m), 7.84 (1H, dd), 7.97 (1H, d), 8.09 (1H, d), 8.19 (1H, d), 8.79 (1H, s), 9.13 (1H, s), 10.02 (1H, s).
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:36][C:37]1[N:41]([CH3:42])[C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[N:38]=1>CN(C=O)C>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:36][C:37]3[N:41]([CH3:42])[C:40]4[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=4[N:38]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1nc2ccccc2n1C
Temperature: 65 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A mixture of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (240 mg, 0.64 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (310 mg, 2.25 mmol), potassium iodide (10 mg, 0.064 mmol) and 2-chloromethyl-1-methylbenzimidazole (153 mg, 0.7 mmol) in DMF (12 ml) was heated at 65° C. for 3 hours. Further 2-chloromethyl-1-methylbenzimidazole (90 mg, 0.41 mmol) and potassium carbonate (165 mg, 1.2 mmol) were added and heating continued for 2 hours. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with water and the solid product collected by filtration, washed with ether and dried under vacuum to give 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-((1-methylbenzoimidazol-2-yl)methoxy)quinazoline (292 mg, 95%). MS-ESI: 506 [MNa]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](Cl)=[C:6]2[S:5][CH:4]=1.[NH2:18][C:19]1[C:20]([CH3:25])=[CH:21][CH:22]=[CH:23][CH:24]=1>C1(OC)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])=[C:6]2[S:5][CH:4]=1
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)c1cnc2c(OC)csc2c1Cl
Solvent: COc1ccccc1
Product: CCOC(=O)c1cnc2c(OC)csc2c1Nc1ccccc1C

Procedure:
Ethyl 3-methoxy-7-chlorothieno[3,2-b]pyridin-6-carboxylate (1.5 g, 0.0055 mol) and o-toluidine (1.18 g, 0.011 mol) in anisole (30 ml) were heated under reflux in an inert atmosphere for twenty hours. The solvent was evaporated under reduced pressure and the residue was taken up in chloroform (200 ml) and washed with 2N hydrochloric acid (3×100 ml). The organic phase was then washed with sodium bicarbonate solution (2×100 ml), and water, dried over magnesium sulphate, filtered and evaporated to give an oil. The oil was purified by flash chromatography using dichloromethane as eluant. The fractions containing the product were combined and evaporated to give a colourless product, 1.12 g. Recrystallisation from ethyl acetate gave the title compound, 0.63 g, m.p. 141°-143°.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: NNc1cccc(Br)c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2cccc(Br)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-bromophenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that the resulting solid was the named product (m.p. 34° C.–35° C.).
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:42]=[N:41][CH:40]=[C:39]([Cl:43])[C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:21][C:22]2[C:25]3([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:24](=[O:31])[C:23]=2[C:32]2[CH2:33][N:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)=[O:6].[H][H]>CCO.[Pt](=O)=O>[Cl:43][C:39]1[CH:40]=[N:41][CH:42]=[C:3]([Cl:2])[C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:21][C:22]2[C:25]3([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[C:24](=[O:31])[C:23]=2[CH:32]2[CH2:37][CH2:36][CH2:35][N:34]([CH3:38])[CH2:33]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC1=C(C2=CC=CN(C)C2)C(=O)C12CCCCC2
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [I-]
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC1=C(C2CCCN(C)C2)C(=O)C12CCCCC2
Yield: 100.1 %

Procedure:
The compound of Example 86 (127 mg, 0.21 mmol) was dissolved in EtOH (10 ml) and hydrogenated over platinum dioxide (50 mg) at room temperature and 1 atmosphere hydrogen for 5 days. The catalyst was removed by evaporation in vacuo to afford the title compound as a yellow oil (129 mg, 100%). δH (DMSO d6) 10.48 (1H, br s), 8.70 (2H, s), 7.59 (2H, d, J 8.1 Hz), 7.30 (2H, d, J 8.1 Hz), 4.25 (1H, m), 4.22 (2H, q, J 4.0 Hz), 3.23 (1H, m), 3.08 (1H, m), 1.70-1.50 (22H, m), 1.26 (3H, m); m/z (ES+, 70V) 613.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>CO.[C].[Pd]>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(-c2ccncc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(C2CCNCC2)cc1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A suspension of 4-(4-(trifluoromethyl)phenyl)pyridine (500 mg, 2.24 mmol, 1.00 equiv), CF3COOH (1.27 g, 11.14 mmol, 5.00 equiv), and palladium carbon (100 mg, 5%) in methanol (50 mL) was hydrogenated overnight under an atmosphere of H2(g) at 30° C. in an oil bath. The reaction mixture was filtered and washed with methanol and concentrated in vacuo. The pH value of the solution was adjusted to 8-9 with aqueous sodium hydroxide (1 M). The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and concentrated under vacuum, yielding 350 mg (68%) of 4-(4-(trifluoromethyl)phenyl)piperidine as brown oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:15]Br>O1CCOCC1>[Br:15][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)[C:12](=[O:14])[CH3:13]
Reactant: BrBr
Reactant: CC(=O)Cc1cccc(S(C)(=O)=O)c1
Solvent: C1COCCO1
Product: CC(=O)C(Br)c1cccc(S(C)(=O)=O)c1
Temperature: 25 °C

