Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)=O)=[CH:2]1.[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][CH2:25][O:26][NH2:27])([CH3:20])([CH3:19])[CH3:18].Cl>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6](=[N:27][O:26][CH2:25][CH2:24][NH:23][C:22](=[O:28])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=C(c1ccoc1)c1cc2ccncc2[nH]1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCON=C(c1ccoc1)c1cc2ccncc2[nH]1
Yield: 45 %

Procedure:
3-Furyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 137) (63 mg, 0.30 mmol) and tert-butyl[2-(aminooxy)ethyl]carbamate (55 mg, 0.31 mmol) were combined in ethanol (5 mL). The pH of the mixture was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the reaction mixture was refluxed for 12 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, and concentrated to a solid. Purification by Biotage chromatography (silica gel, 2 to 18% methanol in dichloromethane) produced tert-butyl 2-[[[(3-furyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate (50 mg, 45%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[CH2:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:42][CH2:38][CH:39]([CH3:41])[CH3:40])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=1[F:36])(=[O:29])=[O:28]
Reactant: CC(C)CN
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Product: CC(C)CNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1
Yield: 14.1 %

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.16 g, 0.27 mmol) and isobutylamine (0.15 g, 2.01 mmol), the title compound was obtained as a pale yellow solid (0.026 g; 14.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 7.84 (d, J=5.3 Hz, 1H), 7.60-7.72 (m, 1H), 7.46-7.51 (m, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.30 (d, J=6.9 Hz, 1H), 7.21 (t, J=9.1 Hz, 2H), 7.12 (d, J=0.5 Hz, 1H), 5.42 (d, J=4.9 Hz, 1H), 3.70 (t, J=4.6 Hz, 4H), 3.44 (t, J=4.6 Hz, 4H), 3.02 (t, J=6.2 Hz, 2H), 0.87 (d, J=6.7 Hz, 9H). MS (ESI) 621.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:23][S:24](O)(=[O:26])=[O:25]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:24]([Cl:23])(=[O:26])=[O:25])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CCc2ccccc21
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CCc2ccc(S(=O)(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.2 %

Procedure:
To a solution of indan-1-carboxylic acid 4-nitro-benzyl ester (2.3 g, 8.1 mmol) in anhydrous CHCl3 (13 mL) at −20° C. was added chlorosulfonic acid (2.8 g, 24.0 mmol) over a period of 10 minutes. The mixture was warmed to ambient temperature and stirred for 16 h. The reaction mixture was combined with ice-water and the resulting layer was extracted with CH2Cl2. The CH2Cl2 layer was washed with brine and was dried over anhydrous Na2SO4. The crude product was purified using flash silica chromatography (0-30% EtOAc/Hex) to yield 0.84 g (27%) of 6-chlorosulfonyl-indan-1-carboxylic acid 4-nitro-benzyl ester.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:32][C:33]([F:38])([F:37])[C:34](O)=[O:35].N1C=CC=CC=1>C(Cl)Cl>[C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH:17][C:34](=[O:35])[C:33]([F:38])([F:37])[F:32])[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Reactant: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1)C(F)(F)F
Reaction time: 8 h
Yield: 10.8 %

