Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.ClCCCl.C(N(CC)CC)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>CO>[F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)nc1I
Reactant: COCCOCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COCCOCOc1ccc(F)nc1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A dry, 100 mL one neck round bottom flask was charged with 6-fluoro-2-iodopyridin-3-ol (2.59 ml, 11.9 mmol), a stirbar, and 50 mL dry DCE. The flask was fitted with an inert atmosphere/vacuum inlet, and the flask was cooled with a ice-water bath. The solution was carefully evacuated to <5 mm Hg, and refilled with nitrogen. The slurry was treated with triethylamine (2.49 ml, 17.9 mmol). To the stirring solution was added 2-methoxyethoxymethyl chloride (1.93 g, 15.5 mmol) dropwise over 30 minutes via syringe pump. The reaction was stirred for 2 h at 0° C., and then treated with 1 mL MeOH. The slurry was filtered cold, and the precipitate was washed with cold DCE (2×50 mL). The combined filtrates were concentrated in vacuo, and heated into 50 mL toluene. The slurry was cooled to room temperature, and then to −5° C. (refrigerator) overnight. The slurry was filtered, and the precipitate was washed with toluene (2×20 mL). The combined filtrates were concentrated in vacuo to afford 6-fluoro-2-iodo-3-((2-methoxyethoxy)methoxy)pyridine (3.91 g, 100% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.36 (s, 3H) 3.53-3.57 (m, 2H) 3.85-3.89 (m, 2H) 5.30 (s, 2H) 6.83 (dd, J=8.71, 3.62 Hz, 1H) 7.46 (dd, J=8.71, 6.46 Hz, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −74.58 (dd, J=5.85, 3.25 Hz, 1 F). 13C NMR (101 MHz, chloroform-d) δ ppm 59.01 (s, 1 C) 68.37 (s, 1 C) 71.39 (s, 1 C) 94.74 (s, 1 C) 106.51 (d, J=14.30 Hz, 1 C) 108.53 (d, J=38.15 Hz, 1 C) 126.55 (d, J=7.80 Hz, 1 C) 152.04 (d, J=4.77 Hz, 1 C) 156.71 (d, J=240.59 Hz, 1 C). HPLC-MS: 1.96 min (93.4%@215 nm; 97.2% @254 nm; m/z=327.9, calculated for C9H11FINO3+H+=328.1).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[CH:33].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:1]([C:5]1[N:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:8]2[NH:13][N:12]=[C:11]([C:33]#[C:32][CH2:31][CH2:30][CH2:29][CH2:28][Cl:27])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(I)c2n1
Reactant: C#CCCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCCl)c2n1
Yield: 52.3 %

Procedure:
A solution of 5-butyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (50 g, 107 mmol), 6-chloro-1-hexyne (18.71 g, 160 mmol), triethylamine (22.37 mL, 160 mmol), bis(triphenylphosphine)palladium(II)dichloride (5.63 g, 8.02 mmol) and copper(I) iodide (3.04 g, 15.94 mmol) in N,N-Dimethylformamide (1000 mL) under nitrogen was heated to 70° C. for 4 hours. The cooled solution was evaporated and the residue was purified by chromatography on a 1.5 kg silica cartridge eluted with 20-80% cyclohexane—EtOAc during 12 column volumes. Appropriate fractions were evaporated to give the title compound as a yellow foam (25.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].CCN(C(C)C)C(C)C.[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 100 %

Procedure:
3-Nitroaniline (6.00 g, 43.4 mmol) was sealed in a flask with stir bar under nitrogen and dissolved with dichloromethane (DCM, 145 mL). The solution was cooled on ice before (i-Pr)2NEt (8.35 ml, 47.8 mmol) and butyryl chloride (5.00 ml, 47.8 mmol) were added. The flask was removed from the ice and stirred for 16 h. The reaction was then diluted with DCM and aq. 1 M HCl, the layers were separated, and the combined organics were washed again with 1 M aq. HCl, then twice with half-saturated aq. NaHCO3, then brine. The organic phase was dried over MgSO4, filtered, and concentrated, yielding a yellow oil (9.04 g, 100%). LRMS (ESI−) (M−H): 207.06. The crude oil was used without further purification in the subsequent reaction.
Reaction SMILES: Br[C:2]1[C:3]([CH3:18])=[C:4]([C:7]([O:14][CH:15]([CH3:17])[CH3:16])=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[C:10]([C:8]1[C:7]([O:14][CH:15]([CH3:17])[CH3:16])=[C:4]([C:3]([CH3:18])=[C:2]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[CH:9]=1)[CH:5]=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(Br)cc(C(C)(C)C)c(OC(C)C)c1C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cc1c(C#C[Si](C)(C)C)cc(C(C)(C)C)c(OC(C)C)c1C=O