Procedure:
A stirred solution of 1-(3-methanesulphonyl-phenyl)-propan-2-one (176b) (0.25 g, 1.18 mmol) in dioxane (10 ml) at 5° C. is treated with bromine (0.131 g, 0.82 mmol) added in two portions. The reaction is stirred and allowed to warm up to room temperature. The solvent is removed in vacuo to yield an orange oil of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(O[BH-](O[C:25](=[O:27])[CH3:26])OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:7][C:6]2[O:27][C:25]3[C:26](=[N:9][CH:4]=[CH:3][CH:8]=3)[CH:5]=2)[CH2:11][CH2:10]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na+]
Product: COc1ccccc1N1CCN(Cc2cc3ncccc3o2)CC1

Procedure:
The product from Example 35B, 1-(2-methoxyphenyl)piperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.85 (br, 4H), 3.19 (br, 4H), 3.85 (s, 3H), 3.88 (s, 2H), 6.93 (m, 5H), 7.20 (dd, 4.75, 8.14 Hz, 1H), 7.74 (m, J=1.02, 7.12 Hz, 1H), 8.54 (br, 1H); MS (DCI/NH3) m/z 324.2 (M+H)+; Anal Calcd for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99. Found: C, 69.72; H, 6.45; N, 12.81.
Reaction SMILES: C(N(CC=C)CC1SC=CC=1)C=C.[CH2:14]([N:17]([CH2:21][C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1)[CH2:18][CH:19]=[CH2:20])[CH:15]=[CH2:16].COC1C=C(C=CC=1)C(NCC1C=CSC=1S(Cl)(=O)=O)=O.CCCCC.C1C(=O)N(Cl)C(=O)C1.[O:65]1[C:69]2([CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[O:68][CH2:67][CH2:66]1.C(N(CC)CC)C>CCOCC.C(Cl)Cl>[CH2:14]([N:17]([CH2:18][CH:19]=[CH2:20])[CH2:21][C:22]1[S:26][C:25]([S:27]([N:72]2[CH2:73][CH2:74][C:69]3([O:68][CH2:67][CH2:66][O:65]3)[CH2:70][CH2:71]2)(=[O:29])=[O:28])=[CH:24][CH:23]=1)[CH:15]=[CH2:16]
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)Cl)s1
Reactant: C1CC2(CCN1)OCCO2
Agent: C=CCN(CC=C)Cc1cccs1
Agent: COc1cccc(C(=O)NCc2ccsc2S(=O)(=O)Cl)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCC
Product: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)s1
Temperature: -74 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
Procedure B (from (122a), without isolation of the sulfonyl chloride (122b). A solution of the allyl-protected thiophene (1a) (29.1 g, 150 mmol) in Et2O (440 g, 617 ml) was placed in a 1-1 three-necked flask (thermometer; argon; septum or SO2 inlet) and cooled to −74° C. by means of an acetone/dry ice bath. A solution of t-BuL in pentane (100 ml, 1.5M, 150 mmol) was added over 5 min whereupon the internal temperature momentarily rose to −64° C. and the mixture turned pink. After 20 min., SO2 (20 g, 312 mmol) was bubbled over 15 min. The SO2 consumption was best monitored by placing the SO2 bottle on a scale during the reaction The reaction mixture, which had turned to a thick, white wax was allowed to warm to room temperature over 2 h. A suspension of NCS (30 g, 226 mmol) was added, and stirring was continued overnight, whereupon the slurry turned purple. The mixture was filtered (fritted glass), and the precipitate was carefully washed with CH2Cl2 (2×300 ml). The combined organic layers were cooled to 0° C. under Ar, and treated with a solution of 1,4-dioxa-8-azaspiro[4,5]decane (27.8 g, 194 mmol) and triethylamine (19.7 g, 194 mmol) in CH2Cl2 (200 ml). After 1 h, the mixture was washed (NaHCO3 sat.; brine), dried (MgSO4), and concentrated to afford 53 g (83%) of the title sulfonamide as yellow oil: 1H NMR (CDCl3) δ7.36 (d, J=3.8 Hz, 1H), 6.90 (br. d, J=3.4 Hz, 1H), 5.92-5.79 (m, 2H), 5.33-5.16 (m, 4H), 3.93 (s, 4H), 3.78 (s, 2H), 3.21 (t, 5.7 Hz, 4H), 3.13 (d, 6.2 Hz, 4H), 1.81 (t, 5.7 Hz, 4H).
Reaction SMILES: O[CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:9][CH:10]=1.P(Br)(Br)[Br:23]>C(COC)OC.C(OCC)(=O)C>[Br:23][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(Cc1cccc(C#CCO)c1)OC(C)C
Reactant: BrP(Br)Br
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cccc(C#CCBr)c1)OC(C)C
Reaction time: 8 h