Procedure:
To a stirred solution of 46 mg (0.1 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 3 mL CH2Cl2 at RT, was added 10 μl (0.1 mmol, 1 eq) trifluoroacetic acid and 80 μl pyridine (1 mmol, 10 eq). Stirring was continued overnight, and the reaction mixture was evaporated to dryness. Column chromatography on silica gel (heptane/EtOAc 6:4) yielded 6 mg (12%) of (RS,SR)-N-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-2,2,2-trifluoro-acetamide as a light yellow powder, MS: 557 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8]1)=[O:6])[CH3:3].[CH2:21]1COCC1.[OH-].[K+].CI>CN(C=O)C>[CH2:2]([O:4][C:5]([C:7]1([CH3:21])[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: C1CCOC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl -1-benzyl-4-oxo-piperidine-3-carboxylate hydrochloride (150 g, 0.504 mol) was suspended in a solvent mixture of 750 ml THF and 750 ml DMF at room temperature. Addition of powdered KOH (56 g, 1.0 mol) was made in two equal lots keeping half an hour interval between two additions. To a clear reaction mixture methyl iodide (78 g, 0.55 mol) was added over period of 10 minutes and it was stirred for three hours at room temperature. The reaction was quenched by adding 4 ltr water followed by 1.5 ltr diethyl ether. Layers were separated. Organic layer was washed with water and dried over Na2SO4. Evaporation of organic solvent afforded a liquid, which was passed through a silica gel column to give 86 g (61%), titled compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]=[C:8]([NH2:10])[N:7]([C:11]([NH:13][CH3:14])=[S:12])[N:6]=1)(=[O:3])[CH3:2].[C:15](OC(OCC)OCC)(=O)C>>[C:1]([NH:4][C:5]1[N:9]=[C:8]2[N:10]=[CH:14][N:13]([CH3:15])[C:11](=[S:12])[N:7]2[N:6]=1)(=[O:3])[CH3:2]
Reactant: CNC(=S)n1nc(NC(C)=O)nc1N
Reactant: CCOC(OCC)OC(C)=O
Product: CC(=O)Nc1nc2ncn(C)c(=S)n2n1
Yield: 87 %

Procedure:
The synthesis method of Example 55 was applied. The compound (1.02 g) obtained in Example 32 and diethoxymethyl acetate (10 ml) were used as reagents. The mixture was reacted at 100° C. for 5.5 hours to give 925 mg of white crystals (yield 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([O:21][CH2:22][C:23]([NH:25][NH2:26])=[O:24])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)[CH:29]=[O:30].C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([O:21][CH2:22][C:23]3[O:24][C:29](=[O:30])[NH:26][N:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc3ncccc3c(OCC(=O)NN)n2)cc1OC
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3ncccc3c(OCc3n[nH]c(=O)o3)n2)cc1OC
Temperature: 70 °C

Procedure:
54 mg [7-(3,4-Dimethoxy-phenyl)-[1,6]-naphthyridine-5-yloxy]-acetic acid hydrazide (I.34) was placed in tetrahydrofuran (10 mL) and N,N-dimethyl formamide (1 mL) at ambient temperature before 37 mg carbonyl diimidazole and 43 μl triethylamine were added. The reaction mixture was heated to 70° C. where it was maintained for 16 h. After this time additional carbonyl diimidazole and triethylamine were added and the reaction was maintained at 70° C. for a further 5 h. After this time additional carbonyl diimidazole and triethylamine were added and the reaction was maintained at 70° C. for a further 19 h. The solvent was then removed under reduced pressure and the crude product that remained was partitioned between dichloromethane and water. The dichloromethane layer was separated and the aqueous phase was extracted with additional dichloromethane (×2). The combined organic fractions were washed with water, saturated sodium chloride solution and then dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification twice by chromatography on silica gel (methanol/ethyl acetate: 0%-5% and then methanol/ethyl acetate: 0%-2%) followed by trituration with dichloromethane provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([O:14][CH3:15])=[CH:10][C:11]=1[O:12][CH3:13])[O:5]COC.[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:22][C:23](=[S:24])[NH:1][C:2]2[CH:3]=[C:4]([OH:5])[C:9]([O:14][CH3:15])=[CH:10][C:11]=2[O:12][CH3:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=Nc1ccccc1
Reactant: COCOc1cc(N)c(OC)cc1OC
Product: COc1cc(OC)c(NC(=S)Nc2ccccc2)cc1O

Procedure:
(3-Amino-4,6-dimethoxyphenoxy)methoxymethane and phenyl isothiocyanate were treated in the same manner as described in Example 1 to give 3-(3-phenylthioureido)-4,6-dimethoxyphenol (melting point: 152°-154° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:41](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C.CO>CO.CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:19]=3[S:20][C:21]=2[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][CH:27]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: COc1ccc2c(C(=O)c3ccc(CN4CCCC4)c(OC)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reaction time: 24 h
Yield: 43.6 %