Procedure:
Following General Procedure D and using 3-bromo-5-tert-butyl-6-isopropoxy-2-methyl-benzaldehyde (Intermediate 141, 0.43 g, 1.37 mmol), triethyl amine, copper(I)iodide (0.021 g, 0.11 mmol), trimethylsilyl acetylene (1 mL), and dichlorobis(triphenylphosphine)palladium(II) (0.077 g, 0.11 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent, the title compound was obtained (0.45 g, ˜100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[C:6]([CH:14]=O)=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S1(CCCC1)(=O)=O.C([BH3-])#N.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C=O)nn2C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 6-bromo-3-formyl-1-isopropyl-1H-indazole-4-carboxylate (4.5 g, 13.84 mmol) in DMF (31.5 mL) was added p-toluenesulfonic acid monohydrate (0.342 g, 1.8 mmol), p-toluenesulfonyl hydrazide (3.35 g, 18.0 mmol) followed by sulfolane (31.5 mL), and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (3.489 g, 55.0 mmol) was added portion wise over a period of 25 min. The resulting reaction mixture was stirred at 100° C. for 2 h and then at RT for 6 h. The reaction mixture was diluted with water and extracted with ethyl acetate (4×300 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue (4.4 g) was purified by silica gel chromatography (eluent: 0-5% ethyl acetate: pet ether) to afford the title compound as an off white solid (2.95 g, 68%). 1H NMR (CDCl3, 400 MHz): δ 1.559 (d, J=6.8 Hz, 6H), 2.674 (s, 3H), 3.976 (s, 3H), 4.667-4.767 (m, 1H), 7.715 (d, J=1.6 Hz, 1H), 7.761 (d, J=1.6 Hz, 1H). LCMS (ES+): 98.63%, 313.06 [M+H] ion present.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=[CH:15][C:8]=3[C:7](=[O:19])[C:6]=2[CH:20]=1.[CH3:21][N:22](C)C=O.C(Cl)(Cl)Cl.[C-]#N.[Na+]>O>[CH:16]([C:13]1[CH:14]=[CH:15][C:8]2[C:7](=[O:19])[C:6]3[CH:20]=[C:2]([C:21]#[N:22])[CH:3]=[CH:4][C:5]=3[CH2:11][O:10][C:9]=2[CH:12]=1)([CH3:18])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(C)c1ccc2c(c1)OCc1ccc(Br)cc1C2=O
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)c1ccc2c(c1)OCc1ccc(C#N)cc1C2=O

Procedure:
Reflux a mixture of 8.39 gm. (0.0253 mole) of 9-bromo-6,11-dihydro-3-isopropyl-11-oxodibenz[b,e]oxepin, 4.83 gm. (0.0539 mole) of cuprous cyanide and 30 ml. of dimethylformamide for 8 hours with vigorous stirring. Cool the reaction mixture and shake with a mixture of 36 ml. of chloroform, 25 ml. of saturated sodium cyanide solution and 25 ml. of water until all solids have dissolved. Separate the organic layer, wash with aqueous sodium cyanide solution and water and dry over anhydrous magnesium sulfate. Remove the solvent under vacuum. Purity the resulting oil (7.01 gm.) by column chromatography on silica gel with benzene as eluant to obtain the title product [yield 2.8 gm., m.p. 101°-108° C., showing a single spot, Rf =0.18 on thin layer chromatography or silica gel with benzene as the solvent system, pmr (CDCl3 1,23(6H, d, (CH3)2CH--), 2.95 (1H,m, (CH3)2CH--), 5.20 (2H,s, CH2O)].
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[CH2:11][NH:12]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[CH:5][C:4]=1[NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=1)#[N:2].N1CCCCC1>CN(C=O)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[CH2:11][NH2:12])=[CH:5][C:4]=1[NH:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[N:33]=1)#[N:2]
Reactant: Cc1cc(C)nc(Nc2cc(NC(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)cnc2C#N)c1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(Nc2cc(NC(=O)CN)cnc2C#N)c1
Reaction time: 1 h

Procedure:
To a suspension of 9H-fluoren-9-ylmethyl [2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)-2-oxoethyl]carbamate (120 mg, 0.23 mmol) in DMF (1.8 mL) was added piperidine (394 mg, 4.63 mmol). After 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (0-70% ethyl acetate/hexanes, linear gradient, followed by 0-12% methanol/dichloromethane, linear gradient) to afford N-{6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}glycinamide. MS ESI calc'd for C15H17N6O [M+H]+ 297. found 297. 1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.85 (d, J=2.1 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H), 6.64 (s, 1H), 6.61 (s, 1H), 3.31 (s, 2H), 2.29 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: C(C[CH2:4][NH:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#N.[N:33]1([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[CH2:38]CN[CH2:35][CH2:34]1>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:6](=[O:32])[N:5]3[CH2:4][CH2:38][N:33]([C:39]4[S:40][CH:41]=[CH:42][N:43]=4)[CH2:34][CH2:35]3)=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: c1csc(N2CCNCC2)n1
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)N1CCN(c2nccs2)CC1