Procedure:
184 mg of Ethyl 3-[3-(3-hydroxy-1-propynyl)phenyl]-2-isopropoxypropanoate was dissolved in 4 ml of dimethoxyethane, and 50 μl of phosphorous tribromide was added. After stirring was continued at room temperature overnight, the reaction mixture was diluted with ethyl acetate and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off. Then, the residue was purified by silica gel column chromatography, to give 209 mg of the title compound in the 20:1 hexane-ethyl acetate fraction.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].O.[C:11]1(C)C=CC(S(O)(=O)=O)=C[CH:12]=1.C(OCC)(OCC)(OCC)C>C(OCCCCCCCC)(=O)C1C(=CC=CC=1)C(OCCCCCCCC)=O>[CH3:11][C:12]12[O:7][CH2:6][C:3]([CH2:8][OH:9])([CH2:4][O:5]1)[CH2:2][O:1]2
Reactant: OCC(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC
Agent: CCOC(C)(OCC)OCC
Solvent: O
Product: CC12OCC(CO)(CO1)CO2
Temperature: 120 °C
Reaction time: 22 h
Yield: 83 %

Procedure:
Pentaerythritol (60 g, 440.7 mmol) was added to a stirring solution of dioctyl phthalate (100 mL) containing trace p-toluene sulfonic acid monohydrate, and heated to 120° C. After triethyl orthoacetate (71.685 g, 81 mL, 441.87 mmol) was added in one portion the reaction was equipped with a distillation apparatus and stirred for 22 h. Upon return, 64 mL of ethanol had distilled (83% of the theoretical amount). TEA (40 drops) was added, stirred for 10 minutes, heated to 160° C. The TEA and remaining ethanol were removed under vacuum. After changing the distillation glassware, the final product, a white solid, was isolated by vacuum distillation at 185° C. and recrystallized using benzene. Yield: 83%, 58.64 g. 1H NMR (CDCl3; 500 MHz) δ ppm: 1.453 (s, 3H, CH3), 1.58 (t, 1H, OH), 3.454 (d, 2H, CCH2OH), and 4.015 (s, 6H, OCH2C). 13C NMR (CDCl3; 125.8 MHz) δ ppm: 23.53 (CH3), 35.71 (CH2CCH2), 61.50 (CCH2OH), 69.41 (OCH2C), and 108.67 (OCCH3). ESI-MS (m/z): 161.06 (161.07 calc'd for C7H12O4 [M+H]+). Elemental analysis calc'd (found) for C7H12O4: C, 52.49 (51.58); H, 7.55 (7.67).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:26])[C:24]=1[F:25]>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:21]4[CH:20]=[C:19]([F:18])[C:24]([F:25])=[C:23]([F:26])[CH:22]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: N#Cc1cc(-c2cc(F)c(F)c(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (71 mg, 83%), MS (ISP) m/z=342.4 [(M+H)+], mp 304.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1.[OH-].[Na+].[C:24]([O:28]C)(=[O:27])[CH:25]=[CH2:26].Cl>O1CCOCC1.ClCCl>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][C:12]1[CH:20]=[CH:21][C:9]([O:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH2:26][CH2:25][C:24]([OH:28])=[O:27])=[CH:10][CH:11]=1
Reactant: C=CC(=O)OC
Reactant: c1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CCN1CCCC1COc1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
The product from Example 167 (125 mg, 0.37 mmol) was treated with 20% NaOH (10 mL) and extracted with EtOAc, dried over Na2SO4 and dried down to give the free base. Dichloromethane (3 mL) and methyl acrylate (1 mL, 7 mmol) were added and the mixture was stirred at ambient temperature overnight. The reaction mixture was dried down to give oil. 4.0M HCl in dioxane was added and the mixture was stirred overnight at ambient temperature. The solvent was evaporated to give the title compound (61 mg, 57%); LC/MS; m/z 343 (M+H) 99%
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[CH3:12][Zn]C>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.O1CCOCC1>[Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: C[Zn]C
Reactant: Brc1cc(I)cc2nnsc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cc(Br)c2snnc2c1
Temperature: 50 °C
Yield: 59.5 %

Procedure:
To a solution of 7-bromo-5-iodo-1,2,3-benzothiadiazole (30 mg, 0.088 mmol), Pd(PPh3)4 (10.2 mg, 0.0088 mmol) and 1,4-dioxane (5 mL) was added dimethylzinc (2 M in toluene, 0.1 mL, 0.210 mmol), and the reaction was heated to 50° C. for 3 h. The solution was quenched with MeOH (1 mL), adsorbed onto silica gel, and purified by ISCO chromatography (1 to 3% EtOAc:heptane) to afford 12 mg (60%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.52 (s, 3 H), 7.58 (s, 1 H), 8.27 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3ccc(Cl)cc3)cc2)no1
Temperature: 90 °C
Yield: 82.4 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 4-chlorophenol (21 mg, 0.16 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 4 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(4-chloro-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (29 mg, 82%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 8.01 (s, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.50-7.65 (m, 3H), 7.26-7.38 (m, 2H), 6.97-7.11 (m, 2H), 5.17 (s, 2H).