Procedure:
To a mixture of (210 mg, 0.37 mmol) of 6-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-(1-pyrrolidinylmethyl)phenyl ketone (Example 163, Part C) in 2.0 mL of MeOH/CH3CN solution (1:9 ratio) was added (0.091 mL, 0.52 mmol) of diisopropylethylamine and (0.26 mL, 0.52 mmol) 2 M (trimethylsilyl)diazomethane in hexanes at room temperature. The reaction was stirred for 24 h. Another portion (0.20 mL, 0.40 mmol) of 2 M (trimethylsilyl)diazomethane in hexanes was added along with 0.5 mL of MeOH, and the solution was stirred at room temperature for 24 h. Another portion (0.10 mL, 0.20 mmol) of 2 M (trimethylsilyl)diazomethane in hexanes was added, and the solution was stirred at room temperature for 24 h. The reaction mixture was concentrated to dryness under reduced pressure and then taken up in 30 mL of H2O and washed with 25 mL of H2O and 1:1 satd. NaHCO3-brine solution which were back extracted with CH2Cl2 (3×30 mL) and EtOAc (1×30 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 7% [10% conc NH4OH in MeOH]/CH2Cl2) afforded 92 mg (43%) of a yellow foam.
Reaction SMILES: CC1N=CN=C2C=1N=CN2[C@@H]1O[C@@H](CO)[C@@H](O)[C@H]1[OH:13].[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CN=C1.II>CN1CCCC1=O>[C:33]1([P:26](=[O:13])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1ncnc2c1ncn2[C@@H]1O[C@@H](CO)[C@@H](O)[C@H]1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: II
Agent: c1c[nH]cn1
Solvent: CN1CCCC1=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
Solid 1d (82 mg, 0.31 mmol), triphenylphosphine (274 mg, 1.03 mmol), and imidazole (140 mg, 2.05 mmol) are blended under argon by magnetic stirring before being dissolved in 1-methyl-2-pyrrolidinone (M-PYROL) (1.5 ml) at room temperature. Beads (1-3 mm) of iodine (261 mg, 1.03 mmol) are added over 5 min with slight heating observed. Further additions of triphenylphosphine, imidazole, and iodine (same quantities as above) are made in the order listed after 5 h, 24 h, and 56 h. More M-PYROL (0.5 ml) is added prior to the last addition. After 124 h, the reaction solution is partitioned between ethyl acetate (40 ml) and 10% sodium thiosulfate (15 ml). The aqueous layer is extracted with more ethyl acetate (3×15 ml). The combined organic layers are washed once with brine (15 ml), dried (MgSO4), and evaporated to a solid. A crop of triphenylphosphine oxide (Ph3PO) is obtained from a chilled ethyl acetate solution of this residue. More Ph3PO is removed by repeating this process with chloroform. Crude 1e is purified by preparative TLC (Analtech GF, 20×20 cm, 2,000 μ) using 9:1 CHCl3/MeOH as developing solvent. Pure 1e crystallized from 2-propanol as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O.O1C2C=CC(C3(C(NC4C=CC(C(OCC(O)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: CN(C)CCO
Agent: COc1ccccc1C(OCC(C)O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(OCCN(C)C)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-(dimethylamino)ethoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-(dimethylamino)ethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7])[CH3:3].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[CH3:1][N:2]([CH2:4][C:5](=[CH2:9])[C:6]([O:8][CH2:15][CH3:16])=[O:7])[CH3:3]
Reactant: CCO
Reactant: C=C(CN(C)C)C(=O)O
Agent: O=S(=O)(O)O
Product: C=C(CN(C)C)C(=O)OCC

Procedure:
A solution of the 2-dimethylaminomethylacrylic acid (35 g) compound prepared as in Example 1 in ethanol (350 ml) and concentrated sulphuric acid (60 ml) were boiled under reflux for three hours. The solution was evaporated to half volume and poured into water (1 liter). The aqueous solution was neutralised by the addition of solid sodium carbonate and extracted with ether. Evaporation of the ether solution gave a pale brown oil which was distilled to give a colourless oil (boiling point 84° C/20 mm). The product was identical with that obtained in Example 4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
A solution of the 2-(4-((3-chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenoxy)propionyl chloride (prepared in Step A) in 50 ml of acetonitrile was added to a mixture of 3.82 g (19.4 mmol) of 4-aminobenzotrifluoride, hydrochloride and 4.90 g (48.4 mmol) of triethylamine in 25 ml of acetonitrile. The reaction mixture was warmed at reflux for 4.0 hours and then poured over crushed ice. The resulting precipitate was collected by filtration and dried. The residual solid was recrystallized from methylcyclohexane to give 9.1 g (93 percent of theoretical) of the above-named product as a tan solid which melted at 140°-143° C. The structure of the product was confirmed by its IR and NMR spectrum. (Compound 1)
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)Cc1ccccc1
Yield: 56.4 %