Procedure:
Compound 108 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with 2-(piperazin-1-yl)thiazole. LCMS (+ESI) m/z=545.3 [M+H]+. 1H NMR (CDCl3) δ 7.93 (d, J=9.6 Hz, 1H), 7.48-7.52 (m, 1H), 7.30-7.32 (m, 1H), 7.19-7.26 (m, 2H), 6.63 (d, J=3.7 Hz, 1H), 4.87 (d, J=9.6 Hz, 1H), 4.82 (s, 2H), 3.87-3.98 (m, 4H), 3.64-3.81 (m, 3H), 3.45-3.58 (m, 3H), 3.18 (br, 2H), 1.11 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([OH:16])=O)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.C(OCC)(=O)C>[CH3:3][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([NH:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:16])[CH3:1]
Reactant: CC(C)Oc1c(C(=O)O)oc2ccccc12
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(=O)NCc2ccccc2)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 1.14 mmol) and 1,1'-carbonyldiimidazole (240 mg, 1.48 mmol) in 7 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and benzylamine (0.75 mL, 6.84 mmol) is added and the reaction mixture is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:4 to 1:3) provides 3-(1-methylethoxy)-N-(phenylmethyl)-2-benzofurancarboxamide in 78% yield as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[F:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(F)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(F)cc(NS(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 76.8 %

Procedure:
(S)—N-(3-Fluoro-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (36 mg, 0.05 mmol) was treated with trifluoroacetic acid (1 ml, 13 mmol) and a solution of ammonia (7N in methanol, 1 ml, 7 mmol) according to the method described in Example 27 to give 22 mg (75% yield) of the title compound. Purity 100%.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.B([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)=[CH:17][CH:16]=1)(O)O>>[O:29]=[S:25]1(=[O:28])[CH2:26][CH2:27][N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:2]3[N:7]4[N:8]=[C:9]([NH2:11])[N:10]=[C:6]4[CH:5]=[CH:4][CH:3]=3)=[CH:16][CH:17]=2)[CH2:23][CH2:24]1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: O=S1(=O)CCN(Cc2ccc(B(O)O)cc2)CC1
Product: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Yield: 79.2 %

Procedure:
5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (368 mg, 1.73 mmol) and 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide (0.512 mg, 1.90 mmol), in a manner analogous to Step 73c. The residue was purified on a 12 g Isco silica gel column using a gradient of 0-15% methanol in dichloromethane as an eluent. 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (490 mg, 79%) was isolated as a beige foam. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 7.93 (d, J=8.5 Hz, 2H), 7.50 (m, 3H), 7.37 (d, J=7.8 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 6.02 (s, 2H), 3.78 (s, 2H), 3.15 (s, 4H), 2.91 (s, 4H). MS=358 (MH)+.
Reaction SMILES: C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH:38]([C:48]2[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=2[F:55])[C:39]2[N:44]=[CH:43][C:42]([C:45](O)=[O:46])=[CH:41][CH:40]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH:38]([C:48]2[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=2[F:55])[C:39]2[CH:40]=[CH:41][C:42]([C:45]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:46])=[CH:43][N:44]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CCCCC1)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 57.9 %

Procedure:
Triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and aminomethylcyclohexane (30 μl, 0.23 mmol) were added to a solution of the [6-[(4-chlorophenylsulfonyl) (2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol), which had been obtained in Example 338, in dichloromethane (5 ml). The resulting mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with dichloromethane, followed by successive washing with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column and a fraction obtained from the elution portion with hexane:ethyl acetate=3:1 was concentrated under reduced pressure, whereby the title compound (58 mg, 0.11 mmol, 59%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])[CH:17]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(CC(C)=O)cc1
Product: COc1ccc(C(=CN(C)C)C(C)=O)cc1

Procedure:
35 g of 3-(4-methoxyphenyl)-2-propanone and 70 ml of dimethylformamide dimethyl acetal are heated at 70° C. for 3 hours. The reaction mixture is then evaporated to dryness in vacuo, and the residue is induced to crystallise with petroleum ether and the crystals are filtered off with suction. 43 g of 4-dimethylamino-3-(4-methoxyphenyl)-3-buten-2-one are obtained. Melting point 51° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:28][CH2:27][C:13]3([O:18][CH2:17][CH2:16][N:15]([C:19]([C:21]4[N:22]=[C:23]([CH3:26])[S:24][CH:25]=4)=[O:20])[CH2:14]3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:26][C:23]1[S:24][CH:25]=[C:21]([C:19]([N:15]2[CH2:14][C:13]3([CH2:27][CH2:28][N:10]([CH2:9][CH2:8][O:7][C:6]4[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:30][CH:29]=4)[CH2:11][CH2:12]3)[O:18][CH2:17][CH2:16]2)=[O:20])[N:22]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CO)cc4)CC3)C2)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(C=O)cc4)CC3)C2)cs1

Procedure:
Manganese dioxide (0.65 g) was added to a solution of (9-(2-(4-(hydroxymethyl)phenoxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylthiazol-4-yl)methanone (0.32 g) (example 1, step i) in DCM (20 mL) and the resulting black suspension heated under reflux for 1 h. After cooling the reaction mixture was passed through a pad of Celite. The pad was washed with DCM (2×30 mL) and the combined filtrate and washings evaporated in vacuo to give the subtitled compound as a gum. Yield 0.25 g.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:9]([F:12])([F:11])[F:10])([C:5]([F:8])([F:7])[F:6])[O-:4].[Li+].[S:16](F)([F:19])([F:18])[F:17]>C(OCCCC)CCC>[F:1][C:2]([F:13])([F:14])[C:3]([C:5]([F:8])([F:7])[F:6])([C:9]([F:11])([F:12])[F:10])[O:4][S:16]([F:19])([F:18])[F:17]
Reactant: FS(F)(F)F
Reactant: [O-]C(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Agent: [Li+]
Solvent: CCCCOCCCC
Product: FC(F)(F)C(OS(F)(F)F)(C(F)(F)F)C(F)(F)F
Temperature: -70 °C
Yield: 20.9 %

Procedure:
A solution of 10.5 g (0.043 mol) of lithium 2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxide in 60 ml of dibutyl ether was added dropwise to a solution of 8 ml (measured at -78° C., 0.15 mol) of sulfur tetrafluoride in 50 ml of dibutyl ether cooled to -70° C. The reaction mixture was warmed to 25° C., and the volatiles were distilled out at reduced pressure and condensed in a cold trap at -78° C. The condensate was fractionated to give (A) 2.91 g of 2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxysulfur trifluoride as a colorless liquid: bp 56° to 60°; 19F NMR (CCl3F) δ -71.4 ppm (q, J=3.0 Hz,9F) and 44.0 ppm (broad, 3F) and (B) 3.60 g of bis[2,2,2-trifluoro-1,1-(trifluoromethyl)ethoxy]sulfur difluoride as a colorless liquid: bp 35° to 37° C. (20 mm); 19F NMR (CCl3F) δ -71.7 ppm (t, J=1.5 Hz, 18F) and +32.1 ppm (broad, 2F).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C(=O)=O.[F:7][C:8]([F:34])([F:33])[S:9]([C:12]1[CH:13]=[CH:14][C:15]2[CH:21]=[CH:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[C:17](=[C:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:16]=2[CH:32]=1)(=[O:11])=[O:10]>CO.C(Cl)(Cl)Cl>[OH:3][CH:1]([N:29]1[CH2:30][CH2:31][C:26](=[C:17]2[C:16]3[CH:32]=[C:12]([S:9]([C:8]([F:34])([F:7])[F:33])(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]=3[CH:21]=[CH:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]2=3)[CH2:27][CH2:28]1)[CH3:2]
Reactant: C1CO1
Reactant: O=S(=O)(c1ccc2c(c1)C(=C1CCNCC1)c1ccccc1C=C2)C(F)(F)F
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(O)N1CCC(=C2c3ccccc3C=Cc3ccc(S(=O)(=O)C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.244 g. of ethylene oxide of 30 ml. of methanol at dry-ice temperature is added to an ice cold solution of 2.55 g. of 4-(3-trifluoromethylsulfonyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine in 15 ml. of chloroform and 75 ml. of methanol. The solution is stirred at ambient temperature overnight. A second quantity (0.25 g.) of ethylene oxide is added as before and the mixture is again stirred overnight. The mixture is concentrated to dryness and the residue is coevaporated in vacuo several times with acetonitrile. The product is recrystallized several times from acetonitrile to give (±)-1-hydroxyethyl-4-(3-trifluoromethylsulfonyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 141°-144° C.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:22]([O:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1)[CH3:23]
Reactant: CCO
Reactant: COC(=O)c1ccc2c(c1C)SCCC2O
Agent: O=S(=O)(O)O
Product: CCOC1CCSc2c1ccc(C(=O)OC)c2C

Procedure:
13.8 g (0.058 mol) of methyl 4-hydroxy-8-methylthiochromane-7-carboxylate are heated below boiling point for 4 hours in 60 ml of ethanol with 1 g of sulfuric acid added. The solvent is then distilled off and the residue is taken up in water. The aqueous phase is extracted using ethyl acetate. The organic phase is washed using sodium hydrogen carbonate solution, dried and concentrated. The product is purified by chromatography.