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with phenacetyl chloride (0.045 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.500 mL) to obtain 0.0205 g (56%) of the title compound.
Reaction SMILES: [Cl-].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[C:12]1([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)CCl>[C:12]1([S:18]([N:21]2[CH:22]=[CH:23][C:24]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:11])=[CH:3][CH:4]=3)=[O:9])=[CH:25]2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C(=O)c2ccn(S(=O)(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.3 %

Procedure:
To a suspension of alminium chloride (4.62 g, 34.7 mmol) in ethylene chloride (50 mL) was added under a nitrogen atmosphere p-toluoyl chloride (4.91 g, 31.8 mmol) in ethylene chloride (5 mL) at room temperature in a period of 10 minutes. After stirring for 30 minutes to the mixture was added 1-benzenesulfonyl-1H-pyrrole (6.00 g, 28.9 mmol) in ethylene chloride (10 mL) in a period of 10 minutes. After stirring for 2 hours at room temperature, the reaction mixture was poured into ice water and the aqueous layer was extracted twice with dichloromethane. The organic layer combined was dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography to give the subject compound (9.9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:23][C:24]#[C:25][CH3:26]>>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([S:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:23][C:24]#[C:25][CH3:26])=[CH:19][CH:20]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:13]
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CC#CCBr
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2ccc(Cl)cc2)cc1
Yield: 69 %

Procedure:
Ethyl{[4-(2-butynyloxy)phenyl]sulfanyl)(4-chlorophenyl)acetate was prepared according to the general method as outlined in example 1 (step 2), starting from ethyl (4-chlorophenyl)[(4-hydroxyphenyl)sulfanyl]acetate (15.37 g, 47.7 mmol) and 4-bromo-2-butyne (4.26 ml, 48.7 mmol); 12.57 g yellow oil. Yield 69%; MS(EI): 374 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:5]([CH2:4][C:3]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=2[F:1])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=2[CH3:15])=[CH:18][CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Product: Cc1c(N(Cc2ccc(OCc3ccccc3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]

Procedure:
The product from Example 33A and benzyl bromide were processed as described in Example 33B to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([NH:14][N:15]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]2[C:21]([O:23]C)=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:25]>O.CCOC(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][N:15]2[C:16]=1[C:21]([OH:23])=[N:25][C:12]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][CH2:10]1)=[N:14]2
Reactant: COC(=O)c1c(Cl)ccn1NC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2nc(O)c3c(Cl)ccn3n2)CC1
Temperature: 110 °C
Yield: 46.3 %

Procedure:
A stirred solution of methyl 1-(1-((tert-butoxycarbonyl)amino)cyclopropanecarboxamido)-3-chloro-1H-pyrrole-2-carboxylate (500 mg, 1.40 mmol) in water (12 mL) was purged with NH3 gas for 5 minutes. The sealed pressure tube was heated at 110° C. for 12 h. The reaction mixture was dissolved in EtOAc (100 mL) and washed with water (50 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using CombiFlash ISCO (REDISEP®, SiO2, 12 g, 50% EtOAc/petroleum ether) to give tert-butyl (1-(5-chloro-4-hydroxypyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (210 mg, 46.3%) as a off-white solid. LCMS Condition B-16: retention time 0.91 min, [M+1]=325.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06-1.10 (m, 2H), 1.37-1.45 (m, 2H), 1.41 (s, 9H), 6.57 (d, J=2.4 Hz, 1H), 7.31 (br s, 1H), 7.51 (d, J=2.4 Hz, 1H), 11.32 (br s, 1H).